Prevalence of heartworm infection in cats with signs of cardiorespiratory abnormalities.
To determine prevalence of heartworm infection in a population of pet cats with cardiorespiratory abnormalities and to determine relative usefulness of clinical signs and tests in diagnosis of heartworm disease. Prospective case series. 100 client-owned cats with clinical signs of cardiorespiratory abnormalities. Cats were evaluated using CBC, modified Knott test, ELISA for serologic detection of heartworm antigen and antibodies to heartworms, thoracic radiography, and echocardiography. Cats were considered infected if they had circulating microfilaria, heartworm antigens in serum, or if heartworms were detected by echocardiography or on necropsy. Cats were considered suspicious for infection if they had 2 of the following: serum antibodies to heartworms, eosinophilia or basophilia, or indicative radiographic findings. 9 cats were infected with heartworms, resulting in a prevalence of 9%; 26 cats had evidence of heartworm exposure (i.e., serum antibodies to heartworms). Twenty cats were considered suspicious for heartworm infection. Some outdoor exposure was reported twice as often in heartworm-infected cats, compared with noninfected and suspicious cats. However, a third of infected cats were reportedly housed totally indoors. Cough and dyspnea were strong indicators of heartworm disease. Eight of 9 infected cats had serum antibodies to heartworms and heartworm antigen in serum. Thoracic radiography and echocardiography indicated heartworm infection in 6 and 7 of the 9 cats, respectively. Cough or dyspnea may indicate heartworm disease in cats; serologic tests, echocardiography, and radiography are most useful diagnostic procedures. Although living indoors is protective, it may not preclude heartworm infection in cats.


Comparison of haplotype inference methods using genotypic data from unrelated individuals.
Haplotypes are gaining popularity in studies of human genetics because they contain more information than does a single gene locus. However, current high-throughput genotyping techniques cannot produce haplotype information. Several statistical methods have recently been proposed to infer haplotypes based on unphased genotypes at several loci. The accuracy, efficiency, and computational time of these methods have been under intense scrutiny. In this report, our aim was to evaluate haplotype inference methods for genotypic data from unrelated individuals. We compared the performance of three haplotype inference methods that are currently in use--HAPLOTYPER, hap, and PHASE--by applying them to a large data set from unrelated individuals with known haplotypes. We also applied these methods to coalescent-based simulation studies using both constant size and exponential growth models. The performance of these methods, along with that of the expectation-maximization algorithm, was further compared in the context of an association study. While the algorithm implemented in the software PHASE was found to be the most accurate in both real and simulated data comparisons, all four methods produced good results in the association study.


Combination therapy of mycophenolate mofetil and tacrolimus in lupus nephritis.
Since most lupus nephritis patients have an incomplete response to mycophenolate mofetil, combination regimens may improve outcomes. Tacrolimus (FK506) has shown some benefit in lupus nephritis in small trials, and combined with mycophenolate mofetil is standard immunosuppression in transplant patients. We investigate the addition of FK506 to mycophenolate mofetil, in patients who were mycophenolate mofetil failures. All patients were part of a prospective cohort, but evaluated retrospectively. Seven lupus nephritis patients (mean age 27.1, 100% female, 42% Caucasian and 42% African American) were evaluated. Three patients had combined ISN class III and V, two ISN class IV, one ISN class V and II and one ISN class IV and V. Six were taking an ACE-inhibitor or angiotensin receptor blocker, 6 hydroxychloroquine and 5 prednisone (mean dose 11.5 mg; range 0-30 mg). Mean mycophenolate mofetil dose at time of tacrolimus addition was 2.8 g (range 2-3 g). Mean tacrolimus dose was 3.4 mg (range 2-8 mg) titrated to a mean level of 4.67 ng/dl (range 2.2-11.8 ng/dl) for a mean of duration of 16 months (range 2-54 months). Two patients continued both therapies, while five discontinued therapy. One patient achieved a complete renal remission, while three achieved partial remission with 82.9%, 77.1%, 55.3% reductions in proteinuria. Toxicity limited the use of combination therapy: diabetic ketoacidosis (one patient), pneumonia (two) and muscle pain (two). These data suggest that adding tacrolimus in patients refractory to mycophenolate mofetil might have some benefit, although complete responses were rare. Unfortunately, tacrolimus toxicity appeared to be prevalent in these systemic lupus erythematosus patients, limiting its long term use.


Free vibrations of an electroelastic body under biasing fields.
We present a systematic analysis of the eigen-value problem associated with free, small-amplitude vibrations superposed on finite biasing fields in an electroelastic body. An abstract formulation is introduced. The operators in the abstract formulation are shown to be self-adjoint, from which a series of fundamental properties of resonant frequencies and modes are proved concisely. A variational formulation and a perturbation analysis of the eigenvalue problem also are given based on the abstract formulation.


A new deepwater species of Stauromedusae, Lucernaria janetae (Cnidaria, Staurozoa, Lucernariidae), and a preliminary investigation of stauromedusan phylogeny based on nuclear and mitochondrial rDNA data.
The deepwater stauromedusan Lucernaria janetae n. sp is described from adult and juvenile specimens collected from the East Pacific Rise. Lucernaria janetae is the first species in the genus recorded from the Pacific Ocean, and differs from its congeners in size and morphology. Mitochondrial (16S) and nuclear (SSU) ribosomal gene sequences from L. janetae were analyzed with those of representative stauromedusan taxa to evaluate stauromedusan monophyly. Both genes recovered a strongly monophyletic Stauromedusae that is the sister group to all other medusozoans. Support of these hypotheses is robust to method of phylogenetic reconstruction and to outgroup selection, buttressing the argument that Stauromedusae should be recognized as the class Staurozoa. The molecular markers used here favor the same topology of relationships among our samples and clearly distinguished between two species, Haliclystus sanjuanensis and H. octoradiatus, that have been considered synonymous by many workers. A stable systematic framework for Stauromedusae appears achievable through comprehensive study of both morphological and sequence data.


Non-opioid drugs for pain management in labour.
Labour is a normal physiological process, but is usually associated with pain and discomfort. Numerous methods are used to relieve labour pain. These include pharmacological (e.g. epidural, opioids, inhaled analgesia) and non-pharmacological (e.g. hypnosis, acupuncture) methods of pain management. Non-opioid drugs are a pharmacological method used to control mild to moderate pain. To summarise the evidence regarding the effects and safety of the use of non-opioid drugs to relieve pain in labour. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 February 2012). Randomised controlled trials (RCTs) using non-opioid drugs (non-steroidal anti-inflammatory drugs (NSAIDs); paracetamol; antispasmodics; sedatives and antihistamines) in comparison with placebo or standard care; different forms of non-opioid drugs (e.g. sedatives versus antihistamines); or different interventions (e.g. non-opioids versus opioids) for women in labour. Quasi-RCTs and trials using a cross-over design were not included. Cluster-randomised RCTs were eligible for inclusion but none were identified for inclusion. Two review authors independently assessed for inclusion all studies identified by the search strategy, carried out data extraction and assessed risk of bias. We resolved any disagreement through discussion with a third author. Data were checked for accuracy. Nineteen studies randomising a total of 2863 women were included in this review. There were three main comparison groups: 15 studies compared non-opioid drugs with placebo or no treatment (2133 women); three studies compared non-opioid drugs with opioids (563 women); and three studies compared one type of non-opioid drug with a different type or dose of non-opioid drug (590 women). Some of the studies included three or more groups and so have been put in more than one comparison. Overall, there was little difference between groups for most of the comparisons. Any differences observed for outcomes were mainly limited to one or two studies. Non-opioid drugs (sedatives) were found to offer better pain relief (mean difference (MD) -22.00; 95% confidence interval (CI) -35.86 to -8.14, one trial, 50 women), better satisfaction with pain relief (sedatives and antihistamines) (risk ratio (RR) 1.59; 95% CI 1.15 to 2.21, two trials, 204 women; RR 1.80; 95% CI 1.16 to 2.79, one trial, 223 women) and better satisfaction with the childbirth experience (RR 2.16; 95% CI 1.34 to 3.47, one trial, 40 women) when compared with placebo or no treatment. However, women having non-opioid drugs (NSAIDs or antihistamines) were less likely to be satisfied with pain relief compared with women having opioids (RR 0.50; 95% CI 0.27 to 0.94, one trial, 76 women; RR 0.73; 95% CI 0.54 to 0.98, one trial, 223 women). Women receiving the antihistamine hydroxyzine were more likely to express satisfaction with pain relief compared with the antihistamine promethazine (RR 1.21; 95% CI 1.02 to 1.43, one trial, 289 women). Women receiving sedatives were more likely to express satisfaction with pain relief compared with antihistamines (RR 1.52; 95% CI 1.06 to 2.17, one study, 157 women). The majority of studies were conducted over 30 years ago. The studies were at unclear risk of bias for most of the quality domains.Opioids appear to be superior to non-opioids in satisfaction with pain relief, while non-opioids appear to be superior to placebo for pain relief and satisfaction with the childbirth experience. There were little data and no evidence of a significant difference for any of the comparisons of non-opioids for safety outcomes. Overall, the findings of this review demonstrated insufficient evidence to support a role for non-opioid drugs on their own to manage pain during labour.


Short-term plasticity of gray matter associated with leptin deficiency and replacement.
Leptin affects neurogenesis, neuronal growth, and viability. We previously reported that leptin supplementation increased gray matter (GM) concentration in the anterior cingulate gyrus (ACG), cerebellum, and inferior parietal lobule, areas that are also involved in food intake. The aim of this study was to report the changes in brain structure at different states of leptin supplementation. We conducted a nonrandomized trial. We studied three adults with congenital leptin deficiency due to a mutation in the leptin gene. Patients received treatment with recombinant methionyl human leptin, with annual 11- to 36-d periods of treatment withholding followed by treatment restoration over 3 yr. GM concentration (by voxel-based morphometry analysis of magnetic resonance scans) was correlated with body mass index (BMI) and leptin supplementation. Annually withholding leptin supplementation for several weeks increased BMI and reversed the original effects of leptin in the cerebellum and ACG. The changes in the ACG were consistent with an indirect effect of leptin mediated through increased BMI. In the cerebellum, where leptin receptors are most dense, GM changes appeared to be direct effects of leptin. Leptin restoration did not lead to recovery of GM in the short term but did lead to an unexpected GM increase in the posterior half of the left thalamus, particularly the pulvinar nucleus. These findings provide the first in vivo evidence of remarkably plastic, reversible, and regionally specific effects of leptin on human brain morphology. They suggest that leptin may have therapeutic value in modulating plasticity-dependent brain functions.


