Feasibility and efficacy of percutaneous transcatheter intraarterial chemotherapy with paclitaxel in albumin nanoparticles for advanced squamous-cell carcinoma of the oral cavity, oropharynx, and hypopharynx.
In view of the promising results of a phase I trial, this phase II trial was conducted to study the efficacy and safety of intraarterial induction chemotherapy with a novel nanoparticle albumin-bound paclitaxel formulation in advanced head and neck cancer. Sixty previously untreated patients with locally advanced squamous-cell carcinoma (SCC) of the oral cavity, oropharynx, or hypopharynx in stage T3/4 and any nodal stage received two to four cycles of nanoparticle albumin-bound paclitaxel by infusion into the external carotid artery or one of its branches, without premedication, at an initial dose of 230 mg/m2 and subsequently a reduced dose of 150 mg/m2. Response was evaluated by physical examination and multidetector computed tomography in all patients, and also by positron emission tomography with [18F]fluorodeoxyglucose in 38 patients. Definitive treatment was surgery, chemotherapy, radiation therapy, or chemoradiation therapy. Intraarterial chemotherapy had a low incidence of complications and produced complete or partial responses in 45 of 60 treated patients (75%). Seven patients (11.67%) had stable disease and eight (13.33%) had disease progression. High-grade bone marrow depression was rare. An unexpected toxicity was reversible facial nerve palsy on the side of infusion, which occurred in six patients at initial dosage. Reduction of the dose eliminated this specific toxicity without any loss of efficacy. The promising response rates and tolerability of intraarterial chemotherapy with nanoparticle albumin-bound paclitaxel justify further investigation of this formulation, alone or in combination with other agents, in advanced SCC of the head and neck.


[An interdisciplinary approach to complex orthodontic-periodontal clinical situations in adult patients].
Between orthodontics and periodontology there are many correlations, especially in the treatment of adults with already-damaged periodontal tissues and malocclusions. Aim of this paper was to emphasize that an interdisciplinary periodontal-orthodontic treatment could be beneficial even in a case that seemed hopelessly. A typical case of an adult patient with extensive bone loss due to periodontal disease, occlusal trauma caused by dental malpositions, spacing due to early loss of teeth in the lateral segments and pathologic tooth migration will be presented. The orthodontic treatment was initiated at 3 months after the stabilization of the periodontal therapy and was done with a fixed appliance. During the orthodontic stage periodontal maintenance visits continued at 2-month intervals. The therapy of"black triangles" occurred due to the loss of interdental gingiva was done by stripping followed by a space-closure procedure. A permanent retainer was applied. Benefits and problems of the comprehensive periodontal-orthodontic therapy and treatment protocols will be presented. In conclusion the interdisciplinary therapy of this patient, with a good compliance, was beneficial, improved esthetics, the periodontal status, the ability of the patient to clean the teeth and also led to best position of the abutments for optimal placement of prosthetic reconstructions.


IL-10 mediates sigma 1 receptor-dependent suppression of antitumor immunity.
Sigma receptors are unique endoplasmic reticulum proteins that mediate signaling for a variety of drugs. We determined the effect of sigma(1) receptor agonists on immune responses in a syngeneic lung cancer model. Sigma(1) receptor agonists, including cocaine, up-regulated splenocyte IL-10 mRNA and protein production in vitro in a sigma receptor-dependent, pertussis toxin-sensitive manner. In vivo, sigma(1) receptor agonists promoted tumor growth and induced IL-10 at the tumor site. Increased tumor growth was prevented by administration of specific Abs to IL-10 or by administration of specific sigma(1) receptor antagonists. We report that sigma(1) receptor ligands, including cocaine, augment tumor growth through an IL-10 dependent mechanism.


Ni nanotube array-based electrodes by electrochemical alloying and de-alloying for efficient water splitting.
The design of cost-efficient earth-abundant catalysts with superior performance for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is extremely important for future renewable energy production. Herein, we report a facile strategy for constructing Ni nanotube arrays (NTAs) on a Ni foam (NF) substrate through cathodic deposition of NiCu alloy followed by anodic stripping of metallic Cu. Based on Ni NTAs, the as-prepared NiSe2 NTA electrode by NiSe2 electrodeposition and the NiFeOx NTA electrode by dipping in Fe3+ solution exhibit excellent HER and OER performance in alkaline conditions. In these systems, Ni NTAs act as a binder-free multifunctional inner layer to support the electrocatalysts, offer a large specific surface area and serve as a fast electron transport pathway. Moreover, an alkaline electrolyzer has been constructed using NiFeOx NTAs as the anode and NiSe2 NTAs as the cathode, which only demands a cell voltage of 1.78 V to deliver a water-splitting current density of 500 mA cm-2, and demonstrates remarkable stability during long-term electrolysis. This work provides an attractive method for the design and fabrication of nanotube array-based catalyst electrodes for highly efficient water-splitting.


Comparative study between latex agglutination and indirect immunofluorescent antibody tests in diagnosis of toxoplasmosis.
The latex agglutination test (Toxolatex) was compared with the indirect immunofluorescent antibody test (IFAT) in investigating one hundred and fifty human sera. Both techniques showed 90.7% agreement. The mean titre of each test was significantly higher in cases with fever or lymphadenopathy than cases without these manifestations. It was concluded that the latex test provides a rapid and simple test in toxoplasmosis that can be used to exclude negative cases as nearly no false negative results were obtained. However, positive cases by latex agglutination should be confirmed and quantitated by another standardized technique.


General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL.
Monoclonal B-cell lymphocytosis (MBL) is classified as chronic lymphocytic leukemia (CLL)-like, atypical CLL, and CD5(-) MBL. The number of B cells per microliter divides CLL-like MBL into MBL associated with lymphocytosis (usually detected in a clinical setting) and low-count MBL detected in the general population (usually identified during population screening). After a median follow-up of 34 months we reevaluated 76 low-count MBLs with 5-color flow cytometry: 90% of CLL-like MBL but only 44.4% atypical CLL and 66.7% CD5(-) MBL persisted over time. Population-screening CLL-like MBL had no relevant cell count change, and none developed an overt leukemia. In 50% of the cases FISH showed CLL-related chromosomal abnormalities, including monoallelic or biallelic 13q deletions (43.8%), trisomy 12 (1 case), and 17p deletions (2 cases). The analysis of the T-cell receptor β (TRBV) chains repertoire showed the presence of monoclonal T-cell clones, especially among CD4(high)CD8(low), CD8(high)CD4(low) T cells. TRBV2 and TRBV8 were the most frequently expressed genes. This study indicates that (1) the risk of progression into CLL for low-count population-screening CLL-like MBL is exceedingly rare and definitely lower than that of clinical MBL and (2) chromosomal abnormalities occur early in the natural history and are possibly associated with the appearance of the typical phenotype.


Construction of a gene inactivation library for Bovine herpesvirus 1 using infectious clone technology.
The application of infectious clone technology to herpesvirus biology has revolutionized the study of these viruses. Previously the ability to manipulate these large DNA viruses was limited to methods dependent on homologous recombination in mammalian cells. However, the construction of herpesvirus infectious clones using bacterial artificial chromosome vectors has permitted the application of powerful bacterial genetics for the manipulation of these viruses. A method is described for the construction and characterization of a gene inactivation library of Bovine herpesvirus 1 using an infectious clone. The method utilizes transposon-mediated gene inactivation, which permits gene inactivation without any prior knowledge of the viral genomic sequence. Furthermore, as the genetic manipulation is performed in bacteria the inactivation of those viral genes that are essential for viral replication is also possible. The method described here can be readily applied to any herpesvirus clone and provides the tools for precise characterization of all the genes contained within a herpesvirus genome.


Protective efficacy of hGSTM1-1 against B[a]P and (+)- or (-)-B[a]P-7,8-dihydrodiol cytotoxicity, mutagenicity, and macromolecular adducts in V79 cells coexpressing hCYP1A1.
Transgenic cell lines were constructed to study the dynamics of competition between activation versus detoxification of benzo[a]pyrene (B[a]P) or B[a]P-7,8-dihydrodiol metabolites. Stably transfected V79MZ cells expressing human cytochrome P4501A1 (hCYP1A1) alone or in combination with human glutathione-S-transferase M1 (hGSTM1) were used to determine how effectively this GST isozyme protects against cytotoxic, genotoxic, and mutagenic effects of B[a]P or the enantiomeric dihydrodiol metabolites (+)-benzo[a]pyrene-7,8-dihydrodiol ((+)-B[a]P-7,8-diol) and (-)-benzo[a]pyrene-7,8-dihydrodiol ((-)-B[a]P-7,8-diol). Expression of hGSTM1 in the presence of hCYP1A1 conferred significant 8.5-fold protection against B[a]P-induced cytotoxicity, but protection against cytotoxicity of either B[a]P-7,8-diol enantiomer was not significant. Mutagenicity of B[a]P at the hprt locus was dose and time dependent in cells that expressed hCYP1A1. Mutagenicity of B[a]P was reduced by 21-32% and mutagenicity induced by the B[a]P-7,8-diols was reduced 20-58% in cells further modified to coexpress hGSTM1-1 compared to cells expressing hCYP1A1 alone. Expression of hGSTM1-1 reduced adducts in total cellular macromolecules by twofold, in good correlation with the reduction in B[a]P mutagenicity. These results indicate that while hGSTM1-1 effectively protects against hCYP1A1-mediated cytotoxicity of B[a]P, a significant fraction of the mutagenicity that results from activation of B[a]P and its 7,8-dihydrodiol metabolites by hCYP1A1 is derived from B[a]P metabolites that are not detoxified by hGSTM1.


