Effects of indapamide on the quality of life of hypertensive patients.
This study analyzed the variation in the parameters characterizing the quality of life and well-being of hypertensive patients treated with indapamide. Thirty patients (10 men and 20 women; mean age, 52.5 +/- 2.1 years, SEM) were selected after a three-week observation period during which patients received placebo. They all had essential hypertension, defined as a diastolic blood pressure between 95 and 120 mm Hg. After the three-week placebo treatment period, indapamide was prescribed as single-agent therapy at a dose of one tablet per day (2.5 mg) for three months. The quality of life and the feeling of well-being of the treated subjects were analyzed on the basis of two self-assessment scales completed by patients and on the responses to a clinical observation scale completed during the consultation by the doctor. The decrease in blood pressure was significant (p less than 0.01) by the first month of treatment and the blood pressure was controlled (diastolic blood pressure less than 90 mm Hg) in 79.3 percent of patients by the third month. Statistical analysis of the modifications in the different scores demonstrated a significant improvement between the start and the end of the indapamide treatment period for the three types of scales (p less than 0.01). Analysis of the results also confirmed the homogeneous and significant concordance between the improvement in the responses to the doctor and patient scales. These results on the improvement in quality of life and well-being observed with indapamide demonstrate the importance of taking these aspects into consideration in the drug treatment for permanent essential hypertension.


Community-Based Long-Term Care Services: If We Build It, Will They Come?
This study examines the relationship between caregivers' perception of community-based long-term care (CBLTC) services and the service use. We used first two waves of the longitudinal data set of 1,416 dyads of care recipients and their caregivers in Singapore. Four perceived attributes of LTC services--service quality, convenience, social connectedness, and affordability--were measured on a 5-point scale. Among the four perceived attributes, perceived affordability was significantly associated with future utilization for all types of CBLTC services. Perceived service quality and convenience was significantly associated with center-based LTC services use. Caregivers are critically involved in the decision of using CBLTC services, and their perception of service characteristics is significantly associated with the uptake of CBLTC services. It is important to incorporate both care recipients' and caregivers' needs and preferences when designing and promoting integrated health care delivery models.


Negative regulation of IL-8 in human astrocytes depends on β-catenin while positive regulation is mediated by TCFs/LEF/ATF2 interaction.
Expression of cytokines/chemokines is tightly regulated at the transcription level. This is crucial in the central nervous system to maintain neuroimmune homeostasis. IL-8 a chemoattractant, which recruits neutrophils, T cells, and basophils into the brain in response to inflammation and/or injury is secreted predominantly by neurons, microglia, and astrocytes. Here, we investigated the mechanism by which astrocytes regulate IL-8 expression. We demonstrate that while β-catenin negatively regulated IL-8 transcription, its canonical transcriptional partners, members of the TCF/LEF transcription factors (TCF1, TCF3, TCF4 and LEF1) and Activating transcription factor 2 (ATF2) positively regulated IL-8 transcription. We further identified a putative TCF/LEF binding site at -175nt close to the minimal transcription region on the IL-8 promoter, mutation of which caused a significant reduction in IL-8 promoter activity. Chromatin immunoprecipitation demonstrated binding of TCF1, TCF4, LEF1 and ATF2 on the IL-8 promoter suggesting that TCFs/LEF partner with ATF2 to induce IL-8 transcription. These findings demonstrate a novel role for β-catenin in suppression of IL-8 expression and for TCFs/LEF/ATF2 in inducing IL-8. These findings reveal a unique mechanism by which astrocytes tightly regulate IL-8 expression.


Comparing right colon adenoma detection rate during water exchange and air insufflation: a double-blind randomized controlled trial.
Randomized controlled trials (RCTs) have reported that water exchange (WE) produced the highest adenoma detection rate (ADR) but did not evaluate right colon adenoma detection rate (rADR) as a primary outcome and only one of the trials employed blinded colonoscopists. The aim of our study was to determine whether, compared with air insufflation, WE significantly increases rADR and right colon serrated lesion detection rate (rSLDR) and decreases adenoma miss rate (rAMR). This prospective, double-blind RCT was conducted at a regional hospital in Taiwan between December 2015 and February 2020. Standard WE and air insufflation were performed. After cecal intubation, the second blinded endoscopist examined the right colon and obtained rADR (primary outcome) and rSLDR. Then, the primary colonoscopist reinserted the scope to the cecum with WE in both groups and performed a tandem examination of the right colon to obtain rAMR. There were 284 patients (50.9% male, mean age 58.9 ± 9.4 years) who were randomized to WE (n = 144) or air insufflation (n = 140). The baseline characteristics were similar. The rADR (34.7% vs. 22.3%, p = 0.025), Boston Bowel Preparation Scale scores (mean, 2.6 ± 0.6vs. 2.2 ± 0.6, p < 0.001), rSLDR (18.1% vs. 7.1%, p = 0.007), and rAMR (31.5% vs. 45.2%, p = 0.038) were significantly different between WE and air insufflation. The current study demonstrated a significantly higher rADR and rSLDR with the WE method performed by blinded colonoscopists. The impact of the significant findings in this report on the occurrence of interval cancers deserves to be studied.


The emergence of a new tumor entity called HER2-low breast cancer leads us to reconsider therapeutic indications in patients whose tumors were usually considered as luminal or triple negative. The development of antibody-drug conjugates (ADCs) allows using HER2 as a vector of a cytoxic drug with significant clinical efficacy in breast cancer with low HER2 expression. Trastuzumab deruxtecan monotherapy is currently evaluated in phase III trials in HER2-low patients, but also in combination in earlier phase studies. Many ADCs are in development, with highly anticipated results. The toxicities of these various ADCs seem manageable and compatible with prolonged administration. Her2-low breast cancer subtype may benefit from dedicated therapeutic strategies in the next few years.


Tributyltin induces premature hatching and reduces locomotor activity in zebrafish (Danio rerio) embryos/larvae at environmentally relevant levels.
Tributyltin (TBT) is an organotin compound that is the active ingredient of many biocides and antifouling agents. In addition to its well established role as an endocrine disruptor, TBT is also associated with adverse effects on the nervous system and behavior. In this study, zebrafish (Danio rerio) embryos were exposed to environmentally relevant concentrations of TBT (0.01, 0.1, 1 nM) to determine how low levels affected development and behavior. Fish exposed to 1 nM TBT hatched earlier when compared to controls. Following a 96-h exposure, total swimming distance, velocity, and activity of zebrafish larvae were reduced compared to controls. To identify putative mechanisms for these altered endpoints, we assessed embryo bioenergetics and gene expression. We reasoned that the accelerated hatch time could be related to ATP production and energy, thus embryos were exposed to TBT for 24 and 48-h exposure prior to hatch. There were no differences among groups for endpoints related to bioenergetics (i.e. basal, ATP-dependent, and maximal respiration). To address mechanisms related to changes in behavioral activity, we measured transcripts associated with muscle function (myf6, myoD, and myoG) and dopamine signaling (th, dat, dopamine receptors) as dopamine regulates behavior. No transcript was altered in expression by TBT in larvae, suggesting that other mechanisms exist that may explain changes in higher level endpoints. These results suggest that endpoints related to the whole animal (i.e. timing of hatch and locomotor behavior) are more sensitive to environmentally-relevant concentrations of TBT compared to the molecular and metabolic endpoints examined here.


The gift of life. Ethical problems and policies in obtaining and distributing organs for transplantation.
The supply of organs and tissues is inadequate to meet the need and demand for transplantation. The article argues for an effective and efficient system for obtaining cadaveric organs that can reduce and perhaps even eliminate scarcity, without violating the principles of justice and respect for persons. The article also examines policies and problems regarding living donors, and analyzes some issues in macroallocation and microallocation.


Perceived discrimination and drug involvement among black primary care patients who use drugs.
Perceived discrimination has been associated with disparities for Black patients on a variety of health outcomes. Studies have suggested that perceived discrimination is associated with drug use in Blacks, but they have been limited by use of samples with little drug use and single measures of drug involvement. The current study examined the association between perceived discrimination and multiple measures of drug involvement among a sample of 203 Black adult primary care patients who were participants in a randomized trial of screening and brief intervention for drug use. The main independent variable was everyday perceived discrimination. The three outcomes were frequency of drug use in the past ninety days, drug-related consequences, and total drug involvement risk severity score from the Alcohol, Smoking, and Substance Involvement Test [ASSIST]. Analyses were conducted using negative binomial regression models for frequency and consequence outcomes and median regression models for drug involvement risk. Greater perceived discrimination was not significantly associated with frequency of use, but was associated with more drug-related consequences and a higher drug use risk level. These findings suggest that perceived discrimination may be an important variable to consider when selecting drug intervention approaches for Black primary care patients.


Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial.
Barrett's esophagus (BE) may lead to high-grade dysplasia (HGD) and adenocarcinoma. The objective was to examine the impact of treating patients with BE and with HGD by using porfimer sodium (POR) and photodynamic therapy (PDT) for ablating HGD and reducing the incidence of esophageal adenocarcinoma. The design was a multicenter, partially blinded (pathology), randomized clinical trial conducted in patients with BE who have HGD. There were 30 contributing centers. A total of 485 patients were screened, with 208 in the intent-to-treat population and 202 in the safety population. Patients were randomized on a 2:1 basis to compare PDT with POR plus omeprazole (PORPDT) with omeprazole only (OM). The main outcome measurement was complete HGD ablation occurring at any time during the study period. There was a significant difference (p < 0.0001) in favor of PORPDT (106/138 [77%]) compared with OM (27/70 [39%]) in complete ablation of HGD at any time during the study period. The occurrence of adenocarcinoma in the PORPDT group (13%) (n=18) was significantly lower (p < 0.006) compared with the OM group (28%) [corrected] (n=20). The safety profile showed 94% of patients in the PORPDT group and 13% of patients in the OM group had treatment-related adverse effects. The limitations of the study were that PDT therapy may have had to be applied more than once and that patients spent more time in treatment. The patients and the physicians were not blinded to the treatment. PORPDT in conjunction with omeprazole is an effective therapy for ablating HGD in patients with BE and in reducing the incidence of esophageal adenocarcinoma.


