Influence of thyroid gland status on the thyroglobulin cutoff level in washout fluid from cervical lymph nodes of patients with recurrent/metastatic papillary thyroid cancer.
The influence of serum thyroglobulin (Tg) and thyroidectomy status on Tg in fine-needle aspiration cytology (FNAC) washout fluid is unclear. A total of 282 lymph nodes were prospectively subjected to FNAC, fine-needle aspiration (FNA)-Tg measurement, and frozen and permanent biopsies. We evaluated the diagnostic performance of several predetermined FNA-Tg cutoff values for recurrence/metastasis in lymph nodes according to thyroidectomy status. The diagnostic performance of FNA-Tg varied according to thyroidectomy status. The optimized cutoff value of FNA-Tg was 2.2 ng/mL. However, among FNAC-negative lymph nodes, the FNA-Tg cutoff value of 0.9 ng/mL showed better diagnostic performance in patients with a thyroid gland. An FNA-Tg/serum-Tg cutoff ratio of 1 showed the best diagnostic performance in patients without a thyroid gland. Applying the optimal cutoff values of FNA-Tg according to thyroid gland status and serum Tg level facilitates the diagnostic evaluation of neck lymph node recurrences/metastases in patients with papillary thyroid carcinoma (PTC). © 2015 Wiley Periodicals, Inc. Head Neck 38: E1705-E1712, 2016.


Establishment of hydrolysis probe system real-time PCR assay for rapid detection of canine circovirus.
In the study, we established a hydrolysis probe-based real-time polymerase chain reaction (PCR) assay to rapidly detect Canine circovirus (CanineCV) DNA in faecal samples. We designed a pair of specific primers and one probe targeting Rep in CanineCV, and sensitivity, specificity, and repeatability tests were performed to evaluate the efficacy of the assay. The assay showed high sensitivity and a minimum detection limit of 8.42 × 101 copies/μL, which is 1000-fold more sensitive compared to traditional PCR. The method was also highly specific, without cross-reaction with other common canine viruses. Moreover, the assay showed high repeatability, and the mean intra-assay and inter-assay coefficients of variation were 0.26 and 0.36%, respectively. The results of the detection of clinical samples showed that the positive detection rate of CanineCV was 14.04% (8/57). Notably, 8% of clinical samples were co-infected with other canine pathogens. In conclusion, the establishment of a hydrolysis probe-based real-time PCR method provides a fast, sensitive, specific, reliable, and repeatable method for CanineCV detection. The online version contains supplementary material available at 10.1007/s13205-021-03031-z.


An analysis of the anatomical basis for the mechanical response to motor nerve stimulation of the rat vas deferens.
1. An anatomical basis was sought for the biphasic motor nerve response of the rat vas deferens. The motor nerve pathway to the tissue was stimulated at different points between the vertebral outflow and the intramural fibres, in the pithed rat and in isolated tissues, to examine the possibility of two anatomically separate groups of neurones. Different preparations of the isolated tissue were devised to detect whether different groups of smooth muscle fibres contributed to the two phases.2. The fibres mediating both phases of the response arose from the upper lumbar vertebral outflows. Both phases were elicited by pre- or post-ganglionic stimulation and could be depressed by hexamethonium. In the pithed rat or with hypogastric nerve stimulation in the isolated tissue, however, the initial ;twitch' phase was relatively resistant to such blockade.3. When the rat vas deferens was perfused through the lumen in situ or in vitro, the perfusion pressure response to motor nerve stimulation exhibited two phases similar to those of the longitudinal contractile response.4. Isolated rat vasa were bisected into portions, each of which was stimulated and longitudinal tension was recorded. The proportions of the two phases of the response varied along the length of the tissue. At the prostatic end the total response was relatively weak with a dominant ;twitch' and at the epididymal end the two phases were comparable in magnitude. The distribution of adrenergic nerve terminals within the muscle layers also varied along the length of the rat vas deferens.5. The effects of drugs were investigated on the motor responses of the above preparations. The ;twitch' phase was relatively susceptible to blockade by reserpine and lysergic acid diethylamide and the ;secondary' phase to phentolamine with both equally sensitive to guanethidine. Each phase had similar susceptibilities to blockade irrespective of which part of the tissue was involved.6. It was concluded that two types of nerve-muscle transmission may be involved in the rat vas deferens with the proportion of each varying along the length of the tissue but both displaying pharmacological characteristics of adrenergic fibres.


Quantitative analysis of lidocaine hydrochloride delivery by diffusion across tissue expander membranes.
Permeability of Silastic tissue expander shells to lidocaine was studied to investigate the feasibility of intraluminal lidocaine injection for pain relief during soft-tissue expansion. Both intact expanders and an apparatus using isolated Silastic membrane segments were used to partition solutions of various lidocaine concentrations, and the rate of diffusion was quantitatively measured using a fluorescence polarization immunoassay. Lidocaine flux was found to follow Fick's law of passive diffusion with respect to time, surface area, and concentration gradient for the first 9 hours, with a permeability coefficient of 10.3 +/- 2.6 micrograms (h.cm2.percent)-1 (mean +/- SD) and diffusion coefficient of 7.5 x 10(-7) cm2/min for an average membrane thickness of 473 +/- 23 microns. After 9 hours, the lidocaine flux decreased exponentially, although the concentration gradient across the membrane remained essentially the same order of magnitude. Plasma proteins in the outer bathing solution and methylparaben used as a preservative in the standard lidocaine formulation had no influence on the change in transport flux with time. At the end of the linear portion of the diffusion curve, less than 2 percent of the total intraluminal lidocaine had crossed the membrane. Potential toxicity in the event of implant rupture limits the maximum total lidocaine dose to approximately 500 mg within an expander at any one time. Within these limits, the capacity for lidocaine delivery of 500 mg lidocaine by a 640-cc tissue expander would be only 6 mg during the first 9 hours after administration.(ABSTRACT TRUNCATED AT 250 WORDS)


Conditioning to time: evidence for a role of hippocampus from unit recording.
Unit activity of the dorsal hippocampus was recorded in partially restrained but awake and undrugged rats during a "conditioning to time". In this type of conditioning, only one stimulus, the equivalent of the unconditioned stimulus of the usual procedures, is used. It is delivered at a constant interval which, in principle, is the conditioned stimulus. In our experiments, the unconditioned stimulus was a mechanical stimulation of a vibrissa; two successive unconditioned stimuli were separated by a 24-s interval. In 11/18 rats, anticipatory movements of a "trained" vibrissa developed at the end of the interstimulus interval. In a number of cases, in parallel to this conditioned behavior, there was a significant change in unit activity, either an increase or a decrease, during the last third of the interstimulus interval. Controls showed that these changes in unit activity did not merely reflect modifications of arousal state or of vibrissa and body movements. From autocorrelograms, it appeared that anticipatory increases in unit activity were associated with the development of a bursting mode of discharge. These data constitute one of the rare examples of a neurophysiological correlate of a "conditioning to time" at the unit level and the first recorded from the dorsal hippocampus of rats.


A generalized physiological hyperreactivity to acute stressors in hypertensives.
Hypertensives have consistently been found to have a more reactive cardiovascular system than normotensives. In the present study, it was examined whether this enhanced cardiovascular stress reactivity generalizes to the hypothalamus-pituitary-adrenal (HPA) axis and the immune system. Forty-two unmedicated hypertensives and 21 normotensive controls performed five passive coping and active coping stressful tasks in the laboratory. In addition to the expected greater mean diastolic blood pressure reactivity to the tasks, hypertensives exhibited enhanced (baseline corrected) task salivary cortisol and secretory immunoglobulin A (S-IgA) levels. Moreover, correlations were found between blood pressure responses and task related cortisol activity and between baseline blood pressure levels and task-induced S-IgA levels. These results indicate that hypertensives not only have a hyperreactive cardiovascular system, but also an enhanced HPA axis and immune system reactivity to stress. A central stress mechanism may be responsible for the heightened generalized stress response in hypertensives.


Effects of coenzyme Q10 supplementation on lipid profiles and liver enzymes of nonalcoholic fatty liver disease (NAFLD) patients: A systematic review and meta-analysis of randomized controlled trials.
As an antioxidant, coenzyme Q 10 (CoQ10) has been proposed as a possible treatment for non-alcoholic fatty liver disease (NAFLD). In the present meta-analysis, we aimed to determine the effects of CoQ10 supplementation on lipid profiles and liver enzymes of NAFLD patients. We searched PubMed, Web of Science, Scopus, and Cochrane Library on 21 April 2022 to retrieve randomized controlled trials on NAFLD patients in which CoQ10 was utilized as a treatment. Data were pooled using the random-effects model and weighted mean difference (WMD) was considered as the summary effect size. The analysis of the six included studies indicated an overall non-significant decrease in the lipid profiles (total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG)), and liver enzymes (aspartate transaminase (AST), alanine transaminase (ALT), and gamma-glutamyltransferase (GGT)) of NAFLD patients who received CoQ10. Sensitivity analysis using "leave-one out" method showed a significant reduction in AST, and GGT after excluding certain studies. Also, subgroup analyses showed significant difference based on CoQ10 dose for TC, AST, and GGT, and also a significant decrease in AST based on the duration of the intervention. No publication bias was found between the studies. Although an overall non-significant decrease was observed in lipid profiles and liver enzymes of NAFLD patients, the results of sensitivity and subgroup analyses showed significant effects of CoQ10 in certain conditions. Further RCTs should be done in light of our findings.


Indium 111 leucocyte scintigraphy in abdominal sepsis. Do the results affect management?
We have studied the clinical utility of indium 111 autologous leucocyte scintigraphy retrospectively in 45 patients presenting with suspected intra-abdominal sepsis. The sensitivity was 95% (21/22) and the specificity was 91% (21/23). Some 34 of the studies (17 positive and 17 negative) were considered helpful in furthering patient management (76%) and 8, unhelpful (18%). In 3, the study results were misleading and led to inappropriate treatment. Indium 111 scintigraphy, whether positive or negative, provides information in patients with suspected intra-abdominal sepsis upon which therapeutic decisions can be based.


