Synthesis, characterization, and antimicrobial evaluation of oxadiazole congeners.
A series of 1,3-oxazole, 1,3-thiazole, isomeric 1,2,4-oxadiazole, 1,3,4-oxadiazole, and 1,2,3,4-tetrazole heterocycles was synthesized. All the compounds shared as a common feature the presence of a 4-hydroxyphenyl substituent. The structures of the synthesized compounds were confirmed by MS, ¹H-NMR, and elemental analysis. In vitro antimicrobial activity for all the newly synthesized compounds at concentrations of 200-25 μg/mL was evaluated against Gram+ve organisms such as methicillin-resistant Staphylococcus aureus (MRSA), Gram-ve organisms such as Escherichia coli (E. coli), and the fungal strain Aspergillus niger (A. niger) by the cup plate method. Ofloxacin and ketoconazole (10 μg/mL) were used as reference standards for antibacterial and antifungal activity, respectively. Compounds 15, 16, and 20 showed notable antibacterial and antifungal activities at higher concentrations (200 μg/mL), whereas 17-19 were found to display significant antibacterial or antifungal activity (25-50 μg/mL) against the Gram+ve, Gram-ve bacteria, or fungal cells used in the present study.


Euglycemic diabetic ketoacidosis caused by dapagliflozin: A case report.
Diabetic ketoacidosis is a serious and potentially life-threatening acute complication of diabetes mellitus (DM). Euglycemic diabetic ketoacidosis (eDKA) is however challenging to identify in the emergency department (ED) due to absence of marked hyperglycemia, often leading to delayed diagnosis and treatment. eDKA has been recently found to be associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors, one of the newest classes of antidiabetics, though there are very limited reports implicating dapagliflozin as the offending agent in ED patients. Here we report a type 2 diabetic patient who presented to the ED with eDKA secondary to dapagliflozin administration. A 61-year-old Asian female with underlying type 2 DM presented to our ED with body weakness, dyspnea, nausea, vomiting, and mild abdominal pain for the past 2 days. These symptoms were preceded by poor oral intake for 1 week due to severe toothache. Dapagliflozin was recently added to her antidiabetic drug regimen of metformin and glibenclamide 2 weeks ago. Arterial blood gases showed a picture of severe metabolic acidosis with an elevated anion gap, while ketones were elevated in blood and positive in urine. Blood glucose was mildly elevated at 180 mg/dL. Serum lactate levels were normal. Our patient was thus diagnosed with eDKA. Our patient was promptly admitted to the intensive care unit and treated for eDKA through intravenous rehydration therapy with insulin infusion. Serial blood gas analyses showed gradual resolution of the patient's ketoacidosis with normalized anion gap and clearance of serum ketones. She was discharged uneventfully on day 4, with permanent cessation of dapagliflozin administration. Life-threatening eDKA as a complication of dapagliflozin is a challenging and easilymissed diagnosis in the ED. Such an ED presentation is very rare, nevertheless emergency physicians are reminded to consider the diagnosis of eDKA in a patient whose drug regimen includes any SGLT2 inhibitor, especially if the patient presents with nausea, vomiting, abdominal pain, dyspnea, lethargy, and is clinically dehydrated. These patients should then be investigated with ketone studies and blood gas analyses regardless of blood glucose levels for prompt diagnosis and treatment.


Thrombocytopenia and bleeding in dental procedures of patients with Gaucher disease.
The risk of bleeding during dental procedures may be increased in patients with Gaucher disease. We aimed to evaluate potential coagulation and platelet function abnormalities and targeted therapy accordingly. Patients with type 1 Gaucher disease who were treated at the Oral and Maxilo-Facial surgery clinic at Sheba Medical Center between 2003 and 2010 comprised the study cohort. Data collected included disease history, enzyme treatment, platelet counts, dental therapy and outcome. Bleeding was defined as excessive bleeding during or immediately following procedure. Coagulation studies and platelet function tests including aggregometry were performed on all patients. Dental procedures (n = 14, including eight teeth extractions, two crown lengthening procedures, one cyst enucleation and three deep dental scaling) of seven patients were studied. Mean platelet count prior to procedure was 73 K ± 14.8 mm(3). Patients bleeding risk score was calculated according to previous history of bleeding tendency, degree of thrombocytopenia, presence of comorbid coagulopathy and the type of dental procedure. Two patients with highest risk score received prophylactic platelet transfusions, three patients (medium-risk) received DDAVP preprocedure and all received systemic tranexamic acid, which was the only systemic therapy for low-risk patients. Meticulous surgical local haemostasis was applied. No excessive intra-operative or postoperative bleeding occurred. Patients with Gaucher disease who have thrombocytopenia and abnormal platelet function tests may be safely treated if meticulous haemostasis is applied along with systemic therapy as required. Platelet transfusions are not mandatory and should be applied considering the procedure-related risk and the patient's calculated haematological risk for bleeding.


Compensation, social trends alter hospital-MD relations.
Changes in physician compensation and social trends are ushering in a new era in hospital-physician group relations, according to experts. Physician payment reform, the shift toward managed care, ongoing primary care physician shortages, and the changing lifestyle preferences of younger physicians are helping to redefine hospital-MD relations for years to come. Still, some health care organizations are ahead of the curve on this issue. Meanwhile, what does it take to lure a city doctor to Weiser, Idaho? Some towns will do almost anything to recruit a physician.


[Personality and transplantation].
The association between personality and medical health has been subject of several studies. The most accepted theoretical models of personality, in this context, are of two kinds: Three factor model (neuroticism, extraversion epsicoticism) and five factor model (neuroticism, extraversion, consciousness, agreeableness, and openess to experience). There are three ways which can explain the interaction between personality and medical illness: Hyperactivity induced by personality, personality and illness independent predisposition, non-healthy behaviours induced by personality. There are several ways of assessing personality in medical illness: taxonomic vs dimensional approaches; Auto vs hetero evaluation; Specific vs non-specific methods. We analyse the arguments against and favourable to any of these approaches. Some of the most used instruments to assess personality in medical context are the NEOPI versions (original NEO-PI, NEO-PI-R, NEO-FFI-60). NEO-PI-R and NEO-FFI-60 are validated to the Portuguese population. According to the few published studies assessing personality in transplanted patients we concluded that neuroticism was associated to a poor quality of life (physical, mental, social) in post-transplantation period; extraversion to a better quality of life (physical, mental, social); type D personality to a worse quality of life and a increased mortality and rejection after transplantation. We also concluded that personality disorders were not associated to an increase of alcohol consumption in alcohol liver disease transplanted patients.


[Antibody avidity indices of the saliva and serum antibodies in salmonellosis patients].
The avidity characteristics of salivary and serum antibodies have been determined in 179 salmonellosis patients by means of the indirect hemagglutination inhibition test. These investigation have shown that, in contrast to serum antibodies, no changes occur in the avidity of salivary antibodies in the course of the disease. This is due to the fact that secretory antibodies belong to IgA which have no tendency to ripening. The regularities thus established reflect the role of secretory and serum antibodies in the pathogenesis of Salmonella infections.


How the new Hologic hip normal reference values affect the densitometric diagnosis of osteoporosis.
In February 1997, Hologic supplied new software to all QDR dual-energy X-ray absorptiometry (DXA) machines replacing the previous femoral normative reference database with the NHANES III normative data. In addition to changing the normative database (and therefore T-scores) for all regions of the hip, the new software has changed the primary region of interest from the femoral neck to the total hip. In the present study we examined how these changes influence the densitometric diagnosis of osteoporosis in a large clinical referral population (n = 2311, mean age 62.7 years). The patients had spine and hip DXA performed at either of two centers using a Hologic QDR-2000 over a 4-year period. T-scores were derived for each patient using both previous and current young normal reference databases. Intraindividual differences in T-scores were calculated. The prevalence of osteoporosis based on the two normative databases and the difference between the prevalence was calculated for each skeletal site. The average paired difference between current and previous T-scores at femoral neck is 0.64, the difference increasing with age. Using the new normative database, the percentage of osteoporotic patients decreases from 49% of all patients at the femoral neck to 28% at the femoral neck and 20% at the total hip. In conclusion, the densitometric diagnosis of osteoporosis will be affected in a significant proportion of women as a result of the implementation of the new hip normative database supplied by Hologic. Whether this will translate into fewer patients being treated remains to be seen.


Ischemic edema in stroke. A parallel study with computed tomography and cerebrospinal fluid markers of disturbed brain cell metabolism.
Thirteen patients with stroke and one with TIA had repeated examinations with computed tomography (CT) of the head, examination of the cerebrospinal fluid (CSF) for adenylate kinase, glutathione, lactate, and albumin and clinical evaluations during the first fortnight after onset. In 9 patients with cerebral infarction edema shown on the CT scans was maximal on days 2--5, after which it diminished. In 2 patients with intracerebral hemorrhage the edema appeared early as a zone of low-attenuation around the high-attenuation area. Most patients with large lesions deteriorated clinically during development of the edema. In 3 patients the CT scans were inconclusive, probably because the lesion was too small. Adenylate kinase activity was present in all CSF samples during the period 6 hours-5 days, while glutathione was occasionally present in the CSF in 12 of the 14 patients. These findings are believed to indicate cell swelling and a leak in the plasma membrane. Based on these observations, it is suggested that initial ischemic edema is intracellular in patients with cerebral infarction, and that adenylate kinase in CSF is a sensitive marker for this type of edema.


The Genie Is Out of the Bottle: What ChatGPT Can and Cannot Do for Medical Professionals.
ChatGPT is a cutting-edge artificial intelligence technology that was released for public use in November 2022. Its rapid adoption has raised questions about capabilities, limitations, and risks. This article presents an overview of ChatGPT, and it highlights the current state of this technology for the medical field. The article seeks to provide a balanced perspective on what the model can and cannot do in three specific domains: clinical practice, research, and medical education. It also provides suggestions on how to optimize the use of this tool.


The ulnar nerve as vascularized nerve transplant. Part I: Anatomy: arterial vascular supply.
The ulnar nerve is supplied basically by the arteries accompanying it in its various locations: in the axillary section, by a branch of the lateral thoracic artery or directly by the axillary artery; in the upper arm, by branches originating from the collateral ulnar superior artery; in the supracondylar section and in the region of the groove for the ulnar nerve, by branches originating from the anastomosis of the collateral arteries and the posterior branch of the recurrent ulnar artery; and in the forearm, by branches of the recurrent ulnar artery and the ulnar artery. Venous return is by the venae comitantes. Since the ulnar nerve possesses a good arterial supply, it may be used with different techniques as a vascularized nerve transplant in traumatic lesions of the brachial plexus, to repair more important missing nerve paths.