Clinical Significance of Stiffness during Endoscopic Surgery for Intracerebral Hemorrhage: A Retrospective Study.
Studies regarding hematoma stiffness and removal difficulty are scarce. This study explored the association between hematoma stiffness and surgical results of endoscopic hematoma removal for intracerebral hemorrhage. It also aimed to clarify factors associated with hematoma stiffness. We classified intracerebral hematoma as either soft or firm stiffness by retrospectively evaluating operative videos by two neurosurgeons. The interobserver reliability of the classification was assessed by calculating the κ values. We investigated the relationship between hematoma stiffness and surgical results. Favorable hematoma removal (FHR) was defined as a residual hematoma volume of ≤15 mL or removal rate of ≥70%. Furthermore, we compared the background characteristics, imaging findings, and laboratory data between the two groups. Forty patients were included in this study. The mean baseline hematoma volume was 69.9 mL (range, 41.3-97.6 mL). FHR was accomplished in 35 cases (87.5%). Thirty-four patients (85%) were in the soft hematoma group (group S). Six patients (15%) were in the firm hematoma group (group F). Classification of hematoma stiffness demonstrated an excellent degree of interobserver agreement (κ score = 0.91). Patients in group S had a high FHR rate (p = 0.018) and short endoscopic procedure times (p = 0.00034). The island sign was present in group S (p = 0.030). Patients in group F had significantly high fibrinogen levels (p = 0.049) and low serum total calcium (p = 0.032), hemoglobin (p = 0.041), and hematocrit (p = 0.011) levels. Hematoma stiffness during endoscopic surgery for intracerebral hemorrhage correlates with surgical results, including the endoscopic procedure time and accomplishing rate of FHR.


Consistency and change in the development of premature infants weighing less than 1,501 grams at birth.
Ninety-four infants with birth weights less than 1,501 g were evaluated on neurologic functioning and mental abilities at 1 year and, again, at 3 to 4 years of age. Results of the examination showed high correspondence in neurologic status and in mental ability between infancy and the preschool period, particularly for children who were diagnosed as clearly normal or abnormal at 1 year. In addition, poorer performance in a test of infant mental ability (which relies primarily on sensorimotor skills), in motor skills, and in neurologic functioning, respectively, were linked to lower IQ, difficulties in expressive language, and articulation deficits at the preschool age. Socioeconomic status predicted 3-year IQ scores and changes in mental ability scores but was not a factor in determining either preschool age neurologic status or changes in neurologic status in the children studied. Socioeconomic status of the children was less predictive of preschool outcome than results of the 1-year examinations.


Stable isotopes reveal the effect of trawl fisheries on the diet of commercially exploited species.
Bottom trawling can change food availability for benthivorous demersal species by (i) changing benthic prey composition through physical seabed impacts and (ii) by removing overall benthic consumer biomass increasing the net availability of benthic prey for remaining individuals. Thus trawling may both negatively and positively influence the quantity and quality of food available. Using δ 13C and δ 15N we investigated potential diet changes of three commercially exploited species across trawling gradients in the Kattegat (plaice, dab and Norway lobster (Nephrops)) and the Irish Sea (Nephrops). In the Kattegat, trawling affected primarily the biomass of benthic consumers, lowering competition. Nephrops showed significant positive relationships for δ 13C and a domed relationship for δ 15N with trawling. In the Irish Sea, intense trawling had a negative effect on benthic prey. δ 13C and δ 15N thus showed the inverse relationships to those observed in the Kattegat. Plaice from the Kattegat, showed a significant relationship with trawling intensity for δ 13C, but not for δ 15N. No relationship was found for dab. Changes of δ 13C and δ 15N correlated with changes in condition of species. The results show that the removal of demersal competitors and benthos by trawling can change the diets of commercial species, ultimately affecting their body condition.


[Study of accidents involving children assisted at an emergency ward].
The aim of this study was identify cases of accidents victimizing children assisted at the emergence ward of a general hospital. Data were collected from January to March, 1999 through a protocol with variables related to the identification of the accidents as well as of the children. The sample in the study consisted of 890 children of whom 56.1% were males and 43.9% were females. The most prevalent accident was fall (46.9%), the age with a major incidence was between 7 and 11 years old, the parents were present to 43.4% of the cases. The children were discharged from hospital after being given care in 95.7% of the cases.


Polyphasic characterization of xanthomonads pathogenic to members of the Anacardiaceae and their relatedness to species of Xanthomonas.
We have used amplified fragment length polymorphism (AFLP), multilocus sequence analysis (MLSA) and DNA-DNA hybridization for genotypic classification of Xanthomonas pathovars associated with the plant family Anacardiaceae. AFLP and MLSA results showed congruent phylogenetic relationships of the pathovar mangiferaeindicae (responsible for mango bacterial canker) with strains of Xanthomonas axonopodis subgroup 9.5. This subgroup includes X. axonopodis pv. citri (synonym Xanthomonas citri). Similarly, the pathovar anacardii, which causes cashew bacterial spot in Brazil, was included in X. axonopodis subgroup 9.6 (synonym Xanthomonas fuscans). Based on the thermal stability of DNA reassociation, consistent with the AFLP and MLSA data, the two pathovars share a level of similarity consistent with their being members of the same species. The recent proposal to elevate X. axonopodis pv. citri to species level as X. citri is supported by our data. Therefore, the causal agents of mango bacterial canker and cashew bacterial spot should be classified as pathovars of X. citri, namely X. citri pv. mangiferaeindicae (pathotype strain CFBP 1716) and X. citri pv. anacardii (pathotype strain CFBP 2913), respectively. Xanthomonas fuscans should be considered to be a later heterotypic synonym of Xanthomonas citri.


A novel and efficient electrochemiluminescence sensing strategy for the determination of trimethylamine oxide in seafood.
A novel and efficient electrochemiluminescence (ECL) sensing strategy and a solid-state ECL sensor was proposed to detect trimethylamine oxide (TMAO), which is widely presented in marine species and has important physiological functions. TMAO was reduced by Fe(II)-EDTA complex to trimethylamine, acting as coreactant, to amplify the ECL response of the Ru (bpy)32+ system. To improve the detection sensitivity and efficiency, a robust solid-state ECL probe was prepared and a flow injection ECL detection system was established with a specially designed flow ECL unit, under the excitation of stepping pulse potentials. Under optimized experimental conditions, the developed ECL sensor worked well for TMAO detection in a wide linear range of 10.00 μM to 1.00 mM with a limit of detection of 3.41 μM. It was successfully applied to determine TMAO in various species of seafood samples. This work provides a promising strategy for TMAO detection.


Star fruit intoxication in a chronic renal failure patient: case report.
Chronic renal failure is a high morbidity and mortality condition, with its terminal phase incidence and prevalence steadily growing year after year. According to the Sociedade Brasileira de Nefrologia [Brazilian Society of Nephrology], the main causes of renal failure are arterial hypertension, glomerulonephritis and diabetes mellitus. Several factors are implied on chronic renal failure patients' risk of mortality, particularly age, diabetes and associated co-morbidities. For patients below 50 years old, the 5 years survival rate is 62% and for those above this age and with diabetes mellitus, just 23%. Star fruit is native from Asia, and widespread in tropical countries; this fruit was reported as having a neurotoxin able to cause serious neurological changes in chronic renal disease patients. These may range from mild features, such as hiccup and confusion, to serious episodes with seizures and death. This neurotoxin apparently inhibits specifically the GABAergic conduction system. This paper describes a case involving a chronic renal disease patient who, after ingesting star fruit, featured malaise, nausea and vomiting, followed by repeated convulsions and died even though undergoing conventional hemodialysis therapy.


Incidence of pocket hematoma after electrophysiological device placement: dual antiplatelet therapy versus low-molecular-weight heparin regimen.
Given the increasing number of patients who require dual antiplatelet (DAP) therapy and electrophysiological device (EPD) placement, perioperative antiplatelet management is a current challenge. In this study, we investigated the incidence of pocket hematoma formation after EPD placement in patients undergoing DAP therapy or an alternative low-molecular-weight heparin (LMWH) regimen. This clinical observational study was performed from July 2010 to July 2012. In total, 171 patients were enrolled in the analysis after meeting the inclusion criteria. These patients were divided into two groups: 86 patients were treated with DAP therapy at the time of device implantation, and the DAP therapy was discontinued for 5 to 7 days and replaced with enoxaparin before device implantation in the other 85 patients. Adenosine phosphate (ADP)-mediated platelet aggregation and arachidonic acid-induced platelet aggregation were tested preoperatively. We compared the incidence of pocket hematoma between the two groups and the association of pocket hematoma development with ADP-mediated platelet aggregation and arachidonic acid-induced platelet aggregation. The incidence of pocket hematoma in the patients who continued DAP was lower than that in the patients who replaced the dual antiplatelet regimen with LMWH (3.49% vs. 16.47%, respectively; X (2) = 6.66, P < 0.01). Among the patients who continued DAP therapies, the rate of ADP-mediated platelet aggregation inhibition in patients with pocket hematomas was higher than that in patients without pocket hematomas. None of the patients undergoing DAP or enoxaparin therapy developed pocket infection, thromboembolic events, or other serious complications. Multiple logistic regression analysis revealed that LMWH therapy was an independent risk factor for the development of pocket hematoma (RR = 0.054, 95%CI = 0.012-0.251). Furthermore, patients undergoing LMWH therapy were 5.1-fold more likely to develop pocket hematomas than were DAP-treated individuals. Continuance of DAP therapy does not increase the risk of pocket hematoma formation after EPD placement.


