If the treatment works, do we need to know why?: the promise of immunotherapy for experimental medicine.
There has been much fanfare, and rightly so, heralding a revolution in the treatment of autoimmune disease using biologic agents-antibodies or other molecules that specifically target known mediators of disease. But not all patients respond to even the most successful biologic agent, which may provide clues about alternate disease mechanisms. Studies aimed at understanding the mechanism of action of biologic agents will yield significant benefits for experimental medicine.


Effect of neurosurgical high observation beds (HOBs) on service provision: a single-centre experience and cost analysis.
To evaluate the effect of level 1, high observation beds (HOBs) compared with high dependency unit (HDU) and neurosurgical intensive care unit (NICU) admission on service provision, such as cancelled operations, and healthcare costs. A retrospective, observational, single-centre cross-sectional study at a single, large UK neurosurgical centre. All adult patients admitted to neurosurgical HOBs between December 2021 and July 2022 were included. The list of cancelled procedures was collected from 2019 to 2022. To evaluate the impact of admission of eligible patients to HOBs, the total bed days, cost per bed day, number of admissions and cost per admission were obtained for all clinical areas the financial years 2019/2020 and 2021/2022. 307 patients were included in the study: 59.7% of HOBs admissions were elective and 37.7% were acute; admissions were for cranial procedures or conservative treatment (64.8%), spinal (32.6%) or other (2.6%). Following admission, 73.3% of patients were stepped down to the ward prior to discharge home. Only seven patients required escalation to level-2 or level-3 care. Overall, 97% of all HOBs patients were discharged home at the end of hospital stay. Occupancy rate was 90.4%.The cost of bed day increased from ward, level 0 (£384), then level 1 (£376), to level 2 (£787-1211) and to level 3 (£1628). From 2019 to 2021, 558 operations had been cancelled, and 140 (37.8%) of 370 were estimated to have been potentially avoided by HOBs admissions due to conflict of scheduling, ward bed capacity and critical care bed capacity. In addition, a minimum total expenditure due to cancelled operations was estimated at £22 923.50 yearly on average. This study recognises HOBs growing role in the management of acutely unwell patients in ward-based environments. While recognising the associated challenges, this study highlighted the potential in reducing healthcare costs. Further studies should evaluate the impact and limitations of HOBs on patients' recovery and outcomes, compared to HDU and NICU.


Transmission of highly virulent community-associated MRSA ST93 and livestock-associated MRSA ST398 between humans and pigs in Australia.
Pigs have been recognised as a reservoir of livestock associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in Europe, Asia and North America. However, little is known about the presence and distribution of MRSA in the Australian pig population and pig industry. This study describes the presence, distribution and molecular characteristics of the human adapted Australian CA-MRSA ST93 isolated from pigs, people, and the environment within a piggery. Isolates were subjected to antibiotic susceptibility testing, DNA microarray, whole genome sequencing, multi locus sequence typing, virulence and resistance gene characterization and phylogenetic analysis. MRSA were isolated from 60% (n = 52) of farm workers where 84% of isolates returned ST93 and the rest ST398. Of the thirty-one pig isolates tested further, an equal number of ST398 and ST93 (15 each) and one as ST30-V were identified. Four of six environmental isolates were identified as ST93 and two as ST398. This study has identified for the first time in Australia the occurrence of CA-MRSA ST93 and LA-MRSA ST398 amongst farm workers, pigs, and the farm environment. Comparative genome analysis indicates that ST398 is likely to have been introduced into Australia from Europe or North America. This study also reports the first linezolid resistant MRSA isolated in Australia.


Irinotecan-associated dysarthria: A single institution case series with management implications in patients with gastrointestinal malignancies.
Irinotecan (Camptosar©, CPT-11), a topoisomerase I inhibitor, is a commonly used cytotoxic chemotherapeutic in the treatment of multiple malignancies, particularly of gastrointestinal origin. Dysarthria secondary to irinotecan has been described as a rare side effect in a few case reports with limited data to recommend appropriate management. We describe herein a large single institution experience of patients with gastrointestinal malignancies who experienced dysarthria while being treated with irinotecan-based chemotherapy regimens (FOLFIRINOX or FOLFIRI+/-bevacizumab). Eighteen patients developed neurological manifestations during irinotecan infusion with the majority ( n = 17) developing dysarthria. Patients also experienced other known side effects including cholinergic effects (abdominal bloating, diarrhea, facial flushing, diaphoresis, and rhinorrhea), nausea, fatigue, perioral paresthesia and musculoskeletal discomfort. The dysarthria occurred as early as with the first infusion of irinotecan ( n = 9), but several patients did not develop symptoms until subsequent infusions (range, 1-6). Dose alterations of irinotecan did not obviously impact the reccurrence or severity of dysarthria. Management strategies included close observation, atropine, slower irinotecan infusion rate, and reassurance. Dysarthria resolved without consequence in all patients within hours of completion of the infusion. Oncologists and pharmacists should be aware of irinotecan-associated dysarthria as a rare, self-limited phenomenon with no long-term sequelae, and appropriately counsel patients and infusion nurses to avoid inadvertently withholding potentially beneficial therapy for patients with gastrointestinal malignancies.


Evaluation of mechanical properties of five cements for orthodontic band cementation.
The aim of this in vitro study was to compare the flexural, compressive and diametral tensile strengths of five cements used in orthodontics for band cementation. Twelve specimens of each cement were tested: 1 - GC Fuji Ortho Band (FJ), GC America Inc.; 2 - Meron (MR), Voco; 3 - Multi-Cure Glass Ionomer Band Cement (MC), 3M Unitek; 4 - Band-Lok (BL), Reliance Orthodontic Products; and 5 - Ketac Cem (KC), 3M ESPE. The results (mean) for diametral tensile strength were: 10.51 MPa (FJ), 9.60 MPa (MR), 20.04 MPa (MC), 42.80 MPa (BL), and 4.08 MPa (KC). The results for compressive strength were (in the same order): 64.50 MPa, 77.71 MPa, 94.21 MPa, 193.88 MPa, and 81.93 MPa. The results for flexural strength were (in the same order): 20.72 MPa, 25.84 MPa, 53.41 MPa, 137.41 MPa, and 20.50 MPa. The statistical analysis was performed by two-way ANOVA and Tukey tests with p-value £ 0.05. In terms of diametral tensile strength, BL showed the highest strength statistically, and MC, the second highest. In terms of compressive tensile strength, BL showed the highest strength statistically, and FJ did not attain the minimum recommended strength. In terms of flexural tensile strength, BL cement was superior to MC, and MR, FJ and KC were equivalent and inferior to BL and MC.


Biogeographic patterns of benthic microbial communities in metal(loid)-contaminated semi-enclosed bay.
Anthropogenic activities can adversely impact biogeochemical processes essential for maintaining ecosystem health in semi-enclosed bays. However, the influence of anthropogenic contaminants such as potentially toxic elements on microbial communities that regulate biogeochemical cycles in semi-enclosed bays is poorly understood. We determined the concentrations of four potentially toxic elements (Cu, Zn, Pb, and As) in sediments from a typical tropical semi-enclosed bay in Guangdong, China. Source apportionment using Pearson's correlation analysis revealed that aquaculture activities were probably the primary source of Cu, Zn, and Pb. Using high-throughput sediment DNA sequencing, we found that Proteobacteria was the dominant phylum in sediments. There was no evidence suggesting site-specific variation in microbial function even though sediments adjacent to aquaculture discharge points had higher microbial diversity. In contrast, pollutant-specific variations were observed; for example, Zn and Pd showed potential adverse effects on the environmental information processing function, while As showed a negative correlation with metabolic function. Based on different environmental characteristics, future research should consider the impact of multiple factors on the bacterial community in aquaculture systems.


The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis.
Elaiophylin is a natural compound and a novel and potent inhibitor of late stage autophagy with outstanding antitumor activity in human ovarian cancer cells. However, the possible biologic effects and functional linkage between elaiophylin and multiple myeloma (MM) have not been explored. This study aimed to assess the effect of elaiophylin on MM cells with mutant TP53 and the possible molecular mechanism. The results suggested that elaiophylin exerted anti-myeloma activity by inducing apoptosis and proliferation arrest. As expected, elaiophylin blocked autophagy flux in MM cells. Subsequently, persistent activation of endoplasmic reticulum (ER) stress was induced. Moreover, the apoptotic effect was to some extent attenuated by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Further studies indicated that elaiophylin effectively suppressed MM cell growth without obvious side effects in zebrafish embryo and mouse xenograft models. Taken together, our data are the first to demonstrate that exposure of human MM cells with mutant TP53 to elaiophylin blocked autophagy flux and thus induced cell death, which partially involved ER stress-associated apoptosis. Targeted disruption of the cellular protein handling system by elaiophylin is therefore a promising therapeutic strategy for overcoming incurable MM, even when TP53 mutations are present.


Utility of intracoronary imaging in the cardiac catheterization laboratory: comprehensive evaluation with intravascular ultrasound and optical coherence tomography.
Intracoronary imaging is an important tool for guiding decision making in the cardiac catheterization laboratory. We have reviewed the latest available evidence in the field to highlight the various potential benefits of intravascular imaging. Coronary angiography has been considered the gold standard test to appropriately diagnose and manage patients with coronary artery disease, but it has the inherent limitation of being a 2-dimensional x-ray lumenogram of a complex 3-dimensional vascular structure. There is well-established inter- and intra-observer variability in reporting coronary angiograms leading to potential variability in various management strategies. Intracoronary imaging improves the diagnostic accuracy while optimizing the results of an intervention. Utilization of intracoronary imaging modalities in routine practice however remains low worldwide. Increased costs, resources, time and expertise have been cited as explanations for low incorporation of these techniques. Intracoronary imaging supplements and enhances an operator's decision-making ability based on detailed and objective lesion assessment rather than a subjective visual estimation. The benefits of intravascular imaging are becoming more profound as the complexity of cases suitable for revascularization increases. While the clinical benefits of intravascular ultrasound have been well validated, optical coherence tomography in comparison is a newer technology, with robust clinical trials assessing its clinical benefit are underway.


Historical and contemporary issues in end-of-life decisions: implications for social work.
End-of-life circumstances have changed dramatically in recent years. In the past century life expectancy has increased by 62 percent and people are living longer with chronic illness. This article discusses evolving health practices and polices in end-of-life decisions. Treatments to prolong life and provide comfort, and interventions that hasten death, are discussed. Recent assisted suicide and euthanasia laws are analyzed and compared. Implications for social work and social work practitioners are addressed.