Kallikreins and proteinase-mediated signaling: proteinase-activated receptors (PARs) and the pathophysiology of inflammatory diseases and cancer.
Proteinases such as thrombin and trypsin can affect tissues by activating a novel family of G protein-coupled proteinase-activated receptors (PARs 1-4) by exposing a 'tethered' receptor-triggering ligand (TL). Work with synthetic TL-derived PAR peptide sequences (PAR-APs) that stimulate PARs 1, 2 and 4 has shown that PAR activation can play a role in many tissues, including the gastrointestinal tract, kidney, muscle, nerve, lung and the central and peripheral nervous systems, and can promote tumor growth and invasion. PARs may play roles in many settings, including cancer, arthritis, asthma, inflammatory bowel disease, neurodegeneration and cardiovascular disease, as well as in pathogen-induced inflammation. In addition to activating or disarming PARs, proteinases can also cause hormone-like effects via PAR-independent mechanisms, such as activation of the insulin receptor. In addition to proteinases of the coagulation cascade, recent data suggest that members of the family of kallikrein-related peptidases (KLKs) represent endogenous PAR regulators. In summary: (1) proteinases are like hormones, signaling in a paracrine and endocrine manner via PARs or other mechanisms; (2) KLKs must now be seen as potential hormone-like PAR regulators in vivo; and (3) PAR-regulating proteinases, their target PARs, and their associated signaling pathways appear to be novel therapeutic targets.


Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study.
Estimations of Lyme disease incidence rates in the United Kingdom vary. There is evidence that this disease is associated with fatigue in its early stage but reports are contradictory as far as long-term fatigue is concerned. A population-based historical cohort study was conducted on patients treated in general practices contributing to IQVIA Medical Research Data: 2,130 patients with a first diagnosis of Lyme disease between 2000 and 2018 and 8,510 randomly-sampled patients matched by age, sex, and general practice, followed-up for a median time of 3 years and 8 months. Main outcome measure was time to consultation for (1) any fatigue-related symptoms or diagnosis; or (2) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Adjusted hazard ratios (HRs) were estimated from Cox models. Average incidence rate for Lyme disease across the UK was 5.18 per 100,000 person-years, increasing from 2.55 in 2000 to 9.33 in 2018. In total, 929 events of any types of fatigue were observed, leading to an incidence rate of 307.90 per 10,000 person-years in the Lyme cohort (282 events) and 165.60 in the comparator cohort (647 events). Effect of Lyme disease on any subsequent fatigue varied by index season: adjusted HRs were the highest in autumn and winter with 3.14 (95%CI: 1.92-5.13) and 2.23 (1.21-4.11), respectively. For ME/CFS, 17 events were observed in total. Incidence rates were 11.76 per 10,000 person-years in Lyme patients (12 events) and 1.20 in comparators (5 events), corresponding to an adjusted HR of 16.95 (5.17-55.60). Effects were attenuated 6 months after diagnosis but still clearly visible. UK primary care records provided strong evidence that Lyme disease was associated with subsequent fatigue and ME/CFS. Albeit weaker on the long-term, these effects persisted beyond 6 months, suggesting patients and healthcare providers should remain alert to fatigue symptoms months to years following Lyme disease diagnosis.


Aging of myelinating glial cells predominantly affects lipid metabolism and immune response pathways.
Both the central and the peripheral nervous systems are prone to multiple age-dependent neurological deficits, often attributed to still unknown alterations in the function of myelinating glia. To uncover the biological processes affected in glial cells by aging, we analyzed gene expression of the Schwann cell-rich mouse sciatic nerve at 17 time points throughout life, from day of birth until senescence. By combining these data with the gene expression data of myelin mouse mutants carrying deletions of either Pmp22, SCAP, or Lpin1, we found that the majority of age-related transcripts were also affected in myelin mutants (54.4%) and were regulated during PNS development (59.5%), indicating a high level of overlap in implicated molecular pathways. The expression profiles in aging copied the direction of transcriptional changes observed in neuropathy models; however, they had the opposite direction when compared with PNS development. The most significantly altered biological processes in aging involved the inflammatory/immune response and lipid metabolism. Interestingly, both these pathways were comparably changed in the aging optic nerve, suggesting that similar biological processes are affected in aging of glia-rich parts of the central and peripheral nervous systems. Our comprehensive comparison of gene expression in three distinct biological conditions including development, aging, and myelin disease thus revealed a previously unanticipated relationship among themselves and identified lipid metabolism and inflammatory/immune response pathways as potential therapeutical targets to prevent or delay so far incurable age-related and inherited forms of neuropathies.


[Amylase/creatinine clearance in the differential diagnosis of acute pancreatitis].
In the Department of Gastroenterology of "El Centro Médico La Raza, I.M.S.S.", three groups of 20 patients were studied: group I with acute pancreatitis; group II with acute abdomen without pancreatic pathology, in both groups the diagnosis was demonstrated surgically or in necropsy; group III was formed by 20 normal voluntary persons, and served as control. A 4 per cent amilase/creatinine clearence index was considered as a high normal value. The diagnosis accuracy in group I was 90 per cent. In group II there was five false positive results, in 80 per cent of the cases the results of the amilase/creatinine clearence index was found within normal limits. The difference between group I and group III was significant (P less than 0.002). The difference between group I and group II was also significant (P less than 0.05). There was no significant difference between group II and group III. The amilase/creatinine clearence index has the advantage that it can be obtained with only one blood and urine samples taken simultaneously. We concluded that amilase/creatine clearence index is useful for the differential diagnosis in acute pancreatitis and that is probably due to an alteration in the tubular renal reabsorption.


Nephrotic syndrome in the first three months of life.
When the nephrotic syndrome develops within the first 3 months of life it is considered as congenital. In a review, different types of renal diseases are found behind the syndrome in early infancy. A classification of these is proposed, based on clinicopathology. Five classes with subgroups are described, and the necessity of recognizing these for prognosis, therapy and genetic counselling is emphasized.


Single-dose pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment<sup/>.
This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUClast; unbound) in mild, moderate, and severe cohorts was 4.1-, 9.8-, 13.4-fold higher, respectively. Terminal half-life trended slightly longer in moderately and severely impaired subjects, but risk of accumulation on repeated dosing appears negligible as half-life did not exceed 10 h. Based on observed effects on exposure, reduced doses are recommended for patients with mild and moderate liver impairment (Child-Pugh Class A and B), whereas 140 mg is considered too high for severely impaired patients (Class-C). A single dose of 140 mg was well tolerated in this study (NCT01767948).


Immunoassay using probe-labelling immunogold nanoparticles with silver staining enhancement via surface-enhanced Raman scattering.
This paper reports a novel immunoassay based on surface-enhanced Raman scattering (SERS) and immunogold labelling with silver staining enhancement. Immunoreactions between immunogold colloids modified by a Raman-active probe molecule (e.g., 4-mercaptobenzoic acid) and antigens, which were captured by antibody-assembled chips such as silicon or quartz, were detected via SERS signals of Raman-active probe molecule. All the self-assembled steps were subjected to the measurements of ultraviolet-visible (UV-vis) spectra to monitor the formation of a sandwich structure onto a substrate. The immunoassay was performed by a sandwich structure consisting of three layers. The first layer was composed of immobilized antibody molecules of mouse polyclonal antibody against Hepatitis B virus surface antigen (PAb) on a silicon or quartz substrate. The second layer was the complementary Hepatitis B virus surface antigen (Antigen) molecules captured by PAb on the substrate. The third layer was composed of the probe-labelling immunogold nanoparticles, which were modified by mouse monoclonal antibody against Hepatitis B virus surface antigen (MAb) and 4-mercaptobenzoic acid (MBA) as the Raman-active probe on the surface of gold colloids. After silver staining enhancement, the antigen is identified by a SERS spectrum of MBA. A working curve of the intensity of a SERS signal at 1585 cm(-1) due to the [small nu](8a) aromatic ring vibration of MBA versus the concentration of analyte (Antigen) was obtained and the non-optimized detection limit for the Hepatitis B virus surface antigen was found to be as low as 0.5 [micro sign]g mL(-1).


Fourth joint meeting of the American Urological Association and the Japanese Urological Association Specialty Society program at the 104th annual meeting of the American Urological Association at Chicago 2009.
We are heartily grateful for the warm support of all of the people concerned, including the moderators and panelists of both societies for giving us the opportunity to hold the 4th American Urological Association/Japanese Urological Association (AUA/JUA) Joint Meeting, held once again at the 104th Annual Meeting of the American Urological Association (25-30 April 2009, Chicago, Illinois, USA). 2009 is a memorable year, being the start of new collaborations between AUA and JUA. The JUA in collaboration with AUA is promoting an academic exchange program whereby outstanding and promising Japanese and American junior faculty members will be given the opportunity to work in the USA and Japan for one month. The program not only allows the sharing of knowledge and experience, but is designed to foster a closer alliance between the AUA and JUA, and assists in identifying future leaders within both organizations. The JUA will have an exhibit booth at the AUA annual meeting, promoting our new joint activities. The Journal of Urology and International Journal of Urology will share reviewers. The JUA will participate in developing AUA guidelines. With all of these activities, the JUA hopes it will provide greater opportunities to young Japanese urologists to participate in educational projects in the US. We would like to thank Professor Robert C. Flanigan, the Secretary General of AUA, Professor Glenn M. Preminger, the Chairman of the AUA Office of Education and the staff of AUA and JUA for supporting our program. We hope to keep holding the joint meeting and have plenty of ideas on themes and forums. We believe that this international program helps to establish a closer relationship between JUA and AUA in the scientific field.


Identification of sperm morphometric subpopulations in two different portions of the boar ejaculate and its relation to postthaw quality.
A statistical approach using sequentially principal component analysis (PCA), clustering, and discriminant analyses was developed to identify sperm morphometric subpopulations in well-defined portions of the fresh boar ejaculate. Semen was obtained as 2 portions (the first 10 mL of the sperm-rich fraction and the rest of the ejaculate, respectively) and frozen using a conventional protocol. Before freezing, an aliquot was used for computer-assisted sperm morphometry analysis (ASMA). Postthaw quality was evaluated using computer-assisted sperm analysis (CASA), and an annexin-V/PI assay evaluated sperm membranes. The PCA revealed that 3 variables represented more than 78% of the cumulative variance in sperm subpopulations. The clustering and discriminant analyses, based on 5780 individual spermatozoa, revealed the existence of 4 sperm subpopulations. The relative percentage of these subpopulations varied between boar and ejaculate portions. Linear regression models based on measured morphometric characteristics could account for up to 36% of the percentage of intact sperm membranes postthaw. The ASMA protocol used in our study was useful to detect subtle morphometric differences between spermatozoa, and the combination of this analysis with a multivariate statistical procedure gave new information on the biological characteristics of boar ejaculates that is not given by conventional sperm analysis.


