The heat-labile enterotoxin of Escherichia coli binds to polylactosaminoglycan-containing receptors in CaCo-2 human intestinal epithelial cells.
The E. coli type I heat-labile enterotoxin (LT-I) shares considerable functional, structural, and immunological homology with cholera toxin (CT). Although the ganglioside GM1 is the sole receptor for CT, LT-I also appears to utilize additional, unique receptors on intestinal cells not recognized by CT. We characterized this second class of LT-I receptors using the human intestinal epithelial cell line, CaCo-2. CaCo-2 cells bound 8-fold more LT-I than CT, and some of these additional LT-I receptors appeared to be functional, as CT-B only partially inhibited LT-I activity at concentrations that completely inhibited CT activity. Membranes from unlabeled or [3H]galactose-labeled cells were incubated with toxin B subunits and extracted with Triton X-100, and the solubilized toxin B-receptor complexes were immunoabsorbed with anti-B bound to protein A-Sepharose. When organic extracts of the complexes were separated by thin-layer chromatography and overlayed with [125I]toxin, both toxins were found to bind only GM1. Separation of the complexes from [3H]galactose-labeled membranes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a series of galactoproteins specifically recognized by LT-I but not by CT. Similar proteins were detected on Western blots probed with [125I]toxin. LT-I activity on intact cells and binding to membranes and the above galactoproteins were enhanced by neuraminidase treatment even in the presence of CT-B. beta-1,4-Galactosidase and endo-beta-1,4-galactosidase, but not beta-1,3-galactosidase, significantly reduced LT-I binding. LT-I binding to fetuin and transferrin exhibited a similar glycosidase sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of nutrition on older people's mental health.
In the context of a rapidly ageing population, with an increasing prevalence of mood disorders and a greater incidence of physical illness in older adults, it is imperative that their healthcare needs are effectively addressed. Nutritional vulnerability increases in later life for various reasons, related to the physiological impact of ageing as well as social and economic challenges. Specific nutrients and overall diet quality may impact on mood. Depression and anxiety in turn impact on interest in and ability to eat and may further distort intake and exacerbate symptoms. Whether working with older adults living at home or in the care setting, nurses need to be aware of and able to identify, refer and support those who need help. This article aims to raise awareness and provides some practical guidance for nurses working with older adults experiencing mood disorders.


The Cognitive Remediation in Bipolar (CRiB) pilot study: study protocol for a randomised controlled trial.
People with bipolar disorder often show difficulties with cognitive functioning, and though these difficulties are identified as important targets for intervention, few treatment options are available. Preliminary evidence suggests that cognitive remediation therapy (a psychological treatment proven beneficial for people diagnosed as having schizophrenia) is helpful for people with bipolar disorders. We are conducting a pilot trial to determine whether individual, computerised, cognitive remediation therapy (CRT) for people with bipolar disorder 1) increases cognitive function; 2) improves global functioning, goal attainment and mood symptoms; 3) is acceptable and feasible for participants; and 4) can be addressed in a comprehensive, larger, randomised, controlled trial. The study is designed as a two-arm, randomised, controlled trial comparing cognitive remediation therapy with treatment-as-usual (TAU) for euthymic bipolar patients. Participants are eligible to take part if aged between 18 and 65 with a diagnosis of bipolar disorder (type I) and currently in euthymic state, and no neurological, substance or personality disorder diagnoses. Sixty participants will be recruited (mainly through secondary and tertiary care) and will be block-randomised to receive either treatment-as-usual alone or in addition to a 12-week course of cognitive remediation therapy totalling 20-40 therapy hours. The intervention will comprise regular sessions with a therapist and computer-based training. Research assessments will take place before and after the intervention period and at a 12-week follow-up, and will include evaluation of neuropsychological, symptom-related, demographic and social factors, as well as collecting qualitative data regarding CRT expectations and satisfaction. Intention-to-treat analyses will examine the efficacy of cognitive remediation therapy primarily on cognition and additionally on functioning, quality of life and mood symptoms. Furthermore, we will examine the acceptability of CRT and undertake a preliminary health economics analysis to ascertain the cost of delivering the intervention. The results of this trial will provide valuable information about whether cognitive remediation therapy may be beneficial for people diagnosed with bipolar disorder in a euthymic state. ISRCTN registry, ISRCTN32290525 . Registered on 2 March 2016.


Professional isolation and performance assessment in New Zealand.
Solo and nonurban practice, nonmembership of a professional group, and aging are all associated with underperformance and may be indicators of professional isolation. Although it may lead to underperformance in physicians, there are no clear measures to assess professional isolation. By mailed questionnaire, experienced performance assessors were asked to list markers of professional isolation. A set of criteria and descriptors for professional isolation was generated, and included personality; solo practice; poor colleague relationships; outlier practice; MOPS or CPD failure; specialist in only private practice; stress, no relief, complaints, job dissatisfaction; locum, itinerant or part-time practice; cultural barriers; male gender. The identification of physicians at risk for professional isolation may enable the prevention of poor performance.


Age-related changes in development of the accessory glands of male Anopheles albimanus.
This study presents the effects of age on the accessory glands of male Anopheles albimanus. The paired oval glands have an outer muscular layer and an inner layer of columnar secretory cells. Male pupae have uniformly long columnar cells and contain only traces of male accessory gland substance (MAGS). In newly emerged males, the posterior section of the gland has short columnar cells that produce an opaque, white MAGS consisting of one type of secretory granules. The anterior section has long columnar cells that produce yellow as well as white MAGS. In 84-h-old males, the columnar cells are short throughout the gland and the glands are replete with both forms of MAGS. The amount of MAGS may control secretory activity of the columnar cells by a feedback mechanism.


Sexual differentiation traits in functional males with female genital apertures (male symbol fga) in the woodlice Armadillidium vulgare Latr. (Isopoda, Crustacea).
This study reports the results of examination of the gonadal morphology and ultrastructural features of the androgenic hormone (AH)-producing androgenic gland cells of laboratory stocks of functional male woodlice, Armadillidium vulgare, with female genital apertures ( male symbol fga), with and without experimentally induced infections of the sex-ratio-distorting endobacterial parasite, Wolbachia. Males ( male symbol fga) have been reported in wild populations containing individuals infected with this maternally transmitted sex-ratio-distorting parasite. We report a reduction of testicular segment (utricle) number, androgenic gland cell hypertrophy, and electron-dense ultrastructural cytological features in male symbol fga males. The presence of the Wolbachia parasite had no effect on the features we examined. These results suggest that male symbol fga males are produced as the result of a delayed expression/action of the male sex-determining AH which causes a "lag-phase" delay in male differentiation in genetic males and is not due to the presence, in genetic females, of a hypothetical, epigenetic "M" gene as suggested by Rigaud and Juchault. Our results favor the interpretation of males as true genetic (ZZ) males in which the delayed AH action appears to involve cellular AH trafficking pathways which may be controlled by an impaired autosomal gene responsible for AH action.


Risk assessment practices of Texas private practitioners for sexually transmitted diseases.
This study describes the sexually transmitted disease (STD) risk assessment practices of a sample of private primary care practitioners in Texas. Elicitation of sexual history was not universal when these clinicians took the health history of their patients. Only 40% of the practices reported conducting a risk assessment for STD with all of their patients. In general, practices in obstetrics and gynecology, physicians providing care for persons infected with human immunodeficiency virus, and female physicians were more likely to indicate that they assess all of their patients for risks of STD. More than 90% of the practitioners conduct risk assessment for STD with all of those patients perceived to be at risk, but the criteria used for determining those patients vary greatly among practitioners. Private physicians in Texas provide care for a large proportion of individuals afflicted with STDs; our findings raise concerns about the lack of uniformity in the process of identifying patients at risk for STD.


Calcium homeostasis in cows, with special reference to parturient hypocalcemia.
Calcium homeostasis is described in terms of controlled, disturbing, and controlling signals. Plasma calcium concentration [( Ca]p) and bone calcium mass (Mb) are the two main controlled signals. Disturbing signals include calcium intake (Vi) and clearance of plasma calcium to feces ( Clf ), bone (Clo+), placenta (Clp), and milk ( Clm ). Clo+ is a disturbing signal for [Ca]p and a controlling signal for Mb. Homeostasis is maintained by input control. Fractional renal calcium reabsorption (alpha r) decreases when calcium entry into plasma is excessive, but usually calcium entry rate (VT) responds effectively to small changes in [Ca]p associated with changes in disturbing signals. With increases in Vi, both fractional calcium absorption (alpha d) and fraction of bone calcium removed (lambda b) decrease to maintain VT at an appropriate level. As Clo+ declines with advancing age, [Ca]p rises slightly but VT decreases: a 1% change in [Ca]p would lead to a 13% change in VT. In heavily lactating cows, this response of VT may be enhanced. Parturient hypocalcemia may be the result of delayed negative feedback responses of lambda b (1 wk) and alpha d (1 day). Positive feedback between [Ca]p and gut motility may lead to transient suppression of VT during hypocalcemia, despite high plasma parathyroid hormone and 1,25-dihydroxyvitamin D3 concentrations. Parturient paresis is an example of a disordered accelerative response in a complex control system amenable to a variety of physiologically rational management procedures.


Relationship of hydrogen ion back-diffusion to histamine liberation from canine oxyntic mucosa.
Pharmacological damage to gastric mucosa results in excessive movement of hydrogen out of the lumen and increased movement of sodium and potassium into the lumen. It has been previously reported that one consequence of H+ back-diffusion is the release of intramucosal histamine which probably adds to the damage by increasing capillary permeability and edema formation. In the present study histamine concentration in the solution irrigating an isolated pouch of the gastric fundus was measured following 15% (w/v) ethanol (EtOH) in either 100 mM HCl, 10 mM HCl, or 0.03 M phosphate buffer. All three solutions effectively broke the mucosal barrier as evidenced by increased net fluxes of sodium and potassium. Significant (P less than 0.05) increases in the histamine content of the fluid irrigating the pouch were observed after all treatments. The histamine output in response to EtOH in acidic solution was significantly greater than the response to EtOH at neutral pH. Instillation of 150, 200, 225, or 250 mM HCl alone into the pouch resulted in progressive increases in H+ back-diffusion. Application of 250 mM HCl alone resulted in a proportionally greater back-diffusion of H+, increases in Na+ and K+ fluxes indicating barrier damage, and the appearance of histamine. These results indicate that the damaging agent ethanol probably acts at two points: (1) it breaks the mucosal barrier, and (2) it liberates histamine. These results suggest that an increase in H+ back-diffusion per se is not solely responsible for gastric mucosal histamine liberation but that histamine is released as a general consequence of breaking the gastric mucosal barrier.