Martial arts, combat sports, and mental health in adults: A systematic review.
Martial arts (MA) and combat sports (CS) are physical activities that may be associated with health-related outcomes. The aim of this systematic review was to synthesize and evaluate the available evidence on the relationship between MA and CS training and mental health of adult practitioners (≥18 years). CochraneLibrary, EBSCOhost, Web-of-Science, and Scopus databases were searched up to September 2022 for measures of self-related constructs, ill-being and well-being, cognition and brain structure/function, in adult MA/CS practitioners. Seventy cross-sectional and two longitudinal studies were retained and submitted to risk of bias assessments through an adapted version of the Cochrane Collaboration's Tool. Associations between MA/CS practice and self-related constructs were inconclusive for both consistency and strength of evidence. Limited evidence of significant associations emerged for sub-domains of ill-being (i.e., externalizing and internalizing emotion regulation), and well-being. In regard to cognitive and brain structural/functional variables, evidence of positive association with MA/CS practice was consistent with respect to perceptual and inhibition abilities but limited with respect to attention and memory. Evidence on negative associations of boxing with changes of brain structure integrity due to concussions was also inconclusive. Functional imaging techniques could shed light onto brain activation mechanisms underlying complex cognitive performance. In relation to moderators, mixed results were found for activity exposure, expertise, level of competitive engagement (which often covary with the length of training) and sex and type of MA/CS. The MA/CS' multifaceted nature may produce different, sometimes conflicting outcomes on mental health. Studies on MA/CS represent a flourishing research area needing extensive improvement in theoretical and practical approaches.


Comparison of the nutritional composition of experimental fermented milk:wheat bulgur blends and commercially available kishk and tarhana products.
Dried, fermented blends of dairy products and cereals, such as kishk and tarhana, are foodstuffs traditionally consumed in many regions as they possess good nutritional qualities and extended storage stability. This study examined the nutritional composition of kishk or tarhana type products and compared with experimental blends of fermented milk and wheat bulgur containing 60-80% milk. The blends with higher milk contents had levels of protein (18.9%) and fat (5.8%) at the concentrations specified in fortified blended foods as outlined by the World Food Program. Higher milk contents were also associated with higher contents of calcium (323.2 mg/100 g), phosphorus (335.3 mg/100 g), vitamin A (486.7 µg/100 g) and α-tocopherol (174.5 µg/100 g). The nutritional content of the experimental fermented milk:wheat bulgur blends compared favourably with that of the commercial samples. These blends may be suitable as base products, to be fortified with micronutrients, for the development of fortified blended foods (FBFs) for humanitarian distribution.


Addressing stereotypes of aging and interest in careers working with older adults through education.
Negative stereotypes about older adults are increasing and contributing to a shortage of professionals in gerontology. Building on the PEACE model (Positive Education about Aging and Contact Experiences), two experiments used education to address stereotypes associated with older adults. Participants were randomly assigned to read brief articles that: challenged stereotypes about older adults (condition 1), challenged stereotypes about careers working with older adults (condition 2), challenged both stereotypes (condition 3), or described careers in general (control; condition 4). In Study 1, 399 undergraduates in all 3 experimental conditions (vs. control participants) reported lower levels of ageism, more positive age perceptions, and more aging knowledge in an immediate and delayed (1-2 weeks) post-test. In Study 2, 446 national community participants (ages 18- 25) in all experimental conditions (vs. control participants) reported greater positive age perceptions, aging knowledge, and interest in psychology and social work careers with older adults in an immediate post-test. These findings highlight the promise of using brief online methods to challenge stereotypes, provide more positive and accurate views of aging and older adults, and increase interest in careers working with older adults. Implications are discussed.


Cost of noninfectious comorbidities in patients with HIV.
We hypothesized that the increased prevalence of noninfectious comorbidities (NICMs) observed among HIV-infected patients may result in increased direct costs of medical care compared to the general population. Our objective was to provide estimates of and describe factors contributing to direct costs for medical care among HIV-infected patients, focusing on NICM care expenditure. A case-control study analyzing direct medical care costs in 2009. Antiretroviral therapy (ART)-experienced HIV-infected patients (cases) were compared to age, sex, and race-matched adults from the general population, included in the CINECA ARNO database (controls). NICMs evaluated included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure. Medical care cost information evaluated included pharmacy, outpatient, and inpatient hospital expenditures. Linear regression models were constructed to evaluate predictors of total care cost for the controls and cases. There were 2854 cases and 8562 controls. Mean age was 46 years and 37% were women. We analyzed data from 29,275 drug prescription records. Positive predictors of health care cost in the overall population: HIV infection (β = 2878; confidence interval (CI) = 2001-3755); polypathology (β = 8911; CI = 8356-9466); age (β = 62; CI = 45-79); and ART exposure (β = 18,773; CI = 17,873-19,672). Predictors of health care cost among cases: Center for Disease Control group C (β = 1548; CI = 330-2766); polypathology (β = 11,081; CI = 9447-12,716); age < 50 years (β = 1903; CI = 542-3264); protease inhibitor exposure (per month of use; β = 69; CI = 53-85); CD4 count < 200 cells/mm(3) (β = 5438; CI = 3082-7795); and ART drug change (per change; β = 911; CI = 716-1106). Total cost of medical care is higher in cases than controls. Lower medical costs associated with higher CD4 strata are offset by increases in the care costs needed for advancing age, particularly for NICMs.


Linkage of TATA-binding protein and proteasome subunit C5 genes in mice and humans reveals synteny conserved between mammals and invertebrates.
The TATA-binding protein (TBP) is a factor required for the transcription of all classes of eukaryotic genes. Here, we demonstrate that in the mouse the TBP-encoding gene (Tbp) resides next to the proteasomal subunit C5-encoding gene (Psmb1). The genes are located on mouse chromosome 17 in the t complex within the Hybrid sterility 1 (Hst1) region. We demonstrate that the homologous human genes (TBP AND PSMB1) are tightly linked on the long arm of chromosome 6, in a region syntenic with the proximal part of mouse chromosome 17. The mouse Tbp and Psmb1 and the human TBP and PSMB1 genes are transcribed in the opposite orientation. The TATA-binding protein and proteasomal subunit C5 genes are also linked on chromosome III of Caenorhabditis elegans, and together they are linked to other genes whose homologs map to human chromosome 6 and mouse chromosome 17. In the Drosophila genome, the housekeeping TATA-binding protein gene maps close to two other genes with homologs in the mammalian major histocompatibility complex. There thus exists conserved synteny of unrelated genes between mammals and invertebrates.


Cdc25B dual-specificity phosphatase inhibitors identified in a high-throughput screen of the NIH compound library.
The University of Pittsburgh Molecular Library Screening Center (Pittsburgh, PA) conducted a screen with the National Institutes of Health compound library for inhibitors of in vitro cell division cycle 25 protein (Cdc25) B activity during the pilot phase of the Molecular Library Screening Center Network. Seventy-nine (0.12%) of the 65,239 compounds screened at 10 muM met the active criterion of > or =50% inhibition of Cdc25B activity, and 25 (31.6%) of these were confirmed as Cdc25B inhibitors with 50% inhibitory concentration (IC(50)) values <50 microM. Thirteen of the Cdc25B inhibitors were represented by singleton chemical structures, and 12 were divided among four clusters of related structures. Thirteen (52%) of the Cdc25B inhibitor hits were quinone-based structures. The Cdc25B inhibitors were further characterized in a series of in vitro secondary assays to confirm their activity, to determine their phosphatase selectivity against two other dual-specificity phosphatases, mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-3, and to examine if the mechanism of Cdc25B inhibition involved oxidation and inactivation. Nine Cdc25B inhibitors did not appear to affect Cdc25B through a mechanism involving oxidation because they did not generate detectable amounts of H(2)O(2) in the presence of dithiothreitol, and their Cdc25B IC(50) values were not significantly affected by exchanging the dithiothreitol for beta-mercaptoethanol or reduced glutathione or by adding catalase to the assay. Six of the nonoxidative hits were selective for Cdc25B inhibition versus MKP-1 and MKP-3, but only the two bisfuran-containing hits, PubChem substance identifiers 4258795 and 4260465, significantly inhibited the growth of human MBA-MD-435 breast and PC-3 prostate cancer cell lines. To confirm the structure and biological activity of 4260465, the compound was resynthesized along with two analogs. Neither of the substitutions to the two analogs was tolerated, and only the resynthesized hit 26683752 inhibited Cdc25B activity in vitro (IC(50) = 13.83 +/- 1.0 microM) and significantly inhibited the growth of the MBA-MD-435 breast and PC-3 prostate cancer cell lines (IC(50) = 20.16 +/- 2.0 microM and 24.87 +/- 2.25 microM, respectively). The two bis-furan-containing hits identified in the screen represent novel nonoxidative Cdc25B inhibitor chemotypes that block tumor cell proliferation. The availability of non-redox active Cdc25B inhibitors should provide valuable tools to explore the inhibition of the Cdc25 phosphatases as potential mono- or combination therapies for cancer.


Novel Ameloblastin Variants, Contrasting Amelogenesis Imperfecta Phenotypes.
Amelogenesis imperfecta (AI) comprises a group of rare, inherited disorders with abnormal enamel formation. Ameloblastin (AMBN), the second most abundant enamel matrix protein (EMP), plays a critical role in amelogenesis. Pathogenic biallelic loss-of-function AMBN variants are known to cause recessive hypoplastic AI. A report of a family with dominant hypoplastic AI attributed to AMBN missense change p.Pro357Ser, together with data from animal models, suggests that the consequences of AMBN variants in human AI remain incompletely characterized. Here we describe 5 new pathogenic AMBN variants in 11 individuals with AI. These fall within 3 groups by phenotype. Group 1, consisting of 6 families biallelic for combinations of 4 different variants, have yellow hypoplastic AI with poor-quality enamel, consistent with previous reports. Group 2, with 2 families, appears monoallelic for a variant shared with group 1 and has hypomaturation AI of near-normal enamel volume with pitting. Group 3 includes 3 families, all monoallelic for a fifth variant, which are affected by white hypoplastic AI with a thin intact enamel layer. Three variants, c.209C>G; p.(Ser70*) (groups 1 and 2), c.295T>C; p.(Tyr99His) (group 1), and c.76G>A; p.(Ala26Thr) (group 3) were identified in multiple families. Long-read AMBN locus sequencing revealed these variants are on the same conserved haplotype, implying they originate from a common ancestor. Data presented therefore provide further support for possible dominant as well as recessive inheritance for AMBN-related AI and for multiple contrasting phenotypes. In conclusion, our findings suggest pathogenic AMBN variants have a more complex impact on human AI than previously reported.