Missed opportunities for HIV testing among patients newly presenting for HIV care at a Swiss university hospital: a retrospective analysis.
To determine the frequency of missed opportunities (MOs) among patients newly diagnosed with HIV, risk factors for presenting MOs and the association between MOs and late presentation (LP) to care. Retrospective analysis. HIV outpatient clinic at a Swiss tertiary hospital. Patients aged ≥18 years newly presenting for HIV care between 2010 and 2015. Number of medical visits, up to 5 years preceding HIV diagnosis, at which HIV testing had been indicated, according to Swiss HIV testing recommendations. A visit at which testing was indicated but not performed was considered an MO for HIV testing. Complete records were available for all 201 new patients of whom 51% were male and 33% from sub-Saharan Africa. Thirty patients (15%) presented with acute HIV infection while 119 patients (59%) were LPs (CD4 counts <350 cells/mm3 at diagnosis). Ninety-four patients (47%) had presented at least one MO, of whom 44 (47%) had multiple MOs. MOs were more frequent among individuals from sub-Saharan Africa, men who have sex with men and patients under follow-up for chronic disease. MOs were less frequent in LPs than non-LPs (42.5% vs 57.5%, p=0.03). At our centre, 47% of patients presented at least one MO. While our LP rate was higher than the national figure of 49.8%, LPs were less likely to experience MOs, suggesting that these patients were diagnosed late through presenting late, rather than through being failed by our hospital. We conclude that, in addition to optimising provider-initiated testing, access to testing must be improved among patients who are unaware that they are at HIV risk and who do not seek healthcare.


Regional material flow accounting and environmental pressures: the Spanish case.
This paper explores potential contributions of regional material flow accounting to the characterization of environmental pressures. With this aim, patterns of material extraction, trade, consumption, and productivity for the Spanish regions were studied within the 1996-2010 period. The main methodological variation as compared to whole-country based approaches is the inclusion of interregional trade, which can be separately assessed from the international exchanges. Each region was additionally profiled regarding its commercial exchanges with the rest of the regions and the rest of the world and the related environmental pressures. Given its magnitude, interregional trade is a significant source of environmental pressure. Most of the exchanges occur across regions and different extractive and trading patterns also arise at this scale. These differences are particularly great for construction minerals, which in Spain represent the largest share of extracted and consumed materials but do not cover long distances, so their impact is visible mainly at the regional level. During the housing bubble, economic growth did not improve material productivity.


Host phylogeny and specialisation in parasitoids.
The host range of insect parasitoids and herbivores is influenced by both preference-related traits which mediate host choice behaviour, and performance-related traits which mediate the physiological suitability of the consumer-resource interaction. In a previous study, we characterised the influence of preference- and performance-related traits on the host range of the aphid parasitoid Binodoxys communis (Hymenoptera: Braconidae) and herein we build upon those data sets by mapping a series of these traits onto the phylogeny of the (aphid) host species. We found a strong effect of host phylogeny on overall parasitoid reproduction on the 20 host species tested, but no effect of the phylogeny of host plants of the aphids. We found an effect of aphid phylogeny on host acceptance and sting rates (related to preference) from behavioural observations and for pupal survivorship (related to performance), showing that both classes of traits show phylogenetic conservatism with respect to host species.


A Digital Health Tool to Understand and Prevent Cannabis-Impaired Driving Among Youth: A Cross-sectional Study of Responses to a Brief Intervention for Cannabis Use.
Cannabis legalization has raised concern about an increased risk of cannabis-impaired driving, particularly among youth. Youth advocates and policy makers require cost-effective tools to target educational resources to promote responsible cannabis use. The objective of this paper is threefold. First, it describes how a youth advocacy organization disseminated a low-cost digital brief intervention to educate and inform young people about responsible cannabis use. Second, it illustrates how digital tools can help promote understanding about attitudes and behaviors toward cannabis while simultaneously offering tailored education. Finally, this paper contributes to examining behavioral factors associated with youth cannabis-impaired driving by quantifying relationships between cannabis users' willingness to drive impaired and self-reported demographic and behavioral factors. This paper analyzed data from 1110 completed Check Your Cannabis (CYC) brief interventions between March 2019 and October 2020. The CYC asks respondents a brief set of questions about their cannabis use and their personal beliefs and behaviors. Respondents receive comprehensive feedback about their cannabis use and how it compares with others. They also receive a summary of reported behaviors with brief advice. An ordered probit model was used to test relationships between cannabis use, demographics, and driving behaviors to gain further insights. The vast majority (817/1110, 73.6%) of respondents reported using cannabis. However, a much smaller share of respondents reported problems associated with their cannabis use (257/1110, 23.2%) or driving after cannabis use (342/1110, 30.8%). We found statistically significant relationships between driving after cannabis use and age; Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) risk score; and polysubstance use. However, we did not find gender to be a significant determinant of driving after cannabis use. We estimated that every 10-point increase in the ASSIST score increased the probability of sometimes driving after cannabis use by 7.3% (P<.001). Relative to respondents who reported never drinking alcohol or using other substances with cannabis, those who sometimes drink or use other substances with cannabis were 13% (P<.001) more likely to sometimes or always drive after using cannabis. The digital health tool cost the youth advocacy organization approximately Can $0.90 (US $0.71) per use. Due to the tool's unlimited use structure, the per-use cost would further decrease with increased use by the organization's target population. Based on our results, public health campaigns and other interventions may consider tailoring resources to frequent cannabis users, youth with high ASSIST scores, and those with polysubstance abuse. The cost-effectiveness of delivering digital brief interventions with unlimited use is attractive, as increased use decreases the per-user cost. Further research examining the efficacy of digital health interventions targeting problematic cannabis use is required.


Ventilation rates and activity levels of juvenile jumbo squid under metabolic suppression in the oxygen minimum zone.
The Humboldt (jumbo) squid, Dosidicus gigas, is a part-time resident of the permanent oxygen minimum zone (OMZ) in the Eastern Tropical Pacific and, thereby, it encounters oxygen levels below its critical oxygen partial pressure. To better understand the ventilatory mechanisms that accompany the process of metabolic suppression in these top oceanic predators, we exposed juvenile D. gigas to the oxygen levels found in the OMZ (1% O(2), 1 kPa, 10 °C) and measured metabolic rate, activity cycling patterns, swimming mode, escape jet (burst) frequency, mantle contraction frequency and strength, stroke volume and oxygen extraction efficiency. In normoxia, metabolic rate varied between 14 and 29 μmol O(2) g(-1) wet mass h(-1), depending on the level of activity. The mantle contraction frequency and strength were linearly correlated and increased significantly with activity level. Additionally, an increase in stroke volume and ventilatory volume per minute was observed, followed by a mantle hyperinflation process during high activity periods. Squid metabolic rate dropped more than 75% during exposure to hypoxia. Maximum metabolic rate was not achieved under such conditions and the metabolic scope was significantly decreased. Hypoxia changed the relationship between mantle contraction strength and frequency from linear to polynomial with increasing activity, indicating that, under hypoxic conditions, the jumbo squid primarily increases the strength of mantle contraction and does not regulate its frequency. Under hypoxia, jumbo squid also showed a larger inflation period (reduced contraction frequency) and decreased relaxed mantle diameter (shortened diffusion pathway), which optimize oxygen extraction efficiency (up to 82%/34%, without/with consideration of 60% potential skin respiration). Additionally, they breathe 'deeply', with more powerful contractions and enhanced stroke volume. This deep-breathing behavior allows them to display a stable ventilatory volume per minute, and explains the maintenance of the squid's cycling activity under such O(2) conditions. During hypoxia, the respiratory cycles were shorter in length but increased in frequency. This was accompanied by an increase in the number of escape jets during active periods and a faster switch between swimming modes. In late hypoxia (onset ~170 ± 10 min), all the ventilatory processes were significantly reduced and followed by a lethargic state, a behavior that seems closely associated with the process of metabolic suppression and enables the squid to extend its residence time in the OMZ.


Cathepsin G-dependent platelet stimulation by activated polymorphonuclear leukocytes and its inhibition by antiproteinases: role of P-selectin-mediated cell-cell adhesion.
Human PMN stimulated by fMLP are able to activate coincubated, autologous platelets. Cathepsin G, a neutral serine protease stored in the azurophilic granules of PMN, is the major platelet activator in this system. We previously proposed that shear-induced close PMN-platelet contact creates the conditions for which cathepsin G activity on platelets is protected against antiproteinases. The aim of this study was to investigate the adhesive mechanisms, possibly creating between PMN and platelet membranes the microenvironment in which cathepsin G, discharged from stimulated PMN onto adherent platelets, is protected against antiproteinases. Microscopic examination showed that under conditions of high shear, 71.3% +/- 6.1% of PMN were associated to platelets forming small clumps. This percentage decreased to 10% +/- 2% and 13% +/- 4%, respectively, in the presence of an inhibitory antibody to P-selectin or 20 mmol/L mannose-1-phosphate and to 10.8% +/- 3.7% when cells were not stirred. Similarly, PMN pretreatment with neuraminidase abolished PMN binding to platelets. These results indicate that P-selectin mediates PMN-platelet adhesion occurring before PMN stimulation. Prevention of PMN-platelet contact significantly potentiated the inhibitory effect of alpha 1-protease inhibitor on subsequent cathepsin G-induced platelet serotonin release. Because anti-P-selectin antibody, mannose-1-phosphate, and neuraminidase treatment of PMN did not modify PMN-induced platelet activation in the absence of antiproteinases, it is suggested that P-selectin-mediated PMN-platelet adhesion results in the formation of a sequestered microenvironment between cell membranes, in which higher amounts of antiproteinases are required to prevent the activity of released cathepsin G. These data add a new functional role to P-selectin-mediated PMN-platelet adhesion that could be important in vivo because of the presence of antiproteinases in plasma.