Percutaneous minimally invasive treatment of transverse patellar fracture using cannulated screws combined with high-strength sutures and Nice knots: a retrospective study.
Patella fractures treated with traditional open approach and tension band fixation are associated with a significant rate of soft tissues complications, including hardware irritation, postoperative adhesions and non-cosmetic scar. An alternative is to utilize cannulated screws and high-strength sutures by the minimally invasive technique. This retrospective study comprised 48 patients who had been treated for unilateral closed transverse patellar fracture, type 34C1 according to the AO Foundation and Orthopaedic Trauma Association (AO/OTA) classification, between June 2018 to June 2020. All patients were treated either by closed reduction and internal fixation using cannulated screws combined with high-strength sutures and Nice knots (the CRIF-NK group, n=24), or traditional open reduction and internal fixation using cannulated screws and tension band wiring (the ORIF-TBW group, n=24). The operative time and intraoperative blood loss for each patient were recorded. All the patients were underwent a regularly clinical and radiological follow-up. The clinical evaluation was performed using the Böstman scale and the Visual Analogue Scale (VAS) for pain. Average follow up was 21.9 months (range, 16-29 months). The mean intraoperative blood loss of the CRIF-NK group (35.21±6.16 mL) was significantly less than that of the ORIF-TBW group (75.42±7.92 mL; P<0.001). The mean VAS scores at 4 and 8 weeks and the mean Böstman scale score at 8 weeks after surgery were significantly better in the CRIF-NK group (3.52±0.42, 1.47±0.40 and 28.13±0.94, respectively) than the ORIF-TBW group (5.16±0.68, 3.14±0.72 and 26.33±1.00, respectively; all P<0.001). No significant differences were observed between the two groups in terms of operative time, Böstman scale score at 1-year follow-up, or fracture healing time. The union rate was 100% (24/24) in both groups. One patient (1/24) in the CRIF-NK group, and all patients (24/24) in the ORIF-TBW group required internal fixation removal. The percutaneous minimally invasive technique using cannulated screws combined with high-strength sutures and Nice knots exhibited some superiority to traditional open reduction with cannulated screws and tension band wiring for treatment of transverse patellar fractures in terms of efficacy and safety by reducing soft-tissue stimulating complications and promoting functional recovery.


Immunosuppressive protocols with tacrolimus after cryopreserved aortal allotransplantation in rats.
The aim of our study was to simulate in rats all aspects and techniques used in our new clinical program of cryopreserved alloarterial transplantation and investigate the influence of two immunosuppressive protocols with tacrolimus on acute rejection of these allografts. Cryopreserved abdominal aortic grafts were transplanted between Brown-Norway and Lewis rats. Tacrolimus (0.2 mg/kg daily) was administered from day 1 to day 30 (TAC1) or from day 7 to day 30 (TAC7), respectively. No immunosuppressed isogeneic (ISO) and allogeneic (ALO) rats combination served as control. Aortal wall infiltration by immunocompetent cells (MHC II+ cells of recipient origin) was studied on day 30 after transplantation. Flow cytometry was used for the analysis of day 30 sera for the presence of donor specific anti-MHC class I and II antibodies. The aortal allografts in both immunosuppressed groups showed regular morphology of aortal wall with no depositions of immunoglobulin G on day 30. The adventitial infiltration of non-immunosuppressed aortal allografts by MHC class II positive cells of recipient origin was significantly higher (ALO 20.7±6.7 cells, P<0.001) compared to both immunosuppressed groups (TAC1 5.9±5.5 cells, TAC7 6.1±5.1 cells). Day 30 sera from the allogeneic non-immunosuppressed animals decreased significantly the binding of fluorescence-labelled MHC class I (46.9±19.4%) and class II (65.8±11.9%) antibody to donors spleen cells compared with day 30 sera from both immunosuppressed groups (TAC1, anti-MHC class I 102.4±4.2%, p < 0.001, anti-MHC class II 102.6±6.0%), (TAC7, anti-MHC class I 79.9±3.3%, p < 0.001, anti-MHC class II 80.9±2.7%). Both immunosuppressed protocols with tacrolimus (administration from day 1 or from day 7 following transplantation) were able to suppress acute cell- and antibody-mediated rejection of cryopreserved abdominal aortic allografts processed in accordance with our new standardized clinical protocol.


Subgingival Microbiota in White Patients With Desquamative Gingivitis: A Cross-Sectional Study.
Presence of epithelial desquamation, erythema, and erosions on gingival tissue is usually described in the literature as desquamative gingivitis (DG). A wide range of autoimmune/dermatologic disorders can manifest as DG, although the two more common are oral lichen planus and mucous membrane pemphigoid. The aim of this study is to investigate prevalence of 11 periodontopathogenic microorganisms in patients with DG and to compare it with the microbiologic status of individuals affected by plaque-induced gingivitis (pGI). Cross-sectional clinical and microbiologic data were obtained from 66 patients (33 in each group). Subgingival plaque samples were analyzed using semiquantitative polymerase chain reaction analysis. Statistically significant difference, but with little clinical significance, was observed in gingival conditions between the two groups, probably due to the worse home control hygiene of patients with DG. Prevalence and levels of Aggregatibacter actinomycetemcomitans, Eikenella corrodens, and Fusobacterium nucleatum/periodonticum were statistically higher in samples from patients with DG than in those with pGI. In multivariate regression models, subgingival colonization of A. actinomycetemcomitans and F. nucleatum/periodonticum was not statistically associated with DG, whereas, high levels of E. corrodens were associated with 13-fold increased odds for DG. Microbiologic differences were found in subgingival plaque for patients with DG and pGI. This may suggest possible association between periodontal pathogens and DG.


Hybrid Approach of Ruptured Type B Aortic Dissection with an Aberrant Subclavian Artery in a Single Patient with Turner Syndrome: A Case Report.
Turner syndrome, also described as 45, X, may present with most serious cardiovascular anomalies including risk of aortic dissection and rupture. In emergency situation, management for aortic dissection with complicated anatomy accompanying vascular anomaly is challenging. Here, we report a rare case of ruptured type B aortic dissection with aberrant subclavian artery and partial anomalous pulmonary venous connection in a Turner syndrome. Through right carotid-subclavian artery bypass and thoracic endovascular aortic repair, successful hybrid endovascular management correlated with a favorable result in this emergency situation.


[5-Fluorouracil concentration in various tissues from cancer patients after oral administration of 5-fluorouracil].
5-Fluorouracil(5-FU)is a widely used antitumor agent for treating patients with adenocarcinoma of gastroenterial tract and breast following intravenous or oral administration. The blood level of 5-FU peaked rapidly after intravenous bolus injection and then decreased in a short time, disappearing 90 minutes after injection. But the blood level of 5-FU peaked from 15 to 30 minutes after oral administration of 5-FU tablets or dry syrup and decreased slowly, frequently showing 0.02 microgram/ml at 120 minutes after oral administration. In cancer chemotherapy, a tissue drug concentration is represented by its serum level in practice, generally because of the difficulty in determining the tissue drug level of the patients. This study was performed to determine the tissue 5-FU level after oral administration of 5-FU. Before surgery, 400 to 600 mg of 5-FU tablets was orally administered to 13 patients including 5 cases of gastric, 5 of breast, 1 of colon and 2 of other types of cancer. Tissue specimens of different sites and serum samples were obtained during the operation: cancer tissues, normal gastric or colon wall, normal breast, lymph nodes and subcutaneous fatty tissues, etc. The materials were frozen immediately at -20 degrees C and sent to Pharmaceutical Research Laboratories, Fuji Plant, Kyowa Hakko Kogyo Co., Ltd. ( Nagaizumimachi , Shuntogun , Shizuoka , Japan). The materials were assayed for 5-FU by bioassay method using Staphylococcus aureus 209P or Micrococcus flavus ATCC 10240 as the test organisms. The 5-FU concentration in mastopathy tissue was traced to all of the agents at 20 to 180 minutes after 400 mg of 5-FU was administered orally in tablet form. 5-FU concentrations in gastric cancer tissues ranged from 0.30 to 1.30 micrograms/g at 163 to 235 minutes after administering 600 mg of 5-FU tablets, whereas in normal gastric wall were much lower than in gastric cancer tissues. That in the breast cancer tissues was 0.042 to 0.12 microgram/g at 100 to 240 minutes after oral administration. 5-FU was maintained at a higher concentration in cancer tissues for a long time, while the serum concentration decreased to trace amounts. 5-FU in non-cancerous tissues was invariably traced in most patients as mastopathy tumors. From the above results, 5-FU tablets proved to be a useful drug in cancer chemotherapy.


[Gene polymorphisms in the dihydrofolate reductase ( dhfr ) and dihydropteroate synthase ( dhps ) genes and structural modelling of the dhps gene in Colombian isolates of Toxoplasma gondii].
There are no reports describing polymorphisms in target genes of anti- Toxoplasma drugs in South American isolates. This study sought to perform cloning and sequencing of the dihydrofolate reductase ( dhfr ) and dihydropteroate-synthase ( dhps ) genes of the reference Rh strain and two Colombian isolates of Toxoplasma gondii . Two isolates were obtained from the cerebrospinal fluid of HIV-infected patients with cerebral toxoplasmosis. A DNA extraction technique and PCR assay for the dhfr and dhps genes were standardized, and the products of amplification were cloned into Escherichia coli and sequenced. One polymorphism (A « G) was found at position 235 of exon 2 in the dhps gene. In addition, two polymorphisms (G « C) at positions 259 and 260 and one polymorphism (T « G) at position 371 within exon 4 of the dhps gene were detected. In this last exon, a bioinformatic analysis revealed a non-synonymous polymorphism in the coding region that could lead to the substitution of Glu (CAA or CAG) for His (encoded by codons AAU or AAC). A structural model of the T. gondii DHPS protein was calculated, and the results revealed modifications in secondary structure due to mutations. The methods described in this study can be used as a tool to search for polymorphisms in samples from patients with different clinical manifestations of toxoplasmosis and to examine their relationship with the therapeutic response.


