Mycobiome analysis for distinguishing the geographical origins of sesame seeds.
Sesame (Sesamum indicum) is one of the most widely cultivated crops in Asia and Africa. The identification of the geographical origins of sesame seeds is important for the detection of fraudulent samples. This study was conducted to build a prediction model and suggest potential biomarkers for distinguishing the geographical origins of sesame seeds using mycobiome (fungal microbiome) analysis coupled with multivariate statistical analysis. Sesame seeds were collected from 25 cities in Korea, six cities in China, and five sites in other countries (Ethiopia, India, Nigeria, and Pakistan). According to the expression of fungal internal transcribed spacer (ITS) sequences in sesame seeds, 21 fungal genera were identified in sesame seeds from various countries. The optimal partial least squares-discriminant analysis model was established by applying two components with unit variance scaling. Based on seven-fold cross validation, the predictive model had 94.4% (Korea vs. China/other countries), 91.7% (China vs. Korea/other countries), and 88.9% (other countries vs. Korea/China) accuracy in determining the geographical origins of sesame seeds. Alternaria, Aspergillus, and Macrophomina were suggested as the potential fungal genera to differentiate the geographical origins of sesame seeds. This study demonstrated that mycobiome analysis could be used as a complementary method for distinguishing the geographical origins of raw sesame seeds.


The Lyme Disease Biobank: Characterization of 550 Patient and Control Samples from the East Coast and Upper Midwest of the United States.
Lyme disease (LD) is an increasing public health problem. Current laboratory testing is insensitive in early infection, the stage at which appropriate treatment is most effective in preventing disease sequelae. The Lyme Disease Biobank (LDB) collects samples from individuals with symptoms consistent with early LD presenting with or without erythema migrans (EM) or an annular, expanding skin lesion and uninfected individuals from areas of endemicity. Samples were collected from 550 participants (298 cases and 252 controls) according to institutional review board-approved protocols and shipped to a centralized biorepository. Testing was performed to confirm the presence of tick-borne pathogens by real-time PCR, and a subset of samples was tested for Borrelia burgdorferi by culture. Serology was performed on all samples using the CDC's standard two-tiered testing algorithm (STTTA) for LD. LD diagnosis was supported by laboratory testing in 82 cases, including positive results by use of the STTTA, PCR, or culture or positive results by two enzyme-linked immunosorbent assays for cases presenting with EM lesion sizes of >5 cm. The remaining 216 cases had negative laboratory testing results. For the controls, 43 were positive by at least one of the tiers and 6 were positive by use of the STTTA. The results obtained with this collection highlight and reinforce the known limitations of serologic testing in early LD, with only 29% of individuals presenting with EM lesion sizes of >5 cm yielding a positive result using the STTTA. Aliquots of whole blood, serum, and urine from clinically characterized patients with and without LD are available to investigators in academia and industry for evaluation or development of novel diagnostic assays for LD, to continue to improve upon currently available methods.


Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators.
Despite the use of aspirin and heparin, patients with acute ischemic syndromes are at risk of myocardial infarction (MI) or refractory ischemia. Therefore, evaluation of more potent antithrombotic therapies is warranted. Patients (n=909) with unstable angina or suspected acute MI without ST-segment elevation were randomized to receive heparin (5000 IU bolus+1000 to 1200 U/h, n=371), low-dose hirudin (LDHir) (0.2 mg/kg bolus+0.10 mg x kg(-1) x h(-1) infusion, n=271), or medium-dose hirudin (MDHir) (0.4 mg/kg bolus+0.15 mg x kg(-1) x h(-1) infusion, n=267) for 72 hours. At 7 days, 6.5% of patients in the heparin group, 4.4% in the LDHir group, and 3.0% in the MDHir group (P=.267 heparin versus low-dose hirudin; P=.047 heparin versus medium-dose hirudin) suffered cardiovascular death, new MI, or refractory angina (primary outcome). The proportions with cardiovascular death, new MI, or refractory or severe angina (secondary outcome) were 15.6%, 12.5%, and 9.4%, respectively (P=.27 for heparin versus LDHir; P=.02 for heparin versus MDHir). The rates of new MI were 4.9%, 2.6%, and 1.9%, respectively (P=.14 heparin versus LDHir; P=.046 heparin versus MDHir). Fewer patients underwent coronary artery bypass graft surgery in the two hirudin groups (3.7% low-dose, 1.1% medium-dose group) compared with heparin (4.0%) (P=.028 for heparin versus MDHir). After cessation of study treatments, there was an increase in ischemic events in the LDHir group at approximately 24 hours and at approximately 5 days in the medium-dose group. Nevertheless, at 180 days, the differences between hirudin and heparin persisted. Hirudin, especially at the medium dose, appears to be superior to heparin in preventing ischemic outcomes in unstable angina or acute MI without ST elevation.


Characterization of a clinical unit for digital radiography based on irradiation side sampling technology.
A characterization of a clinical unit for digital radiography (FUJIFILM FDR D-EVO) is presented. This system is based on the irradiation side sampling (ISS) technology and can be equipped with two different scintillators: one traditional gadolinium-oxysulphide phosphor (GOS) and a needle structured cesium iodide (CsI) phosphor panel. The characterization was achieved in terms of response curve, modulation transfer function (MTF), noise power spectra (NPS), detective quantum efficiency (DQE), and psychophysical parameters (contrast-detail analysis with an automatic reading of CDRAD images). For both scintillation screens the authors accomplished the measurements with four standard beam conditions: RAQ3, RQA5, RQA7, and RQA9. At the Nyquist frequency (3.33 lp/mm) the MTF is about 35% and 25% for CsI and GOS detectors, respectively. The CsI scintillator has better noise properties than the GOS screen in almost all the conditions. This is particularly true for low-energy beams, where the noise for the GOS system can go up to a factor 2 greater than that found for CsI. The DQE of the CsI detector reaches a peak of 60%, 60%, 58%, and 50% for the RQA3, RQA5, RQA7, and RQA9 beams, respectively, whereas for the GOS screen the maximum DQE is 40%, 44%, 44%, and 35%. The contrast-detail analysis confirms that in the majority of cases the CsI scintillator is able to provide improved outcomes to those obtained with the GOS screen. The limited diffusion of light produced by the ISS reading makes possible the achievement of very good spatial resolution. In fact, the MTF of the unit with the CsI panel is only slightly lower to that achieved with direct conversion detectors. The combination of very good spatial resolution, together with the good noise properties reached with the CsI screen, allows achieving DQE on average about 1.5 times greater than that obtained with GOS. In fact, the DQE of unit equipped with CsI is comparable to the best alternative methods available which are based on the same technology, and similar to others based on an a-Se direct conversion detectors.


An acute intake of a walnut-enriched meal improves postprandial adiponectin response in healthy young adults.
A deficit in adiponectin plays an important causal role in insulin resistance and metabolic syndrome. We hypothesized that as seen during the fasting state, the intake of a walnut-enriched meal increased postprandial adiponectin. Twenty-one healthy white men followed a 4-week baseline diet and then consumed 3 fat-loaded meals that included 1 g fat/kg body weight (65% fat) according to a randomized crossover design: olive oil-enriched meal (22% saturated fatty acids [SFA], 38% monounsaturated fatty acids [MUFA], 4% polyunsaturated fatty acids [PUFA]), butter-enriched meal (35% SFA, 22% MUFA, 4% PUFA), and walnut-enriched meal (20% SFA, 24% MUFA, 16% PUFA, and 4% α-linolenic acid). Leptin, resistin, adiponectin, and free fatty acids were determined at 0, 3, 6, and 8.5 hours after the fat load. After the walnut-enriched meal, plasma adiponectin concentrations were higher at 3 and 6 hours (P = .011, P = .046, respectively) compared with the butter-enriched meal and higher at 6 hours compared with the olive oil-enriched meal (P = .036). Free fatty acid levels decreased from baseline at 3 hours after the walnut-enriched meal (P = .001). No differences were observed between the 3 meals for leptin and resistin responses. Our data confirmed a beneficial profile in the postprandial response to walnuts, source of omega-3 PUFA with an increased postprandial adiponectin and lower postprandial free fatty acid responses. These findings suggest that the postprandial state is important for understanding the possible cardioprotective effects associated with omega-3 PUFA dietary fat.


Association between the Type of Diabetes Treatment and Depressive Symptoms among Patients with Diabetes: A Cross-Sectional Study of Korea Community Health Surveys Data, 2011-2016.
The purpose of this study was to examine the association between the different types of treatment for diabetes and depressive symptoms. In particular, this study assessed the presence of depressive symptoms in patients with diabetes who are undergoing pharmacological treatments in terms of sex. This study used data from the 2011-2016 Korea Community Health Survey, which included responses from 50,774 male and 48,978 female participants with diabetes who were receiving pharmacological treatments. Patients aged ≥30 years were included. Logistic regression analysis was conducted to examine the significance of the association. Male participants treated with insulin injection were more likely to experience depressive symptoms than those taking oral hypoglycemic (oral agents) only (odds ratio (OR) = 1.27; 95% confidence interval (CI): 1.04-1.56). Male patients treated with both oral agents and insulin injection had the highest OR value of depressive symptoms among different types of treatments (OR = 1.41, 95% CI: 1.25-1.60). The same tendency was observed in female participants. In female patients, however, the association between depressive symptoms and insulin injection was statistically insignificant (both oral agents and insulin injection OR = 1.35, 95% CI: 1.22-1.50, insulin injection OR = 1.17, 95% CI: 0.98-1.41). The association between depressive symptoms and the type of diabetes treatment was more significant in male than in female patients. Those who were treated with oral agents and insulin injection were more likely to have depressive symptoms than those receiving oral agents of treatment.


