Trimodal system for in vivo skin cancer screening with combined optical coherence tomography-Raman and colocalized optoacoustic measurements.
A new multimodal system for rapid, noninvasive in vivo skin cancer screening is presented, combining optical coherence tomography (OCT) and optoacoustic (OA) modalities to provide precise tumor depth determination with a Raman spectroscopic modality capable of detecting the lesion type and, thus, providing diagnostic capability. Both OA and Raman setups use wide field skin illumination to ensure the compliance with maximum permissible exposure (MPE) requirements. The Raman signal is collected via the OCT scanning lens to maximize the signal-to-noise ratio of the measured signal while keeping radiation levels below MPE limits. OCT is used to optically determine the tumor thickness and for volumetric imaging whereas OA utilizes acoustic signals generated by optical absorption contrast for thickness determination at potentially higher penetration depths compared to OCT. Preliminary results of first clinical trials using our setup are presented. The measured lesion depth is in good agreement with histology results, while Raman measurements show distinctive differences between normal skin and melanocytic lesions, and, moreover, between different skin areas. In future, we will validate the setup presented for reliable detection of pathophysiological parameters, morphology and thickness of suspicious skin lesions.


The efficacy of treatment for malignant epidural spinal cord compression.
The aims of this study were to document the efficacy of treatment and to identify factors that were predictive of the outcome in malignant epidural spinal; cord compression. The medical records of patients treated at the Prince Henry and Prince of Wales Hospitals in the period 1980-1989 with a diagnosis of malignant epidural spinal cord compression were reviewed. A total of 94 patients were eligible for the study and were treated by radiotherapy alone (37), surgery alone (19) and surgery followed by radiotherapy (38). Efficacy was determined by measuring complete resolution of symptoms and signs at 1 month after presentation, and also by using an overall functional improvement score (FIS). Complete resolution of individual pre-treatment symptoms that were measured 1 month after treatment occurred as follows: pain (30/88), sensory disturbance (12/61), weakness (8/17), bladder dysfunction (10/42), and bowel dysfunction (10/36). Complete resolution of motor deficit occurred in 7/82 and of sensory deficit in 9/73. The ability to walk was regained in 19/51 previously non-ambulatory patients, and bladder function improved sufficiently to remove an indwelling catheter in 9/32 previously catheterized patients. As judged by FIS, 67 patients improved, 15 patients remained stable and 12 patients deteriorated. Of the treatments given, a combination of surgery followed by radiotherapy was associated with the greatest functional improvement (P = 0.001). The coexistence of 'liver failure' was the only patient-related factor identified which was associated with outcome (P = 0.041). The treatment of malignant spinal cord compression appears to be worthwhile; however, the outcome of treatment is not easy to predict from pretreatment factors. A 'functional improvement score' may be useful in assessing treatment efficacy.


A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy.
Vaginal misoprostol has been shown to be an effective single agent for medical abortion. This randomized, double-blinded, placebo-controlled trial compared a regimen of mifepristone and misoprostol with misoprostol alone for termination of early pregnancy. 250 women with gestations < or = 56 days were randomized by a random number table to receive either 200 mg mifepristone orally or placebo followed 48 h later by 800 microg vaginal misoprostol. Administration of misoprostol was repeated every 24 h up to three doses if abortion failed to occur. Abortion success was defined as complete abortion without the use of surgical aspiration. Successful medical abortions occurred in 114 out of 119 subjects (95.7%) after mifepristone followed by vaginal misoprostol. In all, 110 out of 125 subjects (88.0%) successfully aborted after placebo and vaginal misoprostol. The higher success rate of complete abortion with the mifepristone and misoprostol regimen was statistically significant compared with the placebo and misoprostol regimen (P < 0.05). A regimen of mifepristone and misoprostol was significantly more effective for termination of pregnancies < or = 56 days than misoprostol alone. The 88% efficacy obtained with vaginal misoprostol alone may be clinically acceptable when mifepristone is not available.


Self-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients.
Laparoscopic transabdominal preperitoneal inguinal hernia repair is a safe and effective technique. In this study we tested the hypothesis that self-gripping mesh used with the laparoscopic approach is comparable to polypropylene mesh in terms of perioperative complications, against a lower overall cost of the procedure. We carried out a prospective randomized trial comparing a group of 30 patients who underwent laparoscopic inguinal hernia repair with self-gripping mesh versus a group of 30 patients who received polypropylene mesh with fibrin glue fixation. There were no statistically significant differences between the two groups with regard to intraoperative variables, early or late intraoperative complications, chronic pain or recurrence. Self-gripping mesh in transabdominal hernia repair was found to be a valid alternative to polypropylene mesh in terms of complications, recurrence and postoperative pain. The cost analysis and comparability of outcomes support the preferential use of self-gripping mesh.


Unexpected malignancy at the time of hysterectomy performed for a benign indication: A retrospective review.
To determine the proportion of patients undergoing hysterectomy for a benign indication who have unexpected malignancy (UM) on postoperative pathology and characterize the nature of UMs. This was a multi-center, retrospective study of patients undergoing hysterectomy for a benign indication from July 2016 to December 2019 at 7 Ontario, Canada hospitals (4 academic, 3 community). Hysterectomies for invasive placentation, malignant, and premalignant indications were excluded. Primary outcome was rate of unexpected malignancy as defined by the number of patients with malignancy on final pathology divided by the total number of hysterectomy cases. Data was extracted from health records and electronic charts. Patient, surgical, and surgeon characteristics were compared between benign and UM groups using bivariate methods. Associations between UM status and perioperative variables were assessed using bivariate logistic regression. In the study period, 2779 hysterectomies were performed. UM incidence was 1.8% (51 malignancies/2779 cases), with one patient having two malignancies (total UMs = 52). The most common UM types were endometrial (27/52, 51.9%) and sarcoma (13/52, 25%). Patients with UM were older (57.2 ± 11.4 years vs. 52.8 ± 12.5 years, p = .015), had more previous laparotomies (2 (1.25, 2.0) vs. 1 (1.0, 1.0), p < .001), and higher BMI (29.7 ± 7.2 kg/m2 vs. 28.0 ± 5.9 kg/m2, p = .049) and ASA class (p < .028). Regarding surgical factors, patients with UM had more adhesions (p = .001), transfusions (p = .020), and blood loss (p = .006) compared to those with benign pathology. Patient characteristics most strongly associated with UM were age (OR 2.57, 95% CI 1.78-3.72, p < .001) and preoperative diagnosis of pelvic mass (OR 2.76, 95% CI 1.11-6.20, p = .019). Incidence of UM at hysterectomy for benign indication was 1.8%. Several perioperative variables are associated with an increased chance of UM.


Detection of oxidation products in individual neurons by fluorescence microscopy.
In the study of the central nervous system, it is necessary to address mechanisms by which cells are injured. In vitro investigations using cells in culture allow sharply focused mechanistic questions to be addressed; however, these studies have often been limited by the sensitivity constraints of assays. Many assays for oxidative products require large amounts of cells that must be disrupted. The extent of oxidation in individual cells is therefore unknown and the results yield an average among different cell types. This is inconvenient in cultures of the nervous system which often have multiple cell types. Using a newly developed method for visualizing oxidation products in individual cells, we have examined oxidation in neurons in culture. The method uses a hydrazide, biotin-4-amidobenzoic hydrazide, to bind carbonyls generated from oxidation. Biotin is detected by streptavidin conjugated with a fluorescent dye. Neurons in culture were exposed to 0.1 to 100 microM ferrous sulfate and fluorescence was visualized and quantitated using confocal laser microscopy. Low levels of oxidation (0.1 microM ferrous sulfate) were easily detected with this method. Iron concentration and fluorescence intensity correlated highly (r = 0.991). As an indicator of the sensitivity of this new method, carbonyl content in the cultures was also quantitated using the 2,4-dinitrophenylhydrazine assay (DNPH). The DNPH assay failed to detect the low levels of oxidation which were detected by the biotin-4-amidobenzoic hydrazide method. Fluorescence intensity partially paralleled loss of neuronal viability. Low concentrations of iron (0.1 and 1.0 microM) did not produce significant neuronal death; however, higher concentrations (10 and 100 microM) produced 19 and 53% neuronal loss, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Rapid adaptation of harmful cyanobacteria to rising CO2.
Rising atmospheric CO2 concentrations are likely to affect many ecosystems worldwide. However, to what extent elevated CO2 will induce evolutionary changes in photosynthetic organisms is still a major open question. Here, we show rapid microevolutionary adaptation of a harmful cyanobacterium to changes in inorganic carbon (Ci) availability. We studied the cyanobacterium Microcystis, a notorious genus that can develop toxic cyanobacterial blooms in many eutrophic lakes and reservoirs worldwide. Microcystis displays genetic variation in the Ci uptake systems BicA and SbtA, where BicA has a low affinity for bicarbonate but high flux rate, and SbtA has a high affinity but low flux rate. Our laboratory competition experiments show that bicA + sbtA genotypes were favored by natural selection at low CO2 levels, but were partially replaced by the bicA genotype at elevated CO2 Similarly, in a eutrophic lake, bicA + sbtA strains were dominant when Ci concentrations were depleted during a dense cyanobacterial bloom, but were replaced by strains with only the high-flux bicA gene when Ci concentrations increased later in the season. Hence, our results provide both laboratory and field evidence that increasing carbon concentrations induce rapid adaptive changes in the genotype composition of harmful cyanobacterial blooms.


GPR44 is a pancreatic protein restricted to the human beta cell.
To address questions regarding onset and progression of types 1 and 2 diabetes (T1D/T2D), surrogate imaging biomarkers for beta cell function and mass are needed. Here, we assess the potential of GPR44 as a surrogate marker for beta cells, in a direct comparison with clinically used biomarker VMAT2. GPR44 surface availability was assessed by flow cytometry of human beta cells. RNA transcription levels in different pancreas compartments were evaluated. The density of GPR44 receptor in endocrine and exocrine tissues was assessed by the radiolabeled GPR44 ligand [(3)H]AZD 3825. A direct comparison with the established beta cell marker VMAT2 was performed by radiolabeled [(3)H]DTBZ. GPR44 was available on the cell surface, and pancreatic RNA levels were restricted to the islets of Langerhans. [(3)H]AZD 3825 had nanomolar affinity for GPR44 in human islets and EndoC-βH1 beta cells, and the specific binding to human beta cells was close to 50 times higher than in exocrine preparations. The endocrine-to-exocrine binding ratio was approximately 10 times higher for [(3)H]AZD 3825 than for [(3)H]DTBZ. GPR44 is a highly beta cell-specific target, which potentially offers improved imaging contrast between the human beta cell and the exocrine pancreas.


