Alpha 4 beta 7 integrin mediates B cell binding to fibronectin and vascular cell adhesion molecule-1. Expression and function of alpha 4 integrins on human B lymphocytes.
Cell-cell and cell-extracellular matrix interactions are mediated by a wide array of cell surface molecules known as adhesion receptors, including the integrin family that comprises numerous alpha beta heterodimers. A new integrin group, the beta 7 subfamily, has been recently defined. Its two members, alpha 4 beta 7 and alpha H beta 7, are involved in the lymphocyte migration to the Peyer's patches and the intestinal mucosa, respectively. We have analyzed the expression of alpha 4 beta 7 integrin on B cells from different cellular compartments and at different activation states. Resting peripheral blood B lymphocytes constitutively express large amounts of alpha 4 beta 7. By contrast, alpha 4 beta 7 integrin, which is absent on resident B cells from different lymphoid tissues, is induced upon activation. Functional studies indicates that alpha 4 beta 7 is mediating B cell attachment to fibronectin and vascular cell adhesion molecule-1 through distinct epitopes on this integrin. Furthermore, the alpha 4 beta 7 integrin is also implicated in intercellular interactions as deduced by the ability of anti-alpha 4 beta 7 mAb to trigger homotypic B cell aggregation. Finally, alpha 4 beta 7 and alpha 4 beta 1 integrins redistribute at the cell membrane in a similar clustering pattern when B cells attach to fibronectin- and vascular cell adhesion molecule-1-coated surfaces. Our studies demonstrate the differential regulation on the expression and function of alpha 4 beta 7 integrin among different human B cell populations.


Vitamin K antagonists in patients with nonvalvular atrial fibrillation: appropriateness and quality of treatment in an Italian cohort.
Vitamin K antagonists (VKA) are highly recommended in patients with atrial fibrillation for their efficacy in preventing stroke. However, there is a lack of data on oral anticoagulation (OAC) with VKA overall treatment (i.e. from writing the prescription to time spent in therapeutic range) in patients discharged from hospital with a diagnosis of atrial fibrillation. The aim of this study was to assess the adherence to stroke prevention guidelines in a cohort of patients discharged with atrial fibrillation from the two hospitals of the Agency for Health Services no. 3 'Upper Friuli'. All patients discharged from the hospitals with a diagnosis of nonvalvular atrial fibrillation during the year 2009 were enrolled in this study. Record linkage for the previous 5 years and pharmaceutical data were used to assess comorbid conditions (ICD9-CM) and to calculate congestive heart failure, hypertension, age at least 75 years, diabetes and stroke (CHADS2) scores. Prescription orders were obtained from discharge letters. Patients' adherence to VKA prescription was assessed through pharmacy records, and prothrombin/international normalized ratios (INR) for a period of 180 days after discharge from the whole 'Upper Friuli' laboratories. A patient was considered to have purchased VKA if at least one drug purchase was found in the pharmacy records. Time in therapeutic range (TTR) was calculated in patients who had at least two INR measurements. In 2009, 509 patients (mean age 80 ± 8 years) were discharged with atrial fibrillation from 'Upper Friuli' hospitals (90% from internal medicine); of these, 284 patients (55.8%) had a CHADS2 score greater than 1 and no contraindications to VKA therapy at discharge. Within this subgroup, 112 patients (39.4%) received VKA prescription at discharge; of these, 84 (29.6%) purchased VKA and 58 patients had a TTR of at least 65% (20.4%). VKA prescription for atrial fibrillation patients is low and not explained by present or past comorbid condition. A second failure is represented by patients' low compliance. Overall, adherence to VKA guidelines in atrial fibrillation is scarce.


A study of abdominal pain in children.
Pain abdomen is a common pediatric complaint that brings patient to the hospital in Nepal. Knowledge about its etiology and frequency helps in its evaluation and management. The present study was undertaken to find out the causes and their frequency of pain abdomen in Nepali children. Children with pain abdomen presenting at the emergency room and pediatric outpatient department of Kathmandu Medical College, Kathmandu from January, 2006 to December 2007 were clinically evaluated and investigated to find out the causes and frequency of their pain abdomen. The outcomes were tabulated and analyzed for interpretation. Of 444 patients attended, 356 completed investigations and came for follow up. Cause of pain abdomen was apparent in 117 (32.9%) only. 91.5% were medical causes, comprising predominantly of diarrheal diseases (28.3%), infantile colic (9.4%), urinary tract infection (7.7%) and acid peptic disease (6.8%). 8.5% causes were related to surgical conditions, which needed operative management. Secondary or extra-abdominal causes were found in 20 cases (17.1%). Pneumonia (2), functional (5), vulvovaginitis (2) and infantile colic (11) were predominant causes. Our study showed that the causes of pain abdomen in children were predominantly medical. Gastroenteritis was the most frequent cause. Secondary causes, including functional and emotional causes were infrequent. Small percentage needing surgical management formed a diagnostic challenge.


[Influence of carbon sources on the biological activity and morphology of Bacillus thuringiensis parasporal crystals].
The influence of the carbon source on biological activity and morphological properties of the parasporal crystals of Bacillus thuringiensis subsp. kurstaki cultivated on three different media has been studied. Biological activity of delta-endotoxins contained in crystals was tested according to their impact on insects and microorganisms. Variations in carbon sources composition resulted in changes of biological activity and morphology of crystals, caused by alterations in synthesis rate of various delta-endotoxins contained in the crystals. Variations in the content of a certain carbon source (e.g. starch) in the medium produced no effect on the crystals properties, and the content variations of the delta-endotoxins content was proportional to the producer biomass. Control of the antibacterial effect of delta-endotoxins allows a valid evaluation of their biological activity under various growth conditions as well as comparison of the biological potential of entomopathogenic chemicals for plant protection containing delta-endotoxins with different specificity of insecticidal activity.


Predicting future onset of depression among middle-aged adults with no psychiatric history.
Depression is a major cause of disability worldwide. Recent data suggest that, in industrialised countries, the prevalence of depression peaks in middle age. Identifying factors predictive of future depressive episodes is crucial for developing prevention strategies for this age group. We aimed to identify future depression in middle-aged adults with no previous psychiatric history. To predict a diagnosis of depression 1 year or more following a comprehensive baseline assessment, we used a data-driven, machine-learning methodology. Our data-set was the UK Biobank of middle-aged participants (N = 245 036) with no psychiatric history. Overall, 2.18% of the study population developed a depressive episode at least 1 year following baseline. Basing predictions on a single mental health questionnaire led to an area under the curve of the receiver operating characteristic of 0.66, and a predictive model leveraging the combined results of 100 UK Biobank questionnaires and measurements improved this to 0.79. Our findings were robust to demographic variations (place of birth, gender) and variations in methods of depression assessment. Thus, machine-learning-based models best predict diagnoses of depression when allowing the inclusion of multiple features. Machine-learning approaches show potential for being beneficial for the identification of clinically relevant predictors of depression. Specifically, we can identify, with moderate success, people with no recorded psychiatric history as at risk for depression by using a relatively small number of features. More work is required to improve these models and evaluate their cost-effectiveness before integrating them into the clinical workflow.


Polyelectrolyte multilayer films under mechanical stretch.
Polyelectrolyte multilayers can be used to design films which respond to mechanical stimuli. The behaviors of three different polyelectrolyte multilayers deposited onto silicone sheets were investigated: PAH/PSS, PDADMA/PSS and PLL/HA films [PAH: poly(allylamine); PSS: poly(styrene sulfonate); PDADMA: poly(diallyldimethylammonium); PLL: poly(-lysine); HA: hyaluronic acid]. While (PLL/HA) and (PDADMA/PSS) multilayers remain undamaged under stretch, (PAH/PSS) films are very brittle and cracks are formed for low elongation degrees. PAH/PSS films behave more like glasses whereas (PLL/HA) and (PDADMA/PSS) multilayers behave rather as gels. (PSS/PAH) and (PSS/PDADMA) multilayers were also deposited as a capping and impermeable layer on top of a (PLL/HA) multilayer acting as a compartment. Whereas (PSS/PAH) barriers exhibit large micrometric cracks under stretch, (PSS/PDADMA) barriers open through nanopore formation for a given stretching degree. When these films are brought back to the non-stretched state, the nanopores close and the barrier becomes tight again. In the case of (PSS/PAH) barriers, only a partial tightening is achieved.


Nutritive value of mixed proteins. 2. As determined by net protein utilization and protein efficiency ratio tests.
1. A fish meal, meat meal, soya-bean meal, groundnut meal and sunflower-seed meal of known amino acid composition were evaluated individually, and combined in all possible pairs, by the estimation of net protein utilization (NPU) and protein efficiency ratio (body-weight gain: crude protein intake; PER) using rats. Each pair provided a total of 100 g protein/kg diet made up so that the amounts of the constituents were (w/w) 100:0, 80:20, 60:40, 20:80, and 0:100. 2. Marked synergistic effects were noted only for mixtures of sunflower-seed meal with soya-bean, fish and meat meals. 3. Chemical score ([amount of limiting amino acid/the rat's requirement for the same amino acid] X100; CS), but not essential amino acid index; geometric mean for the ratio, amount of essential amino acid: the rat's requirement for that amino acid, for all ten essential amino acids; EAAI), successfully predicted the rankings of all mixtures except groundnut meal-meat meal and groundnut meal-soya-bean meal, by both PER and NPU tests. 4. Although there is broad agreement linking results of PER and NPU tests with results obtained by a more practical feeding trial in which the mixtures were evaluated as supplements to cereals, neither of these two standard tests is capable of predicting in every instance the advantages to be gained by mixing protein concentrates.