The impact of nurse prescribing on the clinical setting.
To investigate the impact nurse prescribing has on the organisation, patient and health professional, and to identify factors associated with the growth of nurse prescribing. Systematic search and narrative review. Data obtained through CINAHL, PubMed, Science direct, Online Computer Library Centre (OCLC), databases/websites, and hand searching. English peer-reviewed quantitative, qualitative and mixed-method articles published from September 2009 through to August 2014 exploring nurse prescribing from the perspective of the organisation, health professional and patient were included. Following a systematic selection process, studies identified were also assessed for quality by applying Cardwell's framework. From the initial 443 citations 37 studies were included in the review. Most studies were descriptive in nature. Commonalities addressed were stakeholders' views, prescribing in practice, jurisdiction, education and benefits/barriers. Prescriptive authority for nurses continues to be a positive addition to clinical practice. However, concerns have emerged regarding appropriate support, relationships and jurisdictional issues. A more comprehensive understanding of nurse and midwife prescribing workloads is required to capture the true impact and cost-effectiveness of the initiative.


CD4 CTL, a Cytotoxic Subset of CD4+ T Cells, Their Differentiation and Function.
CD4+ T cells with cytotoxic activity (CD4 CTL) have been observed in various immune responses. These cells are characterized by their ability to secrete granzyme B and perforin and to kill the target cells in an MHC class II-restricted fashion. Although CD4 CTLs were once thought to be an in vitro artifact associated with long-term culturing, they have since been identified in vivo and shown to play important roles in antiviral and antitumor immunity, as well as in inflammation. Functional characterization of CD4 CTL suggests their potential significance for therapeutic purposes. However, in order to develop effective CD4 CTL therapy it is necessary to understand the differentiation and generation of these cells. Although the mechanisms regulating development of various CD4+ Th subsets have been clarified in terms of the cytokine and transcription factor requirement, the CD4 CTL differentiation mechanism remains elusive. These cells are thought to be most closely related to Th1 cells secreting IFNγ and regulated by eomesodermin and/or T-bet transcription factors for their differentiation. However, our studies and those of others have identified CD4 CTLs within other CD4+ T cell subsets, including naïve T cells. We have identified class I-restricted T cell-associated molecule as a marker of CD4 CTL and, by using this marker, we detected a subset of naïve T cells that have the potential to differentiate into CD4 CTL. CD4 CTL develops at sites of infections as well as inflammation. In this review, we summarize recent findings about the generation of CD4 CTL and propose a model with several differentiation pathways.


Clinical features of the yellow nail syndrome.
The yellow nail syndrome is a rare cause of exudative pleural effusions. Diagnosis is based on the presence of typical clinical features, striking nail changes, lymphedema, and pleural effusions of undetermined etiology. There is no direct relationship between the syndrome and primary immunologic disorders, malignancies, endocrine abnormalities, or connective tissue diseases. In patients with symptomatic pleural effusions, pleurodesis is beneficial but no treatment for the nail changes has been devised.


Multicenter report on dialysis and transplantation in Korea, 1986. Korean Society of Nephrology.
Since 1981, the Korean Society of Nephrology began annual report on renal replacement therapy in Korea. The annual number of new patients receiving dialysis treatment in 1986 increased to 957 patients (23.3 per million population) from 825 patients (20.4 per million population) in 1985. And the total number of patients on replacement therapy increased from 1,508 patients (37.3 per million population) to 2,534 patients (61.7 per million population). 1,340 patients (32.6 per million population) of these patients were on hemodialysis, 573 patients (13.9 per million population) on continuous ambulatory peritoneal dialysis (CAPD) and 621 patients (15.1 per million population) on functioning renal graft as of December 31, 1986. The common causes of renal failure of new patients were chronic glomerulonephritis (41.6%) followed by diabetic nephropathy (12.6%), nypertensive nephrosclerosis (7.8%), chronic pyelonephritis (2.5%) and others. The annual mortality rate decreased from 21.9% in 1981 to 13.5 in 1986. The common causes of death in patients on dialysis therapy were cardiac (32.8%), vascular (14.7%), infective (14.7%) and social problems (11.2%) in the order of frequency. Recently, the number of patients requiring dialysis is rapidly increasing due to expanded medical insurance support for dialysis and improved economic status of our country. Therefore, it is necessary to draw up counterplan for a rapid growth of the number of new patients.


Excystation of the encysted metacercariae of Echinostoma trivolvis and Echinostoma caproni in a trypsin-bile salts-cysteine medium and morphometric analysis of the excysted larvae.
A trypsin-bile salts-cysteine (TBC) medium was used to excyst the encysted metacercariae of Echinostoma caproni and Echinostoma trivolvis, 2 allopatric species of Echinostoma. This medium was used to replace a previously used trypsin-bile salts (TB) medium that was no longer effective because of the unavailability of the original stocks of trypsin. The TBC medium maintained at 41 C allowed for 68.6% excystation of E. caproni at 1 hr and 57.5% excystation of E. trivolvis at 2 hr. The cysteine reductant in the TBC medium was necessary; if it was omitted, excystation was nil. Morphometric analysis was done on the excysted metacercariae following fixation of the larvae in hot, 5% neutral buffered formalin and mounting them on slides in glycerin jelly. Body and organ measurements were made on these larvae. The diameter of the acetabulum of E. caproni was significantly greater than that of E. trivolvis. Likewise, the number and diameter of the excretory concretions found in E. caproni were significantly larger than those of E. trivolvis. Morphometric analysis can be used to distinguish structural differences in closely related allopatric species of Echinostoma.


Water-soluble Mo3S4 clusters bearing hydroxypropyl diphosphine ligands: synthesis, crystal structure, aqueous speciation, and kinetics of substitution reactions.
The [Mo(3)S(4)Cl(3)(dhprpe)(3)](+) (1(+)) cluster cation has been prepared by reaction between Mo(3)S(4)Cl(4)(PPh(3))(3) (solvent)(2) and the water-soluble 1,2-bis(bis(hydroxypropyl)phosphino)ethane (dhprpe, L) ligand. The crystal structure of [1](2)[Mo(6)Cl(14)] has been determined by X-ray diffraction methods and shows the typical incomplete cuboidal structure with a capping and three bridging sulfides. The octahedral coordination around each metal center is completed with a chlorine and two phosphorus atoms of the diphosphine ligand. Depending on the pH, the hydroxo group of the functionalized diphosphine can substitute the chloride ligands and coordinate to the cluster core to give new clusters with tridentate deprotonated dhprpe ligands of formula [Mo(3)S(4)(dhprpe-H)(3)](+) (2(+)). A detailed study based on stopped-flow, (31)P{(1)H} NMR, and electrospray ionization mass spectrometry techniques has been carried out to understand the behavior of acid-base equilibria and the kinetics of interconversion between the 1(+) and the 2(+) forms. Both conversion of 1(+) to 2(+) and its reverse process occur in a single kinetic step, so that reactions proceed at the three metal centers with statistically controlled kinetics. The values of the rate constants under different conditions are used to discuss on the mechanisms of opening and closing of the chelate rings with coordination or dissociation of chloride.


Albedo feedbacks to future climate via climate change impacts on dryland biocrusts.
Drylands represent the planet's largest terrestrial biome and evidence suggests these landscapes have large potential for creating feedbacks to future climate. Recent studies also indicate that dryland ecosystems are responding markedly to climate change. Biological soil crusts (biocrusts) ‒ soil surface communities of lichens, mosses, and/or cyanobacteria ‒ comprise up to 70% of dryland cover and help govern fundamental ecosystem functions, including soil stabilization and carbon uptake. Drylands are expected to experience significant changes in temperature and precipitation regimes, and such alterations may impact biocrust communities by promoting rapid mortality of foundational species. In turn, biocrust community shifts affect land surface cover and roughness-changes that can dramatically alter albedo. We tested this hypothesis in a full-factorial warming (+4 °C above ambient) and altered precipitation (increased frequency of 1.2 mm monsoon-type watering events) experiment on the Colorado Plateau, USA. We quantified changes in shortwave albedo via multi-angle, solar-reflectance measurements. Warming and watering treatments each led to large increases in albedo (>30%). This increase was driven by biophysical factors related to treatment effects on cyanobacteria cover and soil surface roughness following treatment-induced moss and lichen mortality. A rise in dryland surface albedo may represent a previously unidentified feedback to future climate.


Effects of storage and cooking on the antioxidant capacity of laying hen eggs.
The aromatic amino acids and carotenoids are the major contributors to the antioxidant properties of egg yolk. This study aimed to evaluate the effect of simulated retail storage and domestic cooking on the antioxidant activity as well as on the aromatic amino acid and carotenoid contents in ordinary table eggs, omega 3/lutein (n-3/lutein) enriched eggs, and eggs from heritage chicken breeds. The oxygen radical scavenging capacity (ORAC) was the highest in n-3/lutein enriched eggs (161.4μmolTE/gsample), while eggs from heritage white leghorns (HW) showed the lowest levels (127.6μmolTE/gsample). Six weeks of storage at refrigerated temperature did not change the ORAC values, as well as the contents of free amino acid, carotenoid, and malondialdehyde (MDA) in egg yolk. Boiling and frying however, significantly reduced the ORAC value, and the contents of free amino acid, lutein and zeaxanthin, and increased the MDA content in eggs. Our results showed that the antioxidant activity is stable during six weeks of simulated retail storage.


The effect of alpha-difluoromethyl-ornithine on tumor growth, acute phase reactants, beta-2-microglobulin and hydroxyproline in kidney and bladder carcinomas.
Multiple oral doses of alpha-difluoromethyl-ornithine (alpha-DFMO), 18-24 g/day for up to 2 months, were administered to 2 patients with invasive and metastatic carcinoma of the bladder and to 3 patients with metastatic renal cancer in an open study. The moderate antigrowth effect of alpha-DFMO in these patients was concluded from the results of serial kidney, liver and bone scintigrams, from the low frequency of a local recurrence of bladder carcinoma and from the survival rate of 4 of 5 patients after 12 months. Increased excretion of hydroxyproline and beta2-microglobulin were measured 1 month following alpha-DFMO treatment suggesting initial tumor necrosis and degradation. Treatment was poorly tolerated with gastrointestinal side effects (e.g. gastritis, vomiting, diarrhea) in all subjects, erythropenia in 2 subjects (associated with thrombocytopenia and leucopenia in 1 subject each), and audiovestibular symptoms in 2 patients. All side effects were reversible and normal function returned 2-4 months after stopping therapy.


