Food banks: Understanding their role in the food insecure population in the UK.
The present paper reviews the growing body of literature on food insecurity and food bank use in the UK. It provides an overview of food insecurity in this context, followed by a description of the emergence of food banks, highlighting how any role that food banks play in the food insecure population is limited. Data on food insecurity and food bank use suggest many people experiencing food insecurity do not receive help from food banks. To better understand the factors influencing the relationship between food insecurity and food bank use, a conceptual framework is outlined, suggesting the relationship is far from straightforward and contingent on many factors. The nature and availability of food banks and other local support services and individual-level factors influence the likelihood of food banks being used in the context of food insecurity. Then, the extent to which food banks can impact food insecurity is also dependent on the quantity and quality of food distributed, as well as other support services offered from food banks. Closing reflections highlight rising living costs and food banks reporting that they do not have capacity to cope with increasing demand, underscoring the need for policy interventions. Reliance on food banks to respond to food insecurity may ultimately impede formulation of effective policy interventions to reduce food insecurity, giving the illusion of widespread available support, whilst food insecurity persists among those receiving help from food banks and those who experience food insecurity but do not use food banks.


The Outcomes of Surgical Separation in Thoracopagus Twins with Conjoined Hearts: An Analysis of the Literature.
We sought to perform a comprehensive review of reported cases of conjoined thoracopagus twins with cardiovascular conjunction to determine the overall survival after separation and factors that might be associated with survival. We performed a systematic review of cases of thoracopagus twins with conjoined cardiovascular systems reported in the English medical literature using Embase, PubMed, Web of Science, and Scopus. We employed standard statistical methods to analyze differences among groups. We identified 102 unique cases of thoracopagus twins (69% female) with some degree of cardiovascular conjunction who had undergone surgical separation. We identified 6 distinct types of cardiovascular union. Median age was 47 days (IQR 12, 120). Survival to at least hospital discharge occurred in 51% (105/204). Median age at separation was lower in emergent (9 days, IQR 1, 25) versus elective cases (93 days, IQR 49, 180) (p < 0.0001). Survival to hospital discharge was higher in those who underwent elective separation (70%, 93/132 total children versus 17%, 12/72) (p < 0.0001). Survival was associated with the type of cardiovascular union (p < 0.0001). The separation of thoracopagus twins with cardiovascular conjunction is higher than expected. Increased survival is associated with elective separation, older age, and shared pericardium only. These findings suggest survival could be improved with better delineation of degree of union and delayed separation.


New Irreversible α-l-Iduronidase Inhibitors and Activity-Based Probes.
Cyclophellitol aziridines are potent irreversible inhibitors of retaining glycosidases and versatile intermediates in the synthesis of activity-based glycosidase probes (ABPs). Direct 3-amino-2-(trifluoromethyl)quinazolin-4(3H)-one-mediated aziridination of l-ido-configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of α-l-iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type I (MPS I). The iduronidase ABPs react covalently and irreversibly in an activity-based manner with human recombinant α-l-iduronidase (rIDUA, Aldurazyme® ). The structures of IDUA when complexed with the inhibitors in a non-covalent transition state mimicking form and a covalent enzyme-bound form provide insights into its conformational itinerary. Inhibitors 1-3 adopt a half-chair conformation in solution (4 H3 and 3 H4 ), as predicted by DFT calculations, which is different from the conformation of the Michaelis complex observed by crystallographic studies. Consequently, 1-3 may need to overcome an energy barrier in order to switch from the 4 H3 conformation to the transition state (2, 5 B) binding conformation before reacting and adopting a covalent 5 S1 conformation. rIDUA can be labeled with fluorescent Cy5 ABP 2, which allows monitoring of the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS I patients.


Enhanced IFN-γ, but not IL-2, response to Mycobacterium tuberculosis antigens in HIV/latent TB co-infected patients on long-term HAART.
HIV-infected individuals with latent TB infection are at increased risk of developing active TB. HAART greatly reduces the incidence rate of TB in HIV-infected patients and reconstitutes Mycobacterium tuberculosis (M. tuberculosis)-specific immune response in the first 12 months of therapy. The durability of the anti-mycobacterial immune restoration after a year of HAART however remains less investigated. A cross-sectional study was conducted to evaluate M. tuberculosis-specific functional immune responses in HIV/latent TB co-infected patients who were on HAART for at least 1.5 up to 9 years as compared to HAART-naïve patients. Three-hundred sixteen HIV-infected patients without active TB were screened by tuberculin skin testing for M. tuberculosis infection and peripheral blood mononuclear cells (PBMCs) were isolated from 61 HIV/latent TB co-infected patients (30 HAART-naïve and 31 HAART-treated). IFN-γ and IL-2 ELISPOT as well as CFSE cell proliferation assays were performed after stimulation with M. tuberculosis antigens PPD and ESAT-6. The median frequency of PPD and ESAT-6 specific IFN-γ secreting cells was significantly higher in the HAART-treated patients as compared to HAART-naïve patients, p = 0.0021 and p = 0.0081 respectively. However, there was no significant difference in the median frequency of IL-2 secreting cells responding to PPD (p = 0.5981) and ESAT-6 (p = 0.3943) antigens between HAART-naïve and-treated groups. Both IFN-γ and IL-2 responses were independent of CD4+ T cell count regardless of the HAART status. Notably, the frequency of PPD and ESAT-6 specific IL-2 secreting cells was positively associated with CD4+ T cell proliferation while inversely correlated with duration of HAART, raising the possibility that M. tuberculosis-specific IL-2 response that promote the antigen-specific CD4+ T cell proliferation diminish with time on antiretroviral therapy in HIV/latent TB co-infected patients. This study shows an increased M. tuberculosis-specific IFN-γ, but not IL-2, response in HIV/latent TB co-infected patients with long-term HAART, consistent with only partial immune restoration. Future studies should, therefore, be done to prospectively define the rate and extent to which functional immune responses to M. tuberculosis are restored after long-term HAART.


Microfluidic ion stripper for removal of trifluoroacetic acid from mobile phases used in HILIC-MS of intact proteins.
Trifluoroacetic acid (TFA) is commonly used as mobile phase additive to improve retention and peak shape characteristics in hydrophilic interaction liquid chromatography (HILIC) of intact proteins. However, when using electrospray ionization-mass spectrometry (ESI-MS) detection, TFA may cause ionization suppression and adduct formation, leading to reduced analyte sensitivity. To address this, we describe a membrane-based microfluidic chip with multiple parallel channels for the selective post-column removal of TFA anions from HILIC. An anion-exchange membrane was used to physically separate the column effluent from a stripper flow solution comprising acetonitrile, formic acid, and propionic acid. The exchange of ions allowed the post-column removal of TFA used during HILIC separation of model proteins. The multichannel design of the device allows the use of flow rates of 0.2 mL/min without the need for a flow splitter, using mobile phases containing 0.1% TFA (13 mM). Separation selectivity and efficiency were maintained (with minor band broadening effects) while increasing the signal intensity and peak areas by improving ionization and reducing TFA adduct formation.


Right-sided invasive metastatic thymoma of the heart.
Cardiac tumours may display diverse symptoms through potential involvement of any structure of the heart. We describe a case of a highly malignant thymoma with involvement of different cardiac structures with important haemodynamic compromise. With the high sensitivity of transthoracic echocardiography for detection of intracardiac masses, computed tomography and magnetic resonance add essential structural preoperative information on the tumour and surrounding tissue as vessels, pleura, lung and mediastinum.


Quantitative assessment of pelvic ileal reservoir emptying with a semisolid radionuclide enema. A correlation with clinical outcome.
Fecal stasis in an ileal reservoir may lead to overgrowth of bacteria and changes in mucosal morphology that are of future concern. Moreover, improper evacuation may lead to increased stool frequency and reduced continence. The aims of this study were: to compare the functional results of two types of ileal reservoirs constructed with an ileoanal anastomosis, to compare their emptying to a normal rectum as assessed by a radionuclide enema, and to correlate functional results with emptying. The reservoirs were made of two (J) or three (S) limbs of terminal ileum. Thirty-three patients (16 with J-pouch and 17 with S-pouch) and ten healthy controls were included in the study. There was no difference in the mean age of patients or interval following diverting ileostomy closure. Functional results were obtained by written questionnaire assessing stool frequency, and soiling, use of medication, need for intubation, and episodes of pouchitis. Emptying was measured with instillation per anus of a semisolid medium labeled with 1.0 mCi of Tc-99. Ileal pouch counts were measured using a scintillation camera and computer before and after spontaneous evacuation. The emptying was defined as the difference in counts divided by preevacuation counts. The functional results were similar in the two groups. Nocturnal soiling occurred more frequently in the S-pouch group. Pouchitis occurred in seven patients. Emptying of the two types of reservoir was similar (J: 72 +/- 4%, S: 67 +/- 5%), but it was less efficient than a normal rectum (90 +/- 3%, P less than 0.004). No correlation was established between age, sex, number of stools, pouchitis, and the efficacy of emptying. The clinical outcome of two patients who emptied less than 30%, however, was greatly improved by intermittent intubation. In conclusion, a semisolid radionuclide enema can be useful to identify patients who would benefit from intubation. No persistent defect in emptying was detected in patients with pouchitis.


Acromegaly.
Acromegaly is due to excessive production of growth hormone (GH), generally by a pituitary GH-secreting adenoma. Its prevalence is estimated at 40-130 cases per million inhabitants. Acromegaly is characterized by slowly progressive acquired somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. The rheumatologic, cardiovascular, respiratory, and metabolic consequences of acromegaly determine the prognosis. The diagnosis is confirmed by elevated serum GH concentrations that cannot be suppressed by an oral glucose load, and by increased levels of insulin-like growth factor 1 (IGF-1). Treatment is aimed at correcting (or preventing) tumor compression of surrounding tissues by excising the disease-causing lesion, and at reducing GH and IGF-1 levels to normal values. When surgery (the usual first-line treatment) fails to correct GH/IGF-1 hypersecretion, medical treatment with dopamine agonists (particularly cabergoline), somatostatin analogs, and/or radiotherapy can be used. The GH receptor antagonist pegvisomant is helpful in patients who are resistant to somatostatin analogs. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most patients, giving them a normal life expectancy. Comorbidities associated with acromegaly generally improve after treatment, but persistent sequelae may nonetheless impair quality of life.