Autoantibodies to coagulation factors: from pathophysiology to diagnosis and therapy.
Autoantibodies may develop against coagulation factors altering their function or promoting their rapid clearance. In non-congenitally deficient patients, they are usually in association with autoimmune diseases, malignancies, pregnancy or advanced age. The possible development of coagulation factor autoantibodies should be considered when a patient presents with bleeding symptoms without any prior bleeding diathesis. The most common disorder associated with coagulation factor autoantibodies is acquired factor VIII deficiency, which is characterized by hemorrhages involving soft tissues, muscles and skin; hemarthroses are less frequent than in the inherited form. Acquired deficiencies of von Willebrand factor and factor XIII due to autoantibodies are emerging conditions. Autoantibodies to the other coagulation factors may be associated with a wide spectrum of clinical manifestations ranging from minimal or no bleeding to life-threatening conditions. The diagnostic approach begins with global coagulation tests: prothrombin time (PT) and activated partial thromboplastin time (aPTT). In case of prolonged times, mixing studies (typically using normal plasma in a 1:1 proportion) should be performed. Specific factor and inhibitor assays, assessment of lupus anticoagulant and eventually enzyme immunoassays for specific anti-factor antibodies complete the evaluation. A prompt diagnosis of specific coagulation factor inhibitors is mandatory for starting an appropriate treatment aimed at overcoming the deficient factor, in case of bleeding, and, if possible, at the suppression of the autoantibody's production.


Comparison of six immunohistochemical markers for the histologic diagnosis of neoplasia in Barrett's esophagus.
In esophageal neoplasms, the histopathologic differentiation between Barrett's esophagus with or without intraepithelial neoplasia and adenocarcinoma is often challenging. Immunohistochemistry might help to differentiate between these lesions. The expression of CDX2, LI-cadherin, mucin 2 (MUC2), blood group 8 (BG8, Lewis(y)), claudin-2, and villin was investigated in normal gastroesophageal (n = 23) and in Barrett's (n = 17) mucosa, in low-grade (n = 12) and high-grade (n = 9) intraepithelial neoplasia (IEN) as well as in esophageal adenocarcinoma (n = 16), using immunohistochemistry. For CDX2 and LI-cadherin, the immunoreactivity score was highest in IEN while for MUC2, BG8, and villin, it dropped gradually from Barrett's via IEN to adenocarcinoma, and expression of Claudin-2 was only weak and focal in all lesions. The expression of MUC2 and LI-cadherin differed significantly between all examined lesions except between low-grade and high-grade IEN. MUC2 and LI-cadherin are useful immunohistochemical markers for the differentiation between normal glandular mucosa, Barrett's mucosa, IEN, and invasive carcinoma of the esophagus; however, none of the examined markers was helpful for the differentiation between low-grade and high-grade IEN.


Learning to Manage Chronic Pain: The Patients' Perspective.
The objective of the present study was to gain insight into patients' experiences in a 4-week interdisciplinary chronic pain management program by determining major themes from patients' written comments on exit questionnaires. Upon completion of the program at the Chronic Pain Management Unit (CPMU), patients fill out program satisfaction (Pain Program Satisfaction Questionnaire) and evaluation of goal accomplishment (Self-Evaluation Scale) forms, sections of which are open-ended. Questionnaire data from 50 patients, admitted into the CPMU between May 2013 and December 2014, were randomly selected for this study. Written responses to open-ended sections were obtained. Comments were stratified by gender and coded using an inductive approach. Codes were grouped into categories which were further combined into several major themes. Six main themes extracted from comments were (1) impact of a strong interdisciplinary team, (2) learning to adapt in order to manage, (3) the Program as a stepping stone, (4) positive effects of a group effort, (5) improved mental health, and (6) benefits of the program. The results of this analysis reinforce the effectiveness of the interdisciplinary CPMU program at improving patients' quality of life. Findings may assist in the promotion of the program to stakeholders such as referral sources. The outcomes may also assist in the development of future programs that have similar goals. Concerns that arise within patients' comments may assist clinicians in this program to make adjustments such that all unique needs are met.


Severe cochlear inflammation and vestibular syndrome in an experimental model of Streptococcus suis infection in mice.
Hearing impairment is a common and frequently permanent sequel of Streptococcus suis meningitis in humans. Nevertheless, mechanisms underlying the development of cochlear damage have not been addressed so far. In the present work, we characterized a mouse model of suppurative labyrinthitis and meningitis induced by a systemic infection with S. suis and studied the impact of the injected bacterial dosage on the progression of such inflammatory events. We observed that high infection doses of bacteria lead to sustained bacteremia, with an increase in the permeability of the blood-labyrinth and blood-brain barriers, causing suppurative labyrinthitis and meningitis, respectively. However, in mice infected with a low dose of S. suis, bacteria disappeared quickly from blood, hence, cochlear inflammation and meningitis were not consistent features. This model of S. suis infection seems ideal to evaluate novel drugs that may help alleviate the negative consequences of such important sequelae of S. suis-induced meningitis and labyrinthitis.


Effects of inhaled prostacyclin as compared with inhaled nitric oxide on right ventricular performance in hypoxic pulmonary vasoconstriction.
Recently, inhalation of prostacyclin (PGI2) has been shown to cause selective pulmonary vasodilation. However, the effects of inhaled PGI2 on right ventricular (RV) performance are still unknown and therefore were compared with those of inhaled nitric oxide (NO). Reported measurements design. Animal research laboratory. Six anesthetized, ventilated dogs (28 +/- 2 kg). Pulmonary hypertension was induced by decreasing FIO2 to 0.09-0.11 ('hypoxic pulmonary vasoconstriction', HPV). Subsequently, a single dose of either NO (50 ppm) or PGI2-aerosol (0.9 +/- 0.3 ng/kg/min) was randomly added to the inspired gas. Measurements were performed before induction of HPV and 10 minutes after application and withdrawal of each drug. Central hemodynamics, global RV function, and local RV function (n = 5, sonomicrometry) were assessed. HPV resulted in an increase of pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), RV stroke work, right coronary artery flow, maximal rate of RV pressure increase (RV dP/dtmax), and maximal velocity of shortening of contractile elements (Vmax). In contrast, RV ejection fraction, RV end-diastolic volume, RV end-diastolic fiber length, and systolic fiber shortening were unchanged. Both PGI2-aerosol and NO attenuated the HPV-induced increase in PAP and PVR without affecting arterial pressure. NO, but not PGI2, resulted in an increase of RV ejection fraction from 42 to 46% (p < 0.05). Right coronary flow dropped from 29 to 21 mL/min during PGI2 (p < 0.05). RV stroke work, RV dP/dtmax, and Vmax decreased subsequent to both NO and PGI2, whereas local RV function was not affected. In pulmonary hypertension induced by HPV, PGI2-aerosol and inhaled NO reduced RV afterload and, hence, RV oxygen demand, with only minor changes of stroke volume and cardiac output, indicating an improvement of overall efficiency of RV contraction. RV ejection fraction increased on NO, but not with PGI2. This might be explained by the fact that the reduction of pulmonary vascular resistance during PGI2 amounted to only 65% of the effect of NO. In summary, both inhaled NO and PGI2-aerosol showed beneficial effects on RV performance and may prove helpful in the treatment of acute pulmonary hypertension.


Gastrointestinal medications and procedures in osteoarthritis patients treated with rofecoxib compared with nonselective NSAIDs.
Patients treated with nonselective cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) often experience dyspepsia and upper gastrointestinal (GI) adverse effects, and frequently require GI comedications and diagnostic procedures. This study combined existing data to test the hypothesis that GI comedications and GI diagnostic procedures occur less frequently in osteoarthritis (OA) patients treated with rofecoxib compared with nonselective NSAIDs. Combined analysis of 8 randomized controlled clinical trials. Rheumatology and general practice clinics. Men and women aged 40 years and older with OA. Random assignment to placebo (n = 514), rofecoxib (n = 3357; 12.5, 25, or 50 mg daily combined; average 24.7 mg), or NSAIDs (n = 1564; ibuprofen 800 mg thrice daily, diclofenac 50 mg thrice daily, or nabumetone 1500 mg daily, combined). The cumulative incidence of patients using GI comedications (antacids, antispasmodics, antiflatulents, antiregurgitants, H2 antagonists, proton pump inhibitors, sucralfate, prostaglandins, other antiulcer therapy) and needing GI procedures (upper GI barium studies, upper or lower GI endoscopies) over 12 months. Compared with those treated with NSAIDs, patients treated with rofecoxib had a significantly lower incidence of GI comedication use (17.5% vs 27.0%, P <.001) and GI procedures (3.3% vs 5.3%, P =.02) over 12 months. Similar results were seen in analyses of protocols with placebo; in these studies, rates of GI comedications and procedures were highest with NSAIDs, while those with rofecoxib and placebo were similar to each other. OA patients treated with rofecoxib for up to 12 months required significantly less GI comedication and significantly fewer GI procedures than those treated with NSAIDs.


A retrospective study of juvenile chronic arthritis.
During a 20 year period 214 patients had been admitted to a teaching hospital with a diagnosis of definite or possible juvenile chronic (rheumatoid) arthritis (JCA). Eighty-seven of these patients were reviewed clinically and were classified as having had JCA. Twelve of the 214 patients were later thought to have had rheumatic fever, while 12 had had an illness consistent with viral arthritis. There was a poor functional outcome in three subgroups of JCA: (i) seropositive polyarticular onset (ii) systemic onset, and (iii) pauciarticular onset, extending to polyarticular involvement. The prevalence of inflammatory eye disease was very low with no significant visual handicap detected in patients in this study.


Post-transcriptional regulation of glutamyl-prolyl-tRNA synthetase in rat salivary gland.
Treatment of rats with isoproterenol resulted in elevated levels of prolyl- and glutamyl-tRNA synthetase activities in the parotid and submandibular glands. This increase in enzyme activity was accompanied by an increase in the bi-functional glutamyl-prolyl-tRNA synthetase and of a low molecular weight form of prolyl-tRNA synthetase. Isoproterenol also induced the synthesis of proline-rich glycoproteins in the parotid and submandibular glands. Withdrawal from the drug was accompanied by a decline in prolyl- and glutamyl-tRNA synthetase activities and by a decline in the levels of proline-rich glycoproteins in the salivary gland. During the time course of isoproterenol treatment, little change in the levels of mRNA encoding the bi-functional glutamyl-prolyl-tRNA synthetase was detected by Northern blot analysis. These results indicate that the synthesis of glutamyl-prolyl-tRNA synthetase is regulated at a post-transcriptional step and that the synthesis of this bifunctional protein may be linked to the utilization of proline and glutamic acid in protein synthesis.


Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells.
The mycotoxin alternariol (AOH) is found in food and beverages infected by Alternaria alternata. Because consumption of foodstuffs contaminated with A. alternata has been implicated in an elevated incidence of esophageal carcinogenesis, we have investigated the estrogenic potential, the effect on cell proliferation, and the genotoxic effect of AOH in cultured mammalian cells. AOH replaced E2 from isolated human estrogen receptors alpha and beta and increased the level of alkaline phosphatase (ALP) mRNA and the enzymatic activity of ALP in a human endometrial adenocarcinoma cell line (Ishikawa cells). The estrogenicity of AOH was about 0.01% of that of E2. The effects in Ishikawa cells were reversed by the ER antagonist ICI 182,780. Analysis of cell proliferation by flow cytometry and microscopy of Ishikawa and Chinese hamster V79 cells revealed that AOH inhibited cell proliferation by interference with the cell cycle. The genotoxic potential was assessed by the micronucleus (MN) assay and immunochemical differentiation between MN containing whole chromosomes (kinetochore-positive) and DNA fragments (kinetochore-negative) in Ishikawa and V79 cells. AOH induced kinetochore-negative MN in both cell lines. This is the first report on the estrogenic potential, inhibition of cell proliferation and clastogenicity of AOH in Ishikawa and V79 cells in vitro.


A gamma camera system for atraumatic rCBF measurement using a new super high sensitivity collimator.
The purpose of this study is to develop a useful gamma camera system for atraumatic rCBF measurement by the 133Xe intravenous injection (i.v.) method. A super high sensitivity slant hole (SHS-SL) collimator was designed for this purpose. The gamma camera used with this collimator was able to move close to the patient's head and obtain satisfactory count rates (130 kcpm-178 kcpm in a hemisphere) with a low dosage (10 mCi) of 133Xe. To validate this rCBF measurement system three studies were carried out: a comparative evaluation was performed against the flow values with the intracarotid 133Xe injection (i.c.) method, reproducibility of flow values was assessed from two serial i.v. measurements, and flow values were compared with clinical severity of the patients. The comparative study showed good correlation in the hemispheric and regional values between the two methods; r values 0.98 and 0.64-0.93 for gray matter flow and 0.96 and 0.78-0.93 for initial slope index. In the reproducibility study, the variation coefficients in the hemispheric and regional values between the two serial measurements were 5.0% and 7.3%-14.2% for gray mater flow, 5.2% and 7.9%-12.9% for initial slope index. The reproducibility in this study was as good as those with the i.c. method reported previously. The hemispheric flow values from our gamma camera system correlated well with the clinical severity of cerebrovascular disease. These results show that the gamma camera system with the SHS-SL collimator is useful for atraumatic rCBF measurement.


Imbalanced cholesterol metabolism in Alzheimer's disease.
Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease that is mainly caused by β-amyloid accumulation. A large number of studies have shown that elevated cholesterol levels may perform a function in AD pathology, and several cholesterol-related gene polymorphisms are associated with this disease. Although numerous studies have shown the important function of cholesterol in AD pathogenesis and development, the underlying mechanism remains unclear. To further elucidate cholesterol metabolism disorder and AD, we first, review metabolism and regulation of the cholesterol in the brain. Second, we summarize the literature stating that hypercholesterolemia is one of the risk factors of AD. Third, we discuss the main mechanisms of abnormal cholesterol metabolism that increase the risk of AD. Finally, the relationships between AD and apolipoprotein E, PCSK9, and LRP1 are discussed in this article.


Survival Implications of Variation in the Thoroughness of Pathologic Lymph Node Examination in American College of Surgeons Oncology Group Z0030 (Alliance).
Accurate pathologic nodal staging mandates effective collaboration between surgeons and pathologists. The American College of Surgeons Oncology Group Z0030 trial (ACOSOG Z0030) tightly controlled surgical lymphadenectomy practice but not pathologic examination practice. We tested the survival impact of the thoroughness of pathologic examination (using the number of examined lymph nodes as a surrogate). We re-analyzed the mediastinal lymph node dissection arm of ACOSOG Z0030, using logistic regression and Cox proportional hazards models. Of 513 patients, 435 were pN0, 60 were pN1, and 17 were pN2. The mean number of mediastinal lymph nodes examined was 13.5, 13.1, and 17.1; station 10 lymph nodes were 2.4, 2.7, and 2.6; station 11 to 14 nodes were 4.6, 6.1, and 6.7; and total lymph nodes were 19.7, 21.3, and 25.4 respectively. The pN category and histologic evaluation were associated with increased number of examined intrapulmonary lymph nodes. Patients with pN1 had more non-hilar N1 nodes than patients with pN0, patients with N2 had more N2 nodes examined than patients with pN0 or pN1. Patients with pN0 had better survival with examination of more N1 nodes; patients with pN1 had better survival with increased mediastinal nodal examination; the likelihood of discovering N2 disease was significantly associated with increased examination of mediastinal and non-hilar N1 lymph nodes. Despite rigorously standardized surgical hilar/mediastinal lymphadenectomy, the number of lymph nodes examined was associated with the likelihood of detecting nodal metastasis and survival. This may indicate an effect of incomplete pathologic examination.


Potassium/magnesium depletion in patients with cardiovascular disease.
Diuretic-induced deficiencies in potassium and magnesium can have significant implications for patients with cardiovascular disease. Hypokalemia, found in up to 50 percent of patients receiving thiazide therapy, is associated with a greater frequency of serious arrhythmias and increased mortality in patients with acute myocardial infarction. Hypomagnesemia has been identified in 42 percent of patients with hypokalemia, and below normal muscle magnesium levels have been found in 43 percent of congestive heart failure patients receiving diuretics. Magnesium is important for maintenance of cell potassium, and infusions of magnesium alone have increased muscle potassium and magnesium levels and significantly decreased the frequency of ventricular ectopic beats. It has been shown that both potassium and magnesium are conserved by potassium-sparing agents. Because serum and tissue magnesium levels are not correlated and correlations for potassium levels are weak, prevention of these electrolyte abnormalities is advised.


Pregnancy in formerly type 2 diabetes obese women following biliopancreatic diversion for obesity.
This study describes the pregnancy of previously obese women with type 2 diabetic who reduced body weight and normalized serum glucose level following biliopancreatic diversion (BPD) for obesity. A subset of ten women who had type 2 diabetes prior to BPD and who developed pregnancy after the operation was retrospectively identified. All pregnancies were completely normal, and serum glucose levels remained within the physiological range throughout all the pregnancy. These post-diabetic women delivered 13 infants in good health with a normal birth weight and no case of macrosomia. These data are a clinical confirmation of the post-BPD improvement of beta-cell response to increased functional demand in obese patients with preoperative type 2 diabetes.


A Non-randomized, Quasi-Experimental Comparison of Effects Between an In-person and Online Delivery of a College Mental Health Literacy Curriculum.
Mental health literacy (MHL) training is essential in college environments. These programs are commonly delivered in-person via workshops or for-credit courses. Campuses now seek high-quality online options. We compare the effectiveness of a for-credit MHL course against a comparison course, focusing on whether online asynchronous delivery was as effective as in-person synchronous delivery. This quasi-experimental pretest/posttest treatment/comparison study included 1049 participants across five semesters (pre-COVID-19) who were 18 years or older and self-selected enrollment in a Mental Health Awareness and Advocacy (MHAA) course (treatment; n = 474) or a general lifespan development course (comparison; n = 575). Using linear mixed effect modeling, changes in MHL were compared across groups and across online/in-person modalities. Students in the treatment group significantly increased their MHL knowledge (β Identifying = .49, p < .001; β Locating = .32, p < .001; β Responding = .46, p < .001) and self-efficacy (β = .27, p < .001), and treatment effects did not differ across modalities. With increased concern regarding mental health issues of isolated college students during the COVID-19 pandemic, this study supports the efficacy of delivering MHL courses online.


The cumulative disadvantage of unemployment: Longitudinal evidence across gender and age at first unemployment in Germany.
Unemployment is an important predictor of one's future employment success. Yet, much about the endurance of unemployment effects on workers' careers remains poorly understood. Our study complements this knowledge gap by examining the rate of recovery in the quality of careers following an unemployment spell among a representative sample of previously unemployed workers with different socio-demographic characteristics in Germany. We apply a new dynamic measure that quantifies the quality of binary sequences, distinguishing between "good" (i.e., employment) from "bad" labor force status activities (i.e., unemployment and inactivity). We use longitudinal data from the German Socio-Economic Panel (GSOEP) before the Great Financial Recession over the period 1984-2005 and deploy a series of hybrid models that control for unobserved heterogeneity. We find a non-linear recovery process after unemployment across gender and age groups. That is, after a period of recovery, career quality worsens. Least impacted are men experiencing unemployment when aged between 25-34 years, while men 55-66 have rather stable, though stronger, penalties. Furthermore, we find that recovery processes are contingent upon when respondents experience unemployment.


Restoration of single-channel currents using the segmental k-means method based on hidden Markov modeling.
Patch-clamp recording provides an unprecedented means for study of detailed kinetics of ion channels at the single molecule level. Analysis of the recordings often begins with idealization of noisy recordings into continuous dwell-time sequences. Success of an analysis is contingent on accuracy of the idealization. I present here a statistical procedure based on hidden Markov modeling and k-means segmentation. The approach assumes a Markov scheme involving discrete conformational transitions for the kinetics of the channel and a white background noise for contamination of the observations. The idealization is sought to maximize a posteriori probability of the state sequence corresponding to the samples. The approach constitutes two fundamental steps. First, given a model, the Viterbi algorithm is applied to determine the most likely state sequence. With the resultant idealization, the model parameters are then empirically refined. The transition probabilities are calculated from the state sequences, and the current amplitudes and noise variances are determined from the ensemble means and variances of those samples belonging to the same conductance classes. The two steps are iterated until the likelihood is maximized. In practice, the algorithm converges rapidly, taking only a few iterations. Because the noise is taken into explicit account, it allows for a low signal/noise ratio, and consequently a relatively high bandwidth. The approach is applicable to data containing subconductance levels or multiple channels and permits state-dependent noises. Examples are given to elucidate its performance and practical applicability.