Health-related quality of life in chronic liver disease: the impact of type and severity of disease.
The type and severity of chronic liver disease may have different effects on health-related quality of life (HRQL). The aim of our study was to determine whether HRQL in patients with chronic liver disease differs by type and severity of disease and to identify which clinical and physiological factors affect this impairment. In this study, HRQL was measured with a generic (Short Form 36) and a liver disease-specific (Chronic Liver Disease Questionnaire) questionnaire. Clinical, demographic, and laboratory data were collected at office visits. Patient's HRQL scores were compared with the published norms and to the chronically ill populations. A total of 353 patients (mean age 50 yr, 51% men) with chronic liver disease, either viral disease (hepatitis B and C), cholestatic disease (primary biliary cirrhosis or primary sclerosing cholangitis), or hepatocellular disease were enrolled in the study. In general, HRQL in patients with chronic liver disease was lower than the normal population and was similar to that of patients with chronic obstructive pulmonary disease or congestive heart failure. In cirrhotic patients, some dimensions of HRQL were less impaired in patients with cholestatic disease than in those with hepatocellular diseases. More severe disease (higher Child's class) was associated with a lower Chronic Liver Disease Questionnaire score and the Short Form 36's physical component summary scores. Older age had a weak negative association with the physical aspects of HRQL. We conclude that chronic liver disease substantially reduces HRQL, and this impact does not differ markedly by type of disease. Older age and measures of disease severity were associated with poorer HRQL.


Aortoiliac occlusive disease - a novel classification system based on anatomical segments and disease severity for management planning.
The aim of this classification system is to provide vascular surgeons with a simple tool that categorises disease severity by anatomical segment in aortoiliac occlusive disease and thus guide decision making and management strategies. Disease of the common femoral arteries is included as the distal extent of disease with respect to access for both open and endovascular intervention is essential to management planning. The classification system designates diseased segment letters and numbers to guide treatment planning. The degree of disease other than stenotic or occluded is not required. In a similar manner to the TNM classification, anatomy and disease severity - based on angiography, CTA, and MRA - are categorised using a simple, user-friendly method. Two clinical cases are presented to exemplify the clinical application of this classification system. A simple and useful classification system is presented and ease of use exemplified by two clinical cases. Management strategies for peripheral artery disease in general, aortoiliac occlusive disease specifically, have evolved rapidly in recent years. Existing classification systems, such as TASC II, steer the clinician towards specific treatment approaches. However, the first step in the management decision-making process is the accurate identification of the arterial segments that require treatment. None of the existing classification systems specifically address anatomy as an entity in itself. This classification system provides an intuitive framework, based on letters and numbers, that provides specific information on arterial segments and disease severity in aortoiliac occlusive disease on which clinicians can base management decisions. It has been developed to bolster this aspect of the vascular surgery armamentarium; to be used as a decision making and management planning tool, in partnership with, not instead of, existing classification systems.


Biopharmaceutical evaluation of surface active ophthalmic excipients using in vitro and ex vivo corneal models.
The objective of this study was to systematically investigate the effects of surface active ophthalmic excipients on the corneal permeation of ophthalmic drugs using in vitro (HCE-T cell-based model) and ex vivo (freshly excised porcine cornea) models. The permeation of four ophthalmic drugs (i.e., timolol maleate, chloramphenicol, diclofenac sodium and dexamethasone) across in vitro and ex vivo corneal models was evaluated in the absence and presence of four commonly used surface active ophthalmic excipients (i.e., Polysorbate 80, Tyloxapol, Cremophor® EL and Pluronic® F68). The concentration and self-aggregation-dependent effects of surface active ophthalmic excipients on ophthalmic drug permeability were studied from the concentration region where only dissolved monomer molecules of surface active ophthalmic excipients exist, as well as the concentration region in which aggregates of variable size and dispersion are spontaneously formed. Neither the surface active ophthalmic excipients nor the ophthalmic drugs at all concentrations that were tested significantly affected the barrier properties of both corneal models, as assessed by transepithelial electrical resistance (TEER) monitoring during the permeability experiments. The lowest concentration of all investigated surface active ophthalmic excipients did not significantly affect the ophthalmic drug permeability across both of the corneal models that were used. For three ophthalmic drugs (i.e., chloramphenicol, diclofenac sodium and dexamethasone), depressed in vitro and ex vivo permeability were observed in the concentration range of either Polysorbate 80, Tyloxapol, Cremophor® EL or Pluronic® F68, at which self-aggregation is detected. The effect was the most pronounced for Cremophor® EL (1 and 2%, w/V) and was the least pronounced for Pluronic® F68 (1%, w/V). However, all surface active ophthalmic excipients over the entire concentration range that was tested did not significantly affect the in vitro and ex vivo permeability of timolol maleate, which is the most hydrophilic ophthalmic drug that was investigated. The results of the dynamic light scattering measurements point to the association of ophthalmic drugs with self-aggregates of surface active ophthalmic excipients as the potential mechanism of the observed permeability-depressing effect of surface active ophthalmic excipients. A strong and statistically significant correlation was observed between in vitro and ex vivo permeability of ophthalmic drugs in the presence of surface active ophthalmic excipients, which indicates that the observed permeability-altering effects of surface active ophthalmic excipients were comparable and were mediated by the same mechanism in both corneal models.


[Hepatic hydrothorax without ascites].
A case of hepatic hydrothorax without clinical ascites is reported. The diagnosis was confirmed by intraperitoneal injection of 99mTc-tin colloid: scintigraphic images taken between 5 min and 18 h p.i. demonstrated a one-way transdiaphragmatic flow into the pleural cavity. The therapy consisted of diuretic treatment, pleural drainage and chemical pleurodesis, and resulted in prompt clinical improvement.


The four self-efficacy trajectories among people with multiple sclerosis: Clinical associations and implications.
Longitudinal studies among people with Multiple Sclerosis (pwMS) have shown that self-efficacy is linked to physical, cognitive and psychological functioning. To determine the distribution of self-efficacy in a large sample of pwMS, examining whether there are distinct groups which show different self-efficacy trajectories over time, and the health status characteristics of any groups identified. Participants completed serial questionnaire packs, including Unidimensional Self-efficacy-MS (USE-MS) scale, for the Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study over an average 46-month period. The resulting longitudinal data were analysed by a group-based trajectory model. 5887 pwMS were studied: mean age 50.2 years (SD 12.0); 73.6% female; Relapsing Remitting MS (61.8%), Secondary Progressive (22.9%), Primary Progressive (11.1%), Rapidly Evolving Relapsing Remitting MS (4.2%). Four distinct self-efficacy trajectories emerged, with declining, slightly declining, stable or improving self-efficacy, each showing different patterns of health status indicators such as EQ-5D-5L, disability and depression. USE-MS ≤ 18 at baseline detected all participants in the two declining groups. Future trials on interventions for self-efficacy should assume a priori that those with low levels of self-efficacy (USE-MS ≤ 18 at baseline) are likely to be on a declining trajectory and may need different interventions from those with stable self-efficacy.


Effects of IGF-1 isoforms on muscle growth and sarcopenia.
The decline in skeletal muscle mass and strength occurring in aging, referred as sarcopenia, is the result of many factors including an imbalance between protein synthesis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin-like growth factor-1 (IGF-1) has been implicated in many anabolic pathways in skeletal muscle. IGF-1 exists in different isoforms that might exert different role in skeletal muscle. Here we study the effects of two full propeptides IGF-1Ea and IGF-1Eb in skeletal muscle, with the aim to define whether and through which mechanisms their overexpression impacts muscle aging. We report that only IGF-1Ea expression promotes a pronounced hypertrophic phenotype in young mice, which is maintained in aged mice. Nevertheless, examination of aged transgenic mice revealed that the local expression of either IGF-1Ea or IGF-1Eb transgenes was protective against age-related loss of muscle mass and force. At molecular level, both isoforms activate the autophagy/lysosome system, normally altered during aging, and increase PGC1-α expression, modulating mitochondrial function, ROS detoxification, and the basal inflammatory state occurring at old age. Moreover, morphological integrity of neuromuscular junctions was maintained and preserved in both MLC/IGF-1Ea and MLC/IGF-1Eb mice during aging. These data suggest that IGF-1 is a promising therapeutic agent in staving off advancing muscle weakness.


Intermediate (skeletin) filaments in heart Purkinje fibers. A correlative morphological and biochemical identification with evidence of a cytoskeletal function.
Cow Purkinje fibers contain a population of free cytoplasmic filaments which consistently differ in ultrastructural appearance from actin and myosin filaments, irrespective of preparation technique. The fixation and staining techniques, however, influenced the filament diameter, which was found to be 7.4--9.5 nm for filaments in plastic-embedded material, and 7.0 nm in cryo-sectioned material, thus intermediate as compared to actin and myosin filaments. Cross-sectional profiles suggested that the intermediate-sized filaments are composed of four subfilaments. To provide a basis for further biochemical investigations on the filaments, extraction procedures were carried out to remove other cell organelles. Electron microscopy showed that undulating bundles of intermediate filaments converging towards desmosomes still remained, after the extractions, together with Z-disk material. In spite of the extensive extraction, the shape of the individual cells and the assemblies of cell bundles remained intact. This confirms that the intermediate filaments of cow Purkinje fibers together with desmosomes do in fact have a cytoskeletal function. On account of (a) the cytoskeletal function of the filaments, (b) the similarities to the smooth muscle "100-A filament" protein subunit skeletin, and (c) the inadequate and confusing existing terminology, we suggest that the filaments be named "skeletin filaments."


[Mechanical ventilation: modern technics and respirators].
The techniques of ventilatory support have been improved during the last few years by two series of modifications: first, the introduction of the trigger and the IMV allows and stimulates greater participation of the patient in the regulation and work of respiration; second, higher levels of PEEP and CPAP produce an improvement in pulmonary gas exchange. The development and perfecting of these techniques has not increased the cost of modern ventilators. This article considers some of the advantages and shortcomings of a number of recent models.


Self-Amplifying Replicon RNA Vaccine Delivery to Dendritic Cells by Synthetic Nanoparticles.
Dendritic cells (DC) play essential roles determining efficacy of vaccine delivery with respect to immune defence development and regulation. This renders DCs important targets for vaccine delivery, particularly RNA vaccines. While delivery of interfering RNA oligonucleotides to the appropriate intracellular sites for RNA-interference has proven successful, the methodologies are identical for RNA vaccines, which require delivery to RNA translation sites. Delivery of mRNA has benefitted from application of cationic entities; these offer value following endocytosis of RNA, when cationic or amphipathic properties can promote endocytic vesicle membrane perturbation to facilitate cytosolic translocation. The present review presents how such advances are being applied to the delivery of a new form of RNA vaccine, replicons (RepRNA) carrying inserted foreign genes of interest encoding vaccine antigens. Approaches have been developed for delivery to DCs, leading to the translation of the RepRNA and encoded vaccine antigens both in vitro and in vivo. Potential mechanisms favouring efficient delivery leading to translation are discussed with respect to the DC endocytic machinery, showing the importance of cytosolic translocation from acidifying endocytic structures. The review relates the DC endocytic pathways to immune response induction, and the potential advantages for these self-replicating RNA vaccines in the near future.