Neuroprotection: VEGF, IL-6, and clusterin: the dark side of the moon.
Growth factors and their respective receptors are key regulators in development and homeostasis of the nervous system, and changes in the function, expression, or downstream signaling of growth factors are involved in many neuropathological disorders. Recently, research has yielded a rich harvest of information about molecules and gene, and currently the assumption "a gene-a protein", where each gene encodes the structure of a single protein, is becoming a paradox. In the past years, the discovery of synergic or antagonistic proteins deriving from the same gene is a novelty upsetting. In some way, the conventional function of proteins involved in DNA repair, cell death/growth induction, vascularization, and metabolism is inhibited or shifted toward other pathways by soluble mediators that orchestrate such change depending on the microenvironment conditions. In this chapter, we focus on the antithetic properties that proteins could exert, depending on the microenvironment that orchestrates the complex networks among proteins and their respective partners.


Improving Glycemic Control Safely in Non-Critical Care Patients: A Collaborative Systems Approach in Nine Hospitals.
Practice variations in insulin management and glycemic adverse events led nine Dignity Health hospitals to initiate a collaborative effort to improve hypoglycemia, uncontrolled hyperglycemia, and glycemic control. Non-critical care adult inpatients with ≥4 point-of-care blood glucose (BG) readings in a ≥2-day period were included. Balanced glucometric goals for each hospital were individualized to improve performance by 10%-20% from baseline or achieve top performance derived from Society of Hospital Medicine (SHM) benchmarking studies. Baseline measures (2011) were compared to mature results (postintervention, 2014). Protocols for insulin management and hypoglycemia prevention were piloted at one facility and were then spread to the cohort. Interventions included standardized order sets, education, mentoring from physician experts, feedback of metrics, and measure-vention (coupling measurement of patients "off protocol" with concurrent intervention to correct lapses in care). The day-weighted mean BG for the cohort improved by 11.4 mg/dL (95% confidence interval [CI]: 11.0-11.8]; all nine sites improved. Eight of the sites reduced severe hyperglycemic days, and the percentage of patient-days with any BG > 299 mg/dL for the total cohort improved from 11.6% to 8.8% (relative risk, 0.76 [95% CI: 0.74-0.78]). The percentage of patient-days with any BG < 70 mg/dL remained unchanged at 3.6%. Eight of the sites either reduced hypoglycemia by 20% or achieved SHM best-quartile rates. Multihospital improvements in glycemic control and severe hyperglycemia without significant increases in hypoglycemia are feasible using portable low-cost toolkits and metrics.


Effect of Virtual Reality Therapy in Reducing Pain and Anxiety for Cancer-Related Medical Procedures: A Systematic Narrative Review.
Virtual reality (VR) has emerged as a novel form of nonpharmacological analgesia therapy. We wished to review the use of VR to treat pain and anxiety in cancer-related medical procedures and chemotherapy. To determine if immersive VR influences pain and/or anxiety outcomes in patients with cancer undergoing medical interventions. To discuss critical limitations in the current evidence base and provide suggestions for future areas of research. A systematic review was performed on Ovid MEDLINE, PubMed, and Google Scholar from 1999 to December 2019. The following search terms were run in each of the databases: Virtual Reality and pain or anxiety. Articles were assessed by two independent authors for inclusion. From 999 retrieved citations, nine studies met inclusion criteria for review. Methodological limitations and small sample sizes preclude strong guidance for clinical applications. Although studies demonstrated a trend toward improvement in pain and anxiety, only two studies reached statistical significance. There is inconclusive evidence on the significance of immersive VR in reducing pain (five studies) or anxiety (six studies) for patients with cancer undergoing medical interventions or receiving chemotherapy. Further research on the effect of immersive VR as a tool for medical procedures and/or patients with cancer undergoing treatment is required.


Breast tomosynthesis: state of the art.
Breast tomosynthesis is a continually improving tool for diagnostic radiologists. This update about tomosynthesis reviews the advantages of the technique both in patients with suspected or known disease and in screening, as well as its limitations, of which the dose of radiation is the most important. The more recent advent of synthesized mammography, computer-assisted detection, and tomosynthesis-guided biopsy have helped to reduce the dose of radiation used and have improved the diagnostic performance of tomosynthesis, so they are also discussed in this review.


Serum amyloid A stimulates lipoprotein-associated phospholipase A2 expression in vitro and in vivo.
Although lipoprotein-associated phospholipase A2 (Lp-PLA2) has been regarded as a biomarker and a causative agent for acute coronary events recently, the mechanism of the regulation of Lp-PLA2 has not been fully elucidated yet. This study was aimed to investigate the influence of serum amyloid A (SAA) on the expression of Lp-PLA2 in THP-1 cells and ApoE-deficient (ApoE(-/-)) mice. THP-1 cells were stimulated by SAA and the mRNA and protein expression of Lp-PLA2 was detected. ApoE(-/-) mice were intravenously injected with murine SAA1 lentivirus. Formyl peptide receptor like-1 (FPRL1) agonist (WKYMVm) and inhibitor (WRW(4)), mitogen-activated protein kinases (MAPKs) inhibitors, and peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and inhibitor were used to investigate the mechanism of regulation of Lp-PLA2. Recombinant SAA up-regulated Lp-PLA2 expression in a dose and time-dependent manner in THP-1 cells. Immunohistochemical analysis of aortic root of ApoE(-/-) mice also demonstrated that the expression of Lp-PLA2 was up-regulated significantly with SAA treatment. WRW(4) decreased SAA-induced Lp-PLA2 production; while WKYMVm could induce Lp-PLA2 expression. ERK1/2, JNK1/2, and p38 inhibition reduced SAA-induced Lp-PLA2 production. Furthermore, the results suggested the activation of PPAR-γ played a crucial role in this process. These results demonstrate that SAA up-regulates Lp-PLA2 production significantly via a FPRL1/MAPKs./PPAR-γ signaling pathway.


New regulation mechanisms of osteoclast differentiation.
Osteoclasts play a crucial role in both physiological and pathological bone resorption. It is, thus, of compelling importance to understand the molecular mechanisms of osteoclast regulation. Because receptor activator of nuclear factor-κB ligand (RANKL) is the key cytokine that induces osteoclast differentiation, we have focused on the investigation of RANKL signaling and RANKL-expressing cells. Here, we summarize the recent advances in the understanding of osteoclastogenic signaling and the cells that express RANKL in the context of osteoimmunology. The scope of osteoimmunology has been extended to now encompass a wide range of molecular and cellular interactions, and its framework provides a scientific basis for future therapeutic approaches to diseases related to the bone and/or immune systems.


Swellable and porous bilayer tablet for gastroretentive drug delivery: Preparation and in vitro-in vivo evaluation.
The purpose of this study was to develop a novel gastroretentive drug delivery system with immediate buoyancy and high wet strength. The proposed bilayer tablet was composed of a drug layer and a highly porous and swellable gastroretentive (GR) layer. The highly porous GR layer was prepared by sublimating the volatile materials after compaction with swellable polymers. This pore-forming process decreased the density of the GR layer and enabled the tablet to float immediately on the dissolution media. The GR layer formulation was optimized by comparing the swelling, erosion, and mechanical properties of candidate swellable polymers. The release rates were conveniently controlled by changing the polymer content in the drug layer, while the swelling and floating properties were provided by the GR layer. The application of percolation theory revealed that the polymer content above the estimated threshold was required for a reliable drug release profile. In vivo study in fed beagle dogs confirmed the enhanced gastric retention time of the tablets compared to that of conventional single layer tablets. Taken together, our data suggest that the proposed system can be a promising platform technology with superior GR properties and a convenient formulation process.


Retroperitoneal packing as part of damage control surgery in a Danish trauma centre--fast, effective, and cost-effective.
Retroperitoneal packing in patients with severe haemorrhage is a cornerstone of modern pelvic fracture management. However, few Danish trauma surgeons have experience with this procedure, and trauma audits show that many hesitate to perform the procedure, indicating a need for hands-on training for this simple and potentially lifesaving procedure. During a six-month period, trauma surgeons were taught the retroperitoneal packing procedure using human corpses at the Department of Pathology at Aarhus University Hospital. The course consisted of a 30 minute long single training session in retroperitoneal packing. Twenty-three sessions were held. Forty-two trauma surgeons (the entire staff at Aarhus Trauma Centre) and ten observers completed the course. Afterwards, all participants felt competent to perform the procedure. All 42 surgeons at our local trauma organisation learned a simple lifesaving operation within a short time period. In the 12 months following the completion of the course, 11 patients were treated with packing without any hesitation and with success. Damage control surgery with packing was cost-effectively implemented at our centre with great ease and rapidity.


Intravenous pulse methylprednisolone in the treatment of uveitis associated with multiple sclerosis.
To demonstrate the safety and effectiveness of intravenous methylprednisolone (IVMP) in the treatment of uveitis in association with multiple sclerosis (MS). Uveitis is an unusual manifestation of MS that may be severe, chronic and require systemic immunosuppression therapy. High-dose IVMP has previously been shown to be effective in the treatment of inflammatory eye disease and MS. Eight episodes of uveitis in five patients with MS were treated over a 10-year period in an open, uncontrolled trial. Two patients had chronic anterior uveitis, one patient had bilateral panuveitis and two patients had intermediate uveitis. All patients responded to IVMP with evidence of a decrease in intraocular inflammatory activity and improved visual acuity (VA) within 2 weeks of commencing treatment. There were no severe ocular or systemic steroid side effects. Intravenous methylprednisolone is an effective, well-tolerated form of therapy for uveitis in patients with MS.


Mechanisms of hypoxemia and hypercapnia in the perioperative period.
There are numerous mechanisms of hypoxemia and hypercapnia during the perioperative period. Mechanisms of hypoxemia include oxygen delivery problems, decreased FAC-CC relationship, hypoventilation, decreased cardiac output, increased oxygen consumption, decreased hypoxic pulmonary vasoconstriction, and increased nonalveolar right-to-left shunting. Mechanisms of hypocapnia include increased carbon dioxide production, increased alveolar dead space, and increased external dead spaces. Pulmonary diseases often involve multiple mechanisms to produce hypoxemia and hypercapnia.


Periodontitis-associated septic pulmonary embolism caused by Actinomyces species identified by anaerobic culture of bronchoalveolar lavage fluid: a case report.
Periodontal disease is a less common but important cause of septic pulmonary embolism (SPE). However, the pathogens causing periodontal disease-associated SPE (PD-SPE) have been poorly understood. Actinomyces species are resident microbiota in the oral cavity. Here we report a case of PD-SPE caused by Actinomyces species, which was identified by anaerobic culture of bronchoalveolar lavage fluid (BAL). A 64-year-old Asian man, complicated with severe chronic periodontitis, was admitted with chest pain and fever. Chest CT revealed multiple bilateral pulmonary nodules located subpleurally. We diagnosed the case as SPE associated with periodontitis. Although blood cultures were negative for the usual 5-day incubation, anaerobic culture of the BAL fluid sample yielded Actinomyces species. Antibacterial therapy alone did not ameliorate the symptoms; however, additional dental treatment, including tooth extraction, promptly did. The patient was discharged 23 days after admission. The 3-month follow-up revealed no recurrence of the symptoms and complete resolution of the lung lesions. This case demonstrated that Actinomyces species can cause PD-SPE. Additionally, clinicians should consider performing appropriate anaerobic culture of BAL fluid to identify the pathogen of SPE, and to ordering dental treatment, if necessary, in addition to antibiotics for the initial management of PD-SPE.