Swallow Magnetic Resonance Imaging Compared to 3D-Computed Tomography for Pouch Assessment and Hiatal Hernias After Roux-en-Y Gastric Bypass.
Weight regain and weight loss failure after bariatric surgery are important issues that may require a weight regain procedure. Three-dimensional-computed tomography (3D-CT) is a well-established method allowing exact measurements of pouch volume. The aims of this study were to prove the applicability of swallow MRI as a non-ionizing procedure and compare it to 3D-CT in patients after weight regain procedures following RYGB. Twelve post-RYGB patients who had a follow-up operation for weight regain before 12/2017 were included in this prospective study. Swallow MRI and 3D-CT were performed in each patient to evaluate the size of the anastomosis, pouch volume, and intrathoracic pouch migration (ITM). Mean pouch volume in swallow MRI and 3D-CT were 40.4 ± 21.0 ml and 43.5 ± 30.2 ml, respectively (p = 0.83), and pouch diameter at the maximal distention was 35.3 ± 5.9 ml (MRI) and 31.0 ± 10.0 ml (CT) (p = 0.16). The rate of ITM was 75% in both examinations (p = 1.0). Swallow MRI is a valid method for the assessment of pouch volume in different phases of the swallowing process and is comparable to 3D-CT. The diagnosis of ITM using swallow MRI was equal to 3D-CT.


Ecological studies on the solitary ectoparasitoid Dirhinus wohlfahrtiae Ferriere (Hymenoptera: Chalcididae).
While Dirhinus wohlfahrtiae was abundant at the moderate weather, it could not be recovered during winter months. The life cycle required 22.86 days at 25 +/- 2 degrees C and 65 +/- 5% R.H., longevity of adult males and females was equal to 35.78 and 39.83 day respectively. Under a constant relative humidity (67%), the development and multiplication of the parasitoid was more optimum at 25 degrees C than at 18 and 35 degrees C.


Quality improvement and rapid PDSA cycles to maintain routine surveillance of pulmonary pathogens during the COVID-19 pandemic in a pediatric cystic fibrosis clinic.
The COVID-19 pandemic necessitated immediate transition from in person to telehealth encounters; novel nursing practices were needed to ensure that children with cystic fibrosis (CF) receive care that approximates evidence-based guidelines. The aim was to ensure that as many children as possible received routine surveillance of pulmonary pathogens by a CF culture sputum culture during a pandemic. Multiple Plan-Do-Study-Act (PDSA) cycles were utilized to implement practice change over four months. Cultures were obtained via curbside appointment with a registered nurse (RN) or at the patients' home with mailed equipment. 133 cultures obtained: 50.37% (67) by RN collection curbside and 49.62% (66) by self/caregiver at home. 120 culture swabs or sterile cups were mailed; 55% (66) were returned. Cost of mailing equipment was $760.16. Nursing utilization of PDSA cycles developed novel processes that ensured guideline-based care during the initial months of the pandemic.


Gene expression differentials driven by mass rearing and artificial selection in black soldier fly colonies.
The micro-evolutionary forces that shape genetic diversity during domestication have been assessed in many plant and animal systems. However, the impact of these processes on gene expression, and consequent functional adaptation to artificial environments, remains under-investigated. In this study, whole-transcriptome dynamics associated with the early stages of domestication of the black soldier fly (BSF), Hermetia illucens, were assessed. Differential gene expression (DGE) was evaluated in relation to (i) generational time within the cultured environment (F2 vs. F3), and (ii) two selection strategies [no artificial selective pressure (NS); and selection for greater larval mass (SEL)]. RNA-seq was conducted on 5th instar BSF larvae (n = 36), representing equal proportions of the NS (F2 = 9; F3 = 9) and SEL (F2 = 9; F3 = 9) groups. A multidimensional scaling plot revealed greater gene expression variability within the NS and F2 subgroups, while the SEL group clustered separately with lower levels of variation. Comparisons between generations revealed 898 differentially expressed genes (DEGs; FDR-corrected p < 0.05), while between selection strategies, 213 DEGs were observed (FDR-corrected p < 0.05). Enrichment analyses revealed that metabolic, developmental, and defence response processes were over-expressed in the comparison between F2 and F3 larvae, while metabolic processes were the main differentiating factor between NS and SEL lines. This illustrates the functional adaptations that occur in BSF colonies across generations due to mass rearing; as well as highlighting genic dynamics associated with artificial selection for production traits that might inform future selective breeding strategies.


[Mechanism of action of interferon is linked to its ability to protect the cell from interstrand cross-linking of DNA, induced by 8-methoxypsoralen, activated by long-wave UV-light].
Treatment of human lymphocytes in the G1 phase of mitotic cycle with human lymphoblastoid interferon (Ly-IFN) decreased the frequencies of chromosome aberrations induced by 8-methoxy-psoralen-induced interstrand cross-links. Anticlastogenic effect of Ly-IFN was accompanied by stimulation of unscheduled synthesis of DNA in the G2 phase of mitotic cycle, as shown by increased percent of labeled cells registered by 3H-thymidine autoradiography. The data obtained seem to indicate that the mechanism of Ly-IFN protection is connected with stimulation of postreplicative repair.


Competency based teaching: the need for a new approach to teaching clinical skills in the undergraduate medical education course.
This paper will argue that undergraduate medical courses are failing to provide students with adequate training in the area of clinical skills. Some of the reasons for this failure include changes in the health system leading to increasing commitments for clinicians, fewer patients as clinical case examples and limitations in current teaching methods. Current clinical teaching methods measure progress through completion of clinical "blocks" of learning and one-off clinical examinations. This paper offers an alternative approach to clinical teaching in undergraduate medicine. In this approach, each student's progress is measured through the attainment of a predetermined level of competency in dealing with a range of clinical conditions. Some of the benefits of a new approach to clinical teaching in undergraduate medicine include flexibility for both students and clinicians in terms of when and where clinical learning can occur, a significant emphasis on active learning, and increased generalization and integration of learning.


Chiral separation by chromatographic and electromigration techniques. A review.
This review gives a survey of different chiral separation principles and their use in high-performance liquid chromatography (HPLC), gas chromatography (GC), supercritical fluid chromatography (SFC), thin-layer chromatography (TLC), capillary electrophoresis (CE) and capillary electrochromatography (CEC) highlighting new developments and innovative techniques. The mechanisms of the different separation principles are briefly discussed and some selected applications are shown.


NMR measurements of the diffusional permeability of water in cultured colonic epithelial cancer cells.
The water residence time and diffusional water permeability in colonic epithelial T84 cancer cells was measured using (1)H NMR spectroscopy; the values estimated were 35.2+/-2.8 ms and (7.4+/-0.6)x10(-3)cms(-1), respectively. Water permeability was inhibited to approximately 10% of its original value by the mercurial diuretic, p-chloromercuribenzenesulfonate (PCMBS; 1mM), and fully restored by dithiothreitol (DTT; 1mM). The permeability was also inhibited reversibly to approximately 55%, by extracellular glibenclamide (1mM), an inhibitor of some ATP-binding cassette (ABC) transporters, including the cystic fibrosis transmembrane conductance regulator (CFTR). Addition of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IMBX; 0.1-1mM) and the adenylate cyclase activator, forskolin (0.1-1mM) did not alter water permeability. It is concluded that in T84 cells water diffuses through the membrane lipid bilayer and via channels that are inhibited by PCMBS, including the channels that are known to be inhibited by glibenclamide.


Pharmacokinetic-pharmacodynamic-efficacy analysis of efalizumab in patients with moderate to severe psoriasis.
Efalizumab is a humanized anti-CD11a monoclonal antibody that demonstrated efficacy in the treatment of patients with psoriasis. The objective of this study was to perform a pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy (E) modeling analysis with intersubject variability assessment to increase our understanding of the interaction of efalizumab with CD11a on T cells and consequent reduction in severity of disease in psoriasis patients. A total of 6,329 samples from 240 patients in five Phase I and II clinical studies were used in the analysis. For the analysis, plasma efalizumab concentration was used as the PK measurement, the percent of predose CD11a was used as the PD measurement, and the psoriasis area and severity index was used as the measure of efficacy. A receptor-mediated PK/PD model was developed that describes the dynamic interaction of efalizumab binding with CD11a. In the efficacy model, the rate of psoriasis skin production is directly proportional to the amount of free surface CD11a on T cells, which is offset by the rate of skin healing. An additional CD11a-independent component to psoriasis skin production accounted for incomplete response to efalizumab therapy. A Monte Carlo parametric expectation maximization method implemented in the ADAPT II program was used to obtain the estimate of population parameters and inter- and intrasubject variability. The final model described the PK/PD/E data in psoriasis patients reasonably well. In addition, simulations using the final model suggested that efalizumab administered less frequently could possibly be more convenient with similar efficacy.


Structure of LRRK2 in Parkinson's disease and model for microtubule interaction.
Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease1 and is also linked to its idiopathic form2. LRRK2 has been proposed to function in membrane trafficking3 and colocalizes with microtubules4. Despite the fundamental importance of LRRK2 for understanding and treating Parkinson's disease, structural information on the enzyme is limited. Here we report the structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported cryo-electron tomography in situ structure5. We propose that the conformation of the LRRK2 kinase domain regulates its interactions with microtubules, with a closed conformation favouring oligomerization on microtubules. We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks the motility of the microtubule-based motors kinesin 1 and cytoplasmic dynein 1 in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce the formation of LRRK2 filaments in cells, whereas inhibitors that stabilize a closed conformation do not. Our findings suggest that LRRK2 can act as a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.


Humoral Immune Status in Relation to Outcomes in Patients with Idiopathic Pulmonary Fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease, in which inflammation is thought to only play a secondary role. Several factors associated with acute exacerbations of IPF (AE-IPF) have been identified, including infections. This study investigated whether humoral immunodeficiency or increased inflammatory markers at diagnosis were associated with AE-IPF and survival. Four-hundred-and-nine patients diagnosed with IPF between 2011 and 2017 were retrospectively included. Immune status investigations at diagnosis included measurement of serum immunoglobulins (available in 38%), leukocyte and lymphocyte subsets in blood and bronchoalveolar lavage (BAL) fluid (available in 58%), as well as response to pneumococcal vaccination (available in 64%). Serum immunoglobulins or IgG subclass levels were below the lower limit of normal in 6%. The response to pneumococcal vaccination was severely impaired in 1%. Thirteen percent of patients developed an AE-IPF (4.7% per year). AE-IPF were associated with elevated lymphocytes in BAL fluid at diagnosis (p = 0.03). Higher serum IgA and IgG at diagnosis were associated with worse survival (p = 0.01; and p = 0.04), as were an increased BAL lymphocyte percentage (p = 0.005), and higher blood leukocytes and neutrophils (p = 0.01; and p = 0.0005). In a multivariate model, only BAL lymphocyte count retained statistical significance (p = 0.007). The prevalence of humoral immunodeficiencies was low in patients with IPF and not associated with AE-IPF or survival. Elevated lymphocytes in BAL were associated with the development of AE-IPF and worse survival. Higher serum immunoglobulins and immune cells in blood were also associated with worse survival. The local immune response in the lungs may be a target for future therapies.


