Combined Molybdenum Gelatine Methacrylate Injectable Nano-Hydrogel Effective Against Diabetic Bone Regeneration.
Bone defects in diabetes mellitus (DM) remain a major challenge for clinical treatment. Fluctuating glucose levels in DM patients lead to excessive production of reactive oxygen species (ROS), which disrupt bone repair homeostasis. Bone filler materials have been widely used in the clinical treatment of DM-related bone defects, but overall they lack efficacy in improving the bone microenvironment and inducing osteogenesis. We utilized a gelatine methacrylate (GelMA) hydrogel with excellent biological properties in combination with molybdenum (Mo)-based polyoxometalate nanoclusters (POM) to scavenge ROS and promote osteoblast proliferation and osteogenic differentiation through the slow-release effect of POM, providing a feasible strategy for the application of biologically useful bone fillers in bone regeneration. We synthesized an injectable hydrogel by gelatine methacrylate (GelMA) and POM. The antioxidant capacity and biological properties of the synthesized GelMA/POM hydrogel were tested. In vitro, studies showed that hydrogels can inhibit excessive reactive oxygen species (ROS) and reduce oxidative stress in cells through the beneficial effects of pH-sensitive POM. Osteogenic differentiation assays showed that GelMA/POM had good osteogenic properties with upregulated expression of osteogenic genes (BMP2, RUNX2, Osterix, ALP). Furthermore, RNA-sequencing revealed that activation of the PI3K/Akt signalling pathway in MC3T3-E1 cells with GelMA/POM may be a potential mechanism to promote osteogenesis. In an in vivo study, radiological and histological analyses showed enhanced bone regeneration in diabetic mice, after the application of GelMA/POM. In summary, GelMA/POM hydrogels can enhance bone regeneration by directly scavenging ROS and activating the PI3K/Akt signalling pathway.


Improved measurement accuracy in optical scatterometry using correction-based library search.
Library search is one of the most commonly used methods for solving the inverse problem in optical scatterometry. The final measurement accuracy of the conventional library search method highly depends on the grid interval selected for each parameter in the signature library, and the time cost of the parameter extraction increases dramatically when the grid interval is decreasing. In this paper, we propose a correction-based library search method to improve the measurement accuracy for a pregenerated signature library. We derive a formulation to estimate the error between the expected solution of the inverse problem and the actually searched solution obtained by the conventional library search method. Then we use the estimate of the error as a correction term to correct the actually searched solution to improve the measurement accuracy. Experiments performed on a photoresist grating have demonstrated that the proposed correction-based library search method can achieve much more accurate measurement with negligible computational penalty to the conventional library search method in the parameter extraction. It has also been observed that the correction-based library search method has higher measurement accuracy and less time cost than the interpolation-based library search method. The proposed correction-based library search method is expected to provide a more practical means to solve the inverse problem in state-of-the-art optical scatterometry.


Tamm-Horsfall urinary glycoprotein. The chemical composition.
1. A revised amino acid and carbohydrate composition of human Tamm-Horsfall glycoprotein is presented. 2. No significant differences were obtained in the amino acid composition of Tamm-Horsfall glycoprotein isolated from patients with cystic fibrosis. 3. The glycoprotein was shown to possess a high half-cystine content of 1 per 11-12 amino acid residues, which has been confirmed by performic acid oxidation and S-alkylation with iodoacetate and iodoacetamide. No thiol groups were detected in the glycoprotein. 4. Treatment of the glycoprotein with 0.5m-sodium hydroxide at 4 degrees C for 2 days did not release heterosaccharide material, which suggests that the predominant carbohydrate-protein linkages present are not of the O-glycosidic type. 5. No N-terminal amino acid was detected in the glycoprotein.


[Controlled study on the possible benefits of combination therapy with chlorimipramine and haloperidol inpatients with endogenous depression].
Ther is some clinical evidence that neuroleptics are able to increase the therapeutic effect of antidepressive drugs. From a theoretical viewpoint this could be due to influences on pharmacokinetic or receptor sensibility. In a controlled trial on 20 endogenous depressives the advantage of a combined medication of 150 mg Chlorimipramine and 9 mg p.d. Haloperidol (given over six days) were tested. Neither during the combined medication, nor after discontinuation of haloperidol, this treatment regimen proved better clinical results. According to the literature serum levels of chlorimipramine were higher in the experimental group, not the levels of desmethyl-chlorimipramine.


Expression of virulence of Mycobacterium tuberculosis within human monocytes: virulence correlates with intracellular growth and induction of tumor necrosis factor alpha but not with evasion of lymphocyte-dependent monocyte effector functions.
We assessed the applicability of an in vitro model of low-level infection of human monocytes to the characterization of the virulence of strains of the Mycobacterium tuberculosis family. Peripheral blood monocytes were infected at a 1:1 ratio with the virulent M. tuberculosis strain H37Rv, the avirulent M. tuberculosis strain H37Ra, and the attenuated M. bovis strain BCG. Both the percentages of cells infected by the three strains and the initial numbers of intracellular organisms were equivalent, as were levels of monocyte viability up to 7 days following infection. Intracellular growth reflected virulence, as H37Rv replicated in logarithmic fashion throughout the assay, BCG growth reached a plateau at 4 days, and H37Ra did not grow at all. The same patterns of growth were observed following infection of human alveolar macrophages with H37Rv and H37Ra. Monocyte production of tumor necrosis factor alpha was significantly higher following infection with virulent H37Rv than with either BCG or H37Ra. In contrast, there was no clear correlation of interleukin 10 production with virulence. Nonadherent cells of purified-protein-derivative-positive donors mediated equivalent degrees of reduction of the intracellular growth of H37Rv, BCG, and H37Ra. Low-level infection of human monocytes with H37Rv, BCG, and H37Ra thus provides an in vitro model for assessment of the virulence of these M. tuberculosis family strains. Furthermore, it is suggested that the virulence of these strains is expressed primarily by their differing abilities to adapt to the intracellular environment of the mononuclear phagocyte.


The immunomodulator AS101 restores T(H1) type of response suppressed by Babesia rodhaini in BALB/c mice.
The immunomodulator AS101 has been previously shown to confer protection upon BALB/c mice infected with the intraerythrocytic parasite Babesia rodhaini (B. rodhaini). The present study focuses on the effect of AS101 administration on the acute phase of babesial infection where T helper cell subset patterns-TH1/TH2-were assessed in heavily infected mice. Secretion of cytokines of the TH1 subset (IL-2, IFN-gamma, IL-12) and of the TH2 subset (IL-10, IL-4) as well as TGF-beta was measured following the administration of AS101 2 weeks before parasite infection. Our results demonstrate that the parasites suppress IL-2 protein and IL-12 mRNA and that AS101 upregulates their secretion: IL-2, 8 u/ml vs 34 u/ml, respectively; IFN-gamma protein, 2370 pg/ml vs 4777 pg/ml, respectively. Conversely, babesial infection results in the upregulation of IL-10 and IL-4 proteins and TGF-beta transcripts, whereas AS101 downregulates their production: IL-10, 1800 pg/ml vs 360 pg/ml, respectively; IL-4, 58.3 pg/ml vs 24.5 pg/ml, respectively. A possible escape mechanism induced by B. rodhaini is suggested, starting with IL-10 inhibition of macrophage activities leading to a suppression of the TH1 response and of IL-2 in particular. It is therefore possible that AS101 may protect infected mice by activating cellular-mediated immunity and concurrently balancing the TH subset responses. It is suggested that AS101 may be effective as an antiparasitic drug.


Age, gender and region-specific differences in drug metabolising enzymes in rat ocular tissues.
Previously we have reported our analyses of cytochrome P450 (CYP) expression in rat ocular tissues and in our current study we have extended these analyses to the different stages of growth in both male and female rats. Additionally, we have examined the expression levels of the different conjugation enzymes, sulfotransferases (SULTs), UDP-glucuronosyl transferases (UGTs) and glutathione S-transferases (GSTs), in ocular tissues. In 5-week-old animals, the CYP genes, CYP2B2 and CYP3A1, were abundantly expressed in the lens, with higher CYP1A1 expression detectable in the extra-lenticular tissues, of both genders. However, the expression of CYP1A2 and CYP2E1 in female ocular tissues was more extensive than in male. Moreover, in females the expression of the phenol-sulfating SULTs, ST1A1, ST1B1 and ST1C1, was more abundant in the extra-lenticular tissues, whereas the levels of the hydroxysteroid-sulfating SULTs, ST2A1 and ST2A5, predominated in the lens. The expression levels of the UGTs, UGT1A1, UGT1A6 and UGT2B1, were also higher in the female extra-lenticular tissues but the expression of the GSTA subfamily (GSTA1 and GSTA2) was very weak in the ocular tissues of both genders. The overall gene expression profiles were found to change with the age of the animals (from 3 to 8 weeks) and, in general, the expression levels of the CYPs and SULTs declined with age, whereas the levels of the UGTs and GSTs increased. These results demonstrate that the expression profiles of drug metabolising enzymes show both region- and gender-specific patterns in rat ocular tissues.


The REACH Trial: A Randomized Controlled Trial Assessing the Safety and Effectiveness of the Spiration® Valve System in the Treatment of Severe Emphysema.
Chronic obstructive pulmonary disease (COPD) has become a leading cause of morbidity and mortality in China, with tobacco smoke, air pollution, and occupational biohazards being the major risk factors. The REACH trial is a multicenter, prospective, randomized controlled trial undertaken in China to assess the safety and effectiveness of the Spiration® Valve System (SVS) compared to standard medical care in COPD patients with severe emphysema. Patients with severe airflow obstruction, hyperinflation, and severe dyspnea with interlobar fissure integrity were evaluated for enrollment. A total of 107 subjects were randomized in a 2: 1 allocation ratio to either the treatment group (SVS valves and medical management) or the control group (medical management alone). The 3-month primary endpoint showed statistically significant improvement in forced expiratory volume in 1 s in the treatment group compared to the control group (0.104 ± 0.18 vs. 0.003 ± 0.15 L, p = 0.001), with the difference being durable through 6 months. Statistically significant target lobe volume reduction was achieved at 3 months (mean change 684.4 ± 686.7 mL) and through 6 months (757.0 ± 665.3 mL). Exercise function and quality of life measures improved in the treatment group, but showed a deterioration in the control group. The serious adverse event (SAE) rate was 33% in the treatment group and 24.2% in the control group. The predominance of SAEs were acute exacerbations of COPD in both groups. There was 1 death in the control group and no deaths in the treatment group. The SVS represents a novel approach for the treatment of severe emphysema with a clinically acceptable risk-benefit profile.