Hearing from parents: the impact of receiving the diagnosis of Williams syndrome in their child.
Healthcare providers often share difficult or life-altering news with their patients yet this challenging and delicate process is frequently met with dissatisfaction by those receiving this news. Articles and guidelines exist to aid providers in sharing diagnoses such as Down syndrome, but relatively few have focused on rare genetic conditions often diagnosed years after birth. For this reason, we sought to learn about the experience of receiving a diagnosis from parents of children with Williams syndrome. We asked members of the Williams Syndrome Association to complete an anonymous online survey about recollections related to the diagnostic process. Responses, both close-ended and open-ended, were received from 600 families across the United States. Analysis revealed a high proportion of families (59.91%) with at least some negative recollections about the experience (and nearly half of those with negative recollections denied recalling anything positive). Factors influencing a more positive overall perception of the experience included receiving written information about Williams syndrome and seeing a genetic counselor. Analysis of open-ended responses identified additional positive and negative themes; for example, nearly one quarter of respondents expressed a desire to be given hope when receiving the diagnosis. Based on these analyses, we offer several specific recommendations for improving the diagnostic process in the future.


Determining nasoenteral feeding tube placement.
Tube feedings have been a common nutritional support technique for decades. Enteral nutrition is safer, easier, and less costly than the alternative, parenteral nutrition. Problems do occur, such as pulmonary complications. In this review, techniques to determine the placement of nasoenteral feeding tubes are evaluated, and implications for research and practice are discussed.


Fe3+ detection, bioimaging, and patterning based on bright blue-fluorescent N-doped carbon dots.
Bright blue fluorescent N-doped carbon dots (N-CDs) with satisfactory yield (54%) were successfully fabricated by one-step hydrothermal treatment of astragalus. The obtained N-CDs possessed superior stability, solubility and high resistance to photo bleaching, and can be used as label-free nanosensors for the determination of Fe3+. The quantitative analysis of Fe3+ showed a linear range of 50 to 250 μM with the detection limit as low as 42 nM. Moreover, the as-prepared N-CDs have been used in cellular imaging owing to their distinct merits of simplicity, convenience, fast response and good selectivity towards Fe3+. Besides, the N-CDs could also be further used as fluorescent inks for drawing luminescent patterns.


Factors related to sense of coherence among dental students at Istanbul University.
The salutogenic model suggests that generalized resistance resources (GRRs) promote the development and maintenance of a strong sense of coherence (SOC), which is a health-promoting factor. This study examined associations between GRRs (sociodemographic characteristics, social support, stress, health practices, and self-rated health) and a strong SOC among dental students at Istanbul University. Data were collected from a convenience sample of 566 students using questionnaires including a sociodemographic section, the SOC scale, the Perceived Stress Scale, the Multidimensional Scale of Perceived Social Support, self-rated health, and health practices. Data were analyzed using descriptive statistics, t-test, chi-square test, and binary multiple logistic regression. Students were classified into a low or strong SOC group by a median split procedure, based on their total score on the SOC scale (median=56, range=22 to 91). Univariate statistics showed that students with a strong SOC reported lower stress levels, higher social support levels, better self-rated health, brushing their teeth more frequently, lower sugar intake between meals, and less frequent smoking than students with a low SOC. Multivariate statistics indicated that being a nonsmoker and having better self-rated health, higher social support levels, lower stress levels, and lower sugar intake between meals were the most important predictors of strong SOC. Taking into account the factors that reinforce a strong SOC may help dental educators develop health promotion programs and create supportive environments for maintaining dental students' health.


Progesterone involvement in breast development and tumorigenesis--as revealed by progesterone receptor "knockout" and "knockin" mouse models.
In light of recent clinical trials, the debate concerning the risks and benefits of progestin-based postmenopausal hormone replacement therapy (HRT) has reached a renewed level of urgency. Irrespective of the position taken, the consensus is that more basic research needs to be performed to address progesterone's fundamental role in mammary development and tumorigenesis. Towards this end, the progesterone receptor knockout (PRKO) mouse demonstrated that progesterone is essential for pregnancy-associated mammary gland ductal side-branching and alveologenesis and that these morphological changes are dependent on progesterone-induced mammary epithelial proliferation. Importantly, the PRKO mouse showed that the progesterone-proliferative signal significantly contributes to mammary tumor susceptibility in an established mammary tumor model. Insight into the cellular mechanism(s) by which progesterone affects mammary morphogenesis has been disclosed by a new PR-LacZ knockin mouse, which revealed that PR's spatial expression pattern undergoes precise choreographed distributional changes that precede key stages in postnatal mammary development. In the case of early pregnancy, the segregation of cells undergoing progesterone-induced proliferation from those that express PR implicates a paracrine mode of action for progesterone-induced mammary epithelial proliferation, whereas the preparturient decline of PR expression underscores the need to remove this signal for full functional differentiation of this tissue. Our findings support the proposal that the mammary gland's normal response to the progesterone-signal is dependent upon specific spatial organizational patterns of PR expression and that derailment in these cellular processes may contribute to abnormal mammary development, including cancer. This review concludes by emphasizing the need to identify the downstream molecular targets that mediate progesterone's effects in this tissue. Identification of such targets will not only enhance our mechanistic understanding of progesterone's role in mammary development and cancer, but may also facilitate the formulation of new design strategies in breast cancer diagnosis and/or treatment.


Deconvoluting the T Cell Response to SARS-CoV-2: Specificity Versus Chance and Cognate Cross-Reactivity.
SARS-CoV-2 infection takes a mild or clinically inapparent course in the majority of humans who contract this virus. After such individuals have cleared the virus, only the detection of SARS-CoV-2-specific immunological memory can reveal the exposure, and hopefully the establishment of immune protection. With most viral infections, the presence of specific serum antibodies has provided a reliable biomarker for the exposure to the virus of interest. SARS-CoV-2 infection, however, does not reliably induce a durable antibody response, especially in sub-clinically infected individuals. Consequently, it is plausible for a recently infected individual to yield a false negative result within only a few months after exposure. Immunodiagnostic attention has therefore shifted to studies of specific T cell memory to SARS-CoV-2. Most reports published so far agree that a T cell response is engaged during SARS-CoV-2 infection, but they also state that in 20-81% of SARS-CoV-2-unexposed individuals, T cells respond to SARS-CoV-2 antigens (mega peptide pools), allegedly due to T cell cross-reactivity with Common Cold coronaviruses (CCC), or other antigens. Here we show that, by introducing irrelevant mega peptide pools as negative controls to account for chance cross-reactivity, and by establishing the antigen dose-response characteristic of the T cells, one can clearly discern between cognate T cell memory induced by SARS-CoV-2 infection vs. cross-reactive T cell responses in individuals who have not been infected with SARS-CoV-2.


Attitudes of Patients and Their Relatives Toward Artificial Intelligence in Neurosurgery.
Artificial intelligence (AI) may favorably support surgeons but can result in concern among patients and their relatives. The aim of this study was to evaluate attitudes of patients and their relatives regarding use of AI in neurosurgery. In a 2-stage cross-sectional survey, a qualitative survey was administered to a focus group of former patients to investigate their perception of AI and its role in neurosurgery. Five themes were identified and used to generate a case-based quantitative survey administered to inpatients and their relatives over a 2-week period. Presented AI platforms were rated appropriate and acceptable using 5-point Likert scales. Demographic data were collected. χ2 test was used to determine whether demographics influenced participants' attitudes. In the first stage, 20 participants responded. Five themes were identified: interpretation of imaging (4/20; 20%), operative planning (5/20; 25%), real-time alert of potential complications (10/20; 50%), partially autonomous surgery (6/20; 30%), and fully autonomous surgery (3/20; 15%). In the second stage, 107 participants responded. Most thought it appropriate and acceptable to use AI for imaging interpretation (76.7%; 66.3%), operative planning (76.7%; 75.8%), real-time alert of potential complications (82.2%; 72.9%), and partially autonomous surgery (58%; 47.7%). Conversely, most did not think that fully autonomous surgery was appropriate (27.1%) or acceptable (17.7%). Demographics did not have a significant influence on perception. Most patients and their relatives believed that AI has a role in neurosurgery and found it acceptable. Notable exceptions were fully autonomous systems, with most wanting the neurosurgeon ultimately to remain in control.


[Apparently benign thoracic trauma: what to be aware of?].
In case of chest trauma, the physician must always carefully evaluate the following parameters before to consider the case as uncomplicated (TTS): 1) the speed and circumstances of the accident; 2) the localization and the intensity of the pain; and 3) the presence of signs of respiratory failure and/or haemodynamic instability. Among patients aged greater than 65, the number of ribs fractured can predict mortality. Patients presenting with TTS, can be discharged from the hospital, provided they are prescribed with adequate analgesic medication and basic physiotherapy exercises, followed by a medical check-up after a five-day period.


A cognitive task analysis of expert surgeons performing the robotic roux-en-y gastric bypass.
The safe and effective performance of a robotic roux-en-y gastric bypass (RRNY) requires the application of a complex body of knowledge and skills. This qualitative study aims to: (1) define the tasks, subtasks, decision points, and pitfalls in a RRNY; (2) create a framework upon which training and objective evaluation of a RRNY can be based. Hierarchical and cognitive task analyses for a RRNY were performed using semi-structured interviews of expert bariatric surgeons to describe the thoughts and behaviors that exemplify optimal performance. Verbal data was recorded, transcribed verbatim, supplemented with literary and video resources, coded, and thematically analyzed. A conceptual framework was synthesized based on three book chapters, three articles, eight online videos, nine field observations, and interviews of four subject matter experts (SME). At the time of the interview, SME had practiced a median of 12.5 years and had completed a median of 424 RRNY cases. They estimated the number of RRNY to achieve competence and expertise were 25 cases and 237.5 cases, respectively. After four rounds of inductive analysis, 83 subtasks, 75 potential errors, 60 technical tips, and 15 decision points were identified and categorized into eight major procedural steps (pre-procedure preparation, abdominal entry & port placement, gastric pouch creation, omega loop creation, gastrojejunal anastomosis, jejunojejunal anastomosis, closure of mesenteric defects, leak test & port closure). Nine cognitive behaviors were elucidated (respect for patient-specific factors, tactical modification, adherence to core surgical principles, task completion, judicious technique & instrument selection, visuospatial awareness, team-based communication, anticipation & forward planning, finessed tissue handling). This study defines the key elements that formed the basis of a conceptual framework used by expert bariatric surgeons to perform the RRNY safely and effectively. This framework has the potential to serve as foundational tool for training novices.