A new LAGE-1 peptide recognized by cytolytic T lymphocytes on HLA-A68 tumors.
Antigens encoded by genes of the LAGE family, including LAGE-1 and NY-ESO-1, are of interest for cancer immunotherapy because they are tumor-specific and shared by tumors of different histological types. Several clinical trials are in progress with NY-ESO-1 peptides, protein, recombinant poxviruses, and dendritic cells pulsed with peptides. In this study, CD8 T lymphocytes from an individual without cancer were stimulated with dendritic cells infected with a recombinant avian poxvirus encoding a complete LAGE-1 protein. A CTL clone was isolated that recognized a new LAGE-1 peptide, ELVRRILSR, which corresponds to position 103-111 of the protein sequence. It is presented by HLA-A6801 molecules. When tumor cells expressing LAGE-1 were transfected with HLA-A68, they were lysed by the CTL clone, indicating that the peptide is processed in tumor cells. These results indicate that the LAGE-1.A68 peptide can be used for antitumoral vaccination. We observed also that specific T cells could be detected in a blood sample with a high sensitivity by using an A68/LAGE-1 fluorescent multimer.


The dark satanic mills: Evaluating patterns of health in England during the industrial revolution.
this research seeks to investigate the impact the industrial revolution had on the population of England. Pre-existing skeletal data from 1154 pre-Industrial (1066-1700 CE) and 4157 industrial (1700-1905) skeletons from 21 cemeteries (N = 5411). Context number, sex, age-at-death, stature and presence/absence of selected pathological conditions were collated. The data were compared using chi square, Kolmogorov-Smirnov, t-tests and logistic regression (α = 0.01). There was a statistically significant increase in cribra orbitalia, periosteal reactions, rib lesions, fractures, rickets, osteoporosis, osteoarthritis, enamel hypoplasia, dental caries and periapical lesions in the industrial period. Osteomyelitis decreased from the pre-industrial to industrial period. Our results confirm the industrial revolution had a significant negative impact on human health, however the prevalence of TB, treponemal disease, maxillary sinusitis, osteomalacia, scurvy, gout and DISH did not change, suggesting these diseases were not impacted by the change in environmental conditions. This is the largest study of health in the industrial revolution that includes non-adults and adults and considers age-at-death alongside disease status to date. This data supports the hypothesis that the rise of industry was associated with a significant decline in general health, but not an increase in all pathological conditions.


Dosimetric verification of modulated photon fields by means of compensators for a kernel model.
The approach in treatment planning of applying beam quality correction factors to model compensator-induced depth-hardening effects is investigated and the present work comprises a dosimetric verification of the model for a common compensator material. Lead sheet modulators for four different phantom shapes were designed using a treatment planning system based on the model. The modulators were designed to yield homogeneous dose in a plane. The calculated modulation created by the lead sheets was re-imported into the treatment planning system and applied to a water phantom geometry for verification purposes. Comparing measurements, a total of 31 different geometries were measured, with calculations in this geometry showing good agreement for depth doses, dose profiles and output data with a maximum deviation of 4% except locally in the penumbra region and close to the edges of the cut lead sheets.


Metoprolol in the treatment of multifocal atrial tachycardia.
Multifocal atrial tachycardia (MAT) is a difficult arrhythmia to treat. Pharmacologic treatment is generally disappointing, and successful conversion in a predictable manner is uncommon. To assess the efficacy of metoprolol, a relatively selective beta 1-adrenergic blocking agent, we administered this agent to 11 patients (aged 71.8 +/- 8.3 yr). All patients had serious pulmonary disease. Hypoxia, hypercarbia, acidosis, and electrolyte abnormalities were corrected before the study. Nine patients were receiving theophylline derivatives and six digoxin. Serum levels for both drugs were in the therapeutic range. Four patients had received verapamil without control of MAT. Mean atrial rate before administration of metoprolol was 142.3 +/- 17.2 beat/min and mean ventricular rate was 131.4 +/- 24.3 beat/min. One to 3 h after metoprolol (25 or 50 mg orally), all patients were restored to sinus rhythm, with a mean ventricular rate of 86.9 +/- 6.8 beat/min (p less than .01). Six patients had 3 to 6 premature atrial contractions per minute. No adverse effects were noted, and arterial blood gases before and after therapy were comparable. Five patients expired from their underlying disease and four were continued on metoprolol to maintain sinus rhythm. Metoprolol is effective in the acute and chronic treatment of MAT and may be given to patients with MAT and respiratory failure without serious adverse effects.


Combined T2 -preparation and multidimensional outer volume suppression for coronary artery imaging with 3D cones trajectories.
To develop a modular magnetization preparation sequence for combined T2 -preparation and multidimensional outer volume suppression (OVS) for coronary artery imaging. A combined T2 -prepared 1D OVS sequence with fat saturation was defined to contain a 90°-60 180°60 composite nonselective tip-down pulse, two 180°Y hard pulses for refocusing, and a -90° spectral-spatial sinc tip-up pulse. For 2D OVS, 2 modules were concatenated, selective in X and then Y. Bloch simulations predicted robustness of the sequence to B0 and B1 inhomogeneities. The proposed sequence was compared with a T2 -prepared 2D OVS sequence proposed by Luo et al, which uses a spatially selective 2D spiral tip-up. The 2 sequences were compared in phantom studies and in vivo coronary artery imaging studies with a 3D cones trajectory. Phantom results demonstrated superior OVS for the proposed sequence compared with the Luo sequence. In studies on 15 healthy volunteers, the proposed sequence had superior image edge profile acutance values compared with the Luo sequence for the right (P < .05) and left (P < .05) coronary arteries, suggesting superior vessel sharpness. The proposed sequence also had superior signal-to-noise ratio (P < .05) and passband-to-stopband ratio (P < .05). Reader scores and reader preference indicated superior coronary image quality of the proposed sequence for both the right (P < .05) and left (P < .05) coronary arteries. The proposed sequence with concatenated 1D spatially selective tip-ups and integrated fat saturation has superior image quality and suppression compared with the Luo sequence with 2D spatially selective tip-up.


Amyotrophic lateral sclerosis with temporal lobe atrophy.
Clinical and neuropathological findings are reported on a 48-year-old man who developed progressive bulbar palsy, muscle atrophy of four extremities, and hyperreflexia. Duration of the illness was about 19 months. Moderate personality changes were observed during his hospitalization. Neuropathological examination revealed the presence of an ALS: severe loss of the large motoneurons in the spinal anterior horns, and degeneration of the corticospinal tract, more prominent on the left side. The hypoglossal, the facial, and the motor trigeminal nuclei were also involved, but the oculomotor, the trochlear and the abducens nuclei were well preserved. There was bilateral, but more pronounced on the right, atrophy of the temporal poles consistent with the lesions of the temporal types of Pick's disease. This case indicates the simultaneous occurrence of degenerative diseases of the CNS, and the correspondence of laterality between the temporal lobe and the spinal cord may suggest a common etiology of these two types of disease processes.


Lateral canthal reconstruction.
After the lateral aspect of both the upper and lower eyelids were excised in six patients, a method of reconstruction was used employing a combination of periosteal flaps from the lateral orbital rim and a transpositional skin flap based in the temporal area. The periosteal flaps were crossed to form a sharp canthal angle and were joined to the tarsal edges creating the posterior lamella. The transpositional skin flap was divided at the distal end to form the anterior lamella of the upper and lower lids. The results have been satisfactory from a functional and cosmetic standpoint.


Bopyrid isopods parasitizing on the cultured fresh water prawn, Macrobrachiummalcolmsonii in South India.
The bopyrid isopods are common in wild Macrobrachium spp. but not common in aquaculture condition. This is the first study that reports the parasitizing of bopyrid isopods on the cultured M. malcolmsonii. Bopyrid isopod (Probopyrus buitendijki) was identified in the branchial cavities of the fresh water prawn, M. malcolmsonii from grow-out culture pond at Kuriyamangalam, India. Macrobrachium malcolmsonii is a new host for P. buitendijki. A total of 1323 M. malcolmsonii were checked for this study. The overall prevalence of the parasitic infestation was reached 46.2 %. The parasitic infection was higher in female (83 %) than in male (3.4 %). Highest prevalence of infestation was found in the median size group (7-8 cm) (58.7 %). Infected females were not berried unlike uninfected prawns. The parasites cause infertility and does not found any organ deformities due to the infestation. The parasite was inversely attached in the gill chamber with no lesion on the gill but the infected branchial chamber became bulged.


SP1 acts as a key factor, contributes to upregulation of ADAM23 expression under serum deprivation.
ADAM23 modulates many cellular functions, alteration of expression causes a number of tumor types; however, the mechanisms controlling ADAM23 expression remain unknown. Here we have identified a SP1 binding site (-202/-190) that binds SP1 at the proximal promoter of human ADAM23 gene; furthermore, serum deprivation enhances open chromatin accessibility and help expose the SP1 binding site; finally, SP1 binding recruits RNA polymerase II, which in turn results in upregulation of endogenous ADAM23 expression. Therefore, the present study delineates the fundamental elements of a core promoter structure that will be helpful for future studies of the regulation of ADAM23 gene.