Vertebral augmentation plus short-segment fixation versus vertebral augmentation alone in Kümmell's disease: a systematic review and meta-analysis.
Osteoporotic vertebral compression fractures of the thoracolumbar spine can progress to Kümmell's disease, an avascular vertebral osteonecrosis. Vertebral augmentation (VA)-vertebroplasty and/or kyphoplasty-is the main treatment modality, but additional short-segment fixation (SSF) has been recommended concomitant to VA. The aim is to compare clinical and radiological outcomes of VA + SSF versus VA alone. Systematic review, including comparative articles in Kümmell's disease, was performed. This study assessed the following outcome measurements: visual analog scale (VAS), Oswestry Disability Index (ODI), anterior vertebral height (AVH), local kyphotic angle (LKA), operative time, blood loss, length of stay, and cement leakage. Six retrospective studies were included, with 126 patients in the VA + SSF group and 152 in VA alone. Pooled analysis showed the following: VAS, non-significant difference favoring VA + SSF: MD -0.61, 95% CI (-1.44, 0.23), I2 91%, p = 0.15; ODI, non-significant difference favoring VA + SSF: MD -9.85, 95% CI (-19.63, -0.07), I2 96%, p = 0.05; AVH, VA + SSF had a non-significant difference over VA alone: MD -3.21 mm, 95% CI (-7.55, 1.14), I2 92%, p = 0.15; LKA, non-significant difference favoring VA + SSF: MD -0.85°, 95% CI (-5.10, 3.40), I2 95%, p = 0.70. There were higher operative time, blood loss, and hospital length of stay for VA + SSF (p < 0.05), but with lower cement leakage (p < 0.05). VA + SFF and VA alone are effective treatment modalities in Kümmell's disease. VA + SSF may provide superior long-term results in clinical and radiological outcomes but required a longer length of stay.


ZmSMK9, a pentatricopeptide repeat protein, is involved in the cis-splicing of nad5, kernel development and plant architecture in maize.
Maize kernel size and weight are essential contributors to its yield. So the identification of the genes controlling kernel size and weight can give us a chance to gain the yield. Here, we identified a small kernel mutant, Zea mays small kernel 9 (Zmsmk9), in maize. Cytological observation showed that the development of the endosperm and embryo was delayed in Zmsmk9 mutants at the early stages, resulting in a small kernel phenotype. Interestingly, despite substantial variation in kernel size, the germination of Zmsmk9 seeds was comparable to that of WT, and could develop into normal plants with upright leaf architecture. We cloned Zmsmk9 via map-based cloning. ZmSMK9 encodes a P-type pentatricopeptide repeat protein that targets to mitochondria, and is involved in RNA splicing in mitochondrial NADH dehydrogenase5 (nad5) intron-1 and intron-4. Consistent with the delayed development phenotype, transcriptome analysis of 12-DAP endosperm showed that starch and zeins biosynthesis related genes were dramatically down regulated in Zmsmk9, while cell cycle and cell growth related genes were dramatically increased. As a result, ZmSMK9 is a novel gene required for the splicing of nad5 intron-1 and intron-4, kernel development, and plant architecture in maize.


Left Ventricular Filling Pressure in Chronic Thromboembolic Pulmonary Hypertension.
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by obstruction of major pulmonary arteries with organized thrombi. Clinical risk factors for pulmonary hypertension due to left heart disease including metabolic syndrome, left-sided valvular heart disease, and ischemic heart disease are common in CTEPH patients. The authors sought to investigate prevalence and prognostic implications of elevated left ventricular filling pressures (LVFP) in CTEPH. A total of 593 consecutive CTEPH patients undergoing a first diagnostic right and left heart catheterization were included in this study. Mean pulmonary arterial wedge pressure (mPAWP) and left ventricular end-diastolic pressure (LVEDP) were utilized for assessment of LVFP. Two cutoffs were applied to identify patients with elevated LVFP: 1) for the primary analysis mPAWP and/or LVEDP >15 mm Hg, as recommended by the current pulmonary hypertension guidelines; and 2) for the secondary analysis mPAWP and/or LVEDP >11 mm Hg, representing the upper limit of normal. Clinical and echocardiographic features, and long-term mortality were assessed. LVFP was >15 mm Hg in 63 (10.6%) and >11 mm Hg in 222 patients (37.4%). Univariable logistic regression analysis identified age, systemic hypertension, diabetes, atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume as significant predictors of elevated LVFP. Atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume remained independent determinants of LVFP in adjusted analysis. At follow-up, higher LVFPs were measured in patients who had meanwhile undergone pulmonary endarterectomy (P = 0.002). LVFP >15 mm Hg (P = 0.021) and >11 mm Hg (P = 0.006) were both associated with worse long-term survival. Elevated LVFP is common, appears to be due to comorbid left heart disease, and predicts prognosis in CTEPH.


Occupational stress and associated factors among health care professionals in Ethiopia: a systematic review and meta-analysis.
Occupational stress is a global health problem which affects employed personals especially health professionals. The burden of stress is not limited at individual level, but also affects the organizations productivity, the quality of care and country in large. In Ethiopia, little concern is given to this problem and individual studies conducted among health care professionals also showed inconsistent result. Therefore, the aim of this study was to assess the pooled prevalence of occupational stress and its associated factors among health care professionals in Ethiopia. Articles were searched from PubMed, Hinari, PsychInfo, Science direct databases, Google and Google scholar. A total of 10 studies were included in this review and meta-analysis. We used a standardized format for data extraction and STATA software version 13 for analysis. A random effect meta-analysis model was used to determine the pooled prevalence of occupational stress and I2 was used to check heterogeneity. Begg's and Egger's tests were conducted to detect publication bias. Furthermore, sensitivity and subgroup analysis was also conducted. Association was expressed by pooled odd ratio with corresponding 95% CI. The pooled prevalence of occupational stress was 52.5 [95% CI: (47.03, 57.96)]. The heterogeneity test was I2 = 89.1% & P < 0.001. The result of the publication bias detection (Begg's and Egger's) tests were p = 0.283 and p = 0.369 respectively. Female sex was identified as a significant predictor for occupational stress with a pooled effect of 3.75 [95% CI: (2.58, 5.45)]. Above half of health care professionals had occupational stress. Being female was significantly associated factor in this review and meta-analysis. Therefore, introduction of policies supporting health care professionals well-being at work in Ethiopia are advisable.


Roflumilast and tadalafil improve learning and memory deficits in intracerebroventricular Aβ1-42 rat model of Alzheimer's disease through modulations of hippocampal cAMP/cGMP/BDNF signaling pathway.
Alzheimer's disease (AD) is the most prevalent age-dependent neurodegenerative disease characterized by progressive impairment of memory and cognitive functions. Cyclic nucleotides like cAMP and cGMP are well-known to play an important role in learning and memory functions. Enhancement of cAMP and cGMP levels in the hippocampus by phosphodiesterase (PDE) inhibitors might be a novel therapeutic approach for AD. Thus, the present study was planned to explore the therapeutic potential of roflumilast (RFM) and tadalafil (TDF) phosphodiesterase inhibitors in intracerebroventricular (ICV) Aβ1-42 induced AD in rats. ICV Aβ1-42 was administered in rats followed by treatment with RFM (0.05 mg/kg) and TDF (0.51 mg/kg) for 15 days. Novel object recognition (NOR), and Morris water maze (MWM) test were performed during the drug treatment schedule. On the day, 22 rats were sacrificed, and hippocampus was separated for biochemical, neuroinflammation, and histopathological analysis. Aβ1-42 infused rats were induce behavioral impairment and increased AChE, BACE-1, Aβ1-42, GSK-3β, phosphorylated tau (p-Tau), pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels, oxidative stress (increased MDA, Nitrite and decreased GSH), histopathological changes, and reduced cAMP, cGMP, and BDNF levels. RFM and TDF significantly attenuated Aβ1-42 induced memory deficits and neuropathological alterations in the hippocampus. The outcomes of the current study indicate that RFM and TDF lead to memory enhancement through upregulation of cAMP/cGMP/BDNF pathway, thus they may have a therapeutic potential in cognitive deficits associated with AD.


Plant hydroperoxide-cleaving enzymes (CYP74 family) function as hemiacetal synthases: Structural proof of hemiacetals by NMR spectroscopy.
Hydroperoxide lyases (HPLs) of the CYP74 family (P450 superfamily) are widely distributed enzymes in higher plants and are responsible for the stress-initiated accumulation of short-chain aldehydes. Fatty acid hydroperoxides serve as substrates for HPLs; however, details of the HPL-promoted conversion are still incompletely understood. In the present work, we report first time the micropreparative isolation and the NMR structural studies of fatty acid hemiacetal (TMS/TMS), the short-lived HPL product. With this aim, linoleic acid 9(S)‑hydroperoxide (9(S)‑HPOD) was incubated with recombinant melon hydroperoxide lyase (CmHPL, CYP74C2) in a biphasic system of water/hexane for 60 s at 0 °C, pH 4.0. The hexane layer was immediately decanted and vortexed with a trimethylsilylating mixture. Analysis by GC-MS revealed a major product, i.e. the bis-TMS derivative of a hemiacetal which was conclusively identified as 9‑hydroxy‑9‑[(1'E,3'Z)‑nonadienyloxy]‑nonanoic acid by NMR-spectroscopy. Further support for the hemiacetal structure was provided by detailed NMR-spectroscopic analysis of the bis-TMS hemiacetal generated from [13C18]9(S)‑HPOD in the presence of CmHPL. The results obtained provide incontrovertible evidence that the true products of the HPL group of enzymes are hemiacetals, and that the short-chain aldehydes are produced by their rapid secondary chain breakdown. Therefore, we suggest replacing the name "hydroperoxide lyase", which does not reflect the factual isomerase (intramolecular oxidoreductase) activity, with "hemiacetal synthase" (HAS).


[Chronic consumption of alcohol and its damaging effects on the body].
It is widely accepted that alcohol metabolism passes through different mechanisms: alcohol dehydrogenase (ADH) activity in stomach epithelial cells, activity of ADH in the liver, microsomal-ethanol-oxydizing system (MEOS), hepatocyte catalase activity, and nonoxydizing metabolic pathway (production of fatty acid ethylesters). Alcohol causes numerous direct and indirect toxic effects on human organism. The first are directed to epithelial cells of stomach and liver cells, as well as the generation of excessive amounts of metabolites: NADH, acetaldehyde and acetate. These amounts of NADH lead to hyperlactacidaemia, hypoalbuminaemia and fat infiltration to the liver. The activity of MEOS causes drug metabolism changes in the liver and increased rate of hepatotoxic and cancerous substances. Acetaldehyde increases lipid peroxidation, immunity disorders, decrease in enzymatic activities and restoration of nucleoproteins, while acetate decreases lipolitic processes in cells.