Transition-Metal-Catalyzed Redox-Neutral and Redox-Green C-H Bond Functionalization.
Transition-metal-catalyzed C-H bond functionalization has become one of the most promising strategies to prepare complex molecules from simple precursors. However, the utilization of environmentally unfriendly oxidants in the oxidative C-H bond functionalization reactions reduces their potential applications in organic synthesis. This account describes our recent efforts in the development of a redox-neutral C-H bond functionalization strategy for direct addition of inert C-H bonds to unsaturated double bonds and a redox-green C-H bond functionalization strategy for realization of oxidative C-H functionalization with O2 as the sole oxidant, aiming to circumvent the problems posed by utilizing environmentally unfriendly oxidants. In principle, these redox-neutral and redox-green strategies pave the way for establishing new environmentally benign transition-metal-catalyzed C-H bond functionalization strategies.


Prescription patterns of pharmacological agents for left ventricular systolic dysfunction among hemodialysis patients.
Recommendations for the management of left ventricular (LV) systolic dysfunction in the general population and patients with end-stage renal disease (ESRD) include the use of angiotensin-converting enzyme (ACE) inhibitors and beta-blockers. Limited data from the literature suggest that these pharmacological agents may be underused in patients with ESRD. The goal of this study is to describe the use of these medications and investigate barriers to their use in dialysis patients. We prospectively studied 420 hemodialysis patients. Diagnosis of systolic dysfunction was based on echocardiogram results. Use of cardiac medication was recorded for all patients with systolic dysfunction, and a questionnaire was administered to nephrologists to determine the basis for decisions concerning ACE-inhibitors and beta-blockers use/nonuse. Forty-seven patients (11%) were found to have an LV ejection fraction of 40% or less. Of those, 72% were administered a beta-blocker and 36% were administered an ACE inhibitor. Only 12 patients (25.5%) were administered a combination of beta-blocker and ACE inhibitor. Reasons indicated by nephrologists for not prescribing these medications were "concern about adverse reactions (eg, hypotension, hyperkalemia)" in 88% of cases, "adequate control of symptoms with ultrafiltration" in 38%, "unproven benefit" in 25%, and "unfavorable risk-benefit ratio" in 17%. Medication costs and concern about patient compliance were not identified as significant concerns by physicians. Only 25.5% of patients with ESRD with LV systolic dysfunction receive appropriate treatment. Concern regarding adverse reactions was the most frequent reason indicated by nephrologists for not prescribing ACE inhibitors and beta-blockers.


Safety of low-dose intrathecal fluorescein in endoscopic cranial base surgery.
Intraoperative identification of cerebrospinal fluid (CSF) leakage is critical in successful closure after endoscopic cranial base surgery. Intrathecal injection of fluorescein is quite useful in identifying CSF leaks. However, complications have been reported with various doses and the technique has fallen out of favor. We explored the safety of low-dose intrathecal fluorescein administered to patients undergoing endoscopic cranial base surgery. A retrospective chart review and postoperative patient survey were performed. The nature and incidence of complications and subjective complaints were recorded in 54 patients who underwent endoscopic, endonasal approaches to the anterior cranial base and received intrathecal fluorescein after premedication with dexamethasone and diphenhydramine. Intraoperative CSF leak was identified with fluorescein in 46.3% of the patients and helped determine the reconstruction technique. Postoperative CSF leak occurred in 9.3% of the patients and resolved with lumbar drainage. There were no seizures. Most side effects were nonspecific, transient, and likely not caused by fluorescein including malaise (57.4%), headache (51.9%), dizziness (31.5%), or nausea/vomiting (24.1%). Three patients (5.6%) experienced persistent subjective lower extremity weakness (n = 2) and numbness (n = 2) postoperatively; however, two of them had undergone lumbar drainage. Low-dose injection of intrathecal fluorescein after premedication with steroid and antihistamine agents is generally safe. Most symptoms are nonspecific and transient, likely caused by the surgery or lumbar drainage. However, fluorescein should be administered with some caution because it may be responsible for occasional lower extremity weakness and numbness.


The effect of intra-arterial versus intravenous cisplatinum in the neoadjuvant treatment of osteosarcoma of the limbs: the experience at the Rizzoli Institute.
The effect of intra-arterial versus intravenous infusion of cisplatinum on the histological response of osteosarcoma of the limbs was evaluated based on the results of three studies in which CDP was preoperatively associated with MTX and ADM (1st study), and with MTX, ADM, and IFO (2nd and 3rd studies). In the chemotherapeutic protocol that involved 3 drugs the percentage of "good histological responses to chemotherapy" (defined as tumor necrosis > 90%) was significantly higher in the 40 patients who were administered CDP by intra-arterial infusion as compared to that observed in the 39 patients treated with CDP by intravenous route (78% versus 46%: P .004). In the two sequential studies where 4 drugs were used, the percentage of good histological responses was essentially the same for patients treated with CDP administered intravenously, and for those treated with CDP administered intra-arterially (78% versus 84%). Regardless of the route of infusion used to administer cisplatinum the percentage of "good" histological responses was significantly higher in the 109 patients treated with the 4-drug protocol as compared to the 79 patients treated with the 3-drug protocol (82% vs 62%; P .04). This difference may essentially be attributed to the higher percentage of good responses observed in the 4-drug protocol in patients treated with CDP administered intravenously (78% vs 46% for patients treated i.v. with the 3-drug protocol; P .006). For the patients instead treated with CDP administered intra-arterially the percentage of good responses was essentially the same with the 4-drug protocol and with the 3-drug protocol (84% vs 78%; P ns). These data lead us to conclude that in the neoadjuvant treatment of osteosarcoma of the limbs a preoperative 4-drug protocol (MTX, CDP, ADM, IFO) is more effective than a 3-drug protocol (MTX, CDP, ADM), and that in a 4-drug preoperative chemotherapy protocol intra-arterial infusion of CDP does not offer particular advantages as compared to intravenous infusion.


[A case of a patient with giant mucinous cystadenocarcinoma who presented with abdominal pain].
We report a case of a patient in whom a giant mucinous cystadenocarcinoma was treated with distal pancreatectomy. A 37-year-old woman was admitted to the hospital complaining of intermittent epigastric pain. The laboratory data revealed a marked increase in serum levels of carcinoembryonic antigen( CEA 22 ng/mL), cancer antigen( CA) 19-9( 258,129 U/ mL), and CA125 (53 U/mL). A computed tomography (CT) scan revealed a cystic tumor, 15 cm in diameter, in the body of the pancreas. The tumor presented as a multilocular cyst with enhanced nodules. On positron emission tomography (PET)-CT,[ 18F] fluorodeoxyglucose uptake by the nodules of the cyst was noted. Under the diagnosis of malignant mucinous cystic neoplasm, we performed distal pancreatectomy, splenectomy, partial gastrectomy, and left adrenalectomy because the tumor was suspected to be invading the stomach and left adrenal gland. The tumor was histologically diagnosed as invasive mucinous cystadenocarcinoma with ovarian-like stroma. The patient survived for 14 months after surgery without tumor recurrence. Invasive mucinous cystadenocarcinoma of the pancreas has high rates of lymph node metastasis and early recurrence after surgery. We believe that we would have had to perform complete tumor resection equivalent to that of invasive ductal carcinoma of the pancreas if the mucinous cystic neoplasm was found to be malignant preoperatively.


Age-varying association between depression and cognitive function among a national sample of older U.S. immigrant adults: the potential moderating role of physical activity.
This study aimed to (1) investigate age-associated trends in depression and cognition, (2) determine whether the association between depression and cognition varies across age, and (3) test whether this association is moderated by different levels of physical activity among older U.S. immigrant adults aged 60 to 80 years. Using national data on elderly U.S. immigrants (N = 375) from the 2011-2014 NHANES, we employed weighted intercept-only linear time-varying effect modeling (TVEM) and weighted linear TVEM to address our research questions. Weighted intercept-only linear TVEM indicated no trend in depression, but its mean peaked at age 67. Cognition consistently decreased with age, reaching its lowest point at age 78. Weighted linear TVEM revealed a significant inverse association between depression and cognition at some age ranges, with the strongest association at around age 66. Yet, we did not find the moderational relation of physical activity to this age-varying association. Although we observed a significant inverse relationship between depression and cognition at a certain age point, physical activity did not moderate the age-varying association. Understanding of age-varying effects on the depression-cognition interaction will promote prevention efforts targeting aging immigrant populations at highest risk for these health outcomes. Further work is needed to test moderating effects of other health behaviors on this association across age. Supplemental data for this article is available online at https://doi.org/10.1080/13607863.2022.2056139 .


Mimicry of physiological urinary FDG excretion: squamous cell carcinoma of esophagus metastasizing to psoas muscle.
Skeletal muscle metastases are rare and usually occur with various malignancies at more advanced stages. FDG PET/CT has been known as a useful tool to detect these lesions because of the character of whole-body scanning and superior contrast between malignant and normal tissues, except in areas with abundant physiological FDG radioactivity, such as the urinary system. We present a patient with esophageal squamous cell carcinoma and an incidental, rare finding of psoas muscle metastasis that was initially omitted because of the similarity of its distribution to physiological urinary FDG excretion in the ureter.


