The enamelin genes in lizard, crocodile, and frog and the pseudogene in the chicken provide new insights on enamelin evolution in tetrapods.
Enamelin (ENAM) has been shown to be a crucial protein for enamel formation and mineralization. Previous molecular analyses have indicated a probable origin early in vertebrate evolution, which is supported by the presence of enamel/enameloid tissues in early vertebrates. In contrast to these hypotheses, ENAM was only characterized in mammals. Our aims were to 1) look for ENAM in representatives of nonmammalian tetrapods, 2) search for a pseudogene in the chicken genome, and 3) see whether the new sequences could bring new information on ENAM evolution. Using in silico approach and polymerase chain reaction, we obtained and characterized the messenger RNA sequences of ENAM in a frog, a lizard, and a crocodile; the genomic DNA sequences of ENAM in a frog and a lizard; and the putative sequence of chicken ENAM pseudogene. The comparison with mammalian ENAM sequences has revealed 1) the presence of an additional coding exon, named exon 8b, in sauropsids and marsupials, 2) a simpler 5'-untranslated region in nonmammalian ENAMs, 3) many sequence variations in the large exons while there are a few conserved regions in small exons, and 4) 25 amino acids that have been conserved during 350 million years of tetrapod evolution and hence of crucial biological importance. The chicken pseudogene was identified in a region that was not expected when considering the gene synteny in mammals. Together with the location of lizard ENAM in a homologous region, this result indicates that enamel genes were probably translocated in an ancestor of the sauropsid lineage. This study supports the origin of ENAM earlier in vertebrate evolution, confirms that tooth loss in modern birds led to the invalidation of enamel genes, and adds information on the important role played by, for example, the phosphorylated serines and the glycosylated asparagines for correct ENAM functions.


Enantioselective syntheses of the proposed structures of kopeolin and kopeolone.
The first total syntheses of the proposed structures of kopeolin (1) and kopeolone (3) have been achieved from a common enantiopure chiral building block obtained by a chemoenzymatic enantioconvergent methodology. The syntheses feature two key steps: a one-pot reduction/diastereoselective protonation followed by a highly diastereoselective addition of an organocerate. The synthetic structures were fully characterized and all stereocenters were confirmed. The results show that the two previously reported structures were not assigned correctly, and suggest an initial structural misassignment during the isolation of the natural products. Thus, two revised structures, 1' for kopeolin and 3' for kopeolone, are proposed.


Do some patients with Helicobacter pylori infection benefit from an extension to 2 weeks of a proton pump inhibitor-based triple eradication therapy?
Seven-day proton pump inhibitor (PPI)-based triple therapies are the first-line anti-Helicobacter pylori regimens; to date, however, there is still no agreement concerning all the predictors of H. pylori cure under these regimens. The aim of this prospective study was to evaluate whether patients with certain pretreatment characteristics may benefit from an extension from 1 to 2 wk of treatment with lansoprazole, amoxycillin, and clarithromycin. A total of 142 patients with H. pylori infection ascertained by means of gastric histopathology and 13C urea breath test (UBT) participated in this study. In all patients H. pylori density was determined at histology both on antral and corpus biopsies, and H. pylori culture with antibiotic susceptibility testing; IgG anti-H. pylori titers were also determined before therapy. Patients were randomized to receive 1-wk versus 2-wk of treatment with lansoprazole (30 mg b.i.d.), clarithromycin (500 mg b.i.d.), and amoxycillin (1 g b.i.d.). The association between eradication and potential predictors was analyzed by means of unconditional logistic regression models and stratified according to the duration of treatment. A stepwise regression analysis was performed to identify variables discriminated between subjects, using eradication status as the dependent variable. The overall eradication rates for 1- and 2-wk treatments were 74.6% and 85.9% (intention-to-treat analysis) and 81.5% and 89.1% (per-protocol analysis), respectively (p = NS). Multivariate discriminant analysis selected as the variables independently related to eradication cigarette smoking (OR = 3.98), delta of 13C-UBT higher than 35 (OR = 9.21) and IgG anti-H. pylori titer > or = 93 (OR = 0.24) for the whole series of subjects. Stratified analysis according to the duration of therapy selected H. pylori density as the only predictor of eradication in the group treated for 1 wk (OR = 8.11). In contrast, no significant predictors were found in the group treated for 2 wk. Patients with a high intragastric bacterial load, as detected by histology (grade 3) or 13C-UBT (delta > 35) may benefit from an extension to 2 wk of triple therapy with lansoprazole, amoxycillin, and clarithromycin.


Biology of developmental and regenerative skeletogenesis.
Embryonic skeletal development involves the recruitment, commitment, differentiation, and maturation of mesenchymal cells into those in the skeletal tissue lineage, specifically cartilage and bone along the intramembranous and endochondral ossification pathways. The exquisite control of skeletal development is regulated at the level of gene transcription, cellular signaling, cell-cell and cell-matrix interactions, as well as systemic modulation. Mediators include transcription factors, growth factors, cytokines, metabolites, hormones, and environmentally derived influences. Understanding the mechanisms underlying developmental skeletogenesis is crucial to harnessing the inherent regenerative potential of skeletal tissues for wound healing and repair, as well as for functional skeletal tissue engineering. In this review, a number of key issues are discussed concerning the current and future challenges of the scientific investigation of developmental skeletogenesis in the embryo, specifically limb cartilage development, and how these challenges relate to regenerative or reparative skeletogenesis in the adult. Specifically, a more complete understanding the biology of skeletogenic progenitor cells and the cellular and molecular mechanisms governing tissue patterning and morphogenesis should greatly facilitate the development of regenerative approaches to cartilage repair.


