In situ developmental responses of tropical sea urchin larvae to ocean acidification conditions at naturally elevated pCO2 vent sites.
Laboratory experiments suggest that calcifying developmental stages of marine invertebrates may be the most ocean acidification (OA)-sensitive life-history stage and represent a life-history bottleneck. To better extrapolate laboratory findings to future OA conditions, developmental responses in sea urchin embryos/larvae were compared under ecologically relevant in situ exposures on vent-elevated pCO2 and ambient pCO2 coral reefs in Papua New Guinea. Echinometra embryos/larvae were reared in meshed chambers moored in arrays on either venting reefs or adjacent non-vent reefs. After 24 and 48 h, larval development and morphology were quantified. Compared with controls (mean pH(T) = 7.89-7.92), larvae developing in elevated pCO2 vent conditions (pH(T) = 7.50-7.72) displayed a significant reduction in size and increased abnormality, with a significant correlation of seawater pH with both larval size and larval asymmetry across all experiments. Reciprocal transplants (embryos from vent adults transplanted to control conditions, and vice versa) were also undertaken to identify if adult acclimatization can translate resilience to offspring (i.e. transgenerational processes). Embryos originating from vent adults were, however, no more tolerant to reduced pH. Sea temperature and chlorophyll-a concentrations (i.e. larval nutrition) did not contribute to difference in larval size, but abnormality was correlated with chlorophyll levels. This study is the first to examine the response of marine larvae to OA scenarios in the natural environment where, importantly, we found that stunted and abnormal development observed in situ are consistent with laboratory observations reported in sea urchins, in both the direction and magnitude of the response.


Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive non-specific channel.
Binding of mitochondrial matrix cyclophilin (CyP) to the rat liver mitochondrial membranes was detected by SDS/PAGE and Western blotting with suitable antipeptide antibodies. Binding was not affected by prior exposure of mitochondria to Ca2+, adenine nucleotides or inhibitors of the adenine nucleotide translocase, but was greatly increased by t-butyl hydroperoxide (tBH), phenylarsine oxide or diamide. These all sensitized the opening of the non-specific mitochondrial pore to [Ca2+], and the effect of tBH was shown to be maintained after washing away the tBH, consistent with it being caused by the enhanced CyP binding. The bound CyP did not demonstrate peptidyl-prolyl cis-trans isomerase activity. CyP-binding was prevented by 5 microM cyclosporin A, but not reversed by cyclosporin treatment of the membranes. The effect of tBH on binding was concentration-dependent and maximal within 30 s.


Hypertrophy-stimulated myogenic regulatory factor mRNA increases are attenuated in fast muscle of aged quails.
Myogenic regulatory factors (MRFs) are a family of skeletal muscle-specific transcription factors that regulate the expression of several muscle genes. This study was designed to determine whether MRF transcripts were increased in hypertrophy-stimulated muscle of adult quails and whether equivalent increases occurred in muscles of older quails. Slow-tonic anterior latissimus dorsi and fast-twitch patagialis muscles of adult, middle-aged, aged, and senescent quails were stretch overloaded for 6, 24, or 72 h, with contralateral muscles serving as controls. RNase protection assays showed that MRF4 and MyoD transcript levels were increased and myogenin and Myf5 transcripts were induced in stretch-overloaded muscles. However, MRF4 and MyoD increases were significantly attenuated in patagialis muscles of older quails. RT-PCR analyses of three MRF-regulated genes showed that increases in the transcription of these genes occurred with stretch overload, but the increases were less in muscles of older quails. In summary, attenuated MRF responses in muscles from aged animals may partially explain why muscles from older animals do not hypertrophy to the same extent as muscles from younger animals.


Normal rabbit alveolar macrophages. II. Their primary and secondary lysosomes as revealed by electron microscopy and cytochemistry.
In this investigation, vacuoles containing tubular myelin proved to be digestive compartments with cytochemical reactivity for acid phosphatase and arylsulfatase. These cytochemical markers identify the secondary lysosomes, known to contain enzymes capable of hydrolyzing phospholipids like surfactant. Therefore, it appears that alveolar macrophages possess the enzymatic machinery for the degradation of the tubular myelin found in their digestive vacuoles. Although it thus appears evident that alveolar macrophages participate in the turnover of surfactant, the quantitative significance of this route of disposal is undetermined. This investigation has also established that acid hydrolases, so prominently displayed in the secondary lysosomes, are also localized in the rough endoplasmic reticulum and in Golgi-endoplasmic reticulum-lysosomes (GERL). Moreover, small vesicles which are produced from GERL serve as primary lysosomes in transporting digestive enzymes to the vacuoles.


Reliability of a Novel Automated Ultrasound Technology for Body Composition Assessment and Comparisons with Dual Energy X-Ray Absorptiometry.
Body composition tools vary in reliability, portability, and accessibility. The purpose of this study was to evaluate test-retest reliability of MuscleSound® (MS) and dual-energy x-ray absorptiometry (DXA) for both two compartment (region) and three compartment (tissue) models. A secondary aim was to compare body composition values produced by both devices. Fifty participants (n = 25 male, n = 25 female) aged 18-39 years completed two body composition assessments, twice in a single session. Participants arrived at the lab after a 12-hour fast. DXA required participants to lay supine for 10-15 minutes during the scanning process. Thereafter, MS was utilized to measure subcutaneous adipose tissue thickness at seven sites: chest, subscapula, triceps, axilla, suprailium, abdomen, and mid-thigh. MS automatically estimated body composition utilizing a modified Jackson-Pollock equation and the Siri equation within the software. The sequence of assessments was then repeated. Statistical analysis included paired T-tests with Pearson correlations, intraclass correlation coefficients (ICC), and least significant change (LSC). Both methods were strongly reliable (ICCMS = .997, ICCDXA-region = .999, ICCDXA-tissue = .999). MS and DXA-region body fat percentages were significantly different (mean difference (%): 2.60 ± 1.32, p < .001) but highly correlated (r = .928, p < .001). Notably, the mean difference was within DXA-region's calculated least significant change of 3.24%. MS is reliable for assessing body fat percentage in young and middle-aged adults and operators can utilize MS to collect body composition data in the field.


Insulin action in cells expressing truncated or kinase-defective insulin receptors. Dissection of multiple hormone-signaling pathways.
An attempt has been made to dissect insulin-signaling pathways by means of in vitro mutagenesis of the insulin receptor. Studies of two mutants are reviewed: a COOH-truncated receptor and a mutant of the ATP-binding site that is tyrosine kinase defective. The COOH-truncated receptor has normal insulin binding and normal endocytosis and undergoes autophosphorylation and activation as a kinase in vitro and in vivo. Loss of the COOH-terminal 43 amino acids has, however, impaired the ability of the receptor to signal metabolic events while augmenting its ability to signal mitogenesis. Thus, domains have been partially identified that are separately involved in metabolic and mitogenic signaling, facilitating future studies of these pathways. The kinase-defective receptor is not only biologically inactive, but has a dominant inhibitory effect on the endogenous insulin receptors in the cell. That is, transfected Rat-1 cells carrying defective human receptors still have normally active rat insulin receptors but are incapable of signaling insulin action. The fact that metabolic signaling by insulinlike growth factor I (IGF-I) is intact in these cells allows definition of separate insulin and IGF-I pathways, leading to stimulation of glucose transport. Analysis of dose responsiveness for mitogenesis implies that mitogenic signaling pathways are shared by insulin and IGF-I, however. The utility of these cell lines in defining these pathways is discussed.


The HIV-positive dentist: balancing the rights of the health care worker and the patient.
We describe a hypothetical case of an HIV-positive dentist without cognitive impairment who uses proper infection control procedures. The dentist's physician notifies the medical officer of health without the dentist's consent. Although HIV-positive health care workers, including dentists, have been identified in the past, proven HIV transmission to patients is very rare. Most authorities recommend that an HIV-positive health care worker be monitored by an expert panel, which could then, if necessary, refer to the regulatory body to revoke or restrict the person's license to practice. Mandatory HIV testing is not required for health care workers because they generally do not pose a risk for infecting their patients; they are, however, ethically and legally obligated to report their HIV status to their profession's regulatory body.


Displacement of optic nerve head in response to short-term intraocular pressure elevation in human eyes.
Mechanical movement, reflecting compression within the lamina cribrosa, has been suggested as an initiating event in the production of damage in glaucoma. Reversible movements within the lamina cribrosa were sought and studied by characterizing the displacement of fine platinum wire following short-term elevation of intraocular pressure in 13 enucleated human eyes. With IOP elevation, maximum movement in the optic nerve occurred near its center, with minimum movement at its periphery. The difference in movement between these two locations increased with increases in IOP. However, the greatest displacement per unit of IOP elevation occurred at the lowest IOP. Resistance to further displacement occurred as higher IOP was reached. The differential mechanical displacement observed may initiate damage in open-angle glaucoma by causing compression of the vessels and/or shearing of axons within the lamina cribrosa.


Establishing a standard for assessing the appropriateness of trauma team activation: a retrospective evaluation of two outcome measures.
Trauma team activation (TTA) is a well-recognised standard of care to provide rapid stabilisation of patients with time-critical, life-threatening injuries. TTA is associated with a substantial use of valuable hospital resources that may adversely impact upon the care of other patients if not carefully balanced. This study aimed to determine which of the two outcome measures would be a better standard for assessing the appropriateness of TTA at a paediatric centre: retrospective major trauma classification as defined within our state, and the use of emergency department high-level resources as recently published by Falcone et al (Falcone Interventions; FI). Trauma registry data and patients' charts between February 2011 and June 2013 were reviewed. Over-triage and under-triage rates for TTA, using both major trauma and FIs as outcome measures, were compared. Totally, 280 patients received TTA, 243 met major trauma definition and 102 received one or more FIs. The rates of over-triage and under-triage were 39.7% (95% CI 35.0 to 44.6%) and 30.5% (95% CI 26.2 to 35.2%), when the major trauma definition was used as the outcome measure, and 67.5% (95% CI 62.2 to 72.5%) and 10.8% (95% CI 7.9 to 14.8%) when FI was used. Only 17.1% (95% CI 11.4% to 24.7%) of the under-triaged patients using the major trauma definition received one or more FIs. Assessment of TTA appropriateness varied significantly based on the outcome measure used. FIs better reflected the use of acute-care TTA-related resources compared with the major trauma definition, and it should be used as the gold standard to prospectively assess and refine TTA criteria.