REPRODUCTIVE OPHTHALMOLOGY: The Intersection of Inherited Eye Diseases and Reproductive Technologies.
To propose a working framework for patients with inherited eye diseases presenting to ophthalmologists who are interested in assisted reproductive technology and preimplantation genetic testing. Retrospective chart review and case series of three families with inherited eye diseases who successfully underwent preimplantation genetic testing, in vitro fertilization, and birth of unaffected children. Preimplantation genetic testing was performed for three families with different inherited eye diseases, which included autosomal dominant retinitis pigmentosa, autosomal recessive achromatopsia, and X-linked Goltz syndrome. Preimplantation genetic testing led to the identification of unaffected embryos, which were then selected for in vitro fertilization and resulted in the birth of unaffected children. A close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases.


Methylphenidate does not affect convergent and divergent creative processes in healthy adults.
An increasing number of healthy people use methylphenidate, a psychostimulant that increases dopamine and noradrenaline transmission in the brain, to help them focus over extended periods of time. While methylphenidate has been shown to facilitate some cognitive functions, like focus and distractor-resistance, the same drug might also contribute to cognitive impairment, for example, in creativity. In this study, we investigated whether acute administration of a low oral dose (20 mg) of methylphenidate affected convergent and divergent creative processes in a sample of young healthy participants. Also, we explored whether such effects depended on individual differences in ADHD symptoms and working memory capacity. Contrary to our expectations, methylphenidate did not affect participants' creative performance on any of the tasks. Also, methylphenidate effects did not depend on individual differences in trait hyperactivity-impulsivity or baseline working memory capacity. Thus, although the effects of methylphenidate on creativity might be underestimated in our study due to several methodological factors, our findings do not suggest that methylphenidate impairs people's ability to be creative.


Detection of disseminated lung cancer cells in lymph nodes: impact on staging and prognosis.
A major reason for the high incidence of tumor recurrences in patients with apparently resectable non-small cell lung cancer is presumably early tumor cell dissemination, which is clearly underestimated by current staging procedures. In this prospective study we assessed the frequency and prognostic significance of early lymphatic tumor cell spread to regional lymph nodes staged as tumor free by conventional histopathology by applying an immunohistochemical assay using monoclonal antibody Ber-Ep4. Ber-Ep4 positive cells were demonstrated in 27 (21.6%) of 125 patients and in 35 (6.2%) of 565 lymph nodes, respectively. Immunohistochemical analysis resulted in an up-staging in 24 of 27 patients. In patients previously staged as having pN0 disease, tumor cells were detected in 11/70 cases (15.7%). Univariate and multivariate survival analysis showed that the detection of minimal nodal tumor cell dissemination was associated with a reduced disease-free survival (log rank test, p = 0.0001; Cox regression model, p = 0.001). The use of immunohistochemistry enables one to identify many patients with regional tumor cell dissemination at the time of operation. These patients might benefit from an adjuvant therapeutic regimen.


On the reducible character of Haldane-Radić enzyme kinetics to conventional and logistic Michaelis-Menten models.
The conceptual and practical issues regarding the reduction of the Haldane-Radić enzymic mechanism, specific for cholinesterase kinetics, to the consecrated or logistically modified Michaelis-Menten kinetics, specific for some mutant enzymes, are here clarified as due to the limited initial substrate concentration, through detailed initial rate and progress curve analysis, even when other classical conditions for such equivalence are not entirely fulfilled.


pH-sensitive carboxymethyl chitosan hydrogels via acid-labile ortho ester linkage as an implantable drug delivery system.
A series of pH-sensitive carboxymethyl chitosan (CMCS) hydrogels were prepared via ortho ester linkage. DOX-loaded gelatin nanoparticles with an average diameter of around 50 nm were incorporated into hydrogels to obtain hybrid hydrogels (DOX-NPs-Gel), which could be locally implanted into tumor site in any shape. The physicochemical and mechanical properties of these hydrogels could be easily controlled by adjusting the proportion of crosslinking agent. DOX-NPs-Gel showed the pH-dependent degradation and drug release, and only 29.9% of DOX was released within 144 h at pH 7.4, while the cumulative release reached 49.3% and 65% at pH 6.5 and 5.0, respectively. In vivo study demonstrated that the implanted DOX-NPs-Gel efficiently improved DOX accumulation in tumor site through continuously degradation in mildly acidic environment of tumor tissues, and the tumor volume at the end of experiment was only 81.53 mm3, while tumor size reached to 229.22 mm3 and 174.15 mm3 after intravenous treatment with free DOX and DOX-NPs, respectively.


Epigenetics of cancer stem cells: Pathways and therapeutics.
Epigenetic alterations including DNA methylation and histone modifications are the key factors in the differentiation of stem cells into different tissue subtypes. The generation of cancer stem cells (CSCs) in the process of carcinogenesis may also involve similar kind of epigenetic reprogramming where, in contrast, it leads to the loss of expression of genes specific to the differentiated state and regaining of stem cell-specific characteristics. The most important predicament with treatment of cancers includes the non-responsive quiescent CSC. The distinctive capabilities of the CSCs make cancer treatment even more difficult as this population of cells tends to remain quiescent for longer intervals and then gets reactivated leading to tumor relapse. Therefore, the current review is aimed to focus on recent advances in understanding the relation of epigenetic reprogramming to the generation, self-renewal and proliferation of CSCs. CSC-targeted therapeutic approaches would improve the chances of patient survival by reducing the frequency of tumor relapse. Differentiation therapy is an emerging therapeutic approach in which the CSCs are induced to differentiate from their quiescent state to a mature differentiated form, through activation of differentiation-related signalling pathways, miRNA-mediated alteration and epigenetic differentiation therapy. Thus, understanding the origin of CSC and their epigenetic regulation is crucial to develop treatment strategy against not only for the heterogeneous population of cancer cells but also to CSCs. Characterizing the epigenetic marks of CSCs and the associated signalling cascades might help in developing therapeutic strategies against chemo-resistant cancers.


Effects of auditory hallucinations on the mismatch negativity (MMN) in schizophrenia as measured by a modified 'optimal' multi-feature paradigm.
The recently developed Optimal-3 multi-feature MMN paradigm, a shortened version of the 'optimal' multi-feature MMN paradigm, allows for the focused recording of the most widely reported MMN deviants (frequency, duration, intensity) within an efficient and time-saving paradigm. The objective of this study was to examine MMN acoustic change detection in schizophrenia (SZ), and elucidate its association with auditory verbal hallucinations (AH), using the Optimal-3. MMN to duration, frequency and intensity deviants were recorded in 12 SZ outpatients (SZs) with persistent AHs and 12 matched healthy controls (HC). Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between groups and were correlated with trait (PSYRATS) and state measures of AH severity and Positive and Negative Syndrome Scale (PANSS) ratings in SZs. SZs showed a significantly smaller duration MMN compared to HCs. Furthermore, in SZs attenuated duration MMN amplitudes were correlated with increased PSYRATS scores, as well as increased PANSS positive symptom, hallucination item and general psychoticism ratings, while attenuated intensity MMN amplitudes were correlated with increased PSYRATS scores. This is the first study to examine MMN in SZ within the modified (Optimal-3) multi-feature MMN paradigm. This study corroborates previous research reporting a robust duration MMN deficit in SZ and supports previous findings suggesting that AHs may contribute to MMN deficits in SZ.


Development of a health-related quality of life instrument for nausea and vomiting of pregnancy.
To develop a questionnaire that measures change in symptoms of nausea and vomiting of pregnancy (NVP). Eligible and consenting callers to the NVP Healthline at the Hospital for Sick Children, Toronto, underwent telephone interview by using a structured questionnaire. Callers were asked to indicate which of 195 items had been a problem for them and the importance of that problem. For each item, the "frequency" (of women who identified the item as problematic) and "mean importance" (mean importance score of women who indicated that the item was problematic) were multiplied to give the "overall impact." Patterns of response were examined by maternal characteristics. Factor analysis was used to explore relationships between factors. Among 500 women enrolled, areas of quality of life impairment were frequent and similar by maternal characteristics. The questionnaire contains 30 items in 4 domains (physical symptoms/aggravating factors, fatigue, emotions, and limitations) and takes 10 minutes to administer. This questionnaire contains topics of quality of life impairment important to women with NVP and shows promise for use as an outcome measure in clinical trials.


Effect of Time Elapsed since Gadolinium Administration on Atherosclerotic Plaque Enhancement in Clinical Vessel Wall MR Imaging Studies.
Vessel wall MR imaging is a useful tool for the evaluation of intracranial atherosclerotic disease. Enhancement can be particularly instructive. This study investigated the impact of the duration between contrast administration and image acquisition. The cohort with the longest duration had the greatest increase in signal intensity change. When using vessel wall MR imaging to assess intracranial atherosclerotic disease, protocols should be designed to maximize the duration between contrast administration and image acquisition to best demonstrate enhancement.


Trpc6 knockout improves behavioral dysfunction and reduces Aβ production by inhibiting CN-NFAT1 signaling in T2DM mice.
As the prevalence of diabetes and health awareness increase, type 2 diabetes mellitus -associated cognitive dysfunction is receiving increasing attention. However, the pathogenesis is not entirely understood. Transient receptor potential cation channel 6 (TRPC6) is highly correlated with intracellular Ca2+ concentrations, and neuronal calcium overload is an important cause of cognitive dysfunction. In the present study, we investigated the effect and mechanism of Trpc6 knockout in high-fat diet and streptozotocin-induced T2DM mice. The body weight and fasting blood glucose were recorded during the experiment. Behavioral dysfunction was detected using the open field test (OFT), elevated plus maze (EPM), hole-board test (HBT), Morris water maze (MWM) test and contextual fear conditioning (CFC) test. Nissl and H&E staining were used to examine neuronal damage. Western blot, quantitative real-time polymerase chain reaction (q-PCR), and immunofluorescence were performed to detect amyloid beta protein (Aβ) deposition and related indicators of neurological impairments in the cerebral cortex and hippocampus. The results indicated that Trpc6 knockout inhibited body weight loss and fasting blood glucose increase, improved spontaneous activity, learning and memory dysfunction, and alleviated neuroinflammation and neuronal damage in T2DM mice. The further results demonstrated that Trpc6 knockout decreased Aβ generation and deposition, and reduced the expressions of inflammasome-related proteins in T2DM mice. In addition, Trpc6 knockout inhibited intracellular calcium overload in diabetic mice and primary cultured hippocampal neurons, which in turn suppressed CN and NFAT1 expression. These data suggest that Trpc6 knockout may inhibit the CN-NFAT1 signaling pathway by decreasing intracellular calcium overload in the brain of T2DM mice, which consequently reduce Aβ deposition and neuroinflammation, and ultimately delay the development of T2DM-associated cognitive dysfunction.