Comparison of Fit Between Zirconia and Metal Copings Fabricated Conventionally or Using Different CAD/CAM Techniques.
This study was designed to assess the fit of cobalt chromium copings fabricated using direct metal laser sintering and to compare with copings fabricated from nickel chromium (traditional casting) and zirconia (milled from partially sintered blanks). For both cobalt chromium and zirconia groups, impressions were generated using direct or indirect digitization. There were 5 experimental groups of 12 copings fabricated for a prepared maxillary right molar. The intimacy of fit (measured at the margin, axial wall and occlusal) was assessed using a replica method technique. The results showed that zirconia copings produced using direct digitization had significantly smaller marginal, axial and occlusal measurements compared to other groups (p⟨0.05). Nevertheless, all groups had a mean marginal gap within accepted clinical values. Though there was a decrease in the intimacy of fit from the margin to axial wall to the occlusal surface. It can be concluded that the fit of zirconia copings fabricated using direct digitization was significantly better than the other groups. However, it can be expected that further enhancement and refinement of additive technology such as direct metal laser sintering will offer clinicians a viable alternative to nickel chromium analogue production methods in the future.


RAC1 regulates adherens junctions through endocytosis of E-cadherin.
The establishment of cadherin-dependent cell-cell contacts in human epidermal keratinocytes are known to be regulated by the Rac1 small GTP-binding protein, although the mechanisms by which Rac1 participates in the assembly or disruption of cell-cell adhesion are not well understood. In this study we utilized green fluorescent protein (GFP)-tagged Rac1 expression vectors to examine the subcellular distribution of Rac1 and its effects on E-cadherin-mediated cell-cell adhesion. Microinjection of keratinocytes with constitutively active Rac1 resulted in cell spreading and disruption of cell-cell contacts. The ability of Rac1 to disrupt cell-cell adhesion was dependent on colony size, with large established colonies being resistant to the effects of active Rac1. Disruption of cell-cell contacts in small preconfluent colonies was achieved through the selective recruitment of E-cadherin-catenin complexes to the perimeter of multiple large intracellular vesicles, which were bounded by GFP-tagged L61Rac1. Similar vesicles were observed in noninjected keratinocytes when cell-cell adhesion was disrupted by removal of extracellular calcium or with the use of an E-cadherin blocking antibody. Moreover, formation of these structures in noninjected keratinocytes was dependent on endogenous Rac1 activity. Expression of GFP-tagged effector mutants of Rac1 in keratinocytes demonstrated that reorganization of the actin cytoskeleton was important for vesicle formation. Characterization of these Rac1-induced vesicles revealed that they were endosomal in nature and tightly colocalized with the transferrin receptor, a marker for recycling endosomes. Expression of GFP-L61Rac1 inhibited uptake of transferrin-biotin, suggesting that the endocytosis of E-cadherin was a clathrin-independent mechanism. This was supported by the observation that caveolin, but not clathrin, localized around these structures. Furthermore, an inhibitory form of dynamin, known to inhibit internalization of caveolae, inhibited formation of cadherin vesicles. Our data suggest that Rac1 regulates adherens junctions via clathrin independent endocytosis of E-cadherin.


Social networking of human neutrophils within the immune system.
It is now widely recognized that neutrophils are highly versatile and sophisticated cells that display de novo synthetic capacity and may greatly extend their lifespan. In addition, concepts such as "neutrophil heterogeneity" and "neutrophil plasticity" have started to emerge, implying that, under pathological conditions, neutrophils may differentiate into discrete subsets defined by distinct phenotypic and functional profiles. A number of studies have shown that neutrophils act as effectors in both innate and adaptive immunoregulatory networks. In fact, once recruited into inflamed tissues, neutrophils engage into complex bidirectional interactions with macrophages, natural killer, dendritic and mesenchymal stem cells, B and T lymphocytes, or platelets. As a result of this cross-talk, mediated either by contact-dependent mechanisms or cell-derived soluble factors, neutrophils and target cells reciprocally modulate their survival and activation status. Altogether, these novel aspects of neutrophil biology have shed new light not only on the potential complex roles that neutrophils play during inflammation and immune responses, but also in the pathogenesis of several inflammatory disorders including infection, autoimmunity, and cancer.


Cardiovascular benefits and safety of non-insulin medications used in the treatment of type 2 diabetes mellitus.
Diabetes mellitus is a growing in exponential proportions. If the current growth trend continues, it may result in every third adult in the United States having diabetes mellitus by 2050, and every 10th adult worldwide. Type 2 diabetes mellitus (T2DM) confers a 2- to 3-fold increased risk of cardiovascular (CV) events compared with non-diabetic patients, and CV mortality is responsible for around 80% mortality in this population. Patients with T2DM can have other features of insulin resistance-metabolic syndrome like hypertension, lipid abnormalities, and obesity which are all associated with increased CV disease and stroke risk even in the absence of T2DM. The management of a T2DM calls for employing a holistic risk factor control approach. Metformin is the first line therapy for T2DM and has been shown to have cardiovascular beneficial effects. Intense debate regarding the risk of myocardial infarction with rosiglitazone led to regulatory agencies necessitating cardiovascular outcome trials with upcoming anti-diabetic medications. Glucagon like peptide-1 agonists and sodium glucose co-transporter-2 inhibitors have shown promising CV safety and additional CV benefit in recent clinical trials. These drugs have favorable effects on traditional CV risk factors. The findings from these studies further support that fact that CV risk factor control plays an important role in reducing morbidity and mortality in T2DM patients. This review article will discuss briefly the cardiovascular safety and benefits of the oral medications which are currently being used for T2DM and will then discuss in detail about the newer medications being investigated for the treatment of T2DM.