[Colitis cystica profunda. A case report].
To present a pathology not previously informed in national literature. Colitis cystica profunda (CCP) is a rare benign entity and with an unknown etiology. There are 148 cases documented in world literature at the present time. Histologically it is defined as the obliteration of lamina propria by fibroblasts and the presence of submucous cysts. It comes in localized, segmental or diffuse forms and associated to other entities as solitary rectal ulcer, rectal prolapse, alterations in the pelvic floor, etc. Treatment can be medical or surgical according to severity of its manifestations. A case of CCP is revised as well as the treatment effectuated. A case of patient with the diagnosis of CCP of localized type is presented, which principal symptom was transanal mucous secretion; on physical exploration a sessile mucous polypoid formation at 8 cm from anal verge was found and was treated with surgical resection with a satisfactory outcome. In a patient with alterations in pelvic floor or puborectal bundle contraction and sigmoidorectal intussusception CCP must be suspected. Treatment can be medical with a high percentage of failure being optimal treatment the surgical one.


Teleneurology in Northern Ireland: a success.
In March 1998 two neurologists and a professor of telemedicine met to solve a clinical problem--how to get neurological expertise to patients admitted acutely to hospitals which had no resident neurologist. Four years later, two new consultant neurologists were appointed in Northern Ireland with sessions in telemedicine, possibly the first such appointments anywhere in the world. This feat was achieved by combining science with politics. First, we chose the most appropriate telemedicine equipment and bandwidth for our needs. Second, we altered our neurological consultation to use the technology efficiently. Third, we were able to show scientifically that teleneurology was reproducible, feasible in practice, safe, acceptable and cost-effective. This required money to pay for a research fellow and equipment, which was obtained initially from some departmental research funds and a local hospital. Conventional research funding bodies were, on the whole, unhelpful. It was serendipitous that a review of neurology services in Northern Ireland was set up by the Department of Health. This identified our original problem as one that it wanted solved and we were in the fortunate position of being able to offer telemedicine as a tested solution. One final political push was required to get the money released. The result of this juxtaposition of science and politics should bring benefit to our neurological patients and will perhaps help others trying to establish similar projects elsewhere.


Transfer facilities for the seriously ill and injured.
The handling of stretchers and trolleys plays an important part in the early management of seriously ill and injured patients. The design of such equipment should include the following features. Stretchers (or carrying sheets) should be interchangeable between the hospital and the ambulance service. They should be made of washable, unshrinkable, antistatic material and should be fitted with loops on either side to facilitate transfer by sliding and to enable them to be used also as carrying sheets when narrow staircases have to be negotiated. Hospital trolleys should be able to rise and fall (to allow transference by sliding on to a standard X-ray table) and to have a back rest hinged at 2 ft 9 in to facilitate erect X-ray examination of the chest. Such trolleys should also carry oxygen and suction, cotsides, dripstand and a tray for clothes and for a chest drainage bottle. Both carrying sheets and trolley tops should be completely pervious to X-rays. A plea is made for a more critical scrutiny of the facilities which are available for the transport of the ill and injured, both inside and outside the hospital.


[Method of postmortem determination of heart chamber volume].
A new method for postmortem determination of volumes of heart chambers has been developed which reflects their vital volume most accurately. Volumetric values of heart chambers have been calculated by comparison of mathematically calculated vital volumes with postmortem ones.


Hepatitis E virus infection dynamics and organic distribution in naturally infected pigs in a farrow-to-finish farm.
The objective of the present study was to determine the pattern of Hepatitis E virus (HEV) infection in a naturally infected, farrow-to-finish herd. For that purpose, a prospective study was conducted in randomly selected 19 sows and 45 piglets. Blood samples were collected from sows at 1 week post-farrowing and from piglets at 1, 3, 6, 9, 12, 15, 18 and 22 weeks of age. Furthermore 3 or 5 animals were necropsied at each bleeding day (but at 1 week of age), and serum, bile, liver, mesenteric lymph nodes and faeces taken. HEV IgG, IgM and IgA antibodies were determined in serum and viral RNA was analysed in all collected samples by semi-nested RT-PCR. Histopathological examination of mesenteric lymph nodes and liver was also conducted. From 13 analysed sows, 10 (76.9%) were positive to IgG, one to IgA (7.7%) and two to IgM (15.4%) antibodies specific to HEV. In piglets, IgG and IgA maternal antibodies lasted until 9 and 3 weeks of age, respectively. IgG seroconversion occurred by 15 weeks of age while IgM and IgA at 12. On individual basis, IgG was detectable until the end of the study while IgM and IgA antibody duration was of 4-7 weeks. HEV RNA was detected in serum at all analysed ages with the highest prevalence at 15 weeks of age. HEV was detected in faeces and lymph nodes for the first time at 9 weeks of age and peaked at 12 and 15 weeks of age. This peak coincided with the occurrence of hepatitis as well as with HEV detection in bile, liver, mesenteric lymph nodes and faeces, and also with highest IgG and IgM OD values at 15 weeks. Finally, different HEV sequences from this farm were obtained, which they clustered within 3 different groups, together with other Spanish sequences, all of them of genotype 3. Moreover, the present study also indicates that the same pig can be infected with at least two different strains of HEV during its productive life. This is the first study characterizing HEV infection in naturally infected pigs with chronological virus detection and its relationship with tissue lesions throughout the productive life of the animals.


Clinical measurement of patellar tendon: accuracy and relationship to surgical tendon dimensions.
Patellar tendon width and length are commonly used for preoperative planning for anterior cruciate ligament reconstruction (ACLR). In the study reported here, we assessed the accuracy of preoperative measurements made by palpation through the skin, and correlated these measurements with the actual dimensions of the tendons at surgery. Before making incisions in 53 patients undergoing ACLR with patellar tendon autograft, we measured patellar tendon length with the knee in full extension and in 90° of flexion, and tendon width with the knee in 90° of flexion. The tendon was then exposed, and its width was measured with the knee in 90° of flexion. The length of the central third of the tendon was measured after the graft was prepared. Mean patellar tendon length and width with the knee in 90° of flexion were 39 mm and 32 mm, respectively. No clinical difference was found between the estimated pre-incision and surgical widths. However, the estimated pre-incision length with the knee in full extension and in 90° of flexion was significantly shorter than the surgical length. Skin measurements can be used to accurately determine patellar tendon width before surgery, but measurements of length are not as reliable.


Lumbosacral Transitional Vertebrae Cause Spinal Level Misconception in Surgeries for Degenerative Lumbar Spine Disorders.
Human lumbar spine usually consists of five vertebrae; however, some individuals have vertebral anomalies with four or six lumbar vertebrae because of sacralized fifth lumbar vertebra (L5 sacralization) or lumbarized first sacral vertebra (S1 lumbarization), respectively. These vertebral anomalies are called lumbosacral transitional vertebra (LSTV). Although LSTV is an asymptomatic anomaly, it is known to cause misconception in spinal counts and in spinal level at lumbar spinal surgery. The purpose of this study is to evaluate how LSTV affects the diagnosis and surgeries in lumbar spine disorders. In 550 consecutive patients who underwent lumbar spinal surgeries, a whole-spine X-ray was taken on admission to assess the true number of lumbar vertebrae. We assessed the coherence between the neurological level diagnosis and the level of spinal canal stenosis on imaging studies before and after the recognition of LSTV to clarify how recognition of LSTV affected pre-operative surgical planning. Out of 550 patients, LSTV was found in 71 (12.9%) patients: 37 cases with L5 sacralization and 34 cases with S1 lumbarization. The number of vertebrae was miscounted at the outpatient department (OPD) in 38 cases (54%): 10 L5-sacralization cases and 28 S1-lumbarization cases. Moreover, surgical spinal levels were altered from the original surgical plans at OPD in 11 cases (15%; 3 L5-sacralization and 8 S1-lumbarization cases), after recognizing the true spinal counts by the whole spine X-ray. To avoid errors in spinal level diagnosis, we should recognize the possibility of LSTV that could be assessed by a whole spine X-ray.


Depletion of extracellular cysteine with hydroxocobalamin and ascorbate in experimental murine cancer chemotherapy.
Treatment of mice bearing P388 lymphocytic leukemia with combined hydroxocobalamin (0.1 mmol/kg) and sodium ascorbate (1.0 mmol/kg) for 10 consecutive days resulted in 70% increase in survival. Treatment with dehydroascorbate (1.0 mmol/kg) similarly increased survival. The extended treatment for 15 days posttumor inoculation failed to improve survival as did lowering the tumor inocula from 10(6) to 10(4) cells in similarly treated mice. P388 cells in primary culture with cystine as a source of cysteine require exogenous thiols or disulfides for growth and also grow with cysteine but only when trace copper is sequestered with bathocuproine sulfonate. This is due to the copper catalyzed oxidation of cysteine to cystine, which these cells cannot utilize. Cells grew in medium preincubated for 8 h with cysteine and bathocuproine sulfonate, but lysed when the preincubated medium included hydroxocobalamin (10 microM) and sodium ascorbate (100 microM). This defect was corrected by resupplementation with cysteine or cystine plus bishydroxyethyl disulfide after addition of the cells. Further support for cysteine depletion as a factor in therapy is obtained by therapeutic interference with 4-thiamethionine (25 mumol/kg). This mixed disulfide of cysteine and methyl mercaptan enters cells as a methionine analogue, is reduced to supply cysteine, and thus withstands the oxidative environment that limits the utilization of cysteine as a nutrient. These results suggest that dehydroascorbate is generated from combined hydroxocobalamin and ascorbate and accounts for the thiol-prive activity of combined hydroxocobalamin and ascorbate therapy. The ultimate failure of therapy by thiol oxidation may be due to the increased availability of cysteine produced by host tissues, possibly infiltrating macrophages, that occurs independently of extended treatment and the size of the tumor inoculum.


Full Blood Count Trends for Colorectal Cancer Detection in Primary Care: Development and Validation of a Dynamic Prediction Model.
Colorectal cancer has low survival rates when late-stage, so earlier detection is important. The full blood count (FBC) is a common blood test performed in primary care. Relevant trends in repeated FBCs are related to colorectal cancer presence. We developed and internally validated dynamic prediction models utilising trends for early detection. We performed a cohort study. Sex-stratified multivariate joint models included age at baseline (most recent FBC) and simultaneous trends over historical haemoglobin, mean corpuscular volume (MCV), and platelet measurements up to baseline FBC for two-year risk of diagnosis. Performance measures included the c-statistic and calibration slope. We analysed 250,716 males and 246,695 females in the development cohort and 312,444 males and 462,900 females in the validation cohort, with 0.4% of males and 0.3% of females diagnosed two years after baseline FBC. Compared to average population trends, patient-level declines in haemoglobin and MCV and rise in platelets up to baseline FBC increased risk of diagnosis in two years. C-statistic: 0.751 (males) and 0.763 (females). Calibration slope: 1.06 (males) and 1.05 (females). Our models perform well, with low miscalibration. Utilising trends could bring forward diagnoses to earlier stages and improve survival rates. External validation is now required.