The effects of neurosteroid allopregnanolone on synaptic dysfunction in the hippocampus in experimental parkinsonism rats: An electrophysiological and molecular study.
The dopaminergic system is a powerful candidate targeted for changes of synaptic plasticity in the hippocampus. Higher incidence of Parkinson's disease (PD) in men than women indicates the influence of sex hormones on the PD development. Previous studies have shown that neurodegenerative diseases such as PD are related to the decline of Allopregnanolon (Allo), a metabolite of progesterone; it is also well known that learning and memory are influenced by oscillations in steroidal hormones. Although abnormalities in hippocampal plasticity have been observed in the toxic models of PD, effects of Allo on hippocampal LTP and hippocampal synaptic protein levels, which play an important role in maintaining the integrity of neural connections, have never been analyzed thus far. Experimental groups subjected to the long-term potentiation (LTP) were studied in the CA1 area of the hippocampus. In addition, the levels of hippocampal postsynaptic density protein 95 (PSD-95), neurexin-1 (Nrxn1) and neuroligin (Nlgn) as synaptic molecular components were determined by immunoblotting. Although dopamine denervation did not alter basal synaptic transmission and pair-pulse facilitation of field excitatory postsynaptic potentials (fEPSPs), the induction and maintenance of LTP were impaired in the CA1 region. In addition, the levels of PSD-95, Nrxn1 and Nlgn were significantly decreased in the hippocampus of 6-OHDA-treated animals. Such abnormalities in synaptic electrophysiological aspects and protein levels were abolished by the treatment with Allo. These findings showed that partial dopamine depletion led to unusual synaptic plasticity in the CA1 as well as the decrease in synaptic proteins in the hippocampus. Our results demonstrated that Allo ameliorated these deficits and preserved pre- and post-synaptic proteins. Therefore, Allo may be an effective factor in maintaining synaptic integrity in the mesolimbic pathway.


[Operative therapy of isolated patellofemoral arthritis. Biomechanics as a guide].
The treatment of patellofemoral arthritis places high demands on orthopedists. The exact analysis of the underlying pathobiomechanical relationships is the basis for every therapy decision. Soft tissue procedures, such as medial patellofemoral ligament (MPFL) reconstruction for stabilization and bone interventions for alignment optimization (e.g. tuberosity transfer and corrective osteotomy) can play a role in treatment. In cases of advanced patellofemoral arthrosis these interventions can be used as well as in combination with partial joint replacement. For the choice of implant the use of anatomical prosthesis types is recommended because with these components the number of additional procedures can be reduced. The success of patellofemoral prosthetics depends mainly on the recognition of biomechanical deviations. If these can be corrected the risk of implant failure can be reduced.


Esophageal manometry findings in patients with refractory symptoms of gastroesophageal reflux disease.
Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder. High-resolution esophageal manometry (HREM) and 24-h pH study help to properly evaluate GERD patients. The aim of the present study was to classify patients with refractory GERD symptoms into various groups based on endoscopic and physiological testing. The present study is a retrospective analysis of patients referred for HREM and 24-h pH recording between 2019 and 2021. We included all adult patients (age > 18 years) who were referred for evaluation of refractory GERD symptoms. Upper gastrointestinal endoscopy findings, HREM, and 24-h pH findings were noted. Patients were divided into erosive reflux disease (ERD), non-erosive reflux disease (NERD), reflux hypersensitivity (RH), and functional heartburn (FH) based on test results. Demographic details and HREM parameters were compared in the four groups. Statistics used are one-way analysis of variance (ANOVA) and Chi-squared tests. A p-value of <0.05 was considered statistically significant. A total of 144 patients were included-NERD (56, 38.9%), ERD (42, 29.2%), RH (28, 19.5%), and FH (18, 12.5%). Age (p 0.74), and sex distribution (p 0.47), and symptom profile (p 0.12) were similar. The presence of type 2/3 esophagogastric junction (EGJ) morphology was commoner in ERD and NERD (p <0.001). Moreover, the esophagogastric junction contractile integral (EGJ-CI) and basal inspiratory pressures were significantly lower in these two groups (p<0.05). EGJ-CI was low in 32 cases of ERD (76.2%), 41 cases with NERD (73.2%), 7 cases with RH (25%), and 3 cases with FH (16.7%), respectively (p-value < 0.00001). FH and RH account for 32% of cases with refractory GERD symptoms. Impaired EGJ function was more common in ERD and NERD patients compared to FH and RH patients.


Accidental cultivation of the European truffle Tuber brumale in North American truffle orchards.
Tuber brumale is a European edible truffle species that is often viewed as a contaminant in truffle orchards, as it visually resembles more valuable black truffles such as T. melanosporum, but differs in aroma and flavor and sells for a much lower price. Although T. brumale is not native to or intentionally cultivated in North America, it was reported to have been accidently introduced into British Columbia in 2014 and North Carolina in 2020. However, in winter of 2021, various truffle orchards in eastern North America produced truffles that differed from the anticipated harvest of T. melanosporum. Molecular analysis of these specimens confirmed T. brumale truffle fruiting bodies from ten orchards distributed across six eastern USA states. Phylogenetic analysis of nuclear ribosomal ITS and 28S DNA sequences indicated that all samples belong to the T. brumale A1 haplogroup, the genetic subgroup of T. brumale that is more common in western Europe. This pattern of widespread fruiting of T. brumale in North American truffle orchards is likely the result of T. brumale being introduced in the initial inoculation of trees used as hosts in T. melanosporum truffle cultivation. We review other examples of introduced non-target truffle species and strategies for limiting their impact on truffle cultivation.


Cetuximab has an inhibitory effect on cell motility in SCC-4 oral squamous cell carcinoma cell line.
Cetuximab is a chimeric monoclonal antibody that acts as a competitive antagonist, by binding to EGFR. This cell signalling pathways regulates tumor progression. The oral squamous cell carcinoma undergoes to regional spreading and distant metastasis. This study aimed to evaluate the effect of treatment with Cetuximab on cell migration and invasion in OSCC cells, by using the SCC-4 cell line. Cell migration and cell invasion assay were performed and actin cytoskeleton of control and treated with Cetuximab cells were evaluated. Differences were considered significant when p<0.05.Cetuximab inhibited the migration of SCC-4 cells at three concentrations: 1 µg/mL, 50 µg/mL and 100 µg/mL (p<0.0001) in a dose-dependent manner. The number of SCC-4 treated cells with 1 μg/mL that migrated through the membrane was statistically different from 50 μg/mL (p<0.001) and 100 μg/mL (p<0.0001), and between 50 μg/mL and 100 μg/mL (p<0.01). Cetuximab 50 μg/mL inhibited cell invasion through the MatrigelTM compared with SCC-4 control cells (p<0.01). Cetuximab 50 μg/mL affected the organization of the actin cytoskeleton. Cetuximab has an inhibitory effect on actin cytoskeleton organization, cell migration and invasion, suggesting that Cetuximab treatment can be important to avoid oral squamous cell carcinoma metastasis.


The Genetics of Brugada Syndrome.
Brugada syndrome is a heritable channelopathy characterized by a peculiar electrocardiogram (ECG) pattern and increased risk of cardiac arrhythmias and sudden death. The arrhythmias originate because of an imbalance between the repolarizing and depolarizing currents that modulate the cardiac action potential. Even if an overt structural cardiomyopathy is not typical of Brugada syndrome, fibrosis and structural changes in the right ventricle contribute to a conduction slowing, which ultimately facilitates ventricular arrhythmias. Currently, Mendelian autosomal dominant transmission is detected in less than 25% of all clinical confirmed cases. Although 23 genes have been associated with the condition, only SCN5A, encoding the cardiac sodium channel, is considered clinically actionable and disease causing. The limited monogenic inheritance has pointed toward new perspectives on the possible complex genetic architecture of the disease, involving polygenic inheritance and a polygenic risk score that can influence penetrance and risk stratification.


Radiation therapy of seminoma: 17-year experience at the Joint Center for Radiation Therapy.
One hundred and sixteen patients with stage I and II primary testicular seminoma were treated at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1984. Complete follow-up is available for 114 patients (98%) with a median follow-up time of 6 years. Actuarial relapse-free survival (RFS) and survival for the entire group at 10 years were 94 and 86%, respectively, with 27 patients still at risk beyond 10 years. Actuarial RFS and survival at 10 years by stage were 97 and 92% for stage I, 93 and 81% for stage IIa, 100 and 100% for stage IIb, but only 75 and 51% for stage IIc. The difference in actuarial survival between stage IIc patients and stage I, IIa and IIb patients was significant (p less than 0.01). These results indicate that radiation therapy is excellent treatment for stage I and II seminomas as long as the largest mass of disease is not greater than 5 cm (stage IIc). Patients with stage IIc seminoma are now treated with cisplatin-containing combination chemotherapy followed by radiation therapy to areas of bulk disease. Although the majority of patients with stage II disease in this series received mediastinal irradiation, this is no longer recommended at the JCRT.


Sexual relationship power and malnutrition among HIV-positive women in rural Uganda.
Inequality within partner relationships is associated with HIV acquisition and gender violence, but little is known about more pervasive effects on women's health. We performed a cross-sectional analysis of associations between sexual relationship power and nutritional status among women in Uganda. Participants completed questionnaires and anthropometric measurements. We assessed sexual relationship power using the Sexual Relationship Power Scale (SRPS). We performed logistic regression to test for associations between sexual relationship power and poor nutritional status including body mass index, body fat percentage, and mid-upper arm circumference. Women with higher sexual relationship power scores had decreased odds of low body mass index (OR 0.29, p = 0.01), low body fat percentage (OR 0.54, p = 0.04), and low mid-upper arm circumference (OR 0.22, p = 0.01). These relationships persisted in multivariable models adjusted for potential confounders. Targeted interventions to improve intimate partner relationship equality should be explored to improve health status among women living with HIV in rural Africa.


Serum levels of 25-hydroxycholecalciferol as a diagnostic aid in vitamin D deficiency states.
The measurement of serum levels of 25-hydroxycholecalciferol in the diagnosis of rickets is discussed in the light of recently acquired knowledge of vitamin D metabolism. A useful clinicopathological classification of rickets is presented and various aetiological mechanisms are discussed.


Bis(μ-ferrocene-carboxyl-ato)bis-[aqua--bis(ferrocene-carboxyl-ato)methano-l-erbium(III)] methanol disolvate.
In the centrosymmetric title coordination compound, [Er(2){Fe(C(5)H(5))(C(6)H(4)O(2))}(6)(CH(3)OH)(2)(H(2)O)(2)]·2CH(3)OH, the two Er(III) ions are bridged by two ferrocene-carboxyl-ate anions as asymmetrically bridging ligands, leading to dimeric cores. The Er(III) ion has a distorted dodeca-hedral coordination with six coordinating O atoms derived from the ferrocene-carboxyl-ate ligands and two coordinated O atoms from one water mol-ecule and one methanol mol-ecule. The asymmetric unit comprises a half of the complex mol-ecule and a methanol solvent mol-ecule. Intra-molecular O-H⋯O and C-H⋯O inter-actions occur. In the crystal, mol-ecules are linked by inter-molecular O-H⋯O hydrogen bonds and C-H⋯O as well as C-H⋯π inter-actions.