Patient-Specific Modeling and Model Predictive Control Approach to Personalized Optimal Anemia Management.
In the condition of anemia, kidneys produce less erythropoietin hormone to stimulate the bone marrow to make red blood cells (RBC) leading to a reduced hemoglobin (Hgb) level, also known as chronic kidney disease (CKD). External recombinant human erythropoietin (EPO) is administrated to maintain a healthy level of Hgb, i.e., 10 - 12 g/dl. The semi-blind robust model identification method is used to obtain a personalized patient model using minimum dose-response data points. The identified patient models are used as predictive models in the model predictive control (MPC) framework. The simulation results of MPC for different CKD patients are compared with those obtained from the existing clinical method, known as anemia management protocol (AMP), used in hospitals. The in-silico results show that MPC outperforms AMP to maintain healthy levels of Hgb without over-or-under- shoots. This offers a considerable performance improvement compared to AMP which is unable to stabilize EPO dosage and shows oscillations in Hgb levels throughout the treatment.Clinical Relevance-This research work provides a framework to help clinicians in decision-making for personalized EPO dose guidance using MPC with semi-blind robust model identification using minimum clinical patient dose-response data.


High grade renal trauma due to blunt injury in children: do all require intervention?
The aim of this study was to analyze the presentation and management of major grade renal trauma in children. A retrospective study was performed including data collected from the patients who were admitted in Pediatric surgery with major grade renal injury (grade 3 and more) from January 2015 to August 2018. Demography, clinical parameters, management, duration of hospital stay and final outcome were noted. Out of 13 children (9 males and 4 females), with age range 2-12 years (mean of 8 years), reported self-fall was the commonest mode of injury followed by road traffic accident. The majority (10/13, 75%) had a right renal injury. Eight children had a grade IV injury, one had a grade V injury, and four children had grade III injury. Duration of hospital stay varied from 3 to 28 (mean of 11.7) days. Three children required blood transfusion. One child required image guided aspiration twice and two required pigtail insertion for perinephric collection. All the 13 children improved without readmission or need for any other surgical intervention. Children with major grade renal trauma due to blunt injury can be successfully managed without surgical intervention and minimal intervention may only be needed in select situations.


A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD.
Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown. In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µg/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician. There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µg) compared with the titration-dose group (53.6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µg and 53.6 (31.1, 89.9) µg, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) µg. These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.


Attention to emotional scenes including whole-body expressions in chimpanzees (Pan troglodytes).
Real-life situations provide rich sets of cues that viewers evaluate in terms of their emotional significance. In this study, chimpanzees (Pan troglodytes) viewed a movie depicting naturalistic scenes involving the whole-body expressions of conspecifics to examine how nonhuman primates perceived the combination of these cues and how each cue contributed to the overall perception. Viewing time was measured while the chimpanzees watched movie clips without sound. Among scenes depicting neutrality, general excitement, agonism, and playfulness, chimpanzees looked longest at those depicting agonism. This bias toward agonistic scenes may indicate an attentional sensitivity toward threat/fear-related negative situations among chimpanzees. The effect disappeared when the images were scrambled, ruling out the possible effect of pixel-level properties on the results. In addition, the follow-up analyses revealed that the effect was independent of the presentation order and of the number of individuals in each clip. The manipulation of playback speeds had little effect on the looking times. The elimination of facial cues slightly influenced the looking times but did not change the strong bias toward agonistic scenes. This robustness of the main effect against image manipulations may indicate that the chimpanzees attended directly to the contextual information implied by the cues rather than to the cues per se (e.g., facial expressions, speed of movements).


Analysis of age-at-death estimation using data from a new, modern autopsy sample--part I: pubic bone.
This research tests the accuracy of age estimation from the pubic bone. Specimens were collected from decedents of known age, sex, and race at the Forensic Science Center (FSC) in Phoenix, Arizona. The collection consists of pubic bones and fourth rib ends from 419 males and 211 females, ranging in age from 18 to 99. Age-at-death was estimated by three observers using the Suchey-Brooks method. The correlation results indicate that there are significant differences in the observed versus actual ages (r = 0.68169, p < 0.001) and that there are significant interobserver differences. No significant differences were found in the intra-observer tests. The FSC pubic bones were sorted based on morphology without knowing age. New descriptions and age ranges were created. A phase seven was described and is comprised of males and females over 70 years of age-at-death.


Self-defense: Deflecting Deflationary and Eliminativist Critiques of the Sense of Ownership.
I defend a phenomenological account of the sense of ownership as part of a minimal sense of self from those critics who propose either a deflationary or eliminativist critique. Specifically, I block the deflationary critique by showing that in fact the phenomenological account is itself a deflationary account insofar as it takes the sense of ownership to be implicit or intrinsic to experience and bodily action. I address the eliminativist view by considering empirical evidence that supports the concept of pre-reflective self-awareness, which underpins the sense of ownership. Finally, I respond to claims that phenomenology does not offer a positive account of the sense of ownership by showing the role it plays in an enactivist (action-oriented) view of embodied cognition.