A multicenter study of oral lichen planus in Thai patients.
Oral lichen planus is an oral mucosal disease that affects middle-aged patients. The characteristics of oral lichen planus in Thai patients from a multicenter were studied. Data of 533 patients from the oral medicine clinics at Chulalongkorn and Mahidol (central Thailand), Chiang Mai (northern Thailand), and Khon Kaen (northeastern Thailand) universities during 2002-2007 were analyzed. The diagnosis of patients with oral lichen planus was clinically and/or histopathologically confirmed. There was a greater number of female patients than males (4:1). There were significant differences in age, sex, and some systemic diseases among the oral lichen planus patients from the three centers. Burning sensation was the most common symptom (72.9%), followed by pain (26.5%), roughness (6.4%), and then no other symptoms (7.9%). The most common site of lesions was found at the buccal mucosa (87.1%). Atrophic oral lichen planus was common in Thai patients. There were significant differences in the types of oral lichen planus, including reticular, atrophic, and ulcerative oral lichen planus among these patients from the three centers (P = 0.000). Nine cases (1.7%) showed dysplasia, but one case (0.2%) developed squamous cell carcinoma. Patients with oral lichen planus from the central, northern, and northeastern parts of Thailand presented with distinct characteristics. The malignant transformation of oral lichen planus was low in Thai patients.


Lifespan reduction due to neoplasia is nullified by pseudoexfoliation syndrome.
Pseudoexfoliation syndrome (PES) is a common eye condition, indicating a risk of various eye diseases. Whether or not PES has extra-ocular physiological or even pathophysiological implications has been a matter of controversy for years. In total 1888 persons were examined for PES in 1985-86. Of these, 1864 (98·7%) had died and were therefore available for analysis by 01.01.2016. Age and cause(s) of death were recorded. 9 diagnostic groups (cardiovascular disease, cerebrovascular disease, neoplasms, systemic hypertension, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), Parkinson's disease, aortic aneurysm (AA), and amyloidosis) based on ICD-coding were analyzed for both a possible association between PES and lifespan, as well as PES and specific systemic diseases. In the cardiovascular group, PES was not associated with an alteration in longevity. The subgroups acute myocardial infarction and other cardiovascular diseases revealed significantly reduced and increased lifespan, respectively, compared to the rest of the population. These deviations were independent of PES. The impact of PES on the neoplasm group showed that PES-positive persons lived 1·81 years (p < 0·001) longer than PES-negative persons. No significant differences in the PES prevalence were found in any of the cause of death diagnostic groups. The present study suggests that lifespan reduction due to neoplasia is nullified by PES, and that this phenomenon is not restricted to one specific neoplasm type. Thus, the paradoxical conclusion emerges that PES provides a lifespan benefit to the patient with a neoplasm. For the remaining diagnostic groups, PES was neither associated with an altered lifespan, nor with any cause of death diagnoses.


Antianginal Therapy for Stable Ischemic Heart Disease: A Contemporary Review.
Chronic angina pectoris is associated with considerable morbidity and mortality, especially if treated suboptimally. For many patients, aggressive pharmacologic intervention is necessary in order to alleviate anginal symptoms. The optimal treatment of stable ischemic heart disease (SIHD) should be the prevention of angina and ischemia, with the goal of maximizing both quality and quantity of life. In addition to effective risk factor modification with lifestyle changes, intensive pharmacologic secondary prevention is the therapeutic cornerstone in managing patients with SIHD. Current guidelines recommend a multifaceted therapeutic approach with β-blockers as first-line treatment. Another important pharmacologic intervention for managing SIHD is nitrates. Nitrates can provide both relief of acute angina and can be used prophylactically before exposure to known triggers of myocardial ischemia to prevent angina. Additional therapeutic options include calcium channel blockers and ranolazine, an inhibitor of the late inward sodium current, that can be used alone or in addition to nitrates or β-blockers when these agents fail to alleviate symptoms. Ranolazine appears to be particularly effective for patients with microvascular angina and endothelial dysfunction. In addition, certain antianginal therapies are approved in Europe and have been shown to improve symptoms, including ivabradine, nicorandil, and trimetazidine; however, these have yet to be approved in the United States. Ultimately, there are several different medications available to the physician for managing the patient with SIHD having chronic angina, when either used alone or in combination. The purpose of this review is to highlight the most important therapeutic approaches to optimizing contemporary treatment in response to individual patient needs.


Regression of Liver Steatosis Following Phosphatidylcholine Administration: A Review of Molecular and Metabolic Pathways Involved.
Liver steatosis is a key pathology in non-alcoholic or metabolic associated fatty liver disease. Though largely ignored for decades it is currently becoming the focus of research in hepatology. It is important to consider its origin and current opportunities in terms of pharmacotherapy. Essential phospholipids (EPLs) rich in phosphatidylcholine (PCH) is a widely used treatment option for fatty liver disease, and there is a solid amount of consistent clinical evidence for the regression of steatosis after treatment with EPLs. As knowledge of PCH (a key component of EPLs) pharmacodynamics and mode of action driving this widely observed clinical effect is currently insufficient, we aimed to explore the potential molecular and metabolic pathways involved in the positive effects of PCH on steatosis regression.


Regulation of transforming growth factor alpha messenger RNA expression in a chemically transformed rat hepatic epithelial cell line by phorbol ester and hormones.
Transforming growth factor alpha (TGF-alpha) is produced by many transformed cells, but little is known about the regulation of its expression. We examined TGF-alpha mRNA levels in a set of cloned neoplastic cell lines derived by chemical transformation of a normal rat liver epithelial cell. The untransformed parental cell line, WB-344, did not express a detectable level of TGF-alpha mRNA, whereas GP6ac, a transformed line capable of autonomous growth in soft agar, expressed TGF-alpha. When GP6ac cells were treated with agents thought to regulate protein kinase C activity, e.g., the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), TGF-alpha mRNA levels increased by 8- to 11-fold. The induction of TGF-alpha mRNA was detectable at 2 h, was maximal at 8-12 h, and declined by 24 h. Angiotensin, bradykinin, epinephrine, and epidermal growth factor also increased TGF-alpha mRNA by 2- to 5-fold. In contrast, parental WB cells neither expressed TGF-alpha mRNA, nor responded to TPA. TPA also increased epidermal growth factor receptor mRNA in GP6ac cells but the effect was less prolonged; maximal levels were seen at 4 h after TPA exposure and returned to control levels by 12 h. TPA increased TGF-alpha mRNA in GP6ac cells, in part, by increasing transcription of the TGF-alpha gene as measured by run-on transcription rates in isolated nuclei. In addition, the induction of TGF-alpha by TPA was blocked by concurrent incubation with agents that inhibit protein synthesis. However, if TPA was present for at least 2 h, subsequent addition of cycloheximide enhanced the effect of TPA. This indicates that the induction of TGF-alpha in GP6ac cells is comprised of at least two phases demarcated by the requirement for protein synthesis. The time course of induction and the sensitivity to inhibition of protein synthesis distinguish the effect of TPA on TGF-alpha mRNA from that of other genes regulated by TPA, e.g., c-myc and c-fos. These data also suggest that chemical transformation of rat liver epithelial cells leads to expression of TGF-alpha mRNA, and that once expressed, TGF-alpha mRNA can be modulated in a protein kinase C-dependent manner.


Assessing natural direct and indirect effects for a continuous exposure and a dichotomous outcome.
Recent advances in the literature on mediation have extended from traditional linear structural equation modeling approach to causal mediation analysis using potential outcomes framework. Pearl proposed a mediation formula to calculate expected potential outcomes used in the natural direct and indirect effects definition under the key sequential ignorability assumptions. Current methods mainly focused on binary exposure variables, and in this article, this approach is further extended to settings in which continuous exposures may be of interest. Focusing on a dichotomous outcome, we give precise definitions of the natural direct and indirect effects on both the risk difference and odds ratio scales utilizing the empirical joint distribution of the exposure and baseline covariates from the whole sample analysis population. A mediation-formula based approach is proposed to estimate the corresponding causal quantities. Simulation study is conducted to assess the statistical properties of the proposed method and we illustrate our approach by applying it to the Jackson Heart Study to estimate the mediation effects of diabetes on the relation between obesity and chronic kidney disease. Sensitivity analysis is performed to assess the impact of violation of no unmeasured mediator-outcome confounder assumption.


Variability in risk of gastrointestinal complications with different nonsteroidal anti-inflammatory drugs.
Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) is known to increase substantially the risk of upper gastrointestinal bleeding and/or perforation. A meta-analysis of the available epidemiologic studies has shown that there are wide differences between individual drugs in the risk of inducing gastrointestinal complications. Of the NSAIDs in common use, ibuprofen and diclofenac were found to be associated with the lowest relative risk; indomethacin, naproxen, sulindac, and aspirin were associated with intermediate risk; and azapropazone, tolmetin, ketoprofen, and piroxicam were associated with higher risk. Some of these apparent differences in toxicity may, however, be dose related. The low risk of gastrointestinal complications associated with ibuprofen appears to be attributable to the low doses that are prescribed routinely in clinical practice. Higher doses of ibuprofen were associated with relative risks similar to those of naproxen and indomethacin. Thus, as first-line treatment, patients should be prescribed the lowest effective dose of an NSAID that appears to be associated with a comparatively low risk. This should substantially reduce the morbidity and mortality from serious gastrointestinal complications that are associated with the use of these drugs.