Intensive Outpatient Program Effects on High-need Patients' Access, Continuity, Coordination, and Engagement.
The intensive and varied services required by high-need patients have inspired a number of new care delivery models; however, evidence of their effectiveness is mixed. This study evaluated whether augmenting a patient-centered medical home (PCMH) with intensive outpatient management enhances high-need patients' care processes. Retrospective analysis using differences-in-differences and χ tests. Of 545 high-need patients receiving PCMH care, 140 were previously randomly selected for the intensive outpatient management program; the remaining received usual care. We evaluated program effects on care continuity (proportion of primary care visits with assigned primary care physician); access (proportion of telephone visits out of all primary care encounters, missed appointment rate); care coordination (rate of follow-up after hospital discharge, new telehealth enrollment); and patient engagement (rates of online personal health record registration, advance directive completion). Compared with patients receiving usual care, patients enrolled in intensive management experienced a 5.9% increase in proportion of primary care visits with an assigned primary care physician (P<0.001) and a 17.9% increase in proportion of telephone-based visits (P<0.001). Patients in the program had 7.5% higher rates of telehealth referral (P=0.01), 17.2% higher rates of advance directive completion (P<0.01), and 9.3% higher rates of personal health record registration (P=0.02). There was no effect on missed appointments or posthospital discharge visit rates. Augmenting a PCMH with intensive outpatient management may have positive effects on primary care processes related to continuity, access, coordination, and patient engagement.


Postmenopausal hormone use and symptoms of gastroesophageal reflux.
Previous studies suggest that elevated levels of estrogen and progesterone, either through endogenous or exogenous sources, increase gastroesophageal reflux. To evaluate the relationship between symptoms of gastroesophageal reflux disease (GERD) and postmenopausal hormone (PMH) therapy, including the use of selective estrogen receptor modulators and over-the-counter (OTC) hormone preparations, we performed a prospective cohort study of 51,637 postmenopausal women enrolled in the Nurses' Health Study who provided data on the use of PMH therapy biennially since 1976, and information about symptoms of GERD in 2002. Among eligible participants, 12 018 women (23%) reported GERD symptoms. Compared with women who never used PMHs, the multivariate odds ratio (OR) for the risk of GERD symptoms was 1.46 (95% confidence interval [CI], 1.36-1.56) for past hormone users, 1.66 (95% CI, 1.54-1.79) for current users of estrogen only, and 1.41 (95% CI, 1.29-1.54) for current users of combined estrogen and progesterone. The risk of GERD symptoms increased significantly with increasing estrogen dosage (P < .001) and increasing duration of estrogen use (P < .001). Moreover, current selective estrogen receptor modulator users experienced an OR of 1.39 (95% CI, 1.22-1.59) for GERD symptoms, and women currently using OTC hormone preparations had an OR of 1.37 (95% CI, 1.16-1.62). Postmenopausal use of estrogens, selective estrogen receptor modulators, or OTC hormone preparations is associated with a greater likelihood of symptoms of GERD. This suggests a hormonal component to the pathophysiologic characteristics of GERD in women.


Relations between magnesium, calcium, and plasma renin activity in black and white hypertensive patients.
The heterogeneous status of magnesium and calcium metabolism in the hypertensive population may be related to the plasma renin activity (PRA). This study investigates the relationships between serum and erythrocyte magnesium (Mg2+) and calcium (Ca2+) concentrations and PRA in black and white essential hypertensive patients. Thirty-nine normotensive (20 black, 19 white) and 47 hypertensive (25 black, 22 white) subjects were studied. The PRA was measured by radioimmunoassay, Mg2+ and Ca2+ by atomic absorption spectroscopy, and serum ionized Ca2+ by a specific electrode. PRA and ionized Ca2+ were significantly lower in the black hypertensive as compared with the white hypertensive group (1.99 +/- 0.33 vs. 5.96 +/- 1.02 ng/ml/h for PRA; 1.28 +/- 0.07 vs. 1.42 +/- 0.01 mmol/l for ionized Ca2+: black hypertensives vs. white hypertensives p < 0.05). Ionized Ca2+ was significantly increased (p < 0.05) in the white hypertensive patients as compared with the normotensive controls (1.42 +/- 0.01 vs. 1.29 +/- 0.04 mmol/l). In the black hypertensive group, serum and erythrocyte Mg2+ were significantly (p < 0.05) decreased as compared with the other groups. The erythrocyte Ca2+ concentration was significantly elevated in both black and white hypertensive patients. In the group as a whole, serum Mg2+ and PRA were negatively correlated and ionized Ca2+ and PRA and ionized Ca2+ and erythrocyte Ca2+ positively correlated. However, in the subgroups, these correlations were only significant in the white group: r = -0.67 and p < 0.05 serum Mg2+ vs. PRA; r = 0.64, and p < 0.05 ionized Ca2+ vs. PRA; r = 0.82 and p < 0.01 ionized [Ca2+]i vs. erythrocyte Ca2+. These data suggest a relationship between PRA, Mg2+, and Ca2+ which may be more important in white than in black hypertensive patients.


Oxygen radical formation in anoxic transgression and anoxia-reoxygenation: foe or phantom? Experiments with a hypoxia tolerant bivalve.
Intertidal blue mussels, Mytilus edulis, experience hypoxia reoxygenation during tidal emersion and resubmersion cycles, and this is often suggested to represent a major stress for the animals, especially for their respiratory tissues, the gills. We exposed mussels to experimental short and prolonged anoxia and subsequent reoxygenation and analyzed the respiratory response in excised gill tissue and the effects of treatment on reactive oxygen species (mainly ROS: superoxide anion, O2·- and hydrogen peroxide, H2O2), formation using live imaging techniques and confocal microscopy. Our aim was to understand if this "natural stress" would indeed produce oxidative damage and whether antioxidant defenses are induced under anoxia, to prevent oxidative damage during reoxygenation. Exposure to declining pO2 in the respiration chamber caused an increase of gill metabolic rate between 21 and 10 kPa, a pO2 range in which whole animal respiration is reported to be oxyregulating. Exposure of the animals to severe anoxia caused an onset of anaerobiosis (succinate accumulation) and shifted high and low critical pc values (pc1: onset of oxyregulation in gills, pc2: switch from oxyregulation to oxyconformity) to higher pO2. Concentrations of both ROS decreased strongly during anoxic exposure of the mussels and increased upon reoxygenation. This ROS burst induced lipid peroxidation in the mantle, but neither were protein carbonyl levels increased (oxidative damage in the protein fraction), nor did the tissue glutathione concentration change in the gills. Further, analysis of apoptosis markers indicated no induction of cell death in the gills. To our knowledge, this is the first paper that directly measures ROS formation during anoxia reoxygenation in mussels. We conclude that hypoxia tolerant intertidal mussels do not suffer major oxidative stress in gill and mantle tissues under these experimental conditions.


Assessing the Long-Term Impact of Concussion upon Cognition: A 5-Year Prospective Investigation.
Jockeys have high rates of concussion, with 5% of jockeys receiving at least one concussion annually. The impact of acute concussion upon cognition is well understood, but less is known about the long-term effects of concussion upon cognition. Our aim was to assess the impact of concussion upon jockeys who had provided pre-concussion assessments of cognition using a prospective design. In this study, over a 5-year period, we assessed the cognitive performance of jockeys with ≥1 medically diagnosed concussion (MDC; n = 17, months since concussion, M = 29.18), against those who had not been concussed (NC; n = 41). Jockeys who had not been concussed in the preceding 6 months completed four computer-based cognitive assessments from the CogSport battery. Unlike the majority of the small existing literature, there was no difference (p ≥ .05) between the MDC and NC groups after controlling for age and baseline performance. Additionally, we used a measure of reliable change to assess for clinically meaningful decrements from baseline in each test and composite score 5 years later. None of the jockeys in the MDC group recorded significant decrements on any CogSport measure from baseline (z > -1.65). The findings suggest that the presence of concussion does not result in persistent decrements in cognitive performance and that when findings are considered collectively, assessing factors beyond medically diagnosed concussion (e.g., chronic stress, undiagnosed concussion) may improve the interpretation of our current findings.


Psychogenic facial pain: presentation and treatment.
Ninety three patients took part in a two centre double blind controlled clinical trial designed to assess the efficacy of dothiepin (Prothiaden) as compared with placebo and a soft biteguard in the treatment of psychogenic facial pain. The results showed the superiority of dothiepin over placebo in achieving pain relief; 71% of patients were pain free in the dothiepin group at nine weeks compared with 47% in the placebo group. The biteguard conferred no benefit and compliance in its use was poor. Out of 84 patients followed up for 12 months, 68 (81%) became pain free. An adverse life event before development of pain, minimal previous surgical treatment, and freedom from pain at nine weeks were strong prognostic indicators for successful treatment. These results are clear evidence of the efficacy of dothiepin in psychogenic facial pain, though the drug may be needed for up to a year.


Homologs of the small RNA SgrS are broadly distributed in enteric bacteria but have diverged in size and sequence.
Sugar phosphate stress in Escherichia coli is sensed and managed by the transcriptional regulator SgrR and the small RNA (sRNA) SgrS. SgrS is a dual function RNA that performs base pairing-dependent regulation of mRNA targets and encodes a small protein, SgrT. Homologs of SgrR were analyzed for gene synteny and inter-homolog identity to identify those that are likely to be functionally analogous. These 22 SgrR homologs were used to manually locate adjacent sRNAs functionally analogous to SgrS. SgrS homologs shared little sequence identity with E. coli SgrS, but most shared several structural features. The most conserved feature of SgrS homologs was the base pairing region while the most variable feature was the sgrT-coding sequence. Analyses of predicted interactions between SgrS:ptsG mRNA pairs in different organisms revealed interesting differences in the patterns of base pairing interactions. RNA pairs with more interrupted regions of complementarity had a higher proportion of G:C base pairs than those with longer contiguous stretches of complementarity. The identification of this set of homologous sRNAs and their targets sets the stage for future studies to further elucidate the molecular requirements for regulation by SgrS.