Introduction to the revised Neonatal Resuscitation Program guidelines: questions and answers to get you started.
In October, 2000, the American Academy of Pediatrics (AAP) and the American Heart Association (AHA) introduced revised guidelines for the Neonatal Resuscitation Program (NRP). These revisions affect the practice of neonatal resuscitation as well as the administrative components of the program. This article cannot address every program revision, but introduces the reader to how program changes occurred, guideline revisions that affect practice, and changes in NRP educational tools and resources.


A highly specific BODIPY-based fluorescent probe for the detection of hypochlorous acid.
A fluorescent probe, HKOCl-1, has been successfully developed for the detection of hypochlorous acid on the basis of a specific reaction with p-methoxyphenol. The formation of HOCl has been successfully detected not only in an abiotic system but also in an enzymatic system (myeloperoxidase/H2O2/Cl(-) system) and in living macrophage cells upon stimulation. This new probe might be used as an efficient tool for probing the roles HOCl plays in biological systems.


Diffuse alveolar hemorrhage due to antibasement membrane antibody disease appearing with a polyglandular autoimmune syndrome.
We describe a patient with type 3-C polyglandular autoimmune syndrome who presented with diffuse alveolar hemorrhage and normal renal function. The diagnosis of antibasement membrane antibody disease was established by immunofluorescent staining of transbronchial biopsy specimens. We suggest the incorporation of antibasement membrane antibody disease into the spectrum of diseases that define the polyglandular autoimmune syndromes.


Tissue factor pathway inhibitor, activated protein C resistance, and risk of ischemic stroke due to postmenopausal hormone therapy.
To test whether changes in plasma tissue factor pathway inhibitor (TFPI) levels or activated protein C resistance (normalized activated protein C resistance ratio [nAPCsr]) modify the increased risk of ischemic stroke due to postmenopausal hormone therapy. Nested case-control study of 455 cases of ischemic stroke and 565 matched control subjects in the Women's Health Initiative trials of postmenopausal hormone therapy. Baseline free TFPI was associated with ischemic stroke risk (OR per SD increase, 1.17; 95% CI, 1.01-1.37; P=0.039), but baseline nAPCsr was not (OR per SD increase, 0.89; 95% CI, 0.75-1.05; P=0.15). Baseline TFPI levels and nAPCsr did not modify the effect of postmenopausal hormone therapy on ischemic stroke. Treatment-induced mean changes of -28% in free TFPI and +65% in nAPCsr did not change the risk of ischemic stroke (interaction P=0.452 and 0.971, respectively). In subgroup analyses, baseline nAPCsr was inversely associated with lacunar strokes (OR per SD increase, 0.74; 95% CI, 0.57-0.96; P=0.025) and baseline free TFPI interacted with treatment to increase large vessel atherosclerotic strokes (P=0.008). Procoagulant changes in TFPI or nAPCsr do not modify the increased ischemic stroke risk due to postmenopausal hormone therapy. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT 00000611.


Thymocyte selection in Vav and IRF-1 gene-deficient mice.
T cells undergo a defined program of phenotypic and genetic changes during differentiation within the thymus. These changes define commitment of T-cell receptor (TCR) gamma delta and TCR alpha beta cells and lineage differentiation into CD4+ T helper and CD8+ cytotoxic T cells. T-cell differentiation and selection in the thymus constitute a tightly co-ordinated multistep journey through a network that can be envisaged as a three-dimensional informational highway made up of stromal cells and extracellular matrix molecules. This intrathymic journey is controlled by information exchange, with thymocytes depending on two-way cellular interactions with thymic stromal cells in order to receive essential signals for maturation and selection. Genetic inactivation of surface receptors, signal transduction molecules, and transcription factors using homologous recombination has provided novel insight into the signaling cascades that relay surface receptor engagement to gene transcription and subsequent progression of the developmental program. In this review we discuss molecular mechanisms of T lymphocyte development in mice that harbour genetic mutations in the guanine nucleotide exchange factor Vav and the interferon regulatory transcription factor 1 (IRF-1). We also propose a novel model of T-cell selection based on TCR alpha chain-directed signals for allelic exclusion and TCR alpha-based selection for single receptor usage.


Impact of socioeconomic deprivation and primary pathology on rate of reversal of Hartmann's procedure.
Hartmann's procedure is an operation for left-sided colonic pathology where primary anastomosis is considered unsafe. The aim of this study was to assess the impact of socioeconomic deprivation and primary pathology on the rate of reanastomosis. All patients who underwent Hartmann's procedure between 1992 and 2000 in our unit were included. The deprivation category (DEPCAT) scores from 1 (affluent) to 7 (most deprived) were calculated. An emergency procedure was performed in 118 of 124 patients. Primary pathology was malignant in 40 and benign in 84 patients. The DEPCAT scores were high (6,7) in 76 and intermediate (3 to 5) in 42 patients. Of the 102 patients surviving the postoperative period, only 23 underwent reversal. The reversal rate was lower in patients with malignancy (P = 0.005) and higher DEPCAT scores. Primary diagnosis and socioeconomic deprivation adversely influence the rate of reversal of Hartmann's procedure.


Formulation and stability of a beclomethasone dipropionate enema.
A beclomethasone dipropionate (BDP) enema and a BDP/mesalazine combination enema (containing 2 mg BDP and 1 g mesalazine and 2 mg BDP, respectively per 40 ml) were formulated. BDP and mesalazine were suspended in a carbomer-water gel. No degradation of BDP was measured during the storage period of the BDP enema (4 weeks at 20 degrees C) and of the BDP/mesalazine enema (44 days at 4 degrees C, 20 degrees C and 37 degrees C, respectively). Progressive darkening of colour occurred for the BDP/mesalazine enema during storage at 20 degrees C and at 37 degrees C, probably induced by mesalazine degradation products. Only very slight colouring was observed at 4 degrees C. Hardly any precipitation of BDP and mesalazine was seen during the storage period and the enemas could easily be resuspended.


Platelet-neutrophil interactions. 12S,20- and 5S,12S-dihydroxyeicosapentaenoic acids: two novel neutrophil metabolites from platelet-derived 12S-hydroxyeicosapentaenoic acid.
Dietary marine n-3 polyunsaturated fatty acids have demonstrated an antiinflammatory potential in epidemiologic and intervention studies in humans. Proposed mechanisms, involving only leukocytes, fall short of explaining this potential completely. Enriched by dietary means with eicosapentaenoic acid (EPA), stimulated human platelets release substantial amounts of eicosapentaenoic acid and 12S-hydroxyeicosapentaenoic acid (12S-HEPE) in addition to 12S-hydroxyeicosatetraenoic acid (12S-HETE) derived from arachidonic acid. Human neutrophils metabolize 12S-HETE to 5S,12S-DiHETE when stimulated, whereas unstimulated neutrophils produce 12S,20-DiHETE. This study was undertaken to characterize metabolism of 12S-HEPE in human neutrophils. We demonstrate herein for the first time that 12S-HEPE is metabolized by human neutrophils. In unstimulated neutrophils 20-hydroxylation to 12S,20-DiHEPE occurs, whereas in stimulated neurtrophils 5-lipoxygenation to 5S,12S-DiHEPE takes place. The structures of these metabolites were characterized by their relative retention times on reversed-phase high pressure liquid chromatography, by their UV absorbance spectra, and by gas-liquid chromatography-mass spectrometry. With increasing amounts of 12S-HEPE, stimulated neutrophils produced increasing amounts of 5S,12S-DiHEPE, which is virtually inactive biologically. Concomitantly, production of the potent chemokinetic and chemoattractant arachidonic acid derivative leukotriene B4 decreased. Thus, 12S-HEPE can compete with endogenous arachidonic acid for 5-lipoxygenation in stimulated human neutrophils. 12,20-DiHEPE, LTB5, and 5S,12S-DiHEPE were detectable after coincubating EPA-enriched platelets with unenriched neutrophils, and arachidonic acid-derived 5-lipoxygenase products were decreased. We conclude that 12S-HEPE can participate in platelet-neutrophil interactions in a manner similar to 12S-HETE. By providing competing substrates for neutrophil 5-lipoxygenase, platelets might contribute to the antiinflammatory potential of dietary n-3 fatty acids through platelet-neutrophil interaction.


SYFPEITHI: database for searching and T-cell epitope prediction.
Reverse immunology has been used for about 12 years in order to identify T-cell epitopes from pathogens or tumor-associated antigens. In this chapter, we discuss the advantages and pitfalls of T-cell epitope prediction compared to classical experimental procedures such as epitope mapping and cloning experiments. We introduce our three established programs, SYFPEITHI, PAProc, and SNEP, which are freely accessible at no cost in the World Wide Web for the prediction of either HLA-peptide binding or proteasomal processing of antigens. We demonstrate the performance of our epitope prediction programs with several examples and in comparison to other epitope prediction programs available. We also reflect the actual possibilities and limitations of such computer-aided work.


[Distribution and properties of the alkaline phosphatase in the human gastric mucosa in peptic ulcer].
In duodenal ulcer alkaline phosphatase activity was the highest in mucosa of pyloric region of curvature ventriculi minor and it decreased distinctly in the tissues removed from pylorus. In cases of gastric ulcer, the enzymatic activity was high throughout the curvatura ventriculi minor reaching the maximal value at the ulcerous zone. Alkaline phosphatase from gastric mucosa resembled the enzyme from intestine in its inhibition patterns with 1-phenylalanine and in inactivation properties at 56 degrees within 15 min; but, as distinct from the latter, the enzyme was more stable at 65 degrees within 5 min, maintaining 50% of the initial activity.


[Palliative care in geriatrics - conceptual design and methods of a study to explore the viewpoints of different health care professionals and disciplines].
Palliative care is a comparatively new discipline. In Germany, it predominantly concentrates on patients who suffer from cancer. However, international experiences demonstrate that palliative care approaches could also be very useful in patients with other incurable, nonmalignant diseases, e.g. in geriatrics. A qualitative research project, performed by a study group working in health services research and public health, aims at the exploration of the viewpoints of different health care professionals and disciplines concerning the attitudes towards palliative care approaches in geriatrics as well as the potentials and barriers. This article describes the study design and the methodical approach.