Clinical Findings of Pediatric HIV Infection in a Tertiary Center in Turkey.
Paediatric HIV infection is different from the adult type of disease in many ways, including transmission routes, clinical findings and treatment strategies. To evaluate clinical data of paediatric patients with HIV disease. Retrospective cross-sectional study. The charts of 22 paediatric patients diagnosed with HIV infection in our clinic during a 14 year period through 2001-2015 were retrospectively analysed. Clinical data, laboratory findings, treatment modalities and outcomes were recorded. The mean age of diagnosis 61.9±49.2 months and the mean follow-up period was 60.3±37.5 months. Seven patients (31.8%) were foreigners and the most common transmission route was vertical transmission (n=16, 72.7%). The most common presenting symptom and the sign were history of recurrent upper respiratory tract infections (n=8, 36.4%) and lymphadenopathy (n=12, 54.5%), respectively. Recurrent pneumonia (n=6, 27.3%), prolonged fever (n=5, 22.7%), recurrent otitis media (n=4, 18.2%), and gastroenteritis (n=4, 18.2%) were other clinical symptoms. Other than bacterial sinopulmonary infections, tuberculosis was the most frequent opportunistic infection (n=3, 13.6%). Mortality occurred in two patients (9.1%). Although mostly vertically transmitted, HIV infection may be diagnosed throughout the childhood. Frequently encountered signs and symptoms may be the reason for doctor admission. High clinical suspicion together with detailed anamnestic data and physical findings constitute the basis for pediatric HIV diagnosis.


EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot).
The primary objective of the new ESC-HF Pilot Survey was to describe the clinical epidemiology of outpatients and inpatients with heart failure (HF) and the diagnostic/therapeutic processes applied across 12 participating European countries. This pilot study was specifically aimed at validating the structure, performance, and quality of the data set, for continuing the survey into a permanent registry. The ESC-HF Pilot study is a prospective, multicentre, observational survey conducted in 136 cardiology centres from 12 European countries selected to represent the different health systems and care attitudes across Europe. All outpatients with HF and patients admitted for acute HF were included during the enrolment period (1 day per week for 8 consecutive months). From October 2009 to May 2010, 5118 patients were included in this pilot survey, of which 1892 (37%) were admitted for acute HF and 3226 (63%) for chronic HF. Ischaemic aetiology was reported in about half of the patients. In patients admitted for acute HF, the most frequent clinical profile was decompensated HF (75% of cases), whereas pulmonary oedema and cardiogenic shock were reported, respectively, in 13.3 and 2.3% of the cases. The total in-hospital mortality rate was 3.8% and was cardiovascular in 90.1% of the cases. Lowest and highest mortality rates were observed in hypertensive HF and in cardiogenic shock, respectively. More than 80% of patients with chronic HF were treated with renin-angiotensin-aldosterone system blockers and β-adrenergic blockers. However, target doses of such drugs were reached in one-third to one-fourth of the patients only. The ESC-HF Pilot Survey is an example of the possibility of utilizing an observational methodology to get insights into the current clinical practice in Europe, whose picture will be completed by the 1-year follow-up. Moreover, this study offered the opportunity to refine the organizational structure of a long-term, extended European network.


The predictive values of a deliberative and a paternalistic attitude towards two situations of moral conflict: A study among Dutch nurse practitioners and physician assistants.
In this study, we examined the predictive values of a moral deliberate and paternalistic attitude on the propensity of yielding to pressure. In these hypothesised positive and negative relationships, we further sought to ascertain whether moral disengagement plays a pivotal role when individuals deviate from ethical standards, rules and regulations when yielding to pressure. This study's primary aim was to assess the predictive value of a moral deliberative and paternalistic attitude for yielding to pressure when physician assistants (PAs) and nurse practitioners (NPs) face moral conflicts. This validation study was cross-sectional and based on a convenience sample of Dutch PAs and NPs. The MSQ-DELIB and MSQ-PATER scales indicate a moral deliberate or paternalistic attitude. These scales were assumed to have a predictive value towards the degree of yielding to pressure by PAs and NPs. Yielding to pressure was measured by two vignettes in which respondents faced a moral conflict (vignette 1: prescribing unindicated antibiotics and vignette 2: discharging a difficult patient from the hospital). Only moral deliberation was a significant predictor of yielding to pressure. That is, we found a positive effect in vignette 1 (in which the pressure came from the patient). In contrast, we found a negative relationship in vignette 2 (in which pressure went from the working environment). Paternalism did not affect yielding to pressure in either vignette. This study suggests that PAs and NPs having a moral deliberative attitude makes them receptive to pressure exerted by patients to break moral standards. On the other hand, they are more resilient against doing so when this pressure comes from different sources than the patient. Further research is needed to find more conclusive evidence for this differential effect.


The cognitive effects of recombinant interleukin-2 (rIL-2) therapy: a controlled clinical trial using computerised assessments.
It has been suggested that patients undergoing treatment with recombinant interleukin-2 (rIL-2) may develop cognitive impairment. To evaluate these effects, 17 patients with advanced colorectal cancer took part in a randomised, parallel group study of rIL-2 with chemotherapy (5-fluorouracil and leucovorin) and chemotherapy alone. Assessments were carried out daily whilst patients were in hospital and regularly between cycles of treatment using state-of-the-art computerised cognitive assessment, as well as traditional psychometric tests. Rigorous discontinuation criteria were applied to ensure that the effect of time-related variables did not influence the results. One patient developed repeated transient psychotic episodes associated with rIL-2 infusions and another regularly became confused. Computerised cognitive assessments revealed that immunochemotherapy produced significant impairment in various tasks, especially reaction time, picture recognition and vigilance. These effects were not due to sleep deprivation or pyrexia. For most patients, cognitive functioning was restored to the baseline level within 10 days following the cessation of rIL-2. In conclusion, during infusions of rIL-2, some patients experience severe confusion and amnesia which resembles some of the major cognitive impairments associated with dementias such as Alzheimer's disease. Computerised cognitive assessment using the Cognitive Drug Research system provides a feasible, sensitive and reliable method of evaluating cognitive changes in patients with cancer. It could usefully be included in quality of life assessments in clinical trials where treatment-related cognitive changes need to be evaluated.


[Effect of prostaglandins F2 and F2 alpha on the pentosephosate pathway in human blood platelets].
Rates of glucose-6-phosphate oxidation and formation of sedoheptulose-7-phosphate were increased after 10 min preincubation of human blood platelets with prostaglandins F2 and F2a. When the preincubation was prolonged up to 60 min, the prostaglandins activating effect was manifested only as an increase in sedoheptulose-7-phosphate content. Preincubation of thrombocytes with dibutyryl-cAMP led to an increase in the rate of ribose-5-phosphate consumption as well as of sedoheptulose-7-phosphate formation. Chlorpromazine hydrochloride decreased the rates of glucose-6-phosphate and 6-phosphogluconate oxidation in extracts of human thrombocytes and inhibited the activating effect of prostaglandins on sedoheptulose-7-phosphate formation.


Loss of Estrogen-Regulated MIR135A1 at 3p21.1 Promotes Tamoxifen Resistance in Breast Cancer.
The dysregulation of miRNAs has been increasingly recognized as a critical mediator of cancer development and progression. Here, we show that frequent deletion of the MIR135A1 locus is associated with poor prognosis in primary breast cancer. Forced expression of miR-135a decreased breast cancer progression, while inhibition of miR-135a with a specific miRNA sponge elicited opposing effects, suggestive of a tumor suppressive role of miR-135a in breast cancer. Estrogen receptor alpha (ERα) bound the promoter of MIR135A1 for its transcriptional activation, whereas tamoxifen treatment inhibited expression of miR-135a in ERα+ breast cancer cells. miR-135a directly targeted ESR1, ESRRA, and NCOA1, forming a negative feedback loop to inhibit ERα signaling. This regulatory feedback between miR-135a and ERα demonstrated that miR-135a regulated the response to tamoxifen. The tamoxifen-mediated decrease in miR-135a expression increased the expression of miR-135a targets to reduce tamoxifen sensitivity. Consistently, miR-135a expression was downregulated in ERα+ breast cancer cells with acquired tamoxifen resistance, while forced expression of miR-135a partially resensitized these cells to tamoxifen. Tamoxifen resistance mediated by the loss of miR-135a was shown to be partially dependent on the activation of the ERK1/2 and AKT pathways by miR-135a-targeted genes. Taken together, these results indicate that deletion of the MIR135A1 locus and decreased miR-135a expression promote ERα+ breast cancer progression and tamoxifen resistance.Significance: Loss of miR-135a in breast cancer disrupts an estrogen receptor-induced negative feedback loop, perpetuating disease progression and resistance to therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4915/F1.large.jpg Cancer Res; 78(17); 4915-28. ©2018 AACR.


