Active and resting motor threshold are efficiently obtained with adaptive threshold hunting.
Transcranial magnetic studies typically rely on measures of active and resting motor threshold (i.e. AMT, RMT). Previous work has demonstrated that adaptive threshold hunting approaches are efficient for estimating RMT. To date, no study has compared motor threshold estimation approaches for measures of AMT, yet this measure is fundamental in transcranial magnetic stimulation (TMS) studies that probe intracortical circuits. The present study compared two methods for acquiring AMT and RMT: the Rossini-Rothwell (R-R) relative-frequency estimation method and an adaptive threshold-hunting method based on maximum-likelihood parameter estimation by sequential testing (ML-PEST). AMT and RMT were quantified via the R-R and ML-PEST methods in 15 healthy right-handed participants in an experimenter-blinded within-subject study design. AMT and RMT estimations obtained with both the R-R and ML-PEST approaches were not different, with strong intraclass correlation and good limits of agreement. However, ML-PEST required 17 and 15 fewer stimuli than the R-R method for the AMT and RMT estimation, respectively. ML-PEST is effective in reducing the number of TMS pulses required to estimate AMT and RMT without compromising the accuracy of these estimates. Using ML-PEST to estimate AMT and RMT increases the efficiency of the TMS experiment as it reduces the number of pulses to acquire these measures without compromising accuracy. The benefits of using the ML-PEST approach are amplified when multiple target muscles are tested within a session.


Validation of a Bench-Top Training Model for Retrograde Intrarenal Surgery.
To validate the in-house built Styrofoam box bench-top training model for retrograde intrarenal surgery (RIRS). This study was performed in the setting of a half-day RIRS course. During the course, participants performed RIRS on a locally built bench-top model. We recruited 26 participants, comprising 20 trainees and 6 experts. Trainees and experts were asked to fill a self-administered questionnaire assessing various components of RIRS to assess the face and content validity. For construct validity, experts using Objective Structured Assessment of Technical Skills (OSATS) rated trainees and the mean OSATS score of junior versus senior residents was compared. As per trainees, the model was 86% (4.3/5) realistic, which was backed by experts who found this model to be 87.6% (4.38/5) realistic. The overall face validity of the model was 86.4% (4.32/5). The overall content validity of this model was 83.4% (4.17/5). Majority of the participants thought that this tool is useful for learning technique (4.38 ± 0.49) and safe-conduct (4.31 ± 0.73) of the procedure. The trainees concurred that the skills acquired are transferable to the operating room (4.23 ± 0.76). However, the construct validity by comparing mean OSATS score of junior versus senior residents was 19.5 ± 3.5 and 23 ± 4.5. A p value of 0.11 could not be established. This study has demonstrated the face, content, and construct validity of the bench-top training model for RIRS. Further evaluation is necessary to compare its effectiveness against other available models to demonstrate concurrent validity.


Financial factors and the implementation of medications for treating opioid use disorders.
Despite the established effectiveness of pharmacotherapies for treating opioid use disorders, implementation of medications for addiction treatment (MAT) by specialty treatment programs is limited. This research examined relationships between organizational factors and the program-level implementation of MAT, with attention paid to specific sources of funding, organizational structure, and workforce resources. Face-to-face structured interviews were conducted in 2008 to 2009 with administrators of 154 community-based treatment programs affiliated with the National Institute on Drug Abuse's Clinical Trials Network; none of these programs exclusively dispensed methadone without offering other levels of care. Implementation of MAT was measured by summing the percentages of opioid patients receiving buprenorphine maintenance, methadone maintenance, and tablet naltrexone. Financial factors included the percentages of revenues received from Medicaid, private insurance, criminal justice, the Federal block grant, state government, and county government. Organizational structure and workforce characteristics were also measured. Implementation of MAT for opioid use disorders was low. Greater reliance on Medicaid was positively associated with implementation after controlling for organizational structure and workforce measures, whereas the association for reliance on criminal justice revenues was negative. The implementation of MAT for opioid use disorders by specialty addiction treatment programs may be facilitated by Medicaid but may be impeded by reliance on funding from the criminal justice system. These findings point to the need for additional research that considers the impact of organizational dependence on different types of funding on patterns of addiction treatment practice.


DECOY: Documenting Experiences with Cigarettes and Other Tobacco in Young Adults.
We examined psychographic characteristics associated with tobacco use among Project DECOY participants. Project DECOY is a 2-year longitudinal mixed-methods study examining risk for tobacco use among 3418 young adults across 7 Georgia colleges/universities. Baseline measures included sociodemographics, tobacco use, and psychographics using the Values, Attitudes, and Lifestyle Scale. Bivariate and multivariable analyses were conducted to identify correlates of tobacco use. Past 30-day use prevalence was: 13.3% cigarettes; 11.3% little cigars/cigarillos (LCCs); 3.6% smokeless tobacco; 10.9% e-cigarettes; and 12.2% hookah. Controlling for sociodemographics, correlates of cigarette use included greater novelty seeking (p < .001) and intellectual curiosity (p = .010) and less interest in tangible creation (p = .002) and social conservatism (p < .001). Correlates of LCC use included greater novelty seeking (p < .001) and greater fashion orientation (p = .007). Correlates of smokeless tobacco use included greater novelty seeking (p = .006) and less intellectual curiosity (p < .001). Correlates of e-cigarette use included greater novelty seeking (p < .001) and less social conservatism (p = .002). Correlates of hookah use included greater novelty seeking (p < .001), fashion orientation (p = .044), and self-focused thinking (p = .002), and less social conservatism (p < .001). Psychographic characteristics distinguish users of different tobacco products.


Role of the Escherichia coli glnALG operon in regulation of ammonium transport.
Escherichia coli expresses a specific ammonium (methylammonium) transport system (Amt) when cultured with glutamate or glutamine as the nitrogen source. Over 95% of this Amt activity is repressed by growth of wild-type cells on media containing ammonia. The control of Amt expression was studied with strains containing specific mutations in the glnALG operon. GlnA- (glutamine synthetase deficient) mutants, which contain polar mutations on glnL and glnG genes and therefore have the Reg- phenotype (fail to turn on nitrogen-regulated operons such as histidase), expressed less than 10% of the Amt activity observed for the parental strain. Similarly, low levels of Amt were found in GlnG mutants having the GlnA+ Reg- phenotype. However, GlnA- RegC mutants (a phenotype constitutive for histidase) contained over 70% of the parental Amt activity. At steady-state levels, GlnA- RegC mutants accumulated chemically unaltered [14C]methylammonium against a 60- to 80-fold concentration gradient, whereas the labeled substrate was trapped within parental cells as gamma-glutamylmethylamide. GlnL Reg- mutants (normal glutamine synthetase regulation) had less than 4% of the Amt activity observed for the parental strain. However, the Amt activity of GlnL RegC mutants was slightly higher than that of the parental strain and was not repressed during growth of cells in media containing ammonia. These findings demonstrate that glutamine synthetase is not required for Amt in E. coli. The loss of Amt in certain GlnA- strains is due to polar effects on glnL and glnG genes, whose products are involved in expression of nitrogen-regulated genes, including that for Amt.


[Corneofungimetry: A bioassay for dermato-mycology.].
Corneofungimetry is a bioassay in dermatomycology evaluating the antifungal effect of drugs. It is based on the method of culture of fungi on human stratum corneum harvested by cyanoacrylate skin surface strippings. Using corneofungimetry, it is possible to establish a classification of topical antifungals according to their spectrum of activity and their fungitoxicity. Similarly, the potency of oral antifungals can be evaluated at the level of the stratum corneum.


Pretubulysin: a new option for the treatment of metastatic cancer.
Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-xL, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCF(Fbw7) E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer.


Structural and Functional Synaptic Plasticity Induced by Convergent Synapse Loss in the Drosophila Neuromuscular Circuit.
Throughout the nervous system, the convergence of two or more presynaptic inputs on a target cell is commonly observed. The question we ask here is to what extent converging inputs influence each other's structural and functional synaptic plasticity. In complex circuits, isolating individual inputs is difficult because postsynaptic cells can receive thousands of inputs. An ideal model to address this question is the Drosophila larval neuromuscular junction (NMJ) where each postsynaptic muscle cell receives inputs from two glutamatergic types of motor neurons (MNs), known as 1b and 1s MNs. Notably, each muscle is unique and receives input from a different combination of 1b and 1s MNs; we surveyed multiple muscles for this reason. Here, we identified a cell-specific promoter that allows ablation of 1s MNs postinnervation and measured structural and functional responses of convergent 1b NMJs using microscopy and electrophysiology. For all muscles examined in both sexes, ablation of 1s MNs resulted in NMJ expansion and increased spontaneous neurotransmitter release at corresponding 1b NMJs. This demonstrates that 1b NMJs can compensate for the loss of convergent 1s MNs. However, only a subset of 1b NMJs showed compensatory evoked neurotransmission, suggesting target-specific plasticity. Silencing 1s MNs led to similar plasticity at 1b NMJs, suggesting that evoked neurotransmission from 1s MNs contributes to 1b synaptic plasticity. Finally, we genetically blocked 1s innervation in male larvae and robust 1b synaptic plasticity was eliminated, raising the possibility that 1s NMJ formation is required to set up a reference for subsequent synaptic perturbations.SIGNIFICANCE STATEMENT In complex neural circuits, multiple convergent inputs contribute to the activity of the target cell, but whether synaptic plasticity exists among these inputs has not been thoroughly explored. In this study, we examined synaptic plasticity in the structurally and functionally tractable Drosophila larval neuromuscular system. In this convergent circuit, each muscle is innervated by a unique pair of motor neurons. Removal of one neuron after innervation causes the adjacent neuron to increase neuromuscular junction outgrowth and functional output. However, this is not a general feature as each motor neuron differentially compensates. Further, robust compensation requires initial coinnervation by both neurons. Understanding how neurons respond to perturbations in adjacent neurons will provide insight into nervous system plasticity in both healthy and disease states.