Staging of squamous cell carcinoma of the tongue: extrinsic lingual muscles and the 8th editions of the American Joint Committee on Cancer/Union for International Cancer Control staging manuals.
Our aim was to find out first whether the extrinsic muscles of the tongue are histologically identifiable, and secondly to what degree the use of the new criteria in the 8th editions of the American Joint Committee on Cancer(AJCC)/Union for International Cancer Control (UICC) manuals (which have recognised the importance of depth of invasion of tumour, rather than invasion of the extrinsic muscles of the tongue and extranodal extension), will alter staging of lingual squamous cell carcinoma (SCC). The histological sections from 165 patients who had had primary resection of lingual SCC were reviewed, and one or more extrinsic muscles of the tongue was identified in 100 patients (61%), with the genioglossus seen the most often (in 96). By contrast, the hyoglossus was identified in only eight patients, the styloglossus in two, and the palatoglossus in none. Identification was straightforward only in extensive resections. Applying the criteria from the 8th edition increased the number of pT3 SCC with a simultaneous reduction in pT4a tumours. The number of pN2b SCC was also reduced, but the new category of pN3b meant that overall 53% of tumours were upstaged. The kappa scores for agreement between the two sets of criteria were 0.221 (weighted 0.410) for the pT values, 0.508 (0.713) for pN values (but 0.227, weighted 0.386, if the pN0 values were removed before calculation), and 0.243 (0.514) for overall stage, indicating poor to fair agreement. We conclude that the removal of invasion of extrinsic muscles of the tongue as a criterion for a pT4a SCC is justified, and that many SCC of the tongue will be upstaged as a result of implementation of the 8th editions.


Alar cinch sutures in orthognathic surgery: scoping review and proposal of a classification.
Orthognathic surgery and the Le Fort I osteotomy result in noticeable alterations to the nasal/nasolabial anatomy. The alar base cinch technique is a surgical technique to control lateralization of the base of the nose and is well described in the literature. The aim of this scoping review was to identify every unique alar cinch suture technique reported in orthognathic surgery and to propose a classification for the different techniques described. A search was conducted in the PubMed, Cochrane Library, and Scopus electronic databases covering the period May 1980 to July 2020, which identified 10 articles that were eligible for this review. Among these, there were several proposals for modifications to the technique, and different studies to show the effectiveness of one type among all others. Despite observing multiple techniques and variations of these while performing this review, the lack of a classification for alar cinch suture was noticed. Therefore, we propose a classification of the alar cinch suture that includes four types, which cover all of the cinching techniques described. It is believed that the use of a standardized classification may be useful to avoid duplicate publishing of techniques and to set a standard for further studies.


Prevalence and Risk Factors of Gastroesophageal Reflux Among Jazan University Students, Saudi Arabia: A Cross-Sectional Study.
Gastroesophageal reflux disease (GERD) is a digestive disorder that is commonly seen in adults and characterized by heartburn and regurgitation. The epidemiological aspects of GERD have been studied over the past decade due to the increasing prevalence and complications of the disease. Thus, we aimed in this study to assess the prevalence, risk factors of GERD, and its relationship with academic performance among students at Jazan University. This is a descriptive and analytical cross-sectional study that was conducted among Jazan university students in Jazan Province, Saudi Arabia. Data was collected using a self-administered questionnaire and analysis was performed using SPSS (IBM Corp., Armonk, NY). A total of 953 students participated in this study. The prevalence of GERD was found to be 23.1%. Our findings showed that five or more physical activities for ≥ 30 minutes per week, and fiber-rich foods were found to decrease the odds of developing GERD. However, more than three meals per day and having a family history of GERD were found to increase the odds of GERD. Moreover, age, use of proton pump inhibitors (PPI), and Khat chewing were also statistically significant risk factors for GERD (p<0.05). Our results demonstrated a high prevalence of GERD among Jazan university students. However, risk factors were almost similar to those reported by previous studies. Thus, raising awareness about the modifiable risk factors of GERD is warranted.


Nitrate tolerance. A problem during continuous nitrate administration.
The organic nitrates are effective agents in the management of patients with angina pectoris. They are the agents of choice in the treatment of acute episodes of angina pectoris and are useful in angina prophylaxis. While the organic nitrates are extremely effective in angina prophylaxis during acute therapy, there is increasing evidence that with many dosing regimens for oral and transdermal therapy, substantial attenuation of the antianginal effects develops. Thus, during acute therapy the organic nitrates improve exercise tolerance for many hours, but during sustained therapy designed to provide antianginal efficacy throughout the 24-h period there is significant attenuation of the beneficial effects. It has been documented that treatment regimens designed to provide a period of nitrate washout prevent or reverse nitrate tolerance, and such changes in dosing regimens have been shown to provide continued antianginal protection. It is clear that the objective of providing 24-h antianginal protection with the organic nitrates cannot be achieved. With appropriate dosing schedules, however, it is possible to improve exercise tolerance throughout the major portion of the 24-h dosing period.


Chaperone-Assisted Host-Guest Interactions Revealed by Single-Molecule Force Spectroscopy.
The recent discovery of ultra-high binding affinities in cucurbit[7]uril (CB7)-based host-guest pairs in an aqueous environment has rendered CB7 a rather attractive material in analytical and biomedical applications. Due to the lack of a molecular platform that can follow the same host-guest complex during repetitive mechanical measurements, however, mechanical stabilities of the CB7 system have not been revealed, hindering its potential to rival widely used conjugation pairs, such as streptavidin-biotin. Here, we assembled a DNA template in which a flexible DNA linker was exploited to keep the host (CB7) and guest (adamantane) in proximity. This platform not only increased the efficiency of the single-molecule characterization in optical tweezers but also clearly revealed mechanical features of the same host-guest complex. We found that positively charged adamantane guest demonstrated higher mechanical stability (49 pN) than neutral adamantane (44 pN), a trend consistent with the chemical affinity between guest molecules and the CB7 host. Surprisingly, we found that a hexyl group adjacent to the adamantane served as a chaperone to assist the formation of the adamantane-CB7 pairs. The discovery of an unprecedented chaperone-assisted interaction mechanism provides new approaches to efficiently assemble host-guest-based supramolecules with increased mechanical stabilities, which can be exploited in various biomedical, biosensing, and materials fields.


Synergistic antitumor effect of β-elemene and etoposide is mediated via induction of cell apoptosis and cell cycle arrest in non-small cell lung carcinoma cells.
β-Elemene, an anticancer agent, was isolated from the traditional Chinese medicine plant, curcuma aromatica. In this study, we investigated the synergistic antitumor effect of β-elemene and etoposide phosphate (VP-16) in A549 non-small cell lung carcinoma cells. The cells were treated with β-elemene (20 or 50 µg/ml), VP-16 (15 µg/ml) or the combination of both for 24 h. Compared to the treatment with β-elemene or VP-16 alone, an increased antitumor activity was observed with the combination of both, which was mediated by the cleavage of PARP, the up-regulation of Bax, p53 and p21, and the suppression of cyclin D1. These results suggest that the combination of β-elemene and VP-16 may be a promising therapeutic option for lung cancer.


Oxygenation Indices in Noninvasive Ventilation: Could They Predict Mortality in COVID-19?
D'Silva C. Oxygenation Indices in Noninvasive Ventilation: Could They Predict Mortality in COVID-19? Indian J Crit Care Med 2021;25(8):841-842.


Multichannel recording of tibial-nerve somatosensory evoked potentials.
The topography of the peaks of tibial-nerve somatosensory evoked potential (SEP) varies among healthy subjects, most likely because of differences in position and orientation of their cortical generator(s). Therefore, amplitude estimation with a standard one- or two-channel derivation is likely to be inaccurate and might partly cause the low sensitivity of SEP amplitude to pathological changes. In this study, we investigate whether 128-channel tibial-nerve SEP recordings can improve amplitude estimation and reduce the coefficient of variation. We recorded tibial-nerve SEPs using a 128-channel EEG system in 48 healthy subjects aged 20 to 70 years (47 provided analyzable data). We compared P39, N50, and P60 amplitudes obtained with a 128-channel analysis method (based on butterfly plots and spatial topographies) with those obtained using a one-channel conventional configuration and analysis. Scalp and earlobe references were compared. Tibial-nerve SEP amplitudes obtained with the 128-channel method were significantly higher as compared to the one-channel conventional method. Consequently, the coefficient of variation was lower for the 128-channel method. In addition, in both methods, the N50-peak amplitude was sometimes hard to identify, because of its low amplitude. Besides, in some subjects, the N50 peak, as obtained with the conventional method, rather seemed to be a period between two positivities rather than an activation peak on itself. The 128-channel method can measure tibial-nerve SEP amplitude more accurately and might therefore be more sensitive to pathological changes. Our results indicate that the N50 component is less useful for clinical practice.


Study of the leaching behaviour of ladle slags by means of leaching tests combined with geochemical modelling and mineralogical investigations.
In this study, the leachability of freshly produced ladle slag derived from both austenitic and ferritic stainless steel production, and from electrical and structural steel production, was investigated, in order to determine whether variations in the chemical and mineralogical composition of these slags affect their leaching behaviour. The effect of the method used for slag cooling was also studied. The results obtained by using the single batch test were combined with those obtained by means of more sophisticated characterisation leaching tests, which, in combination with geochemical speciation modelling, helped to better identify the release mechanisms and phases that control the release of individual elements. It was found that, although variations in the chemical composition of the slag can affect the slag's minerology, neither such variations, nor the choice of the slag cooling treatment, have a significant effect on the leachability of individual elements, since the leaching is governed by surface phenomena. In fact, the mineral transformations on the slag surface, rather than the bulk mineral composition, dictate the release of these elements from the ladle slag. The solubility-controlling phases were predicted by multi-element modelling, and verified to the extent made possible by the performed mineralogical investigations.


Implementing Interventions to Address Gender and Power Inequalities in Early Adolescence: Utilizing a Theory of Change to Assess Conditions for Success.
To create a set of criteria to assess facilitators and barriers to implementation among gender transformative interventions that target very young adolescents (VYAs) across different cultural settings. Interventionists and researchers involved in the Global Early Adolescent Study created a Theory of Change (ToC) based on summarizing intervention components from five different gender transformative intervention curricula. Embedded within the ToC is a set of criteria labeled, 'Conditions of Success' which were developed to illustrate that change cannot happen unless interventions are implemented successfully. To test the feasibility of these criteria, implementation data collected across the five interventions in Global Early Adolescent Study were mapped onto the 'Conditions for Success' criteria and used to identify common facilitators and barriers to implementation. Using the 'Conditions for Success' criteria, we found that gender transformative interventions targeting VYAs were most challenged in meeting program delivery and facilitation conditions and needed to build more multisectoral support to shift rigid gender norms. Parents and caregivers also needed to be engaged in the program either as a separate target population or as codesigners and implementers for the interventions. The Conditions for Success criteria provide a useful framework for assessing facilitators and barriers to implementation among gender transformative interventions for VYAs. Additional research is underway to examine whether interventions that meet more conditions of success result in greater program impact, which will be used to further refine the overall ToC.