Successful obstetric management of arrhythmogenic right ventricular cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic myocardial disorder characterized by the replacement of myocardium by fibro-adipose tissue. The proper obstetric management of this disease remains unclear due to the lack of an adequate number of cases reported in the literature. We report the successful management of a pregnant patient with ARVC. A female patient with ARVC presented to our hospital at 9 weeks of gestation. Before pregnancy, she was treated with bisoprolol, which resulted in a reduction in extrasystoles and she never developed palpitations. Periodical cardiological examinations showed clinical stability, and the only therapeutic change consisted of an increase in the bisoprolol dosage. She delivered at term by elective cesarean section. We decided that avoiding changes in the chronic therapy of our patient was the best management because she had reached clinical stability before pregnancy and discontinuation of therapy may pose an addition risk. In our opinion, cesarean section was the best mode of delivery in our ARVC patient to avoid the stress of labor, which may raise heart rate and cause arrhythmia. Our experience and the case reports in the literature suggest that pregnancy is tolerated in female patients with ARVC, but they need to be monitored during pregnancy by a multidisciplinary team.


The DNA binding parvulin Par17 is targeted to the mitochondrial matrix by a recently evolved prepeptide uniquely present in Hominidae.
The parvulin-type peptidyl prolyl cis/trans isomerase Par14 is highly conserved in all metazoans. The recently identified parvulin Par17 contains an additional N-terminal domain whose occurrence and function was the focus of the present study. Based on the observation that the human genome encodes Par17, but bovine and rodent genomes do not, Par17 exon sequences from 10 different primate species were cloned and sequenced. Par17 is encoded in the genomes of Hominidae species including humans, but is absent from other mammalian species. In contrast to Par14, endogenous Par17 was found in mitochondrial and membrane fractions of human cell lysates. Fluorescence of EGFP fusions of Par17, but not Par14, co-localized with mitochondrial staining. Par14 and Par17 associated with isolated human, rat and yeast mitochondria at low salt concentrations, but only the Par17 mitochondrial association was resistant to higher salt concentrations. Par17 was imported into mitochondria in a time and membrane potential-dependent manner, where it reached the mitochondrial matrix. Moreover, Par17 was shown to bind to double-stranded DNA under physiological salt conditions. Taken together, the DNA binding parvulin Par17 is targeted to the mitochondrial matrix by the most recently evolved mitochondrial prepeptide known to date, thus adding a novel protein constituent to the mitochondrial proteome of Hominidae.


Forensic aspects of the aerotoxic syndrome.
Three decades ago, cabin air quality was seemingly not an issue in commercial aviation and the incidence of disease through air borne vectors or toxic fumes was uncommon among passengers and crew. However, it is claimed that modern day jet airliners generally carry the threat of disease through the ventilator systems of these aircraft which are designed for optimum efficiency, leaving them exposed to lapses in the recycling of clean air and blocking fumes from engine exhausts of the jets from entering the inhabited parts of the aircraft. It has been claimed that aerotoxic fumes are most common in the cockpit, and that the technical crew are the most susceptible to the aerotoxic syndrome.


Adherence to apixaban for extended thromboprophylaxis after major abdominal or pelvic surgery for cancer: A prospective cohort study.
Due to lack of data, direct oral anticoagulants are not considered by guidelines for venous thromboembolism (VTE) prophylaxis after cancer surgery. Adherence to low-molecular-weight heparin injections in this setting is sometimes poor. Analysis of adherence to oral apixaban for extended thromboprophylaxis. Consecutive patients discharged after major surgery for abdominal/pelvic cancer and considered eligible for extended prophylaxis were offered apixaban 2.5 mg twice daily. Primary outcomes were adherence metrics-proportion of prescriptions filled, persistence (not prematurely discontinued), proportion of days covered (PDC) based on apixaban pill counts, and modified Morisky medication adherence scale at Days 28-30. Secondary outcomes were bleeding, VTE, and serious adverse events until Day 90. We included 53 patients, 51 were analyzed. Of 45 patients with prescriptions all had it filled (95% confidence interval [CI], 92%-100%). Persistence was 98% (95% CI, 90%-100%). PDC was ≥80% for 48 patients (94%; 95% CI, 84%-99%). We found good adherence (0/6 answers "yes") in 75% and moderate (1/6 answers "yes") in 25%. No major bleed or VTE occurred while on apixaban. Our results support good adherence with apixaban for VTE prophylaxis up to 28 days after major abdominal or pelvic cancer surgery.


Analysis of Evolutionary Processes of Species Jump in Waterfowl Parvovirus.
Waterfowl parvoviruses are classified into goose parvovirus (GPV) and Muscovy duck parvovirus (MDPV) according to their antigenic features and host preferences. A novel duck parvovirus (NDPV), identified as a new variant of GPV, is currently infecting ducks, thus causing considerable economic loss. This study analyzed the molecular evolution and population dynamics of the emerging parvovirus capsid gene to investigate the evolutionary processes concerning the host shift of NDPV. Two important amino acids changes (Asn-489 and Asn-650) were identified in NDPV, which may be responsible for host shift of NDPV. Phylogenetic analysis indicated that the currently circulating NDPV originated from the GPV lineage. The Bayesian Markov chain Monte Carlo tree indicated that the NDPV diverged from GPV approximately 20 years ago. Evolutionary rate analyses demonstrated that GPV evolved with 7.674 × 10-4 substitutions/site/year, and the data for MDPV was 5.237 × 10-4 substitutions/site/year, whereas the substitution rate in NDPV branch was 2.25 × 10-3 substitutions/site/year. Meanwhile, viral population dynamics analysis revealed that the GPV major clade, including NDPV, grew exponentially at a rate of 1.717 year-1. Selection pressure analysis showed that most sites are subject to strong purifying selection and no positively selected sites were found in NDPV. The unique immune-epitopes in waterfowl parvovirus were also estimated, which may be helpful for the prediction of antibody binding sites against NDPV in ducks.


Quantum optical thermodynamic machines: lasing as relaxation.
Motivated by the growing interest in the nanophysics and the field of quantum thermodynamics we study an open quantum system consisting of two spatially separated two-level atoms (spins) coupled to a quantum oscillator (resonator field mode). There is no external driving. The spins of different energy splittings are each linked to a heat bath with different temperature. We find that the temperature gradient imposed on the system together with the oscillator operating as a kind of work reservoir makes this system act as a thermodynamic machine, in particular, as a heat engine (laser). We analyze the properties of the resulting resonator field and of the engine functionality. For the latter problem we use recently developed definitions of heat flux and power as well as a test, in which the resulting field is used as an input for a heat pump.


New silver polypyridyl complexes: synthesis, characterization and biological activity on Leishmania mexicana.
Leishmania parasites are the causal agents of leishmaniasis that currently threatens 350 million people in 88 different countries, in the absence of an effective drug. In order to continue the development of transition metal complexes with planar ligands that show interactions with DNA and activity against Leishmania parasites, the synthesis of the complexes [Ag(dpq)2]NO3 (1) and [Ag(dppz)2]NO3 (2), which were obtained by the reaction of silver nitrate with dpq and dppz, respectively, in a 1:2 molar ratio is reported. These complexes were characterized by elemental analysis and 1H-NMR, IR, and UV-vis spectroscopies. The most probable structure for these complexes is tetrahedral, with two molecules of ligand coordinated to the silver atom and a nitrate as a counter ion. Affinity studies of DNA vs. bovine albumin were carried out, and a strong interaction of the complexes with DNA was observed. Bioassays were undertaken in vitro on promastigotes of Leishmania (L.) mexicana exposed to the silver complexes for 48 h. At 10 micromol/L complex 2 induced a leishmanicidal effect (LD23), whilst complex 1 reduced the parasites growth rate by 55% (LD55). These findings suggest that biological activity could be associated with the interaction of the complexes with the parasitic DNA.


Pollutants in aquatic system: a frontier perspective of emerging threat and strategies to solve the crisis for safe drinking water.
Water is an indispensable natural resource and is the most vital substance for the existence of life on earth. However, due to anthropogenic activities, it is being polluted at an alarming rate which has led to serious concern about water shortage across the world. Moreover, toxic contaminants released into water bodies from various industrial and domestic activities negatively affect aquatic and terrestrial organisms and cause serious diseases such as cancer, renal problems, gastroenteritis, diarrhea, and nausea in humans. Therefore, water treatments that can eliminate toxins are very crucial. Unfortunately, pollution treatment remains a difficulty when four broad considerations are taken into account: effectiveness, reusability, environmental friendliness, and affordability. In this situation, protecting water from contamination or creating affordable remedial techniques has become a serious issue. Although traditional wastewater treatment technologies have existed since antiquity, they are both expensive and inefficient. Nowadays, advanced sustainable technical approaches are being created to replace traditional wastewater treatment processes. The present study reviews the sources, toxicity, and possible remediation techniques of the water contaminants.


Fractional Carbon Dioxide Laser in Treatment of Acne Scars.
Scars appear as a result of skin damage during the process of the skin healing. There are two types of acne scars, depending on whether there is a loss or accumulation of collagen: atrophic and hypertrophic. In 80-90% it comes to scars with loss of collagen compared to smaller number of hypertrophic scars and keloids. The aim of the study was to determine efficiency and safety of fractional carbon dioxide laser in the treatment of acne scars. The study was carried out in Acibadem Sistina Clinical Hospital, Skopje at the Department of Dermatovenerology, with a total of 40 patients treated with fractional carbon dioxide laser (Lutronic eCO2). The study included patients with residual acne scars of a different type. Comedogenic and papular acne in our material were proportionately presented in 50% of cases, while the other half were the more severe clinical forms of acne - pustular inflammatory acne and nodulocystic acne that leave residual lesions in the form of second, third and fourth grade of scars. The experiences of our work confirm the world experiences that the best result with this method is achieved in dotted ice pick or V-shaped acne scars.


Synapsin I in PC12 cells. II. Evidence for regulation by NGF of phosphorylation at a novel site.
NGF treatment of PC12 cells caused a rapid increase in the state of phosphorylation of synapsin I. This phosphorylation of synapsin I is accompanied by a decrease in its electrophoretic mobility on SDS-PAGE. Phosphopeptide fingerprint analysis of the synapsin I revealed that this phosphorylation occurred on a particular phosphopeptide, designated peptide N. Phosphoserine was the only phosphoamino acid detected in peptide N. Partially purified PC12 synapsin I was a substrate for several protein kinases known to be capable of phosphorylating brain synapsin I, but none of these kinases phosphorylated synapsin I on peptide N. The results suggest that the NGF-stimulated phosphorylation of synapsin I may be mediated by a novel protein kinase.