The Relationship Between Supervisor Bottom-Line Mentality and Subordinate Work Performance: Linear or Curvilinear Effects?
Combine the transactional model of stress and coping with the challenge and hindrance stressor framework. This study examined whether there is a linear or curvilinear relationship between supervisor bottom-line mentality (BLM), which emphasizes the pursuit of bottom-line results above all else, and the work performance of subordinates. A total of 284 two-wave dual-source survey data have been collected from an insurance company in China. Analysis was conducted in two steps. First, confirmatory factor analysis (CFA) was used to test the validity of scales. Second, hierarchical regression analysis was conducted to examine the hypotheses. Results show that there has an inverted U-shaped (curvilinear) relationship between supervisor BLM and subordinate work performance. As the level of supervisor BLM increases from low to moderate, subordinate work performance increases; as the level of supervisor BLM increases from moderate to high, subordinate work performance decreases. Moreover, this study finds that the inverted U-shaped relationship between supervisor BLM and subordinates' work performance was stronger when subordinates have higher power distance orientation. Unlike previous studies which found a linear relationship between supervisor BLM and subordinate work performance, this study provided the first empirical examination of our hypothetical inverted U-shaped relationship of supervisor BLM impact on subordinate work performance. In addition, this study found that the relationship was stronger when subordinates had a higher power distance orientation.


Fetal congenital cystic adenomatoid malformations of the lung: a clinicopathologic study of eleven cases.
We describe the pathological examination of 11 cases of fetal congenital cystic adenomatoid malformation of the lung. All patients were treated in utero between 21 and 27 weeks of gestation with either lobectomy or placement of a thoracoamniotic shunt. Ten cases involved a single lobe, and one case involved two lobes. The lesions contained both solid and cystic areas. On the basis of microscopic appearances, we separated the malformations into two distinct types. The first type consisted of seven cases showing scattered bronchiole-like dilated spaces lined by pseudostratified ciliated epithelium with intervening tightly packed small tubules lined by columnar cells with subnuclear vacuoles. This pattern superficially resembled the pseudoglandular period of lung development. The remaining four cases were of the other histologic type. They contained scattered bronchiole-like structures with intervening irregularly branching glands lined by cuboidal epithelium within loose mesenchymal stroma. This pattern superficially resembled the canalicular period of lung development. We observed that the malformations contained cysts of various sizes and that cyst size varied widely within a single lesion. Moreover, predominantly cystic and predominantly solid lesions could not be separated histologically. Thus, we identify two patterns of fetal congenital cystic adenomatoid malformations, pseudoglandular and canalicular, the clinical significance of which is yet to be determined.


Electrostatic calculation of the substituent effect: an efficient test on isolated molecules.
The energy of a disubstituted molecule has often been approximated by simple electrostatic formulas that represent the substituents as poles or dipoles. Herein, we test this approach on a new model system that is more direct and more efficient than testing on acid-base properties. The energies of 27 1,4-derivatives of bicyclo[2.2.2]octane were calculated within the framework of the density functional theory at the B3LYP/6-311+G(d,p) level; interaction of the two substituents was evaluated in terms of isodesmic homodesmotic reactions. This interaction energy, checked previously on some experimental gas-phase acidities, was considered to be accurate and served as reference to test the electrostatic approximation. This approximation works well in the qualitative sense as far as the sign and the order of magnitude are concerned: beginning with the strongest interaction between two poles, a weaker interaction between pole and dipole, and the weakest between two dipoles. However, all the electrostatic calculations yield energies that are too small, particularly for weak interaction, and this fundamental defect is not remedied by some possible improvements. In particular, variation of the effective permittivity would require a physically impossible value less than unity. The explanation must lie in a more complex distribution of electron density than anticipated in the electrostatic model. It also follows that possible conclusions about the transmission of substituent effects "through space" have little validity.


Value of three dimensional-speckle tracking imaging for predicting left ventricular function after non-ST-segment elevation myocardial infarction with percutaneous coronary intervention.
Percutaneous coronary intervention (PCI) is the recommended treatment for high risk patients with non-ST-segment elevation myocardial infarction (NSTEMI). To investigate the application of three dimensional-speckle tracking imaging (3D-STI) on patients diagnosed with NSTEMI undergoing PCI. Forty-four NSTEMI patients and 20 healthy subjects that received basic clinical and laboratory examinations were included in our study. NSTEMI patients were divided into three groups: heart failure (HF) with normal ejection fraction (HF-NEF group, n = 19), heart failure with preserved ejection fraction (HF-PEF group, n = 14) and heart failure with a reduced ejection fraction (HF-REF group, n = 11). The global longitudinal peak systolic strain (GLS), global circumferential peak systolic strain (GCS), global radial peak systolic strain (GRS) and left ventricular (LV) torsion of all subjects were measured by 3D-STI before PCI and 1 month, 3 months after PCI. The high-sensitivity troponin T (hs-TNT), high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were measured in each group. Correlations between these parameters and LV ejection fraction (LVEF) were tested by Pearson correlation analysis. GLS, GCS and torsion were significantly decreased in the 3 NSTEMI groups compared with control group (P < 0.05). GLS, torsion were significantly improved in the three NSTEMI groups at postoperative 1 and 3 months (P < 0.05). HF-REF group showed improved GCS on postoperative 1 and 3 month compared with preoperative data, and improved GLS at 3-month follow-up compared with 1-month follow-up (P < 0.05). The hs-TNT, hs-CRP and NT-pro BNP increased in the three NSTEMI groups before PCI (P < 0.05), and decreased at postoperative 1 and 3 month (P < 0.05). LVEF has the positive correlations with LV endsystolic volume (LVESV) and torsion, as well as the negative correlations with LVGLS, LVGCS, NT-pro BNP (P < 0.05). The combinative detection of 3D-STI and NT-pro BNP is an efficient way to assess the cardiac function in patients diagnosed with NSTEMI undergoing PCI.


Incidental Findings from 16,400 Brain MRI Examinations of Research Volunteers.
Incidental findings are discovered in neuroimaging research, ranging from trivial to life-threatening. We describe the prevalence and characteristics of incidental findings from 16,400 research brain MRIs, comparing spontaneous detection by nonradiology scanning staff versus formal neuroradiologist interpretation. We prospectively collected 16,400 brain MRIs (7782 males, 8618 females; younger than 1 to 94 years of age; median age, 38 years) under an institutional review board directive intended to identify clinically relevant incidental findings. The study population included 13,150 presumed healthy volunteers and 3250 individuals with known neurologic diagnoses. Scanning staff were asked to flag concerning imaging findings seen during the scan session, and neuroradiologists produced structured reports after reviewing every scan. Neuroradiologists reported 13,593/16,400 (83%) scans as having normal findings, 2193/16,400 (13.3%) with abnormal findings without follow-up recommended, and 614/16,400 (3.7%) with "abnormal findings with follow-up recommended." The most common abnormalities prompting follow-up were vascular (263/614, 43%), neoplastic (130/614, 21%), and congenital (92/614, 15%). Volunteers older than 65 years of age were significantly more likely to have scans with abnormal findings (P < .001); however, among all volunteers with incidental findings, those younger than 65 years of age were more likely to be recommended for follow-up. Nonradiologists flagged <1% of MRIs containing at least 1 abnormality reported by the neuroradiologists to be concerning enough to warrant further evaluation. Four percent of individuals who undergo research brain MRIs have an incidental, potentially clinically significant finding. Routine neuroradiologist review of all scans yields a much higher rate of significant lesion detection than selective referral from nonradiologists who perform the examinations. Workflow and scan review processes need to be carefully considered when designing research protocols.


[Tympanoplasty in cholesteatoma otitis media with normal hearing].
Thirteen cholesteatomas, with hearing within 20dB, were operated on from 1985 to 1992. Their mean age was 22.1 years, and the mean follow-up period 1.8 years. Eleven cases were pars flaccid type, and 2 cases pars tensa type. Tympanoplasties were performed by the canal down method (4 cases), the canal up method (3 cases), both transmeatal atticotomy and scutumplasty (4 cases) and both the canal down method and mastoid obliteration (2 cases). Postoperative hearing results of three averaged speech frequencies were within 20dB in 11 cases and between 20 and 30dB in 2 cases. No recurrent cholesteatoma or extrusion of columella occurred during the follow-up period. One of the cases operated on by the canal down method showed postoperative mastoid cavity problems, and one of the cases operated on by the canal up method showed retraction of the pars flaccida. These findings prompted us to operate on cholesteatoma cases with normal hearing and to recommend tympanoplasty with transmeatal atticotomy and scutumplasty.


Sequences of B-chain/domain 1-10/1-9 of insulin and insulin-like growth factor 1 determine their different folding behavior.
Although insulin and insulin-like growth factor-1 (IGF-1) belong to one family, insulin folds into one thermodynamically stable structure, while IGF-1-folds into two thermodynamically stable structures (native and swap forms). We have demonstrated previously that the bifurcating folding behavior of IGF-1 is mainly controlled by its B-domain. To further elucidate which parts of the sequences determine their different folding behavior, by exchanging the N-terminal sequences of mini-IGF-1 and recombinant porcine insulin precursor (PIP), we prepared four peptide models: [1-9]PIP, [1-10]mini-IGF-1, [1-4]PIP, and [1-5]mini-IGF-1 by means of protein engineering, and their disulfide rearrangement, V8 digestion, circular dichroic spectra, disulfide stability, and in vitro refolding were investigated. Among them only [1-9]PIP, like mini-IGF-1/IGF-1, was expressed in yeast as two isomers: isomer 1 (corresponding to swap IGF-1) and isomer 2 (corresponding to native IGF-1), which are supported by the experimental results of disulfide rearrangements, peptide mapping of V8 endoprotenase digests, circular dichroic analysis, in vitro refolding, and disulfide stability analysis. The other peptide models, [1-10]mini-IGF-1, [1-4]PIP, and [1-5]mini-IGF-1, fold into one stable structure as PIP does, which indicates that sequence 1-4 of mini-IGF-1 is important for the folding behavior of mini-IGF-1/IGF-1 but not sufficient to lead to a bifurcating folding. The results demonstrated that the folding information, by which mini-IGF-1/IGF-1-folds into two thermodynamically structures, is encoded/written in its sequence 1-9, while sequences 1-10 of B chain in insulin/PIP play an important role in the guide of its unique disulfide pairing during the folding process.