On the Role of Entropy in the Stabilization of α-Helices.
Protein folding evolves by exploring the conformational space with a subtle balance between enthalpy and entropy changes which eventually leads to a decrease of free energy upon reaching the folded structure. A complete understanding of this process requires, therefore, a deep insight into both contributions to free energy. In this work, we clarify the role of entropy in favoring the stabilization of folded structures in polyalanine peptides with up to 12 residues. We use a novel method referred to as K2V that allows us to obtain the potential-energy landscapes in terms of residue conformations extracted from molecular dynamics simulations at conformational equilibrium and yields folding thermodynamic magnitudes, which are in agreement with the experimental data available. Our results demonstrate that the folded structures of the larger polyalanine chains are stabilized with respect to the folded structures of the shorter chains by both an energetic contribution coming from the formation of the intramolecular hydrogen bonds and an entropic contribution coming from an increase of the entropy of the solvent with approximate weights of 60 and 40%, respectively, thus unveiling a key piece in the puzzle of protein folding. In addition, the ability of the K2V method to provide the enthalpic and entropic contributions for individual residues along the peptide chain makes it clear that the energetic and entropic stabilizations are basically governed by the nearest neighbor residue conformations, with the folding propensity being rationalized in terms of triads of residues.


Trastuzumab alters the expression of genes essential for cardiac function and induces ultrastructural changes of cardiomyocytes in mice.
Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), very successfully improves outcomes for women with HER2-positive breast cancer. However, trastuzumab treatment was recently linked to potentially irreversible serious cardiotoxicity, the mechanisms of which are largely elusive. This study reports that trastuzumab significantly alters the expression of myocardial genes essential for DNA repair, cardiac and mitochondrial functions, which is associated with impaired left ventricular performance in mice coupled with significant ultrastructural alterations in cardiomyocytes revealed by electron microscopy. Furthermore, trastuzumab treatment also promotes oxidative stress and apoptosis in myocardium of mice, and elevates serum levels of cardiac troponin-I (cTnI) and cardiac myosin light chain-1 (cMLC1). The elevated serum levels of cMLC1 in mice treated with trastuzumab highlights the potential that cMLC1 could be a useful biomarker for trastuzumab-induced cardiotoxicity.


Loss of expression of the tumour suppressor gene AIMP3 predicts survival following radiotherapy in muscle-invasive bladder cancer.
The aim of this study was to test the utility of AIMP3, an upstream regulator of DNA damage response following genotoxic stress, as a clinical biomarker in muscle-invasive bladder cancer (MIBC). AIMP3 was identified from a meta-analysis of a global gene-expression dataset. AIMP3 protein expression was determined by immunohistochemistry on a customised bladder cancer tissue-microarray (TMA). The mechanism of gene silencing was probed using methylation-specific PCR. The association between AIMP3 expression, Tp53 transactivity and genomic stability was analysed. In vitro AIMP3 translocation to the nucleus in response to ionising radiation was demonstrated using immunofluorescence. Radiosensitisation effects of siRNA-mediated AIMP3-knockdown were measured using colony forming assays. TMAs derived from patients enrolled in BCON, a Phase III multicentre radiotherapy trial in bladder cancer (ISRCTN45938399) were used to evaluate the association between AIMP3 expression and survival. The prognostic value of AIMP3 expression was determined in a TMA derived from patients treated by radical cystectomy. Loss of AIMP3 expression was frequent in MIBC and associated with impaired Tp53 transactivity and genomic instability. AIMP3-knockdown was associated with an increase in radioresistance. Loss of AIMP3 expression was associated with survival in MIBC patients following radiotherapy (HR = 0.53; 95% CI: 0.36 to 0.78, p = 0.002) but was not prognostic in the cystectomy set. In conclusion, AIMP3 expression is lost in a subset of bladder cancers and is significantly predictive of survival following radiotherapy in MIBC patients.


Vasculitis of the lung.
Many conditions are known to produce vasculitis of the lung but only a few major idiopathic vasculitis syndromes are clinically encountered-- and their diagnosis is very difficult. The authors provide in-depth coverage of these syndromes, focusing on clinical features, pathologic features, and diagnosis and differential diagnosis.


An approach to the patient with urticaria.
Patients with urticaria make up a large proportion of the referrals to allergy clinics. There are many causes of urticaria and it is the clinical history which is most important when attempting to identify potential causes; however, urticaria is very often idiopathic. In a small minority of patients urticaria may be a symptom of a serious underlying medical illness or the allergic symptoms may progress to cause systemic reactions, and it is important to identify these patients and to remember that severe urticaria is a distressing and disabling condition. This review will discuss classification, investigation and treatment of urticaria and will consider some of the more unusual types of urticaria that may be encountered in the out-patient clinic.


Sexual Health for Older Women: Implications for nurses and other healthcare providers.
This article presents findings from a review of the evidence regarding sexual health for older women from MEDLINE, SCOPUS and the Cumulative Index to Nursing and Allied Health (CINHAL) databases. A total of 10 articles based on primary studies, reporting about the sexuality or sexual health of older women (and older people), and published between 2002-2012, were deemed suitable. The major themes that emerged from the available literature suggest that the sexual health of older people is affected by factors such as physical changes, mental health, changes to their relationship with their husband, chronic ill health and other psychosocial situations. It is concluded that nurses and other healthcare providers have a range of interventions that can be adopted to promote sexual health among older women. These interventions may focus on improving the older woman's sexual health assessment; increasing awareness and knowledge about sexuality in later life; pharmacological and psychotherapeutic therapies; using alternative techniques to achieve better sexual functioning; addressing partner and relationship issues, and advocating the importance of sexual health through media and policy development.


Ginsenoside Rd Is Efficacious Against Acute Ischemic Stroke by Suppressing Microglial Proteasome-Mediated Inflammation.
A great deal of attention has been paid to neuroprotective therapies for cerebral ischemic stroke. Our two recent clinical trials showed that ginsenoside Rd (Rd), a kind of monomeric compound extracted from Chinese herbs, Panax ginseng and Panax notoginseng, was safe and efficacious for the treatment of ischemic stroke. In this study, we conducted a pooled analysis of the data from 199 patients with acute ischemic stroke in the first trial and 390 in the second to reanalyze the efficacy and safety of Rd. Moreover, animal stroke models were carried out to explore the possible molecular mechanisms underlying Rd neuroprotection. The pooled analysis showed that compared with placebo group, Rd could improve patients' disability as assessed by modified Rankin Scale (mRS) score on day 90 post-stroke and reduce neurologic deficits on day 15 or day 90 post-stroke as assessed by NIH Stroke Scale (NIHSS) and Barthel Index (BI) scores. For neuroprotective mechanisms, administration of Rd 4 h after stroke could inhibit ischemia-induced microglial activation, decrease the expression levels of various proinflammatory cytokines, and suppress nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IκBα) phosphorylation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation. An in vitro proteasome activity assay revealed a significant inhibitory effect of Rd on proteasome activity in microglia. Interestingly, Rd was showed to have less side effects than glucocorticoid. Therefore, our study demonstrated that Rd could safely improve the outcome of patients with ischemic stroke, and this therapeutic effect may result from its capability of suppressing microglial proteasome activity and sequential inflammation.


[Agonist of V2 vasopressin receptor reduces depressive disorders in post-stroke patients].
Poststroke depression is one of the common psychiatric complications after stroke. Thus, the research of new ways for treatment depressed mood after stroke is actual. The previous researches revealed vasopressin to be effective in patients with memory, speech and motor function disorders after stroke. The purpose of the study was to investigate influence of vasopressin on depression after stroke. Fourteen patients with affective disorders have been treated with subendocrine doses of 1-desamino-8-D-arginin-vasopressin (DDAVP) daily by intranasal application during 1,5-2 months. Vasopressin was effective in correcting both apatoadinamic and anxious depression. Treatment effect was durable, lasts for 0,5-1 year after the first course of therapy. The results of this pilot study demonstrate perspective of using selective agonist of vasopressin V2 receptors, DDAVP, in therapy of post-stroke depression.


Genetic improvement of wild fish populations.
A plan for the genetic improvement of commercially exploited wild animals is presented. It consists of crossing wild with domesticated breeds to produce heterotic hybrids and to upgrade the wild stocks. Empirical evidence is presented from experiments with the carp. Procedures for monitoring the manipulated populations are outlined. The suggested plan is ecologically reasonable and would counteract the negative genetic changes caused by excessive commercial exploitation of many species.


Providing comfort to patients in their palliative care trajectory: experiences of female nurses working in an acute setting.
This study aims to explore the lived experience of nurses who provide comfort to palliative care patients in an acute setting in a small urban hospital in the west of Ireland. A qualitative approach using Gadamerian hermeneutic phenomenology was chosen for the study and data were collected using open interviewing. The main findings revealed four major themes (with sub-themes) that describe the lived experience of providing comfort to palliative care patients in an acute setting: time needed to provide comfort, emotional cost to the nurse in providing comfort, a holistic approach in the provision of comfort, and the role of education and the expert team in providing comfort. The study findings will contribute to a greater understanding of the difficulties and challenges that general non-specialized nurses in the acute setting have to understand and apply the philosophy of palliative care to patients in an acute care setting. The findings should also contribute to a broader appreciation between specialized and non-specialized nurses who are responsible for the delivery of holistic, individual person-centred care to patients requiring palliative care.


Local actions of trimebutine on canine gastrointestinal tract.
The local actions of trimebutine on the circular muscle of canine gastrointestinal tract were studied after close intraarterial injection. The effects resembled those of metenkephalin at all sites. In stomach, trimebutine had no excitatory effects, but inhibited responses mediated by cholinergic post-ganglionic nerves. In small intestine, trimebutine stimulated the quiet gut by probably both neural and direct smooth muscle mechanisms, and it inhibited the field-stimulated phasic contractions. In large intestine, trimebutine had no excitatory actions and only weak inhibitory actions on the field-stimulated gut. Excitatory actions most likely seem to use the mu or delta receptors while inhibitory actions may focus on kappa opiate receptors.