Thromboxane-mediated activation of platelets and enhancement of platelet uptake onto collagen-coated glass or deendothelialized rabbit aorta. Comparative effects of a thromboxane antagonist (EPO45) and a thromboxane synthetase inhibitor (dazoxiben).
The effects of a cyclooxygenase inhibitor (indomethacin), a thromboxane synthetase inhibitor (dazoxiben), and a thromboxane antagonist (EPO45) on rabbit platelet aggregation induced by collagen were studied and compared with effects on platelet uptake both by damaged rabbit aorta and by collagen-coated glass. Platelet aggregation and associated release of serotonin were inhibited to a similar extent both by indomethacin and EPO45. Dazoxiben had a minimal inhibitory effect on aggregation but reduced the release of serotonin by about 40% compared with control. Platelet uptake onto collagen-coated glass was markedly reduced both by indomethacin and EPO45 but not by dazoxiben. In contrast, EPO45 and dazoxiben were equally effective in reducing platelet adhesion to damaged rabbit aorta. At the concentrations used for adhesion studies the formation of thromboxane B2 was reduced both by dazoxiben and by indomethacin (both greater than 95% inhibition compared with control) and to a lesser extent by EPO45 (less than 40% inhibition). The results indicate that thromboxane A2 (and cyclic endoperoxide) released by adherent platelets may enhance thromboxane synthesis and promote platelet uptake both onto collagen-coated glass and onto damaged rabbit aorta. In the presence of vascular tissue, cyclic endoperoxides are readily metabolized and thereby removed. The potential antithrombotic activity of TXA2 synthetase inhibitors could be impaired in situations in which endoperoxide clearance is limited (e.g., accompanying platelet uptake onto artificial surfaces) but not at the damaged vessel wall. Thus, both inhibitors and antagonists are likely to have similar potency as antithrombotic agents in vivo.


Patterns of spatial and temporal cranial muscle development in the African clawed frog, Xenopus laevis (Anura: Pipidae).
The African Clawed Toad, Xenopus laevis, has been a major vertebrate model organism for developmental studies for half a century. Because most studies have focused on the early stages of development, this has had the effect that many aspects of organogenesis and later development remain relatively poorly known in this species. In particular, little is known about cranial muscle development even at the level of morphology and histological differentiation of muscle anlagen and muscle fibers. In this study, we document the morphogenesis and histological differentiation of cranial muscles in X. laevis. We provide a detailed account of the timing of development for each of the cranial muscles, and also describe a new muscle, the m. transversus anterior. The cranial musculature of X. laevis larvae generally develops in a rostrocaudal sequence. The first muscles to differentiate are the extrinsic eye muscles. Muscles of the mandibular and hyoid arches develop almost simultaneously, and are followed by the muscles of the branchial arches and the larynx, and by the mm. geniohyoideus and rectus cervicis. Despite the fact that differentiation starts at different stages in the different muscles, most are fully developed at Stage 14. These baseline data on the timing of muscle differentiation in the X. laevis can serve as a foundation for comparative studies of heterochronic changes in cranial muscle development in frogs and other lissamphibians.


Dysfunctional mitochondrial respiration in the wobbler mouse brain.
The involvement of mitochondrial dysfunction promoting neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), has been suggested. Histopathological and biochemical mitochondrial abnormalities have been reported in both sporadic and familial patients and suggest the contention that mitochondria may play a key role promoting ALS. Animal models of ALS provide a unique opportunity to study this incurable and fatal human disease. In the present study we tested the hypothesis that alterations in mitochondrial physiology occur in the brain of wobbler mice. No significant difference was found in the respiratory control index or adenosine diphosphate/oxygen ratio values between isolated mitochondria of wobbler and control mice. When pyruvate and malate were used as substrates, oxygen consumption was decreased significantly by approximately 33% in mitochondria isolated from wobbler mouse brain compared to controls. Oxygen consumption in the presence of ascorbate and N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) was decreased significantly by approximately 21% in wobbler brain mitochondria compared to controls, which suggests impairment in the function of complex IV. These findings are the first demonstration of mitochondrial respiratory chain dysfunction in the brain of the wobbler mouse.


Longitudinal study of the contractile and electrical properties of single human thenar motor units.
Serial motor unit number estimates have shed important light on the extent and rates of motoneuron losses in aging and amyotrophic lateral sclerosis. However, the estimates alone provide few clues to the health and functional status of surviving motor units. A reliable means for assessing the functional status of the surviving motor units would therefore by a welcome addition to our present tools for studying motor units. Examining the physiological properties of samples of motor units drawn at intervals during the course of a motoneuronal disease suffers from the important limitation that the samples may not be representative of one another. The latter problem could be circumvented by serially studying the same motor units. This study describes a noninvasive technique capable of longitudinally tracking the contractile and electrical properties of specific single thenar motor units in healthy subjects, in some instances over several years. The technique proved to be reasonably reliable and provided information on a wide range of contractile and electrical properties of motor units. Such an approach could serve as a potentially powerful and sensitive means of studying the life histories of single motor units in aging, diseases of the motoneuron, and in the latter instances, the responses of the motoneurons to treatment.


Targeting Mitochondria in Cardiovascular Diseases.
Cardiovascular diseases (CVDs) are one of the main factors responsible for human morbidity and mortality. Since mitochondria play a critical role in the regulation of cardiac tissue homeostasis, this organelle is a critical target for the protective effects of several pharmaceuticals. Although specific mitochondria-targeted antioxidants and some pharmacological agents are described as potential cardioprotective agents, there are still a few effective mitochondrial therapies for the treatment of CVDs. Agents which have potential cardioprotective effects by directly targeting mitochondria in vitro and in vivo are still in pre-clinical or clinical trials, hence their widespread use in the clinic is still far. Also, some of these agents have a decreased bioavailability or show some intrinsic toxicity, which also limits their working mitochondrial concentrations. By initially using PubMed specific queries for literature search, we review here cardiac mitochondrial effects of specific targeted and non-targeted antioxidants and pharmacological agents, including MitoE, MitoQ, MitoSNO, Mito-TEMPOL, SkQ1, SkQR1, carvedilol, trimetazidine, ranolazine, diazoxide and propofol. The present review emphasizes new mitochondrial-targeting strategies which have emerged to address difficulties arising from current approaches. We also describe the strengths and weaknesses of these cardioprotective approaches. Although effective therapies to target mitochondria in the context of CVDs are not under widespread clinical use, the new strategies proposed constitute a real promise for the development of therapies which may effectively prevent CVDs in the near future.


[Use of dimexide in the treatment of acute hematogenic osteomyelitis in children].
Under observation were 132 children with acute hematogenous osteomyelitis. The complex treatment of an acute stage of hematogenic osteomyelitis included also the local use of 33% dimexide (DMSO) solution together with antibiotics. The observations indicated a high efficacy of the suggested therapeutic method.


Complete genome sequence of Erythrobacteraceae bacterium WH01K, a strain isolated from corals (Acropora sp.) in Taiwan.
Here, we report the isolation and genome sequence of a coral-associated Erythrobacteraceae bacterium, strain WH01K. The complete assembly consists of one 2,745,896 bp circular chromosome and one 172,502 bp circular plasmid.


The early nodulin transcript ENOD2 is located in the nodule parenchyma (inner cortex) of pea and soybean root nodules.
A pea cDNA clone homologous to the soybean early nodulin clone pGmENOD2 that most probably encodes a cell wall protein was isolated. The derived amino acid sequence of the pea ENOD2 protein shows that it contains the same repeating pentapeptides, ProProHisGluLys and ProProGluTyrGln, as the soybean ENOD2 protein. By in situ hybridization the expression of the ENOD2 gene was shown to occur only in the inner cortex of the indeterminate pea nodule. The transcription of the pea ENOD2 gene starts when the inner cortical cells develop from the nodule meristem. In the determinate soybean nodule the ENOD2 gene is expressed in the inner cortex as well as in cells surrounding the vascular bundle that connects the nodule with the root central cylinder. The term 'nodule inner cortex' is misleading, as there is no direct homology with the root inner cortex. Therefore, we propose to consider this tissue as nodule parenchyma. A possible role of ENOD2 in a major function of the nodule parenchyma, namely creating an oxygen barrier for the central tissue with the Rhizobium containing cells, is discussed.


Long-term changes in body composition after pancreatoduodenectomy.
Body protein and fat stores were measured in four long-term survivors both before Whipple's procedure for malignancy at the ampulla of Vater and at a mean of 40 months (range 20-64 months) later. The results were compared with predicted well values. At follow-up patients also underwent dietary assessment and measurement of faecal fat losses. A dietary intake of mean (s.d) of 2690 (733) kcal per day and 85 (21) g protein per day met the patients' requirements. There was notable steatorrhoea (faecal fat 28 (21) g per day) but faecal protein losses were normal. Before surgery, body-weight was significantly lower than well-weight (P less than 0.0005), three patients having body fat stores lower than predicted well values. After surgery, body-weight and protein stores did not change significantly but fat stores fell in each patient (P less than 0.04). A curative Whipple's procedure prevents further weight loss in ampullary malignancy but weight gain does not occur because of steatorrhoea, perhaps a result of the accompanying truncal vagotomy.


Short-term traffic related exposures and biomarkers of nitro-PAH exposure and oxidative DNA damage.
Exposure to vehicle exhaust has been associated with cardiac and respiratory disease, lung cancer, and greater overall mortality. We investigated whether amino- polycyclic aromatic hydrocarbon (amino-PAH) metabolites of nitro-PAHs could be used as biomarkers of these exposures. Pre- and post-shift urine samples were collected at the beginning and end of a work week from 82 male U.S trucking industry workers. We used repeated-measures analysis to examine associations of total 1- and 2-aminonaphthalene (1 & 2-AN) and 1-aminopyrene (1-AP) urinary concentrations with microenvironment exposures to particulate matter (PM2.5), elemental and organic carbon, and between 1&2-AN and 1-AP with urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG). There was an association between work week mean PM2.5 levels and post-shift 1 & 2-AN, [141.8 pg/ml increase (95% CI:53.3, 230.2) for each IQR increase (5.54 µg/m3) in PM2.5,] but no associations with other exposure measures. There was a statistically significant increase in 8-OHdG concentrations with 1 & 2-AN (2.38 µg/mg creatinine (95%CI: 0.19, 4.58) per 242.85 pg/mg creatinine increase in 1 & 2-AN), and suggestive associations with all other exposure measures. Our findings suggest associations between urinary amino-PAHs with vehicle exhaust related PM2.5 as well as with a biomarker of oxidative DNA damage.