Technology applications in intervention for preschool-age children with language disorders.
Preschool-age children are capable of using computers and benefiting from developmentally appropriate software. Computer technology has been used successfully in therapy for young children with speech and language disorders; however, the clinician is a crucial factor in such success. Clinicians choose communication goals and appropriate software, plan precomputer activities, provide appropriate models and opportunities during the computer activity, and provide postcomputer activities that ensure the generalization of new skills. In this article, we discuss and illustrate the characteristics of developmentally appropriate computer-based activities and the role of clinicians in planning and implementing these activities for young children.


Intracellular transport of secretory proteins in the pancreatic exocrine cell. I. Role of the peripheral elements of the Golgi complex.
It has been established by electron microscopic radioautography of guinea pig pancreatic exocrine cells (Caro and Palade, 1964) that secretory proteins are transported from the elements of the rough-surfaced endoplasmic reticulum (ER) to condensing vacuoles of the Golgi complex possibly via small vesicles located in the periphery of the complex. To define more clearly the role of these vesicles in the intracellular transport of secretory proteins, we have investigated the secretory cycle of the guinea pig pancreas by cell fractionation procedures applied to pancreatic slices incubated in vitro. Such slices remain viable for 3 hr and incur minimal structural damage in this time. Their secretory proteins can be labeled with radioactive amino acids in short, well defined pulses which, followed by cell fractionation, makes possible a kinetic analysis of transport. To determine the kinetics of transport, we pulse-labeled sets of slices for 3 min with leucine-(14)C and incubated them for further +7, +17, and +57 min in chase medium. At each time, smooth microsomes ( = peripheral elements of the Golgi complex) and rough microsomes ( = elements of the rough ER) were isolated from the slices by density gradient centrifugation of the total microsomal fraction. Labeled proteins appeared initially (end of pulse) in the rough microsomes and were subsequently transferred during incubation in chase medium to the smooth microsomes, reaching a maximal concentration in this fraction after +7 min chase incubation. Later, labeled proteins left the smooth microsomes to appear in the zymogen granule fraction. These data provide direct evidence that secretory proteins are transported from the cisternae of the rough ER to condensing vacuoles via the small vesicles of the Golgi complex.


Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction.
We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drug-seeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.


Unilateral inactivation of the basolateral amygdala attenuates context-induced renewal of Pavlovian-conditioned alcohol-seeking.
Environmental contexts associated with drug use promote craving in humans and drug-seeking in animals. We hypothesized that the basolateral amygdala (BLA) itself as well as serial connectivity between the BLA and nucleus accumbens core (NAC core) were required for context-induced renewal of Pavlovian-conditioned alcohol-seeking. Male Long-Evans rats were trained to discriminate between two conditioned stimuli (CS): a CS+ that was paired with ethanol (EtOH, 20%, v/v) delivery into a fluid port (0.2 mL/CS+, 3.2 mL per session) and a CS- that was not. Entries into the port during each CS were measured. Next, rats received extinction in a different context where both cues were presented without EtOH. At test, responding to the CS+ and CS- without EtOH was evaluated in the prior training context. Control subjects showed a selective increase in CS+ responding relative to extinction, indicative of renewal. This effect was blocked by pre-test, bilateral inactivation of the BLA using a solution of GABA receptor agonists (0.1 mm muscimol and 1.0 mm baclofen; M/B; 0.3 μL per side). Renewal was also attenuated following unilateral injections of M/B into the BLA, combined with either M/B, the dopamine D1 receptor antagonist SCH 23390 (0.6 μg per side) or saline infusion in the contralateral NAC core. Hence, unilateral BLA inactivation was sufficient to disrupt renewal, highlighting a critical role for functional activity in the BLA in enabling the reinstatement of alcohol-seeking driven by an alcohol context.


Online prostate cancer screening decision aid for at-risk men: a randomized trial.
This study examines the efficacy of an online screening decision aid (DA) for men with a family history of prostate cancer. Unaffected Australian men (40-79 years) with at least one affected relative completed the first online questionnaire, were randomized to read either the tailored DA (intervention) or nontailored information about prostate cancer screening (control), then completed a questionnaire postreading and 12 months later. The primary outcome was decisional conflict regarding prostate specific antigen (PSA) testing. The impact of the DA on longitudinal outcomes was analyzed by using random intercept mixed effects models. Logistic and linear regressions were used to analyze the impact of the DA on screening behavior and decision regret. Stage of decision-making was tested as a moderator for decisional conflict and decision regret. The frequency of online material access was recorded. The DA had no effect on decisional conflict, knowledge, inclination toward PSA testing, accuracy of perceived risk, or screening behavior. However, among men considering PSA testing, those who read the DA had lower decision regret compared with men who read the control materials, β = 0.34, p < .001, 95% confidence interval (CI) = [.22, .53]. This is the first study to our knowledge to evaluate the uptake and efficacy of an online screening DA among men with a family history of prostate cancer. Men who were undecided about screening at baseline benefitted from the DA, experiencing less regret 12 months later. In relation to decisional conflict, the control materials may have operated as a less complex and equally informative DA.


Discovery of diverse polyomaviruses in bats and the evolutionary history of the Polyomaviridae.
Polyomaviruses (PyVs) have been identified in a wide range of avian and mammalian species. However, little is known about their occurrence, genetic diversity and evolutionary history in bats, even though bats are important reservoirs for many emerging viral pathogens. This study screened 380 specimens from 35 bat species from Kenya and Guatemala for the presence of PyVs by semi-nested pan-PyV PCR assays. PyV DNA was detected in 24 of the 380 bat specimens. Phylogenetic analysis revealed that the bat PyV sequences formed 12 distinct lineages. Full-genome sequences were obtained for seven representative lineages and possessed similar genomic features to known PyVs. Strikingly, this evolutionary analysis revealed that the bat PyVs were paraphyletic, suggestive of multiple species jumps between bats and other mammalian species, such that the theory of virus-host co-divergence for mammalian PyVs as a whole could be rejected. In addition, evidence was found for strong heterogeneity in evolutionary rate and potential recombination in a number of PyV complete genomes, which complicates both phylogenetic analysis and virus classification. In summary, this study revealed that bats are important reservoirs of PyVs and that these viruses have a complex evolutionary history.