CYP2C19 and clopidogrel response: more than validation in the real world.
Electronic health records (EHRs) coupled to DNA biobanks are potentially powerful but untested resources for pharmacogenomic discoveries. As described in this issue, Delaney and co-workers validated the use of EHRs by demonstrating that loss-of-function CYP2C19*2 was associated with poorer cardiovascular outcomes in clopidogrel-treated patients with an effect size similar to that reported in more controlled clinical trials. Whether studies from real-world EHR-biobanks will supplant randomized clinical trials to provide a sufficient evidence base to change practice is less certain.


Development and testing of the situational judgement test to measure safety performance of healthcare professionals: An explorative cross-sectional study.
To measure safety performance, situational judgement test, which is a method composed of job-related situations, can be used. This study aimed to develop and test its psychometric properties by measuring the safety performance of healthcare professionals in German hospitals. An explorative cross-sectional study. A team of researchers, nurses and physicians developed seven items, which focus on different safety areas. Descriptive statistics were calculated for each item. Cronbach's alpha was calculated as an indication of internal consistency. Spearman's correlation between the items was evaluated as analysis of construct validity. A cross-sectional survey with healthcare professionals in three German hospitals was conducted to test the developed instrument. A total of 168 healthcare professionals participated (response rate: 39.1%). 70.2% were women, and 38.7%, 33.9%, 15.5% and 11.3% were registered nurses, nurses in training, physicians and other healthcare professionals respectively. The situational judgement test demonstrated an acceptable psychometric performance.


Aerobic granulation in a sequencing batch airlift reactor.
Aerobic granular sludge was cultivated in an intensely mixed sequencing batch airlift reactor (SBAR). A COD loading of 2.5 kg Acetate-COD/(m3 d) was applied. Granules developed in the reactor within one week after inoculation with suspended activated sludge from a conventional wastewater treatment plant. Selection of the dense granules from the biomass mixture occurs because of the differences in settling velocities between granules (fast settling biomass), and filaments and flocs (slow settling biomass). At 'steady state' the granules had an average diameter of 2.5 mm, a biomass density of 60g VSS/I of granules, and a settling rate of > 10 m/h. The biomass consisted of both heterotrophic and nitrifying bacteria. The reactor was operated over a long period during which the granular sludge proved to remain stable. The performance of the intermittently fed SBAR was compared to that of the continuously fed biofilm airlift suspension reactor (BASR). The most importance difference was that the density of the granules in the SBAR was much higher than the density of the biofilms in the BASR. It is discussed that this could be due to the fact that the SBAR is intermittently fed, while the BASR is continuously fed.


Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin.
The dose-limiting side effect of taxane, platinum-complex, and other kinds of anticancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given 1 of 3 mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of adenosine triphosphate synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial antioxidant defense system). All 3 toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy-naïve rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A fibers and C fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A fibers and C fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naïve control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention.


Peak oxygen consumption and prognosis in heart failure: 14 mL/kg/min is not a "gender-neutral" reference.
Peak oxygen consumption (VO2) predictive authority in heart failure (HF) has been established from male cohorts. We evaluated the gender impact on the prognostic meaning of low peak VO2. We followed 529 HF patients (116 female), with peak VO2 ≤ 14 mL/kg/min, until cardiovascular death (CVD) and urgent heart transplantation. During follow up, 156 (29%) patients had cardiac events. Female gender, age, left ventricular ejection fraction, peak VO2, peak systolic blood pressure, and beta-blocker treatment all contributed to increase the risk ability of the hierarchical multivariate model. Two-year survival was higher in women: 85 vs 66%; χ(2)=15.7, p<0.0001. Peculiarly, outcome results were similar when only CVD was considered. Females showed a multivariate adjusted hazard ratio (HR) of 0.46. Since a 1-mL/kg/min increment in peak VO2 was equated with a 12% improvement in prognosis, the same gender adjusted HR was achieved when mean peak VO2 was reduced by 5 units in women: thus, a HF woman with peak VO2 of 9 mL/kg/min has the same 2-year outcome as a HF man with peak VO2 of 14 mL/kg/min. Although HF women have a comparatively lower peak VO2 than men, they live longer. We discovered that the traditional cut point value for peak VO2, i.e. ≤ 14 mL/kg/min is not a "gender-neutral" reference since lumping HF men and women together with the same VO2 value is unlikely to describe the true risk. These preliminary findings do underline the need to assimilate gender-specific issues into clinical practice in HF, when appropriate.


Perlecan Facilitates Neuronal Nitric Oxide Synthase Delocalization in Denervation-Induced Muscle Atrophy.
Perlecan is an extracellular matrix molecule anchored to the sarcolemma by a dystrophin-glycoprotein complex. Perlecan-deficient mice are tolerant to muscle atrophy, suggesting that perlecan negatively regulates mechanical stress-dependent skeletal muscle mass. Delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma to the cytosol triggers protein degradation, thereby initiating skeletal muscle atrophy. We hypothesized that perlecan regulates nNOS delocalization and activates protein degradation during this process. To determine the role of perlecan in nNOS-mediated mechanotransduction, we used sciatic nerve transection as a denervation model of gastrocnemius muscles. Gastrocnemius muscle atrophy was significantly lower in perinatal lethality-rescued perlecan-knockout (Hspg2-/--Tg) mice than controls (WT-Tg) on days 4 and 14 following surgery. Immunofluorescence microscopy showed that cell membrane nNOS expression was reduced by denervation in WT-Tg mice, with marginal effects in Hspg2-/--Tg mice. Moreover, levels of atrophy-related proteins-i.e., FoxO1a, FoxO3a, atrogin-1, and Lys48-polyubiquitinated proteins-increased in the denervated muscles of WT-Tg mice but not in Hspg2-/--Tg mice. These findings suggest that during denervation, perlecan promotes nNOS delocalization from the membrane and stimulates protein degradation and muscle atrophy by activating FoxO signaling and the ubiquitin-proteasome system.


A method to estimate the population size of benthic macroinvertebrates in streams.
A method is described by which samples of stream macroinvertebrates can be linked to the roughness of the substratum, the water depth, the velocity, and to a combination of these factors, i.e., Froude number and thickness of the laminar sublayer, at the exact point of sampling. The abundance of Odagmia ornata (Diptera: Simuliidae), the species considered in this study, was not related to roughness, but depended with increasing significance on depth, velocity, Froude number, and laminar sublayer. Therefore, it is suggested that the population size of stream macroinvertebrates can be estimated using the relationships between abundance and the most suitable hydrodynamic factor. For this purpose it is necessary only to measure the physical factors and then to calculate the abundance, using both these measurements and the abundance-hydrodynamic factor relationships formerly established.A longer section of a stream with a relatively wide range of habitats was sampled for 1 week, during which the new method yielded results that reached the level of accuracy per sampling effort obtained to date only when a narrower range of habitats was sampled, usually only one stream riffle. Under the latter conditions, the new method is suggested to yield results of increased accuracy, particularly if samples are taken within a short period.


Optimization of individual and population designs using Splus.
We address the problem of design optimization for individual and population pharmacokinetic studies. We develop Splus generic functions for pharmacokinetic design optimization: IFIM, a function for individual design optimization similar to the ADAPT II software, and PFIM_OPT, a function for population design optimization which is an extension of the Splus function PFIM for population design evaluation. Both evaluate and optimise designs using the Simplex algorithm. IFIM optimizes the sampling times in continuous intervals of times; PFIM_OPT optimizes either, for a given group structure of the population design, only the sampling times taken in some given continuous intervals or, both the sampling times and the group structure, performing then statistical optimization. A combined variance error model can be supplied with the possibility to include parameters of the error model as parameters to be estimated. The performance of the optimization with the Simplex algorithm is demonstrated with two pharmacokinetic examples: by comparison of the optimized designs to those of the ADAPT II software for IFIM, and to those obtained using a grid search or the Fedorov-Wynn algorithm for PFIM_OPT. The influence of the variance error model on design optimization was investigated. For a given total number of samples, different group structures of a population design are compared, showing their influence on the population design efficiency. The functions IFIM and PFIM_OPT offer new efficient solutions for the increasingly important task of optimization of individual or population pharmacokinetic designs.


Neural network models accurately predict discharge disposition after revision total knee arthroplasty?
Based on the rising incidence of revision total knee arthroplasty (TKA), bundled payment models may be applied to revision TKA in the near future. Facility discharge represents a significant cost factor for those bundled payment models; however, accurately predicting discharge disposition remains a clinical challenge. The purpose of this study was to develop and validate artificial intelligence algorithms to predict discharge disposition following revision total knee arthroplasty. A retrospective review of electronic patient records was conducted to identify patients who underwent revision total knee arthroplasty. Discharge disposition was defined as either home discharge or non-home discharge, which included rehabilitation and skilled nursing facilities. Four artificial intelligence algorithms were developed to predict this outcome and were assessed by discrimination, calibration and decision curve analysis. A total of 2228 patients underwent revision TKA, of which 1405 patients (63.1%) were discharged home, whereas 823 patients (36.9%) were discharged to a non-home facility. The strongest predictors for non-home discharge following revision TKA were American Society of Anesthesiologist (ASA) score, Medicare insurance type and revision surgery for peri-prosthetic joint infection, non-white ethnicity and social status (living alone). The best performing artificial intelligence algorithm was the neural network model which achieved excellent performance across discrimination (AUC = 0.87), calibration and decision curve analysis. This study developed four artificial intelligence algorithms for the prediction of non-home discharge disposition for patients following revision total knee arthroplasty. The study findings show excellent performance on discrimination, calibration and decision curve analysis for all four candidate algorithms. Therefore, these models have the potential to guide preoperative patient counselling and improve the value (clinical and functional outcomes divided by costs) of revision total knee arthroplasty patients. IV.