Association between menstruation signs and anxiety, depression, and stress in school girls in Mashhad in 2011-2012.
Menstruation signs are among the most common disorders in adolescents and are influenced by various environmental and psychosocial factors. This study aimed to define the association between menstruation signs and anxiety, depression, and stress in school girls in Mashhad in 2011-2012. This was a cross-sectional study on 407 high school girls in Mashhad who were selected through two-step random sampling. The students completed a questionnaire concerning demographic characteristics, menstruation, Depression, Anxiety, and Stress Scale of 21 questions (DASS-21), and menstruation signs in three phases of their menstruation. Data were analyzed by the statistical tests of Pearson correlation coefficient, Student's t-test, one-way analysis of variance (ANOVA), and regression through SPSS version 14. Based on the findings, 74% of the subjects reported pre-menstruation signs, 94% reported signs during bleeding, and 40.8% reported post-menstruation signs. About 44.3% of the subjects had anxiety, 45.5% had depression, and 47.2% had stress. In addition, Pearson correlation coefficient test showed a significant positive correlation between menstruation signs and depression, anxiety, and stress (P < 0.05). With regard to the association between menstruation signs and psycho-cognitive variables, prevention and treatment of these disorders by the authorities of education and training and the Ministry of Health are essential.


Neurobiological and Cognitive Profile of Young Binge Drinkers: a Systematic Review and Meta-Analysis.
This review provides the first systematic and quantitative synthesis of the literature examining the relationship between binge drinking, cognition, brain structure and function in youth aged 10 to 24 years. PubMed, EMBASE, Medline, PsychINFO and ProQuest were searched for neuroimaging, neurophysiological, and neuropsychological studies. A total of 58 studies (21 neuroimaging, 16 neurophysiological, 21 neuropsychological) met the eligibility criteria and were included in the review. Overall, abnormal or delayed development of key frontal executive-control regions may predispose youth to binge drink. These abnormalities appear to be further exacerbated by the uptake of binge drinking, in addition to alcohol-related neural aberrations in reward-seeking and incentive salience regions, indexed by cognitive deficits and maladaptive alcohol associations. A meta-analysis of neuropsychological correlates identified that binge drinking in youth was associated with a small overall neurocognitive deficit (g = -0.26) and specific deficits in decision-making (g = -1.70), and inhibition (g = -0.39). Using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Evidence Profile, the certainty in outcomes ranged from very low to low. Future prospective longitudinal studies should address concomitant factors, exposure thresholds, and age-related vulnerabilities of binge drinking, as well as the degree of recovery following discontinuation of use.


A novel system for predicting liver histopathology in patients with chronic hepatitis B.
There is currently a lack of reliable, reproducible, and easily applied methods for assessing changes in liver histology in patients in the gray zone phase of chronic hepatitis B (CHB). Therefore, we aimed to develop a novel predictive scoring system to detect significant liver histological changes in these patients.A total of 388 patients in the gray zone phase of CHB who underwent liver biopsy were divided into a training group and a validation group, and their clinical and routinely available laboratory parameters were analyzed using univariate analysis, Spearman correlation analysis, and logistic modeling. A novel scoring system, termed the Significant Histological Model (SHM), was constructed using logistic modeling. The diagnostic accuracy of our novel scoring system was evaluated by the receiving operating characteristic (ROC) method, sensitivity, specificity, and positive and negative predictive values (NPVs).We established the novel SHM scoring system using serum aspartate transaminase (AST), platelet counts (PLTs), albumin (ALB), and hepatitis B virus (HBV) DNA (log10 IU/mL) levels. The area under the ROC curve of the SHM scoring system was 0.763 in the training group and 0.791 in the validation group. For patients with a score of -1.0 or less and no significant histological changes, the sensitivity was 78.9%, specificity was 51.5%, positive predictive value (PPV) was 46.4%, and NPV was 82.0%. In the validation set, the sensitivity, specificity, PPV, and NPV were 80.0%, 66.6%, 56.3%, and 86.2%, respectively.This novel scoring system using AST, PLT, ALB, and HBV DNA (log10 IU/mL) levels identifies patients in the gray zone phase of CHB with and without histological changes with a high degree of accuracy. Here, we provide the experimental basis for the initiation of clinical antiviral treatment without the need for liver biopsy.


β-Ketoiminato-based copper(ii) complexes as CVD precursors for copper and copper oxide layer formation.
The synthesis of ketoiminato copper(ii) complexes [Cu(OCRCHC(CH3)NCH2CH2X)(μ-OAc)]2 (X = NMe2: 4a, R = Me; 4b, R = Ph. X = OMe: 5, R = Me) and [Cu(OCRCHCMeNCH2CH2NEt2)(OAc)] (6, R = Me) from RC(O)CHC(CH3)N(H)CH2CH2X (X = NMe2: 1a, R = Me; 1b, R = Ph. X = NEt2: 1c, R = Me. X = OMe: 2, R = Me) and [Cu(OAc)2·H2O] (3) is reported. The molecular solid-state structures of 4-6 were determined by single crystal X-ray diffraction studies, showing that 4a,b and 5 are dimers which are set up by two [{Cu(μ-OAc)L}] (L = ketoiminato ligand) units featuring a square-planar Cu2O2 core with a distorted square-pyramidal geometry at Cu(ii). In contrast, 6 is monomeric with a tridentate-coordinated OCMeCHCMeNCH2CH2NEt2 ligand and a σ-bonded acetate group, thus inducing a square-planar environment around Cu(ii). The thermal behavior of all complexes was studied by TG (Thermogravimetry) and DSC (Differential Scanning Calorimetry) under an atmosphere of Ar and O2. Complex 4b shows the highest first onset temperature at 213 °C (under O2) and 239 °C (Ar). PXRD studies confirmed the formation of CuO under an atmosphere of O2 and Cu/Cu2O under Ar. TG-MS studies, exemplarily carried out with 4a, indicate the elimination of the ketoiminato ligands with detectable fragments such as m/z = 15, 28, 43, 44, 45, and 60 at a temperature above 250 °C. Vapor pressure measurements displayed that 5 shows the highest volatility of 3.6 mbar at 70 °C (for comparison, 4a, 1.4; 4b, 1.3; 6, 0.4 mbar) and hence 4a and 5 were used as MOCVD precursors for Cu/Cu2O deposition on Si/SiO2 at substrate temperatures of 450 °C and 510 °C. The deposition experiments were carried out under an atmosphere of nitrogen as well as oxygen. The as-obtained layers were characterized by SEM, EDX, XPS, and PXRD, showing that with oxygen as the reactive gas a mixture of metallic copper and copper(i) oxide without carbon impurities was formed, while under N2 Cu films with 53-68 mol% C contamination were produced. In a deposition experiment using precursor 5 at 510 °C under N2 a pure copper film was obtained.


Methods for the analysis of mortality risks across heterogeneous small populations: examination of space-time gradients in cancer mortality in North Carolina counties 1970-75.
A method of analyzing mortality rates in heterogeneous populations is presented. This method, appropriate for the investigation of mortality rates in small geographic areas (e.g., counties) where the forces of mobility operate to selectively "package" person, is applied to the determination of whether a spatial west-east gradient in cancer mortality rates existed in North Carolina over the period 1970 to 1975. A significant gradient (as well as a significant temporal trend) is determined to exist in the data, though only for particular race, age and sex-specific demographic groups. Several alternate hypotheses are presented to explain the existence of the spatial gradient in these particular demographic groups.


Widespread and selective induction of major histocompatibility complex-determined antigens in vivo by gamma interferon.
gamma Interferon (IFN-gamma) caused remarkable increases in class I (H-2Kk) and class II (I-Ak) antigens throughout the body by 6-9 d. Heart, kidney, and adrenals showed increases of 4-8 times their previous levels of class I antigen content, while the pancreas and small intestine increased 13-17-fold. Lesser increases were found in spleen, liver, and lung, which showed higher resting antigenic potency. Increases of class II antigenicity of 6-10-fold were found in heart, kidney, pancreas, lung, liver, adrenal, and small intestine, with lesser increases in thymus and spleen, and none in lymph node. Topographical analysis revealed that IFN-gamma induced class I and II antigens on most tissues in a highly selective fashion. For example, the renal proximal tubules expressed large amounts of both class I and II antigens, whereas the distal tubules and collecting ducts did not. In some epithelial cells class I and II determinants were induced only on the basal aspects of the cell membrane. IFN-gamma caused a remarkable increase in class II-positive dendritic cells in the liver, pancreas, salivary glands, and thyroid. Whether these cells were of local or systemic origin is uncertain, but the finding of a simultaneous depletion of dendritic cells from lymph nodes and spleen raises the possibility that they may have been derived, at least in part, from these sites. The dynamic and selective induction of class I and II antigen expression by IFN-gamma is likely to be important in regulation of the immune response in tissues.


Identifying Undiagnosed Pediatric Mental Illness in the Emergency Department.
It is well known that pediatric psychiatric patients frequent emergency department (ED), but the number of patients with undiagnosed psychiatric illness presenting to an ED is not well known. Identification and referral of these patients may provide an opportunity for improved patient care. The primary study objective was to identify a tool that can screen for unsuspected psychiatric illness in pediatric patients who present to the ED with non-psychiatric-related complaints. The MINI International Neuropsychiatric Interview for Children and Adolescents screening tool was administered to 200 pediatric consenting patients and guardians. The inclusion criteria were English-speaking patients who presented in the ED with a nonpsychiatric complaint who were stable and able to communicate. The study was conducted in a level 1 trauma center ED of an inner-city hospital that serves a predominantly African American and Hispanic population. This study was institutional review board approved. The study populations consisted of 53% African American (107), 45% Hispanic (90), 1% white (2), and 0.5% Asian (1). Their age range was divided, with 49% between 12 and 14 years (98) and 51% between 15 and 17 years (102). The sex was evenly split, with 50% male (100) and 50% female (100). The 41% who did screen positive for an undiagnosed mental illness had a range of diagnoses. The top modules with positive results were oppositional defiant (13.5%, 27), attention-deficit/hyperactivity disorder (13%, 25), depression (10%, 11), conduct disorder (9%, 19), and anxiety (5%, 11). The pediatric Mini International Neuropsychiatric Interview was effective in screening for undiagnosed mental illness in pediatric patients who presented to the ED with no psychiatric-related illness. The screening tool indicated that 41% of pediatric patients screened positive for an undiagnosed mental illness, with attention deficit-related disorders being the most widely seen. Further study should be conducted to test the tools used in a range of ED settings.