Epidemiology of human leptospirosis in Trinidad and Tobago, 1996-2007: a retrospective study.
A retrospective study to describe the epidemiology of human leptospirosis in Trinidad and Tobago during 1996-2007 was conducted. All confirmed cases of leptospirosis was analyzed according to age, sex, seasonality and geographic distribution. A total of 278 cases were recorded, with an average annual incidence rate of 1.84 per 100,000 population. Seventy-five percent of the cases occurred during the wet season, with the highest number of cases recorded in November. A positive correlation was found between number of cases and rainfall. Males constituted 80% of all cases, and the overall male:female ratio was 4.6:1. The total case fatality rate was 5.8%, with deaths among males four times more common than in females. Clinical leptospirosis was greatest in the 10-19 age group and lowest in the 0-9 age group. The total prevalence was 22 per 100,000 population, with the highest prevalence 41 per 100,000 recorded in the regional corporation of Sangre Grande and the lowest (6 per 100,000) in the city of Port of Spain. The lack of important information and active surveillance showed that the level of awareness of the disease is low in the country. The disease is still under-reported, and is considered to be of significant public health importance.


[Pathophysiology of chronic, bronchial hypersecretion (author's transl)].
The biochemical and rheological analysis of sputum allows one to detect abnormalities of the bronchial secretion and to describe the development of the bronchial disease. The main biochemical components of sputum and their biological activities are first described. The fibrillar structure of the mucus is related to heavy weight glycoproteins and these macromolecules contribute to the viscoelastic properties of the bronchial secretion, by their capacity to combine with other proteins such as secretory immunoglobulin A (S-IgA). As the chronic bronchial hypersecretory state progresses, the glandular synthesis of mucins and/or secretory proteins decreases while the passive filtration of blood-derived proteins, such as serumalbumin, increases. Such biochemical changes are frequently associated with a rise in viscosity and a loss in elasticity of sputum. These rheological modifications result in an impairment of the mucociliary clearance and therefore contribute to airway obstruction. The assessment of different indices such as the equilibrium in mucin secretion, S-IgA/serum-albumin ratio, viscosity and elasticity of sputum and its mucociliary transport rate, should lead to a better knowledge of the defense properties of the bronchial mucosa.


[Unexplained physical symptoms: a widespread problem but still low-profile in training programs and guidelines].
Unexplained physical symptoms or functional somatic syndromes that cannot be explained in terms of a defined medical disease are common. If persistent, they can cause significant distress and disability, and lead to absenteeism and social isolation as well as major health-care costs. Unexplained physical symptoms form a spectrum from transient unexplained mild physical symptoms to chronic severe somatoform disorders. Various functional somatic syndromes overlap one another substantially in symptomatology and are often resistant to conventional medical therapy. The 'Vereniging Nederlands Tijdschrift voor Geneeskunde' (Dutch Journal of Medicine Association) recently held a special conference on unexplained physical symptoms. The conclusions were: (a) patients are reluctant to accept the diagnosis of unexplained physical symptoms, because physicians do not have sufficient knowledge, expertise, and skill to diagnose and treat them, (b) patients with unexplained physical symptoms do not necessarily need to be treated by a psychiatrist except in cases of chronic and serious somatoform disorder. Patients with unexplained physical symptoms, who often have multiple and complex problems, are best treated by a team of physicians and allied paramedical professionals; (c) patients with unexplained physical symptoms can be treated effectively by specialists using cognitive behaviour therapy. Different cognitive models are available; the 're-attribution model' focuses on the re-establishment of a liveable life, while 'the consequence model' is directed at reducing the consequences of the unexplained physical symptoms. Management using the attribution model may be followed up by the consequence model approach; (d) the development of a practice guideline for the diagnosis and treatment of patients with both acute and chronic unexplained physical symptoms would improve the quality of patient care, reduce disability, increase the possibility of reintegration, and stimulate scientific research; (e) both theoretical and practical training in the diagnosing and managing of unexplained physical symptoms is inadequate in both university curriculums and postgraduate training programmes for medical specialists. Scientific research for the development of an evidence-based practice guideline is urgently needed.


Immunization with a novel recombinant protein (YidR) reduced the risk of clinical mastitis caused by Klebsiella spp. and decreased milk losses and culling risk after Escherichia coli infections.
The primary objective of this study was to evaluate the protective efficacy of a novel recombinant subunit vaccine containing the protein YidR (rYidR) against clinical mastitis (CM) caused by Klebsiella spp. and Escherichia coli. Given that E. coli infection is known to cause metritis, we also evaluated the effect of rYidR vaccination on the incidence of metritis and conception at the first artificial insemination. Retained placenta and abortion incidence, milk production and composition, and serological responses to specific antigens were also evaluated. In total, 3,107 cows were blocked by parity and randomly allocated into 1 of 3 treatment groups: experimental recombinant subunit vaccine containing the YidR protein (rYidR); commercial vaccine composed of Klebsiella pneumoniae siderophore receptors and porin protein (Kleb-SRP; KlebVax, Epitopix, Willmar, MN); and sterile water adjuvanted with aluminum hydroxide (20%; placebo). Vaccinations were performed at the dry-off for cows, and at 223 ± 3 d of pregnancy for pre-fresh heifers. A second administration was given at 21 ± 3 d after the first injection. Vaccination with rYidR significantly reduced the incidence of CM caused by Klebsiella spp. (3.2%) when compared with the placebo (5.1%) group. No difference was observed on risk of Klebsiella CM between Kleb-SRP (5.9%) and placebo groups. Cows in the rYidR group that experienced E. coli CM had a lower risk of death or culling (12.5%) compared with the Kleb-SRP (27.6%) and placebo groups (27.8%). Furthermore, among cows that developed E. coli CM, rYidR-immunized cows produced more milk than did cows in the placebo and Kleb-SRP groups. Regardless of CM occurrence, rYidR-immunized cows tended to have higher milk production up to the eighth month of lactation than cows in the other groups. No significant effect of treatment was observed on the overall incidence of abortion and metritis; however, the risk of retained placenta tended to be lower for the rYidR group (4.7%) compared with the placebo group (6.7%). In addition, primiparous cows in the rYidR group had the highest conception risk at the first artificial insemination (48.3%) compared with the placebo (39.5%) group, and no significant difference was observed when the Kleb-SRP (40.1%) group was compared with the placebo group. Generally, higher antibody serum titers (IgM and IgG) were observed for the immunized groups compared with the placebo. In conclusion, the rYidR vaccine reduced the risk of CM caused by Klebsiella spp. and the mortality or culling of cows with E. coli infections. Other benefits of the novel vaccine include maintenance of milk production after CM caused by E. coli, and higher conception risk at the first service in primiparous cows compared with cows in the placebo and Kleb-SRP groups.


Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group.
To determine the efficacy, safety and immunogenicity of the heptavalent CRM197 pneumococcal conjugate vaccine against invasive disease caused by vaccine serotypes and to determine the effectiveness of this vaccine against clinical episodes of otitis media. The Wyeth Lederle Heptavalent CRM197 (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a double blind trial; 37,868 children were randomly assigned 1:1 to receive either the pneumococcal conjugate vaccine or meningococcus type C CRM197 conjugate. The primary study outcome was invasive disease caused by vaccine serotype. Other outcomes included overall impact on invasive disease regardless of serotype, effectiveness against clinical otitis media visits and episodes, impact against frequent and severe otitis media and ventilatory tube placement. In addition the serotype-specific efficacy against otitis media was estimated in an analysis of spontaneously draining ears. In the interim analysis in August, 1998, 17 of the 17 cases of invasive disease caused by vaccine serotype in fully vaccinated children and 5 of 5 of partially vaccinated cases occurred in the control group for a vaccine efficacy of 100%. Blinded case ascertainment was continued until April, 1999. As of that time 40 fully vaccinated cases of invasive disease caused by vaccine serotype had been identified, all but 1 in controls for an efficacy of 97.4% (95% confidence interval, 82.7 to 99.9%), and 52 cases, all but 3 in controls in the intent-to-treat analysis for an efficacy of 93.9% (95% confidence interval, 79.6 to 98.5%). There was no evidence of any increase of disease caused by nonvaccine serotypes. Efficacy for otitis media against visits, episodes, frequent otitis and ventilatory tube placement was 8.9, 7.0, 9.3 and 20.1% with P < 0.04 for all. In the analysis of spontaneously draining ears, serotype-specific effectiveness was 66.7%. This heptavalent pneumococcal conjugate appears to be highly effective in preventing invasive disease in young children and to have a significant impact on otitis media.


Sex and time to diagnosis in systemic sclerosis: an updated analysis of 1,129 patients from the Canadian scleroderma research group registry.
A previous study found that time to diagnosis was significantly longer from onset of Raynaud's phenomenon for women compared to men with diffuse systemic sclerosis (SSc) and that, in limited SSc, it was more than twice as long for women than men. That study was limited, however, by the small number of men in disease subtype subgroups. The objective of the present study was to investigate the association of sex with time to diagnosis of SSc using a substantially larger patient sample. Association between sex and time to diagnosis was assessed overall and stratified based on diffuse versus limited disease using Kaplan-Meier curves and Cox proportional hazards models. There were 1,129 patients in the study (median age=56.0 years; 978 [86.6%] women). Time to diagnosis was significantly longer for women (median=1.1 years) than men (median 0.8= years; p=0.037) with diffuse SSc following onset of Raynaud's phenomenon. There were no significant or substantive sex differences in time to diagnosis after Raynaud's onset in limited SSc or from onset of first non-Raynaud's disease manifestation in diffuse or limited SSc. Time to diagnosis was significantly longer for women compared to men with diffuse SSc following onset of Raynaud's phenomenon, but the difference was small and unlikely to be clinically significant. There were no differences in time to diagnosis following Raynaud's onset in limited disease or following onset of first non-Raynaud's disease manifestation in diffuse or limited disease. Overall, sex does not appear to influence time to diagnosis meaningfully.