HLA-DR1 is associated with vitiligo.
In Eastern Hungary, vitiligo is found to be associated with HLA-DR1. When other autoimmune disorders are also present, DR3 is also increased.


Relationship between symptoms rated with the Positive and Negative Syndrome Scale and brain measures in schizophrenia.
The Positive and Negative Syndrome Scale (PANSS) was used to rate clinical symptoms in 42 inpatients with schizophrenia before they were examined by computed tomography. Significantly higher mean size of lateral and third ventricles, and higher mean cortical atrophy were found in schizophrenic patients compared with healthy control subjects. Ventricular enlargement and cortical atrophy were significantly related to low scores on the Composite subscale of the PANSS. Positive correlations were observed mainly with negative items such as blunted affect, emotional withdrawal, difficulties in abstract thinking, passive-apathetic social withdrawal, and lack of spontaneity of conversation. Additional positive correlations were observed with two items from the General Psychopathology subscale (mannerisms and disorientation). Inverse correlations were found with most positive items. These results suggest a relationship between brain structural abnormalities and the symptomatology of schizophrenia recorded with PANSS.


Combined use of botulinum toxin type A and B for forehead rhytides: a randomized, double-blind, split-face study.
This is the first well-controlled study of the combined use of botulinum toxin type A (BoNT-A) and botulinum toxin type B (BoNT-B) for hyperkinetic lines in forehead. To evaluate the effectiveness and safety of a mixture of BoNT-A and BoNT-B with that of equipotent BoNT-A alone for treating patients with forehead rhytides. Fourteen patients with forehead wrinkles completed this clinical study. On day 0, patients received a mixture of BoNT-A (5 U) and B (500 U) on one side of the forehead and BoNT-A (10 U) symmetrically on the other side. Clinical evaluation was made at the beginning and at weeks 1, 2, 4, 8, 12, and 16. Therapeutic efficacy was evaluated using clinical improvement scale by investigators and the subjective wrinkle assessment by patients. According to investigator assessment, the differences between the average improvement scores of the two differently treated sides were not statistically significant at all follow-up visits. Moreover, the plateau of the clinical benefit was achieved at week 4. We observed the equivalent efficacy in the mixture of both toxins and BoNT-A alone.


EDX-analysis of fluoride precipitation on human enamel.
One mechanism of action for the anticaries effect of topical fluoridation is through precipitation of CaF2. In this in vitro study energy-dispersive x-ray spectroscopy (EDX) is used as a semiquantitative method to detect enamel fluoride-precipitation under the influence of acidic and neutral pH-value and absence or presence of a salivary pellicle. Crowns of 30 human caries-free third molars were quartered into four specimens and the enamel surface ground flat and polished. Two specimens each were stored in human saliva (120 minutes pellicle formation). Teeth were randomly allocated into 6 treatment groups: NaF_a (experimental acidic sodium fluoride; 12500 ppmF-, pH 4.75); NaF_n (experimental neutral sodium fluoride; 12500 ppmF-, pH 7.0); GB_a (acidic gel base; 0 ppmF-, pH 4.75); GB_n (neutral gel base; 0 ppmF-, pH 7.0); AmF-NaF_a (experimental acidic amine/sodium fluoride; 12500 ppmF-, pH 4.75); EG_a (acidic amine/sodium fluoride; Elmex Geleé, CP-GABA GmbH; 12500 ppmF-, pH 4.75). Each gel was applied for 60 seconds to one specimen with and one specimen without pellicle. Two specimens served as controls (no gel, without/with pellicle). Atomic percent (At%) of O, F, Na, Mg, P, Ca was measured by EDX. ∆At% and Ca/P-ratios were calculated. EDX could semi-quantify superficial enamel fluoride-precipitation. Only specimens treated with acidic fluoride gels showed fluoride-precipitation, a salivary pellicle tended to decrease At%F.


Hypersensitive carotid sinus syndrome due to neurofibromatosis-1 and manifested by repeated episodes of syncope.
A 28-year-old patient with neurofibromatosis-1 presented with syncope. The exam demonstrated a mass adjacent and inferior to the right occiput that extended to the posterior lateral right-sided neck. Initial invasive and noninvasive testing was negative. Imaging of her head and neck demonstrated a large neurofibroma enveloping her right carotid sinus without vessel occlusion or evidence of malignancy. An event recorder documented asystole. A pacemaker was implanted to avoid the surgical morbidity of removing the neck mass. The patient has since been free of syncope. We believe neurofibromatosis-1 should be included in the differential of syncope.


Ultrasmall graphene oxide for combination of enhanced chemotherapy and photothermal therapy of breast cancer.
Combination of chemotherapy and photothermal therapy (PTT) is an effective way for the treatment of cancer. Graphene oxide (GO) with a large specific surface area and strong near-infrared (NIR) absorbance have been widely used as both the chemotherapeutic carriers and photothermal agents. The smaller lateral size and higher oxidation degree of GO corresponding to better dispersion in water and lower cytotoxicity. Therefore, the preparation of ultrafine GO nanosheets (UGO) with the controlled size and high oxidation degree is of significant importance to meet the demands of biological applications. Herein, we developed a versatile drug delivery nanoplatform based on poly(dopamine) (PDA) modified ultrasmall graphene oxide (UGO) with small size (average size of 30 nm) and high oxidation content (45 wt. %). The fabricated PDA-modified UGO (UGP) exhibits well biocompatibility, excellent photothermal performance and high drug loading capacity of doxorubicin (DOX). Under NIR laser irradiation, the photothermal-induced release of DOX could achieve the combination of chemotherapy and PTT for efficient therapy of breast cancer. This work established UGO as a novel drug delivery with excellent photothermal performance for the combination of chemotherapy and PTT of tumors.


[Preoperative intensity-modulated radiotherapy of rectal cancers: Relevance and modalities].
Preoperative radiotherapy boosted by chemotherapy is a recommended treatment in locally advanced rectal cancers. This treatment is delivered by three dimensional conformal irradiation, which is usually well tolerated but can induce potential toxicity such as rectitis, cystitis and hematologic adverse effects. Intensity-modulated radiotherapy, widely available nowadays, allows optimization of volume covering and sparing of organs at risk such as bladder and bone marrow. This review presents relevant clinical situations and requirements for a beneficial and safe preoperative irradiation of rectal cancers by intensity-modulated technique. This technique is compared to three-dimensional conformal radiotherapy.


mGluR and NMDAR activation internalize distinct populations of AMPARs.
Activation of metabotropic- (mGluRs) or NMDA-type glutamate receptors (NMDARs) each can induce long-term depression (LTD) of synaptic transmission in CA1 hippocampal neurons. These two forms of LTD are triggered by diverse signaling pathways yet both are expressed by the internalization of AMPA-type glutamate receptors (AMPARs). An unanswered question remains as to whether the convergence of the mGluR and NMDAR signaling pathways on AMPAR endocytosis renders these two forms of plasticity functionally equivalent, with both pathways inducing endocytosis of the same population of synaptic AMPARs. We now report evidence that these pathways couple to the endocytosis of distinct populations of AMPARs defined by their mobility in the membrane surface. NMDAR activation enhances removal of surface AMPARs that rapidly cycle into and out of the membrane surface, while activation of mGluRs with DHPG results in the internalization of a non-mobile population of AMPARs. Glutamate Receptor Interacting Proteins 1 and 2 (GRIP1/2) play a key role in defining the non-cycling receptor population. GRIP1/2 knockdown with siRNA increases the proportion of rapidly cycling surface AMPARs and inhibits mGluR- but not NMDAR-mediated AMPAR internalization. Additionally, we find that mGluR activation dissociates surface AMPARs from GRIP1/2 while stimulation of NMDARs elicits the loss of membrane receptors not bound to GRIP1/2. We propose that these two receptor pathways can drive the endocytosis of distinct populations of AMPARs: NMDARs activation induces the endocytosis of rapidly cycling surface AMPARs not directly associated with GRIP1/2 while mGluR activation induces the endocytosis of non-cycling GRIP-bound surface AMPARs.


Synthesis and Screening of a DNA-Encoded Library of Non-Peptidic Macrocycles.
There is considerable interest in the development of libraries of non-peptidic macrocycles as a source of ligands for difficult targets. We report here the solid-phase synthesis of a DNA-encoded library of several hundred thousand thioether-linked macrocycles. The library was designed to be highly diverse with respect to backbone scaffold diversity and to minimize the number of amide N-H bonds, which compromise cell permeability. The utility of the library as a source of protein ligands is demonstrated through the isolation of compounds that bind Streptavidin, a model target, with high affinity.


Proliferation of glial cells induced by lithium in the neural lobe of the rat pituitary is enhanced by dehydration.
Rats dehydrated by 6 days of water deprivation had a low level of mitotic activity in the astrocytes ('pituicytes') of the neural lobe of the pituitary. Mitotic activity in the pituicytes was greatly increased when isotonic lithium was administered in the last 3 days of water deprivation. Rehydration on the last day of the experiment produced a further increase in mitoses. Isotonic solutions of sodium, potassium or rubidium chloride did not increase mitoses. This model of cell proliferation is of interest because the mitotic activity is related to a physiological attempt to maintain homeostasis rather than a response to injury or the development of neoplasia.


Global prevalence of cleft palate, cleft lip and cleft palate and lip: A comprehensive systematic review and meta-analysis.
Birth defect is widely used as a term for congenital anomalies. Children with cleft lip and palate may have serious speech, hearing, nutrition, and mental and social development disorders; therefore, this study was designed to determine the overall prevalence of cleft palate, lip, and cleft palate through systematic review and meta-analysis. In this study, systematic review and meta-analysis of data from studies on the prevalence of cleft lip and palate in Scopus, Embase, Magiran, Web of Science (WoS), PubMed and Science Direct databases were extracted between January 2000 and June 2020. In order to perform the analysis of qualified studies, the model of random effects was used and the inconsistency of studies with I2 index was investigated. Data analysis was performed with Comprehensive Meta-Analysis software (Version 2). According to the results of the present study on cleft palate, the total number of samples entered in the study in 59 studies were 21,088,517 individuals, the prevalence of cleft palate based on the meta-analysis of the reviewed studies in every 1000 live births was obtained 0.33 (95% CI: 0.28-0.38). In the case of cleft lip, the total number of samples entered in the 57 reviewed studies were 17,907,569 individuals. The prevalence of cleft lip obtained based on the meta-analysis of the reviewed studies was 0.3 in every 1000 live births (95% CI: 0.26-0.34), and in the case of cleft lip and palate, the total number of samples entered in the 55 reviewed studies was 17,894,673. The prevalence of cleft lip and palate based on the meta-analysis of the studies reviewed in each 1000 live births was 0.45 (95% CI: 0.38-0.52). Due to the high prevalence of oral clefts such as cleft palate, cleft lip, and cleft lip and palate; health system policymakers need to take precautionary measures to reduce the number of patients, as well as diagnostic and therapeutic measures to reduce the effects of this disorder in children.