Clinical practice guidelines for the foot and ankle in rheumatoid arthritis: a critical appraisal.
Clinical practice guidelines are recommendations systematically developed to assist clinical decision-making and inform healthcare. In current rheumatoid arthritis (RA) guidelines, management of the foot and ankle is under-represented and the quality of recommendation is uncertain. This study aimed to identify and critically appraise clinical practice guidelines for foot and ankle management in RA. Guidelines were identified electronically and through hand searching. Search terms 'rheumatoid arthritis', 'clinical practice guidelines' and related synonyms were used. Critical appraisal and quality rating were conducted using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Twenty-four guidelines were included. Five guidelines were high quality and recommended for use. Five high quality and seven low quality guidelines were recommended for use with modifications. Seven guidelines were low quality and not recommended for use. Five early and twelve established RA guidelines were recommended for use. Only two guidelines were foot and ankle specific. Five recommendation domains were identified in both early and established RA guidelines. These were multidisciplinary team care, foot healthcare access, foot health assessment/review, orthoses/insoles/splints, and therapeutic footwear. Established RA guidelines also had an 'other foot care treatments' domain. Foot and ankle management for RA features in many clinical practice guidelines recommended for use. Unfortunately, supporting evidence in the guidelines is low quality. Agreement levels are predominantly 'expert opinion' or 'good clinical practice'. More research investigating foot and ankle management for RA is needed prior to inclusion in clinical practice guidelines.


Biotechnological methods on the study of nematodes.
During the past several years, a great many advances have been made in obtaining a better understanding of the biology of nematode parasites. Much of the information obtained has been with the use of tools developed in the expanding field of biotechnology, or more specifically, the use of biochemistry, genetics or molecular biology. Advances are being made on speciation of parasites, their function and pathogenesis. Some nematode parasites indigenous to Southeast Asia have been studied, but much more should be done. There is a large group of parasites in Southeast Asia that could be studied. In the past, emphasis has been on human nematodes, but there are many interesting parasites of lower animals that should be investigated. Furthermore, future parasitologists must first be trained in basic parasitology and then be exposed to new technology in order to apply these tools to further our knowledge of round worms.


Arch height and first metatarsal joint axis orientation as related variables in foot structure and function.
This study investigated the association of arch height combined with first metatarsal joint axis vertical (V) orientation to the size of the 1-2 intermetatarsal angle (IMA) and first metatarsal adduction/abduction position simulating foot postures during gait, kinematics commonly affected by bunion. Nine cadaver specimens were mounted in a loading frame. Measures of arch height ratio and IMA were made. With the foot placed in positions seen during normal gait cycle an electromagnetic device measured displacement of the relative angle of rotations between the first metatarsal and navicular, and helical axis (HA) parameters. Canonical correlation analysis assessed the relationship among the variables. A negative relationship (r = -0.73) was found between arch height and first metatarsal HA V-orientation. When considered as combined variables, arch height and metatarsal HA V-orientation accounted for 69% of the variance of IMA and change in first metatarsal adduction/abduction position. Orientation of the first metatarsal joint axis was highly variable between specimens but correlated with arch height. The conjoined factors of arch height and first metatarsal HA V-orientation accounted for most of the variance of IMA and change in first metatarsal adduction/abduction position during the sequence of foot position during simulated gait. These findings suggest that orthotic arch support could reorient the metatarsal joint axis out-of-vertical and in effect, limit the first metatarsal from displacing into an adducted bunion deformity. These findings could help to explain the pathogenesis of bunions.


Histamine and prostaglandin E up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-gamma-induced CXCL10 production by immature human dendritic cells.
Effector memory T helper 2 (Th2) cells that accumulate in target organs (i.e. skin or bronchial mucosa) have a central role in the pathogenesis of allergic disorders. To date, the factors that selectively trigger local production of Th2-attracting chemokines remain poorly understood. In mucosa, at the sites of allergen entry, immature dendritic cells (DC) are in close contact with mast cells. Histamine and prostaglandin E2 (PGE2) are two mediators released by allergen-activated mast cells that favour the polarization of maturing DC into Th2-polarizing cells. We analysed here the effects of histamine and PGE2 on the prototypic, Th2-(CCL17, CCL22) versus Th1-(CXCL10) chemokine production by human DC. We report that histamine and PGE2 dose-dependently up-regulate CCL17 and CCL22 by monocyte-derived immature DC. These effects were potentiated by tumour necrosis factor-alpha, still observed in the presence of the Th1-cytokine interferon-gamma (IFN-gamma) and abolished by the immunomodulatory cytokine interleukin-10. In addition, histamine and PGE2 down-regulated IFN-gamma-induced CXCL10 production by monocyte-derived DC. These properties of histamine and PGE2 were observed at the transcriptional level and were mediated mainly through H2 receptors for histamine and through EP2 and EP4 receptors for PGE2. Finally, histamine and PGE2 also up-regulated CCL17 and CCL22 and decreased IFN-gamma-induced CXCL10 production by purified human myeloid DC. In conclusion, these data show that, in addition to polarizing DC into mature cells that promote naïve T-cell differentiation into Th2 cells, histamine and PGE2 may act on immature DC to trigger local Th2 cell recruitment through a selective control of Th1/Th2-attracting chemokine production, thereby contributing to maintain a microenvironment favourable to persistent immunoglobulin E synthesis.


Proteomic profiling of heat shock proteins: An emerging molecular approach with direct pathophysiological and clinical implications.
The HSP family is one of the most ancient and evolutionarily conserved protective protein families found in nature. Originally discovered as inducible molecules capable of maintaining cellular homeostasis against abrupt temperature changes, HSPs were later determined to represent an adaptive physiological response that copes with a variety of different cellular proteotoxic stresses. These physiological molecular chaperones facilitate the synthesis, folding, assembly, trafficking and secretion of specific proteins in various cellular compartments. Most importantly, these proteins guard the whole cell proteome against misfolding and inappropriate aggregation. A series of diversified proteotoxic stresses, including heat, hypoxia/ischemia, free radicals, acidosis, ATP depletion and toxins are capable of inducing a typical cellular stress response characterised by rapid inhibition of overall protein synthesis, with a concomitant dramatic increase in HSP expression. From a pathophysiological point of view, HSP induction has been observed in a wide spectrum of inflammatory and degenerative diseases (from cancer to prion disease by passing to infective and autoimmune diseases) and, intriguingly, overexpression monitoring seems to have potential implications in terms of diagnosis, prognosis and, above all, therapy. Proteomics studies, identifying a series of modification of HSP expression patterns in different diseases, are confirming these promising clinical applications.


Spouses' daily feelings of appreciation and self-reported well-being.
Research shows that active support provision is associated with greater well-being for spouses of individuals with chronic conditions. However, not all instances of support may be equally beneficial for spouses' well-being. The theory of communal responsiveness suggests that because spouses' well-being is interdependent, spouses benefit most from providing support when they believe their support increases their partner's happiness and is appreciated. Two studies tested this hypothesis. Study 1 was a 7-day ecological momentary assessment (EMA) study of 73 spouses of persons with dementia (74%) and other conditions. In Study 1, spouses self-reported active help, perceptions of how happy the help made the partner and how much the help improved the partner's well-being, and spouses' positive and negative affect at EMA time points. Study 2 was a 7-day daily assessment study of 43 spouses of persons with chronic pain in which spouses reported their emotional support provision, perceived partner appreciation, and their own physical symptoms. Study 1 showed that active help was associated with more positive affect for spouses when they perceived the help increased their partner's happiness and improved their partner's well-being. Study 2 showed that emotional support provision was associated with fewer spouse reported physical symptoms when perceptions of partner appreciation were high. Results suggest that interventions for spouses of individuals with chronic conditions take into account spouses' perceptions of their partners' positive emotional responses. Highlighting the positive consequences of helping may increase spouses' well-being. (PsycINFO Database Record


Long-term unprocessed and processed red meat consumption and risk of chronic obstructive pulmonary disease: a prospective cohort study of women.
Limited studies have examined red meat consumption in relation to risk of chronic obstructive pulmonary disease (COPD), and none have examined the impact of long-term diet on COPD risk. We sought to investigate the association between long-term red meat consumption and risk of COPD. The population-based prospective Swedish Mammography Cohort included 34,053 women, aged 48-83 years, followed for the current analyses from 2002 to 2014. Unprocessed and processed red meat consumption was assessed with a self-administered questionnaire in 1987 and 1997. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Over a mean follow-up of 11.6 years (2002-2014; 393,831 person-years), 1488 COPD cases were ascertained via linkage to the Swedish health registers. A positive association between long-term processed red meat (average from 1987 to 1997) and risk of COPD was observed. In contrast, no association was observed with unprocessed red meat with corresponding HRs of 1.36 (95% CI 1.03-1.79) for processed and 0.87 (95% CI 0.74-1.02) for unprocessed red meat among women who consumed ≥ 50 g/day compared to < 25 g/day. The observed association with processed meat was confined to ex-smokers (P for interaction = 0.30); women consuming of ≥ 50 g/day of processed meat had a 2.3-fold (95% CI 1.24-4.12) higher risk of COPD than those consuming < 25 g/day. No similar associations were observed among current or never smokers. In this prospective cohort of women with moderate red meat consumption, long-term processed red meat consumption was associated with an increased risk of COPD particularly among ex-smokers.


The WD protein Rack1 mediates protein kinase C and integrin-dependent cell migration.
The scaffolding protein, Rack1, is a seven-WD-domain-containing protein that has been implicated in binding to integrin beta subunit cytoplasmic domains and to members of two kinase families (src and protein kinase C, PKC) that mediate integrin bidirectional signaling. To explore the role of Rack1 in integrin function we have transfected this protein in Chinese hamster ovary (CHO) cells. We have observed no effect of Rack1 overexpression on inside-out signaling as the ligand binding properties of CHO cells also expressing constitutively active or inactive integrins were not affected. In contrast, we observed that cells stably or transiently overexpressing Rack1 had decreased migration compared to mock transfected cells. Stable Rack1 transfectants also demonstrated an increased number of actin stress fibers and focal contacts. These effects on motility and cytoskeletal organization did not appear to result from Rack1 inhibition of src function as downstream substrates of this kinase were phosphorylated normally. In addition, expression of an active src construct did not reverse the migratory deficit induced by Rack1 overexpression. On the other hand when we overexpressed a Rack1 variant with alanine substitutions in the putative PKC binding site in its third WD domain, we observed no deficit in migration. Thus the ability of Rack1 to bind, localize and stabilize PKC isoforms is likely to be involved in aspects of integrin outside-in signaling.