Proximal gastric cancer: lymph node metastatic patterns according to different T stages dictate surgical approach.
As a common form of gastric cancer migration, lymph node metastasis largely affects the surgical treatment and prognosis of gastric cancer. Surgery is the fundamental curative option for gastric cancer that varies depending on different stages. The study aimed to compare the clinicopathological characteristics and lymph node metastatic patterns in patients of proximal gastric cancer with different T stages and investigate a reasonable radical gastrectomy approach in terms of the range of lymphadenectomy for proximal gastric cancer. In our retrospective study, the data of 328 patients of proximal gastric cancer with different T stages were analyzed. By comparing the differences of lymph node metastatic rate and ratio, we investigated the clinicopathological characteristics and metastatic patterns of lymph nodes. Also, we were especially interested in the differences in survival rates between patients with and without No. 5 and 6 group metastasis with the same TNM stage. The overall lymph node metastatic rate and ratio of advanced proximal gastric cancer were 73.4% and 23.3%, respectively. The tumors of different T stages were statistically significant in size and differentiation degree (P < 0.05), multivariate analysis showed that the depth of tumor invasion was an independent risk factor for lymph node metastasis in proximal gastric cancer (RR, 12.025; 95% CI, 2.326 to 62.157; P = 0.003). The overall survival rate of patients with No. 5, 6 group lymph node metastasis and those without was significantly different, but the differences in survival rates between patients with and without No. 5 and 6 group metastasis with the same TNM stage were not statistically significant. Different T stages in proximal gastric cancer showed different patterns and characteristics of lymph node metastasis. D2 lymphadenectomy in patients with early gastric cancer had little survival benefit because metastasis to level 2 nodes was rare. Therefore the range of the lymph node dissection in radical gastrectomy for early gastric cancer was considered reasonable. Moreover, to meet the requirements of the lymph node dissection, total gastrectomy plus D2 lymphadenectomy or more are supposed to be applied for the advanced proximal gastric cancer patients. Precise T staging largely determines the range of gastrectomy and lymphadenectomy.


Nicotiana tabacum Tsip1-interacting ferredoxin 1 affects biotic and abiotic stress resistance.
Tsip1, a Zn finger protein that was isolated as a direct interactor with tobacco stress-induced 1 (Tsi1), plays an important role in both biotic and abiotic stress signaling. To further understand Tsip1 function, we searched for more Tsip1-interacting proteins by yeast two-hybrid screening using a tobacco cDNA library. Screening identified a new Tsip1-interacting protein, Nicotiana tabacum Tsip1-interacting ferredoxin 1 (NtTfd1), and binding specificity was confirmed both in vitro and in vivo. The four repeats of a cysteine-rich motif (CXXCXGXG) of Tsip1 proved important for binding to NtTfd1. Virus-induced gene silencing of NtTfd1, Tsip1, and NtTfd1/Tsip1 rendered plants more susceptible to salinity stress compared with TRV2 control plants. NtTfd1- and Tsip1-silenced tobacco plants were more susceptible to infection by Cucumber mosaic virus compared with control plants. These results suggest that NtTfd1 might be involved in the regulation of biotic and abiotic stresses in chloroplasts by interaction with Tsip1.


Cyclic mechanical stretch induces cardiomyocyte orientation and polarization of the gap junction protein connexin43.
Cyclic mechanical stretch (CMS) is an important physiological and pathological factor in the heart. We examined whether CMS can affect localization of gap junctions with regard to the cell axis. Neonatal rat cardiomyocytes were cultured (7 days) on flexible 6-well plates. Thereafter, cells were kept static or stimulated with CMS (1 Hz; 0, 10, 20% elongation) for 0, 24, or 48 hours (with or without 10 micromol/L PD98059, 5 micromol/L BIM I (bisindolylmaleimide I), 2 micromol/L H8 [N-(2-methlyamino-ethyl)-5-isoquinoline-sulfonamid], or 0.1 micromol/L angiotensin II. Additionally, cells were exposed to 24 hours of CMS followed by 24 hours of static recovery. CMS (24 hour, 10%) induced elongation of the cardiomyocytes and orientation 79+/-8 degrees toward the stretch direction. Moreover, the distribution of connexin (Cx)43 together with N-cadherin changed, so that both proteins were accentuated at the cell poles, whereas in nonstretched cells, they were distributed around the cell without preferential localization. Additional angiotensin II reduced polar Cx43 accentuation. The CMS-induced changes in Cx43 were reversible within 24 hours after end of stretch, and could be completely prevented by the MEK1/2 inhibitor PD98059 but not by BIM I or H8. Moreover, stretch resulted in Cx43 protein and Cx43-mRNA upregulation and in a significant upregulation of the phosphorylated forms of ERK1/2, glycogen synthase kinase 3beta and AKT. Furthermore, CMS resulted in a significant increase of the transcription factors activator protein 1 and CREB (cAMP response element-binding protein) in the nucleus. CMS results in self-organization of cardiomyocytes leading to elongated cells orientated transverse to the stretch axis, enhanced Cx43 expression and Cx43 accentuation at the cell poles. The Cx43-changes seem to depend on the ERK1/2 signaling cascade.


Mucosal healing and inflammatory bowel disease: Therapeutic implications and new targets.
Mucosal healing (MH) is vital in maintaining homeostasis within the gut and protecting against injury and infections. Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair. However, when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results, particularly inflammatory bowel disease (IBD). Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions, with the mechanisms of regulation just beginning to be understood. Consequently, there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes, so tissue damage in the gastrointestinal tract of patients, even those in clinical remission, persists. With increased understanding of the molecular mechanisms of IBD and MH, tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body's own healing response. In this review, we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.


A new epidermal growth factor-like domain in the human core protein for the large cartilage-specific proteoglycan. Evidence for alternative splicing of the domain.
A series of cDNA clones for the human core protein of the large cartilage-specific proteoglycan was isolated. Nucleotide sequencing of the clones provided over 2 kilobases of new coding sequences for the human protein. Comparison with published data for cDNA clones covering the same region in rat and chick indicated that domain 8, the lectin-like domain, is highly conserved among species. In contrast, domain 7 is poorly conserved among species. Some of the cDNA clones also contained an additional structural domain between domains 7 and 8 which was not described in the rat or chick sequences. The additional domain of 38 amino acids was highly homologous to epidermal growth factor (EGF)-like sequences seen in other proteins. Because some cDNA clones contained codons for the EGF-like domain and some did not, the results suggested that the EGF-like domain underwent alternative RNA splicing. To confirm alternative splicing of the EGF-like domain, RNA from cartilage cells was used as a template for the polymerase chain reaction. Products of two sizes were obtained. One had the size predicted for mRNA containing the domain and the other had the size predicted for mRNA not containing the domain. Alternative splicing of an EGF-like domain may provide a mechanism of feedback regulation for both the biosynthetic activity and the proliferation of cartilage cells.


Effects of Indwelling Pleural Catheter on Severe Acute Pancreatitis: A Retrospective Study.
Pleural effusion (PE) is an important predictor for severity and prognosis of severe acute pancreatitis (SAP). However, there are few studies focused on the effects and timing of indwelling pleural catheter (IPC) on SAP. Considering this, we designed a retrospective study to verify the relationship between PE and severity of SAP and observe the effects and timing of IPC in SAP. A total of 309 SAP patients were enrolled. Based on the presence or absence of PE and IPC and IPC time, the enrolled patients were divided into 6 groups. Then, baseline parameters, disease severity, critical complications, ventilator supporting time (VST), length of stay (LOS), and 60-day mortality were compared between each two groups. PE was a risk factor for death of SAP, but not an independent risk factor. SAP patients with PE rather without PE had higher critical complication rates (p < 0.001), along with longer VST (p < 0.001) and LOS (p < 0.001). And the critical complication rates were lower in group 1 (IPC within 1 week of onset) than group 2 (IPC after 1 week of onset). Further, patients in group 1 also had shorter LOS (p = 0.042) and VST (p = 0.001) than those in group 2. In addition, the survival analysis showed the risk of death in the PE group was higher than the non-PE group (HR 6.6, 95% CI, 3.67-11.86, and p < 0.001). And the risk of death in group 1 was lower than group 2 (HR 0.26, 95% CI, 0.08-0.84, and p = 0.025). PE is a risk factor for death of SAP, but not an independent risk factor. IPC, especially IPC within 1 week of onset, has clinical practical value in SAP.


The importance of airway management in trauma.
The airway is the most important priority in the management of the severely injured patient. It is essential to open and clear the airway to allow free access of air to the distal endobronchial tree. Manual methods of opening the airway are described. Numerous methods for establishing definitive control of the airway as well as the associated devices currently available to maintain control are described. Once the airway is maintained, it is important to ensure adequate oxygenation and ventilation through the airway. Modern portable devices that monitor the carbon dioxide in the expired air at the end of each breath are currently available. These devices allow the physician to verify the position of the tube in the airway as well as to continuously monitor the efficacy of ventilation.


Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease.
Skeletal muscle atrophy and impaired muscle function are associated with lower health-related quality of life, and greater disability and mortality risk in those with chronic kidney disease (CKD). However, the pathogenesis of skeletal dysfunction in CKD is unknown. We used a slow progressing, naturally occurring, CKD rat model (Cy/+ rat) with hormonal abnormalities consistent with clinical presentations of CKD to study skeletal muscle signaling. The CKD rats demonstrated augmented skeletal muscle regeneration with higher activation and differentiation signals in muscle cells (i.e. lower Pax-7; higher MyoD and myogenin RNA expression). However, there was also higher expression of proteolytic markers (Atrogin-1 and MuRF-1) in CKD muscle relative to normal. CKD animals had higher indices of oxidative stress compared to normal, evident by elevated plasma levels of an oxidative stress marker, 8-hydroxy-2' -deoxyguanosine (8-OHdG), increased muscle expression of succinate dehydrogenase (SDH) and Nox4 and altered mitochondria morphology. Furthermore, we show significantly higher serum levels of myostatin and expression of myostatin in skeletal muscle of CKD animals compared to normal. Taken together, these data show aberrant regeneration and proteolytic signaling that is associated with oxidative stress and high levels of myostatin in the setting of CKD. These changes likely play a role in the compromised skeletal muscle function that exists in CKD.