Tight Regulation of Srs2 Helicase Activity Is Crucial for Proper Functioning of DNA Repair Mechanisms.
Proper DNA damage repair is one of the most vital and fundamental functions of every cell. Several different repair mechanisms exist to deal with various types of DNA damage, in various stages of the cell cycle and under different conditions. Homologous recombination is one of the most important repair mechanisms in all organisms. Srs2, a regulator of homologous recombination, is a DNA helicase involved in DNA repair, cell cycle progression and genome integrity. Srs2 can remove Rad51 from ssDNA, and is thought to inhibit unscheduled recombination. However, Srs2 has to be precisely regulated, as failure to do so is toxic and can lead to cell death. We noticed that a very slight elevation of the levels of Srs2 (by addition of a single extra copy of the SRS2 gene) leads to hyper-sensitivity of yeast cells to methyl methanesulfonate (MMS, a DNA damaging agent). This effect is seen in haploid, but not in diploid, cells. We analyzed the mechanism that controls haploid/diploid sensitivity and arrived to the conclusion that the sensitivity requires the activity of RAD59 and RDH54, whose expression in diploid cells is repressed. We carried out a mutational analysis of Srs2 to determine the regions of the protein required for the sensitization to genotoxins. Interestingly, Srs2 needs the HR machinery and its helicase activity for its toxicity, but does not need to dismantle Rad51. Our work underscores the tight regulation that is required on the levels of Srs2 activity, and the fact that Srs2 helicase activity plays a more central role in DNA repair than the ability of Srs2 to dismantle Rad51 filaments.


A role for aberrant protein palmitoylation in FFA-induced ER stress and β-cell death.
Exposure of insulin-producing cells to elevated levels of the free fatty acid (FFA) palmitate results in the loss of β-cell function and induction of apoptosis. The induction of endoplasmic reticulum (ER) stress is one mechanism proposed to be responsible for the loss of β-cell viability in response to palmitate treatment; however, the pathways responsible for the induction of ER stress by palmitate have yet to be determined. Protein palmitoylation is a major posttranslational modification that regulates protein localization, stability, and activity. Defects in, or dysregulation of, protein palmitoylation could be one mechanism by which palmitate may induce ER stress in β-cells. The purpose of this study was to evaluate the hypothesis that palmitate-induced ER stress and β-cell toxicity are mediated by excess or aberrant protein palmitoylation. In a concentration-dependent fashion, palmitate treatment of RINm5F cells results in a loss of viability. Similar to palmitate, stearate also induces a concentration-related loss of RINm5F cell viability, while the monounsaturated fatty acids, such as palmoleate and oleate, are not toxic to RINm5F cells. 2-Bromopalmitate (2BrP), a classical inhibitor of protein palmitoylation that has been extensively used as an inhibitor of G protein-coupled receptor signaling, attenuates palmitate-induced RINm5F cell death in a concentration-dependent manner. The protective effects of 2BrP are associated with the inhibition of [(3)H]palmitate incorporation into RINm5F cell protein. Furthermore, 2BrP does not inhibit, but appears to enhance, the oxidation of palmitate. The induction of ER stress in response to palmitate treatment and the activation of caspase activity are attenuated by 2BrP. Consistent with protective effects on insulinoma cells, 2BrP also attenuates the inhibitory actions of prolonged palmitate treatment on insulin secretion by isolated rat islets. These studies support a role for aberrant protein palmitoylation as a mechanism by which palmitate enhances ER stress activation and causes the loss of insulinoma cell viability.


Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21(Waf1/Cip1).
We show that the recently discovered tumor suppressor pdcd4 represses the transcription of the mitosis-promoting factor cyclin-dependent kinase (CDK)1/cdc2 via upregulation of p21(Waf1/Cip1). p21(Waf1/Cip1) inhibits CDK4/6 and CDK2. Decrease of CDK4/6 and CDK2 enhances the binding of pRb to E2F/DP, which in turn together bind to and repress the cdc2 promoter. Upregulation of CDK1/cdc2 accompanied by a malignant change was previously reported in colon cancer. We show that expression of pdcd4 as an indirect suppressor of CDK1/cdc2 is lost in progressed carcinomas of lung, breast, colon, and prostate. Furthermore, it seems that localization and expression of pdcd4 directly correlate with tumor progression. Finally, the CDK1/cdc2 inhibitor roscovitine reduces the proliferation of several tumor cell lines, suggesting that inhibition of CDK1/cdc2 may be a useful strategy against malignant transformation. Therefore, pdcd4 might serve as a novel target for antineoplastic therapies.


Clinical characteristics of gastric cancer in patients with familial adenomatous polyposis.
Familial adenomatous polyposis is an autosomal dominant hereditary disease leading to the development of numerous colorectal polyps with malignant potential. Extra-colonic neoplasms are observed often in patients with familial adenomatous polyposis, but clinical characteristics of gastric cancer associated with familial adenomatous polyposis are not well understood. We studied the clinical characteristics of five Japanese patients who developed gastric cancer after undergoing colectomy for familial adenomatous polyposis. Gastric cancer was found on gastroduodenal endoscopy performed during postoperative follow-up in all five patients. Mean ages at the time of colectomy and at the time of diagnosis of gastric cancer were 39.2 and 58 years, respectively. Importantly, gastric fundic gland polyps were undetectable in these five patients. The mean duration between colectomy and diagnosis of gastric cancer was more than 20 years in three of five patients (mean: 19 years and 1 month). Cancers were multiple in three of five patients. Two patients developed metachronous gastric cancer in the gastric remnant. All five patients presented with well to moderately differentiated adenocarcinoma; four of the five patients were stage IA. Characteristics of the gastric cancer with familial adenomatous polyposis include a long duration between occurrence of gastric cancer and colectomy, metachronous cancers, multicentric lesions, and a high rate of well to moderately differentiated adenocarcinoma. Long-term and periodic gastroduodenal surveillance endoscopy is recommended for patients with FAP who underwent colectomy.


Surveillance of Shiga toxin-producing Escherichia coli associated bloody diarrhea in Argentina.
In Argentina, hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC-HUS) infection is endemic, and reliable data about prevalence and risk factors have been available since 2000. However, information about STEC-associated bloody diarrhea (BD) is limited. A prospective study was performed during the period October 2018-June 2019 in seven tertiary-hospitals and 18 referral units from different regions, aiming to determine (i) the frequency of STEC-positive BD cases in 714 children aged 1-9 years of age and (ii) the rate of progression of bloody diarrhea to HUS. The number and regional distribution of STEC-HUS cases in the same hospitals and during the same period were also assessed. Twenty-nine (4.1%) of the BD patients were STEC-positive, as determined by the Shiga Toxin Quik Chek (STQC) test and/or the multiplex polymerase chain reaction (mPCR) assay. The highest frequencies were found in the Southern region (Neuquén, 8.7%; Bahía Blanca, 7.9%), in children between 12 and 23 month of age (8.8%), during summertime. Four (13.8%) cases progressed to HUS, three to nine days after diarrhea onset. Twenty-seven STEC-HUS in children under 5 years of age (77.8%) were enrolled, 51.9% were female; 44% were Stx-positive by STQC and all by mPCR. The most common serotypes were O157:H7 and O145:H28 and the prevalent genotypes, both among BD and HUS cases, were stx2a-only or -associated. Considering the endemic behavior of HUS and its high incidence, these data show that the rate of STEC-positive cases is low among BD patients. However, the early recognition of STEC-positive cases is important for patient monitoring and initiation of supportive treatment.


Cardiotoxicities of novel cancer immunotherapies.
Immunotherapy revolutionised oncology by harnessing the native immune system to effectively treat a wide variety of malignancies even at advanced stages. Off-target immune activation leads to immune-related adverse events affecting multiple organ systems, including the cardiovascular system. In this review, we discuss the current literature describing the epidemiology, mechanisms and proposed management of cardiotoxicities related to immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers. ICIs are monoclonal antibody antagonists that block a co-inhibitory pathway used by tumour cells to evade a T cell-mediated immune response. ICI-associated cardiotoxicities include myocarditis, pericarditis, atherosclerosis, arrhythmias and vasculitis. ICI-associated myocarditis is the most recognised and potentially fatal cardiotoxicity with mortality approaching 50%. Recently, ICI-associated dysregulation of the atherosclerotic plaque immune response with prolonged use has been linked to early progression of atherosclerosis and myocardial infarction. Treatment strategies include immunosuppression with corticosteroids and supportive care. In CAR T-cell therapy, autologous T cells are genetically engineered to express receptors targeted to cancer cells. While stimulating an effective tumour response, they also elicit a profound immune reaction called cytokine release syndrome (CRS). High-grade CRS causes significant systemic abnormalities, including cardiovascular effects such as arrhythmias, haemodynamic compromise and cardiomyopathy. Treatment with interleukin-6 inhibitors and corticosteroids is associated with improved outcomes. The evidence shows that, although uncommon, immunotherapy-related cardiovascular toxicities confer significant risk of morbidity and mortality and benefit from rapid immunosuppressive treatment. As new immunotherapies are developed and adopted, it will be imperative to closely monitor for cardiotoxicity.


Mind full of life: Does mindfulness confer resilience to suicide by increasing zest for life?
Mindfulness is a trainable skill that may enhance resilience to suicidality among vulnerable groups such as young people. The current study examined whether mindfulness protects against suicidal desire in the face of heightened risk and adversity by increasing zest for life in a sample of university students. In a prospective design, participants (N = 233) were assessed at two time points over eight weeks. Online surveys included the Mindful Attention and Awareness Scale, Zest for Life Scale, Interpersonal Needs Questionnaire, Kessler Psychological Distress Scale, and items assessing suicidal ideation and suicidal intent. Baseline mindfulness was associated with lower suicidal ideation and intent at follow-up. Moderated mediation analyses confirmed the effects of mindfulness on ideation and intent were mediated by zest for life and these indirect effects were stronger at higher versus lower levels of general (psychological distress) and suicide-specific (perceived burdensomeness and thwarted belongingness) risk. Single item assessments of suicidal desire. Findings suggest that mindfulness protects against suicidal desire in conditions of heightened risk and adversity by enhancing one's orientation towards a life worth living. Theories of suicide should consider the dynamic interplay between risk and life-sustaining resilience, while clinicians treating suicidality could use mindfulness strategies to strengthen the desire to (re)engage with life, thereby complementing direct amelioration of suicide risk factors.