Extensive in silico analysis of Mimivirus coded Rab GTPase homolog suggests a possible role in virion membrane biogenesis.
Rab GTPases are the key regulators of intracellular membrane trafficking in eukaryotes. Many viruses and intracellular bacterial pathogens have evolved to hijack the host Rab GTPase functions, mainly through activators and effector proteins, for their benefit. Acanthamoeba polyphaga mimivirus (APMV) is one of the largest viruses and belongs to the monophyletic clade of nucleo-cytoplasmic large DNA viruses (NCLDV). The inner membrane lining is integral to the APMV virion structure. APMV assembly involves extensive host membrane modifications, like vesicle budding and fusion, leading to the formation of a membrane sheet that is incorporated into the virion. Intriguingly, APMV and all group I members of the Mimiviridae family code for a putative Rab GTPase protein. APMV is the first reported virus to code for a Rab GTPase (encoded by R214 gene). Our thorough in silico analysis of the subfamily specific (SF) region of Mimiviridae Rab GTPase sequences suggests that they are related to Rab5, a member of the group II Rab GTPases, of lower eukaryotes. Because of their high divergence from the existing three isoforms, A, B, and C of the Rab5-family, we suggest that Mimiviridae Rabs constitute a new isoform, Rab5D. Phylogenetic analysis indicated probable horizontal acquisition from a lower eukaryotic ancestor followed by selection and divergence. Furthermore, interaction network analysis suggests that vps34 (a Class III PI3K homolog, coded by APMV L615), Atg-8 and dynamin (host proteins) are recruited by APMV Rab GTPase during capsid assembly. Based on these observations, we hypothesize that APMV Rab plays a role in the acquisition of inner membrane during virion assembly.


Epididymal cribriform hyperplasia. A variant of normal epididymal histology.
We describe a case of orchiectomy for testicular germ cell neoplasm with a peculiar associated cribriform hyperplasia of the epididymis. The process, which we have termed epididymal cribriform hyperplasia (ECH), is tantalizingly akin to patterns of cribriform ductal carcinoma in situ of the female breast and is characterized by complex arcades and cellular bridges spanning dilated epididymal lumina. The cells lining these interconnecting arches have hyperchromatic nuclei, but lack significant atypia or mitotic activity. A limited search of the Vanderbilt University Medical Center (Nashville, Tenn) surgical pathology files produced 30 cases with evaluable epididymis, 15 of which had some degree of ECH. The ECH occurred in a broad age range with a mean of 40 years. No association of ECH with testicular germ cell neoplasia, adenomatous hyperplasia of the rete testis, or parenchymal atrophy could be documented. We conclude that ECH is a seldom recognized variant of normal epididymal histologic appearance that may be present in up to half of epididymides.


Experimental evidence and modeling studies support a synchronizing role for electrical coupling in the cat thalamic reticular neurons in vivo.
Thalamic reticular (RE) neurons are crucially implicated in brain rhythms. Here, we report that RE neurons of adult cats, recorded and stained intracellularly in vivo, displayed spontaneously occurring spikelets, which are characteristic of central neurons that are coupled electrotonically via gap junctions. Spikelets occurred spontaneously during spindles, an oscillation in which RE neurons play a leading role, as well as during interspindle lulls. They were significantly different from excitatory postsynaptic potentials and also distinct from fast prepotentials that are presumably dendritic spikes generated synaptically. Spikelets were strongly reduced by halothane, a blocker of gap junctions. Multi-site extracellular recordings performed before, during and after administration of halothane demonstrated a role for electrical coupling in the synchronization of spindling activity within the RE nucleus. Finally, computational models of RE neurons predicted that gap junctions between these neurons could mediate the spread of low-frequency activity at great distances. These experimental and modeling data suggest that electrotonic coupling within the RE nucleus plays an important role in the generation and synchronization of low-frequency (spindling) activities in the thalamus.


Protective effects of melatonin and ghrelin on spermatogenesis: A narrative review of the literature.
Spermatocytogenesis starts from lumens of seminiferous cords and after migration to the basal membrane ends to the lumens again. We attempt to review the protective effects of melatonin and ghrelin on Spermatocytogenesis and in particular on spermatogonial stem cells, as two rather newly-discovered hormones. Testicular freezing prior to chemotherapy and radiotherapy is one of the ways of preserving fertility in children with cancer. The freezing has two methods of slow-freezing (cryopreservation) and rapid-freezing (vitrification). Administration of melatonin can maintain the quality of the germ cells underwent such processes, as well as ghrelin, can protect germ cells from the toxicities secondary to ischemic injuries, and pathologic apoptosis. This review indicates that in vitro or in vivo administration of melatonin or ghrelin, could be effective to preserve fertilization and also they can be used in assisted reproductive technologies to improve the quality of sperms. Future original studies should be propelled toward human studies, of course with observing the ethics.


Theory development and its relevance for nursing.
If the nursing profession is to continue to make advancements, it must envision new ways of perceiving the phenomena peculiar to nursing and must propose meaningful explanations for these perceptions. The approaches to nursing theory development are spread out over a theory practice continuum, ranging from Martha Roger's pure scientific approach to Dickoff and James' practice approach. The very existence of this continuum signifies nursing's problem in deciphering the nature of the relationship between nursing theory and nursing practice. While the development of nursing theory is essential to the establishment of a theoretical body of knowledge unique to nursing as a science, this must not be its only function. Theory development must be integrated with nursing practice if the profession is to survive and grow.


Intracranial calcification and brachydactyly mimicking Albright's hereditary osteodystrophy in an adult patient with lingual thyroid and prolactinoma-like lesion.
Hyperprolactinemia and prolactinoma in patients with long-term primary hypothyroidism have been recognized for decades. We report a case of 57-year-old female patient with lingual thyroid and cretinism who had a high serum prolactin level (greater than 200 ng/ml) and a pituitary tumor with suprasellar and parasellar extension. The tumor regressed to a size undetectable by CT scan after 2 years of thyroid hormone replacement therapy, but complete normalization of the hyperprolactinemia required additional bromocriptine therapy. This patient showed generalized short metacarpal and phalangeal bones, calcification of the basal ganglia and dentate nuclei bilaterally, and subcutaneous calcification at both gluteal regions, while serum calcium, phosphorus and c-PTH levels were all normal. Thus in addition to short stature, brachydactyly, a round face, and obesity, which are related to hypothyroidism, she also presented features uniquely mimicking the Albright's hereditary osteodystrophy seen in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism. Since she had no family history of pseudohypoparathyroidism and had a normal level of Gs alpha protein on the membrane of the red blood cells, there is no evidence of pseudopseudohypoparathyroidism. The cause of the ectopic calcification remains unknown.


Unusually stable palladium(IV) complexes: detailed mechanistic investigation of C-O bond-forming reductive elimination.
This communication describes the synthesis of a family of unusually stable palladium(IV) complexes containing two chelating 2-phenylpyridine ligands and two benzoates. These complexes undergo clean C-O bond-forming reductive elimination upon heating, and the mechanism of this catalytically relevant process has been studied in detail. Solvent effects, crossover experiments, Eyring plots (which show DeltaS of -1.4 +/- 1.9 and 4.2 +/- 1.4 in CDCl3 and DMSO, respectively), and Hammett analysis (which shows rho = -1.36 +/- 0.04 upon substitution of the para-benzoate substituent) all suggest that reductive elimination does not proceed via initial dissociation of a benzoate ligand. Instead, an unusual mechanism involving pre-equilibrium dissociation of the N-arm of the phenylpyridine ligand is proposed.


Balloon dilatation of the prostate: technique and early results.
Fourteen men with outflow obstruction were treated by balloon dilatation of the prostatic urethra using 25 and 30 mm balloon catheters. Significant improvement in objective measurement of outflow obstruction was noted in only 2 patients.


Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer.
The purpose of these studies was to compare efficacy and toxicity of docetaxel alone with the combination of gemcitabine and docetaxel for treatment of metastatic esophageal carcinoma. These studies enrolled patients with histopathologically verified squamous cell carcinoma or adenocarcinoma of the esophagus or cardia. Between March 1997 and June 1999, 52 patients were enrolled in the initial Phase II study (Study 1). They were scheduled for treatment with docetaxel 100 mg/m2 every third week as a 1-h infusion. The second Phase II study between September 2000 and March 2003 included 65 patients (Study II). They were given docetaxel 30 mg/m2, administered as a 30-min i.v. infusion weekly for four times, followed by 2 weeks of rest, and gemcitabine starting with a dose of 750 mg/m2 (if well-tolerated 1,000 mg/m2) on days 1 and 15, followed by 3 weeks of rest. A new cycle began on day 36. Patients were premedicated with betamethasone 8 mg p.o. on the evening before, and 8 mg i.v. 30-60 min before the docetaxel infusion. Response was confirmed by computed tomography and assessed at 12 and 24 weeks. Toxicity was assessed according to WHO scales. In study I, 38 out of the 52 enrolled patients were valuable. Two patients experienced complete remission (CR) (5%), 10 patients partial remission (PR) (26%), nine patients stable disease (SD) (24%), and 17 patients showed progressive disease (PD) (45%). Toxicity mainly involved leukopenia, which in some cases required hospitalization and treatment with antibiotics. In Study II, 46 out of the 65 enrolled patients (70%) were assessable. Out of these, three patients (7%) had CR, eight patients (17%) had PR, 10 patients (22%) had SD, and 25 (54%) PD. Overall response was 24% while an additional 22% showed stable disease. Toxicity mainly consisted of leucopenia and pain. Docetaxel as a single agent is active in esophageal cancer, both in treatment naive and in previously treated patients with recurrent disease. The overall response rate was 31%, with a good-safety profile. The addition of gemcitabine is well tolerated, but adds no efficacy. Weekly administration of docetaxel may be less effective. It demonstrates moderate efficacy and the doses used provide an acceptable safety profile.


[Topography of the thalamo-cortical projections on trunk representation demonstrated by fluorescent neuro-tracers].
With the aim to study the detailed topography of the thalamo-cortical neurones projecting to the trunk representation zone of the first somatosensory area (SI), punctate injections of three different fluorescent tracers (Evans Blue, Nuclear Yellow and Fast Blue) were performed in the three physiologically defined subareas forming the trunk region of SI. These injections resulted in the labelling of three different cell aggregates, narrow in dorsoventral and mediolateral extent but elongated rostrocaudally, located in topographically distinct regions of the nucleus ventralis posterio-lateralis. The results suggest that the highly organized topography of the trunk representation of area SI is imposed by the thalamo-cortical input from VPL.