Immortalization and characterization of bone marrow stromal fibroblasts from a patient with a loss of function mutation in the estrogen receptor-alpha gene.
A male patient with abnormal postpubertal bone elongation was shown earlier to have a mutation in both alleles of the estrogen receptor, resulting in a nonfunctional gene. Marrow stromal fibroblasts (MSFs) derived from this patient were called HERKOs (human estrogen receptor knock outs), and in order to obtain continuous HERKO cell lines, they were immortalized using a recombinant adenovirus-origin-minus SV40 virus. MSFs are unique cells because they support hematopoesis and contain a mixed population of precursor cells for bone, cartilage, and fat. Three established cell lines (HERKO2, HERKO4, and HERKO7) were characterized and compared with the heterogeneous population of nonimmortalized HERKOs for their osteogenic potential. We performed Northern analysis of matrix genes implicated in bone development and metabolism and an in vivo bone formation assay by transplanting the cells subcutaneously into immunodeficient mice. All three HERKO lines expressed high amounts of collagen 1A1, osteopontin, osteonectin, fibronectin, decorin, biglycan, and alkaline phosphatase. Except for osteopontin, expression of these genes was slightly lower compared with nonimmortalized HERKOs. In the in vivo bone formation assay, the heterogeneous population of nonimmortalized HERKOs formed bone with high efficiency, while the HERKO lines induced a high-density, bone-like matrix. Finally, all HERKO cell types secreted high levels of insulin-like growth factor I and interleukin-6 into the culture medium relative to cells of normal human subjects. In summary, these lines of HERKO cells retain several of the phenotypic traits of MSFs after immortalization, including matrix and cytokine production, and provide a valuable source of a unique human material for future studies involving estrogen action in bone and bone marrow metabolism.


A toy story: Association between young children's knowledge of fast food toy premiums and their fast food consumption.
Fast food restaurants spend millions of dollars annually on child-targeted marketing, a substantial portion of which is allocated to toy premiums for kids' meals. The objectives of this study were to describe fast food toy premiums, and examine whether young children's knowledge of fast food toy premiums was associated with their fast food consumption. Parents of 3- to 5-year old children were recruited from pediatric and WIC clinics in Southern New Hampshire, and completed a cross-sectional survey between April 2013-March 2014. Parents reported whether their children usually knew what toys were being offered at fast food restaurants, and whether children had eaten at any of four restaurants that offer toy premiums with kids' meals (McDonald's, Burger King, Subway, Wendy's) during the 7 days preceding the survey. Seventy-one percent of eligible parents participated (N = 583); 48.4% did not receive any education beyond high school, and 27.1% of children were non-white. Half (49.7%) the children had eaten at one or more of the four fast food restaurants in the past week; one-third (33.9%) had eaten at McDonald's. The four restaurants released 49 unique toy premiums during the survey period; McDonald's released half of these. Even after controlling for parent fast food consumption and sociodemographics, children were 1.38 (95% CI = 1.04, 1.82) times more likely to have consumed McDonald's if they usually knew what toys were offered by fast food restaurants. We did not detect a relationship between children's toy knowledge and their intake of fast food from the other restaurants. In this community-based sample, young children's knowledge of fast food toys was associated with a greater frequency of eating at McDonald's, providing evidence in support of regulating child-directed marketing of unhealthy foods using toys.


[Acute disseminated encephalomyelitis (ADEM) associated with cytomegalovirus infection--a case report].
A 60-year-old woman was admitted to our hospital because of developing fever, visual loss, weakness in right upper limb, walking difficulty and difficulties of urination and defecation. There were memory disturbance, optic neuritis, ataxia and myelopathy. CSF cells and protein were increased. Cytomegalovirus (CMV) antibodies in the CSF were increased. T2-weighted images of brain MRI showed diffuse high signal intensity lesions in white matter. Gadolinium-enhanced MRI of cervical spinal cord showed diffuse spotty enhanced lesions. Corticosteroid treatment improved clinical symptoms and anti-CMV antibodies in the CSF. This is the first case report of ADEM associated with CMV infection.


Educational programs in US medical schools.
As described in the introduction, the data presented in this report can be viewed in both a historical and an environmental context. From a historical perspective, there has been change in many areas of medical education. The number of applicants to medical schools has risen sharply in the past few years, a result seemingly inconsistent with the dissatisfaction with medicine expressed by many physicians and with the uncertainties about the eventual outcomes of health system reform. The number of minority applicants and enrollees is slowly rising, but at rates below the goals identified by such initiatives as the Association of American Medical Colleges' "Project 3000 by 2000." Even with the expansion of the applicant pool, however, most medical schools do not anticipate enrollment increases. Medical school tuition also continues to increase significantly, in both public and private schools. The number of faculty members in the clinical disciplines also has continued to rise, although the rate of increase has become less marked. The decrease in the number of basic science faculty members that occurred this year will need to be monitored to ensure that appropriate faculty resources are available for teaching, especially with the initiatives to introduce more active learning formats during the basic science years. The medical curriculum continues to evolve at differing rates across schools. Many "innovations" have become part of the curricular repertoire; for example, medical schools have incorporated educational formats, such as problem-based learning or computer-assisted instruction, which emphasize active student learning, although in a number of cases they are limited to a small portion of the curriculum. In addition, the availability of clinical experiences during the first 2 years of the curriculum, especially those located in ambulatory settings, gives students an early glimpse of the world of actual medical practice. The use of standardized patients provides system and structure in the teaching and evaluation of clinical skills. Therefore, a look at medical education as a whole in the historical context reveals many positive changes (for example, an increase in student diversity over time, the introduction of alternative instructional formats, and attempts to evaluate student clinical competence more reliably). Within the context of environmental expectations, however, many challenges still remain. Medical schools are experiencing pressure to solve perceived problems with the specialty distribution of their graduates and with the specialty distribution of the general physician population, even though factors outside the control of the medical school, such as reimbursement and the practice environment, also influence specialty choice.(ABSTRACT TRUNCATED AT 400 WORDS)


Identification and Quantitation of Circulating Tumor Cells.
Circulating tumor cells (CTCs) are shed from the primary tumor into the circulatory system and act as seeds that initiate cancer metastasis to distant sites. CTC enumeration has been shown to have a significant prognostic value as a surrogate marker in various cancers. The widespread clinical utility of CTC tests, however, is still limited due to the inherent rarity and heterogeneity of CTCs, which necessitate robust techniques for their efficient enrichment and detection. Significant recent advances have resulted in technologies with the ability to improve yield and purity of CTC enrichment as well as detection sensitivity. Current efforts are largely focused on the translation and standardization of assays to fully realize the clinical utility of CTCs. In this review, we aim to provide a comprehensive overview of CTC enrichment and detection techniques with an emphasis on novel approaches for rapid quantification of CTCs.


Vacuum-Assisted Wound Closure Therapy in Pediatric Lower Limb Trauma.
Although the importance of vacuum-assisted wound closure therapy has been well established as road to definitive treatment of trauma wound in the adult population, its use in pediatric patients is not well described in the literature. This study was conducted to evaluate the outcome of vacuum-assisted wound closure therapy in pediatric patients. Twenty-two patients were prospectively treated for soft tissue defect in lower limb using vacuum-assisted wound closure device, as these wounds were not amenable for primary closure. After wound evaluation, thorough wound debridement was done. Vacuum-assisted wound closure dressing was applied once hemostasis was achieved. Dressings were changed as per protocol. After the development of healthy granulation tissue, wound coverage was achieved with skin graft or flaps. Mean age of patients was 9.455 years, ranging from 4 to 14 years. Early, healthy granulation tissue had formed in all patients. The average number of vacuum-assisted closure (VAC) dressings required was 2.682. Average duration of VAC therapy was 8.045 days. The sizes of soft tissue defects reduced from an average 69.18 cm2 to 50.73 cm2 after VAC therapy with a mean decrease of 26.66%. There was no complication because of VAC therapy. Vacuum-assisted wound closure therapy accelerated the process of healthy granulation tissue formation, and thus shortened the healing time. VAC therapy lessens the morbidity and pain associated with large wounds in pediatric patients and brings cheer and smile in growing children.


Rapid Intravenous Glyceryl Trinitrate in Ischemic Damage (RIGID) After Stroke: Rationale, Design and Protocol for a Prospective Randomized Controlled Trial.
Background: Despite intravenous thrombolysis and endovascular therapy for acute ischemic stroke (AIS), many survivors still have varying degrees of disability. Glyceryl trinitrate (GTN), a nitric oxide (NO) donor, has been previously reported to induce neuroprotection after AIS. The use of GTN to reduce brain damage after stroke remains yet to be elucidated. This study was designed to explore the safety, feasibility, and preliminary efficacy of intravenous administration of GTN after AIS. Methods: A prospective randomized controlled trial is proposed with AIS patients. Participants will be randomly allocated to GTN group and control group with a 1:1 ratio (n = 40). Both groups will be treated with standard therapies according to the current stroke guidelines. Participants allocated to the GTN group will receive intravenous administration of GTN (5 mg GTN in 50 ml saline at a rate of 0.4 mg/h that is continued for 12.5 h/day for 2 days) within 24 h of symptom onset. Participants allocated to the control group will receive intravenous administration at equal capacity of 0.9% normal saline (NS) (total 50 ml/day at 4 ml/h that is continued for 12.5 h/day for 2 days). The primary outcome is safety [systolic blood pressure (SBP) <110 mmHg, headache], while the secondary outcomes include changes in functional outcome and infarction volume. Discussion: Rapid Intravenous Glyceryl Trinitrate in Ischemic Damage (RIGID) is a prospective randomized controlled trial that aims to ascertain the safety, feasibility, and preliminary efficacy of intravenous GTN as a neuroprotection strategy after AIS. These results will provide parameters for future studies as well as provide insights into treatment effects. Any possible neuroprotective qualities of GTN in AIS will also be elucidated. Trial Registration:www.chictr.org.cn, identifier: ChiCTR2100046271.