Procedure for prolapse and hemorrhoids vs traditional surgery for outlet obstructive constipation.
To compare the clinical efficacies of two surgical procedures for hemorrhoid rectal prolapse with outlet obstruction-induced constipation. One hundred eight inpatients who underwent surgery for outlet obstructive constipation caused by internal rectal prolapse and circumferential hemorrhoids at the First Affiliated Hospital of Xinjiang Medical University from June 2012 to June 2013 were prospectively included in the study. The patients with rectal prolapse hemorrhoids with outlet obstruction-induced constipation were randomly divided into two groups to undergo either a procedure for prolapse and hemorrhoids (PPH) (n = 54) or conventional surgery (n = 54; control group). Short-term (operative time, postoperative hospital stay, postoperative urinary retention, postoperative perianal edema, and postoperative pain) and long-term (postoperative anal stenosis, postoperative sensory anal incontinence, postoperative recurrence, and postoperative difficulty in defecation) clinical effects were compared between the two groups. The short- and long-term efficacies of the two procedures were determined. In terms of short-term clinical effects, operative time and postoperative hospital stay were significantly shorter in the PPH group than in the control group (24.36 ± 5.16 min vs 44.27 ± 6.57 min, 2.1 ± 1.4 d vs 3.6 ± 2.3 d, both P < 0.01). The incidence of postoperative urinary retention was higher in the PPH group than in the control group, but the difference was not statistically significant (48.15% vs 37.04%). The incidence of perianal edema was significantly lower in the PPH group (11.11% vs 42.60%, P < 0.05). The visual analogue scale scores at 24 h after surgery, first defecation, and one week after surgery were significantly lower in the PPH group (2.9 ± 0.9 vs 8.3 ± 1.1, 2.0 ± 0.5 vs 6.5 ± 0.8, and 1.7 ± 0.5 vs 5.0 ± 0.7, respectively, all P < 0.01). With regard to long-term clinical effects, the incidence of anal stenosis was lower in the PPH group than in the control group, but the difference was not significant (1.85% vs 5.56%). The incidence of sensory anal incontinence was significantly lower in the PPH group (3.70% vs 12.96%, P < 0.05). The incidences of recurrent internal rectal prolapse and difficulty in defecation were lower in the PPH group than in the control group, but the differences were not significant (11.11% vs 16.67% and 12.96% vs 24.07%, respectively). PPH is superior to the traditional surgery in the management of outlet obstructive constipation caused by internal rectal prolapse with circumferential hemorrhoids.


Length of hospitalisation for people with severe mental illness.
In high income countries, over the last three decades, the length of hospital stays for people with serious mental illness has reduced drastically. Some argue that this reduction has led to revolving door admissions and worsening mental health outcomes despite apparent cost savings, whilst others suggest longer stays may be more harmful by institutionalising people to hospital care. To determine the clinical and service outcomes of planned short stay admission policies versus a long or standard stay for people with serious mental illnesses. We searched the Cochrane Schizophrenia Group's register of trials (July 2007). We included all randomised trials comparing planned short with long/standard hospital stays for people with serious mental illnesses. We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a fixed effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated fixed effects weighted mean differences (WMD). We included six relevant trials. We found no significant difference in hospital readmissions between planned short stays and standard care at one year (n=651, 4 RCTs, RR 1.26 CI 1.0 to 1.6). Short hospital stay did not confer any benefit in terms of 'loss to follow up compared with standard care (n=453, 3 RCTs, RR 0.87 CI 0.7 to 1.1). There were no significant differences for the outcome of 'leaving hospital prematurely' (n=229, 2 RCTs, RR 0.77 CI 0.3 to 1.8). More post-discharge day care was given to participants in the short stay group (n=247, 1 RCT, RR 4.52 CI 2.7 to 7.5, NNH 3 CI 2 to 6) and people from the short stay groups were more likely to be employed at two years (n=330, 2 RCTs, RR 0.61 CI 0.5 to 0.8, NNT 5 CI 4 to 8). Economic data were few but, once discharged, costs may be more for those allocated to an initial short stay. The effects of hospital care and the length of stay is important for mental health policy. We found limited data, although outcomes do suggest that a planned short stay policy does not encourage a 'revolving door' pattern of admission and disjointed care for people with serious mental illness. More large, well-designed and reported trials are justified.


Self-Medication With Over-the-counter Medicines Among the Working Age Population in Metropolitan Areas of Thailand.
Background and Objectives: Self-medication with over-the-counter (OTC) medicines is becoming an increasingly popular practice around the world. The global prevalence rate of self-medication ranges from 11.2% to 93.7%, depending on the target population and country. However, there is a lack of data on the prevalence and practices of self-medication among the working-age population, particularly in Thailand metropolitan areas. The current study describes the prevalence of self-medication practices, adverse drug reactions and severity, reasons for self-medication, and basic medication knowledge among people of working age in metropolitan areas in Thailand. Methods: We conducted an online cross-sectional study between December 2020 and January 2021. Descriptive statistics were used to analyze self-medication data. A chi-square test was used to assess the association between self-medication and sociodemographic characteristics. Results: This study found high prevalence of self-medication among the working-age population in metropolitan areas of Thailand (88.2%). The most commonly used drug groups were NSAIDs (34.8%) and antibiotics (30.2%). Minor illness and easy access to pharmacies were the most common reasons for self-medication. Almost half of the participants' illnesses (42.6%) for which they self-medicated were not always completely cured, necessitating treatment at a hospital or clinic. Although only a small number of participants (ranged from 0.6 to 6.6%) experienced adverse drug reactions as a result of self-medication, some had severe symptoms that disrupted their daily lives or required hospitalization. In terms of basic medication knowledge, we discovered that study participants misunderstood some antibiotic drug concepts. Conclusions: According to the study findings, it is recommended that more information about the risks of self-medication, drug adverse reactions, antibiotic stewardship, more supervision of the prohibition of over-the-counter drugs and selling practices, and adequate facilities for peoples access to medical services be provided at the policy level.


Melatonin and cannabinoids: mitochondrial-targeted molecules that may reduce inflammaging in neurodegenerative diseases.
Generally, the development and progression of neurodegenerative diseases are associated with advancing age, so they are usually diagnosed in late adulthood. A primary mechanism underlying the onset of neurodegenerative diseases is neuroinflammation. Based on this background, the concept of "neuroinflammaging" has emerged. In this deregulated neuroinflammatory process, a variety of immune cells participate, especially glial cells, proinflammatory cytokines, receptors, and subcellular organelles including mitochondria, which are mainly responsible for maintaining redox balance at the cellular level. Senescence and autophagic processes also play a crucial role in the neuroinflammatory disease associated with aging. Of particular interest, melatonin, cannabinoids, and the receptors of both molecules which are closely related, exert beneficial effects on the neuroinflammatory processes that precede the onset of neurodegenerative pathologies such as Parkinson's and Alzheimer's diseases. Some of these neuroprotective effects are fundamentally related to its anti-inflammatory and antioxidative actions at the mitochondrial level due to the strategic functions of this organelle. The aim of this review is to summarize the most recent advances in the study of neuroinflammation and neurodegeneration associated with age and to consider the use of new mitochondrial therapeutic targets related to the endocannabinoid system and the pineal gland.


Reflection magnitude as a predictor of mortality: the Multi-Ethnic Study of Atherosclerosis.
Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11-1.55; P=0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01-1.51; P=0.04), including the coronary calcium score, ankle-brachial index, common carotid intima-media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in P(b)=2.18; 95% CI=1.21-3.92; P=0.009). Reflection magnitude (HR=1.71; 95% CI=1.06-2.77; P=0.03) and P(b) (HR=5.02; 95% CI=1.29-19.42; P=0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis.


Shotgun proteomic analysis of yeast-elicited California poppy (Eschscholzia californica) suspension cultures producing enhanced levels of benzophenanthridine alkaloids.
The California poppy, Eschscholzia californica, produces benzophenanthridine alkaloids (BPAs), an important class of biologically active compounds. Cell cultures of E. californica were investigated as an alternative and scalable method for producing these valuable compounds; treatment with yeast extract increased production from low levels to 23 mg/g dry weight (DW) of BPAs. A shotgun proteomic analysis of E. californica cell cultures was undertaken to explore changes in metabolism associated with enhanced BPA production. We implemented differential centrifugation and then shotgun proteomics based on nanoliquid chromatography/mass spectrometry (nano-LC-MS/MS) for peptide separation and analysis. A unigene database available for E. californica was translated and utilized for protein identification. Approximately 646 proteins (3% false discovery rate at the protein level) were identified. Differentially abundant proteins observed with elicitation included enzymes involved in (S)-adenosyl methionine (SAM) biosynthesis and BPA biosynthesis. These results demonstrate (1) the identification of proteins from a medicinal plant using shotgun proteomics combined with a well-annotated, translated unigene database and (2) the potential utility of proteomics for exploring changes in metabolism associated with enhanced secondary metabolite production.


Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis.
SEE ZEKERIDOU AND LENNON DOI101093/AWW213 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Little is known about the cerebrospinal fluid autoantibody repertoire. Antibodies against the NR1 subunit of the NMDAR are thought to be pathogenic; however, direct proof is lacking as previous experiments could not distinguish the contribution of further anti-neuronal antibodies. Using single cell cloning of full-length immunoglobulin heavy and light chain genes, we generated a panel of recombinant monoclonal NR1 antibodies from cerebrospinal fluid memory B cells and antibody secreting cells of NMDAR encephalitis patients. Cells typically carried somatically mutated immunoglobulin genes and had undergone class-switching to immunoglobulin G, clonally expanded cells carried identical somatic hypermutation patterns. A fraction of NR1 antibodies were non-mutated, thus resembling 'naturally occurring antibodies' and indicating that tolerance induction against NMDAR was incomplete and somatic hypermutation not essential for functional antibodies. However, only a small percentage of cerebrospinal fluid-derived antibodies reacted against NR1. Instead, nearly all further antibodies bound specifically to diverse brain-expressed epitopes including neuronal surfaces, suggesting that a broad repertoire of antibody-secreting cells enrich in the central nervous system during encephalitis. Our functional data using primary hippocampal neurons indicate that human cerebrospinal fluid-derived monoclonal NR1 antibodies alone are sufficient to cause neuronal surface receptor downregulation and subsequent impairment of NMDAR-mediated currents, thus providing ultimate proof of antibody pathogenicity. The observed formation of immunological memory might be relevant for clinical relapses.