Amplification-based method for microRNA detection.
Over the last two decades, the study of miRNAs has attracted tremendous attention since they regulate gene expression post-transcriptionally and have been demonstrated to be dysregulated in many diseases. Detection methods with higher sensitivity, specificity and selectivity between precursors and mature microRNAs are urgently needed and widely studied. This review gave an overview of the amplification-based technologies including traditional methods, current modified methods and the cross-platforms of them combined with other techniques. Many progresses were found in the modified amplification-based microRNA detection methods, while traditional platforms could not be replaced until now. Several sample-specific normalizers had been validated, suggesting that the different normalizers should be established for different sample types and the combination of several normalizers might be more appropriate than a single universal normalizer. This systematic overview would be useful to provide comprehensive information for subsequent related studies and could reduce the un-necessary repetition in the future.


Suppression of tumor promoter phorbolmyristate acetate-induced chromosome breakage by antioxidants and inhibitors of arachidonic acid metabolism.
To gain insight into the mechanism of formation of chromosomal aberrations by the tumor promoter phorbolmyristate acetate (PMA) in human lymphocytes, we investigated the effect of antioxidants and inhibitors of arachidonic acid metabolism. Among the antioxidants bovine erythrocyte CuZn superoxide dismutase, glutathione peroxidase, mannitol (a scavenger of hydroxyl radicals), butylated hydroxytoluene and butylated hydroxyanisole were anticlastogenic while catalase and dimethylfuran (a scavenger of singlet oxygen) were inactive. These results show that the induction of aberrations by PMA occurs via indirect action, i.e. the intermediacy of superoxide and hydroxyl radicals. The following inhibitors of arachidonic acid metabolism were strongly anticlastogenic: the cyclo-oxygenase inhibitors indomethacin and flufenamic acid and the lipoxygenase inhibitor BN1015. Imidazole, nordihydroguaiaretic acid BN1048 and 5,8,11,14-eicosatetraynoic acid were moderately active. The inhibitor of phospholipase A2, fluocinolone acetonide, was also anticlastogenic. We conclude that the oxidative metabolism of arachidonic acid is involved in the induction of chromosomal aberrations by PMA in human lymphocytes. However, because of the limited selectivity of these drugs, it is not yet possible to identify unambiguously the step(s) in the arachidonic acid cascade responsible for PMA clastogenicity.


Interchromosomal effect in carriers of translocations and inversions assessed by preimplantation genetic testing for structural rearrangements (PGT-SR).
Balanced carriers of structural rearrangements have an increased risk of unbalanced embryos mainly due to the production of unbalanced gametes during meiosis. Aneuploidy for other chromosomes not involved in the rearrangements has also been described. The purpose of this work is to know if the incidence of unbalanced embryos, interchromosomal effect (ICE) and clinical outcomes differ in carriers of different structural rearrangements. Cohort retrospective study including 359 preimplantation genetic testing cycles for structural rearrangements from 304 couples was performed. Comparative genomic hybridisation arrays were used for chromosomal analysis. The results were stratified and compared according to female age and carrier sex. The impact of different cytogenetic features of chromosomal rearrangements was evaluated. In carriers of translocations, we observed a higher percentage of abnormal embryos from day 3 biopsies compared with day 5/6 biopsies and for reciprocal translocations compared with other rearrangements. We observed a high percentage of embryos with aneuploidies for chromosomes not involved in the rearrangement that could be attributed to total ICE (aneuploid balanced and unbalanced embryos). No significant differences were observed in these percentages between types of rearrangements. Pure ICE (aneuploid balanced embyos) was independent of female age only for Robertsonian translocations, and significantly increased in day 3 biopsies for all types of abnormalities. Furthermore, total ICE for carriers of Robertsonian translocations and biopsy on day 3 was independent of female age too. High ongoing pregnancy rates were observed for all studied groups, with higher pregnancy rate for male carriers. We observed a higher percentage of abnormal embryos for reciprocal translocations. No significant differences for total ICE was found among the different types of rearrangements, with higher pure ICE only for Robertsonian translocations. There was a sex effect for clinical outcome for carriers of translocations, with higher pregnancy rate for male carriers. The higher incidence of unbalanced and aneuploid embryos should be considered for reproductive counselling in carriers of structural rearrangements.


Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics.
Understanding the pathogenesis of systemic sclerosis (SSc) is confounded by considerable disease heterogeneity. Animal models of SSc that recapitulate distinct subsets of disease at the molecular level have not been delineated. We applied interspecies comparative analysis of genomic data from multiple mouse models of SSc and patients with SSc to determine which animal models best reflect the SSc intrinsic molecular subsets. Gene expression measured in skin from mice with sclerodermatous graft-versus-host disease (GVHD), bleomycin-induced fibrosis, Tsk1/+ or Tsk2/+ mice was mapped to human orthologs and compared to SSc skin biopsy-derived gene expression. Transforming growth factor β (TGFβ) activation was assessed using a responsive signature in mice, and tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression was measured in SSc patient and mouse skin. Gene expression in skin from mice with sclerodermatous GVHD and bleomycin-induced fibrosis corresponded to that in SSc patients in the inflammatory molecular subset. In contrast, Tsk2/+ mice showed gene expression corresponding to the fibroproliferative SSc subset. Enrichment of a TGFβ-responsive signature was observed in both Tsk2/+ mice and mice with bleomycin-induced skin fibrosis. Expression of TNFRSF12A (the TWEAK receptor/fibroblast growth factor-inducible 14) was elevated in skin from patients with fibroproliferative SSc and the skin of Tsk2/+ mice. This study reveals similarities in cutaneous gene expression between distinct mouse models of SSc and specific molecular subsets of the disease. Different pathways underlie the intrinsic subsets including TGFβ, interleukin-13 (IL-13), and IL-4. We identify a novel target, Tnfrsf12a, with elevated expression in skin from patients with fibroproliferative SSc and Tsk2/+ mice. These findings will inform mechanistic and translational preclinical studies in SSc.


Interaction between neurotransmitter antagonists and effects of sacral neuromodulation in rats with chronically hyperactive bladder.
To investigate to what extent antagonists of spinal neurotransmitters interact with the effects of sacral neuromodulation in a rat model of a chronically hyperactive urinary bladder. In female rats the urinary bladder was instilled with turpentine oil 2.5% to induce cystitis. After surviving for 10 days the rats were anaesthetized with urethane, the bladder catheterized and connected to a pressure transducer. Stimulating electrodes were placed in the sacral foramina bilaterally. The spinal cord was exposed by a laminectomy, and a small pool was placed on the cord for intrathecal administration of neurotransmitter antagonists. Sacral neuromodulation was applied before and after administering the antagonists. The antagonists used were: memantine, an antagonist for N-methyl-D-aspartate (NMDA) receptors; CNQX, an antagonist for non-NMDA receptors, and L-NAPNA, a blocker of nitric oxide synthase. With no electrical neuromodulation, memantine and L-NAPNA abolished the cystitis-induced bladder contractions for approximately 4 and approximately 37 min, respectively. The effect of CNQX was similar to that of artificial cerebrospinal fluid. Electrical sacral modulation with no antagonists also transiently abolished the bladder contractions; at the highest intensity used, the pause was 2-3 min. Superfusion of the spinal cord with CNQX reduced this effect of neuromodulation significantly, whereas memantine had no influence, and L-NAPNA increased the neuromodulation-induced pause. The results suggest that non-NMDA receptors are involved in the effects of sacral neuromodulation, whereas NMDA receptors appear to have no role. Nitric oxide is essential for maintaining the chronic hyperactive state of the urinary bladder.


The Neotropical land snails (Mollusca, Gastropoda) collected by the 'Comisión Científica del Pacífico'.
The land snails collected by the 'Comisión Científica del Pacifíco' (CCP), a Spanish expedition to South and Central America from 1862-1866, are restudied and revised. The historical context of the expedition and the study of its collected material are described. Biographical data is given for the main persons involved. The land snails were previously studied by Joaquin Hidalgo between 1867 and 1893. A total of 3,470 specimens belonging to 211 species are treated in this paper. Of 34 species mentioned by Hidalgo is his catalogue, the corresponding material could not be located. Bulimus visendus Hidalgo, 1869 is now placed in the genus Synapterpes Pilsbry, 1896, a new combination.


Cognitive functioning in post-polio patients with and without general fatigue.
This study examined 2 main hypotheses. First, whether patients with post-polio suffering from general fatigue (n=10) demonstrate cognitive deficits compared with patients with post-polio without general fatigue (n=10). Secondly, by systematically varied test order administration we examined whether such differences varied as a function of increasing cognitive load during cognitive testing. Twenty patients diagnosed with post-polio syndrome, 10 with general fatigue and 10 without fatigue. Neither of the 2 hypotheses were confirmed. The group with general fatigue reported elevated levels of depression. However, no systematic association between level of depression and cognitive performance could be detected. The results of this study provide no evidence that general fatigue or cognitive load affects cognitive functioning in post-polio.


Determinants of low birth weight in India: An investigation from the National Family Health Survey.
This study aimed to estimate the change in prevalence of low birth weight (LBW) over the last decade in India and to identify its associated factors-biological, demographic, socio-economic, and programmatic. We used the data from the National Family Health Survey of 2005-2006 (NFHS-3) and 2015-2016 (NFHS-4). The sample of this study included 11 300 children from NFHS-3 and 99 894 from NFHS-4 data; all these children were the last full-term singleton live-births, born within the last 3 years prior to the survey. In India, the prevalence of LBW has significantly declined from 20.4% (95%CI 19.4-21.4) to 16.4% (95% CI 16.1-16.8) in the last decade. The prevalence of LBW remained high in girl children (OR = 1.2, 95% CI 1.2-1.3; P < .001), whose mothers were adolescent (OR = 1.2, 95% CI 1.1-1.3; P < .001), and were stunted (OR = 1.3, 95% CI 1.3-1.3; P < .001). Prevalence of LBW declined among second or higher birth order child (OR = 0.8, 95% CI 0.8-0.9; P < .001), whose mothers educated up to secondary level and above (OR = 0.6 to 0.8), belonged to rich wealth quintiles (OR = 0.9 to 0.8), were from rural area (OR = 0.9, 95% CI 0.9-1.0; P < .001), received better nutrition and adequate antenatal care (OR = 0.8, 95% CI 0.8-0.8; P < .001), and were from eastern, northeastern, and southern regions of India (OR = 0.9 to 0.5). Although the prevalence of LBW in India has declined over the past decade, the extent of the decline is modest. In the coming years, health programs in India need to gear up with greater convergence between maternal health services and maternal nutrition to reduce LBW.