Variation in laparoscopic anti-reflux surgery across England: a 5-year review.
Laparoscopic anti-reflux surgery (LARS) remains central to the management of gastro-oesophageal reflux disease but the scale and variation in provision in England is unknown. The aims of this study were firstly to examine the processes and outcomes of anti-reflux surgery in England and compare them to national guidelines and secondly to explore potential variations in practice nationally and establish peer benchmarks. All adult patients who underwent LARSin England during the Financial years FY 2011/2012-FY 2016/2017 were identified in the Surgeon's Workload Outcomes and Research Database (SWORD), which is based on the Hospital Episode Statistics (HES) data warehouse. Outcomes included activity volume, day-case rate, short-stay rate, 2- and 30-day readmission rates and 30-day re-operation rates. Funnel plots were used to identify national variation in practice. In total, 12,086 patients underwent LARS in England during the study period. The operation rate decreased slightly over the study period from 5.2 to 4.6 per 100,000 people. Most outcomes were in line with national guidelines including the conversion rate (0.76%), 30-day re-operation rate (1.43%) and 2- and 30-day readmission rates (1.65 and 8.54%, respectively). The day-case rate was low but increased from 7.4 to 15.1% during the 5-year period. Significant variation was found, particularly in terms of hospital volume, and day-case, short-stay and conversion rates. Although overall outcomes are comparable to studies from other countries, there is significant variation in anti-reflux surgery activity and outcomes in England. We recommend that units use these data to drive local quality improvement efforts.


Phase I/II study of recombinant human granulocyte-macrophage colony-stimulating factor in aplastic anemia and myelodysplastic syndrome.
We performed a phase I/II study of the administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients with aplastic anemia or myelodysplastic syndrome. Doses ranging from 15 to 480 micrograms/m2 were administered as a one-hour or four-hour intravenous infusion daily for 7 days or as a 12-hour infusion for 14 days. Temporary improvements were seen in granulocyte counts, monocyte counts, and reticulocyte counts in six of eight patients with aplastic anemia and five of seven patients with myelodysplastic syndromes. The patients with myelodysplastic syndromes had larger increases in granulocyte, monocyte, and reticulocyte counts than did those with aplastic anemia, and they also had increases in the numbers of eosinophils (two of seven), immature myeloid cells (two of seven), and myeloblasts (two of seven) that were not observed in patients with aplastic anemia. There was no reduction in erythrocyte transfusion requirements, and no effect was observed on platelet counts. There was only minimal toxicity consisting of transient low-back discomfort, anorexia, myalgias/arthralgias, and low-grade fever. Our data suggest that GM-CSF is well tolerated and is more likely to result in elevations of blood counts in patients with myelodysplasia than in patients with aplastic anemia, but the role of GM-CSF therapy in these disorders remains to be determined.


Serum Parathyroid Hormone Responses to Vitamin D Supplementation in Overweight/Obese Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Obesity is often associated with vitamin D deficiency and secondary hyperparathyroidism. Vitamin D supplementation typically leads to the reductions in serum parathyroid hormone (PTH) levels, as shown in normal weight individuals. Meanwhile, the dose of vitamin D supplementation for the suppression of PTH may differ in overweight and obese adults. We conducted a systematic review and meta-analysis of randomized controlled trials to determine the dose of vitamin D supplementation required to suppress PTH levels in overweight/obese individuals. We identified 18 studies that examined overweight or obese healthy adults who were supplemented with varying doses of vitamin D3. The primary outcomes examined were changes in PTH and serum 25-hydroxyvitamin D (25OHD) levels from baseline to post-treatment. The results of the meta-analysis showed that there was a significant treatment effect of vitamin D supplementation on PTH, total standardized mean difference (SMD) (random effects) = -0.38 (95% CI = -0.56 to -0.20), t = -4.08, p < 0.001. A significant treatment effect of vitamin D supplementation was also found on 25OHD, total SMD (random effects) = 2.27 (95% CI = 1.48 to 3.06) t = 5.62, p < 0.001. Data from available clinical trials that supplemented adults with D3 ranging from 400 IU to 5714 IU, showed that 1000 IU of vitamin D supplementation best suppressed serum PTH levels, total SMD = -0.58, while vitamin D supplementation with 4000 IU showed the greatest increase in serum 25OH levels. Vitamin D and calcium supplementation of 700 IU and 500 mg, respectively, also showed a significant treatment effect on the suppression of PTH with a total SMD = -5.30 (95% CI = -9.72 to -0.88). In conclusion, the meta analysis of available clinical trials indicates that 1000 IU vitamin D supplementation can suppress serum PTH levels, while 4000 IU of vitamin D was associated with the largest increase in serum 25OHD levels in the overweight and obese population.


Teratogenic plants.
Abnormal, defective offspring are a significant problem in livestock as well as in humans. Congenital malformations have been observed since ancient times and were once thought to be primarily of genetic origin. Knowledge relating to congenital anomalies has greatly increased in recent years. Numerous hazardous plants are abundant on many of the ranges grazed by livestock. Many of the plants, when ingested during certain stages of gestation, induce congenital defects. The defects can vary from minor changes to striking abnormalities. The final manifestations of abnormal intrauterine differentiation and development are death, resulting in reabsorption or abortion, malformation, suppression of growth, and disordered function. It appears that the type of malformation induced in a conceptus depends more upon the developmental stages in which the injurious agent operates than upon the type of the agent. The etiology and pathogenesis of congenital defects are complex. With time, and additional studies, other plants will probably prove to be teratogenic. Teratogenic studies and findings in animals have had beneficial influences for the livestock industry and for veterinary and human medicine.


Effects of fetal genotype and uterine environment on placental development in equids.
Measurement of the concentrations of equine chorionic gonadotrophin (eCG) in the serum of pregnant mares and Jenny donkeys carrying normal intraspecies and hybrid interspecies pregnancies suggested that the production of this hormone may be influenced by parental gene imprinting. Specifically, a differential expression of maternal and paternal genes may control the size and secretory activity of the structures that secrete eCG, the fetal endometrial cups. However, bisection of an interspecies mule embryo followed by transfer of the resulting demi-embryos and other intact mule embryos to horse and donkey recipients resulted in striking differences in the size, secretory activity and lifespan of the endometrial cups in two types of surrogate mother. This finding has therefore demonstrated the ability of uterine factors to alter profoundly the development and characteristic phenotype of the specialized invasive chorionic girdle portion of the equine trophoblast that gives rise to the endometrial cups.


A homochiral microporous hydrogen-bonded organic framework for highly enantioselective separation of secondary alcohols.
A homochiral microporous hydrogen-bonded organic framework (HOF-2) based on a BINOL derivative has been synthesized and structurally characterized to be a uninodal 6-connected {3(3)5(5)6(6)7} network. This new HOF exhibits not only a permanent porosity with the BET of 237.6 m(2) g(-1) but also, more importantly, a highly enantioselective separation of chiral secondary alcohols with ee value up to 92% for 1-phenylethanol.


Effects of the long-acting calcium channel blocker barnidipine hydrochloride on 24-h ambulatory blood pressure.
The effect of the long acting calcium channel blocker, barnidipine hydrochloride (barnidipine) on 24-h ambulatory blood pressure (ABP) was evaluated in J-MUBA (Japanese Multicentre Study on Barnidipine with Ambulatory Blood Pressure Monitoring). Following an observation period of two weeks, antihypertensive treatment with barnidipine was continued for at least six months. At the end of each period, ABP were measured. The patients were divided into high- and low-range groups based on ABP measurement. Throughout the 24 h, barnidipine exerted an excellent antihypertensive effect in the high-range group, but not in the low-range group. Barnidipine had comparable effects in the daytime and nighttime in inverted dippers and non-dippers, but it was more effective on daytime ABP than on nighttime ABP in dippers and in extreme dippers. Morning blood pressure before and after waking was evaluated before and after barnidipine administration in 233 patients. Barnidipine inhibited increases in blood pressure before and after waking, especially in surge-type patients whose blood pressure increased rapidly after waking. A positive correlation among 24-h ABP, daytime and night time ABP, morning blood pressure, and clinic blood pressure during the observation period and the antihypertensive effect of barnidipine was observed, with barnidipine exhibiting stronger antihypertensive effects in patients with persistently high blood pressure. It was concluded that the antihypertensive effects of barnidipine are maintained for 24 h but it has no excessive hypotensive effects on lower blood pressure and is thus a safe antihypertensive agent.


Astrocyte reactivity and reactive astrogliosis: costs and benefits.
Astrocytes are the most abundant cells in the central nervous system (CNS) that provide nutrients, recycle neurotransmitters, as well as fulfill a wide range of other homeostasis maintaining functions. During the past two decades, astrocytes emerged also as increasingly important regulators of neuronal functions including the generation of new nerve cells and structural as well as functional synapse remodeling. Reactive gliosis or reactive astrogliosis is a term coined for the morphological and functional changes seen in astroglial cells/astrocytes responding to CNS injury and other neurological diseases. Whereas this defensive reaction of astrocytes is conceivably aimed at handling the acute stress, limiting tissue damage, and restoring homeostasis, it may also inhibit adaptive neural plasticity mechanisms underlying recovery of function. Understanding the multifaceted roles of astrocytes in the healthy and diseased CNS will undoubtedly contribute to the development of treatment strategies that will, in a context-dependent manner and at appropriate time points, modulate reactive astrogliosis to promote brain repair and reduce the neurological impairment.


Effect of betaTCP filled polyetheretherketone on osteoblast cell proliferation in vitro.
Non-resorbable thermoplastic polymers have become more important for reconstructive surgery due to their excellent chemical and physical properties. Polyetheretherketone-beta-tricalcium phosphate (betaTCP-PEEK) composites were developed as alternative materials for load-bearing applications. This study presents the effect of polyetheretherketone (PEEK) specimens incorporated with 5, 10, 20 and 40 wt% beta-tricalcium phosphate (betaTCP) and processed by injection molding on cultivated osteoblast cells. Normal human osteoblast (NHOst) cells were seeded onto polymer discs to evaluate cell viability and proliferation after 24, 72 and 120 h of cultivation by employing the WST-1 assay. Standard tissue culture plastic was used as a control. The osteoblast cells were found to be viable in all PEEK groups, while the cell proliferation was progressively inhibited due to the incorporated beta-tricalcium phosphate. BetaTCP-PEEK showed concentration independent decrease of cell proliferation compared to the unfilled PEEK and the control group. In summary, this study confirms the non-toxic nature of pure PEEK, whereas this could not definitely be verified for betaTCP-PEEK as a composite material in chosen concentrations of beta-tricalcium phosphate in vitro.