Variations in the satellite DNA content of Cucumis melo in relation to dedifferentiation and hormone concentration.
Total DNA from Cucumis melo contains a 1.706 satellite DNA which can be resolved into two components; one of these components has a higher temperature of melting (component I) then the other component II). In this study, we have further investigated these components by thermal denaturation and by Eco R1 digestion. Component I reveals a homogeneous melting profile and is only partially cleaved by Eco R1, whereas component II reveals a heterogeneous melting profile and is entirely digested by Eco R1. A possible mitochondrial origin for component II is discussed. When an in vitro culture of root tissues from Cucumis melo was initiated or when the phytohormone (NAA) concentration of established cultures was modified, a new satellite DNA (1.719) appears transitorily and the satellite DNAs already present in seedlings undergo quantitative and possibly qualitative variations. Satellite DNAs therefore seem to be involved in the response to some physiological variations.


Pharmacokinetics of etilevodopa compared to levodopa in patients with Parkinson's disease: an open-label, randomized, crossover study.
"Dose failures" and "delayed on" phenomena following an intake of levodopa dose in patients with Parkinson's disease (PD) with motor fluctuations may be caused by stagnation of poorly soluble levodopa in the atonic stomach. Etilevodopa is a unique, highly soluble prodrug of levodopa. When ingested, etilevodopa is more readily dissolved in the stomach than levodopa. It passes unchanged through the stomach to the duodenum, where it is rapidly hydrolyzed by local esterases and rapidly absorbed as levodopa. To compare the pharmacokinetics of three different modes of etilevodopa/carbidopa administration with standard levodopa/carbidopa tablets in fluctuating PD patients, 29 patients with PD and response fluctuations were enrolled in an open-label, randomized, four-way crossover study of single doses of 4 treatments: swallowed etilevodopa/carbidopa tablets, etilevodopa/carbidopa tablets dissolved in water, etilevodopa oral solution with carbidopa tablets, and standard levodopa/carbidopa tablets. To measure the maximal concentration (Cmax), time to Cmax (tmax), and area under the curve (AUC) of plasma levodopa, etilevodopa, and carbidopa, blood samples were drawn before drug administration and at intervals up to 240 minutes thereafter. Plasma levodopa tmax was significantly shorter with all three modes of administration of etilevodopa (mean of about 30 minutes) than with levodopa treatment (mean of 54 minutes). During the first 45 minutes after drug ingestion, plasma levodopa AUC was significantly greater after etilevodopa administration than after levodopa administration. Levodopa AUC for 0 to 1 hour and 0 to 2 hours were also significantly greater following administration of etilevodopa/carbidopa swallowed tablets than following administration of levodopa/carbidopa tablets. Mean levodopa Cmax was in the range 2.3 to 2.7 microg/mL for all treatments. Levodopa Cmax was significantly greater following treatment with etilevodopa swallowed tablets than with levodopa tablets. Etilevodopa/carbidopa was well tolerated, with a safety profile comparable to that of levodopa/carbidopa. The shorter levodopa tmax observed with etilevodopa potentially translates to a shorter time to "on". Clinical trials with etilevodopa/carbidopa tablets should be carried out in PD patients with response fluctuations such as "delayed on" and "dose failures".


The tail domain of lamin Dm0 binds histones H2A and H2B.
In multicellular organisms, the higher order organization of chromatin during interphase and the reassembly of the nuclear envelope during mitosis are thought to involve an interaction between the nuclear lamina and chromatin. The nuclear distribution of lamins and of peripheral chromatin is highly correlated in vivo, and lamins bind specifically to chromatin in vitro. Deletion mutants of Drosophila lamin Dm0 were expressed to map regions of the protein that are required for its binding to chromosomes. The binding activity requires two regions in the lamin Dm0 tail domain. The apparent Kd of binding of the lamin Dm0 tail domain was found to be approximately 1 microM. Chromatin subfractions were examined to search for possible target molecules for the binding of lamin Dm0. Isolated polynucleosomes, nucleosomes, histone octamer, histone H2A/H2B dimer, and histones H2A or H2B displaced the binding of lamin Dm0 tail to chromosomes. This displacement was specific, because polyamines or proteins such as histones H1, H3, or H4 did not displace the binding of the lamin Dm0 tail to chromosomes. In addition, DNA sequences, including M/SARs, did not interfere with the binding of lamin Dm0 tail domain to chromosomes. Taken together, these results suggest that the interaction between the tail domain of lamin Dm0 and histones H2A and H2B may mediate the attachment of the nuclear lamina to chromosomes in vivo.


Specific relationship between excitatory inputs and climbing fiber receptive fields in deep cerebellar nuclear neurons.
Many mossy fiber pathways to the neurons of the deep cerebellar nucleus (DCN) originate from the spinal motor circuitry. For cutaneously activated spinal neurons, the receptive field is a tag indicating the specific motor function the spinal neuron has. Similarly, the climbing fiber receptive field of the DCN neuron reflects the specific motor output function of the DCN neuron. To explore the relationship between the motor information the DCN neuron receives and the output it issues, we made patch clamp recordings of DCN cell responses to tactile skin stimulation in the forelimb region of the anterior interposed nucleus in vivo. The excitatory responses were organized according to a general principle, in which the DCN cell responses became stronger the closer the skin site was located to its climbing fiber receptive field. The findings represent a novel functional principle of cerebellar connectivity, with crucial importance for our understanding of the function of the cerebellum in movement coordination.


Diastereoselective Additions of Allylmagnesium Reagents to α-Substituted Ketones When Stereochemical Models Cannot Be Used.
The stereoselectivities of reactions of allylmagnesium reagents with chiral ketones cannot be easily explained by stereochemical models. Competition experiments indicate that the complexation step is not reversible, so nucleophiles cannot access the widest range of possible encounter complexes and therefore cannot be analyzed easily using available models. Nevertheless, additions of allylmagnesium reagents to a ketone can still be stereoselective provided that the carbonyl group adopts a conformation that leads to one face being completely blocked from the approach of the allylmagnesium reagent.


COMPARISON OF THE RECOVERY OF ESCHERICHIA COLI FROM FROZEN FOODS AND NUTMEATS BY CONFIRMATORY INCUBATION IN EC MEDIUM AT 44.5 AND 45.5 C.
The productivity of confirmatory EC broth for the isolation of fecal Escherichia coli was determined at 44.5 and 45.5 C. A variety of frozen pre-cooked foods and an assortment of nutmeats were examined after primary incubation in Lauryl Sulfate Tryptose (LST) broth. In 85.3% of the cases, the parallel tubes of EC broth incubated for 24 hr at 44.5 and 45.5 C gave rise to identical E. coli responses of positive, false positive, and negative. The remaining 14.7% of the reactions represent the qualitative difference between the two temperatures. The EC test at 45.5 C was more specific for E. coli, since two- to threefold fewer false positives were produced at this temperature than at 44.5 C. However, fecal E. coli recoveries were slightly higher (4%) at the lower temperature. Incubating the EC tubes from the interval of 24 to 48 hr gave rise to an additional 4.3% of E. coli recovery, but this was accompanied by an excessive production of false positives (75.9%), representing a 3.5-fold decrease in specificity. It is recommended that, in the confirmatory use of EC broth in the examination of frozen foods and nutmeats for the recovery of fecal E. coli, the test be made at 45.5 C in a water bath and limited to 24 hr of incubation only, to insure optimal specificity. During the study, a "fixed" productivity ratio was noted; E. coli(+)/LST(+) equaled approximately one-fourth or 25%. The significance of this ratio is discussed.


Acute necrotizing colitis and obstruction.
Acute necrotizing colitis is a rare complication of colonic obstruction. Six cases occurring during a 20-month period are described. The presenting features were those of colonic obstruction with shock but without perforation. At laparotomy changes ranged from mucosal necrosis to frank gangrene in the colon proximal to the obstructing lesion. Gram stains of resected colon showed Gram-positive bacilli, resembling clostridia, invading the mucosa and submucosa. Two patients treated by defunctioning colostomy alone died but the remaining 4 survived after total colectomy. The cause is not known but raised intraluminal pressure may result in terminal mucosal ischaemia allowing anaerobic organisms to invade the bowel wall.


Progress in COX-2 inhibitors: a journey so far.
The non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation, since the introduction of acetylsalicylic acid in 1899. Traditional (first generation) NSAIDs exert antiinflammatory, analgesic, and antipyretic effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenase (COX-1 and COX-2) isozymes. Their use is associated with side effects such as gastrointestinal and renal toxicity. A number of selective (second generation) COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. Observation of increased cardiovascular risks in APPROVe (Adenomatous Polyp Prevention on Vioxx) study sent tremors and led to voluntary withdrawn of Vioxx (rofecoxib) by Merck from the market in September 2004 followed by Bextra (valdecoxib) in 2005 raising a question on the safety of selective COX-2 inhibitors. This leads to the belief that these effects are mechanism based and may be class effect. However, some studies suggested association of traditional NSAIDs with similar effects requiring a relook into the whole class of NSAIDs rather than simply victimizing the selective COX-2 inhibitors. Recognition of new avenues for selective COX-2 inhibitors such as cancer, Alzheimer's disease, Parkinson's disease, schizophrenia, major depression, ischemic brain injury and diabetic peripheral nephropathy has kindled the interest in these compounds. This review highlights the various structural classes of selective COX-2 inhibitors developed during past seven years (2003-2009) with special emphasis on diaryl-hetero/carbo-cyclic class of compounds. Molecular modeling aspects are also briefly discussed.