Comparison of diazepam and flurazepam in the treatment of insomnia in general practice.
In a double-blind crossover study in general practice, flurazepam was shown to be significantly better (p less than 0.001) than diazepam in treating sleep disturbance. Fewer patients reported side-effects on flurazepam.


Methods Used to Generate Consensus Statements for Clinical Practice Guidelines: A Primer for the Spine Surgeon.
This was a research methodology study. This review discusses the most commonly utilized consensus group methodologies for formulating clinical practice guidelines and current methods for accessing rigorous up-to-date clinical practice guidelines. In recent years, clinical practice guidelines for the management of several conditions of the spine have emerged to provide clinicians with evidence-based best-practices. Many of these guidelines are used routinely by administrators, payers, and providers to determine the high-quality and cost-effective surgical practices. Most of these guidelines are formulated by consensus groups, which employ methodologies that are unfamiliar to most clinicians. An extensive literature review was performed. The literature was then summarized in accordance with the authors' clinical experience. The Nominal Group Technique, Delphi method, and RAND-UCLA Appropriateness Model are 3 commonly utilized consensus group methodologies employed in the creation of clinical practice guidelines. Each of these methodologies has inherent advantages and disadvantages, is dependent on rigorously performed systematic reviews and meta-analyses to inform the panel of experts, and can be used to answer challenging clinical questions that remain unanswered due to a paucity of class I evidence. This review highlights the most commonly utilized consensus group methodologies and informs spine surgeons regarding options to access current clinical practice guidelines. Level V.


Computational modeling of the cephalic arch with jugulocephalic vein variant predicts hemodynamic profiles in patients with brachiocephalic fistula.
The cephalic vein is often used in for arteriovenous fistula creation; however, the cephalic vein variation is common. This study will propose new theoretical explanations for a new discovered variation of cephalic vein draining into external jugular vein with "T-junction" shape by means of 3D computational hemodynamic modeling, which may provide reference for clinical practice. The precise measurements were conducted for the variant right cephalic vein draining into external jugular vein and for a normal right cephalic vein as a control. After processing the anatomical data, 3D geometrical model was reconstructed. Then, the influent field inside the variant jugulocephalic vein was mathematically modeled to get a detailed description of hemodynamic environment. The anatomical parameters of the "T-junction" jugulocephalic vein variant were much more different from the normal right cephalic vein. The wall shear stress of variant cephalic vein at the corresponding position was higher and changed more rapidly than that of normal cephalic vein. The shear rate contour lines are disordered in several areas of the variant cephalic vein, indicating that the hemodynamic parameters in these areas are unstable. The hemodynamic characteristics at the confluence of the variant cephalic vein are more complex, with more areas where hemodynamic parameters are disrupted. The variation of cephalic arch in a "T-junction" with external jugular vein largely altered the fluid dynamics, especially in hemodialysis patients with brachiocephalic fistula in terms of the simulating flow in 3D computational model. This computational model provides hemodynamic profiles for stabilizing or modulating fluid dynamics in patients with jugulocephalic vein variant after brachiocephalic fistula.


N-(5-Nitro-pyridin-2-yl)-5H-dibenzo[d,f][1,3]diazepine-6-carboxamide.
The title compound, C(19)H(13)N(5)O(3), can be obtained from the corresponding α-amido-α-amino-nitrone in a reaction with biphenyl-2,2'-diamine. The amido-amidine core has distinctive geometrical parameters including: an outstandingly long Csp(2)-Csp(2) single bond of 1.5276 (13) Å and an amidine N-C-N angle of 130.55 (9)°. Intra-molecular N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds occur. In the crystal, mol-ecules form layers parallel to (001) via weak inter-molecular C-H⋯N inter-actions. The layers are linked via N-H⋯O hydrogen bonds and π-π inter-actions along [001] [benzene-pyridine centroid-centroid distance = 3.672 (2) Å].


Six new species of Horniella Raffray from the Oriental region (Coleoptera, Staphylinidae, Pselaphinae).
The Oriental pselaphine genus Horniella Raffray, 1905 currently contains 29 species. In this paper, six new species are described: H. nantouensis Zhang, Hu & Yin, sp. nov. and H. taiwanensis Zhang, Hu & Yin, sp. nov. from Taiwan, China; H. bifurca Zhang & Yin, sp. nov. and H. haucki Zhang & Yin, sp. nov. from Thailand; H. khasiensis Zhang & Yin, sp. nov. from northern India; and H. sabahensis Zhang & Yin, sp. nov. from eastern Malaysia. In addition, H. aculeata Yin & Li, 2015, originally described from Yunnan, China, is newly recorded from Thailand.


Paper point transfer of minimal numbers of microorganisms from a prepared canal in vitro.
A strain of Str. faecalis resistant to 2 mg./c.c. streptomycin was developed, and serial dilutions of known quantities of the organism were introduced into prepared root canals of extracted teeth. The canals were cultured with sterile dry paper points, incubated in tubes of thioglycollate media containing 2 mg./c.c. streptomycin at 37 degrees C. These tubes were checked for growth at 24-hour intervals for 7 days. Some tubes yielded growth on the first day, while those with greater dilutions of sample took 7 days. All samples with bacteria did yield growth by the seventh day. At the time of transfer of the organism into the prepared root canals, an identical sample of suspended organisms were spread on pour plates of brain-heart infusion broth containing 2 mg./c.c. streptomycin. After incubation at 37 degrees C. for 24 hours, the numbers of colonies were counted in order to determine the exact number of organisms in each serial dilution. Taking a culture after introduction of sterile distilled water into a canal and evaluation of the culture at the time of the scheduled filling appointment are recommended clinical procedures.


Correlation between protein abundance and sequence conservation: what do recent experiments say?
Cells evolve in a space of parameter values set by physical and chemical forces. These constraints create associations among cellular properties. A particularly strong association is the negative correlation between the rate of evolution of proteins and their abundance in the cell. Highly expressed proteins evolve slower than lowly expressed ones. Multiple hypotheses have been put forward to explain this relationship, including, for instance, the requirement for higher mRNA stability, misfolding avoidance, and misinteraction avoidance for highly expressed proteins. Here, we review some of these hypotheses, their predictions, and how they are supported to finally discuss recent experiments that have been performed to test these predictions.


An evolving neuro-fuzzy classifier for fault diagnosis of gear systems.
Gear systems (or gearboxes) are widely used in rotating machinery. Reliable gear fault diagnostic techniques and systems are critically needed to provide early warning of a possible defect so as to prevent machinery operation degradation and to reduce costs related to predictive maintenance. In this work, a new evolving neuro-fuzzy (eNF) classifier is proposed for real-time gear system fault diagnostics. In evolving process, the constraints related to gear health states are used to guide the partition of the output space, to prevent possible misleading clusters. A new training algorithm based on the normalized Adadelta function is suggested to improve eNF training convergence and accuracy. The effectiveness of the proposed eNF classifier is tested by simulation and experiment tests.


Neck masses in infants and children.
Neck masses, both inflammatory and tumoral, are common in infants and children, and most are benign. This article examines the imaging characteristics of various neck masses in infants and children. Routine radiographs, ultrasound, CT scan, MR imaging, and nuclear scintigraphy are discussed.


Free L-carnitine in human seminal plasma.
It has often been suggested that determination of free L(-)-carnitine in seminal plasma may provide a good indication of epididymal function. However, there has been disagreement regarding the origin of L(-)-carnitine (epididymis and seminal vesicles) and its concentration in human seminal plasma. In this study, free L(-)-carnitine was determined after deproteinization with an enzymatic spectrophotometric method. In 29 semen samples from fathers and with normal spermiograms (semen volume between 2 and 6 ml, sperm count over 20.10(6)/ml, more than 50% motile spermatozoa), the total free L(-)-carnitine in the seminal plasma was 1010 nmoles (SD: +/- 480), in 16 samples from vasectomized men it was 131 nmoles (SD: +/- 77), and in 5 from men with agenesis of the vas deferens and seminal vesicles it was 21 nmoles (SD: +/- 25). These results suggest that free L(-)-carnitine in the seminal fluid is predominantly of epididymal origin. The results of free L(-)-carnitine determinations in split ejaculates and the absence of a correlation between L(-)-carnitine and fructose concentrations in semen from normal subjects indicate that the seminal vesicles make only on minor contribution to L(-)-carnitine in the seminal plasma.


Diagnostic criteria and clinical procedures in HIV-1 associated progressive multifocal leukoencephalopathy.
The diagnosis of definite progressive multifocal leukoencephalopathy (PML) has been a neuropathological domain. We reviewed all Human Immunodeficiency Virus Type 1 (HIV-1) seropositive patients in our institution between 01.01.1989 and 31.12.1994 and identified 20/823 cases with PML by clinical and imaging criteria. Diagnosis was neuropathologically confirmed in 5 cases. Diagnostic criteria included rapid onset (< 2 weeks) of multifocal neurological signs and symptoms, advanced immunosuppression and asymmetric uni- or multifocal white matter lesions without mass effect, contrast enhancement or cortical atrophy in magnetic resonance imaging (MRI). The overall incidence of PML was stable over the observation period (approximately equal to 2.5%). The mean age at onset (41.7 years) was significantly lower compared to HIV-1 seronegative PML patients (peak in the sixth decade of life), male patients prevailed (100%). Mean survival (3.9 months) was extremely short. Human polyoma virus JC (JCV) polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) demonstrated a considerable rate of possible cerebral co-infection with HIV-1 and JCV as well as subclinical infection with JCV. Therefore demonstration of JCV deoxyribonucleic acid by PCR in the CSF alone is not sufficient for clinical PML diagnosis. We present diagnostic criteria on the basis of epidemiological, neuroradiological and CSF parameters that allow us to make the clinical diagnosis of PML. Although quick and safe, routine stereotactic brain biopsy is not necessary to confirm the diagnosis.