The genus Phytophthora anno 2012.
Plant diseases caused by Phytophthora species will remain an ever increasing threat to agriculture and natural ecosystems. Phytophthora literally means plant destroyer, a name coined in the 19th century by Anton de Bary when he investigated the potato disease that set the stage for the Great Irish Famine. Phytophthora infestans, the causal agent of potato late blight, was the first species in a genus that at present has over 100 recognized members. In the last decade, the number of recognized Phytophthora species has nearly doubled and new species are added almost on a monthly basis. Here we present an overview of the 10 clades that are currently distinguished within the genus Phytophthora with special emphasis on new species that have been described since 1996 when Erwin and Ribeiro published the valuable monograph 'Phytophthora diseases worldwide' (35).


Comparison of the ecarin chromogenic assay and diluted thrombin time for quantification of dabigatran concentrations.
Essentials Routine monitoring is unnecessary but measuring dabigatran levels is helpful in certain situations. We compared ecarin chromogenic assay (STA-ECA-II) and dilute thrombin time (dTT) in patient samples. Both tests provided accurate measurements over a wide range of dabigatran concentrations. Adoption of STA-ECA-II and dTT into routine clinical practice will improve patient care. Background Although routine coagulation monitoring is unnecessary, measuring plasma dabigatran concentrations can be useful for detecting drug accumulation in renal failure or overdose, assessing the contribution of dabigatran to serious bleeding, planning the timing of urgent surgery or intervention, or determining the suitability for thrombolytic therapy for acute ischemic stroke. Dabigatran concentrations can be quantified using chromogenic or clot-based tests, such as the ecarin chromogenic assay (ECA) and the diluted thrombin time (dTT), respectively. Objective The purpose of this study was to compare the results of these assays with dabigatran concentrations measured by the reference standard of mass spectrometry in samples from 50 dabigatran-treated patients collected at peak and trough after at least 4 months of drug intake. Methods Drug levels measured with either the STA Ecarin Chromogenic Assay-II (STA-ECA-II) or dTT were linearly correlated with those determined by mass spectrometry over a wide range of concentrations. Results and Conclusions For detection of levels below 50 ng mL-1 both tests have specificities of at least 96%, suggesting that they accurately detect even low levels of drug. Therefore, regardless of whether a chromogenic or clot-based platform is preferred, the STA-ECA-II and dTT are useful tests for measuring dabigatran concentrations. Unfortunately, neither test is licensed by the United States Food and Drug Administration. Although approved in other jurisdictions, the dTT and STA-ECA-II are not widely or rapidly available in most hospitals. Therefore, cooperation between regulators and hospitals is urgently needed to render these tests readily available to inform patient care.


Lamin B1 and lamin B2 are long-lived proteins with distinct functions in retinal development.
Lamin B1 and lamin B2 are essential building blocks of the nuclear lamina, a filamentous meshwork lining the nucleoplasmic side of the inner nuclear membrane. Deficiencies in lamin B1 and lamin B2 impair neurodevelopment, but distinct functions for the two proteins in the development and homeostasis of the CNS have been elusive. Here we show that embryonic depletion of lamin B1 in retinal progenitors and postmitotic neurons affects nuclear integrity, leads to the collapse of the laminB2 meshwork, impairs neuronal survival, and markedly reduces the cellularity of adult retinas. In stark contrast, a deficiency of lamin B2 in the embryonic retina has no obvious effect on lamin B1 localization or nuclear integrity in embryonic retinas, suggesting that lamin B1, but not lamin B2, is strictly required for nucleokinesis during embryonic neurogenesis. However, the absence of lamin B2 prevents proper lamination of adult retinal neurons, impairs synaptogenesis, and reduces cone photoreceptor survival. We also show that lamin B1 and lamin B2 are extremely long-lived proteins in rod and cone photoreceptors. OF interest, a complete absence of both proteins during postnatal life has little or no effect on the survival and function of cone photoreceptors.


T-cell receptor Vbeta gene usage in CSF lymphocytes in X-linked adrenoleukodystrophy.
X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder with impaired very-long-chain fatty acid (VLCFA) metabolism that produces a neurological disease with significant variability of clinical phenotypes even within kindred. The two most common forms are the cerebral form (CALD) with an important inflammatory reaction at the active edge of demyelinating lesions, resembling some aspects of multiple sclerosis pathology, and adrenomyeloneuropathy (AMN), which involves the spinal cord and in which the inflammatory reaction is mild or absent. One hypothesis is that the phenotypic variability is related to T cell-mediated immune mechanisms playing a primary role in the demyelinating pathogenic process of CALD. The present study aims to test the hypothesis that CSF of patients with the CALD form contains highly restricted T cell populations. The variable regions of the T cell receptor beta chains (TCR Vbeta) were studied in CSF from 29 ALD patients with different phenotypes. RNA was extracted and cDNA synthesized from CSF lymphocytes; TCR Vbeta gene segments were amplified from the cDNA by polymerase chain reaction (PCR) using 20 family-specific primers. PCR products were analyzed by Southern blot. Some amplified Vbeta products were sequenced. The majority of ALD patients (21/29), whatever their phenotype, exhibited oligoclonal T cell expansion. However the overexpression of some TCR Vbeta families was heterogeneous among the different patients without any preponderance of specific Vbeta families or any clustering according to clinical phenotype. In particular a dominant TCR Vbeta utilization was not found in patients with CALD.


Rare lung disease II: pulmonary alveolar proteinosis.
The present article is the second in a series on rare lung diseases. It focuses on pulmonary alveolar proteinosis (PAP), a disorder in which lipoproteinaceous material accumulates in the alveolar space. PAP was first described in 1958, and for many years the nature of the material accumulating in the lungs was unknown. Major insights into PAP have been made in the past decade, and these have led to the notion that PAP is an autoimmume disorder in which autoantibodies interfere with signalling through the granulocyte-macrophage colony-stimulating factor receptor, leading to macrophage and neutrophil dysfunction. This has spurred new therapeutic approaches to this disorder. The discussion of PAP will begin with a case report, then will highlight the classification of PAP and review recent insights into the pathogenesis of PAP. The approach to therapy and the prognosis of PAP will also be discussed.


Feasibility and Timing of Cytoreduction Surgery in Advanced (Metastatic or Recurrent) Gastrointestinal Stromal Tumors During the Era of Imatinib.
The prognosis of advanced gastrointestinal stromal tumors (GISTs) was dramatically improved in the era of imatinib. Cytoreduction surgery was advocated as an additional treatment for advanced GISTs, especially when patients having poor response to imatinib or developing resistance to it. However, the efficacy and benefit of cytoreduction were still controversial. Likewise, the sequence between cytoreduction surgery and imatinib still need evaluation. In this study, we tried to assess the feasibility and efficiency of cytoreduction in advanced GISTs. Furthermore, we analyzed the impact of timing of the cytoreduction surgery on the prognosis of advanced GISTs. We conducted a prospective collecting retrospective review of patients with advanced GISTs (metastatic, unresectable, and recurrent GISTs) treated in Chang Gung memorial hospital (CGMH) since 2001 to 2013. We analyzed the impact of cytoreduction surgery to response to imatinib, progression-free survival (PFS), and overall survival (OS) in patients with advanced GISTs. Moreover, by the timing of cytoreduction to imatinib, we divided the surgical patients who had surgery before imatinib use into early group and those who had surgery after imatinib into late. We compared the clinical response to imatinib, PFS and OS between early and late cytoreduction surgical groups. Totally, 182 patients were enrolled into this study. Seventy-six patients underwent cytoreduction surgery. The demographic characteristics and tumor presentation were similar between surgical and non-surgical groups. The surgical group showed better complete response rate (P < .001) and partial response rate (P = 0.008) than non-surgical group. The 1-year, 3-year, and 5-year PFS were significantly superior in surgical group (P = 0.003). The 1-year, 3-year, and 5-year OS were superior in surgical group, but without statistical significance (P = 0.088). Dividing by cytoreduction surgical timing, the demographic characteristics and tumor presentation were comparable in early and late groups. The late cytoreduction group presented higher R0 resection rate (59.1% vs 31.5%, P = 0.025). However, the PFS and OS were comparable in both groups.Combining imatinib with cytoreduction increased the response rate to imatinib and prolonged PFS in patients with advanced GISTs. Moreover, early and late cytoreduction surgery was comparable in prognosis, although late cytoreduction revealed higher complete resection rate.


An Enhanced SMS Text Message-Based Support and Reminder Program for Young Adults With Type 2 Diabetes (TEXT2U): Randomized Controlled Trial.
Clinic attendance, metabolic control, engagement in self-management, and psychological health are suboptimal in young-onset (age of onset <40 years) type 2 diabetes. We examined the effectiveness of an enhanced SMS text message-based support and reminder program in improving clinic attendance, metabolic control, engagement in self-management, and psychological health in young-onset type 2 diabetes. A 12-month, parallel-arm, randomized controlled trial comparing an enhanced, semipersonalized SMS text message-based intervention (incorporating 1-8 supportive and/or informative text messages per month) against standard care was conducted in a specialized clinic for young adult type 2 diabetes. The primary outcome was maintenance of 100% attendance at scheduled quarterly clinical appointments. Secondary outcomes included (1) metabolic indices, (2) pathology and self-monitored blood glucose (SMBG) data availability, and (3) psychosocial well-being. A total of 40 participants were randomized, and 32 completed their 12-month study visit. The average participant age was 32.7 (SD 5.1) years, 50% (20/40) were male, and baseline glycated hemoglobin A1c (HbA1c) was 7.3% (SD 1.9%) (56 mmol/mol, SD 20). A higher proportion of the intervention group achieved 100% attendance (12/21, 57%, vs 5/19, 26%, for the control group); Kaplan-Meier analysis demonstrated significantly greater cumulative attendance in the intervention group (P=.04). There were no between-group differences in HbA1c, BMI, lipids, or availability of pathology and SMBG data. Odds of recording an improvement in the Diabetes Empowerment Scale-Short Form score were higher in the intervention group at 6 months (odds ratio [OR] 4.3, 95% CI 1.1-17), with attenuation of this effect at study end (OR 3.1, 95% CI 0.9-11). Program acceptability was high; >90% of participants would recommend the program to new patients. An enhanced SMS text message-based support and reminder program doubled scheduled clinic attendance rates for patients with young-onset type 2 diabetes. The program was highly acceptable and provided early support for patient empowerment but had no significant effect on measures of metabolic control or self-management. Australian and New Zealand Clinical Trials Registry (ACTRN12618000479202); https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373579.