Incomplete intrapulmonary lymph node retrieval after routine pathologic examination of resected lung cancer.
Pathologic nodal stage affects prognosis in patients with surgically resected non-small-cell lung cancer (NSCLC). Unlike examination of mediastinal lymph nodes (LNs), which depends on surgical practice, accurate examination of intrapulmonary (N1) nodes depends primarily on pathology practice. We investigated the completeness of N1 LN examination in NSCLC resection specimens and its potential impact on stage. We performed a case-control study of a special pathologic examination (SPE) protocol using thin gross dissection with retrieval and microscopic examination of all LN-like material on remnant NSCLC resection specimens after routine pathologic examination (RPE). We compared LNs retrieved by the SPE protocol with nodes examined after RPE of the same lung specimens and with those of an external control cohort. We retrieved additional LNs in 66 (90%) of 73 patient cases and discovered metastasis in 56 (11%) of 514 retrieved LNs from 27% of all patients. We found unexpected LN metastasis in six (12%) of 50 node-negative patients. Three other patients had undetected satellite metastatic nodules. Pathologic stage was upgraded in eight (11%) of 73 patients. The time required for the SPE protocol decreased significantly with experience, with no change in the number of LNs found. Standard pathology practice frequently leaves large numbers of N1 LNs unexamined, a clinically significant proportion of which harbor metastasis. By improving N1 LN examination, SPE can have an impact on prognosis and adjuvant management. We suggest adoption of the SPE to improve pathologic staging of resected NSCLC.


Ganglionic GFAP + glial Gq-GPCR signaling enhances heart functions in vivo.
The sympathetic nervous system (SNS) accelerates heart rate, increases cardiac contractility, and constricts resistance vessels. The activity of SNS efferent nerves is generated by a complex neural network containing neurons and glia. Gq G protein-coupled receptor (Gq-GPCR) signaling in glial fibrillary acidic protein-expressing (GFAP+) glia in the central nervous system supports neuronal function and regulates neuronal activity. It is unclear how Gq-GPCR signaling in GFAP+ glia affects the activity of sympathetic neurons or contributes to SNS-regulated cardiovascular functions. In this study, we investigated whether Gq-GPCR activation in GFAP+ glia modulates the regulatory effect of the SNS on the heart; transgenic mice expressing Gq-coupled DREADD (designer receptors exclusively activated by designer drugs) (hM3Dq) selectively in GFAP+ glia were used to address this question in vivo. We found that acute Gq-GPCR activation in peripheral GFAP+ glia significantly accelerated heart rate and increased left ventricle contraction. Pharmacological experiments suggest that the glial-induced cardiac changes were due to Gq-GPCR activation in satellite glial cells within the sympathetic ganglion; this activation led to increased norepinephrine (NE) release and beta-1 adrenergic receptor activation within the heart. Chronic glial Gq-GPCR activation led to hypotension in female Gfap-hM3Dq mice. This study provides direct evidence that Gq-GPCR activation in peripheral GFAP+ glia regulates cardiovascular functions in vivo.


[Inducing factors in chronic urticaria].
Causes which have an exacerbating effect on chronic urticaria are described and their approximate incidence is reported. A challenge test battery is described.


Stereotactic radiosurgery for Koos grade IV vestibular schwannoma in patients ≥ 65 years old: a multi-institutional retrospective study.
Surgery is the preferred treatment for large vestibular schwannomas (VS). Good tumor control and cranial nerve outcomes were described in selected Koos IV VS after single-session stereotactic radiosurgery (SRS), but outcomes in elderly patients have never been specifically studied. The aim of this study is to report clinical and radiological outcomes after single-session SRS for Koos IV VS in patients ≥ 65 years old. This multicenter, retrospective study included patients ≥ 65 years old, treated with primary, single-session SRS for a Koos IV VS, and at least 12 months of follow-up. Patients with life-threatening or incapacitating symptoms were excluded. Tumor control rate, hearing, trigeminal, and facial nerve function were studied at last follow-up. One-hundred and fifty patients (median age of 71.0 (IQR 9.0) years old with a median tumor volume of 8.3 cc (IQR 4.4)) were included. The median prescription dose was 12.0 Gy (IQR 1.4). The local tumor control rate was 96.0% and 86.2% at 5 and 10 years, respectively. Early tumor expansion occurred in 6.7% and was symptomatic in 40% of cases. A serviceable hearing was present in 16.1% prior to SRS and in 7.4% at a last follow-up of 46.5 months (IQR 55.8). The actuarial serviceable hearing preservation rate was 69.3% and 50.9% at 5 and 10 years, respectively. Facial nerve function preservation or improvement rates at 5 and 10 years were 98.7% and 91.0%, respectively. At last follow-up, the trigeminal nerve function was improved in 14.0%, stable in 80.7%, and worsened in 5.3% of the patients. ARE were noted in 12.7%. New hydrocephalus was seen in 8.0% of patients. SRS can be a safe alternative to surgery for selected Koos IV VS in patients ≥ 65 years old. Further follow-up is warranted.


[New nutritional screening tool for hospitalized patients with chronic kidney disease: translation, cross-cultural adaptation of Renal iNUT into Spanish and comparison with classic questionnaires].
Introduction: Chronic kidney disease (CKD) is characterized by its high prevalence of malnutrition, difficult to detect as it is underestimated by the usual tools. There is no valid or hospital-level nutritional screening tool in Spanish to identify patients with CKD at risk of malnutrition. Objective: to translate and accomplish the transcultural adaptation of Jackson's questionnaire (Renal Inpatient Nutrition Screening Tool [Renal iNUT]) to Spanish, which detects the risk of malnutrition in CKD inpatients and compares it with other nutritional tools. Methods: phase 1: translation, back-translation and transcultural adaptation of the questionnaire from the English to the Spanish version. A pilot test was carried out by nursing staff together with a satisfaction questionnaire. Phase 2: comparison of Renal iNUT with Malnutrition Universal Screening Tool (MUST) and Subjective Global Assessment (SGA). Results: phase 1: the nursing staff's perception was highly favorable. They found it easy or very easy to use and 90 % of them did it in a maximum of ten minutes. Phase 2: from 48 patients included, Renal iNUT detected 44 % at low risk of malnutrition, 28 % at intermediate risk and 28 % at high risk. Increased sensitivity of Renal iNUT (p < 0.007) vs MUST (62.5 vs 33.3 %) and similar specificity (87.1 vs 90.6 %) were found, together with an acceptable correlation compared to SGA (r = 0.75, 95 % CI: 0.67 to 0.83). Conclusions: the Spanish version of Renal iNUT is a useful and easy-to-understand tool for health professionals. We also confirm its good correlation with SGA, with greater sensitivity than MUST for the risk of malnutrition detection in CKD inpatients.


Purification and characterization of the infectious hypodermal and haematopoietic necrosis virus of penaeid shrimps.
Infectious hypodermal and haematopoietic necrosis (IHHN) is one of the most important viral diseases of cultured penaeid shrimps and is potentially a limiting factor in the development of farming projects for some species of these shrimps. Although the IHHN agent was recognized early as being viral in origin, attempts to characterize it were inconclusive because of difficulties in obtaining sufficient amounts of purified virions to permit its characterization. Recent improvements of purification procedures have allowed the physicochemical characterization of this virus. Purified IHHNV is a non-enveloped icosahedral particle averaging 22 nm in diameter, exhibiting a mean buoyant density of 1.40 g/ml in CsCl. The genome is a single molecule of ssDNA with an estimated size of 4.1 kb by molecule length measurement in transmission electron microscopy. As determined by SDS-PAGE, the particle contains four polypeptides with Mrs of 74K, 47K, 39K and 37.5K, respectively. From its characteristics, this virus could be a member of the Parvoviridae family.


Healthy diets and the subsequent prevalence of nuclear cataract in women.
To assess the association between healthy diet scores and prevalence of nuclear cataract in women. The association between healthy diet scores, which reflect adherence to the US dietary guidelines, and prevalence of nuclear cataract determined 4 to 7 years later was assessed in a sample of Women's Health Initiative Observational Study participants (aged 50-79 years) residing in Iowa, Wisconsin, and Oregon. Scores on the 1995 Healthy Eating Index, which reflect adherence to 1990 guidelines, were assigned from responses to food frequency questionnaires at the Women's Health Initiative baseline (1994-1998). Presence of nuclear cataract was determined from slitlamp photographs and self-reports of cataract extractions were assessed from May 1, 2001, to January 31, 2004, in 1808 women participating in the Carotenoids in Age-Related Eye Disease Study. Having a high 1995 Healthy Eating Index score was the strongest modifiable predictor of low prevalence of nuclear cataract among numerous risk factors investigated in this sample. The multivariate-adjusted odds ratio for high vs low quintile for diet score was 0.63 (95% confidence interval, 0.43-0.91). Higher prevalence of nuclear cataract was also associated with other modifiable factors (smoking and marked obesity) and nonmodifiable factors (having brown eyes, myopia, and high pulse pressure). Vitamin supplement use was not related to cataract. These data add to the body of evidence suggesting that eating foods rich in a variety of vitamins and minerals may contribute to postponing the occurrence of the most common type of cataract in the United States.


Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis.
Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.