Effects of respiratory-burst stimuli on the flow properties of pig blood neutrophils.
Stimulants of the neutrophil respiratory burst, both soluble and crystalline, greatly inhibit the flow of cells through a Nuclepore filter with 5 micron diameter pores. The stimuli appear to reduce cell deformability by a mechanism independent of the activation of respiration, since inhibitors of the respiratory burst (N-phenyl maleimide, quercetin) are without effect on the change. It is suggested that stimuli reduce membrane deformability rather than cause aggregation, since slowing of flow is independent of cell density and is much less when the filter pore size is increased to 8 micron. The technique, recently used to study alterations in erythrocyte deformability, may be appropriate for investigating leucocyte flow in some clinical disorders.


Low Red Blood Cell Vitamin C Concentrations Induce Red Blood Cell Fragility: A Link to Diabetes Via Glucose, Glucose Transporters, and Dehydroascorbic Acid.
Strategies to prevent diabetic microvascular angiopathy focus on the vascular endothelium. Because red blood cells (RBCs) are less deformable in diabetes, we explored an original concept linking decreased RBC deformability to RBC ascorbate and hyperglycemia. We characterized ascorbate concentrations from human and mouse RBCs and plasma, and showed an inverse relationship between RBC ascorbate concentrations and deformability, measured by osmotic fragility. RBCs from ascorbate deficient mice were osmotically sensitive, appeared as spherocytes, and had decreased β-spectrin. These aberrancies reversed with ascorbate repletion in vivo. Under physiologic conditions, only ascorbate's oxidation product dehydroascorbic acid (DHA), a substrate for facilitated glucose transporters, was transported into mouse and human RBCs, with immediate intracellular reduction to ascorbate. In vitro, glucose inhibited entry of physiologic concentrations of dehydroascorbic acid into mouse and human RBCs. In vivo, plasma glucose concentrations in normal and diabetic mice and humans were inversely related to respective RBC ascorbate concentrations, as was osmotic fragility. Human RBC β-spectrin declined as diabetes worsened. Taken together, hyperglycemia in diabetes produced lower RBC ascorbate with increased RBC rigidity, a candidate to drive microvascular angiopathy. Because glucose transporter expression, DHA transport, and its inhibition by glucose differed for mouse versus human RBCs, human experimentation is indicated.


Modulation of yeast alkaline cation tolerance by Ypi1 requires calcineurin.
Ypi1 was discovered as an essential protein able to act as a regulatory subunit of the Saccharomyces cerevisiae type 1 protein phosphatase Glc7 and play a key role in mitosis. We show here that partial depletion of Ypi1 causes lithium sensitivity and that high levels of this protein confer a lithium-tolerant phenotype to yeast cells. Remarkably, this phenotype was independent of the role of Ypi1 as a Glc7 regulatory subunit. Lithium tolerance in cells overexpressing Ypi1 was caused by a combination of increased efflux of lithium, mediated by augmented expression of the alkaline cation ATPase ENA1, and decreased lithium influx through the Trk1,2 high-affinity potassium transporters. Deletion of CNB1, encoding the regulatory subunit of the calcineurin phosphatase, blocked Ypi1-induced expression of ENA1, normalized Li(+) fluxes, and abolished the Li(+) hypertolerant phenotype of Ypi1-overexpressing cells. These results point to a complex role of Ypi1 on the regulation of cation homeostasis, largely mediated by the calcineurin phosphatase.


Histidinomycin, a new antifungal antibiotic.
A new antifungal antibiotic named histidinomycin was isolated from the broth filtrate of a streptomycete, tentatively designated as isolate H 878-MY 1. Histidinomycin was purified as the monohydrochloride and the molecular formula was proposed to be C22H30N8O11.HCl. The antibiotic gave histidine by acid hydrolysis. Histidinomycin showed rather narrow antimicrobial spectrum for only few genera of phytophathogenic fungi.


Distinct proteome pathology of circulating microparticles in systemic lupus erythematosus.
The pathogenesis of systemic lupus erythematosus (SLE) is poorly understood but has been linked to defective clearance of subcellular particulate material from the circulation. This study investigates the origin, formation, and specificity of circulating microparticles (MPs) in patients with SLE based on comprehensive MP proteome profiling using patients with systemic sclerosis (SSc) and healthy donors (HC) as controls. We purified MPs from platelet-poor plasma using differential centrifugation of samples from SLE (n = 45), SSc (n = 38), and two sets of HC (n = 35, n = 25). MP proteins were identified and quantitated after trypsin digestion by liquid chromatography-tandem mass spectrometry. The abundance of specific proteins was compared between the groups using univariate statistics and false discovery rate correction for multiple comparisons. Specific proteins and protein ratios were explored for diagnostic and disease activity information using receiver-operating characteristic curves and by analysis of correlations of protein abundance with disease activity scores. We identify and quantitate more than 1000 MP proteins and show that a subpopulation of SLE-MPs (which we propose to call luposomes) are highly specific for SLE, i.e. not found in MP preparations from HC or patients with another autoimmune, systemic disease, SSc. In SLE-MPs platelet proteins and mitochondrial proteins are significantly diminished, cytoskeletal proteins deranged, and glycolytic enzymes and apoptotic proteins significantly increased. Normal MPs are efficiently removed in SLE, but aberrant MPs, derived from non-lymphoid leukocytes, are less efficiently removed and abundantly produced leading to an altered MP proteome in SLE. The data suggest that an abnormal generation of MPs may partake in the pathology of SLE and that new diagnostic, monitoring, and treatment strategies targeting these processes may be advantageous.


The combination of penile revascularization surgery with penile corrective techniques as an alternative to prosthesis implantation in patients with Peyronie's disease having ED: preliminary results.
The aim of this study was to investigate for the first time the surgical results of combining complex corrective techniques with penile revascularization in patients with Peyronie's disease having ED and consider the technique as an alternative to penile prosthesis implantation. Between 2008 and 2011 penile revascularization surgery along with penile corrective techniques was performed in nine patients with Peyronie's disease having ED. A preoperative urological evaluation was performed with penile color doppler ultrasonography, electromyography of the corpus cavernosum and cavernosometry. The degree of penile angulation was >40° in all patients. All the patients were asked to answer a 15-item questionnaire-the 'International Index of Erectile Function' (IIEF-15)-and a 5-item version of the IIEF (IIEF-5) preoperatively and during the postoperative follow-up. The operation was deemed an improvement or a failure according to the scores on the IIEF-5. The mean age of the patients was 51.4±4.2 years. The mean follow-up period was 18 months. None of the patients reported complications after surgery. Complete penile straightening was achieved in all patients. However, two (22.2%) patients reported penile shortening but did not express any dissatisfaction in this regard. All patients were satisfied with the final surgical results. The mean IIEF-5 score was 9.8±3.1 before the operation and it was reported to be 22.03±2.4 at the end of the follow-up period (P<0.05). The mean erectile function domain score was 12.6±3.7 preoperatively and 24.09±3.9 at the end of the follow-up period (P<0.05). We achieved statistically significant improvements on the IIEF scores, and with this satisfactory preliminary results we suggest that this combination could be an alternative to penile prosthesis implantation in highly selected patients with Peyronie's disease having ED; however, further studies are needed to validate this conclusion.


Calcium channel blockers improve prognosis of patients with coronavirus disease 2019 and hypertension.
Hypertension is considered an important risk factor for the coronavirus disease 2019 (COVID-19). The commonly anti-hypertensive drugs are the renin-angiotensin-aldosterone system (RAAS) inhibitors, calcium channel blockers (CCBs), and beta-blockers. The association between commonly used anti-hypertensive medications and the clinical outcome of COVID-19 patients with hypertension has not been well studied. We conducted a retrospective cohort study that included all patients admitted with COVID-19 to Huo Shen Shan Hospital and Guanggu District of the Maternal and Child Health Hospital of Hubei Province, Wuhan, China. Clinical and laboratory characteristics were extracted from electronic medical records. Hypertension and anti-hypertensive treatment were confirmed by medical history and clinical records. The primary clinical endpoint was all-cause mortality. Secondary endpoints included the rates of patients in common wards transferred to the intensive care unit and hospital stay duration. Logistic regression was used to explore the risk factors associated with mortality and prognosis. Propensity score matching was used to balance the confounders between different anti-hypertensive treatments. Kaplan-Meier curves were used to compare the cumulative recovery rate. Log-rank tests were performed to test for differences in Kaplan-Meier curves between different groups. Among 4569 hospitalized patients with COVID-19, 31.7% (1449/4569) had a history of hypertension. There were significant differences in mortality rates between hypertensive patients with CCBs (7/359) and those without (21/359) (1.95% vs. 5.85%, risk ratio [RR]: 0.32, 95% confidence interval [CI]: 0.13-0.76, χ2 = 7.61, P = 0.0058). After matching for confounders, the mortality rates were similar between the RAAS inhibitor (4/236) and non-RAAS inhibitor (9/236) cohorts (1.69% vs. 3.81%, RR: 0.43, 95% CI: 0.13-1.43, χ2 = 1.98, P = 0.1596). Hypertensive patients with beta-blockers (13/340) showed no statistical difference in mortality compared with those without (11/340) (3.82% vs. 3.24%, RR: 1.19, 95% CI: 0.53-2.69, χ2 = 0.17, P = 0.6777). In our study, we did not find any positive or negative effects of RAAS inhibitors or beta-blockers in COVID-19 patients with hypertension, while CCBs could improve prognosis.