Probabilistic principal component subspaces: a hierarchical finite mixture model for data visualization.
Visual exploration has proven to be a powerful tool for multivariate data mining and knowledge discovery. Most visualization algorithms aim to find a projection from the data space down to a visually perceivable rendering space. To reveal all of the interesting aspects of multimodal data sets living in a high-dimensional space, a hierarchical visualization algorithm is introduced which allows the complete data set to be visualized at the top level, with clusters and subclusters of data points visualized at deeper levels. The methods involve hierarchical use of standard finite normal mixtures and probabilistic principal component projections, whose parameters are estimated using the expectation-maximization and principal component neural networks under the information theoretic criteria.We demonstrate the principle of the approach on several multimodal numerical data sets, and we then apply the method to the visual explanation in computer-aided diagnosis for breast cancer detection from digital mammograms.


Proteoglycan biosynthesis in chondrocytes: protein A-gold localization of proteoglycan protein core and chondroitin sulfate within Golgi subcompartments.
The intracellular pathway of cartilage proteoglycan biosynthesis was investigated in isolated chondrocytes using a protein A-gold electron microscopy immunolocalization procedure. Proteoglycans contain a protein core to which chondroitin sulfate and keratan sulfate chains and oligosaccharides are added in posttranslational processing. Specific antibodies have been used in this study to determine separately the distribution of the protein core and chondroitin sulfate components. In normal chondrocytes, proteoglycan protein core was readily localized only in smooth-membraned vesicles which co-labeled with ricin, indicating them to be galactose-rich medial/trans-Golgi cisternae, whereas there was only a low level of labeling in the rough endoplasmic reticulum. Chondroitin sulfate was also localized in medial/trans-Golgi cisternae of control chondrocytes but was not detected in other cellular compartments. In cells treated with monensin (up to 1.0 microM), which strongly inhibits proteoglycan secretion (Burditt, L.J., A. Ratcliffe, P. R. Fryer, and T. Hardingham, 1985, Biochim. Biophys. Acta., 844:247-255), there was greatly increased intracellular localization of proteoglycan protein core in both ricin-positive vesicles, and in ricin-negative vesicles (derived from cis-Golgi stacks) and in the distended rough endoplasmic reticulum. Chondroitin sulfate also increased in abundance after monensin treatment, but continued to be localized only in ricin-positive vesicles. The results suggested that the synthesis of chondroitin sulfate on proteoglycan only occurs in medial/trans-Golgi cisternae as a late event in proteoglycan biosynthesis. This also suggests that glycosaminoglycan synthesis on proteoglycans takes place in a compartment in common with events in the biosynthesis of both O-linked and N-linked oligosaccharides on other secretory glycoproteins.


Shoulder pain: a comparison of wheelchair athletes and nonathletic wheelchair users.
The purpose of this study was to directly compare the onset and prevalence of shoulder pain in athletic and nonathletic wheelchair users. A questionnaire was distributed to athletic and nonathletic wheelchair-dependent populations. This inquired about presence and duration of shoulder pain, age of subject, level of injury, duration of time since injury, wheelchair use, involvement in sports, and training habits. A total of 257 subjects were involved in the study. The odds of having shoulder pain were twice as high among nonathletes as they were among athletes. This finding represents a significant difference over and above age differences, differences in years spent in a wheelchair, and differences in level of spinal cord injury. Athletes also have an average of 12 yr free of shoulder pain after becoming wheelchair bound, whereas nonathletes have only 8 yr. Promotion of active exercise for wheelchair users is encouraged to decrease shoulder pain, resulting in more functional, pain-free years.


Persistent anthrax as a major driver of wildlife mortality in a tropical rainforest.
Anthrax is a globally important animal disease and zoonosis. Despite this, our current knowledge of anthrax ecology is largely limited to arid ecosystems, where outbreaks are most commonly reported. Here we show that the dynamics of an anthrax-causing agent, Bacillus cereus biovar anthracis, in a tropical rainforest have severe consequences for local wildlife communities. Using data and samples collected over three decades, we show that rainforest anthrax is a persistent and widespread cause of death for a broad range of mammalian hosts. We predict that this pathogen will accelerate the decline and possibly result in the extirpation of local chimpanzee (Pan troglodytes verus) populations. We present the epidemiology of a cryptic pathogen and show that its presence has important implications for conservation.


An overview of the protein tyrosine phosphatase superfamily.
The human genome encodes approximately 100 phosphatases that belong to the protein tyrosine phosphatase (PTP) superfamily, whose substrates range from proteins to phosphoinositides and mRNAs. The hallmark for this superfamily is the active site sequence C(X)5R, also known as the PTP signature motif. The PTPs are key regulatory components in signal transduction pathways and the importance of PTPs in the control of cellular signaling is well established. Furthermore, there are compelling reasons to believe that PTP inhibitors may serve as novel medicinal agents for the treatment of various diseases. Based on structure and substrate specificity, the PTP super-family is divided into four distinct subfamilies: 1). pTyr specific PTPs, 2). dual specificity phosphatases, 3). Cdc25 phosphatases, and 4). LMW PTPs. The PTPs have similar core structures made of a central parallel beta-sheet with flanking alpha-helices containing a beta-loop-alpha loop that encompasses the PTP signature motif. Not surprisingly, they employ a common chemical mechanism for phosphate hydrolysis despite the differences in substrate specificity. Despite the conserved structural and catalytic properties, there are also sufficient differences in the active site pockets and its immediate surrounding environment among different PTPs. Further structural and mechanistic study will continue to be of considerable importance, providing a solid basis for inhibitor design.


Correlation of acetate catabolism and growth yield in Staphylococcus aureus: implications for host-pathogen interactions.
Recently, we reported that the prototypical Staphylococcus aureus strain RN6390 (a derivative of NCTC 8325) had significantly reduced aconitase activity relative to a diverse group of S. aureus isolates, leading to the hypothesis that strain RN6390 has impaired tricarboxylic acid (TCA) cycle-mediated acetate catabolism. Analysis of the culture supernatant from RN6390 confirmed that acetate was incompletely catabolized, suggesting that the ability to catabolize acetate can be lost by S. aureus. To test this hypothesis, we examined the carbon catabolism of the S. aureus strains whose genome sequences are publicly available. All strains catabolized glucose and excreted acetate into the culture medium. However, strains NCTC 8325 and N315 failed to catabolize acetate during the postexponential growth phase, resulting in significantly lower growth yields relative to strains that catabolized acetate. Strains NCTC 8325 and RN6390 contained an 11-bp deletion in rsbU, the gene encoding a positive regulator of the alternative sigma factor sigma(B) encoded by sigB. An isogenic derivative strain of RN6390 containing the wild-type rsbU gene had significantly increased acetate catabolism, demonstrating that sigma(B) is required for acetate catabolism. Taken together, the data suggest that naturally occurring mutations can alter the ability of S. aureus to catabolize acetate, a surprising discovery, as TCA cycle function has been demonstrated to be involved in the virulence, survival, and persistence of several pathogenic organisms. Additionally, these mutations decrease the fitness of S. aureus by reducing the number of progeny placed into subsequent generations, suggesting that in certain situations a decreased growth yield is advantageous.


The Problem with Having Two Watches: Assessment of Fit When RMSEA and CFI Disagree.
The root mean square error of approximation (RMSEA) and the comparative fit index (CFI) are two widely applied indices to assess fit of structural equation models. Because these two indices are viewed positively by researchers, one might presume that their values would yield comparable qualitative assessments of model fit for any data set. When RMSEA and CFI offer different evaluations of model fit, we argue that researchers are likely to be confused and potentially make incorrect research conclusions. We derive the necessary as well as the sufficient conditions for inconsistent interpretations of these indices. We also study inconsistency in results for RMSEA and CFI at the sample level. Rather than indicating that the model is misspecified in a particular manner or that there are any flaws in the data, the two indices can disagree because (a) they evaluate, by design, the magnitude of the model's fit function value from different perspectives; (b) the cutoff values for these indices are arbitrary; and (c) the meaning of "good" fit and its relationship with fit indices are not well understood. In the context of inconsistent judgments of fit using RMSEA and CFI, we discuss the implications of using cutoff values to evaluate model fit in practice and to design SEM studies.


Uveitis and Other Ocular Complications Following COVID-19 Vaccination.
Coronavirus disease 2019 (COVID-19) vaccines can cause transient local and systemic post-vaccination reactions. The aim of this study was to report uveitis and other ocular complications following COVID-19 vaccination. The study included 42 eyes of 34 patients (20 females, 14 males), with a mean age of 49.8 years (range 18-83 years). The cases reported were three herpetic keratitis, two anterior scleritis, five anterior uveitis (AU), three toxoplasma retinochoroiditis, two Vogt-Koyanagi-Harada (VKH) disease reactivations, two pars planitis, two retinal vasculitis, one bilateral panuveitis in new-onset Behçet's disease, three multiple evanescent white dot syndromes (MEWDS), one acute macular neuroretinopathy (AMN), five retinal vein occlusions (RVO), one non-arteritic ischemic optic neuropathy (NAION), three activations of quiescent choroidal neovascularization (CNV) secondary to myopia or uveitis, and one central serous chorioretinopathy (CSCR). Mean time between vaccination and ocular complication onset was 9.4 days (range 1-30 days). Twenty-three cases occurred after Pfizer-BioNTech vaccination (BNT162b2 mRNA), 7 after Oxford-AstraZeneca vaccine (ChAdOx1 nCoV-19), 3 after ModernaTX vaccination (mRNA-1273), and 1 after Janssen Johnson & Johnson vaccine (Ad26.COV2). Uveitis and other ocular complications may develop after the administration of COVID-19 vaccine.


Neonates with congenital heart disease, Part IV: Total anomalous pulmonary venous return.
Significant radiographic findings of TAPVR with unobstructed blood flow include the following: 1. Increased pulmonary vascular markings with dilated pulmonary arteries 2. Cardiomegaly 3. A "snowman" configuration of the heart, seen after pulmonary vascular resistance falls and blood flow through the lungs increases In TAPVR with obstructed blood flow, findings include the following: 1. A hazy, reticular, ground-glass appearance of the lung fields 2. Normal to small cardiac size.