A sensitive, viable-colony staining method using Nile red for direct screening of bacteria that accumulate polyhydroxyalkanoic acids and other lipid storage compounds.
The oxazine dye Nile blue A and its fluorescent oxazone form, Nile red, were used to develop a simple and highly sensitive staining method to detect poly(3-hydroxybutyric acid) and other polyhydroxyalkanoic acids (PHAs) directly in growing bacterial colonies. In contrast to previously described methods, these dyes were directly included in the medium at concentrations of only 0.5 microgram/ml, and growth of the cells occurred in the presence of the dyes. This allowed an estimation of the presence of PHAs in viable colonies at any time during the growth experiment and a powerful discrimination between PHA-negative and PHA-positive strains. The presence of Nile red or Nile blue A did not affect growth of the bacteria. This viable-colony staining method was in particular applicable to gram-negative bacteria such as Azotobacter vinelandii, Escherichia coli, Pseudomonas putida, and Ralstonia eutropha. It was less suitable for discriminating between PHA-negative and PHA-positive strains of gram-positive bacteria such as Bacillus megaterium or Rhodococcus ruber, but it could also be used to discriminate between wax-ester- and triacylglycerol-negative and -positive strains of Acinetobacter calcoaceticus or Rhodococcus opacus. The potential of this new method and its application to further investigations of PHA synthases and PHA biosynthesis pathways are discussed.


Application opportunities of geographic information systems analysis to support achievement of the UNAIDS 90-90-90 targets in South Africa.
In an effort to achieve control of the HIV epidemic, 90-90-90 targets have been proposed whereby 90% of the HIV-infected population should know their status, 90% of those diagnosed should be receiving antiretroviral therapy, and 90% of those on treatment should be virologically suppressed. In this article we present approaches for using relatively simple geographic information systems (GIS) analyses of routinely available data to support HIV programme management towards achieving the 90-90-90 targets, with a focus on South Africa (SA) and other high-prevalence settings in low- and middle-income countries. We present programme-level GIS applications to map aggregated health data and individual-level applications to track distinct patients. We illustrate these applications using data from City of Johannesburg Region D, demonstrating that GIS has great potential to guide HIV programme operations and assist in achieving the 90-90-90 targets in SA.


Retinal surface en face optical coherence tomography: a new imaging approach in epiretinal membrane surgery.
To describe the clinical effectiveness of a new imaging approach: en face spectral domain optical coherence tomography of the retinal surface before and after epiretinal membrane (ERM) and internal limiting membrane peeling. Retrospective analysis of preoperative and postoperative en face spectral domain optical coherence tomography images of the inner face of the macula obtained from 20 eyes of 20 patients undergoing vitrectomy with internal limiting membrane peeling for ERM. Preoperatively, en face spectral domain optical coherence tomography imaging of the retinal surface clearly showed plaques surrounded by radiating folds because of ERM. It could also disclose areas possibly devoid of internal limiting membrane secondary to ERM contraction. A rough retinal surface was visible in the peeled area during the first postoperative month. At 3 months, various amounts of dimples were progressively observed in 13 of 15 eyes (87%). In all these cases, they lasted or increased in size and number at the last follow-up examination. Some residual epiretinal tissue was also detected by this technique. En face spectral domain optical coherence tomography of the retinal surface is an interesting complement to standard retinal optical coherence tomography section that provides an easy-to-understand global overview of the retinal surface. It can detect and classify tiny progressive morphologic changes in the texture of the retinal surface occurring after internal limiting membrane peeling.


Relationship between event-related desynchronization and cortical excitability in healthy subjects and stroke patients.
Relation between cortical excitability and magnitudes of event-related dysynchronizaton (ERD) has not been clarified. This study was investigated that relationshp between cortical excitability and ERD magnitudes in healthy subjects and stroke patients. Ten healthy subjects and four patients with stroke participated in this study. EEGs were recorded over the sensorimotor cortex (left hemisphere in healthy subjects; damaged hemisphere in stroke subjects) to calculate ERD during motor imagery,. Motor-evoked potential (MEP) induced by single-pulse transcranial magnetic stimulation over the primary motor cortex was recorded from the first dorsal interosseus (FDI) muscle at ERD magnitudes of 10% and 30%. MEP significantly increased at 10% and 30% ERD (p<0.01) than that during rest in healthy subjects. The 30% ERD condition showed significantly higher MEP than that at 10% ERD (p<0.05). In stroke patients, MEP increased with ERD induced by motor imagery, but the change of MEP to ERD amplitude was critically different among the subject. ERD magnitude corresponds to corticospinal excitability increases in healthy subjects and patients with hemiplegic stroke. BCI based on motor imagery-induced ERD may be a potential rehabilitation strategy for patients with hemiplegic stroke.


Treatment of severe Crohn's disease using antimycobacterial triple therapy--approaching a cure?
Mycobacterium avium subspecies paratuberculosis is probably the best candidate for a microbial cause of Crohn's disease although arguments to the contrary can be equally convincing. Growing evidence suggests that prolonged antimycobacterial combination therapy can improve Crohn's disease in some patients. To report long-term observations in patients with severe Crohn's disease treated with triple macrolide-based antimycobacterial therapy. A series of 12 patients (7 male, 5 female; aged 15-42 years) with severe, obstructive or penetrating Crohn's disease were recruited. Patients failing maximal therapy were commenced prospectively on a combination of rifabutin (450 mg/d), clarithromycin (750 mg/d) and clofazimine (2 mg/kg/d). Progress was monitored through colonoscopy, histology, clinical response and Harvey-Bradshaw activity index. Follow-up data were available for up to 54 months of therapy Six out of 12 patients experienced a full response to the antiMycobacterium avium subspecies paratuberculosis combination achieving complete clinical, colonoscopic and histologic remission of Crohn's disease. Four of these patients were able to cease treatment after 24-46 months, 3 of whom remained in total remission without treatment for up to 26 months and one patient relapsed after six months off treatment. A partial response to the anti-Mycobacterium avium subspecies paratuberculosis combination was seen in 2 patients showing complete clinical remission with mild histologic inflammation. Return to normal of terminal ileal strictures occurred in 5 patients. Harvey-Bradshaw activity index in patients showing a full or partial response to therapy fell from an initial 13.4 +/- 1. 91 to 0. 5 +/- 0. 47 [n = 8, p < 0. 001) after 52-54 months. Reversal of severe Crohn's disease has been achieved in 6/12 patients using prolonged combination anti-Mycobacterium avium subspecies paratuberculosis therapy alone. Three patients remain in long-term remission with no detectable Crohn's disease off all therapy These results support a causal role for Mycobacterium avium subspecies paratuberculosis in Crohn's disease while also suggesting that a cure may become possible.


The ejaculatory biology of leafcutter ants.
The eusocial ants are unique in that females (queens) acquire and store sperm on a single mating flight early in adult life. This event largely determines the size (possibly millions of workers), longevity (possibly decades) and genetic variation of the colonies that queens found, but our understanding of the fundamental biology of ejaculate production, transfer and physiological function remains extremely limited. We studied the ejaculation process in the leafcutter ant Atta colombica and found that it starts with the appearance of a clear pre-ejaculatory fluid (PEF) at the tip of the endophallus that is followed by the joint expulsion of the remainder of accessory gland (AG) secretion, sperm, accessory testes (AT) secretion, and a small mating plug. PEF, AG secretion and AT secretion all contribute to sperm survival, but PEF and AG secretion also reduce the survival of sperm from other males. We show that PEF is produced in the AGs and is likely identical to AG secretion because protein-banding patterns of PEF and AG secretion were similar on 1D electrophoresis gels, but differed from the protein-banding pattern of AT secretion. We show that proteins in AG secretion are responsible for the incapacitation of rival sperm and infer that transfer of AG secretion prior to sperm may allow these components to interact with rival sperm, while at the same time providing a supportive biochemical environment for the arrival of own sperm.


The impact of growth hormone replacement therapy on adipokines, but not upon Ghrelin.
Besides growth acceleration, growth hormone (GH) therapy of GH deficient (GHD) children improves body composition by decreasing body fat. This effect is due to GH interaction with lipid and carbohydrate metabolism, possibly also mediated by adipokines secreted by adipose tissue, and ghrelin. This study aimed to assess the impact of oneyear GH replacement therapy on the metabolic profile, adipokines, and acylated/ unacylated ghrelin of prepubertal children with GHD. Prospective observational study of 42 non-obese, prepubertal children with GHD followed up for twelve months. Mean lipid, carbohydrate, adipokine profiles, acylated/unacylated ghrelin, and body composition data before therapy onset were compared with measurements obtained after 6 and 12 months of GH therapy. Total body fat content and body fat percentage decreased significantly, while the lipid profile improved over the study period in the 42 GHD children with a mean age of 9.2 ±2.6 years. The levels of leptin and unacylated ghrelin decreased significantly, whereas adiponectin and acylated ghrelin values increased after GH therapy. In regression analysis models, GH treatment (reflected by increased absolute values or standard deviations of IGF1) influences the variation of leptin and adiponectin, but not ghrelin, independently of body composition - lean or fat mass. GH replacement therapy improves body composition, lipid, and adipokine profile in GHD children. Also, GH replacement therapy directly impacts leptin and adiponectin concentrations, independently of body composition. Further research is needed to identify the molecular mechanisms and metabolic pathways by which the GH/IGF1 axis influences adipokines secretion.


The Largest Chinese Cohort Study Indicates Homologous Recombination Pathway Gene Mutations as Another Major Genetic Risk Factor for Colorectal Cancer with Heterogeneous Clinical Phenotypes.
While genetic factors were associated with over 30% of colorectal cancer (CRC) patients, mutations in CRC-susceptibility genes were identified in only 5% to 10% of these patients. Besides, previous studies on hereditary CRC were largely designed to analyze germline mutations in patients with single genetic high-risk factor, which limited understanding of the association between genotype and phenotypes. From January 2015 to December 2018, we retrospectively enrolled 2,181 patients from 8,270 consecutive CRC cases, covering 5 categories of genetic high-risk factors. Leukocyte genomic DNA was analyzed for germline mutations in cancer predisposition genes. The germline mutations under each category were detected and analyzed in association with CRC susceptibility, clinical phenotypes, and prognoses. A total of 462 pathogenic variants were detected in 19.3% of enrolled CRC patients. Mismatch repair gene mutation was identified in 9.1% of patients, most prevalent across all high-risk groups. Homologous recombination (HR) gene mutations were detected in 6.5% of cases, penetrated in early-onset and extra-colonic cancer risk groups. Mutations in HR genes, including BARD1, RAD50, and ATM, were found to increase CRC risk with odds ratios of 2.8-, 3.1-, and 3.1-fold, respectively. CRC patients with distinct germline mutations manifested heterogeneous phenotypes in clinicopathology and long-term prognoses. Thus, germline mutation screenings should be performed for CRC patients with any of those genetic risk factors. This study also reveals that HR gene mutations may be another major driver for increased CRC risk.