Trends in Nutrient Content of Children's Menu Items in U.S. Chain Restaurants.
Restaurant food is widely consumed by children and is associated with poor diet quality. Although many restaurants have made voluntary commitments to improve the nutritional quality of children's menus, it is unclear whether this has led to meaningful changes. Nutrients in children's menu items (n=4,016) from 45 chain restaurants were extracted from the nutrition information database MenuStat. Bootstrapped mixed linear models estimated changes in mean calories, saturated fat, and sodium in children's menu items between 2012 and 2013, 2014, and 2015. Changes in nutrient content of these items over time were compared among restaurants participating in the Kids LiveWell initiative and non-participating restaurants. Types of available children's beverages were also examined. Data were analyzed in 2016. There was a significant increase in mean beverage calories from 2012 to 2013 (6, 95% CI=0.8, 10.6) and from 2012 to 2014 (11, 95% CI=3.7, 18.3), but no change between 2012 and 2015, and no differences in nutrient content of other items over time. Restaurants participating in Kids LiveWell reduced entrée calories between 2012 and 2013 (-24, 95% CI= -40.4, -7.2) and between 2012 and 2014 (-40, 95% CI= -68.1, -11.4) and increased side dish calories between 2012 and 2015 (49, 95% CI=4.6, 92.7) versus non-participating restaurants. Sugar-sweetened beverages consistently constituted 80% of children's beverages, with soda declining and flavored milks increasing between 2012 and 2015. Results suggest little progress toward improving nutrition in children's menu items. Efforts are needed to engage restaurants in offering healthful children's meals.


New approaches to the treatment of nephropathy in diabetes.
In individuals with diabetes, the presence and severity of kidney disease adversely affects their well-being, significantly contributes to burden of morbidity and increases their risk of a premature death. The efficiency of current management strategies for the treatment of diabetic nephropathy, even in optimal combination, is partial, at best. There remains an unmet need for additional renoprotective interventions in patients with diabetes. This review presents a comprehensive summary of some of the ?new contenders? for the treatment of diabetic nephropathy that have been tested or are being tested in randomised clinical trials in patients with diabetes with a predefined renal endpoint, but are not currently indicated for renoprotective therapy. Many of these drugs have been in clinical use for other indications, or initially developed for other purposes. Although substantial progress has been made towards understanding the pathogenesis of diabetic nephropathy, at present there are no new drugs that provide the solutions we want for our patients. Even when used in combination with standard medical care, current data indicate that renal complications are at best only modestly reduced, at the expense of additional pill burden and exposure to off-target effects. Given the ever-growing burden of diabetic kidney disease, there is a substantial opportunity for better and more targeted (?smarter?) therapeutic interventions in this context.


Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties?
Macrocycles are ideal in efforts to tackle "difficult" targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class. A significant number (N = 34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging toward 250 Å(2). Moreover, insight from a group of "de novo designed" oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers or if macrocycles will open up novel oral druggable space.


A new integrated behavioural intervention for knee osteoarthritis: development and pilot study.
Exercise-based approaches have been a cornerstone of physiotherapy management of knee osteoarthritis for many years. However, clinical effects are considered small to modest and the need for continued adherence identified as a barrier to clinical efficacy. While exercise-based approaches focus on muscle strengthening, biomechanical research has identified that people with knee osteoarthritis over activate their muscles during functional tasks. Therefore, we aimed to create a new behavioural intervention, which integrated psychologically informed practice with biofeedback training to reduce muscle overactivity, and which was suitable for delivery by a physiotherapist. Through literature review, we created a framework linking theory from pain science with emerging biomechanical concepts related to overactivity of the knee muscles. Using recognised behaviour change theory, we then mapped a set of intervention components which were iteratively developed through ongoing testing and consultation with patients and physiotherapists. The underlying framework incorporated ideas related to central sensitisation, motor responses to pain and also focused on the idea that increased knee muscle overactivity could result from postural compensation. Building on these ideas, we created an intervention with five components: making sense of pain, general relaxation, postural deconstruction, responding differently to pain and functional muscle retraining. The intervention incorporated a range of animated instructional videos to communicate concepts related to pain and biomechanical theory and also used EMG biofeedback to facilitate visualization of muscle patterns. User feedback was positive with patients describing the intervention as enabling them to "create a new normal" and to be "in control of their own treatment." Furthermore, large reductions in pain were observed from 11 patients who received a prototype version of the intervention. We have created a new intervention for knee osteoarthritis, designed to empower individuals with capability and motivation to change muscle activation patterns and beliefs associated with pain. We refer to this intervention as Cognitive Muscular Therapy. Preliminary feedback and clinical indications are positive, motivating future large-scale trials to understand potential efficacy. It is possible that this new approach could bring about improvements in the pain associated with knee osteoarthritis without the need for continued adherence to muscle strengthening programmes. ISRCTN51913166 (Registered 24-02-2020, Retrospectively registered).


Synthesis and base-pairing properties of the nuclease-resistant alpha-anomeric dodecaribonucleotide alpha-[r(UCUUAACCCACA)].
The non natural oligoribonucleotide alpha-[r(UCUUAACCCACA)] consisting exclusively of alpha-anomeric ribonucleoside units was synthesized according to the phosphoramidite methodology and the solid support technology. For this purpose, the base-protected alpha-ribonucleosides were synthesized and converted into their O-methylphosphoramidites. Assembling was carried out on a DNA synthesizer with an average efficiency of 97% per step. Base composition of this nuclease-resistant alpha-RNA strand was ascertained after chemical and enzymatic hydrolysis and HPLC analysis of the hydrolysate. Whereas no spectroscopic evidence of base pairing was found above 0 degrees C between alpha-[r(UCUUAACCCACA)] and beta-[d(TGTGGGTTAAGA)], a clear UV absorbance transition (Tm 25.5 degrees C) was observed during the hybridization of the same alpha-RNA strand with beta-[d(AGAATTGGGTGT)]. In this latter case, the mixing curve titration suggests formation at low temperature of a triplex involving two alpha-RNA and one beta-DNA strands. Moreover, this alpha-decaribonucleotide complementary in parallel orientation of the splice receptor of HIV-1 tat mRNA was found to inhibit (10 microM less than ED50 less than 20 microM), with apparent lack of sequence specificity, the de novo HIV-1 infection in cultured cells.


Evidence of abundant stop codon readthrough in Drosophila and other metazoa.
While translational stop codon readthrough is often used by viral genomes, it has been observed for only a handful of eukaryotic genes. We previously used comparative genomics evidence to recognize protein-coding regions in 12 species of Drosophila and showed that for 149 genes, the open reading frame following the stop codon has a protein-coding conservation signature, hinting that stop codon readthrough might be common in Drosophila. We return to this observation armed with deep RNA sequence data from the modENCODE project, an improved higher-resolution comparative genomics metric for detecting protein-coding regions, comparative sequence information from additional species, and directed experimental evidence. We report an expanded set of 283 readthrough candidates, including 16 double-readthrough candidates; these were manually curated to rule out alternatives such as A-to-I editing, alternative splicing, dicistronic translation, and selenocysteine incorporation. We report experimental evidence of translation using GFP tagging and mass spectrometry for several readthrough regions. We find that the set of readthrough candidates differs from other genes in length, composition, conservation, stop codon context, and in some cases, conserved stem-loops, providing clues about readthrough regulation and potential mechanisms. Lastly, we expand our studies beyond Drosophila and find evidence of abundant readthrough in several other insect species and one crustacean, and several readthrough candidates in nematode and human, suggesting that functionally important translational stop codon readthrough is significantly more prevalent in Metazoa than previously recognized.


Reorganization of brain activity for multiple internal models after short but intensive training.
Internal models are neural mechanisms that can mimic the input-output properties of controlled objects. Our studies have shown that: 1) an internal model for a novel tool is acquired in the cerebellum (Imamizu et al., 2000); 2) internal models are modularly organized in the cerebellum (Imamizu et al., 2003); 3) their outputs are sent to the premotor regions after learning (Tamada et al., 1999); and 4) the prefrontal and parietal regions contribute to the blending of the outputs (Imamizu et al., 2004). Here, we investigated changes in global neural networks resulting from the acquisition of a new internal model. Human subjects manipulated three types of rotating joystick whose cursor appeared at a position rotated 60 degrees, 110 degrees, or 160 degrees around the screen's center. In a pre-test after long-term training (5 days) for the 60 degrees and 160 degrees joysticks, brain activation was scanned during manipulation of the three joysticks. The subjects were then trained for the 110 degrees for only 25 min. In a post-test, activation was scanned using the same method as the pre-test. Comparisons of the post-test to the pre-test revealed that the volume of activation decreased in most of the regions where activation for the three rotations was observed. However, there was an increase in volume at a marginally significant level (p < .08) only in the inferior-lateral cerebellum and only for the 110 degrees joystick. In the cerebral cortex, activation related to 110 degrees decreased in the prefrontal and parietal regions but increased in the premotor and supplementary motor area (SMA) regions. These results can be explained by a model in which outputs of the 60 degrees and 160 degrees internal models are blended by prefrontal and parietal regions to cope with the novel 110 degrees joystick before the 25-minute training; after the acquisition within the cerebellum of an internal model for the 110 degrees, output is directly sent to the premotor and SMA regions, and activation in these regions increases.