Carnitine--metabolism and functions.
Carnitine was detected at the beginning of this century, but it was nearly forgotten among biochemists until its importance in fatty acid metabolism was established 50 years later. In the last 30 years, interest in the metabolism and functions of carnitine has steadily increased. Carnitine is synthesized in most eucaryotic organisms, although a few insects (and most likely some newborn animals) require it as a nutritional factor (vitamin BT). Carnitine biosynthesis is initiated by methylation of lysine. The trimethyllysine formed is subsequently converted to butyrobetaine in all tissues; the butyrobetaine is finally hydroxylated to carnitine in the liver and, in some animals, in the kidneys (see Fig. 1). It is released from these tissues and is then actively taken up by all other tissues. The turnover of carnitine in the body is slow, and the regulation of its synthesis is still incompletely understood. Microorganisms (e.g., in the intestine) can metabolize carnitine to trimethylamine, dehydrocarnitine (beta-keto-gamma-trimethylaminobutyric acid), betaine, and possibly to trimethylaminoacetone. In some insects carnitine can be converted to methylcholine, presumably with trimethylaminoacetone as an intermediate (see Fig. 3). In mammals the unphysiological isomer (+) carnitine is converted to trimethylaminoacetone. The natural isomer (-)carnitine is excreted unchanged in the urine, and it is still uncertain if it is degraded in mammalian tissues at all (Fig. 2). The only firmly established function of carnitine is its function as a carrier of activated fatty acids and activated acetate across the inner mitochondrial membrane. Two acyl-CoA:carnitine acyltransferases with overlapping chain-length specificities have been isolated: one acetyltransferase taking part in the transport of acetyl and short-chain acyl groups and one palmitoyltransferase taking part in the transport of long-chain acyl groups. An additional octanoyltransferase has been isolated from liver peroxisomes. Although a carnitine translocase that allows carnitine and acylcarnitine to penetrate the inner mitochondrial membrane has been deduced from functional studies (see Fig. 5), this translocase has not been isolated as a protein separate from the acyltransferases. Carnitine acetyltransferase and carnitine octanoyltransferase are also found in the peroxisomes. In these organelles the enzymes may be important in the transfer of acyl groups, which are produced by the peroxisomal beta-oxidation enzymes, to the mitochondria for oxidation in the citric acid cycle. The carnitine-dependent transport of activated fatty acids across the mitochondrial membrane is a regulated process. Malonyl-CoA inh


Interactive medical image segmentation using PDE control of active contours.
Segmentation of injured or unusual anatomic structures in medical imagery is a problem that has continued to elude fully automated solutions. In this paper, the goal of easy-to-use and consistent interactive segmentation is transformed into a control synthesis problem. A nominal level set partial differential equation (PDE) is assumed to be given; this open-loop system achieves correct segmentation under ideal conditions, but does not agree with a human expert's ideal boundary for real image data. Perturbing the state and dynamics of a level set PDE via the accumulated user input and an observer-like system leads to desirable closed-loop behavior. The input structure is designed such that a user can stabilize the boundary in some desired state without needing to understand any mathematical parameters. Effectiveness of the technique is illustrated with applications to the challenging segmentations of a patellar tendon in magnetic resonance and a shattered femur in computed tomography.


Metastatic malignant insulinoma in a patient with type 2 diabetes mellitus: case presentation and literature review.
To describe the occurrence of metastatic malignant insulinoma in a patient with preexisting type 2 diabetes mellitus. We present a detailed case report, with clinical, biochemical, and imaging findings, and summarize the data from 21 similar cases in the literature. The occurrence of malignant insulinoma in a patient with preexisting diabetes is very rare and thus can be a diagnostic challenge. In our patient with type 2 diabetes, endogenous hyperinsulinism was confirmed by demonstrating elevated insulin and C-peptide levels during hypoglycemic episodes in the absence of sulfonylurea on a blood screen. Abdominal computed tomographic scan and magnetic resonance imaging revealed a pancreatic mass as well as metastatic lesions in the liver. The pancreatic mass was removed and confirmed to be a malignant insulinoma. This procedure was followed by disappearance of the hypoglycemic episodes as well as the diabetes for a few months. On follow-up, however, more metastatic lesions appeared in conjunction with a protracted course of hypoglycemia that necessitated treatment with antihypoglycemic agents and, 3 years after the initial surgical intervention, culminated in the death of the patient. Our patient is one of the few subjects known to have a malignant insulinoma in conjunction with preexisting diabetes. A high degree of suspicion for the presence of an insulinoma should be maintained when unexplained hypoglycemic episodes occur in a patient with previously stable diabetes.


Complete restriction of fluoroquinolone use to control an outbreak of Clostridium difficile infection at a community hospital.
To review the effect of interventions, including a complete restriction in the use of fluoroquinolones (FQs), used to control an outbreak of hospital-onset Clostridium difficile infection (HO-CDI) caused primarily by the epidemic North American pulsed-field gel electrophoresis type 1 strain. Retrospective cohort and case-control study of all episodes of HO-CDI both before and after 2 interventions. Community hospital; January 1, 2005, through March 31, 2007. Interventions. Complete, 5-month, facility-wide restriction of fluoroquinolone use, during which a change in the environmental-services contractor occurred. During a 27-month period, 319 episodes of HO-CDI occurred. The hospital-wide mean defined daily doses of antimicrobials decreased 22% after restricting FQ use, primarily because of a 66% decrease in the use of FQs. The interventions were also associated with a significant change in the HO-CDI incidence trends and with an absolute decrease of 22% in HO-CDI cases caused by the epidemic strain (from 66% before the intervention period to 44% during and after the intervention period; P=.02). Univariate analysis revealed that case patients with HO-CDI due to the epidemic strain were more likely than control patients, who did not have diarrhea, to receive a FQ, whereas case patients with HO-CDI due to a nonepidemic strain were not. However, FQ use was not significantly associated with HO-CDI in multivariable analysis. An outbreak of epidemic-strain HO-CDI was controlled at a community hospital after an overall decrease in antimicrobial use, primarily because of a restriction of FQ use and a change in environmental-services contractors. The restriction of FQ use may be useful as an adjunct control measure in a healthcare facilities during outbreaks of epidemic-strain HO-CDI.


Brain magnetic resonance imaging changes after sorafenib and sunitinib chemotherapy in patients with advanced renal cell and breast carcinoma.
The authors report novel imaging findings associated with the treatment of sorafenib (Nexavar) and sunitinib (Sutant), 2 agents used in the treatment of advanced metastatic disease. Patients with renal cell and breast carcinoma metastases to the brain were identified from the prospective database at the Penn State Hershey Medical Center and Penn State Cancer Institute. Four patients who received sorafenib or sunitinib after surgical or radiosurgical treatment of their metastases were identified from the database. Clinical and/or radiographic changes consisting of seizures and cognitive or motor changes were described, associated with an increase in peritumoral edema and enhancement. These findings were observed to improve with discontinuation of the medications. The administration of sorafenib and sunitinib in patients with metastatic breast and renal cell carcinoma may lead to reversible clinical and imaging changes following surgical or radiosurgical treatment of their brain lesions. The authors hypothesize that leakage of the drug across a locally impaired blood-brain barrier contributes to peritumoral edema and inflammation, which may be erroneously interpreted as disease progression.


Quantitative effects of defaunation on rumen fermentation and digestion in sheep.
Studies on the quantitative significance of protozoa on carbon and nitrogen digestion and metabolism in the rumen were carried out in sheep given a diet of pelleted concentrate (500 g/d) and chopped hay (500 g/d). Measurements were made of apparent digestibility; flows of organic matter and dietary and microbial non-ammonia N (NAN) (using 15NH4+) to the duodenum; and rates of production, interconversion and metabolism of the major C fermentation end-products (from mathematical modelling of 14C isotope values). The population density of bacteria in the rumen increased as a result of defaunation (28.6 compared with 8.2 X 10(9) organisms/ml). This high density was associated with greater utilization of volatile fatty acids (VFA) within the rumen. The rate of irreversible loss (IL) of bicarbonate + carbon dioxide from the rumen was greater in the defaunated animals (98.5 v. 57.2 g C/d) but the IL from the blood was greater in the faunated group (138.6 v. 106.1 gC/d). This is consistent with the hypothesis that the high population density of bacteria found in the rumen fluid of defaunated animals may result in increased fermentation of rumen VFA and digestible dietary carbohydrate, thereby increasing the output of CO2 from the rumen and reducing the quantity of VFA (hence energy) available to the host. There was no difference in the flow of organic matter (OM) to the duodenum but there was a higher faecal excretion of OM in defaunated animals (apparent OM digestibility: 0.72 in faunated, 0.67 in defaunated). Defaunation did not significantly increase the flow of NAN to the duodenum, the percentage of duodenal NAN of bacterial origin or the quantity of microbial NAN synthesized/g organic matter fermented. Faecal excretion of NAN was higher in defaunated animals (5.3 v. 3.6 g N/d).


Plasma carotenoids, retinol, tocopherols, and lipoproteins in preeclamptic and normotensive pregnant Zimbabwean women.
We examined the relationship between maternal plasma lipoprotein and antioxidant status with risk of preeclampsia among women delivering at Harare Maternity Hospital, Zimbabwe. One hundred seventy-three pregnant women with preeclampsia and 186 controls were included in a case-control study. Maternal plasma total cholesterol, high-density lipoprotein (HDL), and total triglycerides were measured using enzymatic methods. Plasma carotenoids (alpha-carotene, beta-carotene, lycopene, lutein, beta-cryptoxanthin, zeaxanthin), retinol, and tocopherols (alpha-tocopherol and gamma-tocopherol) were determined using high performance liquid chromatography. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Preeclampsia risk increased with successively higher quartiles of plasma triglyceride (OR: 1.00, 1.70, 2.00, 5.26, with the lowest quartile as referent; P for trend <.001). We noted an inverse association between preeclampsia risk and HDL cholesterol concentrations (OR: 1.00, 0.87, 0.66, 0.68, with the first quartile as the referent group; P for trend =.169), although the trend was not statistically significant. After adjusting for confounders, we noted decreases in preeclampsia risk with increasing concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, and zeaxanthin, respectively. Women with beta-carotene concentrations in the highest quartile, as compared with those in the lowest quartile experienced a 50% decreased risk of preeclampsia (OR = 0.50, 95% CI 0.25-1.00). There was no clear pattern of preeclampsia risk with lycopene concentrations or with concentrations of gamma- and alpha-tocopherol. Our results are consistent with some, although not all, previous reports. Prospective studies are needed to determine the temporal relationship between observed alterations in lipid and antioxidant concentrations in preeclamptic pregnancies.