A dose-response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate.
The objective of this study was to observe the dose-response effects of testosterone (T) treatment on symptoms of sexual dysfunction and the metabolic syndrome. Two cohorts of elderly men with late-onset hypogonadism were followed over 9 months. Group 1, consisting of 28 men (mean age, 61 years; mean T level, 2.07 +/- 0.50 ng/mL), received long-acting T undecanoate (TU; 1000 mg); group 2, composed of 27 men (mean age, 60 years; mean T level, 2.24 +/- 0.41 ng/mL), received T gel (50 mg/day) for 9 months. In patients treated with T gel, plasma T levels rose from 2.24 +/- 0.41 to 2.95 +/- 0.52 (statistically significant) at 3 months, 3.49 +/- 0.89 (statistically significant) at 6 months, and 3.80 +/- 0.73 ng/mL at 9 months (T level at 6 months was compared with T level at 3 months). With TU, plasma T levels rose from 2.08 +/- 0.56 to 4.81 +/- 0.83 (statistically significant) at 3 months, 5.29 +/- 0.91 at 6 months, and 5.40 +/- 0.77 ng/mL at 9 months. With TU, the plasma T levels were statistically significantly higher than with T gel With TU, there was a greater improvement in sexual symptoms and in symptoms of the metabolic syndrome. With both treatments, changes in waist circumference correlated with changes in total, low-density, and high-density lipoprotein cholesterol. Parameters of safety were not different between the 2 treatments. T administration had a beneficial effect on sexual dysfunction and symptoms of the metabolic syndrome in elderly men. The higher plasma levels of T generated with TU than with T gel were clearly more effective, indicating that there is a T dose-effect relationship.


Evaluation and mitigation of the interplay effects of intensity modulated proton therapy for lung cancer in a clinical setting.
The primary aim of this study was to evaluate the impact of the interplay effects of intensity modulated proton therapy (IMPT) plans for lung cancer in the clinical setting. The secondary aim was to explore the technique of isolayered rescanning to mitigate these interplay effects. A single-fraction 4-dimensional (4D) dynamic dose without considering rescanning (1FX dynamic dose) was used as a metric to determine the magnitude of dosimetric degradation caused by 4D interplay effects. The 1FX dynamic dose was calculated by simulating the machine delivery processes of proton spot scanning on a moving patient, described by 4D computed tomography during IMPT delivery. The dose contributed from an individual spot was fully calculated on the respiratory phase that corresponded to the life span of that spot, and the final dose was accumulated to a reference computed tomography phase by use of deformable image registration. The 1FX dynamic dose was compared with the 4D composite dose. Seven patients with various tumor volumes and motions were selected for study. The clinical target volume (CTV) prescription coverage for the 7 patients was 95.04%, 95.38%, 95.39%, 95.24%, 95.65%, 95.90%, and 95.53% when calculated with the 4D composite dose and 89.30%, 94.70%, 85.47%, 94.09%, 79.69%, 91.20%, and 94.19% when calculated with the 1FX dynamic dose. For these 7 patients, the CTV coverage calculated by use of a single-fraction dynamic dose was 95.52%, 95.32%, 96.36%, 95.28%, 94.32%, 95.53%, and 95.78%, with a maximum monitor unit limit value of 0.005. In other words, by increasing the number of delivered spots in each fraction, the degradation of CTV coverage improved up to 14.6%. A single-fraction 4D dynamic dose without rescanning was validated as a surrogate to evaluate the interplay effects of IMPT for lung cancer in the clinical setting. The interplay effects potentially can be mitigated by increasing the amount of isolayered rescanning in each fraction delivery.


Lattice Boltzmann simulations of binary fluid flow through porous media.
The lattice Boltzmann equation is often advocated as a simulation tool that is particularly effective for complex fluids such as multiphase and multicomponent flows through porous media. We construct a three-dimensional 19 velocity lattice Boltzmann model for immiscible binary fluids with variable viscosities and density ratio based on the model proposed by Gunstensen. The model is tested for the following binary fluid flow problems: a stationary planar interface among two fluids; channel flow of immiscible binary fluids; the Laplace problem; and a rising bubble. The results agree well with semi-analytic results in a range of the Eötvös, Morton and Reynolds number. We also present preliminary simulation results for two large-scale realistic applications: the flow of an air-water mixture in a waste-water batch reactor and the saturation hysteresis effect in soil flow. We discuss some limitations of the lattice Boltzmann method in the simulation of realistic and difficult multiphase problems.


Metabolism of central neurotransmitters during development of tolerance to the anticonvulsant effect of clonazepam and of physical dependence on the drug in dogs.
In previous studies, development of functional tolerance to the anticonvulsant effect of clonazepam and physical dependence on the drug have been demonstrated. In the present study, dogs were treated for 6 weeks with clonazepam 0.5 mg/kg b.i.d. Under methohexital anesthesia, cerebrospinal fluid samples were taken before treatment, at 3 days (acute effect), 4 and 5 weeks (tolerance) after the start of treatment, 2 and 8 days after withdrawal and 5 weeks after the end of treatment as another control. The following transmitters or metabolites were determined: HVA, VMA, 5-HIAA, GABA, PGE2, TXB2 and 6-keto PGF1 alpha. 5-HIAA levels showed a significant rise, indicating an increased activity of the serotonergic system in the brain during development both of tolerance and withdrawal. Dopaminergic activity was not altered during treatment, but was increased after cessation of treatment, as indicated by a significant increase in HVA concentrations.


Different Therapeutic Effects of CO2 and Diode Laser Irradiation on Tooth Movement-Related Pain.
Although orthodontic treatment is common, orthodontic force often induced pain. Low-level laser therapy (LLLT) has been investigated to improve therapeutic comfort. In dentistry, LLLT is mainly applied using two types of lasers, CO2 and diode lasers, whose biological actions are thought to be associated with wavelength (CO2: 10,600 nm; diode: 808 nm). The analgesic effect of LLLT on orthodontic treatment-related pain is widely reported but inconsistent. This study aimed to (1) determine whether irradiation with a CO2 or diode laser attenuates orthodontic treatment-related pain using the jaw-opening reflex model, (2) elucidate the optimal irradiation protocol for both lasers to obtain the maximal analgesic effect, (3) evaluate the effects of laser irradiation on other biological features [e.g., tooth movement, glial fibrillary acidic protein (GFAP) expression, and temperature alterations] and (4) investigate the mechanism underlying the analgesic effect of laser irradiation. In this animal model, orthodontic treatment-induced pain manifested as a significantly reduced the threshold for inducing the jaw-opening reflex on the orthodontically treated side compared with the contralateral side. GFAP expression in the bilateral trigeminal ganglia (TGs) was significantly increased by the application of orthodontic force. CO2 laser irradiation of the orthodontically treated region significantly increased the threshold for inducing the jaw-opening reflex and the peripheral temperature. Similar reductions in jaw-opening reflex excitability were induced by surface anesthesia and thermal stimulation but not, the diode laser. Neither CO2 nor diode laser irradiation altered GFAP expression in the TGs. Infiltration anesthesia also significantly increased the threshold for inducing the jaw-opening reflex on each anesthetized side. Irradiation (30 s) by either laser immediately after orthodontic force application (preirradiation) significantly decreased jaw-opening reflex excitability and GFAP expression in the bilateral TGs the next day. However, thermal stimulation immediately after orthodontic force application failed to alter jaw-opening reflex excitability the next day. Laser irradiation did not alter tooth movement; however, an optimized irradiation protocol for aiding tooth movement is suggested. In conclusion, both CO2 and diode lasers are able to prevent orthodontic treatment-related pain. Furthermore, the involvement of temperature alterations and surface anesthesia in the analgesic effect induced by CO2 laser irradiation is suggested.


Analysis of SLC11A1 gene expression in healthy water buffalo (Bubalus bubalis) blood cells using qPCR.
SLC11A1 (solute carrier family 11 member 1 protein) gene influences the initial phase of bacterial cellular infections through macrophage activation. Recent literature on buffalo has attempted to associate the genotype of the polymorphic microsatellite located in the 3'untranslated region (3'UTR) of the gene, with either susceptibility to brucellosis or with improved macrophage function. Carriers of the (GT)16 allele have been reported to be resistant to brucellosis. In this study we analyzed the steady-state level of SLC11A1 expression in a serologically negative herd of 26 animals differing by the number of (GT)n microsatellite repeats by using a reverse transcriptase quantitative real-time polymerase chain reaction approach. We evaluated five different reference genes, which had not been reported previously, for use in gene expression experiments in buffalo blood. However, we did not find any significant difference between buffalo carriers of the different microsatellite alleles, with respect to SLC11A1 expression in whole blood or in blood fractions [peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes/granulocytes (PMN/G)]. Conversely, there was a difference between the blood fractions in their SLC11A1 expression levels, with the PMN/G fraction having a higher expression level than the PBMC fraction (P < 0.015).


Selection of patients for sublingual versus subcutaneous immunotherapy.
Allergen immunotherapy is the sole treatment for IgE-mediated allergic diseases directed at the underlying mechanism. The two widely accepted administration routes are sublingual (SLIT) and subcutaneous (SCIT). We reviewed how patients should best be selected for immunotherapy and how the optimal administration route can be defined. Before deciding SCIT or SLIT, appropriate selection of patients for allergen immunotherapy (AIT) is mandatory. To be eligible for AIT, subjects must have a clear medical history of allergic disease, with exacerbation of symptoms on exposure to one or more allergens and a corresponding positive skin or in vitro test. Then the route of administration should be based on: published evidence of clinical and immunologic efficacy (which varies per allergic disease and per allergen); mono- or multi-allergen immunotherapy, for SLIT multi-allergen immunotherapy was not effective; safety: adverse events with SLIT are more frequent, but less severe; and, costs and patient preferences, closely related to adherence issues. All these are discussed in the article.


Evolving from academic to academic entrepreneur: overcoming barriers to scientific progress and finance.
The overall goal of my career as an academic chemist has always been the design and creation of advanced therapeutics and diagnostics that address unmet medical need in the management of chronic diseases. Realising this goal has been an immensely difficult process involving multidisciplinary problem-driven research at the chemistry-biology-medicine interfaces. With success in the laboratory, I started seriously to question the value of remaining an academic whose career is spent in the pursuit of knowledge and understanding alone without making any significant effort to translate knowledge and understanding gained into products of genuine utility for public benefit. Therefore, I elected by choice to become an academic entrepreneur, seeking opportunities wherever possible for the translation of the best of my personal and collaborative academic research work into potentially valuable and useful products. This choice has brought with it many unexpected difficulties and challenges. Nevertheless, progress bas been made and sufficient learnt to suggest that this would be an appropriate moment to take stock and provide some personal reflections on what it takes to design and create advanced therapeutics and diagnostics in the laboratory then seek to develop, innovate and translate the best towards market.