Henry R. Viets, MD, and the History of Myasthenia Gravis.
Henry R. Viets (1890-1969) was both a noted neurologist and medical historian. While at Harvard Medical School, from which he graduated in 1916, he attracted the attention of Harvey Cushing who directed Viets into these disciplines. Cushing arranged for Viets to take a fellowship in Oxford in the year after his graduation. With Cushing's recommendation, he lived with Sir William and Lady Osler and did research with the famous neurologist Sir Charles Sherrington. Viets was in London in 1935 when he heard about the remarkable success of Mary Walker in treating myasthenia gravis, first with physostigmine and then with neostigmine (Prostigmin). Securing an ampoule of this drug, he took it to the Massachusetts General Hospital where he was an attending neurologist and in March 1935 injected it into a myasthenic patient with great success. He established the first Myasthenia Gravis clinic in the world and was a pioneer in the treatment of this once obscure disease; he evaluated hundreds of patients and published many articles on myasthenia. He continued this association for more than 30 years. Under the tutelage of Cushing and Osler, Viets became a medical historian and bibliophile, publishing hundreds of articles and several books on many different subjects in the history of medicine. He was a president of the American Association for the History of Medicine and curator of the Boston Medical Library that eventually joined with the Harvard Medical School Library. Viets served on the Editorial Board of the New England Journal of Medicine for 40 years.


Corrigendum: Approval of Coercion in Psychiatry in Public Perception and the Role of Stigmatization.
[This corrects the article DOI: 10.3389/fpsyt.2021.819573.].


Sympathetic innervation and noradrenaline content of normal human thyroid tissue from fetal, young, and elderly subjects.
In man, as well as in the mouse, there is morphologic and functional evidence for a direct, stimulatory influence of the sympathetic nervous system on the secretion of thyroid hormone by noradrenaline (NA), released from interfollicular adrenergic nerve terminals. In mice and rats, an age-related reduction of the sympathetic innervation of the thyoid has recently been observed. In the present study, possible age-related variations of the sympathetic innervation and the concentration of NA in human thyroid tissue were examined. Interfollicular adrenergic nerve terminals were studied by fluorescence histochemistry, and the tissue concentration of NA was measured by fluorometry. In apparently normal thyroid tissue, obtained from fetuses, young (20-45), and elderly (greater than 60) euthyroid people with thyroid cancer or hyperparathyroidism, the number of interfollicular adrenergic nerve terminals appeared to be reduced with increasing age, and the thyroid tissue concentration of NA was significantly lower in elderly than in young people. These findings may have functional importance.


An efficient and convenient synthesis of deuterium-labelled seminolipid isotopomers and their ESI-MS characterization.
Seminolipids 1a and 1b and galactosylalkylacylglycerols 2a and 2b, labelled with deuterium on the alkyl or acyl chain, respectively, were obtained isotopically and chemically pure through a straightforward synthesis from protected glycidyl galactoside 3 in an overall 22% yield. The identity and purity of compounds was ascertained by NMR spectroscopy and ESI mass spectrometry analysis. These labelled compounds are important as internal standards for quantification of these lipids by mass spectrometry, and they could also be used in metabolic studies in in vitro and even in vivo systems. Extension of the procedure could provide a route for the preparation of isotopomers of other compounds of the same general class.


Widening the path and window of opportunity for FDA approval of non-vitamin K oral anticoagulant specific antidotes and reversal agents.
There remains a need for safe, immediately effective, and easy to administer antidotes for patients taking novel oral anticoagulants (NOACs) in the settings of major bleeding, need for emergency surgery, and accidental overdose. We review considerations for the successful safety and effectiveness evaluation of potential antidotes currently under development. These compounds are in expedited regulatory approval programs aimed at accelerating the preclinical and clinical evaluation and approval processes for treatments of serious conditions. We review the features of these expedited programs as well as the FDA's efforts to broadly advance the efficiency of drug development and increase the number of new compounds brought to market. The critical path initiative and regulatory science initiative have resulted in numerous successful programs to address current challenges such as a paucity of validated biomarkers and surrogate endpoints as well as unreliable animal models of toxicity. The FDA has also advocated for increased use of pharmacokinetic/pharmacodynamic modeling and adaptive trial design. These efforts foster collaboration between academia, industry and the public sector across interdisciplinary sciences and may continue to widen the pathway for NOAC-specific reversal agents and other novel compounds.


Probabilistic assessment of exposure to cosmetic products by French children aged 0-3 years.
Very few exposure data are available for children in Europe and worldwide. The aim of this study was to assess the exposure to cosmetic products used on children aged 0-3 years using recent consumption data generated for the French population. Exposure was assessed using a probabilistic method for 24 products including cleanser, skin care, fragrance, solar and bottom products. The exposure data obtained in this study for children aged 0-3 years were higher than the values fixed by the SCCS for all common products: liquid shampoo, face moisturizer cream, toothpaste, shower gel and body moisturizer cream. Exposure was assessed for the first time for many products such as sunscreens, Eau de toilette and massage products. These new French exposure values will be useful for safety assessors and for safety agencies.


Staphylococcus aureus colonization in a community sample of HIV-infected and HIV-uninfected drug users.
HIV-infected individuals, especially those with a history of injecting drug use, are at high risk of Staphylococcus aureus infection. Moreover, the use of antimicrobial agents for opportunistic infections may increase nasal colonization by antimicrobial-resistant Staphylococcus aureus in this population and, subsequently, levels of infection with multidrug-resistant Staphylococcus aureus in the community. Between February 1999 and March 2000, 500 subjects from a community-based cohort of drug users completed an interview and underwent a physical exam. Risk factors for colonization by Staphylococcus aureus were examined, the antibiotic susceptibility profiles of all strains were determined, and DNA strain analysis was performed. One hundred twenty (24%) subjects had positive Staphylococcus aureus nasal cultures. Only HIV infection and homelessness were associated with Staphylococcus aureus colonization. Ten (8%) isolates were methicillin-resistant Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus isolates were found more frequently among HIV-infected than HIV-uninfected respondents (14% vs. 3%, P=0.04). Among those colonized and HIV infected, the mean number of resistant isolates was higher for those currently reporting antibiotic use (5.0 vs. 2.3, P<0.001) and for those with CD4+ counts <or =200/ microl (3.8 vs. 2.3, P=0.02). The increased use of antimicrobial agents in HIV-infected individuals colonized with Staphylococcus aureus may be an underlying mechanism that contributes to the presence of multidrug-resistant Staphylococcus aureus in the community.


Prolonged indomethacin treatment in preterm infants with symptomatic patent ductus arteriosus: efficacy, drug level monitoring, and patient selection.
Indomethacin treatment for 1 week monitored by drug level determinations was evaluated in 32 preterm infants with symptomatic patent ductus arteriosus (sPDA). Inter- and intra-individual indomethacin dispositions varied considerably with the need for marked dosage adjustments to maintain the drug level within the proposed therapeutic range. The overall success rate of this prolonged treatment was 63%. There were no significant differences between the groups of responders (n = 20), relapsers (n = 5) and non-responders (n = 7) with respect to postnatal age, sex, total indomethacin dose, and indomethacin serum concentrations. The responders, however, had significantly higher birth weights. Eighty-five percent of infants weighing more than 1000 g (n = 20) were treated successfully. Only four of these children experienced adverse reactions. The benefit-to-risk ratio was lowest in the group of infants weighing 1000 g or less (n = 12) with a success rate of only 25% and, potentially, severe adverse reactions in ten infants. In conclusion, prolonged indomethacin treatment is an alternative to conventional short-term treatment and appears to be particularly efficacious and safe in infants weighing more than 1000 g. In infants weighing 1000 g or less and suffering from severe pulmonary diseases, this treatment cannot generally be recommended. The advantage of on-line drug level monitoring during indomethacin treatment deserves further investigation.


Effect of chronic supplementation with methylsulfonylmethane on oxidative stress following acute exercise in untrained healthy men.
This study was conducted to assess the effects of chronic daily methylsulfonylmethane (MSM) supplementation on known markers of oxidative stress following acute bouts of exercise in untrained healthy young men. Eighteen untrained men volunteered for this study. Participants were randomized in a double-blind placebo-controlled fashion into two groups: MSM (n = 9) and placebo (n = 9). The participants took supplementation or placebo daily for 10 days before running. Participants ran 14 km. The MSM supplementation was prepared in water at 50 mg/kg body weight. The placebo group received water. Serum malondialdehyde (MDA), protein carbonyl (PC) and plasma oxidized glutathione (GSSG) were measured as markers of oxidative stress. The plasma-reduced glutathione (GSH) level and the GSH/GSSG ratio were determined as markers of plasma antioxidant capacity. Acute exercise led to elevated levels of serum MDA, PC and plasma GSSG. MSM supplementation maintained PC, MDA and GSSG at lower levels after exercise than the placebo. The plasma level of GSH and the ratio of GSH/GSSG were significantly higher in the MSM supplemented group. These results suggest that chronic daily oral supplementation of MSM has alleviating effects on known markers of oxidative stress following acute bouts of exercise in healthy young men.


Intrahepatic cholangiocarcinoma: clinical aspects, pathology and treatment.
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary tumor of the liver. To further define its clinicopathology and surgical management, we reviewed our experience. Clinical presentations of 32 patients with ICC was similar to that with hepatocellular carcinoma. Jaundice occurred in only 27 percent. ICC was unresectable due to advanced disease stage in 81 percent. Six patients had curative resections with two 5 year disease free survivors. Underlying liver disease was associated with ICC in 34 percent of patients.