Psychological distress among undergraduate medical students: the influence of excessive daytime sleepiness and family functioning.
Mental health problems among undergraduate medical students is a well-known issue; however, their associated risk factors have been poorly studied. We aimed to assess the hypothesis that medical students have a higher prevalence of psychological distress and to explain this prevalence considering common risk factors for mental disorders. This was a cross-sectional, questionnaire-based descriptive study conducted with 467 Colombian undergraduate medical students from different years of training. Validated and widely used self-report questionnaires of psychological distress, daytime sleepiness, and family functioning were included. In addition, measurements of smoking, alcohol, and caffeine intake were used. We found a prevalence of psychological distress, depressive symptoms and anxiety symptomatology of 65.9%, 75.3%, and 50.5%, respectively. Furthermore, 20.6% showed both psychological distress and excessive daytime sleepiness. Adjusted risk ratio analysis showed that poor family functioning, the presence of excessive daytime sleepiness, and caffeine consumption were significant risk factors for high levels of psychological distress. Additionally, psychological distress and daytime sleepiness were related to the year of training. Our results replicate in part previous findings of poor mental health among undergraduate medical students compared with mental health in general population and provide novel findings that family functioning plays a significant role as an important explanatory factor. The current study has high relevance for future research and interventions focused on prevention of medical errors, conflicts in the physician-patient relationship and the personal safety of undergraduate medical students.


10p for an angiogram: the cardio-oesophageal reflex.
A 57-year-old man presented at our institution with central chest pain. Serial ECGs showed dynamic T-wave changes, suggesting the possibility of unstable angina. Urgent coronary angiography revealed an unexpected finding of a radio-opaque lesion seen in the xiphisternal region during screening. Oesophogastroduodenoscopy confirmed this to be a 10p coin. The coin passed through the gastrointestinal tract without complications and the patient's symptoms and ECG changes resolved. This unusual case is a reminder that many diseases may electrocardiographically imitate an acute coronary syndrome.


[Voice quality assessment via acoustic and spectrographic analysis in patients who had endolaryngeal microsurgery].
In this study, changes in quality of voice in patients who underwent endolaryngeal microsurgery were assessed by objective voice analyses. Thirty patients (17 females, 13 males; mean age 34.3+/-11.5 years; range 17 to 65 years), who underwent endolaryngeal microsurgery because of benign vocal cord pathology and 25 people (12 females, 13 males; mean age 28.7+/-6.6 years; range 22 to 50 years), without laryngeal pathology were included in this study. Voice records, which were taken from the patients pre- and postoperatively, and also from the control group, were analyzed acoustically and spectrographically. Cool-Edit software was used for voice recording, and Praat software was used for voice analysis. Parameters, which were obtained in the study, were compared statistically. When pre- and postoperative acoustic analysis results were compared, it was found out that there was significant difference in all parameters except fundamental frequency. While S/Z ratio, and jitter and shimmer values were significantly decreased postoperatively, maximum phonation time, harmonic/noise ratio, and intensity values were significantly increased. No important changes were detected in fundamental frequency value. Postoperative and control group findings were not significantly different. At long term average spectrum analysis of the phonetically balanced read passage records, postoperative amplitude value was increased significantly, compared to preoperative values. Acoustic and spectrographic voice analyses are objective methods which can be used to assess effects of endolaryngeal microsurgery on quality of voice.


Medical, ethical and legal aspects of somatic gene therapy.
Somatic gene therapy is one of the most fascinating and important medical developments as well as a field bearing unknown risks in human medicine of the nineties. This article tries to give a short survey on the medical applications of this new technique on the one hand and reflects possible ethical and legal implications on the other hand. We conclude that only an international agreement on risk assessment and ethical principles will lead to a adequate approach to somatic gene therapy.


Child sun safety: Application of an Integrated Behavior Change model.
Childhood sun exposure increases risk of skin cancer in later life. Parents of young children play an important role in minimizing childhood sun exposure. The aim of the current study was to identify the motivational, volitional, and implicit antecedents of parents' sun-protective behaviors based on an Integrated Behavior Change model. Parents (N = 373) of 2- to 5-year-old children self-reported their intentions, attitudes, subjective norm, perceived behavioral control, autonomous and controlled motivation, action plans, habit, and past behaviors with respect to sun-protective behaviors for their children. Two weeks later (n = 273), the parents self-reported their participation in sun-protective behaviors for their child. Data were analyzed using variance-based structural equation modeling. Results showed significant direct effects of attitudes, subjective norm, perceived behavioral control, and past behavior on intentions, and significant direct effects of autonomous motivation, perceived behavioral control, intentions, action planning, habit, and past behavior on parents' participation in sun-protective behaviors for their child. There were also significant total indirect effects of autonomous motivation on intentions mediated by attitudes and subjective norm. Current results indicate that parents' sun-protective behaviors toward their children are a function of motivational (autonomous motivation, intentions), volitional (action planning), and implicit (habit) factors. The findings from the current study provide formative data to inform the development of behavior change interventions to increase parents' participation in sun-protective behaviors for their children. (PsycINFO Database Record


Reaction dynamics. Vibrational relaxation and microsolvation of DF after F-atom reactions in polar solvents.
Solvent-solute interactions influence the mechanisms of chemical reactions in solution, but the response of the solvent is often slower than the reactive event. Here, we report that exothermic reactions of fluorine (F) atoms in d3-acetonitrile and d2-dichloromethane involve efficient energy flow to vibrational motion of the deuterium fluoride (DF) product that competes with dissipation of the energy to the solvent bath, despite strong solvent coupling. Transient infrared absorption spectroscopy and molecular dynamics simulations show that after DF forms its first hydrogen bond on a subpicosecond time scale, DF vibrational relaxation and further solvent restructuring occur over more than 10 picoseconds. Characteristic dynamics of gas-phase F-atom reactions with hydrogen-containing molecules persist in polar organic solvents, and the spectral evolution of the DF products serves as a probe of solvent reorganization induced by a chemical reaction.


Hemoglobin is an effective inducer of hyphal differentiation in Candida albicans.
Hemoglobin is an abundant protein in the host vascular compartment and a source of iron, heme, and amino acids for many pathogens. The human fungal pathogen Candida albicans uses hemoglobin as an iron source as well as a signaling molecule to alter gene expression and induce adhesion to several extracellular matrix proteins. We now report that hemoglobin can promote true hyphal morphogenesis. Hemoglobin added to yeast cells at 37 degrees C rapidly induced expression of the hypha-specific genes HWP1 and ECE1 coincident with the pattern of hyphal development. A synthetic medium buffered with phosphate at pH 7.2 and containing physiological glucose (5 mM) and low ammonium ion (0.1 mM) was optimal for the response to hemoglobin. High glucose (110 mM), high ammonium ion (20 mM), and 0.1 mM glutamine were all inhibitory. Heme, free globin, or immobilized hemoglobin could not replicate the activity of hemoglobin to induce germ tubes or hypha-specific gene expression at 37 degrees C under optimized conditions. This implicates the previously described Hb-signaling receptor in hyphal formation. This response was also dependent upon the presence of the morphogenesis regulator Efg1p, but the MAP-kinase specific transcription factor Cph1p was not required. These data define a role for the host-factor hemoglobin in Efg1p-dependent hyphal development.


[The "AMDP-rating scale for obsessive-compulsive symptoms": The 2nd version].
The "Association of Methodology and Documentation in Psychiatry" (AMDP) has developed the 2nd version of a new observer-rated scale for a quick and precise assessment of obsessive-compulsive symptoms. The first version of the scale comprised 20 items on the dimensions "description", "distress and impairment" and "emotion and cognition". The item pool of the 2. version was enlarged to 44 items to accomplish a differentiated assessment of obsessions and compulsions and to assess the associated passive avoidance behaviour. The results of an empirical study (n = 141) demonstrated excellent internal consistency (Cronbach's alpha = 0,93), a split-half reliability of 0,83 (Spearman-Brown), a test-retest reliability of r = 0,84, a high interrater-reliability, a high differential validity and good convergent validity with the Hamburger Zwangsinventar (HZI) and the SCL-90-R. The results are presented and their implications on the final steps of the development of the scale will be discussed.


Protein-DNA binding dynamics predict transcriptional response to nutrients in archaea.
Organisms across all three domains of life use gene regulatory networks (GRNs) to integrate varied stimuli into coherent transcriptional responses to environmental pressures. However, inferring GRN topology and regulatory causality remains a central challenge in systems biology. Previous work characterized TrmB as a global metabolic transcription factor in archaeal extremophiles. However, it remains unclear how TrmB dynamically regulates its ∼100 metabolic enzyme-coding gene targets. Using a dynamic perturbation approach, we elucidate the topology of the TrmB metabolic GRN in the model archaeon Halobacterium salinarum. Clustering of dynamic gene expression patterns reveals that TrmB functions alone to regulate central metabolic enzyme-coding genes but cooperates with various regulators to control peripheral metabolic pathways. Using a dynamical model, we predict gene expression patterns for some TrmB-dependent promoters and infer secondary regulators for others. Our data suggest feed-forward gene regulatory topology for cobalamin biosynthesis. In contrast, purine biosynthesis appears to require TrmB-independent regulators. We conclude that TrmB is an important component for mediating metabolic modularity, integrating nutrient status and regulating gene expression dynamics alone and in concert with secondary regulators.