Sprayed fibrin sealant as the sole hemostatic agent for porcine laparoscopic partial nephrectomy.
Tisseel® is used to control minor bleeding during laparoscopic procedures. The DuploSpray MIS™ spray system allows thin, even application over a larger surface area. We use sprayed Tisseel as the sole agent to control hemorrhage and seal the renal collecting system after severe porcine laparoscopic partial nephrectomy. We performed staged bilateral severe laparoscopic partial nephrectomy in 12 Yucatan pigs using a longitudinal cut from upper to lower pole through the entire collecting system. In each pig 1 kidney was harvested immediately while the other was harvested after 4 weeks. After hilar clamping laparoscopic partial nephrectomy was done with cold scissors in 6 pigs while LigaSure™ was used in the other 6. Sprayed Tisseel was applied, and bleeding and urinary leakage were evaluated. Additional Tisseel was applied for repeat bleeding. We performed retrograde pyelogram (chronic) and burst pressure testing of the arterial and collecting systems. All animals survived 4 weeks. One urinoma was seen on retrograde pyelogram in the cold cut group. Average hilar clamp time was similar in the acute and chronic study arms. Average estimated blood loss was significantly less in the LigaSure group (p = 0.0045). Average arterial burst pressure was significantly different in the chronic and acute groups (605.8 vs 350.4 mm Hg, p = 0.008) but average collecting system burst pressure was similar (186.3 and 149.5 mm Hg, respectively). Sprayed Tisseel without suturing effectively sealed the arterial and collecting system after severe laparoscopic partial nephrectomy in the porcine model.


Diversity and Distribution of Whiteflies Colonizing Cassava in Eastern Democratic Republic of Congo.
The present study characterizes Bemisia tabaci and Bemisia afer from cassava in eastern Democratic Republic of Congo (DRC). The Mitochondrial COI sequencing revealed the occurrence of six cassava B. tabaci mitotypes, which were designated into four haplogroups (SSA-ECA, SSA-CA, SSA2, and SSA-ESA) using KASP SNP genotyping. SSA-ECA (72%) was the most prevalent and occurred in the northern part of the surveyed area, in the Ituri and Nord/Sud-Kivu provinces, whilst SSA-CA (21%) was present in the south, primarily in Haut-Katanga. SSA-ECA was predominant in the areas of north-eastern DRC most severely affected by cassava brown streak disease and was also reported in the new outbreak area in Pweto territory, Haut-Katanga, in the south. Bemisia afer comprised two major clusters with 85.5% of samples in cluster one, while the rest were in cluster two, which has no reference sequence in GenBank. This study provides important information on the genetic diversity of B. tabaci and B. afer in eastern DRC. This knowledge will be used as a basis for further studies to understand and to identify the role of whitefly haplogroups, their population densities and consequences for virus epidemics and spread as well as leading to improved vector and virus management strategies.


Coral environmental memory: causes, mechanisms, and consequences for future reefs.
The apparent ability of corals to acquire and maintain enhanced stress tolerance through a dose-dependent environmental memory, which may persist for multiple years, has critical implications for coral reef conservation research. Such responses are variable across coral species and environmental stressors, with primed corals exhibiting a modified response to secondary stress exposures. While the mechanisms underlying coral memory responses are poorly understood, they likely involve both the coral host and microbiome. With advances in molecular technologies, it is now possible to investigate potential memory mechanisms in non-model organisms, including transcriptional regulation through epigenetic modifications. We integrate evidence of coral environmental memory and suggest future research directions to evaluate the potential for this process to enhance coral resilience under climate change.


Extra-Neural Metastases of Late Recurrent Myxopapillary Ependymoma to Left Lumbar Paravertebral Muscles: Case Report and Review of the Literature.
Ependymomas are commonly classified as low-grade tumors, although they may harbor a malignant behavior characterized by distant neural dissemination and spinal drop metastasis. Extra-CNS ependymoma metastases are extremely rare and only few cases have been reported in the lung, lymph nodes, pleura, mediastinum, liver, bone, and diaphragmatic, abdominal, and pelvic muscles. A review of the literature yielded 14 other case reports metastasizing outside the central nervous system, but to our knowledge, no studies describe metastasis in the paravertebral muscles. Herein, we report the case of a 39-year-old patient with a paraspinal muscles metastasis from a myxopapillary ependymoma. The neoplasm was surgically excised and histologically and molecularly analyzed. Both the analyses were consistent with the diagnosis of muscle metastases of myxopapillary ependymoma. The here-presented case report is first case in the literature of a paraspinal muscles metastasis of myxopapillary ependymoma.


Characterizing the Impact of COVID-19 on Pre-Exposure Prophylaxis (PrEP) Care.
COVID-19 is a public health crisis that has fundamentally altered health care provision. The purpose of this study was to examine the impact of COVID-19 on pre-exposure prophylaxis (PrEP) care. We reviewed all patient records for those who presented for PrEP care at a PrEP program in Providence, Rhode Island from September 1st, 2019 to May 29th, 2020. The number of PrEP encounters decreased but was not significantly different over time (ps > .05). Patients were still able to access PrEP clinical services during the COVID-19 pandemic. Implementing flexible and timely PrEP delivery approaches in this setting likely minimized the disruption of PrEP care during COVID-19.


Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies.
Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer. Primary objective of the dose-escalation study (3 + 3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives included evaluation of antitumor activity of the combination based on KIT mutation status and the capacity of tumor-associated immune biomarkers to predict response. The primary objective to establish the maximum tolerated dose (MTD) was achieved, and the recommended phase II doses are ipilimumab at 3 mg/kg every 3 weeks and imatinib 400 mg twice daily. Of the 35 patients treated in the escalation and GIST expansion, none experienced dose-limiting toxicities. The most common grade 1/2-related adverse events (AEs) were fatigue (66%), nausea (57%), anorexia, vomiting (each 31%), edema (29%), and anemia, diarrhea, and rash (each 23%). Grade 3 AEs occurred in 6 patients (17%) and included fatigue, anemia, fever, rash, and vomiting. There were no grade 4 AEs. In general, the combination was well tolerated. Among all patients, 2 responses were seen: 1 partial response (GIST) and 1 partial response (melanoma). Stable disease was seen in 6 patients lasting an average of 6 months. The melanoma responder was KIT mutated and the GIST responder was wild-type. Our findings suggest that this combination of a targeted agent with checkpoint blockade is safe across multiple tumor types. Low activity with no clear signal for synergy was observed in escalation or GIST expansion cohorts. Assessment of antitumor activity of this combination in the KIT-mutant melanoma population is being evaluated. Clinicaltrials.gov NCT01738139, registered 28 November 2012.


Welcome to the techno highway: development of a health assessment CD-ROM and website.
Traditionally teaching nursing students psychomotor skills took place in a laboratory setting; however, recent developments in computer technology have revolutionised how educators can transfer knowledge. To meet the need for an efficient and interactive learning experience a software product was required to educate nursing students about health assessment techniques. This paper presents how existing 'old technology' of a video was given new life by embracing new technology, resulting in development of an interactive CD-ROM with supporting WebCT. This innovation reflects a more flexible approach to learning as it is dynamic, portable, self-paced and more convenient for adult learners especially those in remote areas.


Inhibition of the antigen activated T cell response by methylprednisolone is caused by inhibition of interleukin-2 (IL-2) production.
A mechanism by which the steroid methylprednisolone inhibits the T cell proliferation normally seen in antigen driven cultures was investigated. At methylprednisolone concentrations less than 10 micrograms ml-1 inhibition of cellular proliferation was almost exclusively via the inhibition of the production of interleukin-2 by activated T cells. The steroid seemed to inhibit IL-2 production directly and not via reduced sensitivity to interleukin-1 by IL-2 producer T cells, or reduced IL-1 production by the antigen presenting monocytes. At methylprednisolone concentrations of greater than 10 micrograms ml-1 direct inhibition of the T cell receptor to antigen complexes presented by cooperating monocytes seemed the most likely explanation. T cells in the presence of antigen and monocytes and MP concentrations of greater than 10 micrograms ml-1 did not produce IL-2 and were incapable of expressing IL-2 receptors. The inhibiting effects of methylprednisolone therefore are via several mechanisms depending on the concentration of the steroid employed.


Regulation of DNA break repair by RNA.
Genomic stability is critical for cell survival and its effective repair when damaged is a vital process for preserving genetic information. Failure to correctly repair the genome can lead to the accumulation of mutations that ultimately drives carcinogenesis. Life has evolved sophisticated surveillance, repair pathways, and mechanisms to recognize and mend genomic lesions to preserve its integrity. Many of these pathways involve a cascade of protein effectors that act to identify the type of damage, such as double-strand (ds) DNA breaks, propagate the damage signal, and recruit an array of other protein factors to resolve the damage without loss of genetic information. It is now becoming increasingly clear that there are a number of RNA processing factors, such as the transcriptional machinery, and microRNA biogenesis components, as well as RNA itself, that facilitate the repair of DNA damage. Here, some of the recent work unravelling the role of RNA in the DNA Damage Response (DDR), in particular the dsDNA break repair pathway, will be reviewed.


Improvement of hand hygiene adherence among staff in long-term care facilities for elderly in Japan.
Hand hygiene is crucial for infection control in long-term care facilities for elderly (LTCFEs), because it can be easily implemented in the low-resource settings of LTCFEs. This study investigated the actual status of hand hygiene adherence in LTCFEs, identified the factors inhibiting its appropriate implementation, and evaluated the effectiveness of a hand hygiene promotion program. In this before-and-after study, participants were staff members (n = 142) at two LTCFEs in Gunma Prefecture, Japan. We modified the World Health Organization's "five moments for hand hygiene" and assessed participants' hand hygiene adherence rates in four situations: (1) Before touching around a resident's mucous membrane area; (2) Before medical practice or clean/aseptic procedures; (3) After body fluid exposure/risk or after touching around a resident's mucous membrane area; and (4) After touching a resident's contaminated environments. The study was divided into four phases. In Phase 1, participants self-assessed their hand hygiene adherence using a questionnaire. In Phase 2, we objectively assessed participants' pre-intervention adherence rates. In Phase 3, an intervention comprising various hand hygiene promotion measures, such as education and hands-on training on hand hygiene practices and timings, was implemented. In Phase 4, participants' post-intervention adherence rates were objectively measured. Although most participants reported high hand hygiene adherence rate in the self-assessment (93.1%), the pre-intervention evaluation revealed otherwise (16.8%). Participants' post-intervention adherence rates increased for all four situations (77.3%). The intervention program helped increase participants' hand hygiene adherence rates, indicating its effectiveness. Similar interventions in other LTCFEs may also improve adherence rates.