[Gut-liver axis in inflammatory bowel disease. A retrospective study].
Examination of the gut-liver axis came into the spotlight worldwide. Liver enzyme elevations are commonly seen in patients with inflammatory bowel disease (IBD), which is a diagnostic challenge in everyday clinical practice. Liver and biliary diseases are common extra-intestinal manifestations in Crohn's disease and ulcerative colitis. The assessment of routine liver function tests could be an inaccurate reflection of liver damage, so its prevalence could be underestimated. There would be a need for non-invasive biomarkers and/or scoring systems, which would help the diagnosis of liver damage associated with intestinal diseases. In our work we considered to highlight the importance of the gut-liver axis significance. We used data of patients suffering from ulcerative colitis, as a model for bowel diseases to understand the underlying factors of the pathogenesis of hepatobiliary manifestations. In our retrospective study, we investigated the data of 100 ulcerative colitis patients (male = 46, female = 54) (mean age: 42.5 ± 12.7) and compared to healthy controls (n = 42) (male = 17, female = 25) (mean age: 40.2 ± 13.5). Liver function tests (ALT, AST, GGT, ALP, bilirubin, albumin, thrombocyte), bile acid levels were determinated, and various free radical markers (global, enzymatic) were used to assess the redox homeostasis of patients. Hydrogen donor activity, reducing power, superoxide dismutase and glutathione peroxidase activity, total antioxidant status and induced chemiluminescence were measured, considering that the patients received 5-aminosalicilate and/or azathioprin and elemental diet treatment. Liver function parameters were increased in ulcerative colitis patients, and total antioxidant status, as well. Reducing power significantly decreased, but there was no significant difference compared to the control group of glutathione peroxidase and H-donor activity, we observed only tendentious decrease. The antioxidant protection of more than 54% of patients had a significantly lower rate, according to all the parameters. With chemiluminescence measurement we measured better free radical scavenging capacity, both in plasma and in erythrocytes as a result of the therapy, however, it showed an increase of superoxide dismutase activity, which warns of inflammatory processes. The cause of the decrease in bile acid levels found in the group of ulcerative colitis patients, can be the accelerated peristaltic. In the daily routine, liver enzyme values do not give an accurate picture of liver damage associated with ulcerative colitis. With the help of various specific parameters determined by us, we can estimate the background processes of the gut-liver axis alterations. The decrease in bile acid levels can be a predictive factor in ulcerative colitis. Our work highlights the need of non-invasive screening for liver diseases in inflammatory bowel disease. Orv Hetil. 2017; 158(26): 1014-1021.


Social Health and Its Influence on Metabolic Health Among a Rural Population: A Cross-Sectional Study.
The aim of this study was to estimate the prevalence of metabolic syndrome (MetS) in a Spanish rural population and assess differences in prevalence according to loneliness level, social isolation, and social support. This is a cross-sectional study of 310 patients. MetS was defined by National Cholesterol Education Program-Third Adult Treatment Panel. The UCLA (University of California, Los Angeles) Loneliness Scale, Multidimensional Scale of Social Support, and Lubben Social Network Scale were used to assess loneliness, perceived social support, and social isolation. Almost half of the participants fulfilled MetS diagnosis criteria. Subjects with MetS showed significantly higher levels of loneliness, less social support, and greater social isolation. Systolic blood pressure was significantly higher in socially isolated rural adults. Environmental factors may play a key role in the prevalence of MetS, so specific screening and prevention programs could help health professionals prevent the increasing rates of MetS in rural populations under these socially specific conditions of vulnerability.


Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber's hereditary optic neuropathy in a mouse model.
To introduce DNA into mitochondria efficiently, we fused adenoassociated virus capsid VP2 with a mitochondrial targeting sequence to carry the mitochondrial gene encoding the human NADH ubiquinone oxidoreductase subunit 4 (ND4). Expression of WT ND4 in cells with the G11778A mutation in ND4 led to restoration of defective ATP synthesis. Furthermore, with injection into the rodent eye, human ND4 DNA levels in mitochondria reached 80% of its mouse homolog. The construct expressed in most inner retinal neurons, and it also suppressed visual loss and optic atrophy induced by a mutant ND4 homolog. The adenoassociated virus cassette accommodates genes of up to ∼5 kb in length, thus providing a platform for introduction of almost any mitochondrial gene and perhaps even allowing insertion of DNA encompassing large deletions of mtDNA, some associated with aging, into the organelle of adults.


Prenatal brain disruption in isolated sulfite oxidase deficiency.
Isolated sulfite oxidase deficiency (ISOD) is a very rare autosomal recessive inherited neurometabolic disease. The most striking postnatal neuroimaging finding is multicystic encephalomalacia, which occurs rapidly within days to weeks after birth and mimics severe hypoxic-ischemic encephalopathy. The aim of this study was to describe the prenatal neuroimaging features in a neonate and a fetus diagnosed with ISOD. We report an 11-day-old female neonate who presented with feeding difficulties, decreased activity, neonatal seizures, and movement disorders within a few days after birth. Brain MRI at 9 days of age showed cystic lesions over the left frontal and temporal areas, diffuse and evident T2 high signal intensity of bilateral cerebral cortex, and increased T2 signal intensity of the globus pallidi. A pronounced low level of plasma cysteine and normal level of plasma uric acid were noted. Mutation analysis of SUOX revealed homozygous c.1200C > G mutations, resulting in an amino acid substitution of tyrosine to a stop codon (Y400X). The diagnosis of ISOD was made. The brain MRI of a prenatally diagnosed ISOD fetus of the second pregnancy of the mother of the index case showed poor gyration and differentiation of cortical layers without formation of cystic lesions at gestational age 21 weeks. Cystic brain destruction might occur prenatally and neurodevelopment of gyration and differentiation of the cortical layers in the developing brain could be affected by sulfite accumulation early during the second trimester in ISOD patients. This is the first description of the prenatal neurodevelopment of brain disruption in ISOD.


Arabidopsis SUMO protease ASP1 positively regulates flowering time partially through regulating FLC stability .
The initiation of flowering is tightly regulated by the endogenous and environment signals, which is crucial for the reproductive success of flowering plants. It is well known that autonomous and vernalization pathways repress transcription of FLOWERING LOCUS C (FLC), a focal floral repressor, but how its protein stability is regulated remains largely unknown. Here, we found that mutations in a novel Arabidopsis SUMO protease 1 (ASP1) resulted in a strong late-flowering phenotype under long-days, but to a lesser extent under short-days. ASP1 localizes in the nucleus and exhibited a SUMO protease activity in vitro and in vivo. The conserved Cys-577 in ASP1 is critical for its enzymatic activity, as well as its physiological function in the regulation of flowering time. Genetic and gene expression analyses demonstrated that ASP1 promotes transcription of positive regulators of flowering, such as FT, SOC1 and FD, and may function in both CO-dependent photoperiod pathway and FLC-dependent pathways. Although the transcription level of FLC was not affected in the loss-of-function asp1 mutant, the protein stability of FLC was increased in the asp1 mutant. Taken together, this study identified a novel bona fide SUMO protease, ASP1, which positively regulates transition to flowering at least partly by repressing FLC protein stability.


Trends in the Use of Chemotherapy before and after Radical Cystectomy in Patients with Muscle-invasive Bladder Cancer in Korea.
We investigated trends in perioperative chemotherapy use, and determined factors associated with neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC) use in Korean patients with muscle-invasive bladder cancer (MIBC). We recruited 1,324 patients who had MIBC without nodal invasion or metastases and had undergone radical cystectomies (RC) between 2003 and 2013. The study's cut-off time for AC was three months after surgery, and the study's timespan was divided into three periods based on NAC use, namely, 2003-2005, 2006-2009, and 2010-2013. Complete remission was defined as histologically confirmed T0N0M0 after RC. NAC and AC were administered to 7.3% and 18.1% of the patients, respectively. The median time interval between completing NAC and undergoing RC was 32 days and the mean number of cycles was 3.2. The median time interval between RC and AC was 43 days and the mean number of cycles was 4.1. Gemcitabine and cisplatin were most frequently used in combination for NAC (49.0%) and AC (74.9%). NAC use increased significantly from 4.6% between 2003 and 2005 to 8.4% between 2010 and 2013 (P < 0.05), but AC use did not increase. Only 1.9% of patients received NAC and AC. Complete remission after NAC was achieved in 12 patients (12.5%). Multivariable modeling revealed that an advanced age, the earliest time period analyzed, and clinical tumor stage ≤ cT2 bladder cancer were negatively associated with NAC use (P < 0.05). While NAC use has slowly increased over time, it remains an underutilized therapeutic approach in Korean clinical practice.


Inferring the conformation of RNA base pairs and triples from patterns of sequence variation.
The success of comparative analysis in resolving RNA secondary structure and numerous tertiary interactions relies on the presence of base covariations. Although the majority of base covariations in aligned sequences is associated to Watson-Crick base pairs, many involve non-canonical or restricted base pair exchanges (e.g. only G:C/A:U), reflecting more specific structural constraints. We have developed a computer program that determines potential base pairing conformations for a given set of paired nucleotides in a sequence alignment. This program (ISOPAIR) assumes that the base pair conformation is maintained through sequence variation without significantly affecting the path of the sugar-phosphate backbone. ISOPAIR identifies such 'isomorphic' structures for any set of input base pair or base triple sequences. The program was applied to base pairs and triples with known structures and sequence exchanges. In several instances, isomorphic structures were correctly identified with ISOPAIR. Thus, ISOPAIR is useful when assessing non-canonical base pair conformations in comparative analysis. ISOPAIR applications are limited to those cases where unusual base pair exchanges indeed reflect a non-canonical conformation.


The environment drives microbial trait variability in aquatic habitats.
A prerequisite to improve the predictability of microbial community dynamics is to understand the mechanisms of microbial assembly. To study factors that contribute to microbial community assembly, we examined the temporal dynamics of genes in five aquatic metagenome time-series, originating from marine offshore or coastal sites and one lake. With this trait-based approach we expected to find gene-specific patterns of temporal allele variability that depended on the seasonal metacommunity size of carrier-taxa and the variability of the milieu and the substrates to which the resulting proteins were exposed. In more detail, we hypothesized that a larger seasonal metacommunity size would result in increased temporal variability of functional units (i.e., gene alleles), as shown previously for taxonomic units. We further hypothesized that multicopy genes would feature higher temporal variability than single-copy genes, as gene multiplication can result from high variability in substrate quality and quantity. Finally, we hypothesized that direct exposure of proteins to the extracellular environment would result in increased temporal variability of the respective gene compared to intracellular proteins that are less exposed to environmental fluctuations. The first two hypotheses were confirmed in all data sets, while significant effects of the subcellular location of gene products was only seen in three of the five time-series. The gene with the highest allele variability throughout all data sets was an iron transporter, also representing a target for phage infection. Previous work has emphasized the role of phage-prokaryote interactions as a major driver of microbial diversity. Our finding therefore points to a potentially important role of iron transporter-mediated phage infections for the assembly and maintenance of diversity in aquatic prokaryotes.