Morphology, Crystallinity, and Molecular Weight of Poly(ε-caprolactone)/Graphene Oxide Hybrids.
A study was carried out to determine the effects of graphene oxide (GO) filler on the properties of poly(ε-caprolactone) (PCL) films. A series of nanocomposites were prepared, incorporating different graphene oxide filler contents (0.1, 0.2, and 0.5 wt%) by the solution mixing method, and an in-depth study was made of the morphological changes, crystallization, infrared absorbance, molecular weight, thermal properties, and biocompatibility as a function of GO content to determine their suitability for use in biomedical applications. The infrared absorbance showed the existence of intermolecular hydrogen bonds between the PCL's carbonyl groups and the GO's hydrogen-donating groups, which is in line with the apparent reduction in molecular weight at higher GO contents, indicated by the results of the gel permeation chromatography (GPC), and the thermal property analysis. Polarized optical microscopy (POM) showed that GO acts as a nucleating point for PCL crystals, increasing crystallinity and crystallization temperature. The biological properties of the composites studied indicate that adding only 0.1 wt% of GO can improve cellular viability and that the composite shows promise for use in biomedical applications.


Towards Better Understanding QBism.
Recently I posted a paper entitled "External observer reflections on QBism". As any external observer, I was not able to reflect all features of QBism properly. The comments I received from one of QBism's creators, C. A. Fuchs, were very valuable to me in better understanding the views of QBists. Some of QBism's features are very delicate and extracting them from articles of QBists is not a simple task. Therefore, I hope that the second portion of my reflections on QBism (or, strictly speaking, my reflections on Fuchs reflections on my earlier reflections) might be interesting and useful for other experts in quantum foundations and quantum information theory (especially, taking into account my previous aggressively anti-QBism position). In the present paper I correct some of my earlier posted critical comments on QBism. At the same time, other critical comments gained new validation through my recent deeper understanding of QBists views on a number of problems.


Very high frequency (13 MHz) ultrasonographic examination of the normal neck: detection of normal lymph nodes and thyroid nodules.
Very high frequency (13 MHz) ultrasonographic examination of the neck successfully visualized one or more normal lymph nodes (weakly echoic oval structures with an echoic central hilum) in 67.6% of 1000 healthy volunteers. Efficacy was not related to recent ear, nose, and throat infection, sex, or age. The longitudinal-transverse diameter ratio was greater than or equal to 2 in 86.2% of cases. No signal was detected with color Doppler imaging. One or more thyroid nodules were also identified in 34.7% of the subjects: the frequency was 44% in women and 42% in subjects over 50 years of age.


Growth conditions regulate the requirements for Caulobacter chromosome segregation.
Growth environments are important metabolic and developmental regulators. Here we demonstrate a growth environment-dependent effect on Caulobacter chromosome segregation of a small-molecule inhibitor of the MreB bacterial actin cytoskeleton. Our results also implicate ParAB as important segregation determinants, suggesting that multiple distinct mechanisms can mediate Caulobacter chromosome segregation and that their relative contributions can be environmentally regulated.


Contact quotient versus closed quotient: a comparative study on professional male singers.
The term "closed quotient" is frequently used for data derived both from inverse filtering and from electroglottography. In the former case, it is defined as the ratio between the closed phase and the period, as measured in flow glottograms (FLOGG), whereas in the latter case, it is defined as the time interval between the falling and rising parts of the electroglottogram (EGG), measured at some percentage of the peak-to-peak amplitude. The study aims at analyzing differences between EGG- and FLOGG-based closed quotients and their relationships with voice source parameters. Comparative study. FLOGG- and EGG-based measures collected from five professional male singers were compared, under different pitch and loudness conditions. Compared with the FLOGG-based quotient, the EGG-based quotient (i) varied more between subjects, (ii) presented greater values, (iii) varied less with subglottal pressure, (iv) varied less with the normalized amplitude quotient (ie, the ratio between the flow pulse amplitude and the product of period and maximum flow declination rate), and (v) varied less with the relative amplitude of the voice source fundamental. Although positively related, FLOGG- and EGG-based closed quotients differ and must not be confused.


Peroxisome proliferator-activated receptors as sensors of fatty acids and derivatives.
Lipid homeostasis requires a strict balance between lipid intake and consumption. This balance is controlled by different systems that regulate food intake, energy storage and energy expenditure. This review focuses on the roles of peroxisome proliferator- activated receptors (PPARs) in some of these regulatory processes. PPARs are transcription factors that bind and are activated by fatty acids and fatty acid derivatives. They act as lipid sensors and adapt the metabolism and development of various tissues to lipid availability. Due to their actions on lipid metabolism, PPARs are bona fide therapeutic targets in the treatment of metabolic syndrome not only by affecting gene expression patterns in several tissues but also by inducing remodeling of tissues such as adipose or skeletal muscle.


An Exploratory Study of Healing Circles as a Strategy to Facilitate Resilience in an Undocumented Community.
Within the United States (U.S.), the COVID-19 pandemic highlighted critical inequalities affecting undocumented communities and resulting in particularly heightened stress for members of these communities. In addition to the stress associated to COVID-19, immigrants in the U.S. were more than ever subjected to a hostile anti-immigrant climate under Trump's administration. Given this compounded stress, the impact of the pandemic on mental health is likely to be disproportionately experienced by undocumented immigrants. In response, a group of psychologists partnered with a leading immigrant rights advocacy organization and formed a reciprocal collaboration to support undocumented communities. A major focus of the collaboration is to foster learning, supporting members of the immigrant community to contribute to their own well-being and others in the community. Accordingly, the collaborative developed and delivered a web-based mental health education session to the immigrant community and to practitioners serving this population. The session presented the use of healing circles as a strength-based approach to building resilience and also sought feedback regarding specific features of healing circles that can enhance their effectiveness in managing distress. Survey data and qualitative findings from this study show that those who participated in the web-based program perceived the session as validating and informative. Findings also underscored the need for creating safe spaces for community members to be vulnerable about their lived experiences while promoting ownership of their narratives. We discuss practical implications pertaining to the development and facilitation of social support groups for immigrants led by non-specialist community members trained for this role.


Investigation on the antimicrobial activities of gingers (Etlingera coccinea (Blume) S.Sakai & Nagam and Etlingera sessilanthera R.M.Sm.) endemic to Borneo.
To investigate the antimicrobial properties of Etlingera coccinea and Etlingera sessilanthera and to isolate and identify the antimicrobial compounds. Extracts were obtained via sequential solvent extraction method using hexane, dichloromethane, ethyl acetate, methanol and water. Antimicrobial activity testing was done using broth microdilution assay against 17 strains of bacteria. The leaf hexane extract of E. coccinea and rhizome hexane extract of E. sessilanthera showed best antimicrobial activities, with minimum inhibitory concentration (MIC) values ranging from 0·016 to 1 mg ml-1 against Gram-positive bacteria. From these active extracts, two antimicrobials were isolated and identified as trans-2-dodecenal and 8(17),12-labdadiene-15,16-dial with MIC values ranging from 4 to 8 μg ml-1 against Bacillus cereus, Bacillus subtilis and Staphylococcus aureus. Etlingera coccinea and E. sessilanthera demonstrated good antimicrobial activities against clinically relevant bacteria strains. The antimicrobial compounds isolated showed low MIC values, hence suggesting their potential use as antimicrobial agents. This study is the first to identify the potent antimicrobials from these gingers. The antimicrobials isolated could potentially be developed further for use in treatment of bacterial infections. Also, this study warrants further research into other Etlingera species in search for more antimicrobial compounds.


The p53 tumor suppressor inhibits transcription of the TATA-less mouse DP1 promoter.
Cell cycle progression is subject to several regulatory controls, of which the p53 protein plays a major role in growth arrest, subsequent to the detection of cellular aberrations. It is well documented that p53 has the ability to inhibit transcription driven by several promoters, possibly via distinct mechanisms. In this report, we show that expression of the cell cycle regulatory transcription factor DP1 is strongly inhibited by p53, at the level of transcription and probably through the basal TATA-less promoter. This inhibitory activity has a relative specificity for the DP1 promoter compared with the functionally related E2F1 promoter or unrelated promoters such as those of the transcription factor ATFa or the thymidine kinase gene. Inhibition of DP1 transcription has implications in one of the several possible mechanisms through which p53 induces cell cycle arrest.


Importance of Molecular Structure on the Thermophoresis of Binary Mixtures.
Using thermal lens spectroscopy, we study the role of molecular structural isomers of butanol on the thermophoresis (or Soret effect) of binary mixtures of methanol in butanol. In this study, we show that the thermal lens signal due to the Soret effect changes its sign for all the different concentrations of binary mixtures of butanol with methanol except for the one containing tertiary-butanol. The magnitude and sign of the Soret coefficients strongly depend on the molecular structure of the isomers of butanol in the binary mixture with methanol. This isomerization dependence is in stark contrast to the expected mass dependence of the Soret effect.


Bedside ultrasonography in the ICU: part 2.
This is the second of a two-part review on the application of bedside ultrasonography in the ICU. In this part, the following procedures will be covered: (1) echocardiography and cardiovascular diagnostics (second part); (2) the use of bedside ultrasound to facilitate central-line placement and to aid in the care of patients with pleural effusions and intra-abdominal fluid collections; (3) the role of hand-carried ultrasound in the ICU; and (4) the performance of bedside ultrasound by the intensivist. The safety and utility of bedside ultrasonography performed by adequately trained intensivists has now been well demonstrated. This technology, as a powerful adjunct to the physical examination, will become an indispensable tool in the management of critically ill patients.


Effect of urban aquifer exploitation on subsurface temperature and water quality.
Groundwater pumping induces changes in the hydrodynamics of aquifer systems. Rapid urbanization and pumping-induced changes in local groundwater flow can change the natural heat and chemical balances of an aquifer. In the Nagaoka Plain, Japan, groundwater is being extracted at 145 × 10(6) m3 /year from a highly permeable aquifer consisting of coarse-grained sediments of Late Pleistocene to Holocene age. We used land-cover and groundwater analyses to investigate the processes that change subsurface temperature and water quality induced by urbanization and intensive groundwater extraction. Comparison of temperature and water quality measurements in 2009 with measurements made between 1977 and 2000 revealed an increase in subsurface temperature (at 18 m depth) of 0.050 °C/year in the main urban area of the Nagaoka Plain, which is equivalent to the rate of increase of mean air temperature during that period. The effects of surface warming are apparent as a warm zone under the urban area. An area with low saturation index of calcite (-3.0 to -2.0) was centered around urban areas in 2009, whereas in 2000 the index there was higher (-1.5 to -0.5). The decrease in this index in the center of Nagaoka City over the last decade is consistent with continuous dissolution of carbonates induced there by changes in recharge water sources due to groundwater pumping. These findings suggest that urbanization, intensive groundwater extraction, and recharge with chemically modified surface water are responsible for changes in thermal and chemical properties under the urban area of the Nagaoka Plain.