Influence of the occlusion effect over the prediction-error feedback cancellation system in hearing aids.
This work presents a theoretical analysis of the prediction-error method-based adaptive feedback canceller in hearing aid applications. The studied scene takes into account the occlusion effect caused by the partial or complete closing of the ventilation opening. Such a situation may occur in high gain applications to avoid undesired whistling. Deterministic recursive equations and steady-state conditions were derived for the mean weight behaviour of the predictor and the adaptive filter. The expected theoretical predictions were compared to Monte Carlo simulations, showing very accurate agreement. The simulation results suggest the steady-state performance of this feedback canceller is not affected by the occlusion effect, however the occlusion is still perceived, being annoying to the user.


CA-125: a marker for persistent gestational trophoblastic disease?
The objective was to determine whether CA-125 levels have any clinical utility in gestational trophoblastic disease. Fifty-one patients with a pathologically confirmed diagnosis of complete hydatidiform mole had a CA-125 level obtained prior to suction molar evacuation. Data were analyzed using chi 2 and Mann-Whitney U test. CA-125 levels were twice as high in persistent gestational trophoblastic disease than those in complete hydatidiform molar patients (85.9 vs 48.3 U/ml; P = 0.004). CA-125 levels were independent of age, gravidity, weeks of amenorrhea, or presence of thecal-luteal cysts. CA-125 levels appear to be of value in predicting which molar patients will develop persistent disease.


Salvage reirradiation for locoregional failure after radiation therapy for prostate cancer: who, when, where and how?
Even in the current era of dose-escalated radiotherapy for prostate cancer, biochemical recurrence is not uncommon. Furthermore, biochemical failure is not specific to the site of recurrence. One of the major challenges in the management of prostate cancer patients with biochemical failure after radiotherapy is the early discrimination between those with locoregional recurrence only and those with metastatic disease. While the latter are generally considered incurable, patients with locoregional disease may benefit from emerging treatment options. Ultimately, the objective of salvage therapy is to control disease while ensuring minimal collateral damage, thereby optimizing both cancer and toxicity outcomes. Advances in functional imaging, including multiparametric prostate MRI, abdominopelvic lymphangio-MRI, sentinel node SPECT-CT and/or whole-body PET/CT have paved the way for salvage radiotherapy in patients with local recurrence, microscopic nodal disease limited to the pelvis or oligometastatic disease. These patients may be considered for salvage reirradiation using different techniques: prostate low-dose or high-dose rate brachytherapy, pelvic and/or lomboaortic image-guided radiotherapy with elective nodal irradiation, focal nodal or bone stereotactic body radiation therapy (SBRT). An individualized approach is recommended. The decision about which treatment, if any, to use will be based on the initial characteristics of the disease, relapse patterns and the natural history of the rising prostate specific antigen (PSA). Preliminary results suggest that more than 50% of patients who have undergone salvage reirradiation are biochemically relapse-free with very low rates of severe toxicity. Large prospective studies with a longer follow-up are needed to confirm the promising benefit/risk ratio observed with salvage brachytherapy and or salvage nodal radiotherapy and/or bone oligometastatic SBRT when compared with life-long palliative hormones.


Transient morphological features of identified ganglion cells in living fetal and neonatal retina.
The function and morphology of retinal ganglion cells in the adult mammalian visual system has been well studied, but little is known about how the adult state is achieved. To address this question, the morphological changes that retinal ganglion cells undergo during development were studied. Ganglion cells were first identified by retrograde labeling with rhodamine latex microspheres deposited in retinorecipient targets in fetal and early postnatal cats. The structure of ganglion cells was then revealed by intracellular injection of Lucifer yellow in living retinas removed and maintained in vitro. As early as 2 weeks before birth, a morphologically diverse assortment of ganglion cells is present, some of which resemble the alpha, beta, and gamma classes found in the adult. However, in contrast to the adult, developing ganglion cells exhibit several transient features, including excessive axonal and dendritic branching and exuberant somatic and dendritic spines. These morphological features indicate that there is a transient network of connectivity that could play an important role in the final determination of retinal ganglion cell form and function.


Photobiomodulation with polychromatic light increases zone 4 survival of transverse rectus abdominis musculocutaneous flap.
The aim of this study was to evaluate the effect of relatively novel approach of application of polychromatic light waves on flap survival of experimental musculocutaneous flap model and to investigate efficacy of this modality as a delay procedure to increase vascularization of zone 4 of transverse rectus abdominis musculocutaneous (TRAM) flap. Twenty-one Wistar rats were randomized and divided into 3 experimental groups (n = 7 each). In group 1 (control group), after being raised, the TRAM flap was sutured back to its bed without any further intervention. In group 2 (delay group), photobiomodulation (PBM) was applied for 7 days as a delay procedure, before elevation of the flap. In group 3 (PBM group), the TRAM flap was elevated, and PBM was administered immediately after the flap was sutured back to its bed for therapeutic purpose. PBM was applied in 48 hours interval from 10 cm. distance to the whole abdominal wall both in groups 2 and 3 for one week. After 7 days of postoperative follow-up, as the demarcation of necrosis of the skin paddle was obvious, skin flap survival was further evaluated by macroscopic, histological and microangiographic analysis. The mean percentage of skin flap necrosis was 56.17 ± 23.68 for group 1, 30.92 ± 17.46 for group 2 and 22.73 ± 12.98 for group 3 PBM receiving groups 2 and 3 revealed less necrosis when compared to control group and this difference was statistically significant. Vascularization in zone 4 of PBM applied groups 2 and 3 was higher compared to group 1 (P = 0.001). Acute inflammation in zone 4 of group 1 was significantly higher compared to groups 2 and 3 (P = 0.025). Similarly, evaluation of zone 1 of the flaps reveled more inflammation and less vascularization among the samples of the control group (P = 0.006 and P = 0.007, respectively). Comparison of PBM receiving two groups did not demonstrate further difference in means of vascularization and inflammation density (P = 0.259). Application of PBM in polychromatic fashion enhances skin flap survival in experimental TRAM flap model both on preoperative basis as a delay procedure or as a therapeutic approach. Lasers Surg. 51:538-549, 2019. © 2019 Wiley Periodicals, Inc.


Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is a highly prevalent disorder, representing the single most common endocrine-metabolic disorder in reproductive-aged women. Currently there are four recognized phenotypes of PCOS: 1) hyperandrogenism+oligo-anovulation+polycystic ovarian morphology; 2) hyperandrogenism+oligo-anovulation; 3) hyperandrogenism+polycystic ovarian morphology; and 4) oligo-anovulation+polycystic ovarian morphology, each with different long-term health and metabolic implications. Clinicians should clearly denote a patient's phenotype when making the diagnosis of PCOS. Polycystic ovary syndrome is a highly inherited complex polygenic, multifactorial disorder. Pathophysiologically abnormalities in gonadotropin secretion or action, ovarian folliculogenesis, steroidogenesis, insulin secretion or action, and adipose tissue function, among others, have been described in PCOS. Women with PCOS are at increased risk for glucose intolerance and type 2 diabetes mellitus; hepatic steatosis and metabolic syndrome; hypertension, dyslipidemia, vascular thrombosis, cerebrovascular accidents, and possibly cardiovascular events; subfertility and obstetric complications; endometrial atypia or carcinoma, and possibly ovarian malignancy; and mood and psychosexual disorders. The evaluation of patients suspected of having PCOS includes a thorough history and physical examination, assessment for the presence of hirsutism, ovarian ultrasonography, and hormonal testing to confirm hyperandrogenism and oligo-anovulation as needed and to exclude similar or mimicking disorders. Therapeutic decisions in PCOS depend on the patients' phenotype, concerns, and goals, and should focus on 1) suppressing and counteracting androgen secretion and action, 2) improving metabolic status, and 3) improving fertility. However, despite significant progress in understanding the pathophysiology and diagnosis of the disorder over the past 20 years, the disorder remains underdiagnosed and misunderstood by many practitioners.


Expression of the HNK-1 epitope is unaltered among early chick epiblast cells despite behavioral transformation by inducing factors in vitro.
Dissociated epiblast cells from pre-streak chick blastoderms have been exposed, in short-term culture on a fibronectin (FN) substratum, to recombinant mammalian activin and to mammalian basic fibroblast growth factor (bFGF). Such cultures have also been made on this substratum pre-conditioned by culture of a transfected cell line expressing the mammalian Wnt-1 gene. The former two factors induce changes of FN adhesiveness and other behavior, such that the cultures after 6 h resemble cultures newly set up from the young primitive streak or substreak hypoblast region of similarly aged blastoderms that have developed onward across the intervening period (see Cooke and Wong, Development 111: 197-212, 1991 for related results). Over 95% of cells are potentially responsive, and with relatively high concentration of activin there is also production of nodular structures due to strong cell-cell adhesion, as in cultures from Hensen's node or the anterior streak. Pre-conditioning of the substratum by transfected Wnt-1-expressing cells does not appear specifically to alter behavior in such epiblast cultures, though these experimental cells, and not control-transfected ones, produce striking alterations of chick development in other experiments (Cooke et al., in preparation). Up to 20% of cells in control cultures from central or 'marginal zone' pre-streak epiblast express the HNK-1 epitope, while up to 60% of cultured early streak cells cleaned of hypoblast do so.(ABSTRACT TRUNCATED AT 250 WORDS)


Protective effect of L-ascorbic acid in lindane intoxicated rats.
Administration of lindane at a dose of 20 mg/kg body weight/day for 15 days to male rats brought about marked growth retardation. Succinic dehydrogenase, Mg2+-ATPase and glucose-6-phosphatase activities were inhibited in different fractions of liver tissues. Mg2+-ATPase, alkaline phosphatase and NADH-dehydrogenase activities were also inhibited in the liver plasma membranes of the lindane treated animals. Stimulation of 5'-nucleotidase activity in liver plasma membrane was observed under lindane intoxication. Supplementation of L-ascorbic acid by separate oral administration to the lindane intoxicated rats neutralized the growth retardation and maintained almost normal values of all the enzymes studied.