How patients spend their time in a hospice and in an oncological unit.
This paper presents the findings from a work sampling study. At 10-minute intervals the activities of patients in a hospice, and in an oncological unit were monitored for a day or a night. In total, 5286 observations of patient activities were recorded. The findings showed that being a patient, especially in the oncological unit, was apparently a very lonely experience with limited social interaction and purposeful activity. Hospice patients, in contrast, were less alone, spending much of their time with their relatives. Although none of the patients at either site spent a major part of either day or night with nurses, hospice patients and nurses spent significantly more time together, and their encounters more often lasted longer. Nursing care at both sites was mainly related to 'doing' rather than 'being', i.e. when with patients, nurses most often had some task to accomplish. The study shows the importance of increasing our understanding of the use of time and the combination of doing and being that reflects good nursing care of the dying.


Effects of mercury on lysosomal protein digestion in the kidney proximal tubule.
The effect of mercury on renal lysosomal protein digestion was studied after administration of mercury in vitro and in vivo. Mercuric chloride or methylmercury chloride was added in vitro to lysosomal enzymes isolated from normal rats, and subsequently, digestion experiments were carried out using 125I-labeled lysozyme or cytochrome c as substrate proteins. Both mercury compounds produced a concentration-dependent inhibition of the degradation of the proteins, mercuric chloride being the strongest inhibitor. Mercuric chloride was also administered to rats in vivo for 5 to 8 months. Renal lysosomal enzymes from these animals also had a decreased ability to digest for the two substrate proteins. Furthermore, the digestion of lysozyme intravenously injected into mercury-intoxicated rats was decreased in renal cortical slices incubated in vitro. Electron microscope autoradiography showed that intravenously injected labeled lysozyme was located primarily over lysosomes in proximal tubule cells 1 hour after injection in both control animals and mercury-intoxicated rats. These results suggest a decreased catabolism of low molecular weight proteins in the kidney during chronic mercury intoxication.


Structural analysis of peptide substrates for mucin-type O-glycosylation.
The structures of three nine-residue peptide substrates that show differential kinetics of O-linked glycosylation catalyzed by distinct recombinant uridine diphosphate-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferases (GalNAc transferases) were investigated by NMR spectroscopy. A combined use of NMR data, molecular modeling techniques, and kinetic data may explain some structural features required for O-glycosylation of these substrates by two GalNAc transferases, GalNAc-T1 and GalNAc-T3. In the proposed model, the formation of an extended backbone structure at the threonine residue to be glycosylated is likely to enhance the O-glycosylation process. The segment of extended structure includes the reactive residue in a beta-like or an inverse gamma-turn conformation and flanking residues in a beta-strand conformation. The hydroxyl group of the threonine to be glycosylated is exposed to solvent, and both the amide proton and carbonyl oxygen of the peptide backbone are exposed to solvent. The exchange rate of the amide proton for the reactive threonine correlated well with substrate efficiency, leading us to hypothesize that this proton may serve as a donor for hydrogen bonding with the active site of the enzyme. The oxygens of the residue to be glycosylated and several flanking residues may also be involved in a set of hydrogen bonds with the GalNAc-T1 and -T3 transferases.


Gluteal Loading Versus Sham Exercises to Improve Pain and Dysfunction in Postmenopausal Women with Greater Trochanteric Pain Syndrome: A Randomized Controlled Trial.
The aim of the current study was to determine the effects of education with targeted or sham exercise on pain and function in postmenopausal women with greater trochanteric pain syndrome (GTPS). Conservative management of GTPS is poorly described, and to date, there have been no studies on education with exercise as an intervention for GTPS. Ninety-four postmenopausal women with GTPS were recruited to participate in this study. Participants were randomized to receive one of two 12-week exercise programs (GLoBE vs. sham). Participants received education on avoiding tendon compression with appropriate activity modification. The Victorian Institute of Sport Assessment-Gluteal tendon (VISA-G) was examined at baseline, 12, and 52 weeks. Secondary outcomes included hip pain and function questionnaires (Hip dysfunction and Osteoarthritis Outcome Score (HOOS), Oxford Hip Score (OHS), and Lateral Hip Pain questionnaire), a global rating of change in symptom questionnaire, and a quality of life measure (Assessment of Quality of Life [AQoL]-8D). Differences between groups were analyzed using intention to treat with analysis of covariance, per-protocol analysis, and responder analysis. Responders to the GLoBE intervention had significantly better VISA-G, HOOS, OHS, and lateral hip pain questionnaire scores compared to responders in the sham group. However, intention to treat analyses showed no between-group differences for the GLoBE intervention and sham exercise groups. Significant improvement in VISA-G score was found for both programs at 12- and 52-weeks time points (p < 0.001). Lack of treatment effect was found with the addition of an exercise program to a comprehensive education on GTPS management. The improved outcomes of the responders in the GLoBE group indicate that there may be a subgroup of patients with a GTPS diagnosis that benefit from a GLoBE intervention program.


Selenium toxicity to honey bee (Apis mellifera L.) pollinators: effects on behaviors and survival.
We know very little about how soil-borne pollutants such as selenium (Se) can impact pollinators, even though Se has contaminated soils and plants in areas where insect pollination can be critical to the functioning of both agricultural and natural ecosystems. Se can be biotransferred throughout the food web, but few studies have examined its effects on the insects that feed on Se-accumulating plants, particularly pollinators. In laboratory bioassays, we used proboscis extension reflex (PER) and taste perception to determine if the presence of Se affected the gustatory response of honey bee (Apis mellifera L., Hymenoptera: Apidae) foragers. Antennae and proboscises were stimulated with both organic (selenomethionine) and inorganic (selenate) forms of Se that commonly occur in Se-accumulating plants. Methionine was also tested. Each compound was dissolved in 1 M sucrose at 5 concentrations, with sucrose alone as a control. Antennal stimulation with selenomethionine and methionine reduced PER at higher concentrations. Selenate did not reduce gustatory behaviors. Two hours after being fed the treatments, bees were tested for sucrose response threshold. Bees fed selenate responded less to sucrose stimulation. Mortality was higher in bees chronically dosed with selenate compared with a single dose. Selenomethionine did not increase mortality except at the highest concentration. Methionine did not significantly impact survival. Our study has shown that bees fed selenate were less responsive to sucrose, which may lead to a reduction in incoming floral resources needed to support coworkers and larvae in the field. If honey bees forage on nectar containing Se (particularly selenate), reductions in population numbers may occur due to direct toxicity. Given that honey bees are willing to consume food resources containing Se and may not avoid Se compounds in the plant tissues on which they are foraging, they may suffer similar adverse effects as seen in other insect guilds.


A role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndrome.
Type 2 brittle cornea syndrome (BCS2) is an inherited connective tissue disease with a devastating ocular phenotype caused by mutations in the transcription factor PR domain containing 5 (PRDM5) hypothesized to exert epigenetic effects through histone and DNA methylation. Here we investigate clinical samples, including skin fibroblasts and retinal tissue from BCS2 patients, to elucidate the epigenetic role of PRDM5 and mechanisms of its dysregulation in disease. First we report abnormal retinal vascular morphology in the eyes of two cousins with BCS2 (PRDM5 Δ exons 9-14) using immunohistochemistry, and mine data from skin fibroblast expression microarrays from patients with PRDM5 mutations p.Arg590* and Δ exons 9-14, as well as from a PRDM5 ChIP-sequencing experiment. Gene ontology analysis of dysregulated PRDM5-target genes reveals enrichment for extracellular matrix (ECM) genes supporting vascular integrity and development. Q-PCR and ChIP-qPCR confirm upregulation of critical mediators of ECM stability in vascular structures (COL13A1, COL15A1, NTN1, CDH5) in patient fibroblasts. We identify H3K9 di-methylation (H3K9me2) at these PRDM5-target genes in fibroblasts, and demonstrate that the BCS2 mutation p.Arg83Cys diminishes interaction of PRDM5 with repressive complexes, including NuRD complex protein CHD4, and the repressive chromatin interactor HP1BP3, by co-immunoprecipitation combined with mass spectrometry. We observe reduced heterochromatin protein 1 binding protein 3 (HP1BP3) staining in the retinas of two cousins lacking exons 9-14 by immunohistochemistry, and dysregulated H3K9me2 in skin fibroblasts of three patients (p.Arg590*, p.Glu134* and Δ exons 9-14) by western blotting. These findings suggest that defective interaction of PRDM5 with repressive complexes, and dysregulation of H3K9me2, play a role in PRDM5-associated disease.


Association between sleep duration and diabetes mellitus: Isfahan Healthy Heart Program.
Recent studies revealed an association between sleep disturbance and metabolic disorders, such as obesity and metabolic syndrome. An aim of this study was to assess the relation between sleep duration and diabetes mellitus in a representative sample of the Iranian population. Participants were 12514 individuals, (6123 men and 6391 women) studied in the baseline survey of a community based program entitled Isfahan healthy heart program (IHHP). Sleep time was obtained by validated questionnaire. Diabetes mellitus was defined as fasting glucose over 126 mg/dl or 2 hour post prandial glucose at glucose tolerance test over 200 mg/dl, or if the patient was on diabetic medication. The relation between the sleep time and diabetes was examined using categorical logistic regression with adjustment for sex, body mass index and waist circumference. Compared with those, sleeping 7-8 hours per night, the individuals with sleeping time of 5 hours or less and aged <60 years had an increased odd ratio for diabetes and an impaired glucose tolerance. (OR = 1.37 and 95% CI = 1.13, 1.67). Sleep duration of 5 hours or less in individuals under age 60 years is associated with an increased prevalence of diabetes mellitus and an impaired glucose tolerance test. This finding should be confirmed in longitudinal studies.