Problems of posterior fields.
Problems arising with the use of posterior fields can be solved by the undercouch technique. Treatment couches with a large window covered with transparent Mylar polyester (D) film can support the patient and do not interfere with the supervoltage beam.


Osteopontin induced vascular endothelial growth factor production in dispersed nasal polyp cells through the phosphatidylinositol 3-kinase-protein kinase B and the extracellular signal-regulated kinase 1/2 pathways.
Osteopontin (OPN) is involved in cell survival, migration, and angiogenesis. The role of OPN in inducing angiogenesis in tumor has been confirmed. In this study, we investigated the expression of OPN in patients with chronic rhinosinusitis (CRS) with nasal polyp (NP) and the relationship of OPN with vascular endothelial growth factor (VEGF) production. We enrolled 45 subjects with CRS (25 with CRS with NPs [CRSwNP] and 20 subjects with CRS without NPs [CRSsNP]), and with 14 normal controls to determine the expression of OPN and VEGF. The distribution, messenger RNA (mRNA), and protein levels of OPN and VEGF were examined by immunohistochemistry, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. The effect of OPN on the VEGF production was tested in dispersed NP cells (DNPC) and the involved signaling pathways were examined by Western blot. In NP tissue of the subjects with CRSwNP, the epithelial cells, interstitial cells, glandular cells, and endothelial cells were positive for OPN and VEGF staining, whereas OPN and VEGF immunoactivity in specimens of subjects with CRSsNP and in normal controls was significantly reduced. We found that the immunostainings, the mRNA expression, and the protein levels of OPN and VEGF were significantly increased in NPs compared with normal controls. OPN induced VEGF production by DNPCs in a time- and dose-dependent manner through phosphatidylinositol 3-kinase- protein kinase B and the extracellular signal-regulated kinase 1/2 pathway. Moreover, VEGF also induced OPN production, which formed a positive feedback between OPN and VEGF. Our findings demonstrated that OPN and VEGF were overproduced in NPs and that OPN induced VEGF production, which indicated that OPN-VEGF axis might contribute to angiogenesis in NPs.


Association of alcohol and drug use disorders and completed suicide: an empirical review of cohort studies.
This study updated and expanded upon Harris and Barraclough's empirical review [Harris, E.C., Barraclough, B., 1997. Suicide as an outcome for mental disorders. A meta-analysis, Br. J. Psychiatry 170, 205-228] of retrospective and prospective cohort studies of alcohol and drug use disorders and suicide. Studies presenting data on alcohol and drug use disorders and suicide originally identified by Harris and Barraclough were used in this study. To find additional studies, (1) the location of English language reports on MEDLINE (1994-2002) were identified with the search terms 'substance-disorders' with 'mortality' and 'follow-up', (2) read throughs were conducted of four prominent alcohol and drug specialty journals from 1966 through 2002, and (3) the reference sections of studies that met criteria were searched for additional reports. This strategy yielded 42 new studies meeting eligibility criteria. The estimated standardized mortality ratios (SMR; 95% confidence interval) for suicide were as follows: alcohol use disorder (979; 95% CI 898-1065; p < 0.001), opioid use disorder (1351; 95% CI 1047-1715; p < 0.001), intravenous drug use (1373; 95% CI 1029-1796; p < 0.001), mixed drug use (1685; 95% CI 1473-1920; p < 0.001), heavy drinking (351; 95% CI 251-478; p < 0.001). SMR estimates stratified by sex were also calculated. Additional studies on the association of suicide and mixed drug use, heavy drinking, and alcohol use disorders in women augmented the findings of Harris and Barraclough, along with a novel estimate for intravenous drug use, a byproduct of intensive research on HIV in the past decade. There is a large empirical literature on alcohol use disorders and suicide and a moderate literature on suicide and opioid use disorders and IV drug use. There remains limited prospective data on the association of suicide and other drug use disorders (e.g., cocaine, cannabis).


Hedgehog Pathway Inhibition for the Treatment of Basal Cell Carcinoma.
Globally, basal cell carcinoma is the most commonly diagnosed cancer. While most cases are amenable to surgery, treatment options for advanced basal cell carcinoma, including locally advanced basal cell carcinoma and metastatic basal cell carcinoma, have proved more difficult. Recent advances regarding the role of hedgehog signaling in the pathogenesis of basal cell carcinoma and the identification of hedgehog pathway inhibitors have facilitated the development of treatment options with improved clinical outcomes. The hedgehog signaling pathway regulates development, cell proliferation, and tissue repair. The pathway is tightly regulated under normal physiological conditions. However, dysregulated hedgehog signaling in human cancers was first described in patients with basal cell carcinoma nevus syndrome and sporadic basal cell carcinoma, in which germline or somatic mutations in pathway components (e.g., smoothened [Smo] and patched-1) lead to constant activation. Subsequently, inhibitors blocking hedgehog signaling either at the level of Smo (i.e., vismodegib, sonidegib, patidegib, and itraconazole) or via an unknown mode of action (arsenic trioxide) were identified. The hedgehog inhibitor vismodegib is approved for the treatment of locally advanced basal cell carcinoma and metastatic basal cell carcinoma while sonidegib is approved for the treatment of locally advanced basal cell carcinoma in the USA and Europe; and for locally advanced basal cell carcinoma and metastatic basal cell carcinoma in Switzerland and Australia. The most common treatment-emergent adverse events associated with approved hedgehog inhibitors include muscle spasms, dysgeusia, and alopecia. This review addresses the challenges associated with appropriately diagnosing locally advanced basal cell carcinoma, provides an overview of hedgehog signaling in basal cell carcinoma, and discusses the pharmacology of hedgehog inhibitors and their efficacy, and adverse events associated with hedgehog inhibitor use, and their management.


Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is characterized by the recruitment of leukocytes and the accumulation of inflammatory mediators within the synovial compartment. Release of the chemokine CCL18 has been widely attributed to antigen-presenting cells, including macrophages and dendritic cells. This study investigates the production of CCL18 in polymorphonuclear neutrophils (PMN), the predominant cell type recruited into synovial fluid (SF). Microarray analysis, semiquantitative and quantitative reverse transcriptase polymerase chain reaction identified SF PMN from patients with RA as a novel source for CCL18 in diseased joints. Highly upregulated expression of other chemokine genes was observed for CCL3, CXCL8 and CXCL10, whereas CCL21 was downregulated. The chemokine receptor genes were differentially expressed, with upregulation of CXCR4, CCRL2 and CCR5 and downregulation of CXCR1 and CXCR2. In cell culture experiments, expression of CCL18 mRNA in blood PMN was induced by tumor necrosis factor alpha, whereas synthesis of CCL18 protein required additional stimulation with a combination of IL-10 and vitamin D3. In comparison, recruited SF PMN from patients with RA were sensitized for CCL18 production, because IL-10 alone was sufficient to induce CCL18 release. These results suggest a release of the T cell-attracting CCL18 by PMN when recruited to diseased joints. However, its production is tightly regulated at the levels of mRNA expression and protein synthesis.


Molecular mechanisms of renal ammonia transport.
Acid-base homeostasis to a great extent relies on renal ammonia metabolism. In the past several years, seminal studies have generated important new insights into the mechanisms of renal ammonia transport. In particular, the theory that ammonia transport occurs almost exclusively through nonionic NH(3) diffusion and NH(4)(+) trapping has given way to a model postulating that a variety of proteins specifically transport NH(3) and NH(4)(+) and that this transport is critical for normal ammonia metabolism. Many of these proteins transport primarily H(+) or K(+) but also transport NH(4)(+). Nonerythroid Rh glycoproteins transport ammonia and may represent critical facilitators of ammonia transport in the kidney. This review discusses the underlying aspects of renal ammonia transport as well as specific proteins with important roles in renal ammonia transport.


New primate fossils from late Oligocene (Colhuehuapian) localities of Chubut Province, Argentina.
New primate fossils have been recovered from the late Oligocene (Colhuehuapian) localities of Gaiman and Sacanana in Patagonian Argentina. The new fossils are provisionally allocated to Dolichocebus gaimanensis and Tremacebus harringtoni, the only primates previously described from these localities. These new dental remains are more primitive than the teeth of any previously known platyrrhines, living or fossil, and conform extremely well with the hypothetical ancestral morphotype for New World monkeys suggested by several authors. They are also very similar to the teeth of Oligocene catarrhines from Egypt such as Aegyptopithecus zeuxis.


Cellular microRNA-miR-548g-3p modulates the replication of dengue virus.
It has been well recognized that microRNA plays a role in the host-pathogen interaction network. The significance of microRNA in the regulation of dengue virus (DENV) replication, however, remains unknown. The objective of our study was to determine the biological function of miR-548g-3p in modulating the replication of dengue virus. Here we report that employment of a microRNA target search algorithm to analyze the 5' untranslated region (5'UTR) consensus sequences of DENV (DENV serotypes 1-4) led to a discovery that miR-548g-3p directly targets the stem loop A promoter element within the 5'UTR, a region essential for DENV replication. Real-time PCR was used to measure the expression levels of miR-548g-3p under DENV infection. We performed overexpression and inhibition assays to test the role of miR-548g-3p on DENV replication. The protein and mRNA levels of interferon were measured by ELISA and real-time PCR respectively. We found that overexpression of miR-548g-3p suppressed multiplication of DENV 1, 2, 3 and 4, and that miR-548g-3p was also found to interfere with DENV translation, thereby suppressing the expression of viral proteins. Our results suggest that miR-548g-3p directly regulates DENV replication and warrant further study to investigate the feasibility of microRNA-based anti-DENV approaches.


Association of SH2 domain-containing protein 1A, immunoglobulins and T lymphocyte subsets with Epstein- Barr virus infections.
We aimed to analyze the levels and associations of SH2 domain-containing protein 1A (SH2D1A), immunoglobulins and T lymphocyte (TL) subsets in children with Epstein-Barr virus (EBV) infections. Sixty children with EBV infections admitted from January 2019 to January 2022 were selected, including 29 cases of infectious mononucleosis (IM group) and 31 cases of chronic active EBV infections (CAEBV group). Another 42 healthy children undergoing physical examination in the same period were selected as a control group. Their changes in SH2D1A, immunoglobulins and TL subsets (CD3+, CD4+ and CD8+) were compared. The levels of CD3+, CD4+ and CD8+ in the IM group were higher than those of the control group (P < 0.05), while they were lower in the CAEBV group than those of the control and IM groups (P < 0.05). The levels of SH2D1A, signaling lymphocyte activation molecule (SLAM) and SLAM-associated protein (SAP) were significantly higher in the IM group than those in the control and CAEBV groups (P < 0.05). The CAEBV group had decreased protein expressions of SLAM and SAP compared with those of the IM group. SH2D1A was positively correlated with immunoglobulin A, immunoglobulin G and TL subsets (CD3+, CD4+ and CD8+) (P < 0.05). Detecting SH2D1A, immunoglobulins and TLs contributes to the diagnosis and differentiation of IM and CAEBV.