Molecular Biology Information Service: an innovative medical library-based bioinformatics support service for biomedical researchers.
Biomedical researchers are increasingly reliant on obtaining bioinformatics training in order to conduct their research. Here we present a model that academic institutions may follow to provide such training for their researchers, based on the Molecular Biology Information Service (MBIS) of the Health Sciences Library System, University of Pittsburgh (Pitt). The MBIS runs a four-facet service with the following goals: (1) identify, procure and implement commercially licensed bioinformatics software, (2) teach hands-on workshops using bioinformatics tools to solve research questions, (3) provide in-person and email consultations on software/databases and (4) maintain a web portal providing overall guidance on the access and use of bioinformatics resources and MBIS-created webtools. This paper describes these facets of MBIS activities from 2006 to 2018, including outcomes from a survey measuring attitudes of Pitt researchers about MBIS service and performance.


Vitamin C is a source of oxoaldehyde and glycative stress in age-related cataract and neurodegenerative diseases.
Oxoaldehyde stress has recently emerged as a major source of tissue damage in aging and age-related diseases. The prevailing mechanism involves methylglyoxal production during glycolysis and modification of arginine residues through the formation of methylglyoxal hydroimidazolones (MG-H1). We now tested the hypothesis that oxidation of vitamin C (ascorbic acid or ASA) contributes to this damage when the homeostatic redox balance is disrupted especially in ASA-rich tissues such as the eye lens and brain. MG-H1 measured by liquid chromatography mass spectrometry is several fold increased in the lens and brain from transgenic mice expressing human vitamin C transporter 2 (hSVCT2). Similarly, MG-H1 levels are increased two- to fourfold in hippocampus extracts from individuals with Alzheimer's disease (AD), and significantly higher levels are present in sarkosyl-insoluble tissue fractions from AD brain proteins than in the soluble fractions. Moreover, immunostaining with antibodies against methylglyoxal hydroimidazolones reveals similar increase in substantia nigra neurons from individuals with Parkinson's disease. Results from an in vitro incubation experiment suggest that accumulated catalytic metal ions in the hippocampus during aging could readily accelerate ASA oxidation and such acceleration was significantly enhanced in AD. Modeling studies and intraventricular injection of 13 C-labeled ASA revealed that ASA backbone carbons 4-6 are incorporated into MG-H1 both in vitro and in vivo, likely via a glyceraldehyde precursor. We propose that drugs that prevent oxoaldehyde stress or excessive ASA oxidation may protect against age-related cataract and neurodegenerative diseases.


Reduction of quantity smoked predicts future cessation among older smokers.
To examine whether smokers who reduce their quantity of cigarettes smoked between two periods are more or less likely to quit subsequently. Data come from the Health and Retirement Study, a nationally representative survey of older Americans aged 51-61 in 1991 followed every 2 years from 1992 to 1998. The 2064 participants smoking at baseline and the first follow-up comprise the main sample. Smoking cessation by 1996 is examined as the primary outcome. A secondary outcome is relapse by 1998. Spontaneous changes in smoking quantity between the first two waves make up the key predictor variables. Control variables include gender, age, education, race, marital status, alcohol use, psychiatric problems, acute or chronic health problems and smoking quantity. Large (over 50%) and even moderate (25-50%) reductions in quantity smoked between 1992 and 1994 predict prospectively increased likelihood of cessation in 1996 compared to no change in quantity (OR 2.96, P<0.001 and OR 1.61, P<0.01, respectively). Additionally, those who reduced and then quit were somewhat less likely to relapse by 1998 than those who did not reduce in the 2 years prior to quitting. Reducing successfully the quantity of cigarettes smoked appears to have a beneficial effect on future cessation likelihood, even after controlling for initial smoking level and other variables known to impact smoking cessation. These results indicate that the harm reduction strategy of reduced smoking warrants further study.


Critical Care Thresholds in Children with Bronchiolitis.
Reduction in mortality from bronchiolitis in developed health is principally achieved from the availability of critical care. Different health care providers and countries demonstrate considerable variance in admission rates, but globally the use and cost of this resource are increasing. The reasons of this are multifold and include organizational, cultural, and clinical aspects. The organization of care has evolved differently in different health care settings at the threshold of critical need, with local priorities and resources determining the location of care (ward or critical care). Critical care areas adopting high-flow oxygen therapy (HFOT) (a ward-based therapy in some institutions) have seen significant increase in their occupancy, without change in rates of mechanical ventilation. Culturally, some countries appear to have a lower threshold for intubation and mechanical ventilation: United States (18%), Finland (4%), and even in countries with high rates of critical care admission (27% in Australia and New Zealand), intubation rates can decline with time (reducing from 27% to 11%). Baseline clinical characteristics of children admitted to critical care are remarkably similar, children are young (c30-60 days) and often born prematurely (21-46%). Clinical thresholds for admission as predefined by critical care units in online guidance focus on presence of apnea (observed in 7-42% of admissions), low pulse oxygen saturation and subjective measures (exhaustion and reduced consciousness). Clinical characteristics of children at the time of admission are commonly reported in relation to the modified Woods Clinical Asthma Score (mean = 3.8 to ≥7) and raised pCO2 (range = 8.0-8.8 kPa), with pCO2 the only significant parameter in a multivariate analysis of factors associated with intubation. KEY POINTS: · More children are being admitted to intensive care over time with increased costs.. · Cultural, organizational, and clinical variance exist between centers and countries.. · Comparing and aligning admissions is difficult as there are no standardized criteria..


A leptospirosis case presenting with thrombotic thrombocytopenic purpura.
Leptospirosis is a zoonotic disease caused by spirochetes of the genus Leptospira. While the majority of leptospirosis cases occur in the tropics, some cases are also observed in temperate regions of developing countries. The disease has various clinical presentations ranging from a mild influenza-like form to a severe potentially fatal illness accompanied by multi-organ failure. However, atypical presentations of leptospirosis have occasionally been described. Here, a case of leptospirosis presenting as thrombotic thrombocytopenic purpura (TTP) is reported. A 58-years-old male presented with fever, oliguria, darkening of urine, and visual hallucinations. Laboratory investigations revealed anaemia, severe thrombocytopaenia, elevated total bilirubin with indirect predominance, high lactate dehydrogenase, and increased urea (293 mg/dL) and creatinine (7.6 mg/dL) levels. He was diagnosed with TTP. Patient was thought leptospirosis due to atypical clinical manifestations. Leptospirosis was confirmed by strongly positive Microscopic Agglutination Test. Patient recovered completely with antibiotics and plasmapheresis. Leptospirosis may be accompanied by thrombotic thrombocytopenic purpura in particular subtropic regions.


Bipedal posture in rats and its effect on litter size.
Sixty female rats were divided into three groups: twenth were converted to bipeds, twenty to asymmetrics and twenty were raised as a control group. Results of this study show reduction in litter size in the amputated groups, with greater reduction of offspring among the biped group, than in the asymmetric group. The cause of this phenomenon is not clear, but the erect posture and its higher pressure imposed on uterus, and stressed coitus, are the main factors suggested for these disorders.


The Impact of Age and Genetics on Naltrexone Biotransformation.
Naltrexone, an opioid antagonist primarily metabolized by aldo-keto reductase 1C4 (AKR1C4), treats pediatric conditions involving compulsiveness (e.g., autism spectrum, Prader-Willi, eating disorders, non-suicidal self-injury). Pharmacokinetic variability is apparent in adults, yet no data are available for children. This study aimed to examine the impact of age and genetic variation on naltrexone biotransformation. Human liver cytosol (HLC) samples (n = 158) isolated from children and adult organ donors were incubated with therapeutically relevant concentrations of naltrexone (0.1, 1 µM). Naltrexone biotransformation was determined by ultraperformance mass spectrometry quantification of the primary metabolite, 6-beta-naltrexol (6βN), and 6βN formation rates (pmol/mg protein/min) were calculated. HLCs from organ donors, age range 0-79 y (mean 16.0 ± 18.2 y), 37% (n = 60) female, 20% (n = 33) heterozygous and 1.2% (n = 2) homozygous for co-occurring AKR1C4 variants (S145C/L311V) showed >200-fold range in 6βN formation (0.37-76.5 pmol/mg protein/min). Source of donor samples was found to be a substantial contributor to variability. Model estimates for a trimmed data set of source-adjusted pediatric samples (aged 0-18 y) suggested that AKR1C4 genetic variation, age, and sex explained 36% of the variability in 6βN formation. Although activity increased steadily from birth and peaked in middle childhood (2-5 years), genetic variation (S145C/L311V) demonstrated a greater effect on activity than did age. Naltrexone biotransformation is highly variable in pediatric and adult livers and can be partly accounted for by individual factors feasible to obtain (e.g., genetic variability, age, sex). These data may inform a precision therapeutics approach (e.g., exposure optimization) to further study Naltrexone responsiveness in children and adults. SIGNIFICANCE STATEMENT: Biotransformation of the commonly used opioid antagonist naltrexone is highly variable and may contribute to reduced therapeutic response. Age, sex, and genetic variation in the drug-metabolizing enzyme, AKR1C4, are potential factors contributing to this variability. In pediatric samples, genetic variation (S145C/L311V) demonstrates a greater impact on activity than age. Additionally, the source of donor samples was identified as an important contributor and must be accounted for to confidently elucidate the biological variables most impactful to drug biotransformation.


Metabolic susceptibility genes as cancer risk factors: time for a reassessment?
Polymorphisms in metabolic cancer susceptibility genes have not shown a consistent role as cancer risk factors, when only main effects are examined. This is actually to be expected given the limited and specific biochemical role such genes play in the carcinogenic process. However, when particular groups of case populations are examined separately, the importance of these genetic polymorphisms may often become quite clear. Examples from the literature and a hypothetical model are presented to support the view that metabolic gene risk alleles should be studied in subgroups of large case control studies with sound biochemical hypotheses related to the action of the gene product as a function of demographic, environmental, or other genetic variables.