Comparison of efficacy of Salmonella typhimurium A1-R and chemotherapy on stem-like and non-stem human pancreatic cancer cells.
The XPA1 human pancreatic cancer cell line is dimorphic, with spindle stem-like cells and round non-stem cells. We report here the in vitro IC 50 values of stem-like and non-stem XPA1 human pancreatic cells cells for: (1) 5-fluorouracil (5-FU), (2) cisplatinum (CDDP), (3) gemcitabine (GEM), and (4) tumor-targeting Salmonella typhimurium A1-R (A1-R). IC 50 values of stem-like XPA1 cells were significantly higher than those of non-stem XPA1 cells for 5-FU (P = 0.007) and CDDP (P = 0.012). In contrast, there was no difference between the efficacy of A1-R on stem-like and non-stem XPA1 cells. In vivo, 5-FU and A1-R significantly reduced the tumor weight of non-stem XPA1 cells (5-FU; P = 0.028; A1-R; P = 0.011). In contrast, only A1-R significantly reduced tumor weight of stem-like XPA1 cells (P = 0.012). The combination A1-R with 5-FU improved the antitumor efficacy compared with 5-FU monotherapy on the stem-like cells (P = 0.004). The results of the present report indicate A1-R is a promising therapy for chemo-resistant pancreatic cancer stem-like cells.


An endophytic fungus, Gibberella moniliformis from Lawsonia inermis L. produces lawsone, an orange-red pigment.
Lawsone (2-hydroxy-1, 4-napthoquinone), also known as hennotannic acid, is an orange red dye used as a popular skin and hair colorant. The dye is produced in the leaves of Lawsonia inermis L, often referred to as the "henna" tree. In this study, we report the production of lawsone by an endophytic fungus, Gibberella moniliformis isolated from the leaf tissues of Lawsonia inermis. The fungus produced the orange-red dye in potato dextrose agar and broth, independent of the host tissue. Presence of lawsone was confirmed spectrometrically using HPLC and ESI-MS/MS analysis. The fragmentation pattern of lawsone was identical to both standard lawsone and that extracted from plant tissue. This is a first report of lawsone being produced by an endophytic fungus, independent of the host tissue. The study opens up interesting questions on the possible biosynthetic pathway through which lawsone is produced by the fungus.


Thoracoabdominal-median sternotomy for resection of primary adrenal carcinoma extending into inferior vena cava and hepatic vein.
A technique utilizing a combined thoracoabdominal-median sternotomy approach is described for stimulatenous resection of a large adrenal cancer occluding the inferior vena cava and extending into the left hepatic vein. This technique is useful in removint an extensive extension of a renal or adrenal cancer into the inferior vena cava.


National Pediatric Trauma Registry.
The National Pediatric Trauma Registry (NPTR) is a multi-institutional database designed to compile information concerning all aspects of pediatric trauma care. The registry is designed and operated in a manner that maximizes data accuracy and provides this information to all participating investigators. The growth of the database has allowed the NPTR to provide the first accurate epidemiologic description of pediatric trauma as a national disease, as well as to develop national norms for pediatric trauma care. The registry presently contains 10,177 patients, and is undergoing revisions (phase II) to allow a more focused evaluation of various aspects of the clinical care and rehabilitation of the pediatric trauma patient.


[Capsule Endoscopy in Patients with Cardiac Pacemakers and Implantable Cardioverter Defibrillators - Is the Formal Contraindication still Justified?].
Capsule endoscopy is an established tool for investigation of the small intestine. Because of limited clinical experience in patients with cardiac devices the US Food and Drug Administration and the manufacturers recommend not to use capsule endoscopy in these patients. Studies investigating possible interference between small bowel capsule endoscopy and cardiac pacemakers and implanted cardioverters were analysed. For the review we considered studies published in English or German and indexed in PubMed (Medline) as well as relevant abstracts and technical data from the manufacturer. In vitro and in vivo studies applying real capsules revealed no clinically relevant interference with pacemakers and implanted cardioverters. This evidence already has had an impact on clinical practice and recommendations of scientific societies. On the other hand wireless telemetry can interfere with CE video. According to present evidence, small bowel capsule endoscopy can be used in patients with pacemakers and implanted cardioverters after obtaining informed consent concerning the formal existence of contraindication.


Direct conversion of white phosphorus to versatile phosphorus transfer reagents via oxidative onioation.
The main feedstock for the value-added phosphorus chemicals used in industry and research is white phosphorus (P4), from which the key intermediate for forming P(III) compounds is PCl3. Owing to its high reactivity, syntheses based on PCl3 are often accompanied by product mixtures and laborious work-up procedures, so an alternative process to form a viable P(III) transfer reagent is desirable. Our concept of oxidative onioation, where white phosphorus is selectively converted into triflate salts of versatile P1 transfer reagents such as [P(LN)3][OTf]3 (LN is a cationic, N-based substituent; that is, 4-dimethylaminopyridinio), provides a convenient alternative for the implementation of P-O, P-N and P-C bonds while circumventing the use of PCl3. We use p-block element compounds of type RnE (for example, Ph3As or PhI) to access weak adducts between nitrogen Lewis bases LN and the corresponding dications [RnELN]2+. The proposed equilibrium between [RnELN]2+ + LN and [RnE(LN)2]2+ allows for the complete oxidative onioation of all six P-P bonds in P4 to yield highly reactive and versatile trications [P(LN)3]3+.


Hypoxia-mediated impairment of the mitochondrial respiratory chain inhibits the bactericidal activity of macrophages.
In infected tissues oxygen tensions are low. As innate immune cells have to operate under these conditions, we analyzed the ability of macrophages (Mφ) to kill Escherichia coli or Staphylococcus aureus in a hypoxic microenvironment. Oxygen restriction did not promote intracellular bacterial growth but did impair the bactericidal activity of the host cells against both pathogens. This correlated with a decreased production of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates. Experiments with phagocyte NADPH oxidase (PHOX) and inducible NO synthase (NOS2) double-deficient Mφ revealed that in E. coli- or S. aureus-infected cells the reduced antibacterial activity during hypoxia was either entirely or partially independent of the diminished PHOX and NOS2 activity. Hypoxia impaired the mitochondrial activity of infected Mφ. Inhibition of the mitochondrial respiratory chain activity during normoxia (using rotenone or antimycin A) completely or partially mimicked the defective antibacterial activity observed in hypoxic E. coli- or S. aureus-infected wild-type Mφ, respectively. Accordingly, inhibition of the respiratory chain of S. aureus-infected, normoxic PHOX(-/-) NOS2(-/-) Mφ further raised the bacterial burden of the cells, which reached the level measured in hypoxic PHOX(-/-) NOS2(-/-) Mφ cultures. Our data demonstrate that the reduced killing of S. aureus or E. coli during hypoxia is not simply due to a lack of PHOX and NOS2 activity but partially or completely results from an impaired mitochondrial antibacterial effector function. Since pharmacological inhibition of the respiratory chain raised the generation of ROI but nevertheless phenocopied the effect of hypoxia, ROI can be excluded as the mechanism underlying the antimicrobial activity of mitochondria.


Photophysical and cellular uptake properties of novel phosphorescent cyclometalated iridium(III) bipyridine D-fructose complexes.
We report here the synthesis, characterization and photophysical properties of two novel phosphorescent cyclometalated iridium(III) polypyridine D-fructose complexes and their fructose-free counterparts. The cellular uptake of the complexes and their cytotoxicity have also been examined.


Extraocular muscles: basic and clinical aspects of structure and function.
Although extraocular muscle is perhaps the least understood component of the oculomotor system, these muscles represent the most common site of surgical intervention in the treatment of strabismus and other ocular motility disorders. This review synthesizes information derived from both basic and clinical studies in order to develop a better understanding of how these muscles may respond to surgical or pharmacological interventions and in disease states. In addition, a detailed knowledge of the structural and functional properties of extraocular muscle, that would allow some degree of prediction of the adaptive responses of these muscles, is vital as a basis to guide the development of new treatments for eye movement disorders.


Resident assistant training level is not associated with patient spinal fusion outcomes.
A hallmark of surgical training is resident involvement in operative procedures. While resident-assisted surgeries have been deemed generally safe, few studies have rigorously isolated the impact of resident post-graduate year (PGY) level on post-operative outcomes in a neurosurgical patient population. The objective of this study is to evaluate the relationship between resident training level and outcomes following single-level, posterior-only lumbar fusion, after matching on key patient demographic/clinical characteristics and attending surgeon. This coarsened-exact matching (CEM) study analyzed 2338 consecutive adult patients who underwent single-level lumbar fusion with a resident assistant surgeon at a multi-hospital university health system from 2013 to 2019. Primary outcomes were 30-day and 90-day readmissions, Emergency Department (ED) visits, reoperations, surgical complications, and mortality. First, univariate logistic regression examined the relationship between PGY level and outcomes. Then, CEM was used to control for key patient characteristics - such as race and comorbid status - and supervising attending surgeon, between the most junior (PGY-2)-assisted cases and the most senior (PGY-7)-assisted cases, thereby isolating the relationship between training level and outcomes. Among all patients, resident training level was not associated with risk of adverse post-surgical outcomes. Similarly, between exact-matched cohorts of PGY-2- and PGY-7-assisted cases, no significant differences in adverse events or discharge disposition were observed. Patients with the most senior resident assistant surgeons demonstrated longer length of stay (mean 100.5 vs. 93.8 h, p = 0.022) and longer duration of surgery (mean 173.5 vs. 159.8 min, p = 0.036). Training level of the resident assistant surgeon did not impact adverse outcomes provided to patients in the setting of single-level, posterior-only lumbar fusion. These findings suggest that attending surgeons appropriately manage cases with resident surgeons at different levels of training.


Serum transferrin as a predictor of prognosis for hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma.
We recently reported that the iron chelator deferoxamine (DFO) is efficacious in advanced hepatocellular carcinoma (HCC) patients. Iron regulation may thus have an important impact in HCC therapy. Because transferrin is a native chelator that regulates iron homeostasis, it may act as an anticancer agent in a similar manner as DFO. The objective of this study was to evaluate serum transferrin as a prognostic predictor in advanced HCC patients undergoing hepatic arterial infusion chemotherapy (HAIC). We retrospectively studied 44 patients receiving HAIC and analyzed various parameters for their possible use as prognostic predictors. The 1-, 2- and 3-year cumulative survival rates were 36.4%, 18.2% and 8.5%, respectively, and the median survival time (MST) was 7.0 months. The survival rates of patients who had serum transferrin of 190 mg/dL or more (MST, 12.0 months) were significantly better than those of patients who had serum transferrin of less than 190 mg/dL (MST, 4.9 months). Multivariate analysis identified serum transferrin of 190 mg/dL or more (hazard ratio [HR], 0.282; 95% confidence interval [CI], 0.132-0.603; P = 0.001) and Child-Pugh score B (HR, 1.956; 95% CI, 1.034-3.700; P = 0.039) as independent prognostic predictors. There was a significant correlation between serum transferrin level and therapeutic effect (P < 0.001). Serum transferrin could be useful as a prognostic predictor in advanced HCC patients before HAIC treatment.