Operant conditioning to increase ankle control or decrease reflex excitability improves reflex modulation and walking function in chronic spinal cord injury.
Ankle clonus is common after spinal cord injury (SCI) and is attributed to loss of supraspinally mediated inhibition of soleus stretch reflexes and maladaptive reorganization of spinal reflex pathways. The maladaptive reorganization underlying ankle clonus is associated with other abnormalities, such as coactivation and reciprocal facilitation of tibialis anterior (TA) and soleus (SOL), which contribute to impaired walking ability in individuals with motor-incomplete SCI. Operant conditioning can increase muscle activation and decrease stretch reflexes in individuals with SCI. We compared two operant conditioning-based interventions in individuals with ankle clonus and impaired walking ability due to SCI. Training included either voluntary TA activation (TA↑) to enhance supraspinal drive or SOL H-reflex suppression (SOL↓) to modulate reflex pathways at the spinal cord level. We measured clonus duration, plantar flexor reflex threshold angle, timed toe tapping, dorsiflexion (DF) active range of motion, lower extremity motor scores (LEMS), walking foot clearance, speed and distance, SOL H-reflex amplitude modulation as an index of reciprocal inhibition, presynaptic inhibition, low-frequency depression, and SOL-to-TA clonus coactivation ratio. TA↑ decreased plantar flexor reflex threshold angle (-4.33°) and DF active range-of-motion angle (-4.32°) and increased LEMS of DF (+0.8 points), total LEMS of the training leg (+2.2 points), and nontraining leg (+0.8 points), and increased walking foot clearance (+ 4.8 mm) and distance (+12.09 m). SOL↓ decreased SOL-to-TA coactivation ratio (-0.21), increased nontraining leg LEMS (+1.8 points), walking speed (+0.02 m/s), and distance (+6.25 m). In sum, we found increased voluntary control associated with TA↑ outcomes and decreased reflex excitability associated with SOL↓ outcomes.


Systemic AAV vectors for widespread and targeted gene delivery in rodents.
We recently developed adeno-associated virus (AAV) capsids to facilitate efficient and noninvasive gene transfer to the central and peripheral nervous systems. However, a detailed protocol for generating and systemically delivering novel AAV variants was not previously available. In this protocol, we describe how to produce and intravenously administer AAVs to adult mice to specifically label and/or genetically manipulate cells in the nervous system and organs, including the heart. The procedure comprises three separate stages: AAV production, intravenous delivery, and evaluation of transgene expression. The protocol spans 8 d, excluding the time required to assess gene expression, and can be readily adopted by researchers with basic molecular biology, cell culture, and animal work experience. We provide guidelines for experimental design and choice of the capsid, cargo, and viral dose appropriate for the experimental aims. The procedures outlined here are adaptable to diverse biomedical applications, from anatomical and functional mapping to gene expression, silencing, and editing.


Decreased chance of a live born child in women with rheumatoid arthritis after assisted reproduction treatment: a nationwide cohort study.
No studies have examined the efficacy of assisted reproductive technology (ART) treatment in women with rheumatoid arthritis. Therefore, we examined the chance of live birth after ART treatment in women with rheumatoid arthritis compared with women without rheumatoid arthritis. Our cohort study is based on nationwide Danish health registries, comprising all women with an embryo transfer during 1 January 1994 through 30 June 2017. The cohorts comprised 1149 embryo transfers in women with rheumatoid arthritis, and 198 941 embryo transfers in women without rheumatoid arthritis. Our outcome was live birth per embryo transfer, and we controlled for multiple covariates in the analyses. In subanalyses, we examined a chance of biochemical/clinical pregnancy after ART and a possible impact of corticosteroid use prior to embryo transfer. The adjusted OR (aOR) for a live birth per embryo transfer in women with rheumatoid arthritis, relative to women without rheumatoid arthritis, was 0.78 (95% CI 0.65 to 0.92). The aORs for biochemical and clinical pregnancies were 0.81 (95% CI 0.68 to 0.95) and 0.82 (95% CI 0.59 to 1.15), respectively. Corticosteroid prescription prior to embryo transfer increased the OR for live birth (aOR=1.32 (95% CI 0.85 to 2.05)). The chance of a live birth was significantly reduced in women with rheumatoid arthritis receiving ART treatment, relative to women without rheumatoid arthritis, and our result suggested that the problem was related to an impaired chance of embryo implantation. The role of corticosteroid use prior to embryo transfer must be a subject for further research.


The pre-diabetic epidemiological study in Depok, West Java.
To recognize the prevalence of impaired fasting glucose level (IFG) and impaired glucose tolerance (IGT) in general population of Depok Area, West Java. the study was conducted in a population with age > or = 25 years, in Depok Area, West Java, which was selected by using two stage random sampling. Data were collected by using the Step Wise Approach of WHO. Subjects without previous diabetes history were categorized as diabetes if their fasting blood glucose level > or = 126 mg/dL, and or the 2-hour-after 75 gram glucose load > or = 200 mg/dL. While pre-diabetes was defined as IFG when the fasting blood glucose > or = 100 mg/dL to < 126 mg/dL or IGT when the 2-hour-after 75 gram glucose load level > or = 200 mg/dL (ADA 2003). of 1200 participants, there were 975 participants who fulfilled the invitation and there were 969 eligible participants to be evaluated. Among the participants aged > or = 25 years, there were 40 (4.13%) subjects with isolated IFG and 234 (24.25%) subjects with isolated IGT, 55 subjects (5.68%) with mixed IFG/IGT. the prevalence of isolated impaired fasting blood glucose in population with age > or = 25 years is 4.13%; while the prevalence of isolated impaired glucose tolerance is 24.25%. Mixed IFG/IGT is 5.68%. The total prevalence of pre-diabetic patients is 33.96%.


Fabrication of three-dimensional woodpile photonic crystals in a PbSe quantum dot composite material.
Incorporating active media into three-dimensional (3D) photonic crystals (PCs) is a useful step towards exploring the functionalities of PCs. Here we report, for the first time, on the fabrication of 3D woodpile PCs with a commercial PbSe quantum dot (QD) composite material by using the two-photon polymerization technique. The fabricated crystals possess photonic band gaps in the near-infrared wavelength region, which have a suppression rate of ~50% in the stacking direction, measured with an angle-resolved Fourier-transform infrared spectrometer. The woodpile structures fabricated under different conditions are also characterized by using a scanning near-field optical microscope, providing a useful feedback towards optimizing the fabrication of 3D woodpile PCs in QD composites.


Sustained high-efficiency daily diafiltration using a mediator-adsorbing membrane (SHEDD-fA) in the treatment of patients with severe sepsis.
Sustained high-efficiency daily diafiltration using a mediator-adsorbing membrane (SHEDD-fA) is an effective, intensive modality for sepsis treatment. Here we describe the effectiveness of SHEDD-fA, which makes the best use of three principles: dialysis, filtration and adsorption, for mediator removal in the treatment of severe sepsis. SHEDD-fA was initiated after adequate fluid resuscitation and catecholamine support had been provided. A large (2.1 m(2)) polymethylmethacrylate membrane dialyzer was placed in the blood circuit. Operation conditions were as follows: blood flow rate 150 ml/min, filtration rate 1,500 ml/h (post-dilution), and dialysate flow rate 300-500 ml/min over 8-12 h daily. 55 consecutive patients with severe sepsis were studied. The following results were obtained: pressure catecholamine index significantly decreased at 3 h after initiation of septic shock, PaO(2)/F(IO2) significantly increased at 1 h after initiation of septic acute respiratory distress syndrome, a significant decrease in interleukin (IL)-6 level for 3 days was observed, and IL-6 was effectively adsorbed in one pass through the filter. The average sequential organ failure assessment score of patients was 10.1 and the mortality at 28 days was 16.4% (46 survived, 9 died). Because SHEDD-fA is an intensive and high-efficiency modality, removal of useful drugs or nutrients may be observed. Despite the fact that removal of useful substances cannot be ignored, we believe that an appropriate stage or timing can be identified so that we can avoid a vicious cycle and use blood purification with effective diffusion, filtration and adsorption. We demonstrate that SHEDD-fA may be an effective, intensive modality for the treatment of patients with severe sepsis and is a possible modality for cytokine modulation therapy.


[The associations of HLA-DQB1 gene with onset age and autoantibodies in type 1 diabetes].
To evaluate the associations of human leukocyte antigen (HLA) DQB1 gene with onset age and autoantibodies in type 1 diabetes mellitus(T1DM) in Chinese Han population in Sichuan area. Forty-six type 1 diabetic patients and 52 healthy control subjects were involved in this study. HLA-DQB1 typing was performed by polymerase chain reaction-sequence specific primer(PCR-SSP). Glutamic acid decarboxylase antibody (GADA) and islet cell antibody (ICA) were qualitatively analyzed by enzyme linked immunosorbent assay (ELISA). The positive rate of DQB1*0201 was higher in T1DM than in controls (OR=18, P<0.005), but those of DQB1*0601, *0602 were higher in controls than in T1DM(OR=0.07, 0.31 respectively, both P<0.05).The positive rate of DQB1*0602 in type 1 diabetic patients with onset age>or=20 years was higher than that in the patients with onset age <20 years (P<0.05). GADA was more frequent in DQB1*0201(+) patients than in DQB1*0201 (-) patients (P<0.025). The findings show that DQB1*0201 is susceptible to T1DM, whereas DQB1*0601, *0602 are protective in Chinese Han population in Sichuan area. DQB1*0602 may delay the onset of T1DM. The positive rate of DQB1*0201 correlates positively with that of GADA.


Defective thyroglobulin endocytosis and hydrolysis in thyroid cold nodules.
The catabolic phase of thyroid secretion has been studied by incubating thyroid slices with 0.1 % 125-I thyroglobulin (Tg) in the following cases: 11 follicular adenomas (FA), 8 hyerplastic nodules in multinodular glands (NM), 3 carcinomas (follicular or papillary, FC, PC) and normal (N) or micronodular tissue (M). Tg pinocytosis is severely impaired in all cold nodules (25 to 60 % reduction). In the follicular tumours (FA, FC), Tg hydrolysis is more affected than would be expected based only on reduced Tg endocytosis: the hydrolysis products remain in the phagolysosomes instead of being secreted. As far as the acid hydrolases are concerned these enzymatic activities are increased in nearly all nodules, in particular in follicular adenomas and carcinomas.