Rb deficiency during Drosophila eye development deregulates EMC, causing defects in the development of photoreceptors and cone cells.
Retinoblastoma tumor suppressor protein (pRb) regulates various biological processes during development and tumorigenesis. Although the molecular mechanism by which pRb controls cell cycle progression is well characterized, how pRb promotes cell-type specification and differentiation is less understood. Here, we report that Extra Macrochaetae (EMC), the Drosophila homolog of inhibitor of DNA binding/differentiation (ID), is an important protein contributing to the developmental defects caused by Rb deficiency. An emc allele was identified from a genetic screen designed to identify factors that, when overexpressed, cooperate with mutations in rbf1, which encodes one of the two Rb proteins found in Drosophila. EMC overexpression in an rbf1 hypomorphic mutant background induces cone cell and photoreceptor defects but has negligible effects in the wild-type background. Interestingly, a substantial fraction of the rbf1-null ommatidia normally exhibit similar cone cell and photoreceptor defects in the absence of ectopic EMC expression. Detailed EMC expression analyses revealed that RBF1 suppresses expression of both endogenous and ectopic EMC protein in photoreceptors, thus explaining the synergistic effect between EMC overexpression and rbf1 mutations, and the developmental defect observed in rbf1-null ommatidia. Our findings demonstrate that ID family proteins are an evolutionarily conserved determinant of Rb-deficient cells, and play an important role during development.


Investigating the effects of ongoing-task bias on prospective memory.
Event-based prospective memory (PM) refers to the cognitive processes required to perform a planned action upon encountering a future event. Event-based PM studies engage participants in an ongoing task (e.g., lexical decision-making) with an instruction to make an alternative PM response to certain items (e.g., items containing "tor"). The Prospective Memory Decision Control (PMDC) model, which provides a quantitative process account of ongoing-task and PM decisions, proposes that PM and ongoing-task processes compete in a race to threshold. We use PMDC to test whether, as proposed by the Delay Theory of PM costs, PM can be improved by biasing decision-making against a specific ongoing-task choice, so that the PM process is more likely to win the race. We manipulated bias in a lexical decision task with an accompanying PM intention. In one condition, a bias was induced against deciding items were words, and in another, a bias was induced against deciding items were non-words. The bias manipulation had little effect on PM accuracy but did affect the types of ongoing-task responses made on missed PM trials. PMDC fit the observed data well and verified that the bias manipulation had the intended effect on ongoing-task processes. Furthermore, although simulations from PMDC could produce an improvement in PM accuracy due to ongoing-task bias, this required implausible parameter values. These results illustrate the importance of understanding event-based PM in terms of a comprehensive model of the processes that interact to determine all aspects of task performance.


The ATHENA HPV study underrepresents "other" high-risk HPV genotypes when compared with a diverse New York City population.
Persistent infection with oncogenic high risk HPV (hrHPV) types causes virtually all cases of cervical cancer. HPV 16 and 18 have been targeted for individual genotyping and vaccination because of their presence in 71% of invasive cervical cancers worldwide. Montefiore Medical Center, Bronx, New York serves a population known for ethnic and racial diversity. Given this diversity it is possible that HPV genotypes not individually detected by current testing are causing significant disease. We conducted a retrospective analysis of liquid based cervicovaginal cytology and Cobas HPV results reported between October 5, 2015 and March 30, 2016. This included 20 483 samples from patients aged 16-95 (average age 42), with racial distribution including: African-American 32.4%, Other (includes denied, unknown, mixed, Hispanic) 52.1%, Caucasian 14.5%, Asian 0.7%, American Indian/Alaskan Native 0.3%. In all, 14 938 samples (72.9%) were submitted for clinically requested COBAS 4800 HPV testing, which separately reports HPV 16, 18 and a pool of 12 other hrHPV. A total of 3180 (21.5%) tested hrHPV positive. The percentage of patients with cytologic diagnosis of HSIL (high-grade squamous intraepithelial lesion) that were positive only for HPV 16 was 19.4% vs 1.8% for all cytologic diagnoses. However, only one of the HSIL cases was HPV 18 positive along with other hrHPV (OHR). Surprisingly, a majority (64.5%) was positive for only OHR. Further evaluation is needed to determine if this pool of other hrHPV includes individual genotypes that in our population carry a higher risk of persistence and progression to cancer.


Raman and scanning probe microscopy for differentiating surface imprints of E. coli and B. cereus.
Molecularly imprinted polymers (MIPs) are artificial recognition materials mimicking biological recognition entities such as antibodies. The general model of imprinting assumes that functional monomers interact with functional groups present on the target species which leads to cavities complementing the template in surface chemistry and shape thus ensuring recognition. However, to date there is little independent experimental evidence supporting that the surface chemistry in the imprints is tailored to analyte recognition and thus differs from the surface chemistry of the surrounding polymer. Herein, we investigate such chemical differences between imprints of Escherichia coli and Bacillus cereus in poly(styrene-co-DVB) and a commercial acrylate-based polymer by the means of confocal Raman microscopy and PLS-DA. The MIPs were generated using a stamping approach. Peak-force QNM measurements were conducted to rule out residues of bacterial cells in the imprints. While imprints of E. coli and B. cereus could be distinguished based on their Raman spectra in the acrylate-based polymer, differentiation in poly(styrene-co-DVB) was not significant. This could be a result of a higher potential of acrylate functional groups for interacting with lipopolysaccharides and peptidoglycans on bacteria surfaces compared to the phenyl groups of poly(styrene-co-DVB) and emphasizes the importance of the right choice of functional monomers for a specific target analyte.


Factor structure of the VABS-3 Comprehensive Parent/Caregiver form in autistic individuals: Poor fit of three-factor and unidimensional models.
Adaptive behavior is a broad set of skills needed to function in everyday life. The Vineland Adaptive Behavior Scales (VABS-3) is commonly used to measure adaptive behavior. It divides adaptive behavior into three domains, Communication, Daily Living Skills, and Socialization, each of which are split into subdomains. Analyses of this three-part structure of the first version of VABS used the instrument as an interview, but now it is done as a questionnaire as well. The structure has not been well supported in samples of autistic people, who often have different strengths and challenges in adaptive behavior compared with non-autistic people. Because adaptive behavior is an important concept in autism research and online-administered questionnaires are increasingly common, it is important to ensure the structure of the VABS-3 Comprehensive Parent/Caregiver Form (VABS-3:CPCF; a questionnaire) works well for autistic individuals across a range of abilities. This study aimed to investigate whether VABS-3:CPCF measures adaptive behavior similarly in verbal and minimally verbal autistic people. However, the data didn't fit the structure in the first step of the analysis, so this could not be investigated. The next analyses also found the three-domain structure didn't fit in different age and language groups. In addition, the data didn't fit a structure combining all the domains into 1 (unidimensional). These results suggest that neither the three-factor or unidimensional structure fit the VABS-3:CPCF, cautioning against interpretation of domain or overall adaptive behavior composite scores in autistic individuals and further encouraging careful consideration of administration format.


Thyroid fine-needle aspiration biopsy: progress, practice, and pitfalls.
To provide an updated review of the current progress in, and the practice and pitfalls of, thyroid fine-needle aspiration (FNA) biopsy. The medical literature on the topic was reviewed, and the current methods, advantages, and controversies concerning FNA biopsy of thyroid nodules are summarized. Thyroid nodules are a common clinical problem, with an estimated prevalence ranging from 19 to 35%. Most thyroid cancers manifest as thyroid nodules; however, only a small fraction of all thyroid nodules harbor malignant disease. Certain clinical features increase the likelihood of malignant involvement, but the absence of such features does not exclude the possibility of cancer. Of all currently available methods of evaluating nodular thyroid disease, FNA biopsy has been found to have the greatest diagnostic accuracy, approaching 95%, and its widespread use has resulted in substantial cost savings and has allowed a much better selection of patients in need of surgical treatment. The procedure, however, has two major limitations: nondiagnostic yield and indeterminate results. The approach to the management of patients with thyroid nodules is summarized. FNA is the most reliable and cost-effective method of distinguishing benign from suspicious or malignant thyroid nodules.


Are the original Donnan assumptions applicable to serum?
Analyses of the diffusible fraction of serum for sodium, potassium, and chloride have indicated that the ratios of the levels of the protein solution to those of the filtrate do not follow the predicted Donnan values. Specifically, measurements by sodium glass electrode showed that sodium activities are the same for both protein solution and filtrate in contradiction to the Donnan model which predicts greater activity for the sodium in the protein solution because of its greater analyzed content. An alternative model that fits the experimental findings is discussed, and calculations made possible by this model are presented that give reasonable values for bound sodium, bound water, and a radius for an assumed spherical albumin molecule. A review of Donnan's original data discloses discrepancies in his assumptions.


Segmenting patients and physicians using preferences from discrete choice experiments.
People often form groups or segments that have similar interests and needs and seek similar benefits from health providers. Health organizations need to understand whether the same health treatments, prevention programs, services, and products should be applied to everyone in the relevant population or whether different treatments need to be provided to each of several segments that are relatively homogeneous internally but heterogeneous among segments. Our objective was to explain the purposes, benefits, and methods of segmentation for health organizations, and to illustrate the process of segmenting health populations based on preference coefficients from a discrete choice conjoint experiment (DCE) using an example study of prevention of cyberbullying among university students. We followed a two-level procedure for investigating segmentation incorporating several methods for forming segments in Level 1 using DCE preference coefficients and testing their quality, reproducibility, and usability by health decision makers. Covariates (demographic, behavioral, lifestyle, and health state variables) were included in Level 2 to further evaluate quality and to support the scoring of large databases and developing typing tools for assigning those in the relevant population, but not in the sample, to the segments. Several segmentation solution candidates were found during the Level 1 analysis, and the relationship of the preference coefficients to the segments was investigated using predictive methods. Those segmentations were tested for their quality and reproducibility and three were found to be very close in quality. While one seemed better than others in the Level 1 analysis, another was very similar in quality and proved ultimately better in predicting segment membership using covariates in Level 2. The two segments in the final solution were profiled for attributes that would support the development and acceptance of cyberbullying prevention programs among university students. Those segments were very different-where one wanted substantial penalties against cyberbullies and were willing to devote time to a prevention program, while the other felt no need to be involved in prevention and wanted only minor penalties. Segmentation recognizes key differences in why patients and physicians prefer different health programs and treatments. A viable segmentation solution may lead to adapting prevention programs and treatments for each targeted segment and/or to educating and communicating to better inform those in each segment of the program/treatment benefits. Segment members' revealed preferences showing behavioral changes provide the ultimate basis for evaluating the segmentation benefits to the health organization.