Stability analysis of SEIR model related to efficiency of vaccines for COVID-19 situation.
This work is aimed to formulate and analyze a mathematical modeling, S E I R model, for COVID-19 with the main parameters of vaccination rate, effectiveness of prophylactic and therapeutic vaccines. Global and local stability of the model are investigated and also numerical simulation. Local stability of equilibrium points are classified. A Lyapunov function is constructed to analyze global stability of the disease-free equilibrium. The simulation part is based on two situations, the US and India. In the US circumstance, the result shows that with the rate of vaccination 0.1% per day of the US population and at least 20% effectiveness of both prophylactic and therapeutic vaccines, the reproductive numbers R 0 are reduced from 2.99 (no vaccine) to less than 1. The same result happens in India case where the maximum reproductive number R 0 in this case is 3.38. To achieve the same infected level of both countries, the simulation shows that with the same vaccine's efficiency the US needs a higher vaccination rate per day. Without vaccines for this pandemic, the model shows that a few percentages of the populations will suffering from the disease in the long term.


von Willebrand factor/factor VIII concentrate (Humate-P) for management of elective surgery in adults and children with von Willebrand disease.
von Willebrand disease (VWD) is the most common inherited bleeding disorder. Treatment guidelines recommend the use of von Willebrand factor/factor VIII (VWF/FVIII) concentrate for VWD patients with type 2 or 3 VWD undergoing surgery, and type 1 patients undergoing surgery who are unresponsive, or for whom desmopressin acetate is contraindicated. This prospective, open-label, multinational study evaluated the safety, efficacy and optimal dosing of a VWF/FVIII concentrate (Humate-P) in subjects with VWD undergoing elective surgery. Dosing was based on VWF ristocetin cofactor (VWF:RCo) and FVIII pharmacokinetic assessments performed before surgery. Pharmacokinetic assessments were completed in 33 adults and 9 children. Haemostatic efficacy was assessed on a 4-point scale (excellent, good, moderate/poor or none). Overall effective haemostasis was achieved in 32/35 subjects. Median terminal VWF:RCo half-life was 11.7 h, and median incremental in vivo recovery was 2.4 IU dL(-1) per IU kg(-1) infused. Major haemorrhage occurred after surgery in 3/35 cases despite achieving target VWF and FVIII levels. Median VWF/FVIII concentrate loading doses ranged from 42.6 IU VWF:RCo kg(-1) (oral surgery) to 61.2 IU VWF:RCo kg(-1) (major surgery), with a median of 10 (range, 2-55) doses administered per subject. Adverse events considered possibly treatment-related (n = 6) were generally mild and of short duration. The results indicate that this VWF/FVIII concentrate is safe and effective in the prevention of excessive bleeding during and after surgery in individuals with VWD.


Improved purification and characterization of the OXA-2 beta-lactamase.
An improved and scaled-up procedure has been developed for purifying the OXA-2 plasmid-mediated beta-lactamase. This has enabled us to improve the characterization of this enzyme, including a revised determination of its amino acid composition and the sequence of the N-terminal region of the protein.


Histone demethylase KDM6B inhibits breast cancer metastasis by regulating Wnt/β-catenin signaling.
Tumor metastasis remains a major challenge for patients with breast cancer. Aberrant epigenetic factor lysine-specific demethylase 6B (KDM6B) has been associated with tumor progression. Here, we show that KDM6B is significantly down-regulated in human breast cancer tissues, and its low expression is associated with poor prognosis of patients with breast cancer. Furthermore, overexpression of KDM6B remarkably inhibited cell proliferation, invasion, migration and epithelial-mesenchymal transition markers of breast cancer cells in vitro and tumor growth and lung metastasis in vivo. Notably, the expression of KDM6B in breast cancer tissues was negatively correlated with that of β-catenin, and overexpression of KDM6B decreased the expression of β-catenin and its accumulation in the nucleus of breast cancer cells. Overall, our findings provide novel insights into suppression of metastasis of breast cancer cells by KDM6B via β-catenin and suggest involvement of the KDM6B-Wnt/β-catenin axis in breast cancer progression.


From chattel to consenter: adolescents and informed consent: 2009 Grover Powers Lecture.
Angela Holder was to give the Grover Powers Memorial Lecture at the weekly Grand Rounds conducted by the Yale Department of Pediatrics on Wednesday, May 27, 2009, but unfortunately, she died one month earlier, on April 22, leaving behind her prepared address, "From Chattel to Consenter: Adolescents and Informed Consent," which she had regarded as the pinnacle of a remarkable career, much of it spent at Yale. As the Grover Powers honoree, the department's highest honor, Ms. Holder was only the fourth woman of 46 recipients and the first who was not a physician. On the date scheduled for her address, tributes were presented by her son, John Holder, and her longtime colleague, Dr. Robert Levine, co-founder of Yale's Interdisciplinary Bioethics Center. Their comments follow Angela Holder's completed but undelivered Grover Powers address. - Myron Genel, MD, Professor Emeritus of Pediatrics.


Ethical considerations for human-animal neurological chimera research: mouse models and beyond.
Research that uses stem cell-based chimeras promises to advance our understanding of human developmental biology, as well as new medical interventions, such as generating transplantable human organs in livestock. However, along with these exciting research possibilities come moral concerns about the moral humanization of animals, especially when it comes to the potential effects of human cells in the brains of experimental animals. Recent work involving neurologically chimeric mice may suggest that such worries are reasonable. However, this overlooks the crucial social and neurological conditions for enabling the development of conscious self-awareness, the absence of which leaves us only with animal welfare to monitor and consider.


Young adults' perceptions of using wearables, social media and other technologies to detect worsening mental health: A qualitative study.
Technological interventions may help support and improve mental health. However young peoples' perspectives on using different technologies to detect deteriorating mental health in those already diagnosed with a mental health condition is lacking. The study aim was to explore the perspectives of young patients on the feasibility and acceptability of using wearables, social media and technologies to detect mental health deterioration. The study was co-produced with young adults with past mental health difficulties. Semi-structured interviews were conducted with young adults with a severe mental health condition in a private room at a community mental health site. Data was triangulated by comparing codes and ideas across the two co-researchers and two researchers over two virtual meetings. Themes were finalised and presented in a thematic map. Sixteen participants were interviewed (81% female). There were four main themes: dealing with mental health symptoms, signs of mental health deterioration, technology concerns and technological applications to identify worsening mental health. Wearables and mobile apps were considered acceptable and feasible to detect mental health deterioration in real-time if they could measure changes in sleep patterns, mood or activity levels as signs of deterioration. Getting help earlier was deemed essential particularly in reference to dissatisfaction with the current non-technological mental health services. However, patients identified issues to consider before implementation including practicality, safeguarding and patient preference. Wearables and mobile apps could be viable technological options to help detect deterioration in young people in order to intervene early and avoid delay in accessing mental health services. However, immediate action following detection is required for the patient to trust and use the intervention.


Engineered channels enhance cellular density in perfused scaffolds.
Scaffold-based tissue engineering provides cells with an engineered matrix to enhance and direct cell attachment, proliferation and differentiation. One critical limitation to current tissue engineering approaches is the inability to create densely populated constructs thicker than a few 100 μm. We hypothesized that development of porous, channeled scaffolds would increase cell density and uniformity of their spatial distribution through scaffold channel perfusion. Patterned polyurethane sheets were fabricated using a sprayed phase separation technique and laminated together to form 1.5 mm thick channeled scaffolds. Hydraulic permeability testing confirmed the presence of functional channels throughout the multilaminate construct. A continuous flow bioreactor was used to perfuse the construct with medium during the culture period. Cross-sectional cell densities and spatial uniformities were measured in channeled and nonchanneled scaffolds under different seeding and culture conditions. Channeled scaffolds were found to have higher densities of human mesenchymal stem cells than nonchanneled samples. Perfused scaffolds had more uniform spatial distribution of cells within the scaffold compared to statically cultured scaffolds. In conclusion, we have shown the channeled scaffolds to be a promising approach toward creating thick tissue-engineered constructs.


Effect of dermatological consultation on survival in patients with checkpoint inhibitor-associated cutaneous toxicity.
Cutaneous immune-related adverse events (cirAEs) are a common side-effect of immune checkpoint inhibitors (ICIs). However, prior work examining these toxicities in detail has considered only the fraction of events evaluated by dermatologists. Associations between dermatology referral, cirAE treatment and survival outcomes remain underexplored across care settings. To comprehensively categorize cirAE patterns among all patients treated with immunotherapy at our institution, and to evaluate: (i) the effect of dermatology referral on cirAE treatment and (ii) the impact of cirAE treatment on survival. This was a retrospective cohort analysis of patients with cancer who initiated ICI therapy between 1 January 2016 and 8 March 2019 and developed one or more cirAEs, as screened for using International Classification of Diseases 10th revision codes and confirmed via manual chart review (n = 358). All relevant information documented prior to 31 March 2020 was included. CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred (odds ratio 6·08, P < 0·001). Patients who received any cirAE treatment had improved progression-free survival [hazard ratio (HR) 0·59, P = 0·001] and overall survival (HR 0·58, P = 0·007) compared with those who did not. CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred, and patients who received any treatment for a cirAE had improved survival outcomes.


Sputtering control of Ag2O decoration configurations on ZnO nanorods and their surface arrangement effects on photodegradation ability toward methyl orange.
In this study, a combinational strategy for synthesizing ZnO nanorod arrays interlaced with Ag2O particles was proposed. Hydrothermally derived ZnO nanorod templates were sputter coated with Ag2O particles. The sputtered Ag2O particles can be decorated on the surfaces of the ZnO nanorod arrays with a randomly dispersive or continuous coverage characteristic by controlling the sputtering duration. Structural analysis revealed the formation of satisfactory crystalline ZnO-Ag2O composite nanorods through the hydrothermal and sputtering methods. The ZnO-Ag2O composite nanorods exhibited a significantly enhanced photoactivity compared with that of pristine ZnO nanorods under light irradiation. Moreover, the Ag2O content and the coverage feature of the ZnO-Ag2O composite nanorods influence the photodegradation of methyl orange solution by the composite nanorods under light irradiation. The photodegradation efficiency of the ZnO nanorods was substantially enhanced when the Ag2O particles were decorated on the surfaces in a dispersive manner. This can be attributed to the optimal content of Ag2O particles and their randomly dispersive characteristic on the surface of the composite nanorods, which resulted in the efficient transfer of photocarriers and markedly suppressed the electron-hole recombination rate.