Retinol-binding protein and transthyretin expressed in HeLa cells form a complex in the endoplasmic reticulum in both the absence and the presence of retinol.
To establish a suitable experimental system for studies of the interaction of retinol-binding protein (RBP) with transthyretin (TTR) we have expressed the corresponding cDNAs in HeLa cells. To investigate whether complex formation might occur already in the endoplasmic reticulum (ER), the C-terminal ER retention signal, KDEL, was attached to TTR. The tetrameric TTR-KDEL fusion protein was retained in the ER of HeLa cells. When RBP was co-expressed with TTR-KDEL, RBP was retained intracellularly. A cDNA-encoding purpurin, a protein which is 50% identical to RBP, was then expressed together with TTR-KDEL. Purpurin was not retained intracellularly and did not bind to TTR coupled to Sepharose. The effect of the vitamin A status on the secretion of TTR and RBP was examined. While TTR expressed alone was not retained intracellularly, TTR was retained in vitamin A-deficient cells when co-expressed with RBP. Addition of retinol stimulated rapid secretion of both proteins. These results demonstrate that TTR can form a complex with RBP in the ER. The data suggest that RBP and TTR are secreted as a complex.


Bioethics for clinicians: 18. Aboriginal cultures.
Although philosophies and practices analogous to bioethics exist in Aboriginal cultures, the terms and categorical distinctions of "ethics" and "bioethics" do not generally exist. In this article we address ethical values appropriate to Aboriginal patients, rather than a preconceived "Aboriginal bioethic." Aboriginal beliefs are rooted in the context of oral history and culture. For Aboriginal people, decision-making is best understood as a process and not as the correct interpretation of a unified code. Aboriginal cultures differ from religious and cultural groups that draw on Scripture and textual foundations for their ethical beliefs and practices. Aboriginal ethical values generally emphasize holism, pluralism, autonomy, community- or family-based decision-making, and the maintenance of quality of life rather than the exclusive pursuit of a cure. Most Aboriginal belief systems also emphasize achieving balance and wellness within the domains of human life (mental, physical, emotional and spiritual). Although these bioethical tenets are important to understand and apply, examining specific applications in detail is not as useful as developing a more generalized understanding of how to approach ethical decision-making with Aboriginal people. Aboriginal ethical decisions are often situational and highly dependent on the values of the individual within the context of his or her family and community.


Bisphosphonamidate clodronate prodrug exhibits potent anticancer activity in non-small-cell lung cancer cells.
Bisphoshonates are used clinically to treat disorders of calcium metabolism, hypercalcemia and osteoporosis, and malignant bone disease. Although these agents are commonly used in cancer patients and have potential direct anticancer effects, their use for the treatment of extraskeletal disease is limited as a result of poor cellular uptake. We have designed and synthesized bisphosphonamidate prodrugs that undergo intracellular activation to release the corresponding bisphosphonate and require only two enzymatic activation events to unmask multiple negative charges. We demonstrate efficient bisphosphonamidate activation and significant enhancement in anticancer activity of two bisphosphonamidate prodrugs in vitro compared to the parent bisphosphonate. These data suggest a novel approach to optimizing the anticancer activities of commonly used bisphosphonates.


C-Met as a potential novel prognostic marker in squamous cell carcinoma and adenocarcinoma of esophagus: evidence from a meta-analysis.
INTRODUCTIONː The prognostic value of c-Met in patients with esophageal cancer (EC) remains inconsistent and controversial. Our study aims to clarify the correlation between c-Met overexpression and clinical outcome in EC patients. EVIDENCE ACQUISITIONː We performed a comprehensive search of EMBASE, PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) (from inception to May 1, 2016) for published literature regarding the potential association between c-Met overexpression and clinical outcome in EC patients. A fixed-effects or random-effects model according to heterogeneity was applied to calculate the pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS). EVIDENCE SYNTHESISː Nine eligible studies totaling 1062 patients were identified in this meta-analysis. C-Met overexpression was significantly associated with shorter OS (HR: 2.04, 95% CI: 1.66-2.52, P<0.001) and DSS (HR: 3.03, 95% CI: 2.04-4.48, P<0.001) in patients with EC. However, no significant relationship between high expression of c-Met and DFS that was found (HR: 1.81, 95% CI: 0.77-4.26, P=0.176). For OS, similar associations were demonstrated in either esophageal squamous cell carcinoma (ESCC) (HR: 2.17, 95% CI: 1.62-2.90, P<0.001) or esophageal adenocarcinoma (EAC) (HR: 1.92, 95% CI: 1.42-2.59, P<0.001). Additionally, further subgroup analyses according to publication year, ethnicity, the sample size, and statistical methodology all revealed a significant association between high expression of c-Met and OS in patients with EC. CONCLUSIONSː The current evidence indicated that c-Met overexpression is significantly associated with a poorer prognosis in EC. C-Met may serve as a potential novel prognostic biomarker for EC patients.


The Post-mortem Examination in Ruminants and its Possible Benefit to Ruminant Clinical Medicine.
To highlight the important role of post-mortem examination of ruminants and to identify possible benefits for modern ruminant medicine, a comparison of clinical and pathological diagnoses was conducted and influencing factors were identified. For this purpose, results from 2,000 ruminants that had undergone necropsy examination at the University of Zurich, Switzerland, were analysed retrospectively. Both clinical and pathological diagnoses were available for 81.40% of cattle, 80.22% of sheep and 66.66% of goats; no diagnoses were available for 3.86% of cattle, 3.30% of sheep and 7.41% of goats. In the remaining cases, either the pathological diagnosis or the clinical diagnosis was unavailable. The greatest influences on the presence of diagnoses were the way in which the animal died, the type of necropsy examination and the age of the animal. The majority of diagnoses were attributed to digestive and respiratory disorders in cattle and digestive, neurological and urinary disorders in small ruminants. The main clinical diagnoses was confirmed pathologically in 86.20% of cattle, 85.51% of sheep and 82.00% of goats, while 7.03% of diagnoses in cattle, 12.26% in sheep and 11.00% in goats could not be confirmed by post-mortem or histopathological examinations. Relevant additional information or specification of diagnoses was given in 70.87% of cattle, 45.21% of sheep and 56.66% of goats. The concurrence of diagnoses and diagnosis specification was most influenced by the way in which the animal died, the type of necropsy examination that was conducted, the performance of histopathology following the necropsy examination and whether the animal was submitted in connection with a livestock health problem. This study highlighted the abiding importance of the post-mortem examination in modern ruminant medicine, despite technical advances in clinical technologies, both as a diagnostic tool and for quality control.


Effect of a unilateral hind limb orthotic lift on upper body movement symmetry in the trotting horse.
In trotting horses, movement asymmetry is associated with ground reaction force asymmetry. In humans, limb length differences influence contralateral force production. Here we investigate whether horses, in immediate reaction to limb length changes, show movement asymmetry adaptations consistent with reported force differences. Aim of this study was to quantify pelvic and compensatory head and withers movement asymmetry as a function of limb length changes after application of orthotic lifts. In this experimental study movement asymmetry of eleven trotting horses was calculated from vertical displacement of poll, withers, sacrum and left and right tuber coxae with inertial sensors. Horses were assessed in-hand under 5 conditions (all with hind limb boots): without orthotic lifts, and with a 15mm or 30mm orthotic lift applied to the left hind or right hind. A linear mixed model investigated the influence of orthotic lift condition (P<0.05, pairwise posthoc Bonferroni correction). Pelvic movement asymmetry showed increased pelvic downward movement during stance of the shorter limb and increased pelvic upward movement during and after stance of the longer limb (P<0.001) with asymmetry changes of 3-7mm (4-10mm) for 15mm (30mm) lifts. Hip hike (tuber coxae movement asymmetry) was unaffected (P = 0.348). Head and withers movement asymmetry were affected less consistently (2 of 3 respectively 1 of 3 head or withers parameters). The small sample size of the study reduced generalizability, no direct force measurements were conducted and only immediate effects of orthotic lifts were assessed with no re-assessments days or weeks after. Conclusions about mechanical consequences (weight bearing, pushoff) are based on published movement-force associations. Pelvic movement asymmetry with an artificial change in limb length through application of an orthotic lift indicates increased weight support with the shorter limb and increased pushoff with the longer limb. This may be of relevance for the management of horses with different hoof shapes between contralateral limbs, for example some chronically lame horse.


Receptor binding by H10 influenza viruses.
H10N8 follows H7N9 and H5N1 as the latest in a line of avian influenza viruses that cause serious disease in humans and have become a threat to public health. Since December 2013, three human cases of H10N8 infection have been reported, two of whom are known to have died. To gather evidence relating to the epidemic potential of H10 we have determined the structure of the haemagglutinin of a previously isolated avian H10 virus and we present here results relating especially to its receptor-binding properties, as these are likely to be major determinants of virus transmissibility. Our results show, first, that the H10 virus possesses high avidity for human receptors and second, from the crystal structure of the complex formed by avian H10 haemagglutinin with human receptor, it is clear that the conformation of the bound receptor has characteristics of both the 1918 H1N1 pandemic virus and the human H7 viruses isolated from patients in 2013 (ref. 3). We conclude that avian H10N8 virus has sufficient avidity for human receptors to account for its infection of humans but that its preference for avian receptors should make avian-receptor-rich human airway mucins an effective block to widespread infection. In terms of surveillance, particular attention will be paid to the detection of mutations in the receptor-binding site of the H10 haemagglutinin that decrease its avidity for avian receptor, and could enable it to be more readily transmitted between humans.


Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720.
Cancer and Leukemia Group B (CALGB) 9720 evaluated subcutaneous low-dose recombinant interleukin-2 (rIL-2) maintenance immunotherapy as a strategy for prolonging remission in older patients with acute myeloid leukemia (AML). AML patients age 60 years and older in first complete remission after induction and consolidation chemotherapy were randomly assigned to no further therapy or a 90-day regimen of 14-day cycles of low-dose rIL-2, aimed at expanding natural killer (NK) cells, followed by 3-day higher doses aimed at activating cytotoxicity of expanded NK cells to lyse residual AML cells. All randomly assigned patients were included in an intention-to-treat analysis. A total of 163 (64%) of 254 patients who completed induction and consolidation chemotherapy on CALGB 9720 were randomly assigned to rIL-2 (n = 81) or no further therapy (n = 82); the most common reasons for lack of random assignment were patient refusal and relapse. Fifteen patients randomly assigned to rIL-2 never initiated it because of refusal, intercurrent medical problems, or relapse, and 24 patients initiated rIL-2 but stopped early because of toxicity or relapse. Grade 4 toxicities during rIL-2 therapy included thrombocytopenia (65%) and neutropenia (64%), and grade 3 toxicities included anemia (33%), infection (24%) and malaise/fatigue (14%). Forty-two patients (52%) randomly assigned to rIL-2 completed the full 90-day course. Patients in both arms had similar distributions of both disease-free (combined median = 6.1 months; P = .47) and overall survival (combined median = 14.7 months; P = .61) after random assignment. Moreover, the 42 patients who completed all planned therapy did not show prolongation of disease-free or overall survival. Low-dose rIL-2 maintenance immunotherapy is not a successful strategy in older AML patients.