Adaptation of the carbon metabolism of Trichomonas vaginalis to the nature and availability of the carbon source.
The anaerobic parasitic protist Trichomonas vaginalis was adapted in chemostats to eight different conditions defined by different growth rates and carbon regimens. Glucose or maltose was used as carbon and energy source. Cells cultured under well-defined steady states were tested in short-term experiments. The kinetics of glucose and maltose uptake were determined and their glucokinase and alpha-glucosidase activities were measured. Uptake in 20 min was measured with radiolabelled glucose and maltose, rather than analogues, using the silicone oil centrifugation technique. Hence, the accumulated label represents both transport and metabolic activity. The total uptake of glucose was highest in organisms that had been starved for glucose during growth. The kinetics of glucose uptake can be understood by assuming rate-limitation by transport across the plasma membrane at low external concentrations and by the subsequent metabolism at concentrations exceeding a cross-over value. The specific glucokinase activity correlated in only four out of eight cases with the saturation uptake. The kinetics of maltose uptake indicated rate-limitation at low maltose concentrations by a diffusion-limited step and at higher levels by metabolic steps. The uptake of maltose was primarily affected by the growth rate during culture, the highest growth rates resulting in most uptake. Maltose uptake was determined only partially by the cellular alpha-glucosidase activity. The activities of both transport and metabolic enzymes changed due to the culture conditions suggesting that the control over glucose and maltose metabolism is shared by several steps in the pathway.


Comparison of a New 68Ga-Radiolabelled PET Imaging Agent sCD146 and RGD Peptide for In Vivo Evaluation of Angiogenesis in Mouse Model of Myocardial Infarction.
Ischemic vascular diseases are associated with elevated tissue expression of angiomotin (AMOT), a promising molecular target for PET imaging. On that basis, we developed an AMOT-targeting radiotracer, 68Ga-sCD146 and performed the first in vivo evaluation on a myocardial infarction mice model and then, compared AMOT expression and αvβ3-integrin expression with 68Ga-sCD146 and 68Ga-RGD2 imaging. After myocardial infarction (MI) induced by permanent ligation of the left anterior descending coronary artery, myocardial perfusion was evaluated by Doppler ultrasound and by 18F-FDG PET imaging. 68Ga-sCD146 and 68Ga-RGD2 PET imaging were performed. In myocardial infarction model, heart-to-muscle ratio of 68Ga-sCD146 imaging showed a significantly higher radiotracer uptake in the infarcted area of MI animals than in sham (* p = 0.04). Interestingly, we also observed significant correlations between 68Ga-sCD146 imaging and delayed residual perfusion assessed by 18F-FDG (* p = 0.04), with lowest tissue fibrosis assessed by histological staining (* p = 0.04) and with functional recovery assessed by ultrasound imaging (** p = 0.01). 68Ga-sCD146 demonstrated an increase in AMOT expression after MI. Altogether, significant correlations of early post-ischemic 68Ga-sCD146 uptake with late heart perfusion, lower tissue fibrosis and better functional recovery, make 68Ga-sCD146 a promising radiotracer for tissue angiogenesis assessment after MI.


Halitosis: From diagnosis to management.
Halitosis is formed by volatile molecules which are caused because of pathological or nonpathological reasons and it originates from an oral or a non-oral source. It is very common in general population and nearly more than 50% of the general population have halitosis. Although halitosis has multifactorial origins, the source of 90% cases is oral cavity such as poor oral hygiene, periodontal disease, tongue coat, food impaction, unclean dentures, faulty restorations, oral carcinomas, and throat infections. Halitosis affects a person's daily life negatively, most of people who complain about halitosis refer to the clinic for treatment but in some of the people who can suffer from halitosis, there is no measurable halitosis. There are several methods to determine halitosis. Halitosis can be treated if its etiology can be detected rightly. The most important issue for treatment of halitosis is detection etiology or determination its source by detailed clinical examination. Management may include simple measures such as scaling and root planning, instructions for oral hygiene, tongue cleaning, and mouth rinsing. The aim of this review was to describe the etiological factors, prevalence data, diagnosis, and the therapeutic mechanical and chemical approaches related to halitosis.


Contractile activity is required for the expression of neonatal myosin heavy chain in embryonic chick pectoral muscle cultures.
The expression of neonatal myosin heavy chain (MHC) was examined in developing embryonic chicken muscle cultures using a monoclonal antibody (2E9) that has been shown to be specific for that isoform (Bandman, E., 1985, Science (Wash. DC), 227: 780-782). After 1 wk in vitro some myotubes could be stained with the antibody, and the number of cells that reacted with 2E9 increased with time in culture. All myotubes always stained with a second monoclonal antibody that reacted with all MHC isoforms (AG19) or with a third monoclonal antibody that reacted with the embryonic but not the neonatal MHC (EB165). Quantitation by ELISA of an extract from 2-wk cultures demonstrated that the neonatal MHC represented between 10 and 15% of the total myosin. The appearance of the neonatal isoform was inhibited by switching young cultures to medium with a higher [K+] which has been shown to block spontaneous contractions of myotubes in culture. Furthermore, if mature cultures that reacted with the neonatal antibody were placed into high [K+] medium, neonatal MHC disappeared from virtually all myotubes within 3 d. The effect of high [K+] medium was reversible. When cultures maintained in high [K+] medium for 2 wk were placed in standard medium, which permitted the resumption of contractile activity, within 24 h cells began to react with the neonatal specific antibody, and by 72 h many myotubes were strongly positive. Since similar results were also obtained by inhibiting spontaneous contractions with tetrodotoxin, we suggest that the development of contractile activity is not only associated with the maturation of myotubes in culture, but may also be the signal that induces the expression of the neonatal MHC.


Measurement Instrument for Scientific Teaching (MIST): A Tool to Measure the Frequencies of Research-Based Teaching Practices in Undergraduate Science Courses.
The Scientific Teaching (ST) pedagogical framework provides various approaches for science instructors to teach in a way that more closely emulates how science is practiced by actively and inclusively engaging students in their own learning and by making instructional decisions based on student performance data. Fully understanding the impact of ST requires having mechanisms to quantify its implementation. While many useful instruments exist to document teaching practices, these instruments only partially align with the range of practices specified by ST, as described in a recently published taxonomy. Here, we describe the development, validation, and implementation of the Measurement Instrument for Scientific Teaching (MIST), a survey derived from the ST taxonomy and designed to gauge the frequencies of ST practices in undergraduate science courses. MIST showed acceptable validity and reliability based on results from 7767 students in 87 courses at nine institutions. We used factor analyses to identify eight subcategories of ST practices and used these categories to develop a short version of the instrument amenable to joint administration with other research instruments. We further discuss how MIST can be used by instructors, departments, researchers, and professional development programs to quantify and track changes in ST practices.


Impact odorants contributing to the fungus type aroma from grape berries contaminated by powdery mildew (Uncinula necator); incidence of enzymatic activities of the yeast Saccharomyces cerevisiae.
Powdery mildew due to the fungus Uncinula necator is an important disease for the vineyard. The development of the fungus at the surface of the berries leads to the occurrence of a very characteristic and sometimes intense mushroom-type odor cited as an important default for grapes quality. Gas chromatography/olfactometry, gas chromatography, and multidimensional gas chromatogaphy/mass spectrometry techniques were used to investigate the most important odorants of grapes diseased by powdery mildew. Among 22 odorants detected, strongly odorant compounds were identified or tentatively identified in purified extracts obtained from grapes diseased by powdery mildew. Aroma extraction dilution analysis (AEDA) analysis revealed that 1-octen-3-one (mushroom odor), (Z)-1,5-octadien-3-one (geranium-leaf odor), and an unidentified odorous zone (fishy-mushroom like odor) were the most potent volatiles of the diseased grapes. In the presence of nonproliferating Saccharomyces cerevisiae yeast cells, and consequently during alcoholic fermentation, the enzymatic reduction of 1-octen-3-one and (Z)-1,5-octadien-3-one to much less odorant compounds, namely 3-octanone and (Z)-5-octen-3-one, was shown. Those results explain to some extent the disappearance of the fungal aroma specific to powdery mildew grapes during alcoholic fermentation.


High capacity gas capture and selectivity properties of triazatruxene-based ultramicroporous hyper-crosslinked covalent polymer.
Tuning the selective sorption features of microporous organic networks is of great importance for subsequent applications in gas uptake and hiding, while it is more attractive in terms of being both time and cost effective to realize these optimizations without using functional groups in the core and linker. "Knitting" is one of the easiest and most used method to obtain a broad scope of hyper-crosslinked polymers on a large scale from aromatic structures that do not contain functional groups for polymerization. By the use of Knitting method, a hypercrosslinked covalent ultramicroporous organic polymer was obtained via stepwise process from using triazatruxene (TAT) as core -a planar indole trimer- through anhydrous FeCl3 catalyzed Friedel-Crafts alkylation using dimethoxybenzene as a linker. The resulting microporous polymer, namely TATHCCP was completely identified by analytical and spectral techniques after examined for gas properties (CO2, CH4, O2, CO, and H2) and selectivity (CO2/N2, CO2/O2, for CO2/CO and CO2/CH4) up to 1 bar and increased temperatures (273 K, 296 K and 320 K). Although it has a relatively low (Brunauer-Emmett-Teller) BET specific surface area around 557 m2/g, it was seen to have a high CO2 capture capacity approaching 10% wt. at 273 K. In accordance with (ideal adsorbed solution theory) IAST computations, it was revealed that interesting selectivity features hitting up to 60 for CO2/N2, 45 for CO2/O2, 35 for CO2/CO, 13 for CO2/CH4 at lower temperatures revealed that the material has much better selectivity values than many HCP (hyper-crosslinked polymer) derivatives in the literature even from its most similar analog dimethoxymethane derivative TATHCP, which has a surface area of 950 m2/g.