Consumer feedback on nursing care and discharge planning.
Gaining consumer feedback about nursing care and discharge planning is especially important given the changes that have occurred in acute inpatient mental health facilities. Consumers can best define the quality of the service they receive and surveys are considered to be good sources of information about nursing care and discharge planning. The aims of this study were to clarify consumer discharge needs, ascertain consumer perceptions of helpful practice, identify areas that require improvement, identify resources consumers deem important, ascertain satisfaction with specific aspects of services, and obtain baseline data to improve future discharge planning. Satisfaction-with-services and discharge questionnaires were completed by clients (39 and 45, respectively) prior to discharge from three acute inpatient mental health units over a 2-month period. Findings indicated that clients were most satisfied with the respect they received from staff, attention staff gave to concerns and worries, quality of service provided by nurses, way treatment met client needs and overall stay in hospital. The majority of respondents (95%) indicated that their discharge arrangements were explained to them and 90% were satisfied with these. Whilst over two-thirds indicated that the information provided in hospital to assist with discharge had been helpful, they highlighted some areas for service improvement. Resources to prepare them better for discharge included increased contact with consumer consultants and more information about mental health problems, medication and relapse prevention. This study constitutes another small step towards decreasing the gap between consumer expectations and actual treatment by asking consumers about their perceptions of discharge planning. The findings provide the basis for the development of more appropriate strategies to improve the continuity of services between hospital and community mental health settings.


Preventive effect of aspirin on peripherally inserted central catheter-related vein thrombosis in patients with malignant tumors.
The majority of patients receiving chemotherapy undergo PICC catheterization. However, PICCs are significantly associated with catheter related complications, including deep vein thrombosis, blood infection, fibrin sheath, catheter prolapse, catheter displacement and blockage. Of all the risks, PICC-related VT was the most prevailing clinic symptom and resulted in a high risk of death. The study aimed to investigate the preventive efficacy and safety of aspirin for patients with malignant tumors receiving venous thrombosis (VT) related with peripherally inserted central catheters (PICC) treatment. A randomized controlled trial was conducted. Participants with malignant tumors receiving chemotherapy who accepted PICC insertion operation were randomly allocated to the aspirin treatment group (n = 235) or the control group (n = 246). The patients in the aspirin group were administrated aspirin (100mg) for 30 days, whereas the patients in control group were administrated a placebo drug. The incidence of PICC-related VT in both groups and the aspirin related adverse effects were evaluated. The incidence of PICC-related VT was 0.4% in the aspirin group, compared with 3.3% in the control group (P = 0.038). In addition, aspirin related bleeding was not observed. PICC-related VT could be effectively prevented by aspirin in patients with malignant tumors.


Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis: a model for compartment-specific androgen action in the skeleton.
Androgens are anabolic hormones that affect many tissues, including bone. However, an anabolic effect of androgen treatment on bone in eugonadal subjects has not been observed and clinical trials have been disappointing. The androgen receptor (AR) mediates biological responses to androgens. In bone tissue, both AR and the estrogen receptor (ER) are expressed. Since androgens can be converted into estrogen, the specific role of the AR in maintenance of skeletal homoeostasis remains controversial. The goal of this study was to use skeletally targeted overexpression of AR in differentiated osteoblasts as a means of elucidating the specific role(s) for AR transactivation in the mature bone compartment. Transgenic mice overexpressing AR under the control of the 2.3-kb alpha1(I)-collagen promoter fragment showed no difference in body composition, testosterone, or 17ss-estradiol levels. However, transgenic males have reduced serum osteocalcin, CTx and TRAPC5b levels, and a bone phenotype was observed. In cortical bone, high-resolution micro-computed tomography revealed no difference in periosteal perimeter but a significant reduction in cortical bone area due to an enlarged marrow cavity. Endocortical bone formation rate was also significantly inhibited. Biomechanical analyses showed decreased whole bone strength and quality, with significant reductions in all parameters tested. Trabecular morphology was altered, with increased bone volume comprised of more trabeculae that were closer together but not thicker. Expression of genes involved in bone formation and bone resorption was significantly reduced. The consequences of androgen action are compartment-specific; anabolic effects are exhibited exclusively at periosteal surfaces, but in mature osteoblasts androgens inhibited osteogenesis with detrimental effects on matrix quality, bone fragility and whole bone strength. Thus, the present data demonstrate that enhanced androgen signaling targeted to bone results in low bone turnover and inhibition of bone formation by differentiated osteoblasts. These results indicate that direct androgen action in mature osteoblasts is not anabolic, and raise concerns regarding anabolic steroid abuse in the developing skeleton or high-dose treatment in eugonadal adults.


Pharmacologic treatment of geriatric depression: key issues in interpreting the evidence.
A framework for critical appraisal of antidepressant trial literature involving geriatric subjects is presented. Among older adults, treatment decisions are complicated by comorbid medical and cognitive illness, the variable course of recovery, and the overlap of depressive symptoms with other disease symptoms. Consumers of the literature on competing antidepressant therapies for older adults must consider disease and population-specific outcome assessment issues. An appraisal guide, adapted for geriatric depression, is developed from literature on methodological challenges of outcome assessment and published clinical trials comparing competing antidepressant therapies in older subjects. The clinical utility of pharmacologic treatment of depression can be difficult to assess because depression scales in current use provide an important but limited perspective on treatment outcome and because the scales vary in actual content and ability to detect change. The use of indicators of function, independence, and self-perceived well-being as outcomes offers additional patient relevance and should be included. Key considerations involve (1) general characteristics: whether the depression outcome measure is valid and reproducible for the aged population under study, whether the outcome measure is sensitive to treatment-related change, and whether the time-frame of outcome assessment is appropriate for the treatment goal; (2) cognitive impairment: how subjects with dementia are assessed, and whether the impact of the intervention on caregivers and healthcare systems is considered as a relevant outcome; (3) pharmacologic issues: whether the comparator agent is a reasonable usual-care standard in the older adult and whether ascertainment for adverse effects is similar for all agents under study; and (4) broader general health status issues: whether functional or quality of life measures are used as outcome indicators.


Management of viral hepatitis C.
The hepatitis C virus was first identified in 1989. It causes chronic hepatitis, cirrhosis and hepatocellular carcinoma. Global anti-HCV prevalence is 1-3%. Contaminated blood product, dirty needles and instruments, and injection drug use are the main parenteral routes of transmission. Cultural practices, such as acupuncture, tattoo, body piercing and scarring, also play a role. Universal precaution is the mainstay for prevention before vaccine is developed. Therapy for chronic hepatitis C (CHC) with interferon (IFN) is not satisfactory. Non-response and early relapse reduce sustained response (SR). In 1997, National Institute of Health consensus recommended IFN therapy only for selected patients with compensated CHC, raised ALT and moderate to severe histologic disease activity; 15-20% SR is expected. Major advances in CHC therapy is combination therapy. Ribavirin in combination with IFN significantly increases SR to 30-40%. Even patients with high viral load, genotype 1, significant fibrosis or cirrhosis respond better. EASL and APASL Consensus in 1999 recommended IFN-ribavirin combination as the first line therapy. Recent data on pegylated IFN showed very encouraging results. Combined with ribavirin, 60% SR was achieved. It benefits patients with severe bridging necrosis and also cirrhosis. However, 23-27% of patients receiving combination therapy with either IFN type, experienced adverse events and required therapy discontinuation. Many important issues remained unsolved. Therapy for children, the elderly, patients with comorbidity and extra-hepatic syndromes need to be addressed. Therapy is too expensive and not affordable to the majority of patients in developing countries.


Systems mapping: how to improve the genetic mapping of complex traits through design principles of biological systems.
Every phenotypic trait can be viewed as a "system" in which a group of interconnected components function synergistically to yield a unified whole. Once a system's components and their interactions have been delineated according to biological principles, we can manipulate and engineer functionally relevant components to produce a desirable system phenotype. We describe a conceptual framework for mapping quantitative trait loci (QTLs) that control complex traits by treating trait formation as a dynamic system. This framework, called systems mapping, incorporates a system of differential equations that quantifies how alterations of different components lead to the global change of trait development and function through genes, and provides a quantitative and testable platform for assessing the interplay between gene action and development. We applied systems mapping to analyze biomass growth data in a mapping population of soybeans and identified specific loci that are responsible for the dynamics of biomass partitioning to leaves, stem, and roots. We show that systems mapping implemented by design principles of biological systems is quite versatile for deciphering the genetic machineries for size-shape, structural-functional, sink-source and pleiotropic relationships underlying plant physiology and development. Systems mapping should enable geneticists to shed light on the genetic complexity of any biological system in plants and other organisms and predict its physiological and pathological states.


Parvalbumin is expressed in glutamatergic and GABAergic corticostriatal pathway in mice.
The connections between the cortex and the striatum are critically involved in control and execution of voluntary movements. Here we focused on the expression of calcium binding protein parvalbumin (PV) in the corticostriatal pathway. Injections of Fluorogold into the striatum gave rise to retrograde labeling of PV-positive neurons in the retrosplenial cortex and somatosensory cortex. The PV-positive corticostriatal projection neurons were mainly found in layer V, but occasionally seen in layers II, III, and VI. The PV immunoreactivity of retrogradely labeled cells was weaker than that of nonlabeled cells. Although it was rather difficult to analyze the morphology of Fluorogold-labeled neurons that exhibited PV immunoreactivity, some of them showed distinct apical dendrites and were considered pyramidal cells. The main target of PV-positive cortical afferents was the caudal striatum on the ipsilateral side. Next, we tested whether PV-positive corticostriatal projection neurons were GABAergic or not, because previous studies emphasized that PV was an important marker for cortical GABAergic neurons. Unexpectedly, we found that the majority of PV-positive corticostriatal projection neurons were glutamic acid decarboxylase (GAD)-negative, while some of them were GAD-positive. Finally, an anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) injection into the somatosensory cortex resulted in many PV-positive corticostriatal terminals that were vesicular glutamate transporter 1-positive, whereas some of the PV-positive PHA-L-labeled terminals were GAD-positive. Our results provide anatomical evidence for expression of PV in glutamatergic and GABAergic corticostriatal pathway in mice and suggest that a subset of cortical afferents may exert some inhibitory influence on striatal activity.