Tumor-Triggered Geometrical Shape Switch of Chimeric Peptide for Enhanced in Vivo Tumor Internalization and Photodynamic Therapy.
Geometrical shape of nanoparticles plays an important role in cellular internalization. However, the applicability in tumor selective therapeutics is still scarcely reported. In this article, we designed a tumor extracellular acidity-responsive chimeric peptide with geometrical shape switch for enhanced tumor internalization and photodynamic therapy. This chimeric peptide could self-assemble into spherical nanoparticles at physiological condition. While at tumor extracellular acidic microenvironment, chimeric peptide underwent detachment of acidity-sensitive 2,3-dimethylmaleic anhydride groups. The subsequent recovery of ionic complementarity between chimeric peptides resulted in formation of rod-like nanoparticles. Both in vitro and in vivo studies demonstrated that this acidity-triggered geometrical shape switch endowed chimeric peptide with accelerated internalization in tumor cells, prolonged accumulation in tumor tissue, enhanced photodynamic therapy, and minimal side effects. Our results suggested that fusing tumor microenvironment with geometrical shape switch should be a promising strategy for targeted drug delivery.


[Beta-2-microglobulin and rheumatoid factor levels in the synovial fluid (author's transl)].
The object of this study was to determine whether levels of beta-2-microglobulin and of rheumatoid factor measured by an enzyme-immunoassay allowed good discrimination between inflammatory and degenerative arthropathies. A multiparametric study of synovial fluid was performed on 85 specimens from patients with rheumatoid arthritis, chondrocalcinosis, mechanical arthritis and traumatic arthopathies. A beta-2-microglobulin level of less than 4 mg/l is a result very mich in favor of a non-inflammatory arthropathy (48/49 cases). The quantification of intra-articular rheumatoid factor allows for reclassification in the context of sero-negative rheumatoid arthritis.


Predictors of readmissions after head and neck cancer surgery: A national perspective.
Surgical oncology patients have multiple comorbidities and are at high risk of readmission. Prior studies are limited in their ability to capture readmissions outside of the index hospital that performed the surgery. Our goal is to evaluate risk factors for readmission for head and neck cancer patients on a national scale. A retrospective cohort study of head and neck cancer patients in the Nationwide Readmissions Database (2013). Our main outcome was 30-day readmission. Statistical analysis included 2-sided t tests, χ2, and multivariate logistic regression analysis. Within 30days, 16.1% of 11,832 patients were readmitted and 20% of readmissions were at non-index hospitals, costing $31million. Hypopharyngeal cancer patients had the highest readmission rate (29.6%), followed by laryngeal (21.8%), oropharyngeal (18.2%), and oral cavity (11.6%) cancers (P<0.001). Half of readmissions occurred within 10days and were often associated with infections (27%) or wound complications (12%). Patients from lower household income areas were more likely to be readmitted (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.16-2.05). Patients with valvular disease (OR, 2.07; 95% CI, 1.16-3.69), rheumatoid arthritis/collagen vascular disease (OR, 2.05; 95% CI, 1.27-3.31), liver disease (OR, 2.02, 95% CI, 1.37-2.99), and hypothyroidism (OR 1.30; 95% CI, 1.02-1.66) were at highest risk of readmission. The true rate of 30-day readmissions after head and neck cancer surgery is 16%, capturing non-index hospital readmissions which make up 20% of readmissions. Readmissions after head and neck cancer surgery are most commonly associated with infections and wound complications.


Mitochondrial Proteolysis and Metabolic Control.
Mitochondria are metabolic hubs that use multiple proteases to maintain proteostasis and to preserve their overall quality. A decline of mitochondrial proteolysis promotes cellular stress and may contribute to the aging process. Mitochondrial proteases have also emerged as tightly regulated enzymes required to support the remarkable mitochondrial plasticity necessary for metabolic adaptation in a number of physiological scenarios. Indeed, the mutation and dysfunction of several mitochondrial proteases can cause specific human diseases with severe metabolic phenotypes. Here, we present an overview of the proteolytic regulation of key mitochondrial functions such as respiration, lipid biosynthesis, and mitochondrial dynamics, all of which are required for metabolic control. We also pay attention to how mitochondrial proteases are acutely regulated in response to cellular stressors or changes in growth conditions, a greater understanding of which may one day uncover their therapeutic potential.


Novel phase separation and spin dynamics of lightly doped La2-xSr2CuO4 probed by La-nuclear quadrupole resonance.
We report novel magnetic properties in the slightly hole-doped Mott-insulator La(2-x)SrxCuO4 via the La-nuclear quadrupole resonance (NQR) measurements. At x=0.018, the antiferromagnetic (AFM) La-NQR spectrum affected by internal fields comes out as the temperature decreases below T(N) approximately 150 K, whereas the nonmagnetic one persists to be observed down to a temperature T(f) approximately 20 K at which the nuclear-relaxation rate has a pronounced peak. This demonstrates that the phase separation of nonmagnetic and AFM phases occurs between T(f) and T(N). The novel phase separation is suggested as due to the partial destruction of the AFM phase caused by mobile holes via the formation of an extended spin-singlet state between Cu-derived spins and hole spins.


The Brucella abortus vaccine strain B19 carries a deletion in the erythritol catabolic genes.
Brucella abortus B19, an avirulent strain obtained by spontaneous mutation, is used worldwide as a vaccine for the control of bovine brucellosis. B19 differs from other B. abortus strains in its sensitivity to erythritol. We took advantage of a previously obtained erythritol sensitive Tn5 insertion mutant of B. abortus 2308 to clone the chromosomal region containing erythritol catabolic genes from this representative pathogenic strain and from the vaccine strain B19. Physical mapping with restriction endonucleases and nucleotide sequence determination revealed the existence of a 702 bp long deletion, occurring between two short direct repeats, in the chromosome of B19. This deletion rendered the B19 strain sensitive to erythritol. Two oligonucleotides whose sequences flank this deletion provided an easy method to differentiate B19 from all other B. abortus isolates.


GH Responsiveness to Combined GH-Releasing Hormone and Arginine Administration in Obese Patients with Fibromyalgia Syndrome.
Reportedly, fibromyalgia (FM) is frequently associated with reduced IGF-1 levels and GH hyporesponsiveness to different GH stimulation tests. Since there is a high prevalence of obesity in FM, and obesity itself is characterized by hyposomatotropism, the aim of this study was to assess IGF-1 levels and GH responsiveness in sixteen severely obese women suffering from FM, who, subdivided into two subgroups on the basis of their age-dependent IGF-1 values (> or <-2 SDS), underwent the combined GHRH plus arginine test. Four out of 16 obese women with FM (25%) had low IGF-1 SDS values, 2 cases of this subgroup (12.5%) failing also to normally respond to the test. Among patients with normal GH responses, 4 showed a delayed GH peak. The subgroup with low IGF-1 SDS values had higher BMI than that with normal IGF-1 SDS. GH peak and area under the curve were not correlated with CRP, ESR, or tender point score, while significant correlations were found with fat-free mass and fat mass. In conclusion, this study shows the existence of a high prevalence of GH-IGF-1 dysfunction in patients with both FM and obesity, presumably as a consequence of the obese rather than fibromyalgic condition.


Rapid localized heating of graphene coating on a silicon mold by induction for precision molding of polymer optics.
In compression molding of polymer optical components with micro/nanoscale surface features, rapid heating of the mold surface is critical for the implementation of this technology for large-scale applications. In this Letter, a novel method of a localized rapid heating process is reported. This process is based on induction heating of a thin conductive coating deposited on a silicon mold. Since the graphene coating is very thin (∼45 nm), a high heating rate of 10∼20°C/s can be achieved by employing a 1200 W 30 kHz electrical power unit. Under this condition, the graphene-coated surface and the polymer substrate can be heated above the polymer's glass transition temperature within 30 s and subsequently cooled down to room temperature within several tens of seconds after molding, resulting in an overall thermal cycle of about 3 min or shorter. The feasibility of this process was validated by fabrication of optical gratings, micropillar matrices, and microlens arrays on polymethylmethacrylate (PMMA) substrates with very high precision. The uniformity and surface geometries of the replicated optical elements are evaluated using an optical profilometer, a diffraction test setup, and a Shack-Hartmann wavefront sensor built with a molded PMMA microlens array. Compared with the conventional bulk heating molding process, this novel rapid localized induction heating process could improve replication efficiency with better geometrical fidelity.


Feedback in clinical education: untying the Gordian knot.
Feedback is essential to clinical education, especially in the era of competencies, milestones, and entrustable professional activities. It is, however, an area where medical educators often fall short. Although educational leaders and faculty supervisors provide feedback in a variety of clinical settings, surveys show important gaps in medical student and resident satisfaction with the feedback received, suggesting lost opportunities to identify performance problems as well as to help each learner reach his or her greatest potential.In this issue of Academic Medicine, Telio and colleagues extend the empirically validated concept of a "therapeutic alliance" to propose the "educational alliance" as a framework for enhancing feedback in medical education. They highlight the importance of source credibility, which depends on the teacher-learner relationship and alignment of values, the teacher's understanding of the learner's role and goals, the teacher's direct observation of the learner, and the learner's perception of the teacher's good intentions. The author of this Commentary suggests that the educational alliance framework should prompt medical educators to reconsider feedback and explore opportunities for optimizing it. Most medical schools and graduate medical education programs are not designed in a way that supports the education alliance model, but the Commentary author offers suggestions for cultivating educational alliances, including rethinking supervisor selection criteria. Such interventions should be combined with ongoing faculty development and efforts to improve coaching and mentoring for students, residents, and fellows. Untying the Gordian knot of effective feedback will require innovative approaches, exchange of successful strategies, and continued research.


First Drug to Reduce Proteinuria in Berger's Disease.
Budesonide (Tarpeyo) has received accelerated approval to reduce proteinuria in adults with primary immunoglobulin A nephropathy, also known as Berger's disease.Nurses should assess if any coprescribed drugs could induce a drug-drug interaction via the cytochrome P-450 isoenzyme system. Because budesonide causes immunosuppression, patients are at high risk for developing infections and should be told to avoid anyone who is known to have an infection.


Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity.
Nutrient-driven O-GlcNAcylation of key components of the transcription machinery may epigenetically modulate gene expression in metazoans. The global effects of GlcNAcylation on transcription can be addressed directly in C. elegans because knockouts of the O-GlcNAc cycling enzymes are viable and fertile. Using anti-O-GlcNAc ChIP-on-chip whole-genome tiling arrays on wild-type and mutant strains, we detected over 800 promoters where O-GlcNAc cycling occurs, including microRNA loci and multigene operons. Intriguingly, O-GlcNAc-marked promoters are biased toward genes associated with PIP3 signaling, hexosamine biosynthesis, and lipid/carbohydrate metabolism. These marked genes are linked to insulin-like signaling, metabolism, aging, stress, and pathogen-response pathways in C. elegans. Whole-genome transcriptional profiling of the O-GlcNAc cycling mutants confirmed dramatic deregulation of genes in these key pathways. As predicted, the O-GlcNAc cycling mutants show altered lifespan and UV stress susceptibility phenotypes. We propose that O-GlcNAc cycling at promoters participates in a molecular program impacting nutrient-responsive pathways in C. elegans, including stress, pathogen response, and adult lifespan. The observed impact of O-GlcNAc cycling on both signaling and transcription in C. elegans has important implications for human diseases of aging, including diabetes and neurodegeneration.


Global redistribution and local migration in semi-discrete host-parasitoid population dynamic models.
Host-parasitoid population dynamics is often probed using a semi-discrete/hybrid modeling framework. Here, the update functions in the discrete-time model connecting year-to-year changes in the population densities are obtained by solving ordinary differential equations that mechanistically describe interactions when hosts become vulnerable to parasitoid attacks. We use this semi-discrete formalism to study two key spatial effects: local movement (migration) of parasitoids between patches during the vulnerable period; and yearly redistribution of populations across patches outside the vulnerable period. Our results show that in the absence of any redistribution, constant density-independent migration and parasitoid attack rates are unable to stabilize an otherwise unstable host-parasitoid population dynamics. Interestingly, inclusion of host redistribution (but not parasitoid redistribution) before the start of the vulnerable period can lead to stable coexistence of both species. Next, we consider a Type-III functional response (parasitoid attack rate increases with host density), where the absence of any spatial effects leads to a neutrally stable host-parasitoid equilibrium. As before, density-independent parasitoid migration by itself is again insufficient to stabilize the population dynamics and host redistribution provides a stabilizing influence. Finally, we show that a Type-III functional response combined with density-dependent parasitoid migration leads to stable coexistence, even in the absence of population redistributions. In summary, we have systematically characterized parameter regimes leading to stable/unstable population dynamics with different forms of spatial heterogeneity coupled to the parasitoid's functional response using mechanistically formulated semi-discrete models.


Cost-effectiveness analysis of onabotulinumtoxinA (BOTOX(®)) for the management of urinary incontinence in adults with neurogenic detrusor overactivity: a UK perspective.
To evaluate the cost effectiveness of onabotulinumtoxinA (BOTOX(®), 200 units [200 U]) for the management of urinary incontinence (UI) in adults with neurogenic detrusor overactivity (NDO) due to subcervical spinal cord injury or multiple sclerosis that is not adequately managed with anticholinergic drugs (ACHDs). UK National Health Service (NHS) perspective. A Markov state-transition model was developed, which compared onabotulinumtoxinA + best supportive care (BSC) with BSC alone (comprising behavioural therapy and pads, alone or in combination with clean intermittent catheterization and possibly with ACHDs). Non-responders were eligible for invasive procedures. Health states were defined according to the reduction in UI episodes. Efficacy data and estimates of resource utilization were pooled from 468 patients on onabotulinumtoxinA in two phase III clinical trials. Drug costs (2013) and administration costs (NHS Reference Costs 2011-2012) were obtained from published sources. The time horizon of the model was 5 years, and costs and benefits were discounted at 3.5%. Scenario, one-way and probabilistic sensitivity analyses (PSAs) were conducted to explore uncertainties around the assumptions. In the base case, treatment with onabotulinumtoxinA + BSC over 5 years was associated with an increase in costs of £1,689 and an increase in quality-adjusted life-years (QALYs) of 0.4, compared with BSC alone, resulting in an incremental cost-effectiveness ratio of £3,850 per QALY gained. Sensitivity analyses showed that utility values had the greatest influence on model results. PSA suggests that onabotulinumtoxinA + BSC had a 100 % probability of being cost effective at a willingness to pay of <£20,000. For adult patients with NDO who are not adequately managed with ACHDs, onabotulinumtoxinA + BSC appears to be a cost-effective use of resources in the UK NHS.


Electrophoretic component of electric pulses determines the efficacy of in vivo DNA electrotransfer.
Efficient DNA electrotransfer can be achieved with combinations of short high-voltage (HV) and long low voltage (LV) pulses that cover two effects of the pulses, namely, target cell electropermeabilization and DNA electrophoresis within the tissue. Because HV and LV can be delivered with a lag up to 3000 sec between them, we considered that it was possible to analyze separately the respective importance of the two types of effects of the electric fields on DNA electrotransfer efficiency. The tibialis cranialis muscles of C57BL/6 mice were injected with plasmid DNA encoding luciferase or green fluorescent protein and then exposed to various combinations of HV and LV pulses. DNA electrotransfer efficacy was determined by measuring luciferase activity in the treated muscles. We found that for effective DNA electrotransfer into skeletal muscles the HV pulse is prerequisite; however, its number and duration do not significantly affect electrotransfer efficacy. DNA electrotransfer efficacy is dependent mainly on the parameters of the LV pulse(s). We report that different LV number, LV individual duration, and LV strength can be used, provided the total duration and field strength result in convenient electrophoretic transport of DNA toward and/or across a permeabilized membrane.


Calcium binding, but not a calcium-myristoyl switch, controls the ability of guanylyl cyclase-activating protein GCAP-2 to regulate photoreceptor guanylyl cyclase.
Guanylyl cyclase-activating protein 2 (GCAP-2) is a recoverin-like calcium-binding protein that regulates photoreceptor guanylyl cyclase (RetGC) (Dizhoor, A. M., and Hurley, J. B. (1996) J. Biol. Chem. 271, 19346-19350). It was reported that myristoylation of a related protein, GCAP-1, was critical for its affinity for RetGC (Frins, S., Bonigk, W., Muller, F., Kellner, R., and Koch, K.-W. (1996) J. Biol. Chem. 271, 8022-8027). We demonstrate that the N terminus of GCAP-2, like those of other members of the recoverin family of Ca2+-binding proteins, is fatty acylated. However, unlike other proteins of this family, more GCAP-2 is present in the membrane fraction at low Ca2+ than at high Ca2+ concentrations. We investigated the role of the N-terminal fatty acyl residue in the ability of GCAP-2 to regulate RetGCs. Myristoylated or nonacylated GCAP-2 forms were expressed in Escherichia coli. Wild-type GCAP-2 and the Gly2 --> Ala2 GCAP-2 mutant, which is unable to undergo N-terminal myristoylation, were also expressed in mammalian HEK293 cells. We found that compartmentalization of GCAP-2 in photoreceptor outer segment membranes is Ca2+- and ionic strength-sensitive, but it does not require the presence of the fatty acyl group and does not necessarily directly reflect GCAP-2 interaction with RetGC. The lack of myristoylation does not significantly affect the ability of GCAP-2 to stimulate RetGC. Nor does it affect the ability of the Ca2+-loaded form of GCAP-2 to compete with the GCAP-2 mutant that constitutively activates RetGC. We conclude that while Ca2+ binding plays a major regulatory role in GCAP-2 function, it does not operate through a calcium-myristoyl switch similar to the one found in recoverin.


Leukotrienes in health and disease.
The leukotrienes (LTs) are 5-lipoxygenase metabolites of arachidonic acid. The synthesis and release of LTs have been demonstrated in many cells and organs, and LTs are considered to be normal products of continuous metabolism of arachidonic acid. However, although evidence in favor of a critical role for LTs in regulation of physiological functions is still scarce, a growing body of evidence suggests a role for LTs in mediation of several pathophysiological processes such as generalized or local immune reactions, inflammation, asthma, shock, and trauma. LTs have been shown to have potent actions on many essential organs and systems, including the cardiovascular system (heart, blood vessels, microcirculation), the pulmonary system (lung, airways), the central nervous system (neural, glial, and vascular elements), the gastrointestinal tract, and the immune system. In these organs the effects of LTs are mediated by specific LT receptors. Identification of LTs and characterization of their regional and systemic pathological effects, together with characterization of their receptors and elucidation of their structure-activity relationships, are fundamental to developing LT antagonists or synthesis inhibitors that might prevent or reverse LT-dependent reactions. Preliminary reports have already shown that such pharmacological agents ameliorate some aspects of disease processes in experimental animals as well as in humans. In this brief review we intend to highlight the evidence that implicates LTs in normal physiological functions as well as in disease processes.


Evaluation of biochemical and ultrasonographic measurements as indicators of undernutrition in cattle.
Body condition scoring (BCS) gives an indication of the nutritional status of an animal and it is thus an invaluable management tool in domestic livestock systems. It is, however, subjective. This study aimed at identifying biochemical indicators which could be objectively used as an indicator of undernutrition in ruminants. Blood samples were collected from 50 cattle with BCS < or =1 and from 50 cattle with BCS > or =2.5, using a 0-5 scale, and analysed for albumin, urea, creatinine, fructosamine, beta-hydroxybutyrate, non-esterified fatty acids, total serum protein and haematocrit. Rumpfat and ribfat thickness and marbling relative index were determined ultrasonographically in 15 of the low BCS group and 13 of the high BCS group. The laboratory measure with the best predictive ability for severe undernutrition was albumin, which correctly classified 94% of cattle, using a cut-off of 31.5 g/l. In contrast to a previous study, our study did not find the fructosamine:albumin ratio to be an accurate test to indicate undernutrition in cattle. Ultrasonic measurement of subcutaneous rumpfat and ribfat proved to reliably predict undernutrition, but may, however be impractical for routine use under most field conditions.