Somatotropic Axis and Obesity: Is There Any Role for the Mediterranean Diet?
Obesity is associated with reduced spontaneous and stimulated growth hormone (GH) secretion and basal insulin-like growth factor I (IGF-1) levels-which in turn is associated with increased prevalence of cardiovascular risk factors. The aim of this study was to investigate: (1) the association of somatotropic axis with cardiometabolic status; (2) the association of somatotropic axis with the Mediterranean diet and nutritional pattern in people with obesity. Cross-sectional observational study was carried out in 200 adult women, aged 36.98 ± 11.10 years with severe obesity (body mass index-BMI of 45.19 ± 6.30 kg/m2). The adherence to the Mediterranean diet and the total calorie intake was assessed. Anthropometric measurements, body composition and biochemical profile were determined along with Growth Hormone (GH)/Insulin like Growth Factor 1 (IGF-1) axis and insulin resistance (homeostatic model assessment for insulin resistance-HoMA-IR). The enrolled subjects were compared after being divided according to GH peak response and according to IGF-1 standard deviation scores (SDS). Derangements of GH peak were detected in 61.5% of studied patients while IGF-1 deficiency was detected in 71% of the population. Both blunted GH peak response and IGF-1 SDS were indicators of derangements of somatotropic axis and were associated with comparable results in terms of cardiometabolic sequelae. Both GH peak and IGF-1 levels were inversely associated with anthropometric and metabolic parameters. The adherence to the Mediterranean diet predicts GH peak response. Fatty liver index (FLI), fat mass (FM) and phase angle (PhA) were predictive factors of GH peak response as well. In conclusion derangements of somatotropic axis is associated with a worse cardiometabolic profile in people with obesity. A high adherence to the Mediterranean diet-and in particular protein intake-was associated with a better GH status.


Physician Practice Patterns for Performing Thoracentesis in Patients Taking Anticoagulant Medications.
Patients undergoing thoracentesis often have comorbid conditions or take medications that potentially put them at higher bleeding risk. Direct oral anticoagulant (DOAC) use has also increased significantly. There are no published guidelines or consensus on when to perform thoracentesis in patients on anticoagulants. Recent studies support the safety of a more liberal approach for thoracentesis among patients with coagulopathy. We conducted a survey to ascertain the practices of physicians regarding thoracentesis in patients with increased bleeding risk. The survey was administered to the email distribution lists of the American Association of Bronchology and Interventional Pulmonology and of the American Thoracic Society. The survey was completed by 256 attending physicians. Most of them were general pulmonologists practicing at academic medical centers. Most of them would perform a thoracentesis in patients receiving acetylsalicylic acid or prophylactic doses of unfractionated heparin or low molecular weight heparin (96%, 89%, and 88%, respectively). Half of the respondents would perform a thoracentesis in patients on antiplatelet medications (clopidogrel and ticagrelor, 51%; ticlopidine, 53%). A minority would perform thoracentesis in patients on direct oral anticoagulants or infused thrombin inhibitors (19% and 12%, respectively). The only subgroup that had a higher proclivity for performing thoracentesis without holding medications were attending physicians practicing for under 10 years. Relative to noninterventional pulmonologists, there were no significant differences in the responses of interventional pulmonologists. There was variation in the practice patterns of attending physicians in performing thoracentesis in patients with elevated bleeding risk. Further data and guidelines regarding the safety of thoracentesis in these patients are needed.


Physician associates and GPs in primary care: a comparison.
Physician associates [PAs] (also known as physician assistants) are new to the NHS and there is little evidence concerning their contribution in general practice. This study aimed to compare outcomes and costs of same-day requested consultations by PAs with those of GPs. An observational study of 2086 patient records presenting at same-day appointments in 12 general practices in England. PA consultations were compared with those of GPs. Primary outcome was re-consultation within 14 days for the same or linked problem. Secondary outcomes were processes of care. There were no significant differences in the rates of re-consultation (rate ratio 1.24, 95% confidence interval [CI] = 0.86 to 1.79, P = 0.25). There were no differences in rates of diagnostic tests ordered (1.08, 95% CI = 0.89 to 1.30, P = 0.44), referrals (0.95, 95% CI = 0.63 to 1.43, P = 0.80), prescriptions issued (1.16, 95% CI = 0.87 to 1.53, P = 0.31), or patient satisfaction (1.00, 95% CI = 0.42 to 2.36, P = 0.99). Records of initial consultations of 79.2% (n = 145) of PAs and 48.3% (n = 99) of GPs were judged appropriate by independent GPs (P<0.001). The adjusted average PA consultation was 5.8 minutes longer than the GP consultation (95% CI = 2.46 to 7.1; P<0.001); cost per consultation was GBP £6.22, (US$ 10.15) lower (95% CI = -7.61 to -2.46, P<0.001). The processes and outcomes of PA and GP consultations for same-day appointment patients are similar at a lower consultation cost. PAs offer a potentially acceptable and efficient addition to the general practice workforce.