Soluble, dimeric HLA DR4-peptide chimeras: an approach for detection and immunoregulation of human type-1 diabetes.
Still there are no effective methods to predict or cure type 1 diabetes (T1D) in humans. Soluble, dimeric MHC class II-peptide (DEF) chimeras have potential for both early diagnosis and immunospecific therapy. DEF chimeras prevent and reverse diabetes in mice by stimulating antigen-specific type 1 T regulatory cell (Tr1)-like cells. We also showed that diabetes could be predicted by changes in the phenotype of autoreactive CD4 T cells in peripheral blood. Herein, we demonstrated that human DEF (HLA-DR*0401/Fcgamma1) chimeras expressing peptides of beta-cell antigens stimulate Tr1-like cells in blood of patients with T1D, non-diabetic relatives, and controls. Furthermore, the specific and stable binding of DEF chimeras to cognate TCR and CD4 coreceptor allowed quantification and phenotyping of autoreactive CD4 T cells in non-stimulated blood by FACS. Our results indicate that (1) autoreactive CD4 T cells to GAD65 autoantigen are commonly present in humans expressing diabetes-susceptible HLA-DR*0401 molecules; (2) these autoreactive T cells undergo avidity maturation upon encountering the self antigen early in life; (3) the disease is associated with an imbalance between autoreactive CD4+CD25+ and CD4+CD69+ T cells specific for GAD65. Based on this, we propose a model to explain the kinetics of autoreactive CD4 T cells in blood during the natural history of T1D.


Evaluation of clinical and laboratory variables as prognostic indicators in hospitalised gastrointestinal colic horses.
The present prospective study included 106 horses referred to the Department of Large Animal Sciences, The Norwegian School of Veterinary Science, as non-responders to the initial colic treatment in general practise. In 14 of these cases a required surgical treatment was not performed due to economical or other reasons and were excluded from the study. Clinical and laboratory data were obtained at the arrival in the hospital. The outcome for all analyses was survival/ non-survival. A multivariable logistic regression was performed. The analyses were used in medically (46 horses) and surgically treated cases (46 horses) separately. The same analyses were also run for all 92 horses in a simulated "field" situation, where only clinical variables and D-dimer values were included. The fraction of survivors was 78% in the medical and 48% in the surgical cases. In total 63% of the horses survived. In the final multivariable logistic regression model packed cell volume (PCV) was the only important predictor for medically treated cases, and heart rate and presence of hyperaemic or cyanotic mucous membranes were the predictors in the surgically treated cases as well as in the simulated "field" situation. In conclusion, traditional variables as heart rate, mucous membranes and PCV were the important predictors for the outcome in hospitalised colic cases.


The occhiolino (occ) mutant Zebrafish, a model for development of the optical function in the biological lens.
Zebrafish visual function depends on quality optics. An F3 screen for developmental mutations in the Zebrafish nervous system was conducted in wild-type (wt) AB Zebrafish exposed to 3 mM of N-ethyl-N-nitrosourea (ENU). Mutant offspring, identified in an F3 screen, were characterized by a small pupil, resulting from retinal hypertrophy or hyperplasia and a small lens. Deficits in visual function made feeding difficult after hatching at approximately 5-6 days postfertilization (dpf). Special feeding conditions were necessary for survival of the occhiolino (occ) mutants after 6 dpf. Optokinetic response (OKR) tests measured defects in visual function in the occ mutant, although electroretinograms (ERGs) were normal in the mutant and wt. Consistent with the ERGs, histology found normal retinal structure in the occ mutant and wt Zebrafish. However, lens development was abnormal. Multiphoton imaging of the developmental stages of live embryos confirmed the formation of a secondary mass of lens cells in the developing eye of the mutant Zebrafish at 3-4 dpf, and laminin immunohistochemistry indicated the lens capsule was thin and disorganized in the mutant Zebrafish. The occ Zebrafish is a novel disease model for visual defects associated with abnormal lens development. Developmental Dynamics 246:915-924, 2017. © 2017 Wiley Periodicals, Inc.


Passive and dynamic properties of the eustachian tube: quantitative studies in a model.
To question the conception of Eustachian tube (ET) dysfunction by investigating some of its passive and active properties. Middle ear (ME) fluid accumulation accompanied by a negative pressure is generally accepted to be induced by ET dysfunction, implying that the origin of pathology is within the tube. Pressure changes were continuously and directly measured in a ME model having human dimensions, constructed with a patent ET, and employing different mastoid sizes. Various liquids were introduced into the ME chamber while maintaining atmospheric pressure. The model was tilted to a 45 degrees angle below the horizon, causing the liquid to block the tympanic inlet of the ET. Then either the ME was opened to the atmosphere (simulating an insertion of a ventilating tube) and the ET was inspected for liquid passage through it, or the cartilaginous ET was compressed and opened, imitating the "pumping" action of the ET at the process of deglutition. ET blockage produced a ME negative pressure in the range of -8 to -10 mm H2O. ET pumping caused a ME pressure change of 2 to 60 mm H2O, a greater change when a smaller mastoid was used. ET obstruction by intratympanic fluid may cause a negative pressure in an ME having a normal, patent ET. Clearance of such fluid would be facilitated according to its viscosity. The ET pumping mechanism may play a major role in fluid transport and pressure regulation of the ME.


Mode of action of a formulation containing hydrazones and saponins against leishmania spp. Role in mitochondria, proteases and reinfection process.
Toxicity and poor adherence to treatment that favors the generation of resistance in the Leishmania parasites highlight the need to develop better alternatives. Here, we evaluated the in vitro effectiveness of hydrazone derived from chromanes 2-(2,3-dihydro-4H-1-benzothiopyran-4-ylidene) hydrazide (TC1) and 2-(2,3-dihydro-4H-1-benzopyran-4-ylidene) hydrazide (TC2) and the mixture of triterpene saponin hederagenin-3-O-(3,4-O-diacetyl-ß-D-xylopyranosyl-(1à3)-a-L- rhamnopyranosyl-(1à2)-a-L-arabinofuranoside, hederagenin-3-O-(3,4-O-diacetyl-a-L- arabinopyranosyl-(1à3)-a-L-rhamnopyranosyl-(1à2)-a-L-arabinofuranoside and, hederagenin-3-O-(4-O-acetyl-ß-D-xylopyranosyl-(1à3)-a-L-rhamnopyranosyl-(1à2)-a-L-arabinofuranoside from Sapindus saponaria (SS) on L. braziliensis and L. pifanoi. Mixtures of TC1 or TC2 with saponin were formulated for topical application and the therapeutic effectiveness was evaluated in the model for cutaneous leishmaniasis (CL) in golden hamster. The mode of action of these compounds was tested on various parasite processes and ultrastructural parasite modifications. TC1, TC2 and SS showed moderate cytotoxicity when tested independently but toxicity was improved when tested in combination. The compounds were more active against intracellular Leishmania amastigotes. In vivo studies showed that combinations of TC1 or TC2 with SS in 1:1 ratio (w/w) cured 100% of hamsters with no signs associated with toxicity. The compounds did cause changes in the mitochondrial activity of the parasite with a decrease in ATP levels and depolarization of membrane potential and overproduction of reactive oxygen species; nevertheless, these effects were not related to alterations in membrane permeability. The phagolysosome ultrastructure was also affected impacting the survival of Leishmania but the function of the lysosome nor the pH inside the phagolysosome did not change. Lastly, there was a protease inhibition which was directly related to the decrease in the ability of Leishmania to infect and multiply inside the macrophage. The results suggest that the combination of TC1 and TC2 with SS in a 1:1 ratio is capable of curing CL in hamsters. This effect may be due to the ability of these compounds to affect parasite survival and the ability to infect new cells.


DNA methylation analysis in human cancer.
Many tumor suppressor genes (such as p16, Rb, VHL, E-cadherin, and hMLH1) that are silenced by mutation are also inactivated by gene silencing through DNA methylation. Characterization of genes hypermethylated in human cancers but not in normal tissues not only provides insights into cancer biology but also permits the use of methylation-specific polymerase chain reaction-based assays that could serve as diagnostic tests for the early detection and early diagnosis of this disease. To this end, research aimed at the identification and characterization of the methylation status of known and candidate tumor suppressor genes is one strategy for finding putative diagnostic markers. This chapter describes several methods of methylation analysis.


Adolescent Stress Questionnaire: reliability and validity of the Greek version and its description in a sample of high school (lyceum) students.
Adolescence is a crucial phase of human life characterized by enhanced exposure and vulnerability to various stressful stimuli. The Adolescent Stress Questionnaire (ASQ) is a useful measure to evaluate possible sources of stressors affecting the adolescent equilibrium. The present study examines the scientific properties of the Greek version of ASQ to measure perceived stress among 250 Greek adolescents. The confirmatory factor analysis (CFA) results showed a good fit of the original structure of ASQ to the observed data in the Greek sample. A good internal reliability was also confirmed by high Cronbach's alpha values. In line with previous research, girls reported more stress than boys. Overall, the Greek ASQ is a valid and reliable instrument for evaluating adolescent stress.


Effects of integrin-mediated cell adhesion on plasma membrane lipid raft components and signaling.
Anchorage dependence of cell growth, which is mediated by multiple integrin-regulated signaling pathways, is a key defense against cancer metastasis. Detachment of cells from the extracellular matrix triggers caveolin-1-dependent internalization of lipid raft components, which mediates suppression of Rho GTPases, Erk, and phosphatidylinositol 3-kinase in suspended cells. Elevation of cyclic adenosine monophosphate (cAMP) following cell detachment is also implicated in termination of growth signaling in suspended cells. Studies of integrins and lipid rafts, however, examined mainly ganglioside GM1 and glycosylphosphatidylinositol-linked proteins as lipid raft markers. In this study, we examine a wider range of lipid raft components. Whereas many raft components internalized with GM1 following cell detachment, flotillin2, connexin43, and Gα(s) remained in the plasma membrane. Loss of cell adhesion caused movement of many components from the lipid raft to the nonraft fractions on sucrose gradients, although flotillin2, connexin43, and H-Ras were resistant. Gα(s) lost its raft association, concomitant with cAMP production. Modification of the lipid tail of Gα(s) to increase its association with ordered domains blocked the detachment-induced increase in cAMP. These data define the effects of that integrin-mediated adhesion on the localization and behavior of a variety of lipid raft components and reveal the mechanism of the previously described elevation of cAMP after cell detachment.