ACE ID genotype affects blood creatine kinase response to eccentric exercise.
Unaccustomed exercise may cause muscle breakdown with marked increase in serum creatine kinase (CK) activity. The skeletal muscle renin-angiotensin system (RAS) plays an important role in exercise metabolism and tissue injury. A functional insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene (rs4646994) has been associated with ACE activity. We hypothesized that ACE ID genotype may contribute to the wide variability in individuals' CK response to a given exercise. Young individuals performed maximal eccentric contractions of the elbow flexor muscles. Pre- and postexercise CK activity was determined. ACE genotype was significantly associated with postexercise CK increase and peak CK activity. Individuals harboring one or more of the I allele had a greater increase and higher peak CK values than individuals with the DD genotype. This response was dose-dependent (mean +/- SE U/L: II, 8,882 +/- 2,362; ID, 4,454 +/- 1,105; DD, 2,937 +/- 753, ANOVA, P = 0.02; P = 0.009 for linear trend). Multivariate stepwise regression analysis, which included age, sex, body mass index, and genotype subtypes, revealed that ACE genotype was the most powerful independent determinant of peak CK activity (adjusted odds ratio 1.3, 95% confidence interval 1.03-1.64, P = 0.02). In conclusion, we indicate a positive association of the ACE ID genotype with CK response to strenuous exercise. We suggest that the II genotype imposes increased risk for developing muscle damage, whereas the DD genotype may have protective effects. These findings support the role of local RAS in the regulation of exertional muscle injury.


In silico and in vitro characterization of mGBP4 splice variants.
In a systematic approach to identify interferon-gamma (IFN-gamma)-regulated host effector molecules, we found several members of the 65 kDa guanylate-binding proteins (GBPs) highly upregulated. During extensive characterization of these guanosine triphosphatases (GTPases), we identified discrepancies between the cloned and published sequences of the murine GTPase mGBP4. Two splice variants of mGBP4 could be detected. One variant led to a premature stop codon after 312 bp. The second variant resulted in a transcript with a disrupted G2 domain and was deposited as mGBP4.1 to the GenBank. Interestingly, only mGBP4, not mGBP4.1 mRNA, was highly upregulated in mice after infection with Listeria monocytogenes.


[Primary choriocarcinoma of the bladder. A case report with immunohistochemical and ultrastructural study].
Some tumors frequently encountered in other organs and usually with a high grade of malignancy and a poor prognosis have been recently described in the urinary bladder, very often in close relationship with a pre-existing transitional cell carcinoma. Of these, primary choriocarcinoma of the urinary bladder is one of the most uncommon and its histogenesis much discussed. It is important to identify this tumor type, since a change in the oncologic treatment may be warranted. We report an additional case of this rare bladder tumor with clinicopathologic study and discuss the histogenetic and therapeutic aspects.


Inflammasomes link vascular disease with neuroinflammation and brain disorders.
The role of inflammation in neurological disorders is increasingly recognised. Inflammatory processes are associated with the aetiology and clinical progression of migraine, psychiatric conditions, epilepsy, cerebrovascular diseases, dementia and neurodegeneration, such as seen in Alzheimer's or Parkinson's disease. Both central and systemic inflammatory actions have been linked with the development of brain diseases, suggesting that complex neuro-immune interactions could contribute to pathological changes in the brain across multiple temporal and spatial scales. However, the mechanisms through which inflammation impacts on neurological disease are improperly defined. To develop effective therapeutic approaches, it is imperative to understand how detrimental inflammatory processes could be blocked selectively, or controlled for prolonged periods, without compromising essential immune defence mechanisms. Increasing evidence indicates that common risk factors for brain disorders, such as atherosclerosis, diabetes, hypertension, obesity or infection involve the activation of NLRP3, NLRP1, NLRC4 or AIM2 inflammasomes, which are also associated with various neurological diseases. This review focuses on the mechanisms whereby inflammasomes, which integrate diverse inflammatory signals in response to pathogen-driven stimuli, tissue injury or metabolic alterations in multiple cell types and different organs of the body, could functionally link vascular- and neurological diseases and hence represent a promising therapeutic target.


Characteristics of the injuries of Syrian refugees sustained during the civil war.
During a war, many civilians are severely injured by firearms, bombs, and shrapnel. The triage of war injuries involves difficult and complicated processes requiring surgical procedures and patient monitoring in the Intensive Care Unit (ICU) of hospitals. In this study, we examine the demographic, traumatic, and critical care characteristics of cases injured during the civil war in Syria and requiring emergency surgery. Electronic data of the traumatic, surgical, and ICU monitoring features of 707 patients admitted to Kilis Public Hospital between March 2012 and January 2013 were analyzed retrospectively RESULTS: Most of the patients reported having been injured due to firearms (83.75%). Of the 707 cases studied in this work, 93.2% was male. Male patients reported a mean age of 26.1±12.1 years, while pediatric cases reported a mean age of 11.7±3.41 years. The most frequently injured region of the body was the head-neck region (52.7%). The New Injury Severity Score (NISS) of the cases was 42.5±11.2 and their American Society of Anesthesiologists (ASA) score was 3.2±0.7. The number of cases with intraoperative exitus was 7, while the number of cases who had undergone damage control surgery was 204. The number of cases hospitalized in the ICU during the postoperative period was 233, and the average hospitalization duration in the ICU was 4.67±1.32 days. Among survivor patients, the first 24-hour invasive measurements (i.e., pH, hemoglobin, body temperature, and mean arterial blood pressure) and international normalized ratio were found to be high. The number of blood products used for surviving patients was fewer relative to that used for non-surviving patients, and these NISS of these patients was 29.7±10.1. The mortality rate of all patients followed up in the ICU after emergency surgery was 45%, and neurosurgical cases showed the lowest level of survival (24.1%). The results of this study indicated that head-neck, chest-abdomen, and multiple body injuries are the most widely seen among civilians brought to Turkey because of gunshot injuries sustained during the Civil War in Syria. The number of emergency operations performed in the study sample was high, and critical care follow-up durations were long. In addition, the NISS and ASA scores of mortal cases were fairly high.


[Zonisamide and neuropathic pain].
In neuropathic pain, as occurs in epilepsy, researchers are striving to find a drug capable of inhibiting the pain-generating ectopic discharges that are produced as a result of neuronal hyperexcitability. This is mediated by ionic exchanges across the channels of the synaptic membrane. This is why the drugs that act on the different types of channels involved in this transmission can regulate neuronal hyperexcitability and therefore have an effect on the pain. In recent years researchers have gained a deeper understanding of the mechanisms of action of antiepileptic drugs and, since the discovery of their action on one or several synaptic channels, the use of these agents to treat neuropathic pain has become increasingly common. Patients suffering from central pain are also beginning to benefit from the administration of these drugs, especially agents that have proved to be capable of acting with several mechanisms of action and on several channels at the same time. In addition, fewer and less severe side effects are produced, something that is fundamental if we bear in mind the characteristics of patients with central pain, most of whom are adults and elderly. This, together with the fact that there are fewer interactions with other drugs, has led to the new antiepileptic drugs' becoming the preferred medication for this pathology today. Zonisamide acts on several types of channels and it is known to have four different mechanisms of action, which means it can be effective in treating these patients, although further studies are required (above all randomised double-blind trials) in order to really evaluate the usefulness of these drugs in the treatment of neuropathic pain.


Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for quantification of SR1001, an inverse agonist of retinoid-related orphan receptors, and its application to pharmacokinetic studies in streptozotocin-induced diabetic mice.
Retinoic acid receptor-related orphan receptors (RORs) play critical roles in the onset and progression of type I diabetes, an autoimmune disease characterized by the destruction of pancreatic β-cells. SR1001, an ROR inverse agonist, has been proven to be an effective diabetes treatment in the non-obese diabetic (NOD) mouse model. However, optimization of this treatment is challenging because knowledge of SR1001 pharmacokinetic (PK) behaviors in type I diabetic animals is limited. The aim of our study was to develop and validate a specific and sensitive ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to measure the concentrations of SR1001 in plasma and biological samples. Using the developed UPLC-MS/MS method, SR1001 linearity ranges in biological matrices were determined to be 5-1000ng/mL, with correlation coefficients of >0.99. The limit of detection (LOD) and limit of quantification (LOQ) values of SR1001 were 1 and 5ng/mL, respectively. And the intra-day and inter-day variances were less than 10%, and accuracy was within 90%-110%. The extraction recoveries of SR1001 were ≥80%, and no significant matrix effect was observed. Using the validated UPLC-MS/MS method, levels of SR1001 in plasma and six major organs (heart, liver, spleen, lung, kidney, and brain) were determined in streptozotocin (STZ) -induced diabetic mice. The PK parameters of SR1001 were also calculated. The SR1001 drug concentration-time curves for organs and plasma showed similar trends, and the elimination half-lives of SR1001 in diabetic mice were about 12h. SR1001 was highly bound to plasma protein, resulting in a much higher maximum concentration (Cmax=144394ng/mL) and area under the concentration-time curve (AUC0-t=2728258ng/mL*h), but a low tissue/plasma partition coefficient (Kp) value of <0.3.