[Current problems of lactase deficiency].
The tests with lactose loading followed by the assay of blood sugar were conducted in 500 normal subjects, aged from 18 to 89 years, and 262 patients with gastro-intestinal diseases, aged from 25 to 55 years. When lactose malabsorption was detected, aspiration biopsy of the small intestine mucosa was performed followed by the study of the structure and the level of a number of disaccharidases (lactase, maltase, saccharase). Lactose malabsorption was detected in 72 (14.4%) out of 500 normal subjects (10.6%--aged 18-59, and 20%--aged 60-89 years), among them there were 12.5% of Russians, 13% of Byelorussians and 5.8% of Ukrainians (aged 25-55 years). The secondary lactose malabsorption was recorded in 44% of patients with ulcerative colitis, in 33% of patients with chronic enterocolitis, in 11.5% of patients with gastric ulcer, in 8% of those with duodenal ulcer, in 23.5% of patients with chronic gastritis attended by lowered secretory function, and in 8% of those with enhanced secretory function.


[The forensic medical significance of morphometry of the spleen in drug addiction and chronic alcoholic intoxication].
Data on histomorphologic damage to the spleen in chronic narcotic and alcoholic intoxication are described. The below features are recommended for the diagnosis of chronic exogenous intoxication: thickening and sclerosis of the spleen connective structures and a lower count of lymphocytes in the white pulp. The diagnosis criteria of chronic intoxication by intravenously administered opiates are: hyperplasia of the spleen follicles as well as a higher quantity of plasmocytes and of eosinophiles in the white pulp. Hypotrophy of the spleen lymphoid follicles and higher counts of monocytes and macrophages in the lymphoid follicles should be also regarded as a sign of chronic alcoholic intoxication. The obtained data can be used by forensic medical experts in the diagnosis of chronic narcotic intoxication and in its differential diagnosis versus alcoholic intoxication.


Structural ordering of disordered ligand-binding loops of biotin protein ligase into active conformations as a consequence of dehydration.
Mycobacterium tuberculosis (Mtb), a dreaded pathogen, has a unique cell envelope composed of high fatty acid content that plays a crucial role in its pathogenesis. Acetyl Coenzyme A Carboxylase (ACC), an important enzyme that catalyzes the first reaction of fatty acid biosynthesis, is biotinylated by biotin acetyl-CoA carboxylase ligase (BirA). The ligand-binding loops in all known apo BirAs to date are disordered and attain an ordered structure only after undergoing a conformational change upon ligand-binding. Here, we report that dehydration of Mtb-BirA crystals traps both the apo and active conformations in its asymmetric unit, and for the first time provides structural evidence of such transformation. Recombinant Mtb-BirA was crystallized at room temperature, and diffraction data was collected at 295 K as well as at 120 K. Transfer of crystals to paraffin and paratone-N oil (cryoprotectants) prior to flash-freezing induced lattice shrinkage and enhancement in the resolution of the X-ray diffraction data. Intriguingly, the crystal lattice rearrangement due to shrinkage in the dehydrated Mtb-BirA crystals ensued structural order of otherwise flexible ligand-binding loops L4 and L8 in apo BirA. In addition, crystal dehydration resulted in a shift of approximately 3.5 A in the flexible loop L6, a proline-rich loop unique to Mtb complex as well as around the L11 region. The shift in loop L11 in the C-terminal domain on dehydration emulates the action responsible for the complex formation with its protein ligand biotin carboxyl carrier protein (BCCP) domain of ACCA3. This is contrary to the involvement of loop L14 observed in Pyrococcus horikoshii BirA-BCCP complex. Another interesting feature that emerges from this dehydrated structure is that the two subunits A and B, though related by a noncrystallographic twofold symmetry, assemble into an asymmetric dimer representing the ligand-bound and ligand-free states of the protein, respectively. In-depth analyses of the sequence and the structure also provide answers to the reported lower affinities of Mtb-BirA toward ATP and biotin substrates. This dehydrated crystal structure not only provides key leads to the understanding of the structure/function relationships in the protein in the absence of any ligand-bound structure, but also demonstrates the merit of dehydration of crystals as an inimitable technique to have a glance at proteins in action.


Recommendations and Improvements for the Evaluation of Integrated Community-Wide Interventions Approaches.
Background. Integrated community-wide intervention approaches (ICIAs) are implemented to prevent childhood obesity. Programme evaluation improves these ICIAs, but professionals involved often struggle with performance. Evaluation tools have been developed to support Dutch professionals involved in ICIAs. It is unclear how useful these tools are to intended users. We therefore researched the facilitators of and barriers to ICIA programme evaluation as perceived by professionals and their experiences of the evaluation tools. Methods. Focus groups and interviews with 33 public health professionals. Data were analysed using a thematic content approach. Findings. Evaluation is hampered by insufficient time, budget, and experience with ICIAs, lack of leadership, and limited advocacy for evaluation. Epidemiologists are regarded as responsible for evaluation but feel incompetent to perform evaluation or advocate its need in a political environment. Managers did not prioritise process evaluations, involvement of stakeholders, and capacity building. The evaluation tools are perceived as valuable but too comprehensive considering limited resources. Conclusion. Evaluating ICIAs is important but most professionals are unfamiliar with it and management does not prioritise process evaluation nor incentivize professionals to evaluate. To optimise programme evaluation, more resources and coaching are required to improve professionals' evaluation capabilities and specifically the use of evaluation.


Intrinsic structural disorder in cytoskeletal proteins.
Cytoskeleton, the internal scaffold of the cell, displays an exceptional combination of stability and dynamics. It is composed of three major filamentous networks, microfilaments (actin filaments), intermediate filaments (neurofilaments), and microtubules. Together, they ensure the physical and structural stability of the cell, whereby also mediating its large-scale structural rearrangements, motility, stress response, division, and internal transport. All three cytoskeletal systems are built upon the same basic design: they have a central repetitive scaffold assembled from folded building elements, surrounded and regulated by accessory regions/proteins that regulate its formation and mediate its countless interactions with its environment, serving to send regulatory signals to and from the cytoskeleton. Here, we elaborate on the idea that the opposing features of stability and dynamics are also manifest in the dichotomy of the structural status of its components, the core being highly structured and the accessory proteins/regions being highly disordered, and are responsible for most of the regulatory (post-translational) input promoting adaptive responses and providing dynamics necessary for each of the cytoskeletal systems. This pattern entails special consequences, in which the manifold functional advantages of structural disorder, most pronounced in regulatory and signaling functions, are all exploited by nature.


Psycho-social characteristics of cannabis abusing youth.
It is a well known fact that drug abuse is most common in early adolescence. The most popular substances among youth are cannabis products (made from Cannabis sativa L., Cannabaceae). The majority of heroin and cocaine addicts have started with marijuana. The aim of this study is to show some psycho-social characteristics of adolescents who abuse cannabis. Research conducted during the year 2001 was epidemiological and prospective. The study group included 600 adolescents of equal gender and age distribution. Q 2000 questionnaire was used, as a comprehensive tool for all aspects of adolescent life. The results show strong peer impact on one's behavior. Youth who use cannabis had 2-3 friends of the same behavior, compared to others who had none. We found positive correlation between life stressful events and cannabis abuse. We also noticed tendency to delinquent behavior related to cannabis abuse (35%).


Plasmodium species identification by ELISA for sporozoites removed from dried dissection slides.
This study tested the feasibility of identifying salavary gland sporozoites to species by Plasmodium falciparum ELISA by drying them on slides or in vials. The glands were dissected from Anopheles gambiae Giles s.l. and An. funestus Giles collected in western Kenya. In 119 gland infections containing a geometric mean of 1,222 sporozoites, a mean of 72.5% of sporozoites were removed in 60 microliters saline from slides at the time of dissection. Each of the 119 samples was divided into three 18 microliters aliquots. Subsamples were stored at -70 degrees C, dried in vials, or dried on a microslide. When tested by Plasmodium falciparum ELISA, positive reactions were observed in 86.6% of frozen samples, 70.6% of samples held dry in vials, and 50.4% of samples held dry on microslides for 1 mo. Of 90 gland infections where coverslips were removed and slides were left to dry for 1 mo before adding blocking buffer, 81.1% were positive for P. falciparum. This was not significantly different from either frozen gland samples (where 85.5% of 392 infections were identified or frozen gland plus corresponding thorax samples where 86.2% of 160 samples were identified). In malaria field studies, where it is not always practical to freeze samples, sporozoites from dissected mosquitoes can be preserved adequately for ELISA identification by simply removing coverslips and drying dissection slides.


Indigenous healers in the North West Province: a survey of their clinical activities in health care in the rural areas.
The purpose of this study was to explore the clinical conditions brought to indigenous healers by people in the rural areas in search of health care. The demographic variables and preventive, promotive, curative and follow-up activities of indigenous healers were investigated. Data were collected from a simple random sample of 35 indigenous healers. A questionnaire designed by Mogoba (1984) for investigation of training and functioning of traditional doctors in Southern Africa was modified and used to collect data. Findings showed that indigenous healers deal with the same health problems confronting formal health workers, especially in the paediatric field. Infertility, mental illness problems and sexually transmitted diseases ranked high in the adult conditions brought to the healers. There seem to be conditions that can be handled only by the indigenous healers due to their cultural nature. Findings also show that the services of indigenous healers are not confined to any specific group or social class within black population.


Treatment of community-acquired pneumonia.
Lower respiratory tract infections are the major cause of death due to infectious disease in the developed and developing world. Despite substantial progress in defining pathogens and in therapeutic options, there continues to be major controversies in the clinical management of these infections. This report reviews the guidelines for community-acquired pneumonia from the Infectious Diseases Society of America (IDSA), updated from the initial publication. Diagnosis should include a chest X-ray to differentiate acute bronchitis from pneumonia. The decision for hospitalization should be based on social factors and evaluation of severity of illness. Identification of an etiological agent for inpatients should include two pretreatment cultures, one pretreatment sputum specimen, with seriously ill patients requiring studies for Legionella spp. Recommendations for empiric treatment of outpatients are doxycycline, a macrolide or a fluoroquinolone. Recommendations for empiric treatment of hospitalized patients are a cephalosporin plus a macrolide, or a fluoroquinolone alone. Recommendations for ICU patients are a beta-lactam combined with either a macrolide or a fluoroquinolone. While concern has arisen about increasing resistance to fluoroquinolones, arguments in favor of these agents include the fact that they have good in vitro activity against nearly all treatable pathogens except some anaerobes. Clinical trials have shown equivalence or superiority compared to other standard agents. They are well tolerated, and can be administered intravenously or orally, once daily. A recent retrospective review has shown superior outcome with fluoroquinolone treatment compared to cephalosporins, including a 36% reduction in mortality.