Meat allergy: II--Effects of food processing and enzymatic digestion on the allergenicity of bovine and ovine meats.
This study was designed to evaluate whether peptic treatment of BSA and OSA affects their allergenicity and to evaluate the effect of technological treatments of meat for infant feeding on the allergenicity of these proteins. Twelve children (8 males and 14 females) suffering from atopic dermatitis (AD), aged 12 months to 4.33 years (mean age 2.21 +/- 1.05 years). Children suffering from atopic dermatitis (AD), (AD), clinically reactive and SPT-positive to beef, underwent skin prick testing (SPT) and radioallergosorbent test (RAST) with BSA and OSA, before and after peptic treatment. They were tested also with commercially available homogenized bovine meat (HBM) and with freeze-dried bovine (FDBM) and ovine (FDOM) meats. Peptic digestion of BSA and OSA was carried out in a Dubnoff's water bath containing 0.05 mg/ml of pepsin. SPT and RAST were performed for 1 mg/ml of BSA and OSA digested 5 minutes, 2 hours and 4 hours with pepsin; homogenized bovine meat, and FDBM and FDOM. SPT results were expressed as diameters (in mm) of the wheal obtained after SPT; a diameter > or = 3 mm was considered as positive. RAST was considered positive for IgE values 5 > UI/ml. SPT to native BSA and OSA were positive in all patients. Only 2 of the 12 children were SPT-positive to HBM, FDBM, and FDOM. After digestion, SPTs and were positive as follows: for BSA, 4/12 after 5 minutes peptic treatment, 2/12 after 2 hours and 2/12 after 4 hours; for OSA, 3/12 after 5 minutes peptic treatment, none after 2 and 4 hours. None of RASTs was positive after peptic attack. Both proteolytic digestion and technological treatment reduced the allergenic potential of meat products.


Overexpression of ubiquitin specific protease 44 (USP44) induces chromosomal instability and is frequently observed in human T-cell leukemia.
Cdc20-anaphase promoting complex/cyclosome (Cdc20-APC/C) E3 ubiquitin ligase activity is essential for orderly mitotic progression. The deubiqituinase USP44 was identified as a key regulator of APC/C and has been proposed to suppress Cdc20-APC/C activity by maintaining its association with the inhibitory protein Mad2 until all chromosomes are properly attached to the mitotic spindle. However, this notion has been challenged by data in which a lysine-less mutant of Cdc20 leads to premature anaphase, suggesting that it's ubiquitination is not required for APC/C activation. To further evaluate its role in checkpoint function and chromosome instability, we studied the consequences of over-expression of mouse Usp44 in non-transformed murine embryonic fibroblasts. Here we show that cells with high Usp44 are prone to chromosome segregation errors and aneuploidization. We find that high Usp44 promotes association of Mad2 with Cdc20 and reinforces the mitotic checkpoint. Surprisingly, the APC/C-Cdc20 substrate cyclin B1 is stabilized in G2 when Usp44 is over-expressed, but is degraded with normal kinetics once cells enter mitosis. Furthermore, we show that USP44 expression is elevated in subset of T-cell leukemias. These data are consistent with an important role for USP44 in regulating Cdc20-APC/C activity and suggest that high levels of this enzyme may contribute to the pathogenesis of T-ALL.


Patient-oriented evidence that matters (POEMs)™ suggest potential clinical topics for the Choosing Wisely™ campaign.
We propose a method of identifying clinical topics for campaigns like Choosing Wisely. In the context of an ongoing continuing medication education program, we analyzed ratings on every patient-oriented evidence that matters (POEM) synopsis delivered in 2012 and 2013. Given the objective of the Choosing Wisely campaign, we focused this analysis on 1 specific item in the validated questionnaire used by physicians to rate POEMs. This questionnaire item is about "avoiding an unnecessary diagnostic test or treatment." For each POEM, we calculated frequencies and proportions for this item, then we identified the 20 POEMs that were most commonly associated with this item in 2012 and 2013. Finally, we determined whether the clinical topic of each of these POEMs was mentioned in the Choosing Wisely master list. In 2012 and 2013 we received 506,809 completed questionnaires (or ratings) linked to 530 POEMs, for an average of 956 ratings per POEM. In 59% of these POEMs (n = 312), the most commonly expected type of health benefit was "avoiding an unnecessary diagnostic test or treatment." We then identified the top 20 POEMs most commonly associated with this item in each year by ranking all 312 POEMs from the top down. The clinical topic addressed by 29 of these 40 POEMs was not addressed in the Choosing Wisely master list. These topics fell into 3 categories: diagnostic tests, medical interventions, and surgical interventions. "Big data" can identify clinical topics relevant to campaigns such as Choosing Wisely. This process represents a new way to inform the expert panel approach.


Optotype and grating visual acuity in preschool children.
To investigate the contribution of stimulus and response differences to the different developmental courses of grating and optotype visual acuity at the preschool age range. Binocular visual acuity at 228 cm was assessed in 205 children in 7 age groups between 2.5 and 6 years and in 12 adults. Acuities were obtained in three tasks: detection of a grating in one of two positions, discrimination of the orientation of a single grating, and discrimination of the orientation of the gap in an uncrowded Landolt-C optotype. The three paradigms were as similar as possible in stimulus contrast, luminance, presentation mode, and psychophysical procedure. Mean grating and optotype acuities were lower than adult acuities at all ages. Optotype acuity was overall higher and increased faster with age than grating acuities. Grating orientation acuity was slightly but not significantly lower than grating detection acuity in all but one age group. The grating detection task was successful at earlier ages (100% at 3.5 years) than both the optotype acuity task (100% at 4.5 years) and the grating orientation task (100% at 5.75 years). Optotype and grating acuities follow a different developmental course in children between 3 and 6 years of age, with optotype acuity growing superior to grating acuity in that age range. The similarity of grating orientation to grating detection acuities and the difference between grating and optotype acuities suggest that superior optotype acuity is due to stimulus characteristics rather than to the complexity of the response required.


Efficacy and safety of bivalirudin versus heparin in patients with diabetes mellitus undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials.
The efficacy and safety of bivalirudin (Biva) versus heparin in patients with diabetes mellitus (DM) who undergo percutaneous coronary intervention (PCI) remain controversial. Our meta-analysis was undertaken to evaluate the efficacy and safety of Biva compared with those of heparin in patients with diabetes undergoing PCI. We searched PubMed, EMBASE, Cochrane Library, and Clinical Trials.gov databases for randomized controlled trials (RCTs). The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE), and the primary safety endpoint was the incidence of major bleeding. Secondary efficacy endpoints were incidence of net adverse clinical events (NACE), myocardial infarction (MI), and death. The pooled risk ratio (RR) with the corresponding 95% confidence intervals (CIs) were used to assess the efficacy and safety of Biva versus heparin. Eleven RCTs met the inclusion criteria, and 8428 patients were included. No significant difference was observed in the subgroup and overall risk of MACE (RR 0.87; 95% CI 0.74-1.02; P = .08; I = 39%) and NACE (RR 0.81; 95% CI 0.61-1.07; P = .14; I = 71%). Biva had an effect similar to that of heparin on the endpoint of death (RR 0.75; 95% CI 0.56-1.02; P = .07; I = 0) and MI (RR 0.92; 95% CI 0.67-1.26; P = .59; I = 0) but decreased the risk of major bleeding (RR 0.63; 95% CI 0.52-0.75; P < .00001; I = 0%). The use of Biva and heparin is associated with a similar risk of MACE, NACE, death, and MI. Biva decreases the risk of major bleeding more significantly than heparin.


A new theoretical discrete growth distribution with verification for microbial counts in water.
Living microbes are discrete, not homogeneously distributed in environmental media, and the form of the distribution of their counts in drinking water has not been well established. However, this count may "scale" or range over orders of magnitude over time, in which case data representing the tail of the distribution, and governing the mean, would be represented only in impractically long data records. In the absence of such data, knowledge of the general form of the full distribution could be used to estimate the true mean accounting for low-probability, high-consequence count events and provide a basis for a general environmental dose-response function. In this article, a new theoretical discrete growth distribution (DGD) is proposed for discrete counts in environmental media and other discrete growth systems. The term growth refers not to microbial growth but to a general abiotic first-order growth/decay of outcome sizes in many complex systems. The emergence and stability of the DGD in such systems, defined in simultaneous work, are also described. The DGD is then initially verified versus 12 of 12 simulated long-term drinking water and short-term treated and untreated water microbial count data sets. The alternative Poisson lognormal (PLN) distribution was rejected for 2 (17%) of the 12 data sets with 95% confidence and, like other competitive distributions, was not found stable (in simultaneous work). Sample averages are compared with means assessed from the fitted DGD, with varying results. Broader validation of the DGD for discrete counts arising as outcomes of mathematical growth systems is suggested.