Flexible information coding in human auditory cortex during perception, imagery, and STM of complex sounds.
Auditory cortex is the first cortical region of the human brain to process sounds. However, it has recently been shown that its neurons also fire in the absence of direct sensory input, during memory maintenance and imagery. This has commonly been taken to reflect neural coding of the same acoustic information as during the perception of sound. However, the results of the current study suggest that the type of information encoded in auditory cortex is highly flexible. During perception and memory maintenance, neural activity patterns are stimulus specific, reflecting individual sound properties. Auditory imagery of the same sounds evokes similar overall activity in auditory cortex as perception. However, during imagery abstracted, categorical information is encoded in the neural patterns, particularly when individuals are experiencing more vivid imagery. This highlights the necessity to move beyond traditional "brain mapping" inference in human neuroimaging, which assumes common regional activation implies similar mental representations.


[Transcription of ribosomal genes in nuclei of different ploidy].
It has been shown previously that the production of "mature" (27S and 18S) ribosomal RNA's (rRNA) at late stages of embryonic development of the loach (Misgurnus fossilis) does not depend on the degree of ploidy, the haploid (1n) embryos making, per cell, as much rRNA as do the diploid (2n) ones. In order to investigate the mechanims of the compensation of rRNA production in 1n embryos, incorporation of labelled nucleosides in different RNA fractions was compared in two genetical variants. The kinetic and sedimentation analysis showed that in 1n cells a compensatory increase in the production of 36S precursor of rRNA (pre-rRNA) takes place. Chase experiments showed that the rate of the processing and decay of the pre-rRNA was similar in the two genetic forms. Saturation hybridization of labelled, purified 27S rRNA with DNA isolated from the nuclei of 1n and 2n embryos failed to reveal any significant differential increase (amplification) in the proportion of ribosomal cistrons (rDNA) in the haploid genome. It is concluded that the compensation of the production of rRNA in the haploid embryos is accounted for by a greater rate of transcription of the totality of the ribosomal cistrons per single chromosome set.


Ultrasound-guided, long-axis, in-plane, infraclavicular axillary vein cannulation: A 6-year experience.
Despite its potential advantages, ultrasound-guided cannulation of the axillary vein in the infraclavicular area is still rarely used as an alternative to other techniques. There are few large series demonstrating the safety and feasibility of this approach. Retrospective analysis of data on patients undergoing ultrasound-guided, long-axis, in-plane infraclavicular axillary vein cannulation for the incidence of complications and the failure rate from two secondary-care hospitals. The analysis included 710 successful attempts of axillary vein long-axis, in-plane, US-guided cannulation, and 24 (3.3%) failed attempts. We recorded a 96.7% success rate with an overall incidence of complications of 13%, mainly malposition (8.1%). There was one case of pneumothorax (0.14%), five cases of arterial puncture (0.7%), and two cases of brachial plexus injury. The US-guided axillary central venous cannulation (CVC) access technique can be undertaken successfully in patients, even in challenging circumstances. Taken together with existing work on the utility and safety of this technique, we suggest that it should be adopted more widely in clinical practice.


Upregulation of an opioid-mediated antinociceptive mechanism in transgenic mice over-expressing substance P in the spinal cord.
In transgenic mice expressing ectopic substance P fibres in the spinal white matter, a normally innocuous mechanical stimulus induces hyperalgesia and allodynia which are reversed by substance P and N-methyl-D-aspartate receptor antagonists. This period of enhanced excitation is followed by a rebound overshoot in these animals. As previous evidence indicates opioid mechanisms in a similar rebound in normal animals, the present study was done to determine the effects of systemic administration of morphine and the opiate receptor antagonist, naloxone, on the stimulus-induced responses in the tail withdrawal reflex. Once baseline reaction times had been taken, different combinations of saline, naloxone and morphine were administered intraperitoneally to transgenic and control mice of either sex. A mechanical conditioning stimulus of 450g was then applied to the tip of the tail for 2s. This stimulus was innocuous in control mice given saline or naloxone, but provoked a nociceptive response in transgenic mice given these compounds. In control and transgenic mice, following morphine administration there was an antinociceptive effect. In control mice the subsequent mechanical stimulus had no effect. However, in transgenic mice the mechanical stimulus produced a further antinociception. Naloxone blocked the effect of morphine and the subsequent conditioning stimulus in both control and transgenic mice. The results indicate that while morphine is equally effective on the withdrawal reflex in both types of animal, in the transgenic mice morphine reveals an intrinsic, naloxone-sensitive antinociceptive mechanism. The data are interpreted to suggest that over-expression of substance P or some other factor in the spinal cord of transgenic mice is associated with the up-regulation or facilitation of an opiate-mediated intrinsic antinociceptive mechanism. This is a novel observation because the genetic manipulation in this transgenic mouse results in a transient over-expression of nerve growth factor during development that leads to the formation of ectopic primary afferent fibres in the spinal cord containing substance P. These fibres persist indefinitely after the nerve growth factor levels return to normal. Opioid mechanisms, which are likely of dorsal horn origin, do not fall under the direct influence of nerve growth factor mechanisms and therefore the intriguing possibility is raised that opioid mechanisms in the spinal cord are regulated at least in part by substance P-related mechanisms.


The role of monocytes and macrophages in the dynamic permeability of the blood-perilymph barrier.
The blood-perilymph barrier serves a critical role by separating the components of blood from inner ear fluids, limiting traffic of cells, proteins and other solutes into the labyrinth, and allowing gas (O2-CO2) exchange. Inflammation produces changes in the blood-perilymph barrier resulting in increased vascular permeability. It is commonly thought that compromise of the blood-inner ear barrier would lead to hearing impairment through loss of the endocochlear potential (EP). In fact, the effect of increasing cochlear vascular permeability on hearing function and EP is poorly understood. We used a novel method to measure the integrity of the blood-perilymph barrier and demonstrated the effects of barrier compromise on ABR threshold and EP. We also investigated the contribution of CX3CR1 cochlear macrophages and CCR2 inflammatory monocytes to barrier function after systemic exposure to lipopolysaccharide (LPS). We found that systemic LPS induced a profound change in vascular permeability, which correlated with minimal change in ABR threshold and EP. Macrophage depletion using CX3CR1-DTR mice did not alter the baseline permeability of cochlear vessels and resulted in preservation of barrier function in LPS-treated animals. We conclude that cochlear macrophages are not required to maintain the barrier in normal mice and activated macrophages are a critical factor in breakdown of the barrier after LPS. CCR2 null mice demonstrated that LPS induction of barrier leakiness occurs in the absence of CCR2 expression. Thus, enhanced aminoglycoside ototoxicity after LPS can be linked to the expression of CCR2 in inflammatory monocytes, and not to preservation of the blood-perilymph barrier in CCR2 knockout mice.


Structural insights into mis-regulation of protein kinase A in human tumors.
The extensively studied cAMP-dependent protein kinase A (PKA) is involved in the regulation of critical cell processes, including metabolism, gene expression, and cell proliferation; consequentially, mis-regulation of PKA signaling is implicated in tumorigenesis. Recent genomic studies have identified recurrent mutations in the catalytic subunit of PKA in tumors associated with Cushing's syndrome, a kidney disorder leading to excessive cortisol production, and also in tumors associated with fibrolamellar hepatocellular carcinoma (FL-HCC), a rare liver cancer. Expression of a L205R point mutant and a DnaJ-PKA fusion protein were found to be linked to Cushing's syndrome and FL-HCC, respectively. Here we reveal contrasting mechanisms for increased PKA signaling at the molecular level through structural determination and biochemical characterization of the aberrant enzymes. In the Cushing's syndrome disorder, we find that the L205R mutation abolishes regulatory-subunit binding, leading to constitutive, cAMP-independent signaling. In FL-HCC, the DnaJ-PKA chimera remains under regulatory subunit control; however, its overexpression from the DnaJ promoter leads to enhanced cAMP-dependent signaling. Our findings provide a structural understanding of the two distinct disease mechanisms and they offer a basis for designing effective drugs for their treatment.


Patients with irritable bowel syndrome have greater pain tolerance than normal subjects.
A low tolerance for pain has been postulated as a factor in the expression of symptoms in patients with irritable bowel syndrome. This has been based on previous work demonstrating reduced intestinal thresholds for rectal pain induced by balloon distention in patients with irritable bowel syndrome. As the disease may alter the rectal response to distention, inferences regarding pain perception and reporting behavior cannot be drawn from these data. In this study, using electrocutaneous stimulation, we found that patients with irritable bowel syndrome had pain reporting behavior comparable to patients with Crohn's disease. Both patient groups were less likely than normals to report a noxious stimulus as painful. This suggests that pain perception and reporting is attenuated in patients with chronic abdominal pain and, accordingly, a generalized reduction in the threshold for reporting pain is not a factor in the expression of symptoms in the irritable bowel syndrome.


Bistability explains threshold phenomena in protein aggregation both in vitro and in vivo.
Neurodegenerative disease can originate from the misfolding and aggregation of proteins, such as Amyloid-beta, SOD1, or Huntingtin. Fortunately, all cells possess protein quality control machinery that sequesters misfolded proteins, either refolding or degrading them, before they can self-associate into proteotoxic oligomers and aggregates. This activity is largely performed by the stress response chaperones (i.e., Hsp70). However, the expression level of molecular chaperones varies widely among cell types. To understand the potential consequence of this variation, we studied the process of protein aggregation in the presence of molecular chaperones using mathematical modeling. We demonstrate that protein aggregation, in the presence of molecular chaperones, is a bistable process. Bistability in protein aggregation offers an explanation for threshold transitions to high aggregate concentration, which are observed both in vitro and in vivo. Additionally, we show that slight variations in chaperone concentration, due to natural fluctuations, have important consequences in a bistable system for the onset of protein aggregation. Therefore, our results offer a possible theoretical explanation for neuronal vulnerability observed in vivo and the onset of neurodegenerative phenotypes in neurons lacking an effective heat-shock response.


Educating family physicians to care for the chronically mentally ill.
More than 50 percent of the chronically mentally ill receive their medical, psychiatric, and social support services from primary care physicians in the general health sector. Despite this high level of involvement with these patients, the majority of family physicians consider their training in the management of patients with mental disorders to be inadequate. This paper describes six categories of critical competencies that should be included in the mental health curricula of family physician training programs: therapeutic attitudes and skills, diagnosis and differential diagnosis, functional assessment, psychopharmacology, management of emergencies, and psychosocial treatments. It outlines the manner in which specific competencies could be incorporated in medical school, in family practice residency training, and in postgraduate continuing medical education as well as the specific elements included in each. The discussion is based on the assumption that more effective participation by family physicians in the treatment of chronic psychiatric illness requires active attention throughout the continuum of medical education.