Semi-automated vs. visual reading of urinalysis dipsticks.
Semi-automated reflectance readings of urinalysis dipsticks showed better precision than visual readings in the case of artificially prepared urine samples containing glucose, ketone, and protein. Actual pathological specimens containing glucose, protein, and nitrite also showed that instrumental readings were better than visual. Results of repeated visual readings spread over three different color blocks for certain concentrations of glucose, ketone, and protein, whereas repeated instrumental readings were never spread greater than two color blocks. Subjectivity can be reduced by semi-automated dipstick urinalysis.


Proteomic analysis of the outer membrane of Protochlamydia amoebophila elementary bodies.
Chlamydiae are obligate intracellular bacteria, comprising some of the most important bacterial pathogens of animals and humans. During their unique developmental cycle they have to attach to and enter their eukaryotic host cells, a process mediated by proteins in the chlamydial outer membrane. So far the only experimental data for chlamydial outer membrane proteins are available from members of the Chlamydiaceae, a family comprising exclusively human and animal pathogens. To get further insights into the evolution of the protein composition of the chlamydial outer membrane and into host-dependent differences, we performed an extensive experimental analysis of outer membrane fractions of Protochlamydia amoebophila elementary bodies, which constitute the infectious form of this non-pathogenic member of the Chlamydiae that thrives as a symbiont in Acanthamoeba spp. We used 1-D and 2-DE in combination with MALDI-TOF, MALDI-TOF/TOF and nanoLC-ESI-MS/MS, and compared our experimental results with a previously published in silico analysis of chlamydial outer membrane proteins. This resulted in the identification of 38 proteins supported by both studies and therefore very likely to be located in the P. amoebophila outer membrane. The obtained experimental data provide the first comprehensive overview of outer membrane proteins of a chlamydial organism outside the Chlamydiaceae. They reveal both fundamental differences and convergent evolution between pathogenic and symbiotic chlamydiae.


Premature termination codon in the aggrecan gene of nanomelia and its influence on mRNA transport and stability.
To analyze the influence of the premature termination codon on mRNA transport and stability Chondrocyte mRNA was isolated from homozygous and heterozygous nanomelic 17-days old embryos and examined by RT-PCR analysis. To analyze aggrecan mRNA stability, mRNA synthesis was inhibited with DRB [5,6 dichloro-1-(-D-ribofuranosyl benzimidazole)], a specific inhibitor of RNA polymerase II. Visualization of the aggrecan alleles was performed by in situ hybridization. The level of mutant aggrecan mRNA within the nucleus was equal to that of the control, but no mutant mRNA was observed in the cytoplasm. RT-PCR revealed that the mutant transcript was only detectable in the nucleus, compared with house-keeping glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene or collagen type II. A restriction site induced by premature termination codon TAA allowed the distinction of normal and mutant transcripts in chondrocytes derived from embryos heterozygous for the nanomelic mutation. After the treatment with DRB, identical decay rates were demonstrated for both transcripts within the heterozygous nucleus. In situ hybridization showed no abnormal mRNA accumulation. This is the first evidence suggesting that the transcript of the mRNA with the premature termination codon within an exon does exit the nucleus.


Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo.
Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is found in cerebral neurons, and its expression is increased after hypoxic or ischemic injury, which also stimulates neurogenesis. To investigate the possible role of HB-EGF in hypoxic-ischemic induction of neurogenesis, we measured its expression, effects, and target receptors in embryonic murine cerebral cortical cultures and in adult rat brain. Hypoxia increased HB-EGF expression by approximately 50% in cortical cultures, where expression was associated with mature and immature neurons. HB-EGF (5-100 ng/ml) stimulated by approximately 80% the incorporation of bromodeoxyuridine (BrdU) into cultured cells that expressed the HB-EGF receptors epidermal growth factor receptor (EGFR)/avian erythroblastic leukemia viral oncogene homolog 1 (ErbB1) and N-arginine dibasic convertase (NRDc). Intracerebroventricular administration of HB-EGF in adult rats increased BrdU labeling in the subventricular zone and in the subgranular zone of dentate gyrus, where EGFR/ErbB1 and NRDc were also expressed and where ischemia-induced neurogenesis is observed. We conclude that HB-EGF stimulates neurogenesis in proliferative zones of the adult brain that are also affected in ischemia and that it does so by interacting with EGFR/ErbB1 and possibly NRDc. Therefore, HB-EGF may help to trigger proliferation of neuronal precursors in brain after hypoxic or ischemic injury.


Insulin: carrier potential for enzyme and drug therapy.
Several carrier systems and targeting agents have been considered as means of delivering enzymes and drugs to specific tissues or cells. In this report insulin is shown to be effective in delivering enzyme-albumin conjugates to cells and tissues rich in insulin receptors. The complex is transported into cells by a process that resembles receptor-mediated endocytosis and can be identified in a lysosomal fraction. The enzyme-albumin-insulin complex retains its enzymatic activity and its ability to bind antibodies to insulin. It also has a hypoglycemic effect; however, plasma glucose concentrations can be maintained by glucose administration.


Building successful collaborations between Public Health and Primary Health Care.
Public Health (PH) and Primary Health Care (PHC) need to be better integrated, at different levels of the healthcare system, in order to improve health and social outcomes. The aim of this study was to review international models and approaches supporting the integration of PH and PHC and to classify these according to their main focus. A literature search was performed using the main scientific databases, to identify national and international journal publications regarding models to support integration between PH and PHC. The final set of the documents provided a broad coverage of the topic. Four models of integration were identified: general integration, chronic disease prevention, targeted prevention or care delivery and infection control. Models differed in their levels of implementation, stages of development and focus. This review, by classifying the main characteristics and results of the experiences retrieved, indicates a relatively scarce use of integration models in the global health care landscape, with the exception of Canada. In fact, Canada has been a leader in developing models of integrated health systems that combine tailored approaches to influence personal health behaviour and community-oriented approaches to influence the health of the population. The review also revealed a general lack of experience in evaluating the sustainability of integration between PH and PHC, not only in terms of cost-effectiveness, but also in terms of better health and work conditions and self-perceived quality of care in the population. Collaboration between PH and PHC seems to be an important strategy for achieving principles of equity and access in health care and for ensuring a more equal distribution of health care services.


Interactions between Multiple Organs and Nutritional Metabolism in the Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease.
Steatotic liver disease (SLD) is a condition characterized by an accumulation of fat in the liver [...].


Transrectal periprostatic lidocaine injection anesthesia for transrectal prostate biopsy: a prospective study.
Transrectal ultrasound (TRUS)-guided biopsy remains the mainstay of the diagnosis of prostate cancer. Although this diagnostic method is a safe procedure and well tolerated by most patients a significant number of patients report discomfort and pain during prostate biopsy. In order to define the best method of anesthesia, many studies, in which different methods were compared, have been performed. To determine the effectiveness of local injection anesthesia in TRUS-guided prostate biopsy, we designed and performed this prospective study in order to evaluate the utility of periprostatic nerve block for pain management. A total of 100 patients who had elevated total prostate-specific antigen (tPSA) and/or abnormal digital rectal examination (DRE) were included in this study. Half of the patients received periprostatic injection anesthesia (group I) and the remaining half received placebo (group II). Patients received 10 cm3 (5 cm3 each side) 1% lidocaine injected into the periprostatic nerve plexus under transrectal ultrasonic guidance. Pain during biopsy was assessed using a 10-point modified visual analog scale (VAS). In groups I and II, mean patient age was 66.8+2.5 and 65.6+11.5 y, mean tPSA was 7.87+/-3.6 and 11.3+/-1.7 ng/ml, mean biopsy duration was 6.5+/-2.5 and 6.6+/-2.2 min and mean pain score during TRUS-guided biopsy was 1.46+/-2.2 and 4.5+/-2.1, respectively. No statistically significant difference was observed with respect to age, tPSA and mean biopsy duration between these groups. Mean pain VAS score was statistically or significantly better (P=0.0001) in the lidocaine injection group (group I), and furthermore no patient had a VAS pain score > or =5 in this group. Only minor and transient complications occurred in both groups. This study reinforces the usage of periprostatic nerve block as a standard method of pain management during TRUS-guided prostate biopsy, because it is simple, safe, uncostly and significantly effective without requiring additional time.


Exploring the Association of Hypertension With Risk for Depression: Evidence for Tamed Neurobehavioral Arousal Versus Central Emotional Dysregulation.
Depression is an established predictor of adverse cardiovascular disease outcomes. Less is known about cardiovascular risk factors as predictors of depression. In this issue of Psychosomatic Medicine (2018;80:508-514), Patel et al. report data indicating that pre-existing hypertension may be inversely associated with the atypical but not typical form of depression. We highlight here the strengths and limitations of the article and discuss the findings in light of research linking blood pressure and emotion regulation. In general, evidence suggests that higher blood pressure is associated with reduced expression of negative emotions and pain. Two prominent models of interaction have been proposed and supported by epidemiological and experimental research: one assumes that elevations in blood pressure lead to reduced arousal and pain sensitivity through baroreceptor activation and possibly additional afferent mechanisms. Operant conditioning may then result in (chronic) hypertension. The other one posits that impaired emotion processing as indicated by dampened emotion recognition may lead to disinhibition of hypothalamic centers and thereby result in sustained increases in blood pressure. These models are described in context of the current literature and open research questions are formulated.