Prevalence of High-Risk Human Papillomavirus in Tonsil Tissue in Healthy Adults and Colocalization in Biofilm of Tonsillar Crypts.
The pathogenesis of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is currently an important topic of elucidation. The presence of latent HPV infection in tonsil tissue of healthy adults may provide an explanation for a component of this process and contribute to the understanding of HPV-associated squamous cell carcinoma oncogenesis of the oropharynx. To determine the prevalence of oropharyngeal HPV and to determine the spatial relationship between the virus and crypt biofilm in tonsil tissue. A retrospective, cross-sectional study was carried out using samples obtained from tonsils that were archived at a university hospital following elective nononcologic tonsillectomy from 2012 to 2015. Samples consisted of formalin-fixed paraffin embedded samples of tumor-free tonsil tissue from 102 adults between the ages of 20 and 39 years. Human papillomavirus status was assessed by polymerase chain reaction, and high-risk subtypes 16 and 18 were assessed with quantitative polymerase chain reaction assay. Samples that demonstrated presence of HPV were then analyzed by in situ hybridization to localize the viral capsid protein. These samples were then stained with concanavalin A to establish biofilm presence and morphology. These samples were also stained with diamidino-phenylindole (DAPI) to visualize location of the virus in relation to cell nuclei. These data were then assembled for aggregate analysis to colocalize HPV in the biofilm of the tonsillar crypts. Outcome measurements were determined prior to data collection and include prevalence of high-risk HPV types 16 and 18 in tonsil tissue of otherwise healthy adults, as well as demonstration with immunohistochemistry of HPV in tonsillar crypt biofilm. In 102 otherwise healthy adults (55 [53.9%] female; age range, 20-39 years), the overall prevalence of HPV in tonsils was 4.9% (n = 5); and high-risk type 16 or 18, 3.9% (n = 4). In this sample population, in situ hybridization colocalized HPV virus to the biofilm of the tonsillar crypts. Biofilm is present in the tonsillar crypts in a considerable proportion of tonsil tissues and may be reproducibly identified. Human papillomavirus is demonstrated to colocalize to the crypt biofilm. This has important implications with respect to the determination of HPV prevalence rates in the oropharynx. It may also play a role in the pathogenesis of HPV-related oropharyngeal carcinoma.


[An investigation on smoking situation among middle school students in Japan and in Jiangxi, China].
The past smoking rate among middle school students in Jiangxi was 30.5%, which was higher than that in Japan (25.4%). However, the present smoking rate and the frequent smoking rate among middle school students in Jiangxi are 5.8% and 1.1%, respectively, which are far lower than those in Japan (8.7% and 5.3%). The past smoking rate among boy students at each academic year in Jiangxi was higher than that in Japan, but the statistical indices of the present smoking rate and of the frequent smoking rate among boy students and among girl students at each academic year are lower than those in Japan. In Japan, the smoking rate among middle school students in cities was higher than that in the countryside, but vice versa in Jiangxi. The average number of cigarettes consumed per day in Japan was higher than that in Jiangxi. This investigation indicates that the smoking rate among middle school students was much influenced by their friends and relatives, health education in schools, self-feelings about school life and attitude towards smoking, etc.


Rauniticine-allo-oxindole B methanol monosolvate.
The title penta-cyclic oxindole alkadoid, isolated from Uncaria longiflora, crystallizes as a methanol solvate, C(20)H(22)N(2)O(4)·CH(4)O. The five-membered ring comprising the indole fused ring is nearly planar [maximum atomic deviation = 0.031 (2) Å], whereas the five-membered ring having alphatic C atoms adopts an envelope shape (with the tertiary N atom representing the flap). The six-membered ring that shares an N atom with the envelope-shaped ring adopts a chair shape; the six-membered ring having an O atom is sofa-shaped. The carb-oxy-lic acid group acts as a hydrogen-bond donor to a methanol mol-ecule; this, in turn, acts as a hydrogen-bond donor to the double-bond carboxyl O atom of an adjacent mol-ecule, generating a chain. Adjacent chains are linked by N-H⋯O hydrogen bonds, forming a layer motif.


The Contribution of an Infectious Workup in Understanding Stillbirth.
This study was aimed to assess the utility of diagnostic tests of maternal and fetal infection in the evaluation of stillbirth. A single-center retrospective study from January 2011 to December 2016 of all women presenting to the hospital with intrauterine fetal death at or after 20 weeks of gestation. Standard evaluation included review of medical records, clinical and laboratory inflammatory workup, maternal serologies, fetal autopsy, placental pathology, and fetal and placental cultures. A suspected infectious etiology was defined as meeting at least two diagnostic criteria, and only after exclusion of any other identifiable stillbirth cause. During the 7-year study period, 228 cases of stillbirth were diagnosed at our center. An infectious etiology was the suspected cause of stillbirth in 35 cases (15.3%). The mean gestational age of infection-related stillbirth was 28 1/7 (range: 22-37) weeks, while for a noninfectious etiology, it was 34 0/7 (range: 25-38) weeks (p = 0.005). Placental histological findings diagnostic of overt chorioamnionitis and funisitis were observed in 31 (88.5%) cases. In 16 (45.7%) cases the placental and fetal cultures were positive for the same pathogen. Serology of acute infection was positive in three (8.5%) of the cases. Maternal and fetal infectious workup is valuable in the investigation of stillbirth, particularly before 30 weeks of gestation and should be considered a part of standard evaluation.


Religiosity and remission of depression in medically ill older patients.
The effects of religious belief and activity on remission of depression were examined in medically ill hospitalized older patients. Consecutive patients aged 60 years or over who had been admitted to medical inpatient services at a university medical center were screened for depressive symptoms. Of 111 patients scoring 16 or higher on the Center for Epidemiologic Studies Depression Scale, 94 were diagnosed with depressive disorder (DSM-III major depression or subsyndromal depression) by a psychiatrist using a structured psychiatric interview. After hospital discharge, depressed patients were followed up by telephone at 12-week intervals four times. At each follow-up contact, criterion symptoms were reassessed, and changes in each symptom over the interval since last contact were determined. The median follow-up time for 87 depressed patients was 47 weeks. Religious variables were examined as predictors of time to remission by means of a multivariate Cox model, with controls for demographic, physical health, psychosocial, and treatment factors. During the follow-up period, 47 patients (54.0%) had remissions; the median time to remission was 30 weeks. Intrinsic religiosity was significantly and independently related to time to remission, but church attendance and private religious activities were not. Depressed patients with higher intrinsic religiosity scores had more rapid remissions than patients with lower scores. In this study, greater intrinsic religiosity independently predicted shorter time to remission. To the authors' knowledge, this is the first report in which religiosity has been examined as a predictor of outcome of depressive disorder.


Patient Selection for Bronchoscopic Lung Volume Reduction.
Bronchoscopic lung volume reduction (BLVR) is a valuable treatment option for carefully selected patients with severe COPD. There is limited knowledge about the characteristics and outcomes of patients referred to a specialized center for BLVR. The study objectives were to investigate the selection rate for BLVR treatment in patients referred for this treatment and to investigate the differences between patients that were selected for BLVR and patients that were not. We performed a retrospective analysis of patients with severe COPD who were referred to our hospital to assess eligibility for BLVR treatment. Our parameters included demographics, comorbidity, chest computed tomography characteristics, reasons for rejection from BLVR treatment and patient survival. In total, 1500 patients were included (mean age 62 years, 50% female and forced expiratory volume in 1 s 33% of predicted). Out of this group, 282 (19%) patients were selected for BLVR treatment. The absence of a suitable target lobe for treatment, an unsuitable disease phenotype and insufficient lung hyperinflation were the most important factors for not being selected. Patients that were selected for any BLVR option lived significantly longer than the group of patients that were not selected for BLVR (median 3060 versus 2079 days, P<0.001). We found that only a small proportion of patients that are referred for BLVR treatment is eligible for a BLVR treatment, indicating a need for both better referral tools and for the development of new therapies for this group of patients. Furthermore, our data suggest that selection for BLVR is associated with a significant survival benefit.


Role of signal recognition particle in the membrane assembly of Sindbis viral glycoproteins.
We have investigated the role of signal recognition particle (SRP) in the biosynthesis of Sindbis glycoproteins by translating the viral 26S mRNA in a wheat-germ cell-free system. SRP was shown to have no effect on the synthesis or proteolytic processing of the cytoplasmic C protein. In contrast, the membrane integration and the proteolytic processing of the viral glycoproteins PE2 and E1 were demonstrated to be SRP-dependent. In the absence of microsomal membranes, SRP caused an arrest of the synthesis of the viral glycoproteins. This arrest could be released by the addition of salt-extracted microsomal membranes. Synchronization experiments indicated that the uncleaved signal sequence of PE2 was recognized by SRP after at most 130 amino acids of PE2 had been polymerized. No apparent interaction of SRP with a putative signal sequence of E1 and/or a 6-kDa peptide could be detected.


Purification and NMR studies of [methyl-13C]methionine-labeled truncated methionyl-tRNA synthetase.
A procedure for the rapid purification of a truncated form of the Escherichia coli methionyl-tRNA synthetase has been developed. With this procedure, final yields of approximately 3 mg of truncated methionyl-tRNA synthetase per gram of cells, carrying the plasmid encoding the gene for the truncated synthetase [Barker, D.G., Ebel, J.-P., Jakes, R., & Bruton, C.J. (1982) Eur. J. Biochem. 127, 449], can be obtained. The catalytic properties of the purified truncated synthetase were found to be identical with those of the native dimeric and trypsin-modified methionyl-tRNA synthetases. A rapid procedure for obtaining milligram quantities of the enzyme is necessary before the efficient incorporation of stable isotopes into the synthetase becomes practical for physical studies. With this procedure, truncated methionyl-tRNA synthetase labeled with [methyl-13C]methionine was purified from an Escherichia coli strain auxotrophic for methionine and containing the plasmid encoding the gene for the truncated methionyl-tRNA synthetase. Both carbon-13 and proton observe-heteronuclear detect NMR experiments were used to observe the 13C-enriched methyl resonances of the 17 methionine residues in the truncated synthetase. In the absence of ligands, 13 of the 17 methionine residues could be resolved by carbon-13 NMR. Titration of the synthetase, monitoring the chemical shifts of resonances B and M (Figure 3), with a number of amino acid ligands and ATP yielded dissociation constants consistent with those derived from binding and kinetic data, indicating active site binding of the ligands under the conditions of the NMR experiment.(ABSTRACT TRUNCATED AT 250 WORDS)


Continuous blockade of the lumbar plexus after knee surgery--postoperative analgesia and bupivacaine plasma concentrations. A controlled clinical trial.
In a double blind, randomised, controlled investigation the analgesic effect of a continuous block of the lumbar plexus with bupivacaine compared with sodium chloride was examined in 20 patients with postoperative pain after knee-joint surgery. The infusion was given through a catheter inserted in the neurovascular fascial sheath of the femoral nerve, according to the three-in-one block technique. The patients treated with bupivacaine had significantly lower pain scores and a significantly lower demand for morphine. Side effects related to the catheters or the infusions of bupivacaine were not observed.