Parental reasoning about growth attenuation therapy: report of a single-case study.
In 2006 a case report was published about a 6-year-old girl, Ashley, who has profound developmental disabilities and was treated with oestrogen patches to limit her final height, along with a hysterectomy and the removal of her breast buds. Ashley's parents claimed that attenuating her growth would make it possible for them to lift and move her more easily, facilitating greater involvement in family activities and making routine care more straightforward. The 'Ashley treatment' provoked public comment and academic debate and remains ethically controversial. As more children are being referred for such treatment, there is an urgent need to clarify how clinicians and ethics committees should respond to such requests. The controversy surrounding the Ashley treatment exists, at least in part, because of gaps in the literature, including a lack of empirical data about the outcomes for children who do and do not receive such treatment. However, we suggest in this paper that there is also merit in examining the parental decision-making process itself, and provide empirical data about the reasoning of one set of parents who ultimately chose part of this treatment for their child. Using the interview data, we illuminate some important points regarding how these parents characterise benefits and harms and their responsibilities as surrogate decision-makers. This analysis could inform decision-making about future requests for growth attenuation and might also have wider relevance to healthcare decision-making for children with profound cognitive impairment.


Cocaine self-administration in humans.
Studies are described in which normal healthy volunteers were tested with a wide range of intravenous doses of cocaine of d-amphetamine. Physiological measurements included heart rate, electrocardiogram, blood pressure, respiration rate, and temperature. Behavioral measures included the use of the Profile of Mood States to assess drug-related mood changes, the Addiction Research Center Inventory to assess drug-related changes in verbal reports of their effects, and ratings comparing drug effects of experimentally administered and "street" drugs. In addition, plasma levels of cocaine were monitored to correlate with physiological and behavioral effects. Subjects were also allowed to choose between intravenous injections of cocaine or saline. As with nonhuman research subjects, cocaine was consistently chosen over saline by all subjects tested. The self-administration data and data describing the subjective and cardiovascular spectrum of action were combined to yield a more complete profile of cocaine's action in humans.


Clinical and molecular overlap between myopathies and inherited connective tissue diseases.
This review presents an overview of myopathies and inherited connective tissue disorders that are caused by defects in or deficiencies of molecules within the extracellular matrix (ECM). We will cover the myopathies caused by defects in transmembrane protein complexes (dystroglycan, sarcoglycan, and integrins), laminin, and collagens (collagens VI, XIII, and XV). Clinical characteristics of several of these myopathies imply skin and joint features. We subsequently describe the inherited connective tissue disorders that are characterized by mild to moderate muscle involvement in addition to the dermal, vascular, or articular symptoms. These disorders are caused by defects of matrix-embedded ECM molecules that are also present within muscle (collagens I, III, V, IX, lysylhydroxylase, tenascin, fibrillin, fibulin, elastin, and perlecan). By focussing on the structure and function of these ECM molecules, we aim to point out the clinical and molecular overlap between the groups of disorders. We argue that clinicians and researchers dealing with myopathies and inherited connective tissue disorders should be aware of this overlap. Only a multi-disciplinary approach will allow full recognition of the wide variety of symptoms present in the spectrum of ECM defects, which has important implications for scientific research, diagnosis, and for the treatment of these disorders.


"Neural reactivity to rewards and losses in offspring of mothers and fathers with histories of depressive and anxiety disorders": Correction to Kujawa, Proudfit, and Klein (2014).
Reports an error in "Neural reactivity to rewards and losses in offspring of mothers and fathers with histories of depressive and anxiety disorders" by Autumn Kujawa, Greg Hajcak Proudfit and Daniel N. Klein (Journal of Abnormal Psychology, 2014[May], Vol 123[2], 287-297). In the article there was an error in the Measures section. The article stated that the EEG data were band-pass filtered with cutoffs of 0.1 and 30 Hz and baseline corrected using the 200 ms interval prior to feedback. Instead, the data were actually filtered with cutoffs of 0.01 and 30 Hz and baseline corrected using the 500 ms interval prior to feedback. (The following abstract of the original article appeared in record 2014-22133-001.) Depression appears to be characterized by reduced neural reactivity to receipt of reward. Despite evidence of shared etiologies and high rates of comorbidity between depression and anxiety, this abnormality may be relatively specific to depression. However, it is unclear whether children at risk for depression also exhibit abnormal reward responding, and if so, whether risk for anxiety moderates this association. The feedback negativity (FN) is an event-related potential component sensitive to receipt of rewards versus losses that is reduced in depression. Using a large community sample (N = 407) of 9-year-old children who had never experienced a depressive episode, we examined whether histories of depression and anxiety in their parents were associated with the FN following monetary rewards and losses. Results indicated that maternal history of depression was associated with a blunted FN in offspring, but only when there was no maternal history of anxiety. In addition, greater severity of maternal depression was associated with greater blunting of the FN in children. No effects of paternal psychopathology were observed. Results suggest that blunted reactivity to rewards versus losses may be a vulnerability marker that is specific to pure depression, but is not evident when there is also familial risk for anxiety. In addition, these findings suggest that abnormal reward responding is evident as early as middle childhood, several years prior to the sharp increase in the prevalence of depression and rapid changes in neural reward circuitry in adolescence. (PsycINFO Database Record


Neural prosthetic control signals from plan activity.
The prospect of assisting disabled patients by translating neural activity from the brain into control signals for prosthetic devices, has flourished in recent years. Current systems rely on neural activity present during natural arm movements. We propose here that neural activity present before or even without natural arm movements can provide an important, and potentially advantageous, source of control signals. To demonstrate how control signals can be derived from such plan activity we performed a computational study with neural activity previously recorded from the posterior parietal cortex of rhesus monkeys planning arm movements. We employed maximum likelihood decoders to estimate movement direction and to drive finite state machines governing when to move. Performance exceeded 90% with as few as 40 neurons.


Identification of aerosols by their backscattered Mueller images.
We have simulated the elastic light scattering by small dielectric particles with different shapes as well as different compositions. Backscattered angularly resolved Mueller images are obtained from the simulation. Our results show that the images are not only sensitive to the shape, size and orientation of the particle, but also sensitive to the composition. Thus the Mueller images act in reality like a Mueller-microscope, and can thus lead to the detection and classification of aerosols.


The netrin receptor frazzled is required in the target for establishment of retinal projections in the Drosophila visual system.
Retinal axons in Drosophila make precise topographic connections with their target cells in the optic lobe. Here we investigate the role of the Netrins and their receptor Frazzled in the establishment of retinal projections. We find that the Netrins, although expressed in the target, are not required for retinal projections. Surprisingly, Frazzled, found on both retinal fibers and target cells, is required in the target for attracting retinal fibers, while playing at best a redundant role in the retinal fibers themselves; this finding demonstrates that target attraction is necessary for topographic map formation. Finally, we show that Frazzled is not required for the differentiation of cells in the target. Our data suggest that Frazzled does not function as a Netrin receptor in attracting retinal fibers to the target; nor does it seem to act as a homotypic cell adhesion molecule. We favor the possibility that Frazzled in the target interacts with a component on the surface of retinal fibers, possibly another Netrin receptor.


Using the IPTG-Inducible Pgrac212 Promoter for Overexpression of Human Rhinovirus 3C Protease Fusions in the Cytoplasm of Bacillus subtilis Cells.
Expression and secretion of recombinant proteins in the endotoxin-free bacterium, Bacillus subtilis, has been thoroughly studied, but overexpression in the cytoplasm has been limited to only a few proteins. Here, we used the robust IPTG-inducible promoter, Pgrac212, to overexpress human rhinovirus 3C protease (HRV3C) in the cytoplasm of B. subtilis cells. A novel solubility tag, the N-terminal domain of the lysS gene of B. subtilis coding for a lysyl-tRNA synthetase was placed at the N terminus with a cleavage site for the endoprotease HRV3C, followed by His-HRV3C or His-GST-HRV3C. The recombinant protease was purified by using a Ni-NTA column. In this study, the His-HRV3C and His-GST-HRV3C proteases were overexpressed in the cytoplasm of B. subtilis at 11% and 16% of the total cellular proteins, respectively. The specific protease activities were 8065 U/mg for His-HRV3C and 3623 U/mg for His-GST-HRV3C. The purified enzymes were used to cleave two different substrates followed by purification of the two different protein targets, the green fluorescent protein and the beta-galactosidase. In conclusion, the combination of an inducible promoter Pgrac212 and a solubility tag allowed the overexpression of the HRV3C protease in the cytoplasm of B. subtilis. The resulting fusion protein was purified using a nickel column and was active in cleaving target proteins to remove the fusion tags. This study offers an effective method for producing recombinant proteins in the cytoplasm of endotoxin-free bacteria.


Conversion of phospholipids to free fatty acids in response to acquisition of polymyxin resistance in Pseudomonas aeruginosa.
The readily extractable lipids from a Pseudomonas aeruginosa isolate stepwise adapted to polymyxin resistance were compared with those of the susceptible parent and of a revertant strain which regained susceptibility. Significant qualitative and quantitative lipid alterations accompany the acquisition of resistance. Changes include the appearance of a major unidentified lipid (lipid X) unique to the readily extractable lipids of resistant cells. Comparative studies with parent and revertant strains indicated a significant decrease in the phospholipid content of resistant cells. Thin-layer chromatography of resistant-cell readily extractable lipids demonstrated: (i) the emergence of lipid X (36% of total readily extractable lipids), (ii) a decrease in phosphatidylethanolamine and phosphatidylglycerol, and (iii) an increase in diphosphatidylglycerol. Lipid X was purified by preparative silicic acid column chromatography and thin-layer chromatography and characterized by analytical thin-layer chromatography, column adsorption chromatography, and gas-liquid chromatography. Data from this study indicated that lipid X was a mixture of free fatty acids. The fatty acids present in lipid X were qualitatively and quantitatively the same as the fatty acids esterified to the phospholipids in the readily extractable lipids.