A 32-kilodalton protein binds to AU-rich domains in the 3' untranslated regions of rapidly degraded mRNAs.
An AU-rich sequence present within the 3' untranslated region has been shown to mark some short-lived mRNAs for rapid degradation. We demonstrate by label transfer and gel shift experiments that a 32-kDa polypeptide, present in nuclear extracts, specifically interacts with the AU-rich domains present within the 3' untranslated region of human granulocyte-macrophage colony-stimulating factor, c-fos, and c-myc mRNAs and a similar domain downstream of the poly(A) addition site of the adenovirus IVa2 mRNA. Competition experiments and partial protease analysis indicated that the same polypeptide interacts with all four RNAs. A single AUUUA sequence in a U-rich context was sufficient to signal binding of the 32-kDa polypeptide. Insertion of three copies of this minimal recognition site led to markedly reduced accumulation of beta-globin RNA, while the same insert carrying a series of U-to-G changes had little effect on RNA levels. Steady-state levels of beta-globin-specific nuclear RNA, including incompletely processed RNA, and cytoplasmic mRNA were reduced. Cytoplasmic mRNA containing the AU-rich recognition sites for the 32-kDa polypeptide exhibited a half-life shorter than that of mRNA with a mutated insert. We suggest that binding of the 32-kDa polypeptide may be involved in the regulation of mRNA half-life.


[Myocardial diastolic elasticity in chronic adriamycin lesion].
Isolated hearts of the majority of rats receiving 20 mg/kg adriamycin for 10 weeks exhibited normal pump function. Left ventricular diastolic stiffness of these hearts was approximately 1.5 times higher, as compared to control hearts, with the filling pressure in the range of 5 to 20 cm H2O and diastolic pause 23% longer due to bradycardia. Pacing-induced increase in the heart rate up to the control level resulted in further increase in left ventricular diastolic stiffness due to the rise in myocardial stiffness, associated with a fall in cardiac output by 36%. The heart and right atrial compliance determined in separate experiments did not differ significantly from the control. The results suggest that increased left ventricular diastolic stiffness of adriamycin-treated rats seems to be rather due to energy-dependent disturbance in myofibril relaxation than to usually arising myocardial fibrosis.


Horizon scan of DNA-based methods for quality control and monitoring of herbal preparations.
Herbal medicines and preparations are widely used in healthcare systems globally, but concerns remain about their quality and safety. New herbal products are constantly being introduced to the market under varying regulatory frameworks, with no global consensus on their definition or characterization. These biologically active mixtures are sold through complex globalized value chains, which create concerns around contamination and profit-driven adulteration. Industry, academia, and regulatory bodies must collaborate to develop innovative strategies for the identification and authentication of botanicals and their preparations to ensure quality control. High-throughput sequencing (HTS) has significantly improved our understanding of the total species diversity within DNA mixtures. The standard concept of DNA barcoding has evolved over the last two decades to encompass genomic data more broadly. Recent research in DNA metabarcoding has focused on developing methods for quantifying herbal product ingredients, yielding meaningful results in a regulatory framework. Techniques, such as loop-mediated isothermal amplification (LAMP), DNA barcode-based Recombinase Polymerase Amplification (BAR-RPA), DNA barcoding coupled with High-Resolution Melting (Bar-HRM), and microfluidics-based methods, offer more affordable tests for the detection of target species. While target capture sequencing and genome skimming are considerably increasing the species identification resolution in challenging plant clades, ddPCR enables the quantification of DNA in samples and could be used to detect intended and unwanted ingredients in herbal medicines. Here, we explore the latest advances in emerging DNA-based technologies and the opportunities they provide as taxa detection tools for evaluating the safety and quality of dietary supplements and herbal medicines.


NCOA4 Regulates Iron Recycling and Responds to Hepcidin Activity and Lipopolysaccharide in Macrophages.
Macrophages, via erythrophagocytosis, recycle iron from effete erythrocytes to newly developing red blood cells. Conversion of potentially cytotoxic levels of iron from its heme into nonheme form during iron recycling is safely accomplished via coordinated regulations of cellular iron transport and homeostasis. Herein, we demonstrate the roles and regulation of NCOA4 (nuclear receptor coactivator 4)-mediated ferritinophagy in macrophages after erythrophagocytosis using the mouse macrophage cell line J774 cells. Ferritin in J774 cells increased with the rise of nonheme iron by erythrocyte ingestion and declined when total cellular iron contents subsequently decreased. NCOA4, a selective autophagic cargo receptor for ferritin, was responsible for the control of cellular ferritin and total iron contents at the later stage of erythrophagocytosis. A hepcidin analog, which limits the flux of iron through iron-recycling by inhibiting iron export at the plasma membrane, repressed NCOA4 expression and led to accumulation of ferritin in the mouse macrophages. Transcriptome analyses revealed a functional association of immune response with NCOA4-dependent gene expressions, and we confirmed repression of Ncoa4 by lipopolysaccharide (LPS) in J774 cells and the spleen of mice. Collectively, our studies indicate that NCOA4 facilitates cellular ferritin turnover and the release of iron by macrophages after erythrophagocytosis and functions as a regulatory target for molecular signals of systemic iron overload and inflammation. These identify macrophage NCOA4 as a potential therapeutic target for disorders of systemic iron dysregulation, including anemia of inflammation and hemochromatosis.


[Gene technology in production of modern drugs].
In the last years gene technology has influenced dramatically medical and biological disciplines. With the help of molecular biology it is possible to produce a variety of proteins in alternative ways. Further, substances can be produced which exist in nature only in trace amounts, and therefore can not be produced with conventional methods. However, there is no other scientific discipline which is discussed so controversially in public like genetic engineering. The "new" biology comprises a multitude of disciplines which are difficult to understand for non experts. Unfortunately, gene technology has become the new symbol for "uncontrolled" technology development. In this review article the basic concepts of genetic engineering will be explained. Further, the production of some recombinant drugs, which are already used in practice, will be demonstrated. Finally, some safety aspects concerning about risk assessment are discussed.


Functional analysis-based interventions for challenging behaviour in dementia.
Functional analysis (FA) for the management of challenging behaviour is a promising behavioural intervention that involves exploring the meaning or purpose of an individual's behaviour. It extends the 'ABC' approach of behavioural analysis, to overcome the restriction of having to derive a single explanatory hypothesis for the person's behaviour. It is seen as a first line alternative to traditional pharmacological management for agitation and aggression. FA typically requires the therapist to develop and evaluate hypotheses-driven strategies that aid family and staff caregivers to reduce or resolve a person's distress and its associated behavioural manifestations. To assess the effects of functional analysis-based interventions for people with dementia (and their caregivers) living in their own home or in other settings. We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 3 March 2011 using the terms: FA, behaviour (intervention, management, modification), BPSD, psychosocial and Dementia. Randomised controlled trials (RCTs) with reported behavioural outcomes that could be associated with functional analysis for the management of challenging behaviour in dementia. Four reviewers selected trials for inclusion. Two reviewers worked independently to extract data and assess trial quality, including bias. Meta-analyses for reported incidence, frequency, severity of care recipient challenging behaviour and mood (primary outcomes) and caregiver reaction, burden and mood were performed. Details of adverse effects were noted. Eighteen trials are included in the review. The majority were in family care settings. For fourteen studies, FA was just one aspect of a broad multi-component programme of care. Assessing the effect of FA was compromised by ill-defined protocols for the duration of component parts of these programmes (i.e. frequency of the intervention or actual time spent). Therefore, establishing the real effect of the FA component was not possible.Overall, positive effects were noted at post-intervention for the frequency of reported challenging behaviour (but not for incidence or severity) and for caregiver reaction (but not burden or depression). These effects were not seen at follow-up. The delivery of FA has been incorporated within wide ranging multi-component programmes and study designs have varied according to setting - i.e. family care, care homes and hospital, with surprisingly few studies located in care homes. Our findings suggest potential beneficial effects of multi-component interventions, which utilise FA. Whilst functional analysis for challenging behaviour in dementia care shows promise, it is too early to draw conclusions about its efficacy.


Association between chronic exposure to arsenic and slow nerve conduction velocity among adolescents in Taiwan.
The association between chronic exposure to arsenic and peripheral neuropathy has been controversial in previous studies, which may be due to the influence of factors, such as age, gender, chronic diseases, occupational injuries, and arsenic exposure. To clarify the question of this association, a cross-sectional study was designed. In total, 130 junior high school students aged 12-14 years were included and examined for the motor and sensory nerve conduction velocity of peripheral nerves in their right-upper and lower limbs. Concentrations of arsenic in well-water and history of drinking well-water were retrieved from a baseline database created in 1991. After adjustment for gender and height, a significant odds ratio of 2.9 (95% confidence interval [CI] 1.1-7.5) was observed for the development of slow nerve conduction velocity of the sural sensory action potential (SAP) among the study subjects with a cumulative arsenic dosage of>100.0 mg. In addition, a borderline statistical significance with odds ratio of 7.8 (95% CI 1.001-69.5) for the development of slow nerve conduction velocity of sural SAP was also observed among the study subjects who drank well-water containing arsenic concentrations of >50.0 microg/L and with a cumulative arsenic dosage of >100.0 mg. The study found that chronic exposure to arsenic might induce peripheral neuropathy. It also found that the slowing of the nerve conduction velocity of sural SAP might be an early marker of chronic arsenic neuropathy.


Rnd proteins: multifunctional regulators of the cytoskeleton and cell cycle progression.
Rnd3/RhoE has two distinct functions, regulating the actin cytoskeleton and cell proliferation. This might explain why its expression is often altered in cancer and by multiple stimuli during development and disease. Rnd3 together with its relatives Rnd1 and Rnd2 are atypical members of the Rho GTPase family in that they do not hydrolyse GTP. Rnd3 and Rnd1 both antagonise RhoA/ROCK-mediated actomyosin contractility, thereby regulating cell migration, smooth muscle contractility and neurite extension. In addition, Rnd3 has been shown to have a separate role in inhibiting cell cycle progression by reducing translation of cell cycle regulators, including cyclin D1 and Myc. We propose that Rnd3 could act as a tumour suppressor to limit proliferation, but when mutations bypass this activity of Rnd3, it can promote cancer invasion through its effects in the actin cytoskeleton.


Management of the feline blood donor.
The feline blood donor should be considered a valuable asset to the veterinary clinic. As public awareness increases, so will the demand for high-quality blood products. Meeting this demand will require planning and a blood donor management program tailored to the clinic's needs. Consideration should be given to the areas of blood value, donor selection, blood collection, and maintaining donor health when developing a donor management program. Suggestions for reducing the stress and aggravation often associated with feline blood collection are provided.