Exercise interventions in multiple sclerosis rehabilitation need better reporting on comorbidities: a systematic scoping review.
To identify the extent to which exercise intervention studies in multiple sclerosis rehabilitation are addressing comorbidities and if researchers consider comorbidities as possible moderators or mediators of exercise outcomes. Five databases were searched from inception to January 8, 2016, for exercise-related terms in combination with multiple sclerosis. Studies were screened and limited to randomized control trials, full text, and English language. We assessed whether comorbidities were excluded or included, how they were reported and described, and if they were examined as possible moderators or mediators of exercise outcomes. We reviewed 99 articles that included various exercise interventions, where the most common were general multi-faceted exercise training ( n=34), cardiovascular training ( n=18), progressive-resistance training ( n=12), and balance and gait training ( n=12). In total, 77 of 99 studies reported one or more comorbidities as an exclusion criterion. The most commonly excluded comorbidities were cardiovascular diseases, cognitive impairments or psychiatric disorders, and unspecified conditions or contraindications. Only nine studies reported details on excluded participants with comorbidities. Across studies that reported comorbidities of included participants ( n=8), none examined comorbidities as possible moderators or mediators of exercise outcomes. Although a variety of exercise interventions have positive outcomes, there is limited evidence that these interventions are generalizable to people with multiple sclerosis who have comorbid conditions.


Activation of individual extrinsic thumb muscles and compartments of extrinsic finger muscles.
Mechanical and neurological couplings exist between musculotendon units of the human hand and digits. Studies have begun to understand how these muscles interact when accomplishing everyday tasks, but there are still unanswered questions regarding the control limitations of individual muscles. Using intramuscular electromyographic (EMG) electrodes, this study examined subjects' ability to individually initiate and sustain three levels of normalized muscular activity in the index and middle finger muscle compartments of extensor digitorum communis (EDC), flexor digitorum profundus (FDP), and flexor digitorum superficialis (FDS), as well as the extrinsic thumb muscles abductor pollicis longus (APL), extensor pollicis brevis (EPB), extensor pollicis longus (EPL), and flexor pollicis longus (FPL). The index and middle finger compartments each sustained activations with significantly different levels of coactivity from the other finger muscle compartments. The middle finger compartment of EDC was the exception. Only two extrinsic thumb muscles, EPL and FPL, were capable of sustaining individual activations from the other thumb muscles, at all tested activity levels. Activation of APL was achieved at 20 and 30% MVC activity levels with significantly different levels of coactivity. Activation of EPB elicited coactivity levels from EPL and APL that were not significantly different. These results suggest that most finger muscle compartments receive unique motor commands, but of the four thumb muscles, only EPL and FPL were capable of individually activating. This work is encouraging for the neural control of prosthetic limbs because these muscles and compartments may potentially serve as additional user inputs to command prostheses.


From diagnosis through survivorship: health-care experiences of colorectal cancer survivors with ostomies.
The journey from diagnosis through treatment to survivorship can be challenging for colorectal cancer (CRC) survivors with permanent ostomies. Memories of both the positive and negative health-care interactions can persist years after the initial diagnosis and treatment. The purpose of this paper is to describe the health-care experiences of long-term (>5 years) CRC survivors with ostomies. Thirty-three CRC survivors with ostomies who were members of Kaiser Permanente, an integrated care organization, in Oregon, southwestern Washington and northern California participated in eight focus groups. Discussions from the focus groups were recorded, transcribed, and analyzed for potential categories and themes. Health-care-related themes described CRC survivors' experiences with diagnosis, treatment decision-making, initial experiences with ostomy, and survivorship. Participants discussed both positive and negative health-care-related experiences, including the need for continued access to trained nurses for ostomy self-care, access to peer support, and resources related to managing persistent, debilitating symptoms. Long-term CRC survivors with ostomies have both positive and negative health-care experiences, regardless of health-related quality of life (HRQOL) and gender. Long-term support mechanisms and quality survivorship care that CRC survivors with ostomies can access are needed to promote positive adjustments and improved HRQOL. The current literature in CRC survivorship suggests that HRQOL concerns can persist years after treatment completion. The coordination of care to manage persistent late- and long-term effects are still lacking for CRC survivors living with an ostomy. Findings from this qualitative analysis will aid in the development of support strategies that foster more positive adjustments for CRC survivors living with an ostomy and support their ongoing ostomy-related needs.


Assessment of arterial elasticity among HIV-positive participants with high CD4 cell counts: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.
Both HIV infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Assessments of vascular function and structure can be used to study the pathogenesis and progression of CVD, including the effects of ART and other interventions. The objective of this report is to understand methods to assess vascular (dys)function and report our experience in the Arterial Elasticity Substudy in the Strategic Timing of AntiRetroviral Treatment (START) trial. We review literature and analyze baseline data from the Arterial Elasticity Substudy, which estimated vascular (dys)function through analysis of the diastolic blood pressure (BP) waveform. Linear regression was used to study cross-sectional associations between baseline clinical factors and small or large arterial elasticity. Arterial elasticity measurement was chosen for its improved measurement reproducibility over other methodologies and the potential of small arterial elasticity to predict clinical risk. Analysis of baseline data demonstrates that small artery elasticity is impaired (lower) with older age and differs by race and between geographical regions. No HIV-specific factors studied remained significantly associated with arterial elasticity in multivariate models. Longitudinal analyses in this substudy will provide essential randomized data with which to study the effects of early ART initiation on the progression of vascular disease among a diverse global population. When combined with future biomarker analyses and clinical outcomes in START, these findings will expand our understanding of the pathogenesis of HIV-related CVD.


Application of metagenomics in the human gut microbiome.
There are more than 1000 microbial species living in the complex human intestine. The gut microbial community plays an important role in protecting the host against pathogenic microbes, modulating immunity, regulating metabolic processes, and is even regarded as an endocrine organ. However, traditional culture methods are very limited for identifying microbes. With the application of molecular biologic technology in the field of the intestinal microbiome, especially metagenomic sequencing of the next-generation sequencing technology, progress has been made in the study of the human intestinal microbiome. Metagenomics can be used to study intestinal microbiome diversity and dysbiosis, as well as its relationship to health and disease. Moreover, functional metagenomics can identify novel functional genes, microbial pathways, antibiotic resistance genes, functional dysbiosis of the intestinal microbiome, and determine interactions and co-evolution between microbiota and host, though there are still some limitations. Metatranscriptomics, metaproteomics and metabolomics represent enormous complements to the understanding of the human gut microbiome. This review aims to demonstrate that metagenomics can be a powerful tool in studying the human gut microbiome with encouraging prospects. The limitations of metagenomics to be overcome are also discussed. Metatranscriptomics, metaproteomics and metabolomics in relation to the study of the human gut microbiome are also briefly discussed.


Deletion analysis of recombinant human factor V. Evidence for a phosphatidylserine binding site in the second C-type domain.
Human coagulation factor V is an integral component of the prothrombinase complex. Rapid activation of prothrombin is dependent on the interactions of this nonenzymatic cofactor with factor Xa and prothrombin in the presence of calcium ions and a phospholipid or platelet surface. Factor V is similar structurally and functionally to the homologous cofactor, factor VIII, which interacts with factor IXa to accelerate factor X activation in the presence of calcium and phospholipids. Both of these cofactors, when activated, possess homologous heavy and light chains. Binding to anionic phospholipids is mediated by the light chains of these two cofactors. In bovine factor Va, a phosphatidylserine-specific binding site has been localized to the amino-terminal A3 domain of the light chain. In human factor VIII, on the other hand, a region within the carboxyl-terminal C2 domain of the light chain has been shown to interact with anionic phospholipids. We have constructed a series of recombinant deletion mutants lacking domain-size fragments of the light chain of human factor V (rHFV). These mutants are expressed and secreted as single-chain proteins by COS cells. Thrombin and the factor V activator from Russell's viper venom process these deletion mutants as expected. The light chain deletion mutants possess essentially no procoagulant activity, nor are they activated by treatment with factor V activator from Russell's viper venom. Deletion of the second C-type domain results in essentially complete loss of phosphatidylserine-specific binding whereas the presence of the C2 domain alone (rHFV des-A3C1, which lacks the A3 and C1 domains of the light chain) results in significant phosphatidylserine-specific binding. The presence of the A3 domain alone (rHFV des-C1C2) does not mediate binding to immobilized phosphatidylserine. Increasing calcium ion concentrations result in decreased binding of recombinant human factor V and the mutant rHFV des-A3C1 to phosphatidylserine, similar to previous studies with purified plasma factor V and phospholipid vesicles. These results indicate that human factor V, similar to human factor VIII, possesses a phosphatidylserine-specific binding site within the C2 domain of the light chain.


Novalis frameless image-guided noninvasive radiosurgery: initial experience.
To evaluate our initial experience with Novalis (BrainLAB, Heimstetten, Germany) frameless image-guided noninvasive radiosurgery. The system combines the dedicated Novalis linear accelerator with ExacTrac X-Ray 6D, an infrared camera and a kilovolt stereoscopic x-ray imaging system, a noninvasive mask system, and ExacTrac robotics for patient positioning in six degrees of freedom. Reference cranial skeletal structures are radiographically imaged and automatically fused to digital reconstructed radiographs calculated from the treatment planning computed tomographic scan to find the target position and accomplish automatic real-time tracking before and during radiosurgery. We present the acceptance testing and initial experience in 15 patients with 19 intracranial lesions treated between December 2005 and June 2006 at the Charité by frameless image-guided radiosurgery with doses between 12 and 20 Gy prescribed to the target-encompassing isodose. Phantom tests showed an overall system accuracy of 1.04 +/- 0.47 mm, with an average in-plane deviation of 0.02 +/- 0.96 mm for the x-axis and 0.02 +/- 0.70 mm for the y-axis. After infrared-guided patient setup of all patients, the overall average translational deviation determined by stereoscopic x-ray verification was 1.5 +/- 1.3 mm, and the overall average rotational deviation was 1.0 +/- 0.8 degree. The data used for radiosurgery, after stereoscopic x-ray verification and correction, demonstrated an overall average setup error of 0.31 +/- 0.26 mm for translation and 0.26 +/- 0.23 degree for rotation. This initial evaluation demonstrates the system accuracy and feasibility of Novalis image-guided noninvasive radiosurgery for intracranial benign and malignant lesions.