Cyclic di-GMP signaling regulates invasion by Ehrlichia chaffeensis of human monocytes.
Cyclic di-GMP (c-di-GMP) is a bacterial second messenger produced by GGDEF domain-containing proteins. The genome of Ehrlichia chaffeensis, an obligatory intracellular bacterium that causes human monocytic ehrlichiosis, encodes a single protein that contains a GGDEF domain, called PleD. In this study, we investigated the effects of c-di-GMP signaling on E. chaffeensis infection of the human monocytic cell line THP-1. Recombinant E. chaffeensis PleD showed diguanylate cyclase activity as it generated c-di-GMP in vitro. Because c-di-GMP is not cell permeable, the c-di-GMP hydrophobic analog 2'-O-di(tert-butyldimethylsilyl)-c-di-GMP (CDGA) was used to examine intracellular c-di-GMP signaling. CDGA activity was first tested with Salmonella enterica serovar Typhimurium. CDGA inhibited well-defined c-di-GMP-regulated phenomena, including cellulose synthesis, clumping, and upregulation of csgD and adrA mRNA, indicating that CDGA acts as an antagonist in c-di-GMP signaling. [(32)P]c-di-GMP bound several E. chaffeensis native proteins and two E. chaffeensis recombinant I-site proteins, and this binding was blocked by CDGA. Although pretreatment of E. chaffeensis with CDGA did not reduce bacterial binding to THP-1 cells, bacterial internalization was reduced. CDGA facilitated protease-dependent degradation of particular, but not all, bacterial surface-exposed proteins, including TRP120, which is associated with bacterial internalization. Indeed, the serine protease HtrA was detected on the surface of E. chaffeensis, and TRP120 was degraded by treatment of E. chaffeensis with recombinant E. chaffeensis HtrA. Furthermore, anti-HtrA inhibited CDGA-induced TRP120 degradation. Our results suggest that E. chaffeensis invasion is regulated by c-di-GMP signaling, which stabilizes some bacterial surface-exposed proteins against proteases.


Prophylactic colectomy for children with familial adenomatous polyposis: resource utilization and outcomes for open and laparoscopic surgery.
Laparoscopic approach for the surgical management of familial adenomatous polyposis (FAP) has become increasingly common for pediatric patients. The purpose of this study was to compare short-term outcomes and resource utilization between open and laparoscopic surgery for prophylactic colectomy in children with FAP. The Kids' Inpatient Database (2009 and 2012) was analyzed for children (age ≤20 years) with FAP that underwent prophylactic total colectomy or proctocolectomy. Patient demographics, treating hospital characteristics, hospital charges, and short-term outcomes were compared according to the surgical technique utilized (open versus laparoscopic). Overall, we identified 216 patients with FAP that underwent elective total colectomy, of which 95 cases were performed by open surgery and 121 were done laparoscopically. The majority of patients were treated at large, not-for-profit, urban teaching hospitals, and the median age was equal (16 years) in both groups. Complications that were more common for open procedures included accidental perforation or hemorrhage (4% vs. 0%, P=0.023), reopening of surgical site (3% vs. 0%, P=0.049), and pneumonia (3% vs. 0%, P=0.049). Simultaneous proctectomy was performed more commonly in the open cohort (91% vs. 71%, P<0.001) as well as ileostomy creation (74% vs. 49%, P<0.001). The median length of stay was similar in the open and laparoscopic groups (7 vs. 6 days, P=0.712). Median total hospital charges were also similar ($67,334 vs. $68,717, P=0.080). A laparoscopic approach for prophylactic colectomy can be safely performed in children with FAP, and total hospital charges are equivalent compared to open surgery. However, simultaneous proctectomy was performed less often with laparoscopic surgery.


Synthesis and secretion of interstitial retinol-binding protein by the human retina.
Interstitial retinol-binding protein (IRBP) is a soluble glycoprotein present between the retina and pigmented epithelium, which may function to shuttle vitamin A derivatives between these tissues. While previous studies have shown that the retina is solely responsible for IRBP synthesis, the specific retinal cell(s) in which this occurs has not been established. Since the carbohydrate moiety of IRBP contains fucose, the authors have analyzed the sites of incorporation of 3H-fucose in the human retina in vitro, using autoradiography. Following a 30-min pulse incubation, all retinal layers exhibited incorporation of label; however, the rod photoreceptor inner segments contained one- to two-fold more radioactivity than was present in any other retinal compartment. In autoradiographs of retinas recovered following a 4 hr chase incubation, all retinal layers retained similar levels of radioactivity with the exception of the rod photoreceptors, cone photoreceptors and cells in the inner nuclear layer, which lost 75, 11, and 14 percent, respectively of the radioactivity present immediately following the 30-min pulse. Proteins present in the chase incubation medium were analyzed by polyacrylamide gel electrophoresis and fluorography. The principal labeled component in the chase medium was identified as IRBP by immunoprecipitation with antibovine-IRBP immunoglobulins. Thus, the major loss of 3H-fucose radioactivity from rod photoreceptors coupled with the appearance of 3H-labeled IRBP in the incubation media suggests that the rod photoreceptors are primarily responsible for the synthesis and secretion of IRBP.


Critical illness polyneuropathy: a summary of the literature on rehabilitation outcome.
To evaluate the available literature on outcome of critical illness polyneuropathy (CIP) and to identify rehabilitation problems. A literature search in electronic databases. Primary articles on outcome in CIP using the classification of ICIDH or Quality of Life were enrolled in this study. Because of the types of study design, the lack of information regarding validity and the variability, a quantitative analysis was not possible. Instead, the overall results were evaluated in a qualitative approach. In the literature minimal attention was given to the rehabilitation aspects and long-term outcome of patients with CIP. Outcome measures were mainly used on the level of impairments and in lesser extent on the level of disabilities. One year after the onset of CIP, muscle weakness and decreased sensory function were frequently observed. Reported functional disabilities were dependency in Activities of Daily Living (ADL) and walking disabilities. The specific course and long-term outcome of CIP remains unclear. Research on the course and long-term functional outcome in CIP is necessary in order to identify rehabilitation problems and to formulate treatment strategies specifically directed towards the outcome of CIP.


Improving risk assessment of violence among military veterans: an evidence-based approach for clinical decision-making.
Increased media attention to post-deployment violence highlights the need to develop effective models to guide risk assessment among military Veterans. Ideally, a method would help identify which Veterans are most at risk for violence so that it can be determined what could be done to prevent violent behavior. This article suggests how empirical approaches to risk assessment used successfully in civilian populations can be applied to Veterans. A review was conducted of the scientific literature on Veteran populations regarding factors related to interpersonal violence generally and to domestic violence specifically. A checklist was then generated of empirically-supported risk factors for clinicians to consider in practice. To conceptualize how these known risk factors relate to a Veteran's violence potential, risk assessment scholarship was utilized to develop an evidence-based method to guide mental health professionals. The goals of this approach are to integrate science into practice, overcome logistical barriers, and permit more effective assessment, monitoring, and management of violence risk for clinicians working with Veterans, both in Department of Veteran Affairs settings and in the broader community. Research is needed to test the predictive validity of risk assessment models. Ultimately, the use of a systematic, empirical framework could lead to improved clinical decision-making in the area of risk assessment and potentially help prevent violence among Veterans.


The impact of a history of sexual abuse on high-risk sexual behaviors among females attending alternative schools.
The goal of this study was to explore whether a history of sexual abuse is associated with high-risk sexual behaviors among female adolescents attending alternative schools in a large urban city in the southwestern United States, and to examine the role of depression and substance abuse in explaining this association. One hundred eighty-four sexually active female adolescents constituted the sample for this analysis. Forty-nine (26.6%) reported that they were forced to have sex. Having a history of sexual abuse substantially increased sexual risk behaviors. Adolescents reporting a history of sexual abuse, compared to those who did not report such a history, were significantly more likely to have initiated sexual activity (intercourse) before age 14, to have had three or more sexual partners in the last 3 months, and to have had a history of sexually transmitted diseases. These associations remained significant after controlling for age, ethnicity, and family income. Depression and substance abuse did not explain the association between sexual abuse and high-risk sexual behaviors. It seems reasonable to conclude that adolescents with a history of sexual abuse have greater difficulty practicing safe sexual behaviors than do those who have not been sexually abused. Given the prevalence of child sexual abuse and the extent of its impact, it is critical that intervention strategies for adolescent females address the issue of abuse and help them adopt self-protective sexual behaviors. The findings also highlight the importance of targeting adolescents who attend alternative schools.


Association of anxiety disorders and depression with incident heart failure.
Depression has been associated with increased risk of heart failure (HF). Because anxiety is highly comorbid with depression, we sought to establish if anxiety, depression, or their co-occurrence is associated with incident HF. A retrospective cohort (N = 236,079) including Veteran's Administration patients (age, 50-80 years) free of cardiovascular disease (CVD) at baseline was followed up between 2001 and 2007. Cox proportional hazards models were computed to estimate the association between anxiety disorders alone, major depressive disorder (MDD) alone, and the combination of anxiety and MDD, with incident HF before and after adjusting for sociodemographics, CVD risk factors (Type 2 diabetes, hypertension, hyperlipidemia, obesity), nicotine dependence/personal history of tobacco use, substance use disorders (alcohol and illicit drug abuse/dependence), and psychotropic medication. Compared with unaffected patients, those with anxiety only, MDD only, and both disorders were at increased risk for incident HF in age-adjusted models (hazard ratio [HR] = 1.19 [ 95% confidence interval {CI} = 1.10-1.28], HR = 1.21 [95% CI = 1.13-1.28], and HR = 1.24 [95% CI = 1.17-1.32], respectively). After controlling for psychotropics in a full model, the association between anxiety only, MDD only, and both disorders and incident HF increased (HRs = 1.46, 1.56, and 1.74, respectively). Anxiety disorders, MDD, and co-occurring anxiety and MDD are associated with incident HF in this large cohort of Veteran's Administration patients free of CVD at baseline. This risk of HF is greater after accounting for protective effects of psychotropic medications. Prospective studies are needed to clarify the role of depression and anxiety and their pharmacological treatment in the etiology of HF.