Epigenetic profiling of social communication trajectories and co-occurring mental health problems: a prospective, methylome-wide association study.
While previous studies suggest that both genetic and environmental factors play an important role in the development of autism-related traits, little is known about potential biological mechanisms underlying these associations. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined prospective associations between DNA methylation (DNAm: nbirth = 804, nage 7 = 877) and trajectories of social communication deficits at age 8-17 years. Methylomic variation at three loci across the genome (false discovery rate = 0.048) differentiated children following high (n = 80) versus low (n = 724) trajectories of social communication deficits. This differential DNAm was specific to the neonatal period and not observed at 7 years of age. Associations between DNAm and trajectory membership remained robust after controlling for co-occurring mental health problems (i.e., hyperactivity/inattention, conduct problems). The three loci identified at birth were not replicated in the Generation R Study. However, to the best of our knowledge, ALSPAC is the only study to date that is prospective enough to examine DNAm in relation to longitudinal trajectories of social communication deficits from childhood to adolescence. Although the present findings might point to potentially novel sites that differentiate between a high versus low trajectory of social communication deficits, the results should be considered tentative until further replicated.


A lipochito-oligosaccharide, Nod factor, induces transient calcium influx in soybean suspension-cultured cells.
Lipochito-oligosaccharides (Nod factors) produced by Rhizobium or Bradyrhizobium are the key signal molecules for eliciting nodulation in their corresponding host legumes. To elucidate the signal transduction events mediated by Nod factors, we investigated the effects of Nod factors on the cytosolic [Ca2+] of protoplasts prepared from roots and suspension-cultured cells of soybean (Glycine max and G. soja) using a fluorescent Ca2+ indicator, Fura-PE3. NodBj-V (C18:1, MeFuc), which is a major component of Nod factors produced by Bradyrhizobium japonicum, induces transient elevation of cytosolic [Ca2+] in the cells of soybean within a few minutes. This effect is specific to soybean cells and was not observed in the tobacco BY-2 cells. Furthermore, NodBj-V without MeFuc did not induce any cytosolic [Ca2+] elevation in soybean cells. Exclusion of Ca2+ from the medium, as well as pre-treatment of the cells with an external Ca2+ chelator or with a plasma membrane voltage-dependent Ca2+ channel inhibitor, suppressed the Nod factor-dependent cytosolic [Ca2+] elevation. These results indicate that transient Ca2+ influx from extracellular fluid is one of the earliest responses of soybean cells to NodBj-V (C18:1, MeFuc) in a host-specific manner.


Combinatorial Optimization of Sequence-Defined Oligo(ethanamino)amides for Folate Receptor-Targeted pDNA and siRNA Delivery.
Cationic polymers present a versatile platform for the nonviral delivery of therapeutic nucleic acids. In order to achieve effective nucleic acid transfer, polymeric carriers ought to comprise multiple functionalities. Precise chemistries for site-specific placements of the different delivery modules within the carriers present the basis for uncovering structure-activity relationships required for further optimization. Here we present the design and systematic evaluation of a library of 42 sequence-defined oligo(ethanamino)amides generated by solid-phase assisted syntheses. The carriers contained two- or four-arm topologies of different artificial oligoamino acid domains for nucleic acid complexation, terminated by cysteines for disulfide-triggered polyplex stabilization, linked with monodisperse polyethylene glycol (PEG) for surface shielding and terminal folic acid for receptor specific cellular uptake. Additional functional elements included histidines for endosomal escape and/or tyrosine trimers for enhanced hydrophobic polyplex stabilization. In vitro screening of the oligomer library identified a folate-PEG-linked two-arm oligocation structure comprising histidines and tyrosine trimers as the most effective class of carriers for the delivery of pDNA and siRNA.


Prevalence of the Minimally Conscious State Among Institutionalized Patients in the Netherlands: A Nationwide Study.
The minimally conscious state (MCS) is a prolonged disorder of consciousness (pDoC) and one of the most severe outcomes of acquired brain injury. Prevalence data are scarce. The aim of this study was to establish the nationwide point prevalence of institutionalized patients in MCS in the Netherlands. This was a descriptive cross-sectional study in which all 86 Dutch hospitals, all 5 specialized pDoC rehabilitation facilities, and all 274 nursing homes were asked whether they were treating patients with a pDoC on the point prevalence date of September 15, 2021. Each patient's legal representative provided informed consent for their inclusion. Patient level of consciousness was verified using the Coma Recovery Scale-Revised (CRS-R) in a single assessment session performed in the facility of residence by an experienced physician. Data on patient demographics, etiology, level of consciousness, facility of residence, and clinical status were collected from a questionnaire by the treating physician. The prevalence of institutionalized patients in MCS of per 100,000 members of the Dutch population was calculated, based on actual census data. Seventy patients were reported to have a pDoC, of whom 6 were excluded. The level of consciousness was verified for 49 patients while for 15, it could not be verified. Of the patients verified, 38 had a pDoC, of whom 32 were in MCS (mean age 44.8 years, 68.8% male). The prevalence of institutionalized patients in MCS is 0.2-0.3 per 100,000 Dutch inhabitants. Traumatic brain injury was present in 21 of 32 patients (65.6%). Specialized pDoC rehabilitation was received by 17 of 32 patients (53%), with the rest admitted to nursing homes. The most frequent signs of consciousness on the CRS-R were visual pursuit, reproducible movement to command, and automatic motor response. This nationwide study revealed a low prevalence of institutionalized patients in MCS in the Netherlands. These findings are now being used to organize pDoC care in this country.


Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy.
To evaluate the therapeutic value of resection and the potential benefits of and indications for adjuvant and definitive radiation therapy for desmoid tumors. We performed a retrospective review of 189 consecutive cases of desmoid tumor treated with surgical resection, resection and radiation therapy, or radiation therapy alone. Treatment was surgery alone in 122 cases, surgery and radiation therapy in 46, and radiation therapy alone in 21. Median follow-up was 9.4 years. Overall, 5- and 10-year actuarial relapse rates were 30% and 33%, respectively. Uncorrected survival rates were 96%, 92%, and 87% at 5, 10, and 15 years, respectively. For the patients treated with surgery, the actuarial relapse rates were 34% and 38% at 5 and 10 years, respectively. Among 78 patients with negative margins, the 10-year recurrence rate was 27%, whereas 40 margin-positive patients had a 10-year relapse rate of 54% (P = .003). Tumors located in an extremity also had a poorer prognosis than did those in the trunk. For patients treated with radiation therapy for gross disease, the 10-year actuarial relapse rate was 24%. For patients treated with combined resection and radiation therapy, the 10-year actuarial relapse rate was 25%. The addition of radiation therapy offset the adverse impact of positive margins seen in the surgical group. Wide local excision with negative pathologic margins is the treatment of choice for most desmoid tumors. Function-sparing resection is appropriate because adjuvant radiation therapy can offset the adverse impact of positive margins. Unresectable disease should be treated with definitive radiation therapy.


Insulin-like growth factor I levels and the diagnosis of adult growth hormone deficiency.
The current guidelines state that, within the appropriate clinical context, the diagnosis of adult growth hormone (GH) deficiency must be made biochemically using provocative tests. Measurement of insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) levels cannot always distinguish between healthy and GH-deficient individuals. In particular, IGFBP-3 as a marker of GH status is clearly less sensitive than IGF-I and there is general agreement that its measurement does not provide useful diagnostic information. However, the diagnostic value of measuring IGF-I levels has been revisited recently. It has been confirmed that normal IGF-I levels do not rule out severe GH deficiency (GHD) in adults, in whom the diagnosis has therefore to be based on the demonstration of severe impairment of the peak GH response to provocative tests. It has also been emphasized that very low IGF-I levels in patients with high suspicion of GHD could be considered to be definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitary deficiencies acquired in adulthood. In addition, the use of IGF-I levels to monitor the efficacy and adequacy of recombinant human GH replacement remains widely accepted.


A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value.
To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high-resolution single nucleotide polymorphism mapping array analysis in 114 samples alongside 258 samples analyzed by U133 Plus 2.0 expression array (Affymetrix). We examined DNA copy number alterations and loss of heterozygosity (LOH) to define the spectrum of minimally deleted regions in which relevant genes of interest can be found. The most frequent deletions are located at 1p (30%), 6q (33%), 8p (25%), 12p (15%), 13q (59%), 14q (39%), 16q (35%), 17p (7%), 20 (12%), and 22 (18%). In addition, copy number-neutral LOH, or uniparental disomy, was also prevalent on 1q (8%), 16q (9%), and X (20%), and was associated with regions of gain and loss. Based on fluorescence in situ hybridization and expression quartile analysis, genes of prognostic importance were found to be located at 1p (FAF1, CDKN2C), 1q (ANP32E), and 17p (TP53). In addition, we identified common homozygously deleted genes that have functions relevant to myeloma biology. Taken together, these analyses indicate that the crucial pathways in myeloma pathogenesis include the nuclear factor-κB pathway, apoptosis, cell-cycle regulation, Wnt signaling, and histone modifications. This study was registered at http://isrctn.org as ISRCTN68454111.


Changeable Conditional Survival Rates and Associated Prognosticators in Patients with Metastatic Renal Cell Carcinoma Receiving First Line Targeted Therapy.
In this study we evaluated conditional survival probabilities in patients with metastatic renal cell carcinoma who underwent first line tyrosine kinase inhibitor therapy. We also identified predictors of conditional survival with time. We retrospectively reviewed clinical data on 1,659 individuals with metastatic renal cell carcinoma in the Korean Renal Cancer Study Group database, of whom the records of 1,131 were finally analyzed. The primary end point was conditional overall survival. Kaplan-Meier survival analysis was used to calculate conditional overall survival probabilities using the formula, conditional survival (α│β) = S(α + β)/S(β), indicating the likelihood of additional α years survivorship in person who has already survived for β years after initial therapy. S(χ) represents the actual survival rate. Multivariate Cox regression model was used to identify predictors of conditional survival with time. Six, 12, 18, 24 and 36-month conditional overall survival gradually increased in patients at all additional survival times after initial treatment compared to patient baseline survival estimations. While the actual overall survival rate decreased with time, the 36-month conditional overall survival rate was calculated as 7.3% higher in patients who had already survived 36 months compared to baseline estimations at the time of initial tyrosine kinase inhibitor treatment. Furthermore, predictors of conditional overall survival changed with time. Only previous metastasectomy remained a key prognosticator of conditional overall survival until 36 months of survival following initial tyrosine kinase inhibitor treatment. Conditional survival improved with time after initial tyrosine kinase inhibitor treatment in patients with metastatic renal cell carcinoma. Our study offers valuable information for practical survival estimations and relevant prognosticators in patients with metastatic renal cell carcinoma who receive first line tyrosine kinase inhibitor.