Anthocyanin-rich fraction from Thai berries interferes with the key steps of lipid digestion and cholesterol absorption.
Several studies have documented the hypolipidemic effect of anthocyanin-rich plants in vitro and in vivo. The objective of this study was to elucidate the inhibitory activity of anthocyanin-rich fraction from Thai berries against fat digestive enzymes. The ability of Thai berries to bind bile acid, disrupt cholesterol micellization and the cholesterol uptake into Caco-2 cells was also determined. The content of total phenolics, flavonoid and anthocyanin in Prunus domestica L. (TPE), Antidesma bunius (L.) Spreng, Syzygium cumini (L.) Skeels, and Syzygium nervosum A. Cunn. Ex DC was 222.7-283.5 mg gallic acid equivalents, 91.2-184.3 mg catechin equivalents, and 37.9-49.5 mg cyanidin-3-glucoside equivalents/g extract, respectively. The anthocyanin-rich fraction of all extracts inhibited pancreatic lipase and cholesterol esterase with the IC50 values of 90.6-181.7 μg/mL and 288.7-455.0 μg/mL, respectively. Additionally, all extracts could bind primary and secondary bile acids (16.4-36.6%) and reduce the solubility of cholesterol in artificial micelles (53.0-67.6%). Interestingly, TPE was the most potent extract on interfering the key steps of lipid digestion among the tested extracts. In addition, TPE (0.10-0.50 mg/mL) significantly reduced the cholesterol uptake into Caco-2 cells in a concentration-dependent manner. These results demonstrate a new insight into the role of anthocyanin-rich Thai berry extract on interfering the key steps of lipid digestion and absorption.


Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer.
Multitarget drugs have emerged as a promising treatment modality in modern anticancer therapy. Taking advantage of the synergy of NAMPT and EGFR inhibition, we have developed the first compounds that serve as dual inhibitors of NAMPT and EGFR. On the basis of CHS828 and erlotinib, a series of hybrid molecules were successfully designed and synthesized by merging of the pharmacophores. Among the compounds that were synthesized, compound 28 showed good NAMPT and EGFR inhibition, and excellent in vitro anti-proliferative activity. Compound 28, which is a new chemotype devoid of a Michael receptor, strongly inhibited the proliferation of several cancer cell lines, including H1975 non-small cell lung cancer cells harboring the EGFRL858R/T790M mutation. More importantly, it imparted significant in vivo antitumor efficacy in a human NSCLC (H1975) xenograft nude mouse model. This study provides promising leads for the development of novel antitumor agents and valuable pharmacological probes for the assessment of dual inhibition in NAMPT and EGFR pathway with a single inhibitor.


Risk for preterm and very preterm delivery in women who were born preterm.
To evaluate whether women who themselves were born preterm are at increased risk of preterm delivery and, if so, whether known maternal complications of preterm birth such as hypertension or diabetes explain this risk. We conducted a population-based cohort study of all women born preterm (51,148) and term (823,991) in Québec, Canada, between 1976 and 1995; after frequency matching 1:2 preterm to term, we examined the relationship of preterm birth between women and their offspring. The study included 7,405 women who were born preterm (554 before 32 weeks of gestation and 6,851 at 32-36 weeks of gestation) and 16,714 women born term, who delivered 12,248 and 27,879 newborns, respectively. Overall, 14.2% of women born before 32 weeks of gestation, 13.0% of 32-36 weeks of gestation, and 9.8% of those born term delivered prematurely at least once during the study period, including 2.4%, 1.8%, and 1.2%, respectively, who delivered very preterm (both P<.001 for trend). After adjustment for factors including own birth weight for gestational age and pregnancy complications, the overall odds of preterm first live delivery associated with being born preterm was elevated by 1.63-fold (95% confidence interval [CI] 1.22-2.19) for women born before 32 weeks of gestation and 1.41-fold (95% CI 1.27-1.57) for those born at 32-36 weeks of gestation relative to women born term. Women who themselves were born preterm are at increased risk of delivering their neonates prematurely. This is independent of prematurity risks associated with hypertension and diabetes. II.


Differential expression of c-kit and CD43 in histological subtypes of adenoid cystic carcinoma of salivary gland.
Adenoid cystic carcinoma (ACC) of the salivary gland is characterized by a prolonged but inevitably unfavorable clinical course. Recent studies have suggested that the transmembrane tyrosine kinase receptor, c-kit proto-oncogene is involved in ACC pathogenesis. CD43 is a sialoglycoprotein that is typically expressed by hematopoietic cells and their derivative neoplasms, although positivity in epithelial tumors has only been recognized recently. The aim of this study was to evaluate c-kit and CD43 immunoreactivity in ACCs and to compare the extent of their expression in various histologically defined subgroups of ACC, and their probable involvement in ACC pathogenesis. Formalin-fixed paraffin-embedded sections from 35 ACCs were immunostained for c-kit and CD43 using monoclonal antibodies. Cytoplasmic and membranous c-kit immunoreactivity was detected in 25/35 ACCs (71.4%) with strong immunostaining observed in solid pattern of ACC. Cytoplasmic and membranous CD43 immunoreactivity was detected in 18/35 (51.4%) of ACCs with strong immunostaining seen in the cribriform pattern. These results suggested that c-kit could be used as a prognostic marker for ACC and specific c-kit tyrosine kinase inhibitors such as imatinib, might be used in future therapeutic approaches against subgroups of ACC. CD43 appears to be preferentially expressed in salivary gland ACCs. Its expression decreased with cellular dedifferentiation and there was an inverse relationship between immunoexpression of c-kit and CD43 among ACC of salivary gland.


Managing iliofemoral deep venous thrombosis of pregnancy with a strategy of thrombus removal is safe and avoids post-thrombotic morbidity.
Extensive deep venous thrombosis (DVT) during pregnancy is usually treated with anticoagulation alone, risking significant post-thrombotic syndrome (PTS) in young patients. Catheter-directed thrombolysis (CDT) and operative venous thrombectomy have been safely and effectively used in nonpregnant patients, demonstrating significant reduction in post-thrombotic morbidity. This report reviews short- and long-term outcomes of 13 patients with extensive DVT of pregnancy treated with a strategy of thrombus removal. From 1999 to 2013, 13 patients with iliofemoral DVT during pregnancy were offered CDT, pharmacomechanical thrombolysis (PMT), and/or venous thrombectomy. Gestational age ranged from 8 to 34 weeks. Fetal monitoring was performed throughout hospitalization. Radiation exposure was minimized with pelvic lead shields, focal fluoroscopy, and limited angiographic runs. Follow-up included objective vein evaluation using venous duplex and PTS assessment using the Villalta scale. CDT and/or PMT were used in 11 patients. Two patients underwent venous thrombectomy alone, and one patient had operative thrombectomy as an adjunct to CDT and PMT. Each patient had complete or near-complete thrombus resolution and rapid improvement in clinical symptoms. Eight of 11 having CDT or PMT underwent venoplasty and stenting of the involved iliac veins. Twelve of the 13 delivered healthy infants at term. One patient opted for termination of her pregnancy. Mean patient and gestational ages were 26 years and 26 weeks, respectively. Mean follow-up was 1.3 years, with only one recurrence. Duplex ultrasonography demonstrated patent veins in all but one patient and normal valve function in 10 patients. Eleven patients had Villalta scores <5 (considered normal), with a mean score of 0.7. Extensive DVT of pregnancy can be effectively and safely treated with a strategy of thrombus removal, resulting in a patent venous system, normal valve function in many, prevention of PTS, and reduction in recurrence.


Circadian rhythm of extracellular pH in crayfish at different levels of oxygenation.
The extracellular pH regulation was studied in the crayfish Astacus leptodactylus (a night animal) as a function of circadian rhythm. The venous acid-base balance (ABB) was determined in the morning (10 a.m.-12 a.m.) and in the evening (10 p.m.-12 p.m.) at PO2 ranging from 29 to 6 kPa and constant ABB in the water at 13 degrees C. In the morning the venous pH (pHv) was maintained constant by metabolic means independently of PO2 from 29 to 10 kPa. In the evening pHv again was constant and independent of PO2 but it was more alkaline by 0.1 unit corresponding to a shift along the in vitro buffer line. At that time, the ventilation required for providing a unit quantity of O2 (i.e. the ventilatory requirement) increased more than for simply providing O2. The related circadian changes of sensitivity of the ventilatory control system were assessed by comparing morning and evening ventilatory responses to 1-h periods of hypoxia and then hypercapnia. In the evening, the amplitude of the responses to both O2 and CO2 increased but the increase in CO2 sensitivity was proportionally more important. This is consistent with the increase of ventilatory requirement and the related decrease of hemolymph PCO2 during this period. It is concluded that in this animal there exists a circadian rhythm of extracellular pH that is achieved by controlling the CO2 partial pressure in the hemolymph. Results are discussed in terms of O2 transport processes and metabolic modulation through pH adjustments.


Heart Rate and Outcomes in Hospitalized Patients With Heart Failure With Preserved Ejection Fraction.
A lower heart rate is associated with better outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Less is known about this association in patients with HF with preserved ejection fraction (HFpEF). The aims of this study were to examine associations of discharge heart rate with outcomes in hospitalized patients with HFpEF. Of the 8,873 hospitalized patients with HFpEF (EF ≥50%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 6,286 had a stable heart rate, defined as ≤20 beats/min variation between admission and discharge. Of these, 2,369 (38%) had a discharge heart rate of <70 beats/min. Propensity scores for discharge heart rate <70 beats/min, estimated for each of the 6,286 patients, were used to assemble a cohort of 2,031 pairs of patients with heart rate <70 versus ≥70 beats/min, balanced on 58 baseline characteristics. The 4,062 matched patients had a mean age of 79 ± 10 years, 66% were women, and 10% were African American. During 6 years (median 2.8 years) of follow-up, all-cause mortality was 65% versus 70% for matched patients with a discharge heart rate <70 versus ≥70 beats/min, respectively (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93; p < 0.001). A heart rate <70 beats/min was also associated with a lower risk for the combined endpoint of HF readmission or all-cause mortality (HR: 0.90; 95% CI: 0.84 to 0.96; p = 0.002), but not with HF readmission (HR: 0.93; 95% CI: 0.85 to 1.01) or all-cause readmission (HR: 1.01; 95% CI: 0.95 to 1.08). Similar associations were observed regardless of heart rhythm or receipt of beta-blockers. Among hospitalized patients with HFpEF, a lower discharge heart rate was independently associated with a lower risk of all-cause mortality, but not readmission.