Mindfulness-Based Stress Reduction, Cognitive Behavioral Therapy, and Acupuncture in Chronic Low Back Pain: Protocol for Two Linked Randomized Controlled Trials.
Nonpharmacologic mind-body therapies have demonstrated efficacy in low back pain. However, the mechanisms underlying these therapies remain to be fully elucidated. In response to these knowledge gaps, the Stanford Center for Low Back Pain-a collaborative, National Institutes of Health P01-funded, multidisciplinary research center-was established to investigate the common and distinct biobehavioral mechanisms of three mind-body therapies for chronic low back pain: cognitive behavioral therapy (CBT) that is used to treat pain, mindfulness-based stress reduction (MBSR), and electroacupuncture. Here, we describe the design and implementation of the center structure and the associated randomized controlled trials for characterizing the mechanisms of chronic low back pain treatments. The multidisciplinary center is running two randomized controlled trials that share common resources for recruitment, enrollment, study execution, and data acquisition. We expect to recruit over 300 chronic low back pain participants across two projects and across different treatment arms within each project. The first project will examine pain-CBT compared with MBSR and a wait-list control group. The second project will examine real versus sham electroacupuncture. We will use behavioral, psychophysical, physical measure, and neuroimaging techniques to characterize the central pain modulatory and emotion regulatory systems in chronic low back pain at baseline and longitudinally. We will characterize how these interventions impact these systems, characterize the longitudinal treatment effects, and identify predictors of treatment efficacy. Participant recruitment began on March 17, 2015, and will end in March 2023. Recruitment was halted in March 2020 due to COVID-19 and resumed in December 2021. This center uses a comprehensive approach to study chronic low back pain. Findings are expected to significantly advance our understanding in (1) the baseline and longitudinal mechanisms of chronic low back pain, (2) the common and distinctive mechanisms of three mind-body therapies, and (3) predictors of treatment response, thereby informing future delivery of nonpharmacologic chronic low back pain treatments. ClinicalTrials.gov NCT02503475; https://clinicaltrials.gov/ct2/show/NCT02503475. PRR1-10.2196/37823.


Use of Recursive Partitioning Analysis in Clinical Trials and Meta-Analysis of Randomized Clinical Trials, 1990-2016.
Recursive Partitioning Analysis (RPA) is a very flexible non parametric algorithm that allows classification of individuals according to certain criteria, particularly in clinical trials, the method is used to predict response to treatment or classify individuals according to prognostic factors. In this paper we examine how often RPA is used in clinical trials and in meta-analysis. We reviewed abstracts published between 1990 and 2016, and extracted data regarding clinical trial phase, year of publication, type of treatment, medical indication and main evaluated endpoints. One hundred and eighty three studies were identified; of these 43 were meta-analyses and 23 were clinical trials. Most of the studies were published between 2011 and 2016, for both clinical trials and meta-analyses of randomized clinical trials. The prediction of overall survival and progression free survival were the outcomes most evaluated, at 43.5% and 51.2% respectively. Regarding the use of RPA in clinical trials, the brain was the most common site studied, while for meta-analytic studies, other cancer sites were also studied. The combination of chemotherapy and radiation was seen frequently in clinical trials. Recursive partitioning analysis is a very easy technique to use, and it could be a very powerful tool to predict response in different subgroups of patients, although it is not widely used in clinical trials.


[Late ventricular potentials in patients with cardiological X syndrome and their association with ventricular arrhythmias].
The purpose of the study was to explore late ventricular potentials (LVPs) in patients with cardiological X syndrome (XS), their association with ventricular arrhythmias (VA), with the structure and function of the heart. Fifty-two patients were examined. A control group comprised 17 healthy individuals. LVPs were determined by recording a signal-averaged high resolution (AHR) ECG by means a Megacart-400 device ("Siemens"). It was shown that there was a relationship between LVPs and high-grade VA in patients with XS. The patients with the recorded LVPs were observed to have the enlarged left ventricle (LV) and a significant ST-segment depression during bicycle ergometric tests. Those with LVPs were ascertained to have a relationship between the end LV systolic volume and the values of a single of AHR ECG. At the same time, there was no correlation between the values of a single of AHR ECG and the magnitude of ST-segment depression.


Emerging Applications of Boron Nitride Nanotubes in Energy Harvesting, Electronics, and Biomedicine.
Boron nitride nanotubes (BNNTs) are structurally and mechanically similar to carbon nanotubes (CNTs). In contrast, BNNTs exhibit unique properties for being electrically insulating and optically transparent due to the polarized boron nitride bonds. All these properties have prevented the use of BNNTs for energy harvesting and electronic devices for more than 25 years. During the past few years, researchers have started to demonstrate a series of novel applications of BNNTs based on unique properties not found on CNTs. For example, these novel applications include osmotic power harvesting using the charged inner surfaces of BNNTs, room-temperature single-electron transistors using insulating BNNTs as the tunneling channels, high-brightness fluorophores that can be 1000-times brighter than regular dyes, and transistors based on Tellurium atomic chains filled inside BNNTs. We have reviewed some of these emerging applications and provided our perspective for future work.


The effects of sodium-glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a unique class of oral anti-hyperglycaemic medications that act to reduce glucose reabsorption in the renal proximal tubules, thereby enhancing urinary glucose excretion. Large randomized placebo-controlled trials in people with diabetes at high cardiovascular risk have demonstrated that SGLT2 inhibitors reduce heart failure hospitalization within months of commencing therapy. These findings are of considerable interest, as diabetes is associated with an increased risk of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. In addition, left ventricular (LV) hypertrophy and impaired diastolic function is thought to be more prevalent in people with diabetes. Although many hypotheses have been proposed, the underlying mechanisms through which SGLT2 inhibitors reduce the risk of heart failure in people with diabetes are not fully understood. Given the rapid reduction in heart failure hospitalization, it is conceivable that the benefits of SGLT2 inhibitors are due to favourable haemodynamic and metabolic effects on LV function. Several clinical studies have been conducted to investigate the effect of SGLT2 inhibitors on LV structure and function and have found that LV mass index and diastolic function improve following SGLT2 inhibitor therapy in people with type 2 diabetes. If these findings are confirmed in future studies utilizing novel cardiac imaging modalities and large randomized controlled trials, then this will bring new hope for the prevention and management of heart failure with preserved ejection fraction, for which no current treatments have been shown to reduce mortality. At the present time, SGLT2 inhibitors are indicated for the treatment of type 2 diabetes; however, the results of ongoing trials in participants with heart failure but without diabetes are eagerly awaited. The purpose of this review is to summarize current knowledge regarding the effects of SGLT2 inhibitors on LV function, particularly the findings from clinical studies, proposed biological mechanisms, and future directions.


Autophagy restricts proliferation driven by oncogenic phosphatidylinositol 3-kinase in three-dimensional culture.
Autophagy is a tightly regulated lysosomal self-digestion process that can both promote and impede tumorigenesis. Here, we utilize a three-dimensional (3D) culture model to address how interactions between autophagy and the phosphatidylinositol 3-kinase(PI3K)/Akt/mammalian target of rapamycin pathway impact the malignant behavior of cells carrying a tumor-derived, activating mutation in PI3K (PI3K-H1047R). In this model, autophagy simultaneously mediates tumor-suppressive and -promoting functions within individual glandular structures. In 3D culture, constitutive PI3K activation overcomes proliferation arrest and promotes resistance to anoikis in the luminal space, resulting in aberrant structures with filled lumen. Inhibiting autophagy in PI3K-H1047R structures triggers luminal cell apoptosis, resulting in lumen clearance. At the same time, autophagy gene depletion strongly enhances PI3K-H1047R cell proliferation during 3D morphogenesis, revealing an unexpected role for autophagy in restricting proliferation driven by PI3K activation. Intriguingly, overexpression of the autophagy cargo receptor p62/SQSTM1 in PI3K-H1047R cells is sufficient to enhance cell proliferation, activate the extracellular signal-related kinase/mitogen-activated protein kinase pathway and to promote epidermal growth factor-independent proliferation in 3D culture. Overall, these results indicate that autophagy antagonizes specific aspects of oncogenic PI3K transformation, with the loss of autophagy promoting proliferation.


Plasma kisspeptin levels in male cases with hypogonadism.
The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not. In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism. The results showed a variety of plasma kisspeptin levels: 6.0 fmol/ml in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/ml in a male with Kallmann's syndrome, 40.7 fmol/ml in a male with azoospermia, 323.2 fmol/ml in a male with hypergonadotropic hypogonadism, and 12.3 ± 2.5 fmol/ml (mean ± SD) in seven normal controls. Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic-pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids. The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis. In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism.


Symptom word documentation: A novel approach to identifying and managing hospital-acquired infections.
An interprofessional team developed a symptom word documentation tool based on surveillance definitions for specific types of infections published by the Centers for Disease Control and Prevention. Nursing documentation was monitored pre- and postimplementation of the tool, revealing increased compliance with symptom documentation. Although symptom word documentation does not reduce the number of infections, it may impact the central line-associated bloodstream infection (CLABSI) rate by better differentiating CLABSI from other infection sources, as was observed in this institution.


MCP-1 protects mice in lethal endotoxemia.
The overzealous production of proinflammatory cytokines in sepsis can result in shock, multiorgan dysfunction, and even death. In this study, we assessed the role of monocyte chemoattractant protein-1 (MCP-1) as a mediator of sepsis in endotoxin-challenged mice. Intraperitoneal administration of LPS to CD-1 mice induced a substantial time-dependent increase in MCP-1 in plasma, lung, and liver. The passive immunization of mice with rabbit antimurine MCP-1 antiserum 2 h before endotoxin administration resulted in a striking increase in LPS-induced mortality from 10% in control animals to 65% in anti-MCP-1-treated animals. Importantly, the administration of anti-MCP-1 antibodies to endotoxin-challenged mice resulted in increases in peak TNF-alpha and IL-12 levels, and also in a trend toward decreased serum levels of IL-10. Conversely, the administration of recombinant murine MCP-1 intraperitoneally significantly protected mice from endotoxin-induced lethality, and resulted in an increase in IL-10 levels, a decrease in IL-12 levels, and a trend toward decreased levels of TNF. In conclusion, our findings indicate that MCP-1 is a protective cytokine expressed in murine endotoxemia, and does so by shifting the balance in favor of antiinflammatory cytokine expression in endotoxin-challenged animals.