Review of tests for monitoring doxorubicin-induced cardiomyopathy.
The objective of this review is to make physicians aware of new radionuclide methods to detect cardiac effects of chemotherapeutic drugs. This knowledge is important because of the limitations of the physical examination and the electrocardiogram for detecting early reversible cardiac damage. Presently left ventricular ejection fraction (LVEF) is routinely used to screen for cardiotoxicity. Since LVEF obtained by radionuclide angiocardiography is more accurate than the LVEF estimated by echocardiography, serial radionuclide LVEF monitoring is most commonly used to monitor cardiotoxicity. Diastolic measurements of left ventricular function (such as peak filling rate) are now being added to routine LVEF measurements to enhance standard radionuclide evaluation. This screening test should be done prior to beginning therapy and at appropriate points based on the baseline study, therapy scheme and the patient's clinical status. At some centers, exercise LVEF methods are being used to determine if cardiac reserve is adequate for the patient to tolerate additional chemotherapy when cardiac injury may be present. Previously, endomyocardial biopsy was needed to detect and confirm early anthracycline cardiotoxicity. This invasive test may be replaced by a new noninvasive in vivo method using radioactive monoclonal antibodies against cardiac muscle (indium-111-antimyosin). Because cardiac failure has been associated with adrenergic neuron injury, it has been proposed that radioactive methyliodobenzylguanine may detect the adrenergic abnormality which may predict future development of congestive heart failure or sudden death months after therapy is discontinued. Advantages and disadvantages of these methods in evaluating cardiotoxicity, and an algorithm to optimally monitor antitumor therapy-induced cardiomyopathy are discussed.


Angiogenic effects of ionic dissolution products released from a boron-doped 45S5 bioactive glass.
In regenerative medicine of vascularized tissues, there is a great interest in the use of biomaterials that are able to stimulate angiogenesis, a process necessary for rapid revascularization to allow the transport and exchange of oxygen, nutrients, growth factors and cells that take part in tissue repair and/or regeneration. An increasing number of publications have shown that bioactive glasses stimulate angiogenesis. Because it has been established that boron (B) may play a role in angiogenesis, the aim of this study was to assess the in vivo angiogenic effects of the ionic dissolution products that from a bioactive glass (BG) in the 45S5 system doped with 2 wt% B2O3 (45S5.2B). The pro-angiogenic capacity of 45S5.2B BG was assessed on the vasculature of the embryonic quail chorioallantoic membrane (CAM). Ionic dissolution products from 45S5.2B BG increased angiogenesis. This is quantitatively evidenced by the greater expression of integrin αvβ3 and higher vascular density in the embryonic quail CAM. The response observed at 2 and 5 days post-treatment was equivalent to that achieved by applying 10 µg mL-1 of basic fibroblast growth factor. These results show that the ionic dissolution products released from the bioactive glass 45S5.2B stimulate angiogenesis in vivo. The effects observed are attributed to the presence the ionic dissolution products, which contained 160 ± 10 µM borate.


Operation of the voltage sensor of a human voltage- and Ca2+-activated K+ channel.
Voltage sensor domains (VSDs) are structurally and functionally conserved protein modules that consist of four transmembrane segments (S1-S4) and confer voltage sensitivity to many ion channels. Depolarization is sensed by VSD-charged residues residing in the membrane field, inducing VSD activation that facilitates channel gating. S4 is typically thought to be the principal functional component of the VSD because it carries, in most channels, a large portion of the VSD gating charge. The VSDs of large-conductance, voltage- and Ca(2+)-activated K(+) channels are peculiar in that more gating charge is carried by transmembrane segments other than S4. Considering its "decentralized" distribution of voltage-sensing residues, we probed the BK(Ca) VSD for evidence of cooperativity between charge-carrying segments S2 and S4. We achieved this by optically tracking their activation by using voltage clamp fluorometry, in channels with intact voltage sensors and charge-neutralized mutants. The results from these experiments indicate that S2 and S4 possess distinct voltage dependence, but functionally interact, such that the effective valence of one segment is affected by charge neutralization in the other. Statistical-mechanical modeling of the experimental findings using allosteric interactions demonstrates two mechanisms (mechanical coupling and dynamic focusing of the membrane electric field) that are compatible with the observed cross-segment effects of charge neutralization.


[Acute and fulminant liver failure: experimental models].
Fulminant hepatic failure (FHF) is a complex clinical syndrome, with an invariably high mortality rate, that follows many possible and different infectious, pharmacologic and surgical liver injuries. The appearance of the syndrome is similar whatever the etiology, but the mechanisms which lead to the development of FHF are greatly varied. In order to understand the possible pathways which drive to FHF, experimental animal models have been used for a long time. Six requirements should be fulfilled by any FHF animal model: 1) reversibility; 2) reproducibility; 3) death from liver failure; 4) the presence of a therapeutic window; 5) the need of large laboratory animal; 6) minimal hazard to personnel involved in the study. In the present paper a number of models are reported and described, and advantages and disadvantages are discussed. It is concluded that with respect to the aforementioned criteria, no available experimental model is yet as satisfactory as expected.


Toxic Shock Syndrome Toxin 1 Evaluation and Antibiotic Impact in a Transgenic Model of Staphylococcal Soft Tissue Infection.
Nonmenstrual toxic shock syndrome (nmTSS), linked to TSST-1-producing CC30 Staphylococcus aureus, is the leading manifestation of toxic shock syndrome (TSS). Due to case rarity and a lack of tractable animal models, TSS pathogenesis is poorly understood. We developed an S. aureus abscess model in HLA class II transgenic mice to investigate pathogenesis and treatment. TSST-1 sensitivity was established using murine spleen cell proliferation assays and cytokine assays following TSST-1 injection in vivo HLA-DQ8 mice were infected subcutaneously with a tst-positive CC30 methicillin-sensitive S. aureus clinical TSS-associated isolate. Mice received intraperitoneal flucloxacillin, clindamycin, flucloxacillin and clindamycin, or a control reagent. Abscess size, bacterial counts, TSST-1 expression, and TSST-1 bioactivity were measured in tissues. Antibiotic effects were compared with the effects of control reagent. Purified TSST-1 expanded HLA-DQ8 T-cell Vβ subsets 3 and 13 in vitro and instigated cytokine release in vivo, confirming TSST-1 sensitivity. TSST-1 was detected in abscesses (0 to 8.0 μg/ml) and draining lymph nodes (0 to 0.2 μg/ml) of infected mice. Interleukin 6 (IL-6), gamma interferon (IFN-γ), KC (CXCL1), and MCP-1 were consistent markers of inflammation during infection. Clindamycin-containing antibiotic regimens reduced abscess size and TSST-1 production. Infection led to detectable TSST-1 in soft tissues, and TSST-1 was detected in draining lymph nodes, events which may be pivotal to TSS pathogenesis. The reduction in TSST-1 production and lesion size after a single dose of clindamycin underscores a potential role for adjunctive clindamycin at the start of treatment of patients suspected of having TSS to alter disease progression.IMPORTANCE Staphylococcal toxic shock syndrome (TSS) is a life-threatening illness causing fever, rash, and shock, attributed to toxins produced by the bacterium Staphylococcus aureus, mainly toxic shock syndrome toxin 1 (TSST-1). TSS was in the past commonly linked with menstruation and high-absorbency tampons; now, TSS is more frequently triggered by other staphylococcal infections, particularly of skin and soft tissue. Investigating the progress and treatment of TSS in patients is challenging, as TSS is rare; animal models do not mimic TSS adequately, as toxins interact best with human immune cells. We developed a new model of staphylococcal soft tissue infection in mice producing human immune cell proteins, rendering them TSST-1 sensitive, to investigate TSS. The significance of our research was that TSST-1 was found in soft tissues and immune organs of mice and that early treatment of mice with the antibiotic clindamycin altered TSST-1 production. Therefore, the early treatment of patients suspected of having TSS with clindamycin may influence their response to treatment.


Changes in gamma-aminobutyric acid tone and extracellular serotonin in the dorsal raphe nucleus over the rat estrous cycle.
Gender differences in serotonin (5-HT) metabolism, synthesis, and release suggest that the gonadal steroids estrogen (E) and progesterone (P) influence 5-HT neurotransmission. Based on the effects of ovarian steroids in forebrain sites, this might involve changes in the strength of GABA afferent tone in the dorsal raphe nucleus (DRN). To test this hypothesis, the present study used in vivo microdialysis to measure basal extracellular 5-HT in the rat DRN across the estrous cycle and changes in 5-HT in response to the GABA(A) receptor antagonists bicuculline (50 microM) and picrotoxin (50 microM). During proestrus and estrus, baseline 5-HT levels were significantly higher compared to ovariectomized (OVX) rats. Mean baseline levels across experiments were 8.4 +/- 1.3 pg/ 30 microl in proestrus, 5.2 +/- 0.8 pg/30 mul in estrus, and 3.1 +/- 0.5 pg/30 microl in the DRN of OVX rats. Bicuculline and picrotoxin produced significantly greater increases in 5-HT during proestrus compared to estrus. Moreover, in the DRN of OVX rats, bicuculline and picrotoxin produced negligible increases in 5-HT. These data provide evidence of decreased 5-HT efflux and GABA tone in the rat DRN associated with low circulating E and P.


Iridium(iii) catalyzed regioselective amidation of indoles at the C4-position using weak coordinating groups.
The C4-aminated indole scaffold is frequently encountered in several natural products and biologically active compounds. Herein we disclose a simple and short synthetic route for the amidation of indoles at the C4 position by employing an aldehyde as a directing group and Ir(iii) as a catalyst. This strategy offers high selectivity for the C4-amidation of unprotected and protected indoles. A simple deprotection of the tosyl group leads to the formation of C4-amino indole derivatives, which are useful synthons for synthesizing natural products in the teleocidin family.