Sequential cytogenetic studies in an ovarian cancer cell line.
Cytogenetic analysis of a human ovarian carcinoma cell line JoN was performed at passages 6, 43, and 89. At passage 6 there were pseudodiploid and pseudotetraploid cells containing up to 22 markers. Pseudodiploid cells predominated. Significant differences were seen in the later analyses. At passages 43 and 89, cells had a modal number of 44 and 88 chromosomes with four new reciprocal translocations and loss of all unidentified markers. There was retention of one identified marker throughout plus one that gradually disappeared. Karyotypes at passages 43 and 89 were identical, suggesting stability of rearrangements. These changes indicate continuing chromosomal rearrangements in culture, not necessarily creating more complexity.


CAD-CAM approach to designing and fabricating a low-maintenance metal-acrylic resin implant-supported fixed complete dental prosthesis: A clinical report.
The metal-acrylic resin implant-supported fixed complete dental prosthesis (IFCDP) is a reliable restorative option. However, clinical complications and laboratory fabrication concerns are associated with these restorations. Maintenance and repair lead to increased chair time, but recently introduced computer-aided design and computer-aided manufacturing (CAD-CAM) materials and technology can improve efficiency and mitigate complications. In this clinical report, the existing design principles and CAD-CAM materials were combined to fabricate a metal-acrylic resin IFCDP that minimized individual tooth fracture and facilitated efficient resurfacing of worn surfaces.


A new system to target the effect-site during propofol sedation.
We evaluated a new, integrated, covariate-adjusted, target-controlled infusion system during sedation with propofol combined with 50% nitrous oxide (N2O) and with propofol only (Air). The protocol consisted of sequential 15-minute cycles in 20 volunteers. After a 15-minute control period, propofol was infused to an initial target effect-site concentration of 0.25 microg x ml-1 (N2O) or 1.5 microg x ml-1 (Air). Subsequently, the target effect-site concentration was increased by 0.25 (N2O) or 0.5 microg x ml-1 (Air) for 15 min This sequence was continued until the volunteers lost consciousness as defined by an Observer's Assessment Alertness/Sedation (OAA/S) score = 2. Venous plasma propofol concentrations at the beginning(9 elapsed minutes) and end(15 elapsed minutes) of the pseudo-steady state period differed by only 0.00 +/- 0.16 microg x ml-1 (P = 0.78) during the N2O and 0.00 +/- 0.25 microg x ml-1 (P = 0.91) during the Air trial. OAA/S scores and bispectral index values, as surrogate measures of pharmacodynamic effect, were not different during this time in either trial. The median(25th, 75th percentiles) of the median performance error (%) was -13 (-24, -1) during the N2O and -18 (-26, -9) during the Air trial. The median absolute performance error (%) was 17 (10, 24) in the N2O and 22 (12, 28) in Air trial. The divergence (%/h) was -10 (-26, 4) in the N2O and 14 (-21, 26) in Air trial. The wobble was 7 (5, 10) in the N2O and 6 (4, 8) in the Air trial. When tested with venous blood samples, our TCI system for propofol, using a covariate-adjusted, integrated pharmacokinetic model to target effect-site concentrations, demonstrated a clinically acceptable accuracy and stability during mild to moderate sedation.


[Pediatric inpatient interdisciplinary multimodal pain treatment in Germany].
Severely disabling chronic pain affects approximately half a million children in Germany. If there is a lack of response to unimodal treatment, an inpatient interdisciplinary multimodal pain treatment (IMPT) can be considered. This review article describes the supply situation of pediatric inpatient IMPT in Germany and presents the current evidence on the effectiveness. Based on a systematic literature search, studies addressing the effectiveness of pediatric inpatient IMPT in Germany were identified. In addition, further sources were used to extract information on pediatric IMPT treatment centers in Germany in order to describe the treatment approaches, the qualification of personnel and characteristics of patients. There are four pediatric pain centers in Germany that are specialized in inpatient IMPT for children and adolescents. Treatment duration ranges between 3 and 4 weeks. The multimodal treatment is carried out by a multiprofessional team and is generally available for patients up to 18 years. The majority of patients are female. The effectiveness of pediatric IMPT in Germany was investigated up to 4 years after treatment. Positive effects were shown for pain characteristics and also for the emotional burden. Additional treatment modules can facilitate further optimization of treatment effects. Further research on the effectiveness of IMPT in Germany is important in order to refine and optimize the available treatment programs.


Stable expression of nucleocapsid proteins of Puumala and Hantaan virus in mammalian cells.
The development of an in vitro-system for the stable expression and the analysis of native hantavirus proteins using hantaviral cDNA is of particular interest. As a first step the expression of the hantavirus nucleocapsid (N) proteins in mammalian cells was studied in more detail. The cDNA of the S-RNA segment of Puumala virus strain CG-1820 and Hantaan virus strain 76-118 was used for the construction of eucaryotic expression vectors that allow the generation and selection of mammalian cells harboring and expressing the N protein genes of hantaviruses. A variety of conventional and novel expression vectors as well as different mammalian cell lines were screened. The expression of the N protein of Puumala virus using the pGRE5-1 vector in which the transcription is under control of inducible glucocorticoid responsive elements (GRE) revealed that the Puumala virus N protein can be expressed in Vero E6 cells efficiently without any detectable cell toxicity. From the variety of expression vectors tested, it was found that pCR3.1 is the vector of choice for stable expression of hantavirus N proteins. The successful establishment of different mammalian cell lines expressing considerable amounts of Puumala and Hantaan virus N protein indicates that the stable and efficient expression of this particular viral protein in the cell lines of three evolutionary distinct species (human, monkey, and mouse) is possible. The system described here represents the experimental basis for further studies of hantavirus infection, replication, and pathogenesis using a reverse genetics approach.


Long-term effectiveness and safety of metreleptin in the treatment of patients with partial lipodystrophy.
To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL). Patients aged ≥ 6 months with PL, circulating leptin < 12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; co-primary endpoints), fasting plasma glucose (FPG), and liver volume were evaluated. Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at month 12, long-term treatment effects, and treatment-emergent adverse events (TEAEs). Significant (p < 0.05) reductions in HbA1c (-0.6%), fasting TGs (-20.8%), FPG (-1.2 mmol/L), and liver volume (-13.4%) were observed in the overall PL population at month 12. In a subgroup of patients with baseline HbA1c ≥ 6.5% or TGs ≥ 5.65 mmol/L, significant (p < 0.05) reductions were seen in HbA1c (-0.9%), fasting TGs (-37.4%), FPG (-1.9 mmol/L), and liver volume (-12.4%). In this subgroup, 67.9% of patients had a ≥ 1% decrease in HbA1c or ≥ 30% decrease in fasting TGs, and 42.9% had a ≥ 2% decrease in HbA1c or ≥ 40% decrease in fasting TGs. Long-term treatment in this subgroup led to significant (p < 0.05) reductions at months 12, 24, and 36 in HbA1c, fasting TGs, and FPG. Metreleptin was well tolerated with no unexpected safety signals. The most common TEAEs were abdominal pain, hypoglycemia, and nausea. In patients with PL, treatment with metreleptin was well tolerated and resulted in improvements in glycemic control, hypertriglyceridemia, and liver volume.


Use of amniotic membrane for radial forearm free flap donor site coverage: clinical, functional and cosmetic outcomes.
To evaluate the clinical, functional and aesthetic outcomes for radial forearm free flap (RFFF) donor sites covered with amniotic membrane (AM). The healing process of patients with RFFF donor sites covered with AM was prospectively followed for 1 year. Additionally at the 12-month evaluation, objective scoring systems were used to assess the aesthetic (Vancouver scar scale, VSS: range 1-13) and functional outcome (skin sensibility, hand/wrist functionality [goniometer], grip strength [score 1 = excellent, 5 = poor]). By using a subjective rating system (score 1 = excellent, 5 = poor), the patient-reported aesthetic and functionality outcome was correlated with objective data analysis. Twenty-one out of 23 patients were followed for 12 months (dropout: 2 patients at 3 months). In 17/23 (73.9%) patients RFFF defect covered with AM showed an uneventful healing period (< 3 months). Prolonged healing periods (> 3 months < 6) for 6 patients (26.1%) were attributed to wound infections (4×), seroma (1×) and inflammation (1×). At the 1-year evaluation, there was a significant (p < 0.01) correlation between subjective (2.0 ± 0.71) and objective aesthetic scores (VVS 3.74 ± 2.18), and a successful grip strength (score 1.67 ± 0.86); however, thumb hyposensibility in 76.2% was seen. A high body mass index (BMI) was in conjunction with a negative (p = 0.012) and the use of antihypertensive medications provided positive effects (p = 0.041) on the aesthetic outcome. RFFF donor site defects covered using AM show excellent clinical, aesthetic and functional outcome representing patient comorbidities (BMI, antihypertensive drugs) might affect the aesthetic outcome. In relation to the excellent outcomes found, the use of AM offers an alternative treatment procedure for RFFF defect covering.


Progenitor hierarchy among parietal epithelial cells depicted at the single-cell level.
The role of parietal epithelial cells (PECs) in kidney function and disease was recently revisited. Building on previous studies of human kidney tissue, in the current issue, Liu et al. further characterize PECs using single-cell RNA sequencing data and confirm the crucial pathophysiological role of PECs in murine kidney biology as a reservoir for different types of progenitors.


Is the delivery mode a critical factor for the microbial communities in the meconium?
Mothers are the primary source of bacteria for newborns, but it is unclear whether mother-to-newborn transmission occurs prior to, during or after birth. Similarly, the effect of the delivery mode on neonatal microorganisms has been the focus of controversy. Healthy maternal and neonatal pairs that underwent vaginal birth and caesarean section were enrolled in this study. Meconium, placenta, membrane and amniotic fluid samples for newborns and vaginal, rectal and oral samples for mothers were collected. All samples were amplified and sequenced by a 16S rRNA gene primer set targeting bacteria and archaea. A total of 550 samples from 36 mother-neonate pairs with vaginal births and 42 mother-neonate pairs with caesarean sections were included in this study. The negative controls showed that the data analysis in this study was not affected by contamination. There was a high diversity of microbial communities in the pregnancy environment of the foetus. Meconium samples could be divided into three distinct types that were not influenced by the delivery method. The distribution patterns of bacterial communities in the meconium, placenta, and foetal membranes were highly similar and had nothing to do with the mode of delivery. For approximately half of the placental microorganisms, the same sequence could be found in the vaginal, rectal, and oral samples of the mother.