SDF-1/CXCL12 regulates cAMP production and ion transport in intestinal epithelial cells via CXCR4.
Human colonic epithelial cells express CXCR4, the sole cognate receptor for the chemokine stromal cell-derived factor (SDF)-1/CXC chemokine ligand (CXCL) 12. The aim of this study was to define the mechanism and functional consequences of signaling intestinal epithelial cells through the CXCR4 chemokine receptor. CXCR4, but not SDF-1/CXCL12, was constitutively expressed by T84, HT-29, HT-29/-18C1, and Caco-2 human colon epithelial cell lines. Studies using T84 cells showed that CXCR4 was G protein-coupled in intestinal epithelial cells. Moreover, stimulation of T84 cells with SDF-1/CXCL12 inhibited cAMP production in response to the adenylyl cyclase activator forskolin, and this inhibition was abrogated by either anti-CXCR4 antibody or receptor desensitization. Studies with pertussis toxin suggested that SDF-1/CXCL12 activated negative regulation of cAMP production through G(i)alpha subunits coupled to CXCR4. Consistent with the inhibition of forskolin-stimulated cAMP production, SDF-1/CXCL12 also inhibited forskolin-induced ion transport in voltage-clamped polarized T84 cells. Taken together, these data indicate that epithelial CXCR4 can transduce functional signals in human intestinal epithelial cells that modulate important cAMP-mediated cellular functions.


The effect of LACE DVD training in new and experienced hearing aid users.
Numerous studies have demonstrated that improving the ability to understand speech in noise can be a difficult task for adults with hearing aids (HAs). If HA users want to improve their speech understanding ability, specific training may be needed. Auditory training (AT) is one type of intervention that may enhance speech recognition abilities for adult HA users. The purpose of this study was to examine the behavioral effects of an AT program called Listening and Communication Enhancement (LACE) in the DVD format in new and experienced HA users. While some research has been conducted using the computer version of this program, no research to date has been conducted on the efficacy of the DVD version of the LACE training program in both new and experienced HA users. An experimental, prospective repeated measures group design, with random assignment. Twenty-nine adults with hearing loss were assigned to one of three groups: new HA plus training, experienced HA plus training, or control (new HA users with no training during the study but provided with training afterward). New HA aid users were randomly assigned to either the training or control group. Participants in the training groups completed twenty 30 min training lessons from the LACE DVD program at home over a period of 4 wk. Participants in both training groups were evaluated at baseline, after 2 wk of training and again after 4 wk of training. Participants in the control group were evaluated at baseline and after 4 wk of HA use. Several objective listening measures were administered including speech in noise, rapid speech, and competing sentences tasks. Subjective measures included evaluating the participants' perception of the intervention as well as their perceptions of functional listening abilities. Findings indicate that both new and experienced users improved their understanding of speech in noise, understanding of competing sentences, and communication function after training in comparison to a control group. Effect size calculations suggested that a larger training effect was observed for new HA users compared to experienced HA users. New HA users also reported greater benefit from training compared to experienced users. AT with the LACE DVD format should be encouraged, particularly among new HA users, to improve understanding in difficult listening conditions.


Cryptococcal Meningitis Reported With Fingolimod Treatment: Case Series.
To describe the characteristics of patients with MS reporting cryptococcal meningitis (CM) while treated with fingolimod. The Novartis safety database was searched for cases with CM between January 26, 2006, and February 28, 2020. The reporting rate of CM was estimated based on the case reports received and exposure to fingolimod in the postmarketing setting during the relevant period. A total of 60 case reports of CM were identified, mostly from the United States. The median age was 48 years, and 51.8% were women. Most of the patients had recovered or were recovering at the time of final report. A fatal outcome occurred in 13 cases. During the study period, the rate of CM in patients with MS receiving fingolimod was estimated to be 8 per 100,000 patient-years (95% CI: 6.0; 10.0). The incidence of CM seemed to increase with duration of treatment; however, this relationship remains uncertain due to wide CIs and missing data. The causal relationship between fingolimod treatment and CM is not yet fully understood. The CM mortality rate in fingolimod-treated patients is similar to that reported in HIV-negative patients. Vigilance for signs and symptoms of CM in patients receiving fingolimod, particularly the new onset of headaches and altered mental status, is essential. Early diagnosis and treatment are critical to reducing CM-associated mortality.


Estimation and analysis of cow-level cumulative lifetime break-even on financial resiliency.
A dairy farm's ability to generate positive profit is dependent on the cow's response to management decisions made in conjunction with input cost management. Therefore, farm managers consider a multifaceted set of choices, managing their herd not as a homogeneous group of animals, but justifying the influence of individual cows on the farm's financial performance. We combined cow-level performance records from Minnesota DHIA and farm-level financials from the University of Minnesota Center for Farm Financial Management database FINBIN (https://finbin.umn.edu/) from 2012 to 2018 to evaluate farm- and cow-level profitability. The objective of this study was to evaluate individual cow performance matched with farm-level input expenses allocated to the cow level to measure a dairy farm's ability to be profitable over time, considering input and milk price fluctuations. Conventional Minnesota dairy farms were divided into 2 groups-financially resilient and non-resilient-based on their adjusted net farm income ratio over time. Yearly farm-level expenses and revenues were allocated to cows based on performance measures provided in monthly DHIA test data, and a cumulative lifetime break-even was calculated for all cows with consecutive farm data from 2012 to 2018. Herd-level and cow-level characteristics were analyzed to test for statistical difference between resilient and non-resilient farms as well as cows who achieved their break-even versus those that did not for resilient and non-resilient farms. Results showed that resilient farms had statistically different and lower expenses than non-resilient farms, with lower heifer raising expenses ($1,839.32 vs. $1,886.20), lifetime feed expenses ($4,197.07 vs. $4,975.39), and lifetime non-feed expenses ($2,761.63 vs. $4,502.67). Resilient farms had 38.3% of cows reach break-even, whereas non-resilient farms had 25.2% of cows break even. On average, cows who achieved their break-even remained in the herd for approximately 1 yr longer for both resilient farms (1,011 d for cows who break even and 627 d for those that do not) and non-resilient farms (1,033 d for cows who break even and 683 d for those that do not). Cows on resilient farms who achieved their lifetime break-even had an average lifetime profit of $1,613.48, which was $3,095.10 higher than the lifetime profit of -$1,481.62 of cows who never reach their break-even. Cows who reached their break-even on non-resilient farms had a lifetime profit of $1,270.51, which was $3,854.11 higher than the lifetime profit of -$2,583.60 for those who did not break even. Therefore, financially resilient dairy farms were utilizing a low-input, low-output model that proved to be successful and resulted in maintained profitability across volatile and fluctuating commodity prices.


Substance P: a potent inhibitor of the canine small intestine in vivo.
Intra-arterially administered substance P inhibited neurally activated contractions of the circular muscle of canine small intestine in vivo (lowest effective dose approximately 10(-13) mol). Excitation of intestine required higher (10(-10) mol) doses. The inhibitory effect required functioning nerves, since tetrodotoxin treatment eliminated it. However, inhibition of neurogenic contraction by substance P was unaffected by nicotinic or opiate receptor antagonists or by catecholamine depletion but was reduced by a selective substance P antagonist. Since the inhibition by substance P was also greatly reduced by treatment with atropine or pirenzepine and acetylcholine given intra-arterially produced a similar inhibitory response, stimulation of release of acetylcholine to inhibitory muscarinic receptors on nerves appeared to be the mechanism of this action. Direct smooth muscle effects were ruled out; substance P did not inhibit contractions to intra-arterial acetylcholine or those following tetrodotoxin. In vitro in ileal strips, no inhibition by substance P of any contractile response was found. We propose that the local release of substance P into the myenteric plexus produces inhibition and suggest that this constitutes a physiological function of the neuropeptide. This action may be absent in vitro.


Transcriptional circuits in B cell transformation.
Loss of IKAROS in committed B cell precursors causes a block in differentiation while at the same time augments aberrant cellular properties, such as bone marrow stromal adhesion, self-renewal and resistance to glucocorticoid-mediated cell death. B cell acute lymphoblastic leukaemias originating from these early stages of B cell differentiation and associated with IKAROS mutations share a high-risk cellular phenotype suggesting that deregulation of IKAROS-based mechanisms cause a highly malignant disease process. Recent studies show that IKAROS is critical for the activity of super-enhancers at genes required for pre-B cell receptor (BCR) signalling and differentiation, working either downstream of or in parallel with B cell master regulators such as EBF1 and PAX5. IKAROS also directly represses a cryptic regulatory network of transcription factors prevalent in mesenchymal and epithelial precursors that includes YAP1, TEAD1/2, LHX2 and LMO2, and their targets, which are not normally expressed in lymphocytes. IKAROS prevents not only expression of these 'extra-lineage' transcription factors but also their cooperation with endogenous B cell master regulators, such as EBF1 and PAX5, leading to the formation of a de novo for lymphocytes super-enhancer network. IKAROS coordinates with the Polycomb repression complex (PRC2) to provide stable repression of associated genes during B cell development. However, induction of regulatory factors normally repressed by IKAROS starts a feed-forward loop that activates de-novo enhancers and elevates them to super-enhancer status, thereby diminishing PRC2 repression and awakening aberrant epithelial-like cell properties in B cell precursors. Insight into IKAROS-based transcriptional circuits not only sets new paradigms for cell differentiation but also provides new approaches for classifying and treating high-risk human B-ALL that originates from these early stages of B cell differentiation.


Abnormal apical cell membrane in cystic fibrosis respiratory epithelium. An in vitro electrophysiologic analysis.
The transepithelial chloride permeability of airway and sweat ductal epithelium has been reported to be decreased in patients with cystic fibrosis (CF). In the present study, we investigated whether the airway epithelial defect was in the cell path by characterizing the relative ion permeabilities of the apical membrane of respiratory epithelial cells from CF and normal subjects. Membrane electric potential difference (PD) and the responses to luminal Cl- replacement, isoproterenol, and amiloride were measured with intracellular microelectrodes. The PD across the apical barrier was smaller for CF (-11 mV) than normal (-29 mV) epithelia whereas the PD across the basolateral barrier was similar, (-26 and -34 mV respectively). In contrast to normal nasal epithelium, the apical membrane in CF epithelia was not Cl- permselective and was not responsive to isoproterenol. Amiloride, a selective Na+ channel blocker, induced a larger apical membrane hyperpolarization and a greater increase in transepithelial resistance in CF epithelia. Both reduced apical cell membrane Cl- conductance and increased Na+ conductance appear to contribute to the abnormal function of respiratory epithelia of CF patients.