Fatty acids suppress autophagic turnover in β-cells.
Recent studies have shown that autophagy is essential for proper β-cell function and survival. However, it is yet unclear under what pathogenic conditions autophagy is inhibited in β-cells. Here, we report that long term exposure to fatty acids and glucose block autophagic flux in β-cells, contributing to their toxic effect. INS1 cells expressing GFP-LC3 (an autophagosome marker) were treated with 0.4 mm palmitate, 0.4 mm oleate, and various concentrations of glucose for 22 h. Kinetics of the effect of fatty acids on autophagy showed a biphasic response. During the second phase of autophagy, the size of autophagosomes and the content of autophagosome substrates (GFP-LC3, p62) and endogenous LC3 was increased. During the same phase, fatty acids suppressed autophagic degradation of long lived protein in both INS1 cells and islets. In INS1 cells, palmitate induced a 3-fold decrease in the number and the acidity of Acidic Vesicular Organelles. This decrease was associated with a suppression of hydrolase activity, suppression of endocytosis, and suppression of oxidative phosphorylation. The combination of fatty acids with glucose synergistically suppressed autophagic turnover, concomitantly suppressing insulin secretion. Rapamycin treatment resulted in partial reversal of the inhibition of autophagic flux, the inhibition of insulin secretion, and the increase in cell death. Our results indicate that excess nutrient could impair autophagy in the long term, hence contributing to nutrient-induced β-cell dysfunction. This may provide a novel mechanism that connects diet-induced obesity and diabetes.


Immunolocalization of dually phosphorylated MAPKs in dividing root meristem cells of Vicia faba, Pisum sativum, Lupinus luteus and Lycopersicon esculentum.
In plants, phosphorylated MAPKs display constitutive nuclear localization; however, not all studied plant species show co-localization of activated MAPKs to mitotic microtubules. The mitogen-activated protein kinase (MAPK) signaling pathway is involved not only in the cellular response to biotic and abiotic stress but also in the regulation of cell cycle and plant development. The role of MAPKs in the formation of a mitotic spindle has been widely studied and the MAPK signaling pathway was found to be indispensable for the unperturbed course of cell division. Here we show cellular localization of activated MAPKs (dually phosphorylated at their TXY motifs) in both interphase and mitotic root meristem cells of Lupinus luteus, Pisum sativum, Vicia faba (Fabaceae) and Lycopersicon esculentum (Solanaceae). Nuclear localization of activated MAPKs has been found in all species. Co-localization of these kinases to mitotic microtubules was most evident in L. esculentum, while only about 50% of mitotic cells in the root meristems of P. sativum and V. faba displayed activated MAPKs localized to microtubules during mitosis. Unexpectedly, no evident immunofluorescence signals at spindle microtubules and phragmoplast were noted in L. luteus. Considering immunocytochemical analyses and studies on the impact of FR180204 (an inhibitor of animal ERK1/2) on mitotic cells, we hypothesize that MAPKs may not play prominent role in the regulation of microtubule dynamics in all plant species.


Effect of chronic maternal ethanol administration on nitric oxide synthase activity in the hippocampus of the mature fetal guinea pig.
Nitric oxide is a novel messenger that is involved in neuronal cell-cell communication and seems to play a neurotrophic role in normal brain development. Chronic prenatal ethanol exposure can produce central nervous system (CNS) teratogenesis, in which one of the target sites is the hippocampus. The main objective of our study was to test the following hypothesis: chronic maternal administration of an ethanol dosage regimen that produces CNS teratogenesis decreases nitric oxide synthase (NOS) activity in the fetal hippocampus. The ontogeny of NOS activity in the hippocampus of the developing guinea pig was further elucidated at two prenatal and two postnatal ages. The effects of chronic maternal oral administration of 4 g of ethanol/kg maternal body weight/day, isocaloric sucrose and pair feeding, or water [given as two equally divided doses 2 hr apart from gestational day (GD) 2 to GD 61] on body, brain, and hippocampal weights and hippocampal NOS activity were determined in the mature fetal guinea pig at GD 62 (term, about GD 68). NOS activity in the 25,000 x g supernatant fraction of hippocampal homogenate was measured using an optimized radiometric assay, based on the oxidation of L-[14C]arginine to L-[14C]citrulline. For the chronic ethanol regimen, the maternal blood ethanol concentration at 1 hr after the second divided dose on GD 57 was 157 +/- 45 mg/dl. Chronic maternal administration of ethanol decreased fetal body, brain, and hippocampal weights, compared with the isocaloric-sucrose/pair-fed and water treatment groups. The rate of L-[14C]citrulline formation and NOS activity in the fetal hippocampus were decreased in the ethanol treatment group, compared with the isocaloric-sucrose/ pair-fed and water treatment groups. There was no difference in the rate of L-[14C]citrulline formation, NOS activity, and fetal hippocampal and body weights between the isocaloric-sucrose/pair-fed and water treatment groups; however, fetal brain weight was decreased in the isocaloric-sucrose group, compared with the water group. Data of this study support the research hypothesis by demonstrating that chronic maternal administration of ethanol decreases fetal hippocampal NOS activity that is correlated with restricted growth of this brain region.


Osteoprotegerin is up-regulated in pancreatic cancers and correlates with cancer-associated new-onset diabetes.
New-onset diabetes might help to yield biomarkers for the early diagnosis of pancreatic cancer (PaC). In this study, we computationally predicted and experimentally validated osteoprotegerin (OPG) being associated with pancreatic cancer related new-onset diabetes. We first performed a meta-analysis on microarray datasets to search for genes specifically highly expressed in PaC, and then filtered for cytokines involved in islet dysfunction. The expression of OPG in PaC and normal pancreas were validated by immunohistochemistry. Serum OPG levels in healthy controls, non-cancerous diabetes and PaC patients with or without diabetes were detected by enzyme-linked immunosorbent assay (ELISA). In silico assay found that OPG up-regulated in PaC tissues in comparison to normal pancreas. Immunohistochemical data further confirmed that OPG was overexpressed in PaC samples. Furthermore, increased expression of OPG in PaC tissues correlated to the occurrence of new-onset diabetes, and adversely affected the patients' overall survival in both univariate and multivariate analysis. In addition, the serum levels of OPG were significantly higher in pancreatic cancer patients with new-onset diabetes than other groups including pancreatic patients without diabetes, new-onset type 2 diabetes and healthy controls. In conclusion, there is a close association between OPG and pancreatic cancer related new-onset diabetes, and OPG might serve as a potential biomarker for the early diagnosis of pancreatic cancer from populations with new-onset diabetes.


Video-assisted endoscopic transtemporal multilayer upper midface lift (MUM-Lift).
Minimally invasive surgery has been used successfully recently to improve brow ptosis and forehead rhytids. Because the face tends to age more vertically, rather than obliquely, it makes sense to perform the correction in a more vertical direction. Therefore, the authors introduce a video-assisted endoscopic transtemporal approach to allow a multiplanar (subperiosteal, sub-SMAS, and subcutaneous) vertical upper midface elevation (MUM-Lift) avoiding extensive lateral temporal and preauricular incisions. Between 1996 and 2003, 53 patients (8 males, 45 females; age, 47 +/- 6 years) underwent MUM-Lift. This includes simultaneous forehead lift, blepharoplasties and video-assisted transtemporal sub-SMAS and subcutaneous upper midface tissue release, vertico-lateral repositioning, and fixation. Using the various planes of release in the midface produces less tension on each layer and provides a natural and improved facial rejuvenation of the forehead, as well as of the upper midface. The results confirmed that limited incision forehead-plasty techniques in combination with a transtemporal sub-SMAS and subcutaneous upper midface lift (MUM-Lift) reduces unnecessary vascular compromise on any particular layer and can be safely and predictably performed over the zygomatic muscle. This newly introduced procedure is an exciting feature that has evolved into a useful modality. It provides natural and improved facial rejuvenation.


[The treatment of femoral neck fractures].
About 5000 people fracture their femoral neck every year in Norway. Mean age is about 83 years and about 3/4 are women. For more than 50 years the alternatives have been internal fixation or arthroplasty. In Norway, the tradition has been internal fixation. Recent studies, however, support the use of arthroplasty. The article provides a review on the treatment of femoral neck fractures. The article is based on literature identified through a non-systematic search in Medline. Internal fixation has a higher risk of treatment failure (30 - 40 % in displaced fractures) than arthroplasty (less than 10 %). In elderly patients with displaced fractures, arthroplasty provides better hip function than internal fixation. Most patients should be treated with hemiarthroplasty, but total hip arthroplasty may give better function in the healthiest and fittest of the elderly patients. In patients younger than 60 - 65 years, internal fixation should be attempted, even though the failure rate is about 30 %. Undisplaced fractures should be treated with internal fixation, irrespective of age. The risk of treatment failure is about 10 %. Elderly patients with displaced femoral neck fractures should be treated with arthroplasty, usually hemiarthroplasty. Osteosynthesis should normally be reserved for undisplaced fractures and fractures in young and otherwise healthy patients.


Altered skeletal muscle metabolic response to exercise in chronic heart failure. Relation to skeletal muscle aerobic enzyme activity.
Exertional fatigue, which frequently limits exercise in patients with chronic heart failure, is associated with early anaerobic metabolism in skeletal muscle. The present study was designed to examine the skeletal muscle metabolic response to exercise in this disorder and determine the relation of reduced muscle blood flow and skeletal muscle biochemistry and histology to the early onset of anaerobic metabolism in patients. We evaluated leg blood flow, blood lactate, and skeletal muscle metabolic responses (by vastus lateralis biopsies) during upright bicycle exercise in 11 patients with chronic heart failure (ejection fraction 21 +/- 8%) and nine normal subjects. In patients compared to normal subjects, peak exercise oxygen consumption was decreased (13.0 +/- 3.3 ml/kg/min versus 30.2 +/- 8.6 ml/kg/min, p less than 0.01), whereas peak respiratory exchange ratio and femoral venous oxygen content were not different (both p greater than 0.25), indicating comparable exercise end points. At rest in patients versus normals, there was a reduction in the activity of hexokinase (p = 0.08), citrate synthetase (p less than 0.02), succinate dehydrogenase (p = 0.0007), and 3-hydroxyacyl CoA dehydrogenase (p = 0.04). In patients, leg blood flow was decreased at rest, submaximal, and maximal exercise when compared to normal subjects (all p less than 0.05), and blood lactate accumulation was accelerated. In patients, during submaximal exercise blood lactate levels were not closely related to leg blood flow but were inversely related to rest citrate synthetase activity in skeletal muscle (r = -0.74, p less than 0.05). At peak exercise there were no intergroup differences in skeletal muscle glycolytic intermediates, adenosine nucleotides, or glycogen, whereas in patients compared to normal subjects less lactate accumulation and phosphocreatine depletion were noted (both p less than 0.05), suggesting that factors other than the magnitude of phosphocreatine depletion or lactate accumulation may influence skeletal muscle fatigue in this disorder. The results of the present study suggest that in patients with chronic heart failure reduced aerobic activity in skeletal muscle plays an important role in mediating the early onset of anaerobic metabolism during exercise. Our findings are consistent with the concept that reduced aerobic enzyme activity in skeletal muscle is, in part, responsible for determining exercise tolerance and possibly the response to chronic intervention in patients with chronic heart failure.