Effects of calcium entry blockade on left ventricular dynamics in exercising dogs.
To study the previously undefined effects of calcium entry blockade on left ventricular (LV) function and coronary blood flow during dynamic exercise we gave intravenous equihypotensive infusions of nifedipine (10 +/- 4 SE micrograms X kg-1 X min-1), diltiazem (60 +/- 8 micrograms X kg-1 X min-1), and verapamil (52 +/- 7 micrograms X kg-1 X min-1) before and after intravenous propranolol (2 mg/kg) to chronically instrumented dogs at rest and while running on a treadmill at 4 and 10 km/h. Prior to beta-blockade, each agent significantly and equivalently (P = NS among drugs) reduced mean arterial pressure during exercise (-13% nifedipine, -8% diltiazem, -15% verapamil at 4 km/h, each P less than or equal to 0.01 vs. exercise alone) but did not significantly alter LV end-diastolic dimension (EDD), heart rate, or cardiac output compared with exercise alone. Only verapamil blunted the positive inotropic response to exercise (LV dP/dtmax decreased 20% at 4 km/h, P less than 0.01 vs. exercise alone). Coronary blood flow was significantly and equivalently increased at rest and during submaximal exercise with each calcium blocker, but this effect was largely offset by propranolol. During exercise after beta-blockade each agent produced significant additional reductions in mean arterial pressure and dP/dtmax at peak exercise but did not alter LVEDD or heart rate compared with results obtained with propranolol alone. Combined beta-blockade and verapamil uniquely diminished myocardial contractility to a greater extent at peak exercise than at rest (dP/dtmax 1,260 +/- 410 peak exercise vs. 1,775 +/- 431 mmHg/s rest, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of pentobarbital on lidocaine toxicity and brainstem concentration.
The effect of pretreatment with 20 mg/kg sodium pentobarbital on the acute intravenous toxicity of 2% lidocaine was determined in rats. Pretreatment increased the LD(50) of lidocaine from 20.2 mg/kg to 26.9 mg/kg (p<0.05). This 25% decrease in lethality was accompanied by similar decreases in the concentrations of lidocaine (relative to the injected dose) in serum and brainstem samples collected immediately after death. Under the conditions of this study, pentobarbital apparently protects against lidocaine lethality by increasing the relative distribution of local anesthetic to tissues outside of the central nervous system.


Diffusion of small solutes in polymer-containing solutions.
Diffusion processes involving polymers are common in scientific and engineering separations and are a major component of biological functions. Analyses of these systems are usually based on versions of the Stokes-Einstein equation, although order of magnitude deviations have been observed. Presented here is a theoretical correction to the Stokes-Einstein equation containing a "local viscosity" function that combines diffusional hydrodynamics with Maxwell's treatment of electrical resistance in inhomogeneous regions. The resulting equation accurately predicts experimental diffusion data within tight bounds for polymer concentrations from 0 to 9 percent. It requires knowledge only of thermodynamics and of pure solvent and solution viscosities.


Top-down spatial categorization signal from prefrontal to posterior parietal cortex in the primate.
In the present study we characterized the strength and time course of category-selective responses in prefrontal cortex and area 7a of the posterior parietal cortex during a match-to-sample spatial categorization task. A monkey was trained to categorize whether the height of a horizontal sample bar, presented in rectangular frame at one of three vertical locations, was "high" or "low," depending on whether its position was above or below the frame's midline. After the display of this sample bar, and after a delay, choice bars were sequentially flashed in two locations: at the top and at the bottom of the frame ("choice" epoch). If the monkey timed its response to the display of the choice bar that matched the sample bar, he was rewarded. We found that cells in prefrontal cortex discriminated category early after the initial sample bar was shown, and continued to differentiate "up" from "down" trials throughout the delay and choice periods. In contrast, parietal cells did not differentiate category until the choice period. Therefore, our results support the notion of a top-down categorical signal that originates in prefrontal cortex and that is only represented in parietal cortex when it is necessary to express the categorical decision through a movement.


Turing patterns with high-resolution formed without chemical reaction in thin-film solution of organic semiconductors.
Regular patterns can form spontaneously in chemical reaction-diffusion systems under non-equilibrium conditions as proposed by Alan Turing. Here, we found that regular patterns can be generated in uphill-diffusion solution systems without a chemical reaction process through both in-situ and ex-situ observations. Organic semiconductor solution is confined between two parallel plates with controlled micron/submicron-meter distance to minimize convection of the liquid and avoid spinodal precipitation at equilibrium. The solvent evaporation concentrates the solution gradually into an oversaturated non-equilibrium condition, under which a phase-transition occurs and ordered concentration-waves are generated. By proper tuning of the experimental parameter, multiple regular patterns with micro/nano-meter scaled features (line, square-grid, zig-zag, and fence-like patterns etc.) were observed. We explain the observed phenomenon as Turing-pattern generation resulted from uphill-diffusion and solution oversaturation. The generated patterns in the solutions can be condensed onto substrates to form structured micro/nanomaterials. We have fabricated organic semiconductor devices with such patterned materials to demonstrate the potential applications. Our observation may serve as a milestone in the progress towards a fundamental understanding of pattern formation in nature, like in biosystem, and pave a new avenue in developing self-assembling techniques of micro/nano structured materials.


Relationship of family history, antisocial personality disorder and personality traits in young men at risk for alcoholism.
Studies examining possible risk factors for the development of alcoholism have focused recently on a variety of personality factors, including those associated with risk-taking behaviors. Alcohol-seeking behavior leading to the abuse of alcohol may be associated with a variety of risk-taking behaviors that derive from certain personality traits. Further, there is evidence that personality traits are transmitted across generations. This study examined the relationship of a family history of alcoholism, antisocial personality disorder (ASP) and alcohol use to several personality traits including the Tri-dimensional Personality Questionnaire (TPQ) in a sample (N = 91) of nonalcoholic, young male volunteers. The men with ASP scored higher than the non-ASP men on the Novelty Seeking Scale of the TPQ, but not on the Harm Avoidance or Reward Dependence subscales. In addition, ASP men scored higher than non-ASP men on a measure of impulsivity and tended to score higher on measures of sensation seeking, psychopathy and monotony avoidance. A family history of alcoholism did not differentiate the young men on any of the childhood behavior problems, personality measures or alcohol-related variables.


Competence of hosts and complex foraging behavior are two cornerstones in the dynamics of trophically transmitted parasites.
Multi-host trophically transmitted parasite (TTP) is a common life cycle where prey and predators are respectively intermediate and definitive hosts of the parasite. In these systems, the foraging response of the predator toward variations in prey community composition underlies the dynamic of the parasite. Therefore, modeling epidemiological dynamic of infectious diseases considering ecological predator-prey interactions is essential to understand the spreading of parasites in ecosystems. However, two important weaknesses of previous TTP models including feeding interaction can be pointed out: (i) the choice of a linear density-dependent contact rate is faintly realistic as it supposes an unlimited ingestion rate with an increase of prey density and (ii) considering only one host prey species prevents the study of host biodiversity effect due to change in the prey community composition where species have different competences to be infected and to transmit the parasite. This article attempts to address the dynamics of parasite in a context of multiple intermediate hosts differentiated by their competences and of complex foraging behavior of the predator. We present and analyze a deterministic one predator-two prey model, which is then used to explore the transmission cycle of the cestode Echinococcus multilocularis. This study examines the foraging condition for the co-existence of the prey, and then, based on the computation of the threshold measure of disease risk, R0, we show that the pattern of feeding interactions changes the relationship between disease risk and prey community composition. Finally, we disentangle the mechanism leading to the counter-intuitive observation of a decrease of disease risk while the population density of intermediate hosts increases.


[Recurrent urinary tract infection].
Recurrent urinary tract infection involves mainly women and exhibits an ecological as well as economical risk. 4% of all urinary tract infection are recurrent and usually secondary to general or local abnormalities. A multidisciplinary medical and surgical team (urology, nephrology, bacteriology, infectious disease) best performs diagnosis and treatment as well as rules out reversible etiology. Treatment relies on behavioral changes before offering cranberry products and/or antibioprophylaxis if necessary.


Exhaled Nitric Oxide Decreases during Academic Examination Stress in Asthma.
Fractional exhaled nitric oxide (FeNO) is known to vary with multiple endogenous and exogenous factors. Laboratory stress and depressive mood have been associated with altered FeNO levels, but little is known about the susceptibility of FeNO to longer-lasting states of psychological stress in asthma. We sought to study changes in FeNO, lung function, and endogenous cortisol levels in students in a low-stress period during the academic term and in high-stress periods of up to 5 days during final exams. One hundred nine participants (35 with asthma) enrolled in a final examination stress study were assessed during the academic term (low stress) and during final exams (high stress). FeNO, spirometric lung function (FEV1, peak flow), salivary cortisol, and negative affect were measured at three time points. Control variables were medication use, cold symptoms, sex, and age. FeNO decreased substantially from low-stress baseline to the high-stress examination periods, with more pronounced decreases occurring in subjects with asthma (-11.5 ppb) than control subjects (-1.2 ppb). FEV1 decreased in both groups. Negative affect and cortisol increased during final exams, but these increases were smaller in asthma. Greater initial depression and greater cortisol increases were related to larger FeNO decreases during the final exam period, the latter only in asthma. Inhaled corticosteroid use did not affect these changes. Psychological stress and depressive mood are accompanied by decreases in both FeNO and lung function in asthma. Fluctuations related to life stress and mood levels should be considered in FeNO monitoring for asthma.