Genetic basis of pediatric epilepsy syndromes.
Childhood epilepsy affects ~0.5-1% in the general population worldwide. Early-onset epileptic encephalopathies are considered to be severe neurological disorders, which lead to impaired motor, cognitive, and sensory development due to recurrence of seizures. Many of the observed epilepsy phenotypes are associated with specific chromosomal imbalances and thus display gene dosage effects, and also specific mutations of a variety of genes ranging from ion channels to transcription factors. High throughput sequencing technologies and whole exome sequencing have led to the recognition of several new candidate genes with a possible role in the pathogenesis of epileptic encephalopathies. The mutations causing channelopathies can be either a gain or a loss of ion channel function and contribute to the pathogenesis of epilepsy syndrome. Nearly 300 mutations of SCN1A gene coding for the Nav1.1 channel protein have been identified that contribute to the pathology of epilepsy. Besides Na, potassium and calcium channels are also implicated in epileptic encephalopathies. Therapeutic management of epileptic encephalopathies has been challenging as the majority of the medications are not efficient and often have many undesirable side effects. A better understanding of the molecular nature of epilepsy in an individual is important to design a personalized medication, considering the number of possible genetic mutations that can contribute to epileptic encephalopathies.


Resistance Training of Inspiratory Muscles After Coronary Artery Disease May Improve Obstructive Sleep Apnea in Outpatient Cardiac Rehabilitation: RICAOS Study.
Obstructive sleep apnea (OSA) affects 5% of the adult population and its prevalence is up to 13 times higher in coronary artery disease (CAD) patients. However, OSA in this population is less symptomatic, leading to lower adherence to positive airway pressure (CPAP). While oropharyngeal exercise showed a significant decrease in apnea-hypopnea index (AHI) in patients with moderate OSA, there have been no studies testing the impact of specific inspiratory muscle training (IMT) for these patients. The aim of our study was to assess the effectiveness of IMT on AHI reduction in CAD patients with moderate OSA. We included patients with CAD involved in a cardiac rehabilitation program and presenting an AHI between 15 and 30. Patients were randomized in a 1:1 allocation to a control group (CTL - classic training) or an IMT group (classic training + IMT). IMT consisted in 60 deep inspirations a day, 6 days a week, into a resistive load device set at 70% of the maximum inspiratory pressure (MIP). After 6 weeks, we compared AHI, neck circumference, Epworth Sleepiness Scale, Pittsburgh Sleep Quality index, and quality of life with the 12-item Short Form Survey before and after rehabilitation. We studied 45 patient (60 ± 9 y, BMI = 27 ± 6 kg.m-2). The IMT group (n = 22) significantly improved MIP ( p < 0.05) and had a significant decrease in AHI by 25% (-6.5 ± 9.5, p = 0.02). In the CTL group (n = 23), AHI decreased only by 3.5% (-0.7 ± 13.1; p = 0.29). Between groups, we found a significant improvement in MIP ( p = 0.003) and neck circumference ( p = 0.01) in favor of the IMT group. However, we did not find any significant improvement of AHI in the IMT group compared to CTL ( p = 0.09). A specific IMT during cardiac rehabilitation contributes to reduce significantly AHI in CAD patients with moderate OSA. Magnitude of the decrease in OSA severity could be enhanced according to implementation of specific IMT in this population.


Breast cancer and ovarian cancer genetics.
Breast and ovarian cancers are the second and fifth leading causes of cancer death, respectively, among women in the United States. Individuals with breast cancer have a 20--30% chance of having at least one relative with the disease. However, only 5--10% of the cases are a direct result of germline mutations in highly penetrable genes, such as BRCA1 and BRCA2 (BRCA1/2) as well as genes TP53 and PTEN. Since 1996, genetic testing for these mutations has been clinically available. A strategy for the management of women at increased familial risk of breast and ovarian cancers is described, which includes genetic assessment, chemoprevention, radiologic screening, and clinical and self-examination. Genetic testing should occur within a cancer genetic clinic after genetic counseling. A blood sample allows determination of the presence of the BRCA1 and BRCA2 genes, the TP53 gene, the PTEN gene, and the ATM gene. Tumor examination has identified a growth factor receptor gene, human epidermal growth factor receptor (HER-2). With regard to diet and lifestyle, women at increased risk of breast cancer could be advised to reduce dietary fat, avoid obesity, decrease alcohol consumption, and take regular exercise. Although chemoprotection is a valuable consideration, it is important to emphasize that the use of Tamoxifen in BRCA1 and BRCA2 mutation carriers is not established, nor is the optimum duration of benefit. An overview of the main outcomes of the current published studies confirms a 38% decrease in breast cancer incidence with Tamoxifen but recommends its use be restricted to women at high risk of breast cancer and low risk for potential side effects. The role of bilateral risk-reducing mastectomy or prophylactic mastectomy has been controversial for several reasons, including the psychosocial significance of the breast in Western cultures, the wide acceptance of breast conservation in surgery for early breast cancer, and the previous lack of data on its efficacy. The surgical procedure should aim to remove substantially all at-risk breast tissue. However, there is a balance between reduction of cancer risk and cosmetic outcome. Bilateral prophylactic oophorectomy can significantly decrease ovarian cancer risk in women who carry BCRA1 mutations. Oophorectomy lowers the risk of breast cancer, even in women who have previously used hormone replacement therapy. There are no published randomized controlled trials examining the effectiveness of mammographic screening in women under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer. under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer.


Review: Ontology and endocrinology of the reproductive system of bulls from fetus to maturity.
This review focuses on current understanding of prenatal, prepubertal and post-pubertal development of the male reproductive system of cattle. The critical developmental events occur during the first 3 to 4 months of gestation and the first ~6 to 9 months after birth. The Wilms Tumor-1 and SRY proteins play critical roles in early development and differentiation of the fetal testis, which in turn drives gestational development of the entire male reproductive system. The hypothalamic-pituitary-gonadal axis matures earlier in the bovine fetus than other domestic species with descent of the testes into the scrotum occurring around the 4th month of gestation. An array of congenital abnormalities affecting the reproductive system of bulls has been reported and most are considered to be heritable, although the mode of inheritance in most cases has not been fully defined. Early postnatal detection of most of these abnormalities is problematic as clinical signs are generally not expressed until after puberty. Development of genomic markers for these abnormalities would enable early culling of affected calves in seedstock herds. The postnatal early sustained increase in lutenising hormone secretion cues the rapid growth of the testes in the bull calf leading to the onset of puberty. There is good evidence that both genetic and environmental factors, in particular postnatal nutrition, control or influence development and maturation of the reproductive system. For example, in Bos taurus genotypes which have had sustained genetic selection pressure applied for fertility, and where young bulls are managed on a moderate to high plane of nutrition puberty typically occurs at 8 to 12 months of age. However, in many Bos indicus genotypes where there has been little selection pressure for fertility and where young bulls are reared on a low plane of nutrition, puberty typically occurs between 15 to 17 months. Our understanding of the control and expression of sexual behavior in bulls is limited, particularly in B. indicus genotypes.


Genetic basis of maize maternal haploid induction beyond MATRILINEAL and ZmDMP.
In maize, doubled haploid (DH) lines are created in vivo through crosses with maternal haploid inducers. Their induction ability, usually expressed as haploid induction rate (HIR), is known to be under polygenic control. Although two major genes (MTL and ZmDMP) affecting this trait were recently described, many others remain unknown. To identify them, we designed and performed a SNP based (~9007) genome-wide association study using a large and diverse panel of 159 maternal haploid inducers. Our analyses identified a major gene near MTL, which is present in all inducers and necessary to disrupt haploid induction. We also found a significant quantitative trait loci (QTL) on chromosome 10 using a case-control mapping approach, in which 793 noninducers were used as controls. This QTL harbors a kokopelli ortholog, whose role in maternal haploid induction was recently described in Arabidopsis. QTL with smaller effects were identified on six of the ten maize chromosomes, confirming the polygenic nature of this trait. These QTL could be incorporated into inducer breeding programs through marker-assisted selection approaches. Further improving HIR is important to reduce the cost of DH line production.


Determination of apoptosis, proliferation status and O6-methylguanine DNA methyltransferase methylation profiles in different immunophenotypic profiles of diffuse large B-cell lymphoma.
Our aim was to investigate the expression of apoptosis-associated proteins (bcl-2, bcl-xl, bax, bak, bid), apoptotic index (AI) and proliferation index (PI) in germinal center B-cell-like immunophenotypic profile (GCB) and non-GCB of diffuse large B-cell lymphoma (DLBCL). The methylation status of the promoter region of O6-methylguanine-DNA yerine O6-methylguanine-DNA methyltransferase (MGMT) gene and its relation with immunophenotypic differentiation of DLBCLs were also investigated. 101 cases were classified as GCB (29 cases) or non-GCB (72 cases). Apoptosis-associated proteins and PI were determined by IHC, and TUNEL method was used to determine AI. MGMT methylation analysis was performed by real-time PCR. The PI was significantly higher in GCB compared with non-GCB (p=0.011). Percentage of cells stained with bcl-6 was positively correlated with the percentage of cells expressing bcl-2 (p=0.023), AI (p=0.006) and PI (p<0.001), while a significant negative correlation was observed with the percentage of cells expressing bax (p=0.027). The percentage of cells stained with MUM1 showed a significantly positive correlation with the percentage of cells expressing bcl-xl (p=0.003), bid (p=0.002), AI (p<0.001), and PI (p=0.001). MGMT methylation analysis was performed in 95 samples, and methylated profile was found in 31 cases (32.6%). GCB was found in 6 cases (22.2%) and non-GCB was determined in 25 cases (36.8%) out of 31 with MGMT methylated samples. There was no significant association between MGMT methylation status and immunophenotypic profiles (p=0.173). These results suggest that bcl-6 protein expression may be responsible for the high PI in GCB. Additionally, we found that apoptosis-associated proteins were not significantly associated with immunophenotypic profiles.