A review of fetal scarless healing.
Wound healing is a complex process involving a number of processes. Fetal regeneration has been shown to have a number of differences compared to scar-forming healing. This review discusses the number of differences identified in fetal regeneration. Understanding these differences may result in new therapeutic targets which may reduce or even prevent scarring in adult healing.


Use of the von Kossa stain in identifying occult calcifications in breast biopsies.
In a two-year series of more than 300 mammographic-directed biopsies with radiographic calcifications, calcium deposits could not be identified in approximately 10% with the use of routine hematoxylin and eosin (H and E) stains. In most of these cases, calcifications, sometimes in surprising amounts, could be identified by use of the von Kossa stain. These included calcium deposits in acinar secretions (nine), cyst fluid (four), ductal ectasia (six), and papillomatosis (five). It would appear that the von Kossa stain is more sensitive for calcium than hematoxylin and is a useful technique when combined with specimen radiography in providing satisfactory radiologic-pathologic correlation.


Differential diagnosis of non-small cell lung carcinoma by circulating microRNA.
More than 70% of lung cancer comprises nonsmall-cell lung carcinoma and is associated with poor survival outcome owing to late diagnosis. Identification of lung cancer in early stages when no clinical signs or symptoms are evident, can drastically improve the prognosis. To this end, we aimed to evaluate the changes occurring at tissue level by assessing the expression of six microRNAs (miRNAs) in lung adenocarcinoma (AC) and squamous cell carcinoma (SCC). Peripheral blood of histopathologically proven cases of lung AC and SCC was collected and processed for the isolation of miRNAs using commercially available kit. Primers against mir-2114, mir-2115, mir-2116, mir-2117, mir-449c, and mir-548q with loading control Caenorhabditis elegans were used. Screening was carried out in thirty cases of both AC and SCC, whereas twenty healthy controls were included. Real-time polymerase chain reaction data revealed that the expression of mir-2114 and mir-449c in AC and mir-2115 in SCC was significantly upregulated. The expression of these miRNAs was also confirmed in lung AC cell line. The differential pattern of expression of these miRNAs can be used for precise diagnosis of lung carcinoma. We have used a noninvasive technique to identify the subtype of lung cancer based on molecular genetic signatures. The results suggest that through molecular profiling of miRNA, we can screen high-risk cases for cancer interception.


Curcumin Transferosome-Loaded Thermosensitive Intranasal in situ Gel as Prospective Antiviral Therapy for SARS-Cov-2.
Immunomodulatory and broad-spectrum antiviral activities have motivated the evaluation of curcumin for Coronavirus infection 2019 (COVID-19) management. Inadequate bioavailability is the main impediment to the therapeutic effects of oral Cur. This study aimed to develop an optimal curcumin transferosome-loaded thermosensitive in situ gel to improve its delivery to the lungs. Transferosomes were developed by using 33 screening layouts. The phospholipid concentration as well as the concentration and type of surfactant were considered independent variables. The entrapment efficiency (EE%), size, surface charge, and polydispersity index (PDI) were regarded as dependent factors. A cold technique was employed to develop thermosensitive in-situ gels. Optimized transferosomes were loaded onto the selected gels. The produced gel was assessed based on shape attributes, ex vivo permeability enhancement, and the safety of the nasal mucosa. The in vitro cytotoxicity, antiviral cytopathic effect, and plaque assay (CV/CPE/Plaque activity), and in vivo performance were evaluated after intranasal administration in experimental rabbits. The optimized preparation displayed a particle size of 664.3 ± 69.3 nm, EE% of 82.8 ± 0.02%, ZP of -11.23 ± 2.5 mV, and PDI of 0.6 ± 0.03. The in vitro curcumin release from the optimized transferosomal gel was markedly improved compared with that of the free drug-loaded gel. An ex vivo permeation study revealed a significant improvement (2.58-fold) in drug permeability across nasal tissues of sheep. Histopathological screening confirmed the safety of these preparations. This formulation showed high antiviral activity against SARS-CoV-2 at reduced concentrations. High relative bioavailability (226.45%) was attained after the formula intranasally administered to rabbits compared to the free drug in-situ gel. The curcumin transferosome gel displayed a relatively high lung accumulation after intranasal administration. This study provides a promising formulation for the antiviral treatment of COVID-19 patients, which can be evaluated further in preclinical and clinical studies.


[[INFLUENCES OF PREOPERATIVE SEVERE LOWER LIMB DEFORMITY ON PROSTHESIS INSTALLATION AND ALIGNMENT RESTORATION IN TOTAL KNEE ARTHROPLASTY].
To investigate the effect of preoperative valgus or varus deformity on the prosthesis installation and alignment restoration in total knee arthroplasty (TKA). Between January 2012 and December 2013, 198 patients (245 knees) with osteoarthritis underwent primary TKA, and the clinical data were retrospectively analyzed. There were 23 males and 175 females, with the average age of 67 years (range, 43-90 years). Single knee and double knees were involved in 151 and 47 cases respectively. The disease duration was from 1 month to 30 years (mean, 8.99 years). The anteroposterior X-ray films of whole lower limbs were taken, and the femorotibial angle (FT) was measured before operation and at 1 week after operation; the mechanical femoral angle (MF) and the anatomical tibial angle (AT) at 1 week after operation were measured. The correlation analysis was made for pre- and post-operative FT, MF, and AT. According to the valgus or varus deformity before operation, all patients were divided into 5 groups: ≥ 20 degrees varus (group A), 10-20 degrees varus (group B), ≤ 10 degrees varus (group C), < 10 degrees valgus (group D), and ≥ 10 degrees valgus (group E), and the above indicators were compared between groups. And the rate of the good limb alignment was recorded after operation. The pre- and post-operative FT were (171.53 ± 9.12) and (177.38 ± 3.57)degrees respectively, and postoperative MF and AT were (89.00 ± 2.68) and (88.62 ± 2.16) respectively. Preoperative FT was associated with postoperative FT and MF (r = 0.375, P = 0.000; r = 0.386, P = 0.000), but it was not correlated with AT (r = 0.024, P = 0.710). Postoperative FT was associated with MF and AT (r = 0.707, P = 0.000; r = 0.582, P = 0.000). Postoperative FT was significantly increased when compared with preoperative FT in each group (P < 0.05). There were significant differences in preoperative FT between groups (P < 0.05). There were significant differences in postoperative FT when compared group A with groups B, C, D, and E (P < 0.05), and when compared groups B and C with groups D and E (P<0.05), but there was no significant difference between groups B and C, and between groups D and E (P > 0.05). The rate of good alignment was 70.2% (172/245); it was 27.8% (5/18), 66.0% (62/94), 74.4% (67/90), 88.9% (32/36), and 85.7% (6/7) in groups A, B, C, D, and E respectively, showing significant differences between groups (P < 0.05). There was no significant difference in postoperative AT between groups (P > 0.05). Except for between group D and group E (P > 0.05), significant difference in MF was shown between the other groups (P < 0.05). The more severe deformity of lower limb before TKA, the higher risk of deviation for prosthesis installation and poor alignment in TKA.


Synthesis of conducting polyaniline nanofibers from single and binary dopant agents.
Conducting polyaniline nanofibers (nf-PANI) were successfully synthesized by simple polymerization of aniline in presence of single and binary dopant agents. Strong hydrochloride acid (HCl), two weak organic acids (poly acrylic acid, PAA, 2-acrylamido-2-methyl-1-propanesulfonic acid, AMPSA) and one anionic surfactant (sodium dodecyl sulfate, SDS) were used to form the binary dopant agents. The binary dopant agent PAA modified the morphology of the single doped PANI, whereas AMPSA and SDS modified the dimensions of the nanofibers: the length size single nanofibers is reduced 1.72 times with binary-doped AMPSA and increased by a factor of 0.7 with SDS. The surface roughness of the films decreases when the dimensions of the nanofibers increase: PANI-SDS film is flatter than PANI-AMPSA film. In general, the conductivity of the single-doped PANI nanofibers (nf-PANI-HCl) was improved by one order of magnitude with binary dopant agents (HCI-PAA, HCl-AMPSA, HCl-SDS). The influence of the binary dopant agents in the nf-PANI-HCl properties is analyzed by Transmission Electron Microscope (TEM), Atomic Force Microscopy (AFM), UV-VIS absorption spectra, thermogravimetric analysis (TGA) and Fourier-Transform infrared spectra (FT-IR).


Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518.
FLT3 is constitutively activated by internal tandem duplications (ITDs) in the juxtamembrane domain or by activation loop mutations in acute myeloid leukemia (AML). We tested the sensitivity of 8 activation loop mutations to the small molecule FLT3 inhibitor, MLN518. Each FLT3 activation loop mutant, including D835Y, D835A, D835E, D835H, D835N, D835V, D835del, and I836del, transformed Ba/F3 cells to factor-independent proliferation and had constitutive tyrosine kinase activation, as assessed by FLT3 autophosphorylation and activation of downstream effectors, including STAT5 and ERK. MLN518 inhibited FLT3 autophosphorylation and phosphorylation of STAT5 and ERK in FLT3-ITD-transformed Ba/F3 cells with an IC(50) (50% inhibition of cell viability) of approximately 500 nM. However, there was a broad spectrum of sensitivity among the 8 activation loop mutants, with IC(50) ranging from approximately 500 nM to more than 10 microM for the inhibition of phosphorylation of FLT3, STAT5, and ERK. The relative sensitivity of the mutants to MLN518 in biochemical assays correlated with the cellular IC(50) for cytokine-independent proliferation of FLT3-transformed Ba/F3 cells in the presence of MLN518. Thus, certain activation loop mutations in FLT3 simultaneously confer resistance to small molecule inhibitors. These findings have implications for the evaluation of responses in clinical trials with FLT3 inhibitors and provide a strategy to screen for compounds that can overcome resistance.