Chromosomes with a life of their own.
B chromosomes (Bs) can be described as 'passengers in the genome', a term that has been used for the repetitive DNA which comprises the bulk of the genome in large genome species, except that Bs have a life of their own as independent chromosomes. As with retrotransposons they can accumulate in number, but in this case by various processes of mitotic or meiotic drive, based on their own autonomous ways of using spindles, especially in the gametophyte phase of the life cycle of flowering plants. This selfish property of drive ensures their survival and spread in natural populations, even against a gradient of harmful effects on the host plant phenotype. Bs are inhabitants of the nucleus and they are subject to control by 'genes' in the A chromosome (As) complement. This interaction with the As, together with the balance between drive and harmful effects makes a dynamic system in the life of a B chromosome, notwithstanding the fact that we are only now beginning to unravel the story in a few favoured species. In this review we concentrate mainly on recent developments in the Bs of rye and maize, two of the species currently receiving most attention. We focus on their population dynamics and on the molecular basis of their structural organisation and mechanisms of drive, as well as on their mode of origin and potential applications in plant biotechnology.


Local excision of rectal cancer for cure: should we always regard rigid pathologic criteria?
The purposes of this study were to assess the relationship between the incidence of recurrence and the pathologic criteria usually applied to the selection of patients for curative local excision of rectal carcinoma and to determine whether failure to fulfill one of these criterias is always an indication for secondary abdominoperineal resection (APR). From 1982 to 1992, 30 patients with rectal carcinoma (mean age: 69 +/- 10 years) were treated by local excision (LE). Univariate analysis of the cancer recurrence rate according to pathologic criteria was performed. The mean follow-up was 57 +/- 40 months (range: 6-145). Five patients (17%) had recurrent disease (local in 3, distant in 1, and local and distant in 1). Two of the three local cases were successfully treated. At the end of follow-up, 90% of the patients had no evidence of recurrence, and the rectal cancer-specific death rate was 10%. Although not significant, tumor penetration beyond the submucosa and vessel or nerve invasion were associated with an increased incidence of cancer recurrence. Tumor size and differentiation, and the presence of a mucinous component were not associated with a significant increase in recurrence. According to the usual pathologic criteria proposed for curative LE, 20 patients should, theoretically, have undergone secondary APR. However, 16 of them (80%) were treated by LE only, and at the end of follow-up, 17 (85%) were alive without recurrence. The rigid rule of systematically performing secondary APR after LE for rectal carcinoma when one or more pathologic selection criteria are not met should perhaps be reconsidered, especially for tumors exceeding 3 cm in diameter, moderately differentiated tumors, and in incidences when a mucinous component is present. However, in cases of vessel, nerve or muscular invasion, secondary APR is probably the best choice for cure.


Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats.
Epidemiological data indicate a high incidence of cerebral aneurysms in postmenopausal women. To elucidate the pathogenesis of cerebral aneurysms, we focused on the contribution of endothelial damage in rats. We induced estradiol deficiency by oophorectomy (OVX), hypertension, or both, and hemodynamic stress in 7-week-old female Sprague-Dawley rats. They were then given hormone-replacement therapy with 17beta-estradiol or an angiotensin II type 1 receptor blocker (ARB). The effects of estradiol, angiotensin II type 1 receptor blocker, or both on cultured endothelial cells were also examined. The number of anomalously shaped endothelial cells was higher in OVX than hypertensive rats (P < 0.05). Rats subjected to hypertension and OVX exhibited a marked increase in the incidence of saccular cerebral aneurysms. Estradiol or angiotensin II type 1 receptor blocker treatment reduced this incidence (P < 0.05). The endothelial nitric oxide synthase (eNOS) mRNA level in the intracranial artery of OVX and hypertensive and OVX rats was low (P < 0.05). Immunohistochemically, the expression of eNOS and estrogen receptor alpha (ERalpha) in the vascular wall of hypertensive and OVX rats was decreased; angiotensin II and the nicotinamide adenine dinucleotide phosphate oxidase subunits nicotinamide adenine dinucleotide phosphate oxidase 4 and p22phox were strongly expressed in cerebral aneurysms. In the absence of estradiol, eNOS was downregulated and nicotinamide adenine dinucleotide phosphate oxidase expression was increased in endothelial cells; angiotensin II augmented these phenomena. The regulation of eNOS was mediated by ERalpha. These results suggest that estrogen deficiency induces endothelial dysfunction and reactive oxygen species generation, triggering endothelial damage that leads to cerebral aneurysms and that hypertension is an additional risk factor. A therapy targeted at the endothelium and management of hypertension may help to prevent cerebral aneurysms.


Comparison of visual 24-hour and spectrophotometric 48-hour MICs to CLSI reference microdilution MICs of fluconazole, itraconazole, posaconazole, and voriconazole for Candida spp.: a collaborative study.
A multicenter (six-center) study evaluated the performance (interlaboratory reproducibility, compatibility with reference methods, and categorical agreement) of 24-h visual and 48-h spectrophotometric MICs. MICs of fluconazole, itraconazole, voriconazole, and posaconazole were compared to reference 48-h microdilution broth visual MICs (CLSI [formerly NCCLS] M27-A2 document) for 71 isolates of Candida spp. that included 10 fluconazole-resistant strains. Twenty readings (5%) were reported as showing no growth at 24 h, mostly for Candida dubliniensis and from a single center. The overall interlaboratory agreement of 24-h visual readings and 48-h spectrophotometric MICs, as well their compatibility with reference values, were excellent with the four triazoles for most of the species (93 to 99%, within 3 dilutions). The categorical agreement between the investigational reading conditions and reference values was good with fluconazole and voriconazole (93 to 97%) but lower with itraconazole (86 to 88%), due primarily to minor errors. There were only 0 to 3% very major errors with these three triazoles; the number of substantial errors (more than three dilutions) was also low (<2%) with posaconazole. These data suggest that the performance of both investigational MIC readings gives results similar to those of reference MICs. Since spectrophotometric MICs are more objective and the 24-h time period would shorten the MIC determination of azoles, the description of either of these two reading conditions in the M27-A2 document should be considered by the CLSI subcommittee in addition to or instead of the longer, less practical, and more subjective 48-h visual MIC reading.


Flavor preferences conditioned by intragastric nutrient infusions in rats fed chow or a cafeteria diet.
Numerous studies demonstrate that chow-fed rats learn to prefer flavors that are associated with the postingestive effects of nutrients. The rats>> limited dietary experience (i.e. only lab chow) may have facilitated preference learning because of the novelty of the training stimuli. This possibility was investigated by comparing nutrient conditioning in rats fed chow or a varied "cafeteria" diet. Rats in Experiment 1 were trained during alternate sessions (30 min/day) to drink two different flavors paired with concurrent intragastric infusions of 16% Polycose or water. Both diet groups displayed similarly strong preferences (89%) for and increased acceptance of the Polycose-paired flavor. A more demanding learning task was used in Experiment 2: new flavors were paired with delayed (15 min) infusions of Polycose or water. The chow and cafeteria groups both showed reduced, but comparable (78%, 77%) preferences for the Polycose-paired flavor. In Experiment 3, new flavors were paired with concurrent infusions of 7.1% corn oil or water. Again, the cafeteria and chow groups developed similar preferences for the nutrient-paired flavor (85%, 78%). Also, both groups preferred the Polycose-paired flavor of Experiment 1 to the oil-paired flavor of Experiment 3 (76%, 78%). These results indicate that dietary variety does not interfere with nutrient-conditioned flavor preference learning in rats.


Electrophysiological and anatomical estimation of the number of motor units in the monkey extensor digitorum brevis muscle.
The electrophysiological technique used to estimate the number of motor units in man (McComas et al., 1971b) was tested in six monkeys. The number of motor units was estimated electrophysiologically in the extensor digitorum brevis (EDB) after deafferentation by excision of the lumbo-sacral dorsal root ganglia. In five animals, the mean number of motor units obtained by the technique was in good agreement with the number of alpha motor fibres counted in the nerve to EDB. However, the results obtained in one animal with partial denervation of the EDB indicate that the technique might be unreliable, at least at certain stages, after a peripheral nerve lesion.


Beyond the new normal: Assessing the feasibility of vaccine-based suppression of SARS-CoV-2.
As the COVID-19 pandemic drags into its second year, there is hope on the horizon, in the form of SARS-CoV-2 vaccines which promise disease suppression and a return to pre-pandemic normalcy. In this study we critically examine the basis for that hope, using an epidemiological modeling framework to establish the link between vaccine characteristics and effectiveness in bringing an end to this unprecedented public health crisis. Our findings suggest that a return to pre-pandemic social and economic conditions without fully suppressing SARS-CoV-2 will lead to extensive viral spread, resulting in a high disease burden even in the presence of vaccines that reduce risk of infection and mortality. Our modeling points to the feasibility of complete SARS-CoV-2 suppression with high population-level compliance and vaccines that are highly effective at reducing SARS-CoV-2 infection. Notably, vaccine-mediated reduction of transmission is critical for viral suppression, and in order for partially-effective vaccines to play a positive role in SARS-CoV-2 suppression, complementary biomedical interventions and public health measures must be deployed simultaneously.


Molecular cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues.
Two mercurial-inhibitable water-transporting proteins have been identified: CHIP28, an erythrocyte water channel also expressed in kidney tubules and selected extrarenal epithelia, and WCH-CD, a kidney collecting duct water channel. In searching for a protein responsible for the high transcellular water permeability in lung alveolus, we cloned a 32-kDa water channel (mercurial-insensitive water channel (MIWC)) from a rat lung cDNA library with several novel features. Water permeability was strongly increased in Xenopus oocytes expressing MIWC in a mercurial-insensitive manner, in contrast to known water channels. By in situ hybridization, MIWC showed an unique distribution in cells that do not express CHIP28, including kidney papillary vasa recta, cells lining the subarachnoid space and ventricles in brain, the inner nuclear layer in retina, and the conjunctival epithelium. An alternatively spliced form of MIWC with a 165-base pair deletion in the coding sequence was also identified; relative expression of the spliced mRNA was tissue-specific. The MIWC water channel may participate in the urinary concentrating mechanism, the absorption of cerebrospinal fluid, and other physiological processes.