The relationship between obstructive sleep apnea and obesity hypoventilation syndrome: a systematic review and meta-analysis.
Obstructive Sleep Apnea and Obesity Hypoventilation Syndrome are two similar diseases. Obstructive Sleep Apnea has been receiving more and more attention while the diagnostic rate of Obesity Hypoventilation Syndrome is not high. Few studies directly evaluated the relationship between them. We systematically analyzed the relevance of the two diseases. MEDLINE®, EMBASE® and the Cochrane Library were carried out to find studies until May 2017. Pooled mean difference and 95% confidence interval were calculated to evaluate the value of clinical and physiologic variables in the prediction of Obesity Hypoventilation Syndrome. 9 Studies (n = 2085) fulfilled the predefined selection criteria. Totally 575 patients (28%) with Obesity Hypoventilation Syndrome were diagnosed from 2085 Obstructive Sleep Apnea patients. Among clearly diagnosed Obstructive Sleep Apnea patients, higher Body Mass Index levels(mean difference:4.72 kg/m2; 95% confidence interval: 4.26 to 5.17; p < 0.00001), higher Apnea-Hypopnea Index (mean difference: 8.36; 95% confidence interval: -3.88 to -2.84; p < 0.00001), greater neck circumference (mean difference:1.01; 95% confidence interval: 0.10 to 1.92; p = 0.03) and lower percent predicted FEV1 (mean difference:-10.28; 95% confidence interval:-11.33 to -9.22; p < 0.00001)were associated with the occurrence with obesity hypoventilation syndrome. We should be highly skeptical of obesity hypoventilation syndrome in Obstructive Sleep Apnea patients with these factors as early identification and appropriate treatment can improve prognosis.


Health effects of parental deaths among adults in Norway: Purchases of prescription medicine before and after bereavement.
We analyse effects of parental deaths on the health of women and men aged 18-59 in 2004-2008, indicated by purchases of prescription medicines. Register data covering the entire Norwegian population were used, and fixed-effects models were estimated to control for unobserved time-invariant individual factors. A parent's death seemed to have immediate adverse consequences in both main age groups considered (18-39, 40-59), although effects were lower in the older group. Some results suggested that this health disadvantage widened with increasing time since the parent's death. However, effects were weak: the annual number of different medicines purchased was only increased by 1-7% as a result of losing a parent. Death of a parent was associated with an immediate increase in purchases of medication for mental diseases, and there were indications of a physical response as well. As time since the parental death increased, there was a decline in the purchase of medication for mental diseases, but an opposite trend with respect to medication for other diseases. On the whole, maternal and paternal deaths had the same impact, and effects on daughters and sons were of the same magnitude.


Lung Circulation.
The circulation of the lung is unique both in volume and function. For example, it is the only organ with two circulations: the pulmonary circulation, the main function of which is gas exchange, and the bronchial circulation, a systemic vascular supply that provides oxygenated blood to the walls of the conducting airways, pulmonary arteries and veins. The pulmonary circulation accommodates the entire cardiac output, maintaining high blood flow at low intravascular arterial pressure. As compared with the systemic circulation, pulmonary arteries have thinner walls with much less vascular smooth muscle and a relative lack of basal tone. Factors controlling pulmonary blood flow include vascular structure, gravity, mechanical effects of breathing, and the influence of neural and humoral factors. Pulmonary vascular tone is also altered by hypoxia, which causes pulmonary vasoconstriction. If the hypoxic stimulus persists for a prolonged period, contraction is accompanied by remodeling of the vasculature, resulting in pulmonary hypertension. In addition, genetic and environmental factors can also confer susceptibility to development of pulmonary hypertension. Under normal conditions, the endothelium forms a tight barrier, actively regulating interstitial fluid homeostasis. Infection and inflammation compromise normal barrier homeostasis, resulting in increased permeability and edema formation. This article focuses on reviewing the basics of the lung circulation (pulmonary and bronchial), normal development and transition at birth and vasoregulation. Mechanisms contributing to pathological conditions in the pulmonary circulation, in particular when barrier function is disrupted and during development of pulmonary hypertension, will also be discussed.


Distribution-preserving data augmentation.
In the last decade, deep learning has been applied in a wide range of problems with tremendous success. This success mainly comes from large data availability, increased computational power, and theoretical improvements in the training phase. As the dataset grows, the real world is better represented, making it possible to develop a model that can generalize. However, creating a labeled dataset is expensive, time-consuming, and sometimes not likely in some domains if not challenging. Therefore, researchers proposed data augmentation methods to increase dataset size and variety by creating variations of the existing data. For image data, variations can be obtained by applying color or spatial transformations, only one or a combination. Such color transformations perform some linear or nonlinear operations in the entire image or in the patches to create variations of the original image. The current color-based augmentation methods are usually based on image processing methods that apply color transformations such as equalizing, solarizing, and posterizing. Nevertheless, these color-based data augmentation methods do not guarantee to create plausible variations of the image. This paper proposes a novel distribution-preserving data augmentation method that creates plausible image variations by shifting pixel colors to another point in the image color distribution. We achieved this by defining a regularized density decreasing direction to create paths from the original pixels' color to the distribution tails. The proposed method provides superior performance compared to existing data augmentation methods which is shown using a transfer learning scenario on the UC Merced Land-use, Intel Image Classification, and Oxford-IIIT Pet datasets for classification and segmentation tasks.


Calmodulin antagonists induce changes in lens permeability and transparency.
Calmodulin has been shown to perform several important functions in the lens including regulation of the plasma membrane Ca(2+)-ATPase. This study investigated the effects of a variety of different CaM antagonists on rat lens membrane potential, membrane resistance, intracellular Na+ and Ca2+ content and transparency, in order to examine the role of CaM in control of lens membrane permeability. W7, calmidazolium and trifluoperazine caused biphasic changes in lens membrane electrical characteristics. Phase 1 consisted of a depolarization of the membrane potential and an increase in resistance, indicating that K+ channels were being blocked. This was confirmed by application of the K+ channel antagonist, quinine, which inhibited Phase 1 changes. Phase 2 was a further depolarization coupled with a decrease in resistance, indicating the activation of a cation conductance. Application of W7 in low Na+ medium slowed the Phase 2 depolarization and decrease in resistance indicating that Na+ is the main charge carrier through the activated conductance. The CaM inhibitors also led to a large increase in the Na+ and Ca2+ contents of the lens. W5, a less potent analogue of W7, caused a depolarization and increase in membrane resistance, but no Phase 2 changes were observed. Na+ and Ca2+ contents were similar to control lenses after 4 hours incubation in 200 microM W5. In addition, exposure to W7, TFP and calmidazolium resulted in a loss of transparency, while W5 treated lenses remained clear. It appears, therefore, that CaM is involved in control of lens membrane permeability. Loss of control of these channels leads to catastrophic changes in the intracellular ionic environment and hence opacification of the lens.


The Quality of Life of Medically Versus Surgically Treated Primary Open-angle Glaucoma Patients at a Nigerian Hospital.
The purpose of this study is to compare the quality of life (QoL) of medically treated versus surgically treated primary open-angle glaucoma (POAG) patients attending Lagos University Teaching Hospital, Lagos, Nigeria. The study was a hospital-based, comparative cross-sectional study. Consecutive consenting POAG participants who met the inclusion criteria were recruited until the sample size was achieved. QoL of all participants was assessed using the glaucoma QoL-15 and National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) questionnaires. Analysis was done using the IBM statistical package for the social sciences version 25.0. The study involved 81 participants who were only on medical treatment for POAG and 81 age- and sex-matched POAG participants who had trabeculectomy surgery. Surgically treated participants had a lower mean intraocular pressure 11.68 mmHg when compared to the medically treated participants 14.82 mmHg. Medically treated participants however had a better overall mean glaucoma QoL using the glaucoma QoL-15 (medical 34.36 ± 10.4, surgical 39.11 ± 13.9 P = 0.015) and NEI-VFQ-25 questionnaires (medical 68.32 ± 15.0, surgical 62.44 ± 18.8 P = 0.029). Controlling for the severity of glaucoma using the glaucoma QoL-15 questionnaire, medically treated participants had a better QoL only among participants with severe POAG (medical 49.13 ± 5.9, surgical 54.06 ± 4.6 P = 0.003). While using the NEI-VFQ-25 questionnaire, medically treated participants had a significantly better QoL only among participants with moderate (medical 74.70 ± 6.6, surgical 67.07 ± 15.6 P = 0.012) and severe POAG (medical 54.52 ± 6.3, surgical 45.51 ± 10.0 P = 0.004). The study demonstrated that although participants that had trabeculectomy had a lower mean intraocular pressure, their overall mean QoL was reduced compared to the medically treated participants.


Direct evidence for predation on trilobites in the Cambrian.
A fossil arthropod similar to Fuxianhuia and displaying an exceptionally well-preserved alimentary canal with in situ gut contents is reported from the lower Middle Cambrian (ca. 510 Myr ago) of South China. Three-dimensionally preserved, paired phosphatic nodules, arranged in series along both sides of the gut and containing spherical bacteria, probably represent serial digestive glands. The gut is filled with fragments of the eodiscoid trilobite, Pagetia. The well-developed digestive glands and the fragmentary trilobite remains suggest (i) that the arthropod was a durophagous, possibly selective predator, and (ii) that small trilobites such as eodiscoids were a major food source in Cambrian marine ecosystems. This fossil association augments the small number of previously described associations providing more or less direct evidence of predator-prey relationships in Cambrian epibenthic communities.


Cholinergic urticaria. A clinical and histologic study.
We studied the natural history, the prevalence of atopy, and the frequency of systemic symptoms during attacks in 35 patients with cholinergic urticaria, the histologic condition of the eruption in seven patients (20%), and the response to intradermal injections of acetylcholine, histamine, and methacholine in 18 patients (51%). In most patients symptoms began between the ages of 10 and 30 years, persisted for many years, and caused them to modify their activities to avoid the provoking factors of exercise, emotion, and heat. The condition usually improved with time, and five patients (14%) had a spontaneous remission. Atopy, present in about 12 (34%) of the patients, was more frequent than in the general population. Systemic symptoms were uncommon during attacks, and patients had no greater responses than controls to the intradermal tests. The histologic study revealed neutrophils in and around the walls of superficial subpapillary dermal vessels.


Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology.
Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, 'Parkinsonism in cirrhosis'. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.


Suppression of prolactin and reduction of milk secretion by effect of cabergoline in lactating dairy ewes.
The effects of cabergoline, an ergot derivative and dopamine receptor agonist, were investigated in 30 ewes of 2 dairy breeds (Manchega; MN, n = 15; Lacaune; LC, n = 15). Ewes were in a similar late-lactation stage, but differed in milk yield according to breed (MN vs. LC, 1.02 ± 0.03 vs. 2.27 ± 0.05 kg/d). Treatments consisted of a single intramuscular injection of cabergoline at different doses per ewe. Cabergoline doses (per ewe) were: low (0.56 mg), high (1.12 mg), and control (CON; 0 mg; 1 mL of saline). Milk yield was recorded daily (d -14 to 25), milk and blood were sampled, and udder traits were measured from d -2 to 14 after injection. No local reaction at the injection site, nor behavior and metabolic indicators of the ewes were detected after the cabergoline injection, but milk yield fell rapidly in both breeds (MN vs. LC, -54% vs. -27%) when compared with CON ewes. Cabergoline effects progressively disappeared after d 5, and no milk yield differences between treatments were detected from d 8 to 25 after injection. Milk fat and protein contents increased similarly (22% and 23%; respectively) in both breeds and at both cabergoline doses until d 5, and the effects disappeared thereafter. Plasma prolactin (PRL) decreased dramatically in the low- and high-treated ewes the day after injection when compared with the CON ewes, and reached values below the detection limit of the assay between d 1 and 5, increasing similarly thereafter. On d 14, PRL values were 58% greater in the low- and high-treated than in the CON ewes, showing that PRL concentrations rebounded when the cabergoline effects ceased. Total udder volume correlated with milk accumulated in the udder (r = 0.77) of all groups of ewes throughout the experiment, suggesting its use as a noninvasive method for the estimation of milk stored in the udder. Udder volume was similar for the low and high ewes, but both values were lower than those of the CON ewes from d 1 to 14 after injection. No other effects on udder size were detected. Cabergoline dramatically inhibited PRL secretion and decreased milk yield and udder volume of lactating dairy ewes. The low dose of cabergoline was as effective as the high dose in the 2 breeds of dairy ewes. These results suggest the use of cabergoline to facilitate the decrease of milk production in dairy ewes (e.g., dry-off, illness care), although further research in pregnant dairy ewes and during the following lactation is still needed.


Pancreatic β-cell Raf-1 is required for glucose tolerance, insulin secretion, and insulin 2 transcription.
Regulation of glucose homeostasis by insulin depends on pancreatic β-cell growth, survival, and function. Raf-1 kinase is a major downstream target of several growth factors that promote proliferation and survival of many cell types, including the pancreatic β cells. We have previously reported that insulin protects β cells from apoptosis and promotes proliferation by activating Raf-1 signaling in cultured human islets, mouse islets, and MIN6 cells. As Raf-1 activity is critical for basal apoptosis and insulin secretion in vitro, we hypothesized that Raf-1 may play an important role in glucose homeostasis in vivo. To test this hypothesis, we utilized the Cre-loxP recombination system to obtain a pancreatic β-cell-specific ablation of Raf-1 kinase gene (RIPCre(+/+):Raf-1(flox/flox)) and a complete set of littermate controls (RIPCre(+/+):Raf-1(wt/wt)). RIPCre(+/+):Raf-1(flox/flox) mice were viable, and no effects on weight gain were observed. RIPCre(+/+):Raf-1(flox/flox) mice had increased fasting blood glucose levels and impaired glucose tolerance but normal insulin tolerance compared to littermate controls. Insulin secretion in vivo and in isolated islets was markedly impaired, but there was no apparent effect on the exocytosis machinery. However, islet insulin protein and insulin 2 mRNA, but not insulin 1 mRNA, were dramatically reduced in Raf-1-knockout mice. Analysis of insulin 2 knockout mice demonstrated that this reduction in mRNA was sufficient to impair in vivo insulin secretion. Our data further indicate that Raf-1 specifically and acutely regulates insulin 2 mRNA via negative action on Foxo1, which has been shown to selectively control the insulin 2 gene. This work provides the first direct evidence that Raf-1 signaling is essential for the regulation of basal insulin transcription and the supply of releasable insulin in vivo.


INSECT TISSUE CULTURE: USE OF BLASTOKINETIC STAGE OF LEAFHOPPER EMBRYO.
To find the proper material for cultivation in vitro of cells of leafhopper vectors of plant viruses, embryonic tissues of the six-spotted aster leaf-hopper (Macrosteles fascifrons) were tested during early developmental stages, during blastokinetic movement, and in late developmental stages. Growing cells were only obtained from the stage of blastokinetic movement. This stage can be determined visually in leafhopper eggs.


Noise around the Knee.
Noise in the knee joint is a common symptom that often leads to outpatient clinic visits. However, there have been no previous review articles regarding noise around the knee despite its high prevalence. We will review the noise characteristics according to sound nature and onset as well as factors for differentiation between physiological and pathological noises. In addition, we will describe causes of the physiological and pathological noises and management of noise in the knee. An appropriate review of the characteristics of noise, its pathophysiology, and factors for differentiation between physiological and pathological noises can facilitate patient guidance. It is important to differentiate between physiological noise and pathologic noise. In most cases, noise after surgery is simply the perception of noise that had been present previously due to emotional concerns. Minor problems associated with surgery, such as postoperative noise, can decrease patient satisfaction, especially among patients with high expectations. Following surgical principles and providing accurate information about physiological noise can decrease the risk of both pathological noise and patient dissatisfaction. In total knee arthroplasty, every attempt should be made to avoid patellar crepitus and clunk by using modern prostheses with proper patellofemoral conformity and by avoiding surgical errors.


Maternal death inquiry and response in India--the impact of contextual factors on defining an optimal model to help meet critical maternal health policy objectives.
Maternal death reviews have been utilized in several countries as a means of identifying social and health care quality issues affecting maternal survival. From 2005 to 2009, a standardized community-based maternal death inquiry and response initiative was implemented in eight Indian states with the aim of addressing critical maternal health policy objectives. However, state-specific contextual factors strongly influenced the effort's success. This paper examines the impact and implications of the contextual factors. We identified community, public health systems and governance related contextual factors thought to affect the implementation, utilization and up-scaling of the death inquiry process. Then, according to selected indicators, we documented the contextual factors' presence and their impact on the process' success in helping meet critical maternal health policy objectives in four districts of Rajasthan, Madhya Pradesh and West Bengal. Based on this assessment, we propose an optimal model for conducting community-based maternal death inquiries in India and similar settings. The death inquiry process led to increases in maternal death notification and investigation whether civil society or government took charge of these tasks, stimulated sharing of the findings in multiple settings and contributed to the development of numerous evidence-based local, district and statewide maternal health interventions. NGO inputs were essential where communities, public health systems and governance were weak and boosted effectiveness in stronger settings. Public health systems participation was enabled by responsive and accountable governance. Communities participated most successfully through India's established local governance Panchayat Raj Institutions. In one instance this led to the development of a multi-faceted intervention well-integrated at multiple levels. The impact of several contextual factors on the death inquiry process could be discerned, and suggested an optimal implementation model. District and state government must mandate and support the process, while the district health office should provide overall coordination, manage the death inquiry data as part of its routine surveillance programme, and organize a highly participatory means, preferably within an existing structure, of sharing the findings with the community and developing evidence-based maternal health interventions. NGO assistance and the support of a development partner may be needed, particularly in locales with weaker communities, public health systems or governance.


Viral meningitis admitted to an infectious diseases hospital: a retrospective case series.
Given its epidemic potential and development of severe forms of disease, viral meningitis (VM) is a serious public health problem. to characterize the main clinical, epidemiologic features, the etiology and treatment of VM cases admitted to the Iasi Infectious Diseases Hospital, in 2012. We retrospectively analyzed the medical records of the patients admitted for viral meningitis at the Iasi "St. Parascheva" Infectious Diseases Hospital in the interval January 1- December 31, 2012 (98 cases). The etiologic diagnosis was made by determining the IgM/IgG antibodies against Coxsackie virus and/or West Nile virus in blood/CSF. There was a fourfold increase in the number of cases as compared to the average for the years 2009-2011. Most cases (73.5%) were children aged 1 to 14 years. 61.8% of patients were males, 51.7% from urban areas. The most common symptom was headache (85.7%), followed by fever (77.6%), and vomiting (66.3%). Neck stiffness was absent in 28.6% cases. In43.5% of the 39 patients serologically investigated a Coxsackie virus infection was confirmed and 1/20 was positive for West Nile virus; three varicella-zoster virus infections and one mumps infection were diagnosed clinically. 68.3% of the patients received first-line antibiotic treatment. The illness mainly affected children, fever and neck stiffness being sometimes absent. The etiology was known in 22.4% of cases; enter viruses being the most frequent causative agent. Most patients received antibiotic therapy. The course was favorable in all cases.


Reinforcement Effects from Nanodiamond in Cellulose Nanofibril Films.
Although research on nanopaper structures from cellulose nanofibrils (CNFs) is well established, the mechanical behavior is not well understood, especially not when CNF is combined with hard nanoparticles. Cationic CNF (Q-CNF) was prepared and successfully decorated by anionic nanodiamond (ND) nanoparticles in hydrocolloidal form. The Q-CNF/ND nanocomposites were filtered from a hydrocolloid and dried. Unlike many other carbon nanocomposites, the Q-CNF/ND nanocomposites were optically transparent. Reinforcement effects from the nanodiamond were remarkable, such as Young's modulus (9.8 → 16.6 GPa) and tensile strength (209.5 → 277.5 MPa) at a content of only 1.9% v/v of ND, and the reinforcement mechanisms are discussed. Strong effects on CNF network deformation mechanisms were revealed by loading-unloading experiments. Scratch hardness also increased strongly with increased addition of ND.