Impairment by covalent modification of the ability of Phaseolus vulgaris phytohemagglutinin to stimulate cultured human lymphocytes: a comparison of different forms of covalent modification.
Phytohemagglutinin (PHA) isolated from Phaseolus vulgaris has been modified by treatment with various chemical reagents and the modified proteins have been tested for their ability to stimulate peripheral lymphocytes from two healthy human donors, in vitro. Reaction of PHA with citraconic anhydride, S-methyl isothiourea, or 2-hydroxy-5-nitrobenzyl bromide produced derivatives which retained the ability to stimulate lymphocytes, at low concentrations. Acylation of the lectin with acetic anhydride or masking of the carboxyl side chains by reaction with glycinamide-carbodiimide impaired stimulation. When PHA was treated with N-bromosuccinimide or with tetranitromethane, the derivatives were ineffective as lymphocyte stimulants. Chemical modifications affected, in some cases, the quaternary structure of the lectin. Glycinamide-, homoarginine-, and nitro-PHA were tetramers whereas acetyl-, citraconyl-, and N-bromosuccinimide-treated lectin were dimers. Antinative lectin antiserum cross-reacted with all the modified proteins, except in the case of the N-bromosuccinimide derivative. The results show that, in the human lymphocyte transformation assay, the mitogenic property of PHA may depend on intact aspartic, glutamic, and tyrosine residues whereas lysine residues do not appear to be essential.


Evaluation of the averaged parasympathetic tone activity and its dynamic variation to assess intraoperative nociception in relation to hemodynamic changes in dogs.
This study aimed to determine the performance of the averaged parasympathetic tone activity (PTAm) and its dynamic variation (ΔPTA) to assess intraoperative nociception in relation to heart rate (HR) and direct mean arterial pressure (MAP) in dogs undergoing laparoscopic ovariectomy. This prospective, observational, clinical study included 32 bitches. The PTAm, HR, MAP, and bispectral index (BIS) were assessed before (pre-stimulus), as well as 1 min and 2 min after, four surgical stimuli: insufflation, introduction of trocars, and removal of the left and right ovaries. A two-way ANOVA was performed to compare PTAm, HR, MAP, and BIS data across surgical stimuli. A ≥ 20% drop in PTAm or a ≥ 20% increase in HR and/or MAP regarding the pre-stimulus values was considered a PTAm-drop and/or a hemodynamic response, respectively. The performance of PTAm pre-stimulus, PTAm 1 min, and ΔPTA in predicting the hemodynamic response was assessed by calculation of the area under the receiver operating characteristic (ROC) curve. At insufflation, PTAm decreased after 1 (p = 0.010) and 2 (p = 0.045)min, and ΔPTA was different (p = 0.005) between dogs that presented hemodynamic response and dogs that did not. At PTAm-drop, MAP increased after 1 min (p = 0.001) and 2 min (p = 0.001) with respect to pre-stimulus value, whereas HR and BIS did not change. ROC curves showed a threshold value of PTAm pre-stimulus ≤51 to detect hemodynamic response (sensitivity 69%, specificity 52%). The PTAm and ΔPTA only assessed intraoperative nociception during insufflation. The PTAm pre-stimulus association to the hemodynamic response in anaesthetized dogs showed poor sensitivity and no specificity.


Pre-analytical phase management: a review of the procedures from patient preparation to laboratory analysis.
The pre-analytical phase encompasses all the procedures before the start of laboratory testing. This phase of the testing process is responsible for the majority of the laboratory errors, since the related procedures involve many sorts of non-laboratory professionals working outside the laboratory setting, thus without direct supervision by the laboratory staff. Therefore, either correct organization or management of both personnel and procedures that regard blood specimen collection by venipuncture are of fundamental importance, since the various steps for performing blood collection represent per se sources of laboratory variability. The aim of this (non-systematic) review addressed to healthcare professionals is to highlight the importance of blood specimen management (from patient preparation to laboratory analyses), as a tool to prevent laboratory errors, with the concept that laboratory results from inappropriate blood specimens are inconsistent and do not allow proper treatment nor monitoring of the patient.


Disease management: Lovelace Health Systems episodes of care--a case study.
The evolving paradigm shift in healthcare emphasizes population health status. Disease management is gaining popularity as a means of providing cost-effective, quality healthcare to an entire population at risk. Outcomes measurements, standardized clinical protocols and commitment by physicians and staff are crucial to a successful program. This article presents a case study from Lovelace Health Systems in Albuquerque, N.M., and identifies key components, cost savings and successes of one of its disease management programs.


Factors associated with high heterogeneity of malaria at fine spatial scale in the Western Kenyan highlands.
The East African highlands are fringe regions between stable and unstable malaria transmission. What factors contribute to the heterogeneity of malaria exposure on different spatial scales within larger foci has not been extensively studied. In a comprehensive, community-based cross-sectional survey an attempt was made to identify factors that drive the macro- and micro epidemiology of malaria in a fringe region using parasitological and serological outcomes. A large cross-sectional survey including 17,503 individuals was conducted across all age groups in a 100 km(2) area in the Western Kenyan highlands of Rachuonyo South district. Households were geo-located and prevalence of malaria parasites and malaria-specific antibodies were determined by PCR and ELISA. Household and individual risk-factors were recorded. Geographical characteristics of the study area were digitally derived using high-resolution satellite images. Malaria antibody prevalence strongly related to altitude (1350-1600 m, p < 0.001). A strong negative association with increasing altitude and PCR parasite prevalence was found. Parasite carriage was detected at all altitudes and in all age groups; 93.2 % (2481/2663) of malaria infections were apparently asymptomatic. Malaria parasite prevalence was associated with age, bed net use, house construction features, altitude and topographical wetness index. Antibody prevalence was associated with all these factors and distance to the nearest water body. Altitude was a major driver of malaria transmission in this study area, even across narrow altitude bands. The large proportion of asymptomatic parasite carriers at all altitudes and the age-dependent acquisition of malaria antibodies indicate stable malaria transmission; the strong correlation between current parasite carriage and serological markers of malaria exposure indicate temporal stability of spatially heterogeneous transmission.


Percutaneous subclavian vein catheterization. Too much of a good thing?
Eighty-one percutaneous subclavian vein catheterizations ( PSVCs ) were randomly selected for retrospective audits. Physicians with varied levels of experience were performing PSVCs in many patient care areas. The incidence of pneumothorax was 12.4%. After impersonal contacts by the audit committee failed to reduce that rate, a concurrent audit process with direct physician contact was initiated. This reduced the complication rate significantly. Because earlier published reports had associated PSVCs with low complication rates, operator caution may have given way to overzealous use by undertrained physicians. Direct physician involvement in quality-assurance programs can enhance patient care.


Dexmedetomidine versus midazolam for sedation during endoscopy: A meta-analysis.
Patients undergoing endoscopy frequently require sedation, which commonly includes the administration of midazolam or dexmedetomidine. Previous meta-analyses have mainly focused on comparing the effects of these two drugs in intensive care unit patients. In the present study, randomized controlled trials (RCTs) that compared the sedative and clinical effectiveness of these two drugs in patients undergoing endoscopy were searched in a number of databases. The meta-analysis showed that dexmedetomidine demonstrated a significantly lower rate of respiratory depression and adverse events compared with those presented upon midazolam administration. A significant difference was also observed in the sedation potency of the sedatives. The current controlled data suggest that dexmedetomidine may be an alternative to midazolam in the sedation for endoscopy. However, more high-quality and well-designed studies are required to further evaluate this conclusion.


ATP/ADP biosensor organoids for drug nephrotoxicity assessment.
Drug nephrotoxicity is a common healthcare problem in hospitalized patients and a major limitation during drug development. Multi-segmented kidney organoids derived from human pluripotent stem cells may complement traditional cell culture and animal experiments for nephrotoxicity assessment. Here we evaluate the capability of kidney organoids to investigate drug toxicity in vitro. Kidney organoids express renal drug transporters, OAT1, OAT3, and OCT2, while a human proximal tubular cell line shows the absence of OAT1 and OAT3. Tenofovir and aristolochic acid (AA) induce proximal tubular injury in organoids which is ameliorated by an OAT inhibitor, probenecid, without damage to podocytes. Similarly, cisplatin causes proximal tubular damage that can be relieved by an OCT inhibitor, cimetidine, collectively suggesting the presence of functional OATs and OCTs in organoid proximal tubules. Puromycin aminonucleoside (PAN) induced segment-specific injury in glomerular podocytes in kidney organoids in the absence of tubular injury. Reporter organoids were generated with an ATP/ADP biosensor, which may be applicable to high-throughput screening in the future. In conclusion, the kidney organoid is a useful tool for toxicity assessment in the multicellular context and may contribute to nephrotoxicity assessment during drug development.


Nephropathy induced by contrast medium in an hispanic population after coronary angiography.
Contrast medium-induced nephropathy (CIN) is regarded as one of the most important complications after intravascular administration of radiographic contrast media and the third most common cause of hospital-acquired acute kidney injury. Contrast-induced nephropathy may develop in up to10% of patient with normal renal function but may be as high 25% in patient with risk factors. A total of 192 medical records were obtained, in which 55 patient were eligible by our inclusion and exclusion criteria. A total four cases of CIN (7%) was identified and all were considered high-risk patients. In the patients that developed CIN only 50% received preventive IV hydration therapy in accordance to guidelines of the Contrast-Induced Nephropathy Consensus Panel. In 51 cases CIN was absent (93%). In the absent CIN group 22 were considered high-risk patients (43%) and 29 patients were low risk (57%). In the high-risk group with absent CIN, 77% received preventive IV hydration. Study didn't show diabetes as a direct contributory factor for CIN development, but glycemia was not properly stratified. Screening and preventive strategies were not diligently complied in our institution, so there is a great need to incorporate a protocol in our institution in accordance to published guidelines.


Novel mouse models based on intersectional genetics to identify and characterize plasmacytoid dendritic cells.
Plasmacytoid dendritic cells (pDCs) are the main source of type I interferon (IFN-I) during viral infections. Their other functions are debated, due to a lack of tools to identify and target them in vivo without affecting pDC-like cells and transitional DCs (tDCs), which harbor overlapping phenotypes and transcriptomes but a higher efficacy for T cell activation. In the present report, we present a reporter mouse, pDC-Tom, designed through intersectional genetics based on unique Siglech and Pacsin1 coexpression in pDCs. The pDC-Tom mice specifically tagged pDCs and, on breeding with Zbtb46GFP mice, enabled transcriptomic profiling of all splenic DC types, unraveling diverging activation of pDC-like cells versus tDCs during a viral infection. The pDC-Tom mice also revealed initially similar but later divergent microanatomical relocation of splenic IFN+ versus IFN- pDCs during infection. The mouse models and specific gene modules we report here will be useful to delineate the physiological functions of pDCs versus other DC types.