Reduction in Healthcare Utilization With Transition to Peptide-Based Diets in Intolerant Home Enteral Nutrition Patients.
Since the introduction of percutaneous endoscopic gastrostomy in the 1980s, the prevalence of home enteral nutrition (HEN) support has increased significantly. Despite these increases, many patients are unable to tolerate standard polymeric formulas (SPFs), resulting in significant healthcare resource utilization. Peptide-based diets (PBDs) have emerged as a viable option in SPF-intolerant patients; however, data in the HEN population are lacking. Retrospective review of our prospectively maintained HEN database was conducted to assess tolerance, efficacy, and impact on healthcare utilization in patients on PBDs. From January 1, 2016, to May 1, 2018, 95 patients were placed on PBDs, with 53 patients being started directly and 42 patients being transitioned from SPFs. In patients transitioned to PBDs, symptoms of nausea and vomiting, diarrhea, abdominal pain, and distention improved significantly. Healthcare utilization also declined significantly, including mean number of phone calls (1.8 ± 1.6 to 1.1 ± 0.9, P = 0.006), mean number of emergency room visits (0.3 ± 0.6 to 0.09 ± 0.3, P = 0.015), and mean number of provider visits (1.3 ± 1.3 to 0.3 ± 0.5, P < 0.0001). Overall, PBDs were well tolerated and resulted in significant improvements in symptoms of gastrointestinal distress and healthcare utilization in patients intolerant to SPFs.


Blow Flies (Diptera: Calliphoridae) and the American Diet: Effects of Fat Content on Blow Fly Development.
Forensic entomology is an important field of forensic science that utilizes insect evidence in criminal investigations. Blow flies (Diptera: Calliphoridae) are among the first colonizers of remains and are frequently used in determining the minimum postmortem interval (mPMI). Blow fly development is influenced by a variety of factors including temperature and feeding substrate. Unfortunately, dietary fat content remains an understudied factor in the development process, which is problematic given the high rates of obesity in the United States. To study the effects of fat content on blow flies we investigated survivorship, adult weight, and development time (overall and by sex) of Lucilia sericata (Meigen) and Phormia regina (Meigen) on ground beef with 10%, 20%, or 27% fat. As fat content increased, survivorship decreased across both species with significant impact to P. regina. While P. regina adults were generally larger than L. sericata across all fat levels, only L. sericata demonstrated a significant (P < 0.05) difference in weight by sex. Overall development times did not vary by fat content, excluding 27% for P. regina. Additionally, development times did not vary by sex for P. regina but did differ (P < 0.05) for L. sericata with females taking longer to develop. These findings provide insight into the effect of fat content on blow fly development, a factor that should be considered when estimating an mPMI. By understanding how fat levels affect the survivorship and development of the species studied here, we can begin improving the practice of insect evidence analysis in casework.


Providers issue brief: scope of practice and prescriptive authority: year end report-2002.
Nonphysician providers continue to achieve enhanced stature, in part by gaining more autonomy in prescribing drugs. There is growing support for the concept that the public health is best served by the broadest access to primary care along with the safe use of pharmaceuticals. The states continue in their efforts to find ways to promote the use of less specialized and less costly providers to help serve the ever-growing population who have access to health care services.


Genomic screening for beta-sarcoglycan gene mutations: missense mutations may cause severe limb-girdle muscular dystrophy type 2E (LGMD 2E).
Autosomal recessive limb-girdle muscular dystrophies (LGMDs) are genetically heterogeneous. A subgroup of these disorders is caused by mutations in the dystrophin-associated sarcoglycan complex. Truncating mutations in the 43 kDa beta-sarcoglycan gene (LGMD 2E) were originally identified in a sporadic case of Duchenne-like muscular dystrophy, and a common missense mutation (T151R) was identified independently in Indiana Amish pedigrees with a milder form of LGMD. To facilitate mutational analysis of larger numbers of patients directly from genomic DNA, as opposed to reverse transcribed RNA from muscle biopsies, we have determined the genomic structure of the beta-sarcoglycan gene. The open reading frame of the beta-sarcoglycan coding region extends over six exons. Primers were designed for PCR amplification of single exons from genomic DNA and subsequent single strand conformation polymorphism (SSCP) analysis. We screened 15 patients from the Brazilian LGMD patient population, 13 of whom followed a severe course. Most of the patients had been assessed previously for deficiency of alpha-sarcoglycan immunofluorescence on muscle biopsy sections as a marker for disease of the sarcoglycan complex. Novel mutations in two familial and two sporadic cases of severe childhood-onset LGMD were identified. Only one of these patients carried a truncating mutation (homozygous 2 bp deletion, FS164TER), while the other three carried missense mutations (homozygous R91P, homozygous M100K, heterozygous recessive L108R; only one allele could be identified in this family). All three missense mutations occurred in exon 3, coding for the immediate extracellular domain. Complete absence for all three of the known sarcoglycans was noted by immunohistochemistry on muscle biopsy sections of the patients.


Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease.
Genome-wide association studies have identified the ORM (yeast)-like protein isoform 3 (ORMDL3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. We sought to investigate in vivo the functional role of ORMDL3 in disease inception. An Ormdl3-deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata was determined. An adeno-associated viral vector was also used to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 knockout mice. Ormdl3 knockout mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response, and ORMDL3 was found to play a critical role in driving the activating transcription factor 6-mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum-associated degradation pathway. In addition, ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen-induced allergic airways disease. This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.


Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study.
We investigated the association of BRCA1 and XPG mutations with response rate (RR), progression-free survival (PFS) and overall survival (OS) in a subset of patients from a phase 3 clinical trial comparing the efficacy and safety of trabectedin + pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with recurrent ovarian cancer. A candidate array was designed based on the Breast Cancer Information Core database for BRCA mutation analyses. An exploratory analysis of BRCA1/XPG mutation status was conducted using a two-sided log-rank test and 0.05 significance in germline DNA samples from 264 women with failed first-line platinum-based chemotherapy, randomized (1 : 1) to trabectedin + PLD or PLD alone. Overall, 41 (16%) of the 264 women had BRCA1(mut) (trabectedin + PLD: n = 24/135, 18%; PLD: n = 17/129; 13%) and 17 (6%) had XPG(mut) (trabectedin + PLD: n = 8/135, 6%; PLD: n = 9/129, 7%). A higher RR was observed in BRCA1(mut) patients (20/41; 49%) versus BRCA1(wt) patients (62/223; 28%). Within the BRCA1(mut) group, trabectedin + PLD-treated patients had longer PFS and longer OS than PLD-treated patients (median PFS 13.5 versus 5.5 months, P = 0.0002; median OS 23.8 versus 12.5 months, P = 0.0086), whereas in BRCA1(wt) patients, OS was not significantly different (median OS: 19.1 versus 19.3 months; P = 0.9377). There were no differences in OS or PFS of patients with XPG(mut) between the two treatment arms. However, trabectedin + PLD-treated patients with XPG(mut) had a trend toward shorter PFS (median PFS: 1.9 versus 7.5 months; P = 0.1666) and OS (median OS: 14.5 versus 20.7 months; P = 0.1774) than those with XPG(wt). In this exploratory analysis, patients with recurrent ovarian cancer carrying the BRCA1(mut) had improved outcomes with trabectedin + PLD treatment compared with PLD alone. Prospective evaluation of BRCA status is likely an important evaluation for DNA-damaging agents and may significantly impact interpretation of clinical studies. XPG may be a biomarker of poor outcome in these patients.


Synapse formation and hypoxic signalling in co-cultures of rat petrosal neurones and carotid body type 1 cells.
1. To investigate synaptic mechanisms mediating chemosensory signalling in the carotid body, we developed co-cultures of chemoreceptor type 1 cell clusters and dissociated petrosal neurones (PNs) from 7- to 14-day-old rat pups and tested for functional connectivity in CO2-HCO3(-)-or Hepes-buffered medium at approximately 35 degrees C. 2. When cultured without type 1 cells, PNs were almost always quiescent (n = 104) and unresponsive to hypoxia (Po2 = 5-25 mmHg) during perforated patch, whole-cell recordings of membrane potential or voltage-activated currents; in contrast, many PNs (77 out of 170) that were juxtaposed to type 1 cell clusters in co-culture displayed spontaneous activity, comprising spikes and subthreshold potentials (SSPs) that resembled synaptic potentials. 3. Additional tests suggested that de novo chemical synapses developed between PNs and type 1 cell clusters in vitro. For example: (i) the spontaneous activity was reversibly suppressed by substituting low calcium-high magnesium in the bath; (ii) SSPs had variable amplitudes and persisted following action potential blockade with TTX (1 microM); (iii) the interval distribution between successive spontaneous events appeared random; and (iv) the frequency of spontaneous potentials was diminished (reversibly) by the nicotinic antagonist hexamethonium (100 microM), suggesting contributions from the spontaneous release of ACh. 4. Many complexes of 'juxtaposed' PNs and type 1 clusters were physiologically functional, since exposure to hypoxia caused a reversible depolarization and/or increased spike discharge in approximately 30% of such neurones (n = 140). The hypoxia-induced spike discharge persisted in the presence of the dopamine D2 receptor blocker spiperone (10-50 microM; n = 5); however, this discharge was reversibly inhibited by 100-200 microM hexamethonium, suggesting that it was mediated, at least in part, by ACh acting through nicotinic receptors. 5. The hypoxia-induced spike discharge and frequency of spontaneous potentials in co-cultured PNs were reversibly suppressed when the buffer was switched from CO2-HCO3- to Hepes (10 mM) at pH 7.4; further, 'functional' PNs that displayed spontaneous activity and/or hypoxia-induced responses in co-culture were encountered more frequently in CO2-HCO3- (> or = 40%) than in Hepes (< or = 26%) buffer. 6. We conclude that functional chemical synapses can develop de novo in cultures of carotid body type 1 cells and PNs and that ACh is probably an important excitatory neurotransmitter secreted from type 1 cells during hypoxic chemotransduction in the rat carotid body.


Successful treatment of epidermodysplasia verruciformis with a combination of 5-aminolevulinic acid photodynamic therapy and surgery.
Epidermodysplasia verruciformis (EV) is a rare inherited immune disease characterized by pityriasis versicolor-like macules, hyperpigmented or hypopigmented warty papules and irregular reddish-brown plaques, mainly on the face, neck and extremities. Some therapeutic options include medications, lifestyle changes, ALA-PDT, surgery and so on. But there is no cure for EV and thus the clinical management is challenging. We report a case of EV that was refractory to multiple therapies and achieved an encouraging result with a combination therapy of surgery and 5-aminolevulinic acid photodynamic therapy (ALA-PDT).