Bin1 mediates apoptosis by c-Myc in transformed primary cells.
The Bin1 gene encodes a c-Myc-interacting adapter protein with tumor suppressor and cell death properties. In this study, we offer evidence that Bin1 participates in a mechanism through which c-Myc activates programmed cell death in transformed primary chick or rat cells. Antisense or dominant inhibitory Bin1 genes did not affect the ability of c-Myc to drive proliferation or transformation, but they did reduce the susceptibility of cells to c-Myc-induced apoptosis. Protein-protein interaction was implicated, suggesting that Bin1 mediates a death or death sensitization signal from c-Myc. Our findings offer direct support for the "dual signal" model of Myc apoptotic function, based on interactions with a binding protein. Loss of Bin1 in human tumors may promote malignant progression in part by helping to stanch the death penalty associated with c-Myc activation.


Interactions between spermatozoa and the crypts, cilia, and mucus of the cervix in the ewe.
In ruminants, minor cervical folds, commonly called crypts, temporarily store spermatozoa for a short interval of time between insemination and fertilization. However, the mechanism by which spermatozoa are transported to these crypts and subsequently to the uterus is not known. To study this problem, cervical tissue, which was removed from ewes that were naturally inseminated by rams at estrus, was examined with the scanning electron microscope to determine the physical associations that occur between the spermatozoa and the structural features of the cervix. The study indicates that the spermatozoa generally are not oriented parallel to the longitudinal axis of the cervix, exhibit no consistent association with the cervical cilia, and do not lie in any well defined channels formed by the cervical secretions. Alternatively, the majority of spermatozoa occur as isolated aggregations that lie in or near the shallow folds or crypts of the cervix. The vast numbers of spermatozoa in these aggregations and the lack of any common orientation suggest that some form of external stimulus, such as cervical contractions, might be responsible for the initial mass movement and distribution of spermatozoa in the cervix of the ewe.


[Comparative evaluation of visual function computer examining methods for early diagnosis of glaucoma].
Computer methods for examining the visual functions are compared: computer-aided campymetry from the time of the sensorimotor reaction, computer-aided color campymetry, visocontrastometry, and threshold static perimetry (program 24-2) with Humphrey's visual field analyzer. These methods were used in examinations of 65 patients (105 eyes) with primary open-angle glaucoma at various stages of the disease. A complex of sufficiently sensitive psychophysical methods for examination of the visual functions has been defined, including computer-aided campymetry and visocontrastometry, which may be used for early diagnosis of glaucoma.


A Framework for Automating Psychiatric Distress Screening in Ophthalmology Clinics Using an EHR-Derived AI Algorithm.
In patients with ophthalmic disorders, psychosocial risk factors play an important role in morbidity and mortality. Proper and early psychiatric screening can result in prompt intervention and mitigate its impact. Because screening is resource intensive, we developed a framework for automating screening using an electronic health record (EHR)-derived artificial intelligence (AI) algorithm. Subjects came from the Duke Ophthalmic Registry, a retrospective EHR database for the Duke Eye Center. Inclusion criteria included at least two encounters and a minimum of 1 year of follow-up. Presence of distress was defined at the encounter level using a computable phenotype. Risk factors included available EHR history. At each encounter, risk factors were used to discriminate psychiatric status. Model performance was evaluated using area under the receiver operating characteristic (ROC) curve and area under the precision-recall curve (PR AUC). Variable importance was presented using odds ratios (ORs). Our cohort included 358,135 encounters from 40,326 patients with an average of nine encounters per patient over 4 years. The ROC and PR AUC were 0.91 and 0.55, respectively. Of the top 25 predictors, the majority were related to existing distress, but some indicated stressful conditions, including chemotherapy (OR = 1.36), esophageal disorders (OR = 1.31), central pain syndrome (OR = 1.25), and headaches (OR = 1.24). Psychiatric distress in ophthalmology patients can be monitored passively using an AI algorithm trained on existing EHR data. When paired with an effective referral and treatment program, such algorithms may improve health outcomes in ophthalmology.


Tumor-resident regulatory T cells in pancreatic cancer express the αvβ5 integrin as a targetable activation marker.
Pancreatic ductal adenocarcinoma (PDAC) has abundant immunosuppressive regulatory T cells (Tregs), which contribute to a microenvironment resistant to immunotherapy. Here, we report that Tregs in the PDAC tissue, but not those in the spleen, express the αvβ5 integrin in addition to neuropilin-1 (NRP-1), which makes them susceptible to the iRGD tumor-penetrating peptide, which targets cells positive for αv integrin- and NRP-1. As a result, long-term treatment of PDAC mice with iRGD leads to tumor-specific depletion of Tregs and improved efficacy of immune checkpoint blockade. αvβ5 integrin + Tregs are induced from both naïve CD4 + T cells and natural Tregs upon T cell receptor stimulation, and represent a highly immunosuppressive subpopulation of CCR8 + Tregs. This study identifies the αvβ5 integrin as a marker for activated tumor-resident Tregs, which can be targeted to achieve tumor-specific Treg depletion and thereby augment anti-tumor immunity for PDAC therapy.


Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial.
Peanut oral immunotherapy, using a variety of approaches, has been previously shown to induce desensitization in peanut-allergic subjects, but no products have been approved for clinical use by regulatory agencies. We performed the first phase 2 multicentered study to assess the safety and efficacy of AR101, a novel oral biologic drug product. A randomized, double-blind, placebo-controlled trial was conducted at 8 US centers. Eligible subjects were 4 to 26 years old, sensitized to peanut, and had dose-limiting symptoms to ≤143 mg of peanut protein in a screening double-blind, placebo-controlled food challenge (DBPCFC). Subjects were randomized 1:1 to daily AR101 or placebo and gradually up-dosed from 0.5 to 300 mg/day. The primary endpoint was the proportion of subjects in each arm able to tolerate ≥443 mg (cumulative peanut protein) at exit DBPCFC with no or mild symptoms. Fifty-five subjects (29 AR101, 26 placebo) were enrolled. In the intention-to-treat analysis, 23 of 29 (79%) and 18 of 29 (62%) AR101 subjects tolerated ≥443 mg and 1043 mg at exit DBPCFC, respectively, versus 5 of 26 (19%) and 0 of 26 (0%) placebo subjects (both P < .0001). Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs and modulated peanut-specific cellular and humoral immune responses. Gastrointestinal (GI) symptoms were the most common treatment-related adverse events (AEs) in both groups, with 6 AR101 subjects (21%) withdrawing, 4 of those due primarily to recurrent GI AEs. In this study, AR101 demonstrated an acceptable safety profile and demonstrated clinical activity as a potential immunomodulatory treatment option in peanut-allergic children over the age of 4, adolescents, and young adults.


Complete genome sequence of a novel Plum pox virus strain W isolate determined by 454 pyrosequencing.
The near-complete (99.7 %) genome sequence of a novel Russian Plum pox virus (PPV) isolate Pk, belonging to the strain Winona (W), has been determined by 454 pyrosequencing with the exception of the thirty-one 5'-terminal nucleotides. This region was amplified using 5'RACE kit and sequenced by the Sanger method. Genomic RNA released from immunocaptured PPV particles was employed for generation of cDNA library using TransPlex Whole transcriptome amplification kit (WTA2, Sigma-Aldrich). The entire Pk genome has identity level of 92.8-94.5 % when compared to the complete nucleotide sequences of other PPV-W isolates (W3174, LV-141pl, LV-145bt, and UKR 44189), confirming a high degree of variability within the PPV-W strain. The isolates Pk and LV-141pl are most closely related. The Pk has been found in a wild plum (Prunus domestica) in a new region of Russia indicating widespread dissemination of the PPV-W strain in the European part of the former USSR.


Higher torsional mode suppression in a pipe for enhancing the first torsional mode by using magnetostrictive patch transducers.
Small-sized defects in pipes can be better detected if the first nondispersive torsional mode is used in a higher frequency range. However, dispersive higher torsional modes accompany the first mode if the actuation frequency is above the first cutoff frequency, thereby making the detection difficult. This study proposes a new technique that is particularly useful for guided torsional waves in a pipe; it enhances the desired first nondispersive mode and suppresses the undesired second mode. The technique uses two transmitting transducers separated by an optimized distance and actuated with an optimized delay time. Unlike previous methods, such as a method tuning the delay time for desired mode enhancement and tuning the distance for undesired mode suppression, the proposed approach determines both the distance and delay time mainly to suppress the undesired second mode. With the selected values, the desired first mode is substantially enhanced. This phenomenon is unique in torsional waves, not longitudinal waves, for which delay time and distance controlling methods have been developed. After wave simulations were carried out to show why the proposed method is more effective for the case of torsional waves, several experiments using magnetostrictive transducers were performed to demonstrate the effectiveness of the proposed method.