Cognitive Function during the Prodromal Stage of Alzheimer's Disease in Down Syndrome: Comparing Models.
Accurate identification of the prodromal stage of Alzheimer's disease (AD), known as mild cognitive impairment (MCI), in adults with Down syndrome (MCI-DS) has been challenging because there are no established diagnostic criteria that can be applied for people with lifelong intellectual disabilities (ID). As such, the sequence of cognitive decline in adults with DS has been difficult to ascertain, and it is possible that domain constructs characterizing cognitive function in neurotypical adults do not generalize to this high-risk population. The present study examined associations among multiple measures of cognitive function in adults with DS, either prior to or during the prodromal stage of AD to determine, through multiple statistical techniques, the measures that reflected the same underlying domains of processing. Participants included 144 adults with DS 40-82 years of age, all enrolled in a larger, multidisciplinary study examining biomarkers of AD in adults with DS. All participants had mild or moderate lifelong intellectual disabilities. Overall AD-related clinical status was rated for each individual during a personalized consensus conference that considered performance as well as health status, with 103 participants considered cognitively stable (CS) and 41 to have MCI-DS. Analyses of 17 variables derived from 10 tests of cognition indicated that performance reflected three underlying factors: language/executive function, memory, and visuomotor. All three domain composite scores significantly predicted MCI-DS status. Based upon path modeling, the language/executive function composite score was the most affected by prodromal AD. However, based upon structural equation modeling, tests assessing the latent construct of memory were the most impacted, followed by those assessing visuomotor, and then those assessing language/executive function. Our study provides clear evidence that cognitive functioning in older adults with DS can be characterized at the cognitive domain level, but the statistical methods selected and the inclusion or exclusion of certain covariates may lead to different conclusions. Best practice requires investigators to understand the internal structure of their variables and to provide evidence that their variables assess their intended constructs.


The Role of Tissue Factor in Atherothrombosis and Coronary Artery Disease: Insights into Platelet Tissue Factor.
The contribution of vessel wall-derived tissue factor (TF) to atherothrombosis is well established, whereas the pathophysiological relevance of the blood-borne TF is still a matter of debate, and controversies on the presence of platelet-associated TF still exist. In the past 15 years, several studies have documented the presence of TF in human platelets, the capacity of human platelets to use TF mRNA to make de novo protein synthesis, and the increase in the percentage of TF positive platelets in pathological conditions such as coronary artery disease (CAD). The exposure of vessel wall-derived TF at the site of vascular injury would play its main role in the initiation phase, whereas the blood-borne TF carried by platelets would be involved in the propagation phase of thrombus formation. More recent data indicate that megakaryocytes are committed to release into the bloodstream a well-defined number of TF-carrying platelets, which represents only a fraction of the whole platelet population. These findings are in line with the evidence that platelets are heterogeneous in their functions and only a subset of them is involved in the hemostatic process. In this review we summarize the existing knowledge on platelet associated TF and speculate on its relevance to physiology and to atherothrombosis and CAD.


Characterization of the proteasome using native gel electrophoresis.
Several features of the proteasome make it an excellent subject for analysis by native gel electrophoresis: its size, the multiplicity of variant complexes having proteasome activity, the ease of in-gel assays for proteasome activity, and even its relatively high cellular abundance. Accordingly, native gels have been used to analyze the composition, assembly, gating activity, and binding characteristics of the proteasome. This chapter describes methods for preparing, running, and developing native gels and the proteasome species that are routinely visualized. Additionally, the use of native gels to resolve proteasome complexes present in lysate and to characterize proteasome ligands are described. Following native gel electrophoresis, secondary analyses can be performed, such as activating the core particle, making specific activity assessments, Western blotting of the native gel, resolving native complexes with subsequent SDS-PAGE, and protein identification by mass spectrometry.


Knowledge and attitudes about pharmacotherapy for alcoholism: a survey of counselors and administrators in community-based addiction treatment centres.
Medications, when combined with psychosocial therapy, can improve treatment outcomes in alcoholics; however, medications are not widely utilized in community-based addiction treatment centres. Of interest is how non-medical addiction treatment professionals in these facilities view adjunctive pharmacotherapies for alcoholism. The present report focuses on baseline data collected during the course of an educational intervention project and explores predictors of positive attitudes about adjunctive pharmacotherapies among community addiction counselors and administrators. Questionnaires were administered to 84 counselors and administrators at six community-based addiction treatment centres in South Carolina. Demographic data were collected, and knowledge and attitudes regarding the value of pharmacotherapies in the treatment of alcoholism were assessed. Correlation coefficients were explored, and follow-up multiple regression analyses were conducted to examine variables that predict scores reflecting the degree to which one values adjunctive pharmacotherapies for alcoholism. Respondents had little knowledge of naltrexone, with average test scores reflecting no better than chance performance. In addition, most participants believed that adjunctive pharmacotherapy is ineffectual. Higher valuation of adjunctive pharmacotherapy was related to knowledge about naltrexone, having a post-baccalaureate degree, and years of experience in the addictions treatment field. These data support that more widespread use of adjunctive pharmacotherapy for alcoholism may be impeded by the fact that addictions counselors, who are often the first contact for treatment-seeking individuals, have a lack of knowledge and a lack of confidence in the effectiveness of such treatments. Directed educational interventions are warranted for this population.


Use of Hirulog in the prevention of venous thrombosis after major hip or knee surgery.
The study objective was to determine whether Hirulog, a direct thrombin inhibitor, has potential efficacy and safety in the prevention of deep vein thrombosis (DVT) in orthopedic patients. A phase 2 open-label, dose-escalating design was used to study 222 unselected patients undergoing major hip or knee surgery in tertiary-care, university-affiliated hospitals. Subcutaneous Hirulog was initiated postoperatively. Patients were evaluated for bleeding and symptomatic pulmonary embolism, and mandatory bilateral venography was performed before discharge. Dose escalations were made on the basis of observed rates of bleeding and venous thrombosis. There were five dosage regimens used: 0.3 mg/kg every 12 hours, 0.6 mg/kg every 12 hours, 1.0 mg/kg every 12 hours for 3 days followed by 0.6 mg/kg every 12 hours for up to 11 days, 1.0 mg/kg every 12 hours, and 1.0 mg/kg every 8 hours. One hundred seventy-seven patients who had technically adequate bilateral venography or objectively documented pulmonary embolism were included in the primary analysis of efficacy. The highest dosage regimen (1.0 mg/kg every 8 hours) provided the lowest rates of total DVT (17%) and proximal DVT (2%), both of which were significantly lower (P = .010 and P = .023, respectively) than the pooled rates of total (43%) and proximal (20%) DVT seen with the first four regimens. Bleeding rates were low (< 5%) with all regimens. This study demonstrates that 1.0 mg/kg Hirulog every 8 hours started postoperatively is potentially efficacious and safe for the prevention of DVT after major hip or knee surgery.


Low temperature absorption spectra of chlorophyll a in polar and nonpolar solvents.
Absorption spectra of chlorophyll a were measured in polar and non-polar solvents, as a function of temperature from 298 degrees to 77 degrees K. Both dilute and concentrated solutions were examined. In both types of solvents at room temperature, the absorption spectra of concentrated solutions differ from dilute ones in that the half width of the main red absorption band is greater, and all bands are shifted to longer wavelengths. These differences are largely due to the presence of dimers when the pigment concentration is high. In dilute ethanol solutions, where the chlorophyll is unassociated, cooling causes a red shift in all bands which is due to the increased polarity of the solvent at low temperature. On cooling at high concentrations in ethanol and EPA, a new band appears near 700 nm. This band is attributed to dimers present prior to cooling, but absorbing at shorter wavelengths at room temperature. In nonpolar solvents, a band near 700 nm appears at the solvent freezing point. In these solvents, the "700" nm absorption is attributed to dimers, and/or small polymers, partly formed by cooling. A change in aggregate geometry when the solvent becomes viscous or frozen can account for the appearance of this "700" nm absorption band at low temperature, in polar and nonpolar media.


Role of aggregates and microstructure of mixed-ionic-electronic-conductors on charge transport in electrochemical transistors.
Synthetic efforts have delivered a library of organic mixed ionic-electronic conductors (OMIECs) with high performance in electrochemical transistors. The most promising materials are redox-active conjugated polymers with hydrophilic side chains that reach high transconductances in aqueous electrolytes due to volumetric electrochemical charging. Current approaches to improve transconductance and device stability focus mostly on materials chemistry including backbone and side chain design. However, other parameters such as the initial microstructure and microstructural rearrangements during electrochemical charging are equally important and are influenced by backbone and side chain chemistry. In this study, we employ a polymer system to investigate the fundamental electrochemical charging mechanisms of OMIECs. We couple in situ electronic charge transport measurements and spectroelectrochemistry with ex situ X-ray scattering electrochemical charging experiments and find that polymer chains planarize during electrochemical charging. Our work shows that the most effective conductivity modulation is related to electrochemical accessibility of well-ordered, interconnected aggregates that host high mobility electronic charge carriers. Electrochemical stress cycling induces microstructural changes, but we find that these aggregates can largely maintain order, providing insights on the structural stability and reversibility of electrochemical charging in these systems. This work shows the importance of material design for creating OMIECs that undergo structural rearrangements to accommodate ions and electronic charge carriers during which percolating networks are formed for efficient electronic charge transport.


Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin- 3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation.
BAD is a proapoptotic member of the BCL-2 family of proteins, which play a major role in regulating apoptosis in cytokine-dependent hematopoietic cells. The function of BAD is regulated by reversible phosphorylation. Deprivation of survival factors induces BAD dephosphorylation, resulting in apoptosis. Serine-threonine phosphatase activity dephosphorylated BAD in interleukin-3-dependent FL5.12 lymphoid cells. Inhibition of PP2A activity by treatment of cells with PP2A-selective inhibitors, okadaic acid and fostriecin, prevented BAD dephosphorylation in these cells. Conversely, BAD dephosphorylation was not inhibited by the PP1-selective inhibitor tautomycin. In cell-free extracts, BAD phosphatase activity was also inhibited by the PP2A-selective inhibitors okadaic acid and fostriecin, but not by the PP1-specific protein inhibitor I-2. Dissociation of 14-3-3 from BAD was a prerequisite for BAD dephosphorylation in vitro, suggesting a mechanism by which 14-3-3 can regulate the activation of the proapoptotic function of BAD in vivo. Significantly, the inhibition of BAD phosphatase activity rescued cell death induced by survival factor withdrawal in FL5.12 cells expressing wild-type BAD but not phosphorylation-defective mutant BAD. These data indicate that PP2A, or a PP2A-like enzyme, dephosphorylates BAD and, in conjunction with 14-3-3, modulates cytokine-mediated survival.