Risk factors of Non-fatal Unintentional Home Injuries among Children under 5 Years Old; a Population-Based Study.
In addition to the annual mortality rate, unintentional home injury may result in temporary or permanent disability and requires medical attention and continuous care in millions of children. This study aimed to explore features and risk factors of these injuries. In this cross-sectional study, demographic variables and epidemiologic pattern of home injuries among children under 5 years of age were collected via a population-based survey in seven main cities of Khuzestan province, southwest Iran, during September 2011 to December 2012. Developing a risk stratification model, independent risk factors of unintentional home injury were determined and put to multivariate logistic regression analysis. 2693 children with the mean age of 27.36 ± 15.55 months (1 to 60) were evaluated (50.9% boy). 827 (30.7%) cases had a history of at least one home injury occurrence since birth to study time. The most common injury mechanisms were burning with 291 (38.4%) cases, falling with 214 (28.3%) and poisoning with 66 (8.7%) cases, respectively. The independent risk factors of unintentional home injury were age ≥ 24 month (p<0.001), residency in Ahvaz city (p<0.001), mother's illiteracy (p<0.014), ethnicity (p<0.001), private housing (p=0.01), birth weight (p<0.001), and being the first child (p=0. 01). Sensitivity, specificity, and area under the ROC curve of the model designed by multivariate analysis were 53.5%, 84.8%, and 0.75 (95% CI: 0.73- 0.77; P < 0.001, figure 1), respectively. According to the findings of this study, 30.7% of the studied children were injured at least once since birth. Burning, falling, poisoning, swallowing objects, choking, and biting were the main home injury mechanisms. Age ≥ 24 months, being the first child, living in a private house, being a resident of Ahvaz city, and having an illiterate mother were found to be risk factors of home injury.


Clinical outcome in periradicular surgery: effect of patient- and tooth-related factors--a multicenter study.
To evaluate the effect of patient- and tooth-related factors on the outcome of apical surgery in a multicenter study. A total of 281 teeth in 255 patients undergoing periradicular surgery were investigated clinically and radiographically 6 to 12 months postoperatively. The overall success rate was 88.0%. Sex was a significant (P = .024) predictor, with a success rate of 89.8% in females and 84.0% in males. The success rate was significantly higher in patients 31 to 40 years of age. The treatment of premolars resulted in a significantly higher success rate (91.9%) than the treatment of anterior teeth (86.1%, P = .042) and molars (86.4 %, P = .026). The loss of the buccal bone plate and the extension of apical osteolysis to the furcation area in molars resulted in a considerably lower success rate. Lesion size, preoperative pain, tenderness to percussion, fistula, and resurgery were significant factors. There are several factors influencing the success rate of apical surgery that must be taken into account when considering apical surgery as a treatment alternative.


Slime capsule and fimbriae on Salmonella typhimurium var. cop.--electron microscopic study.
On Salmonella typhimurium var. cop. we found, under special culture conditions, on the same cell simultaneously fimbriae and mucoid material which was histochemically identified as an acid mucopolysaccharide. Membrane vesicles or invaginations of the cytoplasmic membrane are mentioned as a possible place of the slime production and the function of the glycocalyx is discussed regarding tenacity, as a diffusion barrier and attachment factor.


Effect of anxiolytic drug silexan on sleep - a narrative review.
Silexan is an orally administered, proprietary essential oil from Lavandula angustifolia with significant anxiolytic and sleep improving properties. Here we present a narrative review that provides an overview of the available evidence of the effects of silexan on sleep. We start with a summary of the pharmacological background and continue with presenting sleep-related results from controlled clinical trials with silexan. Then we report on a meta-analysis of item 'insomnia' from the Hamilton Anxiety Scale, which includes data from all randomised, placebo-controlled clinical trials with silexan in which the scale was administered. Finally, we summarise the results of a mediation analysis that was performed to elucidate the pathway of the effect of silexan on sleep. In randomised, placebo-controlled trials in patients suffering from anxiety disorders silexan had a significant anxiolytic effect and improved sleep along with recovery from anxiety. Mediation analysis demonstrates that more than 98% of the effect of silexan on sleep was mediated by its anxiolytic effect while the direct effect on sleep was marginal. Silexan improves sleep as a result of its anxiolytic effect.


A Fully Actuated Body-Mounted Robotic Assistant for MRI-Guided Low Back Pain Injection.
This paper reports the development of a fully actuated body-mounted robotic assistant for MRI-guided low back pain injection. The robot is designed with a 4-DOF needle alignment module and a 2-DOF remotely actuated needle driver module. The 6-DOF fully actuated robot can operate inside the scanner bore during imaging; hence, minimizing the need of moving the patient in or out of the scanner during the procedure, and thus potentially reducing the procedure time and streamlining the workflow. The robot is built with a lightweight and compact structure that can be attached directly to the patient's lower back using straps; therefore, attenuating the effect of patient motion by moving with the patient. The novel remote actuation design of the needle driver module with beaded chain transmission can reduce the weight and profile on the patient, as well as minimize the imaging degradation caused by the actuation electronics. The free space positioning accuracy of the system was evaluated with an optical tracking system, demonstrating the mean absolute errors (MAE) of the tip position to be 0.99±0.46 mm and orientation to be 0.99±0.65°. Qualitative imaging quality evaluation was performed on a human volunteer, revealing minimal visible image degradation that should not affect the procedure. The mounting stability of the system was assessed on a human volunteer, indicating the 3D position variation of target movement with respect to the robot frame to be less than 0.7 mm.


Rechallenge with EGFR-TKI after failure of immunotherapy is considered an effective treatment for advanced lung adenocarcinoma patients with EGFR exon 19 deletion: a case report.
In advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have an excellent and long-lasting therapeutic response; however, virtually all patients eventually develop drug resistance and experience disease progression. The use of immunotherapy after EGFR-TKIs may be a successful therapeutic option for individuals who are resistant to them. It is still unclear if EGFR-TKIs can be administered again after immunotherapy has failed. We describe a case of a 37-year-old woman who was found to have T4N3M1a stage IVa lung adenocarcinoma. Amplification refractory mutation system PCR (ARMS-PCR) genetic testing suggested EGFR exon 19 deletion. The patient was initially treated with a regimen of icotinib (125 mg tid) combined with anlotinib (8 mg qd d1-d14) with an optimal efficacy rating of partial response (PR) and was granted a PFS of 7 months. In second-line treatment, the patient received three cycles of a KN046 (KN046 is a bispecific antibody inhibitor of PD-L1 and CTLA-4) 295 mg d1, pemetrexed 800 mg d1, plus carboplatin 750 mg d1 regimen, with an optimal efficacy rating of stable disease (SD) on CT. The third-line therapy was chosen to be afatinib with docetaxel, and the patient was evaluated for PR on CT. Up to 15 August 2022, the patient had a progression free survival (PFS) of 14 months. The successful treatment of this patient is a reminder that EGFR-TKI rechallenge in EGFR exon 19 deletion patients with EGFR-TKI resistance, in which immunotherapy has failed, may be effective.


Case for persuasion in parental informed consent to promote rational vaccine choices.
There have been calls for mandatory vaccination legislation to be introduced into the UK in order to tackle the national and international rise of vaccine-preventable disease. While some countries have had some success associated with mandatory vaccination programmes, the Royal College of Paediatrics and Child Health (RCPCH) insist this is not a suitable option for the UK, a country which has seen historical opposition to vaccine mandates. There is a lack of comprehensive data to demonstrate a direct link between mandatory vaccination legislation and increased uptake. While there are examples whereby there has been an improvement, some studies suggest that comparable results can be obtained by strongly recommending vaccinations instead. The RCPCH insist that healthcare workers are ideally placed to engage and inform parents to make every interaction a 'vaccine opportunity'. This paper calls for a principled, rational approach to interpretations of autonomy which underpin parental informed consent. MacLean's concept of mutual persuasion could be a vehicle to ensuring parents are suitably informed of both the material risks associated with vaccine choices and to consider the rationality of their decisions, while ultimately upholding parental autonomy. It is argued that this, alongside infrastructural improvement, could create a more sustainable, long-term improvement in childhood vaccination rates in the UK than mandatory vaccination.


Host Carbon Dioxide Concentration Is an Independent Stress for Cryptococcus neoformans That Affects Virulence and Antifungal Susceptibility.
The ability of Cryptococcus neoformans to cause disease in humans varies significantly among strains with highly related genotypes. In general, environmental isolates of pathogenic species such as Cryptococcus neoformans var. grubii have reduced virulence relative to clinical isolates, despite having no differences in the expression of the canonical virulence traits (high-temperature growth, melanization, and capsule formation). In this observation, we report that environmental isolates of C. neoformans tolerate host CO2 concentrations poorly compared to clinical isolates and that CO2 tolerance correlates well with the ability of the isolates to cause disease in mammals. Initial experiments also suggest that CO2 tolerance is particularly important for dissemination of C. neoformans from the lung to the brain. Furthermore, CO2 concentrations affect the susceptibility of both clinical and environmental C. neoformans isolates to the azole class of antifungal drugs, suggesting that antifungal testing in the presence of CO2 may improve the correlation between in vitro azole activity and patient outcome.IMPORTANCE A number of studies comparing either patient outcomes or model system virulence across large collections of Cryptococcus isolates have found significant heterogeneity in virulence even among strains with highly related genotypes. Because this heterogeneity cannot be explained by variations in the three well-characterized virulence traits (growth at host body temperature, melanization, and polysaccharide capsule formation), it has been widely proposed that additional C. neoformans virulence traits must exist. The natural niche of C. neoformans is in the environment, where the carbon dioxide concentration is very low (∼0.04%); in contrast, mammalian host tissue carbon dioxide concentrations are 125-fold higher (5%). We have found that the ability to grow in the presence of 5% carbon dioxide distinguishes low-virulence strains from high-virulence strains, even those with a similar genotype. Our findings suggest that carbon dioxide tolerance is a previously unrecognized virulence trait for C. neoformans.


Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients.
The prevalence of apparent amiodarone-related hepatic injury in 104 patients followed prospectively is compared to that reported in the literature. Asymptomatic elevation of serum aminotransferase levels was detected in approximately one-fourth of the patients, a figure similar to the average of reported cases. The frequency of extrahepatic organ toxicity was increased in patients with elevated levels. Symptomatic "hepatitis" developed in 3% of this series and in less than 1% of cases in the literature. Evidence of hepatic phospholipidosis and the development of pseudoalcoholic liver injury is most likely due to the biochemical effects of the drug and to possible metabolic idiosyncrasy, respectively. Serial blood enzyme measurements, as recommended by the manufacturer, may offer some protection against the development of more serious liver injury. However, levels of amiodarone may persist in various tissues for weeks to months following withdrawal, and stopping the drug does not guarantee the prompt reversal of any organ toxicity. Accordingly, the risks posed and benefits offered by amiodarone should be carefully weighed prior to discontinuing the drug, as the risk of sudden cardiac death may outweigh the hazards of ongoing hepatic, pulmonary or other toxicity.