Small saphenous vein aneurysm diagnosis and treatment.
Venous aneurysms are rare, particularly those arising from the superficial venous system. Current limited evidence suggests that congenital weakness of the vein wall, degenerative changes, trauma and inflammation are among potential causes. Surgical management has been the mainstay treatment modality of venous aneurysms. Surgical approaches and techniques should be tailored on a case-by-case basis, taking into consideration aneurysm location, size, shape and presence of complications (ie, rupture or thrombosis). In this report, we present a male patient in his late thirties who presented with right leg swelling and achiness 2 years following right lower extremity blunt trauma and was found to have a 3 cm small saphenous vein aneurysm extending to the saphenopopliteal junction. The patient was successfully treated with excision of the aneurysm via a posterior approach. This case report adds to the current literature and may help to define future treatment recommendations.


Safety and Upper Respiratory Pharmacokinetics of the Hemagglutinin Stalk-Binding Antibody VIS410 Support Treatment and Prophylaxis Based on Population Modeling of Seasonal Influenza A Outbreaks.
Seasonal influenza is a major public health concern in vulnerable populations. Here we investigated the safety, tolerability, and pharmacokinetics of a broadly neutralizing monoclonal antibody (VIS410) against Influenza A in a Phase 1 clinical trial. Based on these results and preclinical data, we implemented a mathematical modeling approach to investigate whether VIS410 could be used prophylactically to lessen the burden of a seasonal influenza epidemic and to protect at-risk groups from associated complications. Using a single-ascending dose study (n = 41) at dose levels from 2 mg/kg-50 mg/kg we evaluated the safety as well as the serum and upper respiratory pharmacokinetics of a broadly-neutralizing antibody (VIS410) against influenza A (ClinicalTrials.gov identifier NCT02045472). Our primary endpoints were safety and tolerability of VIS410 compared to placebo. We developed an epidemic microsimulation model testing the ability of VIS410 to mitigate attack rates and severe disease in at risk-populations. VIS410 was found to be generally safe and well-tolerated at all dose levels, from 2-50 mg/kg. Overall, 27 of 41 subjects (65.9%) reported a total of 67 treatment emergent adverse events (TEAEs). TEAEs were reported by 20 of 30 subjects (66.7%) who received VIS410 and by 7 of 11 subjects (63.6%) who received placebo. 14 of 16 TEAEs related to study drug were considered mild (Grade 1) and 2 were moderate (Grade 2). Two subjects (1 subject who received 30 mg/kg VIS410 and 1 subject who received placebo) experienced serious AEs (Grade 3 or 4 TEAEs) that were not related to study drug. VIS410 exposure was approximately dose-proportional with a mean half-life of 12.9 days. Mean VIS410 Cmax levels in the upper respiratory tract were 20.0 and 25.3 μg/ml at the 30 mg/kg and 50 mg/kg doses, respectively, with corresponding serum Cmax levels of 980.5 and 1316 μg/mL. Using these pharmacokinetic data, a microsimulation model showed that median attack rate reductions ranged from 8.6% (interquartile range (IQR): 4.7%-11.0%) for 2% coverage to 22.6% (IQR: 12.7-30.0%) for 6% coverage. The overall benefits to the elderly, a vulnerable subgroup, are largest when VIS410 is distributed exclusively to elderly individuals, resulting in reductions in hospitalization rates between 11.4% (IQR: 8.2%-13.3%) for 2% coverage and 30.9% (IQR: 24.8%-35.1%) for 6% coverage among those more than 65 years of age. VIS410 was generally safe and well tolerated and had good relative exposure in both serum and upper respiratory tract, supporting its use as either a single-dose therapeutic or prophylactic for influenza A. Including VIS410 prophylaxis among the public health interventions for seasonal influenza has the potential to lower attack rates and substantially reduce hospitalizations in individuals over the age of 65. Visterra, Inc.


Testosterone induces testicular development but reduces GnRH-I fiber density in the brain of the House Finch, Carpodacus mexicanus.
Testosterone (T) in male birds generally inhibits the activity of the hypothalamo-pituitary-gonadal axis, but the androgen can also be gonadostimulatory. The mechanisms responsible for this stimulation are unknown. To address this question, adult male House Finches, Carpodacus mexicanus, held on short day length to inhibit reproductive function, received 20-mm long T-filled Silastic capsules either for 74 days (T+; n=5; Day 1-74) or for 66 days followed by eight days without capsules (T-; n=5), or empty capsules for 74 days (controls, C, n=10). At sacrifice on Day 74, plasma T concentrations were elevated in T+ males and low, and similar in T- and C males. Testes were enlarged in T+ males (136.5+/-57.2mg), small in T- males (16.2+/-9.5 mg), and undeveloped in C males (5.4+/-3.6 mg). The three groups had similar numbers and sizes of hypothalamic gonadotropin-releasing hormone-I immunoreactive (GnRH-I ir) perikarya, but perikaryon GnRH-I ir labelling was lighter in T+ than C males. T+ males also had lower density of GnRH-immunolabelled fibers in the preoptic area and lower intensity of GnRH immunolabelling in the median eminence than C males, suggesting an inhibition of GnRH-I neuronal activity. Plasma luteinizing hormone in the three experimental groups was uniformly low and did not differ. Thus, T administration-induced testicular development was associated with an inhibition of the reproductive neuroendocrine system, demonstrating a direct stimulatory effect of T on testes. Stimulation of testicular function by endogenous T in seasonal breeders may contribute to the rapid gonadal maturation that takes place in response to photostimulation.


Cholesterol levels after 3 days of high-dose simvastatin in patients at moderate to high risk for coronary events.
Elevated levels of low-density lipoprotein cholesterol (LDL-C) impair vascular function by a variety of mechanisms. HMG CoA reductase inhibitors (statins) improve endothelial function by lowering LDL-C and possibly by other "pleiotropic" effects. How rapidly statins can lower LDL-C has not been thoroughly studied. We examined the lipid response to 3 days of high-dose simvastatin in a randomized prospective double-blind placebo-controlled crossover study. Twenty-seven subjects at moderate to high risk for coronary heart disease (CHD) received either simvastatin 80 mg/day for 3 days followed by placebo for 3 days or placebo followed by simvastatin. After a washout period of 10 to 14 days, subjects received the opposite treatment. Nonfasting blood lipid levels, including total cholesterol, direct LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides, were obtained before randomization and after each 3-day treatment period. The mean LDL-C level at baseline was 107 mg/dl and decreased 24% in patients receiving simvastatin and 5.6% in patients receiving placebo (P < 0.001). Statistically significant reductions were also achieved in the total cholesterol and cholesterol/HDL-C ratio: 14% and 12%, respectively. Changes in HDL-C and triglyceride levels were not significant. Treatment with simvastatin for only 3 days results in a 24% drop in the LDL-C level. As defined by ATPIII, this decrease is comparable to that necessary to lower the LDL-C from one risk level to a lower one and is, therefore, both clinically and statistically significant.


Studies of arthritis and other lesions induced in rats by injection of mycobacterial adjuvant. V. Changes affecting the skin and mucous membranes. Comparison of the experimental process with human disease.
A generalized disease is induced experimentally in the rat by administration of Freund's adjuvant. The primary clinical and pathologic lesions are arthritis, periarthritis, peritendinitis, and periostitis in the joints of the extremities and tail. Accompanying the arthritis in some cases, and never observed in its absence, are other specific tissue lesions including iridocyclitis, nodular lesions in the glabrous skin (ear, genitalia, feet, tail), transient rashes, a chronic skin disease, genitourinary lesions, and diarrhea. These make up a striking and characteristic picture. The arthritis usually precedes the other lesions and, together with the skin disease may show a prolonged and fluctuating course. Visceral lesions do not occur. Histologically, the basic lesion is a lymphocytic and histiocytic infiltration, initially perivascular and subsequently more disseminated. In addition, in the region of the joints and in the corpora cavernosa of the penis, there is extensive proliferation of mesenchymal cells, especially fibroblasts. Foci of fibrinoid necrosis are seen in the articular and nodular lesions, and destructive lesions of the joints are common. Such a combination of tissue lesions has not previously been described in experimental pathology. The experimental disease is shown to have both similarities to and differences from Reiter's syndrome, rheumatoid arthritis, and certain other disorders which occur in man.


OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes.
Dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104. The in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH). OXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor. These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH.


Avian reovirus nonstructural protein p17-induced G(2)/M cell cycle arrest and host cellular protein translation shutoff involve activation of p53-dependent pathways.
The effects of avian reovirus (ARV) p17 protein on cell cycle progression and host cellular protein translation were studied. ARV infection and ARV p17 transfection resulted in the accumulation of infected and/or transfected cells in the G(2)/M phase of the cell cycle. The accumulation of cells in the G(2)/M phase was accompanied by upregulation and phosphorylation of the G(2)/M-phase proteins ATM, p53, p21(cip1/waf1), Cdc2, cyclin B1, Chk1, Chk2, and Cdc25C, suggesting that p17 induces a G(2)/M cell cycle arrest through activation of the ATM/p53/p21(cip1/waf1)/Cdc2/cyclin B1 and ATM/Chk1/Chk2/Cdc25C pathways. The G(2)/M cell cycle arrest resulted in increased virus replication. In the present study, we also provide evidence demonstrating that p17 protein is responsible for ARV-induced host cellular protein translation shutoff. Increased phosphorylation levels of the eukaryotic translation elongation factor 2 (eEF2) and initiation factor eIF2alpha and reduced phosphorylation levels of the eukaryotic translation initiation factors eIF4E, eIF4B, and eIF4G, as well as 4E-BP1 and Mnk-1 in p17-transfected cells, demonstrated that ARV p17 suppresses translation initiation factors and translation elongation factors to induce host cellular protein translation shutoff. Inhibition of mTOR by rapamycin resulted in a decrease in the levels of phosphorylated 4E-BP1, eIF4B, and eIF4G and an increase in the levels eEF2 but did not affect ARV replication, suggesting that ARV replication was not hindered by inhibition of cap-dependent translation. Taken together, our data indicate that ARV p17-induced G(2)/M arrest and host cellular translation shutoff resulted in increased ARV replication.