Hepatitis B virus infection in Chinese patients with hepatitis C virus infection: prevalence, clinical characteristics, viral interactions and host genotypes: a nationwide cross-sectional study.
Little is known about hepatitis B virus (HBV) infection in patients with hepatitis C virus (HCV) infection in China. This study aimed to evaluate the prevalence, clinical characteristics, viral interactions and host genotypes of HBV/HCV dual infection compared with HCV monoinfection. A cross-sectional study. China. 997 patients with HCV from 28 university-affiliated hospitals in China were enrolled in this research. Patients were divided into two subgroups. The prevalence of HBV infection in patients with HCV was 4.11% (41/997). The age-specific prevalence of HBsAg was 0.70%, 3.97% and 5.85% in groups aged 18-30, 30-50 and >50 years old (p=0.057), respectively. Patients with HBV/HCV dual infection and patients with HCV monoinfection had similar HCV viral loads (5.80±0.89 vs 5.83±1.00 log10 IU/mL, p=0.904). The dominant HCV genotype was 1b in both groups (53.65% vs 56.90%, p=0.493). The protective C allele in IL-28B (rs12979860) was also the dominant allele type in both patient groups (85.36% vs 83.99%, p=0.814). Patients with HBV/HCV dual infection had a higher ratio of liver cirrhosis and hepatic decompensation than patients with HCV monoinfection (39.02% vs 17.69%, p=0.001; 31.70% vs 12.13%, p=0.001). The HBV burden was moderate in HCV-infected patients in China. Liver cirrhosis was more common in patients with HBV/HCV dual infection, suggesting the need for closer monitoring of dual-infected individuals. NCT01293279; Post-results.


Getting messages on the air: findings from the 1982 Alcohol Abuse Prevention Campaign.
A necessary step in an effective public education campaign is obtaining sufficient broadcast time to reach substantial numbers of a target audience. By this criterion, the 1982 Alcohol Abuse Prevention Campaign was very successful. Between February and December 1982, 17,409 alcohol-related public service announcements (PSAs) were broadcast in 75 major media markets around the country. Campaign messages reached target audiences with sufficient frequency to have had likely effects on attitudes and behavior. Key elements in the success of the effort were producing high quality broadcast materials, providing technical assistance to aid state and local groups in the message dissemination process, and providing for state and local control over the timing and release of materials.


Membrane Recruitment as a Cancer Mechanism: A Case Study of Akt PH Domain.
Evidence from multiple laboratories has suggested the possibility that defective membrane recruitment, triggered by mutations in conserved lipid binding domains, could be a common molecular mechanism underlying carcinogenesis. Now a recent paper by Carpten et al. in Nature has identified and analyzed one such mutation; specifically, E17K in the lipid binding pocket of the Akt plextrin homology (PH domain). This study is a tour de force that (i) pinpoints a mutation widespread in human cancers, (ii) analyzes the effect of this mutation on lipid binding domain structure, (iii) shows that the mutation enhances plasma membrane recruitment, and (iv) demonstrates that such recruitment is linked to Akt pathway superactivation, cellular transformation and tumor formation. Overall, the work provides the most convincing illustration to date that a mutation altering the membrane docking of a lipid binding domain can directly trigger cancer. Furthermore, the findings raise intriguing questions regarding the mechanism by which the highly carcinogenic E17K mutation drives enhanced recruitment of the Akt PH domain to the plasma membrane.


Efficacy of Acupuncture in the Treatment of Elderly Patients with Hypertension in Home Health Care: A Randomized Controlled Trial.
Objective: To evaluate the efficacy of acupuncture in helping antihypertensive drugs lower the hypertension of elderly patients in home health care. Design: Randomized controlled trial. Setting: Subjects were recruited from Branch of Linsen, Chinese Medicine, and Kunming, Taipei City Hospital, Taipei, Taiwan. Subjects: A total of 70 participants with hypertension in home health care were assigned randomly to the acupuncture group (35 participants) or the control group (35 participants). Interventions: The acupuncture group received antihypertensive drugs plus acupuncture twice a week for 12 weeks, and the control group received antihypertensive drugs only. Acupuncture points SP10, SP6, LR3, ST36, and LI4 were used bilaterally. Each acupuncture treatment session lasted 30 min. All the subjects were instructed not to alter their diet, physical activity, or use of drugs. Outcome measurements: Blood pressure (BP), heart rate variability, and the Constitution in Chinese Medicine Questionnaire (CCMQ) were assessed at baseline and at 6 and 12 weeks from the baseline between 9 am and 10 am in all subjects. Results: A total of 31 participants in each group completed the study. Within-group differences were observed in systolic BP (SBP) (p < 0.001), diastolic BP (p < 0.001), standard deviation of normal sinus beat intervals (SDNN) (p = 0.01), low frequency (p = 0.05), high frequency (p = 0.01), total power (TP) (p = 0.01), percentage of successive intervals that differ by more than 50 msec (PNN50) (p = 0.01), qi deficiency (p = 0.003), blood stasis (p = 0.02), and qi depression (p = 0.03) constitution. Significant between-group differences were observed in SBP (p = 0.001), SDNN (p = 0.008), and TP (p = 0.04). Conclusions: This study suggested that in the home health care hypertension population, antihypertensive drugs plus acupuncture may be more beneficial in lowering BP and in regulating autonomic nervous system activity than drugs alone. A longer follow-up and larger sample size should be considered in future studies to reveal the precise effect of acupuncture followed by evidence-based practice.


Regulation of memory antibody levels: the role of persisting antigen versus plasma cell life span.
Protective Ab levels can be maintained for years upon infection or vaccination. In this study, we studied the duration of Ab responses as a function of the life span of plasma cells and tested the role of persisting Ag in maintaining B cell memory. Our analysis of B cell responses induced in mice immunized with virus-like particles demonstrates the following: 1) Ab titers are long-lived, but decline continuously with a t(1/2) of approximately 80 days, which corresponds to the life span of plasma cells; 2) the germinal center (GC) reaction, which lasts for up to 100 days, is dependent on Ag associated with follicular dendritic cells; and 3) early GCs produce massive numbers of plasma and memory B cell precursors, whereas the late Ag-dependent GCs are dispensable for the maintenance of Ab levels and B cell memory.


Seizure frequency, quality of life, behavior, cognition, and sleep in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol.
To evaluate the effects of oral pharmacological cannabidiol (CBD) on seizures, side effects, quality of life, behavior, mood, and sleep in children with drug-resistant epilepsy (DRE) during a phase II, prospective, open-label clinical study. During a phase II expanded access program (EAP) study to evaluate the safety and efficacy of using cannabidiol (CBD) for the long-term treatment of children with drug-resistant epilepsy, secondary outcome measures were also performed, including quality of life (QOLCE), behavior (aberrant behavior checklist ABC), and sleep (children's sleep habit questionnaire, CSHQ). Participants between the ages of 2 and 16 years of age with drug-resistant epilepsy (n = 35) were included in this EAP. Primary outcomes included change in parent-recorded seizure frequency relative to baseline, as well as the safety and tolerability over the course of 24 months of CBD treatment. Secondary outcomes observed in the first 12 months included changes in child behavior, and cognitive function, and sleep quality. The median change in overall seizure frequency decreased from baseline (n = 33) by -61.3% ([n = 33], Inter Quartile Range (IQR): 43-88%) at month 3, -62.9% at month 6 ([n = 29], IQR: 48-92%), -74.7% at month 12 ([n = 29], IQR: 64-96%), and finally -83.7% ([n = 28], IQR: 68-100%) at the conclusion of 24 months of treatment. Seven (20%) of the 35 patients enrolled withdrew from treatment and observation by month 24: 2 failed inclusion criteria at baseline, 4 due to lack of treatment efficacy, and 1 was lost to follow-up. The 12-month recording of secondary measures revealed a significant improvement in Irritability (-39.4%, [n = 28], ABC), Hyperactivity (-45.4%, [n = 28], ABC), Cognition in Quality of Life (+14.2%, [n = 28], QOLCE), Behavioral function (+14.7%, [n = 28], QOLCE), General Health (+14.7%, [n = 28], QOLCE), Sleep duration (-33.9%, [n = 28], CSHQ), Daytime sleepiness (-23.8%, [n = 28], CSHQ), and nocturnal arousals (-36.2%, [n = 28], CSHQ). The results of this phase II open-label study demonstrate that pharmacological CBD significantly reduces seizure frequency, and improves QOL, behavior deficits, and sleep disruption, in children with drug-resistant epilepsy. The results also suggest that CBD is efficacious in controlled seizures over a 2-year period in childhood DRE.


Serum alpha-fetoprotein--a biochemical indicator of prenatal hypothyroidism.
Serum alpha-fetoprotein (AFP) was analysed at 10-30 days of age in infants with positive TSH screening tests for congenital hypothyroidism. These levels were significantly higher in infants with true positive screening tests than in those with false positive tests; 27 of 43 infants with congenital hypothyroidism had serum AFP levels above the age-related reference range. The postnatal rate of elimination of AFP from serum did not differ in hypothyroid and euthyroid infants, indicating that the difference in serum AFP was due to more extensive synthesis in hypothyroid individuals. The level of serum AFP was inversely correlated with the roentgenological skeletal maturation index. It is postulated that increased serum AFP is caused by prenatal hypothyroidism and that analysis of serum AFP is a valuable tool to identify those infants with congenital hypothyroidism who are at risk of neuropsychological sequelae.


Measures of excellence: the search for the gold standard.
Questions concerning some of the values we hold as librarians and the goals, standards, and other evaluation tools we derive from them are discussed in the context of the history of our profession and the present period of rapid change. The concepts of stable and changing paradigms and of "scientific communities" provide the foundation for consideration of how a changing conceptual framework can affect values and their application in the evaluation process. One of many possible scenarios for the future is briefly outlined to demonstrate how some traditional values may fare.


The genetic basis of human erythrocyte pyridoxal kinase activity variation.
Thirty years ago we reported that erythrocyte pyridoxal kinase activity of African-Americans was strikingly lower than that of persons with European ancestry in a tissue-specific manner. At the time, it was impossible to elucidate the mechanism by which evolution had selectively lowered the enzyme activity in one cell type but not in others. We have now identified a promoter mutation with potential erythroid-specific properties that could be the basis of a novel mechanism of controlling cell-specific decreased activity of an essential enzyme.