Preparing nurses to use microcomputers for the work of management.
Communications and information systems are expanding rapidly in health care organizations today. That nurses must not only be computer literate but also consumers of information technologies emerges as a professional imperative. This is especially true for nurses in management and administration. Therefore, exposing them to current technologies becomes crucial in their academic experience. Educating students to use business software applications and to understand their output will yield a leading edge to those preparing for management decision-making.


HIV infection among transport workers operating through Siliguri-Guwahati national highway, India.
A community-based cross-sectional study was conducted in July 2004 to understand the problem of HIV and other sexually transmitted infections among long-distance transport workers operating through the Siliguri-Guwahati national highway. The study included 301 transport workers who were contacted at different transport workers' stops on the Siliguri-Guwahati national highway. Informed consent was obtained. Participants were interviewed for their socio-demographic characteristics, risk behavior, and risk perceptions. Blood testing for HIV, hepatitis B virus, and syphilis (at least 1:8 dilution) showed seroprevalence rates of 2.3%, 3.7%, and 6.3%, respectively. About 67% said they visited sex workers. The reported condom use rate was 58%. About 27% sustained a sexually transmitted infection within the last year. The existing HIV prevalence among transport workers appears to be low, but in view of their risk behavior and high rate of sexually transmitted infection, HIV rates may increase unless a suitable behavioral intervention is urgently initiated toward them.


Pathophysiology and clinical management of coronavirus disease (COVID-19): a mini-review.
An unprecedented global pandemic caused by a novel coronavirus named SARS-CoV-2 has created a severe healthcare threat and become one of the biggest challenges to human health and the global economy. As of July 2023, over 767 million confirmed cases of COVID-19 have been diagnosed, including more than 6.95 million deaths. The S protein of this novel coronavirus binds to the ACE2 receptor to enter the host cells with the help of another transmembrane protease TMPRSS2. Infected subjects that can mount an appropriate host immune response can quickly inhibit the spread of infection into the lower respiratory system and the disease may remain asymptomatic or a mild infection. The inability to mount a strong initial response can allow the virus to replicate unchecked and manifest as severe acute pneumonia or prolonged disease that may manifest as systemic disease manifested as viremia, excessive inflammation, multiple organ failure, and secondary bacterial infection among others, leading to delayed recovery, hospitalization, and even life-threatening consequences. The clinical management should be targeted to specific pathogenic mechanisms present at the specific phase of the disease. Here we summarize distinct phases of COVID-19 pathogenesis and appropriate therapeutic paradigms associated with the specific phase of COVID-19.


Measurement of bistability in a multidimensional parameter space.
Bistability plays an important role to generate two stable states for alternative cell fates, or to promote cellular diversity and cell cycle oscillations. Positive feedback loops are necessary for the existence of bistability and ultrasensitive reactions in the loops broaden the parameter range of bistability. The broader parameter range a system's bistability covers, the more robust the two states are. It is challenging to determine the bistable range of a parameter because noise and transient processes induce transitions between the two states. We found that a threshold of transition rates coincides with the bistability boundaries determined by the open-loop approach. With this threshold, we estimated the boundaries for various synthetic single-gene positive feedback loops in yeast in a two dimensional parameter space: the inducer concentration and promoter dynamic range. While the bistable range of inducer concentration was influenced by many factors, the promoter dynamic range was more informative. The narrowest promoter dynamic range at which bistability can emerge revealed whether the full potential of an ultrasensitive reaction, such as dimerization, is exploited in the feedback loop. The convenient control of basal expression to adjust the promoter dynamic range permits a practical and reliable comparison of robustness of related positive feedback loops.


Effect of training and lifting equipment for preventing back pain in lifting and handling: systematic review.
To determine whether advice and training on working techniques and lifting equipment prevent back pain in jobs that involve heavy lifting. Medline, Embase, CENTRAL, Cochrane Back Group's specialised register, CINAHL, Nioshtic, CISdoc, Science Citation Index, and PsychLIT were searched up to September-November 2005. The primary search focused on randomised controlled trials and the secondary search on cohort studies with a concurrent control group. Interventions aimed to modify techniques for lifting and handling heavy objects or patients and including measurements for back pain, consequent disability, or sick leave as the main outcome were considered for the review. Two authors independently assessed eligibility of the studies and methodological quality of those included. For data synthesis, we summarised the results of studies comparing similar interventions. We used odds ratios and effect sizes to combine the results in a meta-analysis. Finally, we compared the conclusions of the primary and secondary analyses. Six randomised trials and five cohort studies met the inclusion criteria. Two randomised trials and all cohort studies were labelled as high quality. Eight studies looked at lifting and moving patients, and three studies were conducted among baggage handlers or postal workers. Those in control groups received no intervention or minimal training, physical exercise, or use of back belts. None of the comparisons in randomised trials (17,720 participants) yielded significant differences. In the secondary analysis, none of the cohort studies (772 participants) had significant results, which supports the results of the randomised trials. There is no evidence to support use of advice or training in working techniques with or without lifting equipment for preventing back pain or consequent disability. The findings challenge current widespread practice of advising workers on correct lifting technique.


Distinct effects of ketamine and acetyl L-carnitine on the dopamine system in zebrafish.
Ketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1-0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression.


Ligniera junci, a plasmodiophorid re-discovered in roots of Juncus in Austria.
Ligniera junci, a plasmodiophorid parasite of Juncus spp. was found at three locations in Tyrol. The morphologically similar plasmodiophorid of Poaceae Polymyxa graminis was found to co-occur at two of these locations. This is the first record of these species in Austria. Colour photographs of resting spores of Ligniera junci in roots of Juncus triglumis and Polymyxa graminis in roots of Poaceae are given. A description of Ligniera junci supported by light micrographs of different stages of the life-cycle (sporosori, zoosporangia, zoospores) is presented.


Successfully Managing Diabetes in a Community Setting: Evidence From the YMCA of Greater Richmond Diabetes Control Program.
Purpose The purpose of this study was to describe how a community-academic partnership developed and implemented a shared goal of evaluating the impact of a large community-based diabetes self-management program on diabetes care and mental health outcomes. Methods Data came from the YMCA of Greater Richmond Diabetes Control Program (DCP), a 12-week, group-format self-management program led by lay health coaches. Adults with type 2 diabetes (N = 312) completed baseline assessments of sociodemographic characteristics, diabetes history, and mental health. Four outcomes were assessed pre- and post-DCP on 141 participants who completed the program: hemoglobin A1C (A1C), weight, depressive symptoms (Patient Health Questionnaire-8), and glucose monitoring. The team worked with a Community Advisory Board throughout the research process. Results The DCP had wide geographic reach, including lower-income neighborhoods. The average age of the participants was 53.9 years, 71.4% were female, and 69% were African American. During the DCP, A1C declined from 8.4% to 7.6% (P < .001), but weight was unchanged (229.2 vs 227.9, P < .282). During the DCP, the proportion of participants with clinically significant depressive symptoms declined from 32.4% to 15.5% (P < .001), and frequency of glucose monitoring significantly increased. Conclusions The YMCA of Greater Richmond DCP has wide reach into underserved populations throughout the metropolitan area. This program is effective at improving diabetes self-management and mental health. Findings have implications for supporting academic-community partnerships to address diabetes disparities.


In vitro effects of household products on Calliphoridae larvae development: implication for forensic entomology.
Several parameters can delay the first arrival of flies on a corpse and the subsequent development of the larvae. This study focuses on the development of Lucilia sericata (Diptera: Calliphoridae) (Meigen, 1826) on household chemical-contaminated substrates. bleach, perfume, hydrochloric acid, caustic soda, insecticide, mosquito repellent, and gasoline in quantities consistent with an amount that could possibly be spilled on a corpse were mixed with beef liver to simulate contaminated fleshes. Larvae were bred at 25 °C on these media until emergence. Four developmental parameters were followed: survival rates, development times, sex ratios, and adult sizes. Hydrochloric acid, insecticide, and gasoline killed all larvae. In low quantities, caustic soda and mosquito repellent increased the development time and decreased the adult size. However, high quantities of these chemicals killed all larvae. Lastly, bleach and perfume did not affect the survival rate and barely impacted the development time or adult size. These results demonstrate common household products spilled on a corpse can strongly affect the development of Calliphoridae larvae. The effects of such products should be considered in forensic entomology cases.


Agricultural Compounds in Water and Birth Defects.
Agricultural compounds have been detected in drinking water, some of which are teratogens in animal models. The most commonly detected agricultural compounds in drinking water include nitrate, atrazine, and desethylatrazine. Arsenic can also be an agricultural contaminant, although arsenic often originates from geologic sources. Nitrate has been the most studied agricultural compound in relation to prenatal exposure and birth defects. In several case-control studies published since 2000, women giving birth to babies with neural tube defects, oral clefts, and limb deficiencies were more likely than control mothers to be exposed to higher concentrations of drinking water nitrate during pregnancy. Higher concentrations of atrazine in drinking water have been associated with abdominal defects, gastroschisis, and other defects. Elevated arsenic in drinking water has also been associated with birth defects. Since these compounds often occur as mixtures, it is suggested that future research focus on the impact of mixtures, such as nitrate and atrazine, on birth defects.


Type 2 diabetes in pregnancy: Rates of fetal malformations and level of preconception care.
An observational study was performed to assess the prevalence of fetal malformations and the level of preconception care in women with Type 2 diabetes. Pregnant women with Type 2 diabetes who delivered between 2002 and 2010 were recruited to the study. The fetal malformation rate of patients with Type 2 diabetes was compared with the rate in a control group; the general population. The malformation rate was 3.2 (7.2-2.2%; p < 0.0001) greater in the diabetes group. In addition, only 4% of women with Type 2 diabetes had preconception care. Despite evidence of benefits in women receiving preconception care, patients with Type 2 diabetes do not attend for preconception counselling and the malformation rate is high.