Syndrome of the defective lysosome--the genetic mucopolysaccharidoses.
The genetic mucopolysaccharidoses represent the group of disorders recognized in the early 1900's. In half a century, it was recognized that these were disorders of polyanionic macromolecules known as glycosaminoglycans. Within the past five years, these disorders have been identified as prototypes of lysosomal diseases, are a genetically heterogeneous group and this heterogeneity is recognizable in in vitro systems. Finally, these disorders represent prototypes for the development of methods of enzyme replacement therapy.


Effects of hydroxyapatite/Zr and bioglass/Zr coatings on morphology and corrosion behaviour of Rex-734 alloy.
To improve corrosion resistance of metallic implant surfaces, Rex-734 alloy was coated with two different bio-ceramics; single-Hydroxyapatite (HA), double-HA/Zirconia(Zr) and double-Bioglass (BG)/Zr by using sol-gel method. Porous surface morphologies at low crack density were obtained after coating and sintering processes. Corrosion characteristics of coatings were determined by Open circuit potential and Potentiodynamic polarization measurements during corrosion tests. Hardness and adhesion strength of coating layers were measured and their surface morphologies before and after corrosion were characterized by scanning electron microscope (SEM), XRD and EDX. Through the SEM analysis, it was observed that corrosion caused degradation and sphere-like formations appeared with dimples on the coated surfaces. The coated substrates that exhibit high crack density, the corrosion was more effective by disturbing and transmitting through the coating layer, produced CrO3 and Cr3O8 oxide formation. It was found that the addition of Zr provided an increase in adhesion strength and corrosion resistance of the coatings. However, BG/Zr coatings had lower adhesion strength than the HA/Zr coatings, but showed higher corrosion resistance.


Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain.
ATP-sensitive potassium (K-ATP) channels are ubiquitously expressed on the plasma membrane of cells in several organs, including the heart, pancreas, and brain, and they govern a wide range of physiological processes. In pancreatic β-cells, K-ATP channels composed of Kir6.2 and SUR1 play a key role in coupling blood glucose and insulin secretion. A tryptophan residue located at the cytosolic end of the transmembrane helix is highly conserved in eukaryote and prokaryote Kir channels. Any mutation on this amino acid causes a gain of function and neonatal diabetes mellitus. In this study, we have investigated the effect of mutation on this highly conserved residue on a KirBac channel (prokaryotic homolog of mammalian Kir6.2). We provide the crystal structure of the mutant KirBac3.1 W46R (equivalent to W68R in Kir6.2) and its conformational flexibility properties using HDX-MS. In addition, the detailed dynamical view of the mutant during the gating was investigated using the in silico method. Finally, functional assays have been performed. A comparison of important structural determinants for the gating mechanism between the wild type KirBac and the mutant W46R suggests interesting structural and dynamical clues and a mechanism of action of the mutation that leads to the gain of function.


Electrorheological fluids.
Suspensions of polarizable particles in nonpolarizable solvents form fibrillated structures in strong electric fields. The resulting increase in viscosity of these "electrorheological" fluids can couple electrical to hydraulic components in a servomechanism. The physical properties of these fluids are unusual owing to the long-range, anisotropic nature of the interparticle forces. Immediately after the electric field is applied, elongated chains or columns of particles form parallel to the field. This structure then coarsens as a result of thermal forces between the columns. In shear flows, fluids show yielding behavior at low stresses followed by shear-thinning behavior at higher stresses.


Effect of aspoxicillin on anaerobic bacteria.
Aspoxicillin (ASPC), a semisynthetic penicillin has a broad spectrum of antibacterial activities against Gram-positive and Gram-negative anaerobic bacteria. Its in vitro antibacterial activity was less than those of cefoxitin against Peptostreptococcus and Veillonella, but was significantly high against Bacteroides fragilis, one of the most clinically important anaerobe. The therapeutic and/or protective effect of ASPC in experimental subcutaneous abscess or experimental intraabdominal mixed infection due to beta-lactamase producing B. fragilis and non-producing Escherichia coli were much stronger than those of ticarcillin. In order to account the superiority of ASPC in vivo, the effects of ASPC and other beta-lactams on B. fragilis were compared and the results were analyzed in relation to their in vitro bactericidal activities, stability against the beta-lactamase, binding properties with penicillin-binding proteins and pharmacokinetic properties. Interestingly, administration of ASPC did not increase the bacterial counts of Clostridium difficile in caecal contents, but piperacillin, ticalcillin, carbenicillin, ampicillin and cefotaxime increased the counts.


Investigation of antioxidant and rosmarinic acid variation in the sage collection of the genebank in Gatersleben.
The total phenolic and flavonoid contents and 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reduction antioxidant power (FRAP) antioxidant capacities of 19 accessions of Salvia officinalis from the sage collection of the genebank in Gatersleben (Germany) were evaluated. The major phenolic compounds of sage, that is, rosmarinic acid, caffeic acid, carnosol, and carnosic acid, were quantified by reverse-phase high-performance liquid chromatography. The aerial parts of different individual plants of each accession were collected in two consecutive years from the same experimental field at the beginning of their flowering period. The results demonstrated a high variability between accessions. A general decreasing tendency from 2007 to 2008 was observed in most of the estimated parameters, that is, total phenolic, total flavonoid, rosmarinic acid, and caffeic acid contents and DPPH antioxidant activity. A slight opposite trend was obtained with the FRAP antioxidant capacity. Low but variable quantities of carnosol and carnosic acid were evaluated in the sample extracts. Individual plants within accessions were identified with high phenolic content and strong antioxidant activity. The rosmarinic acid content showed up to 8-fold differences between the lowest and the highest values. Overall, the study demonstrated a high variability in secondary metabolites present in sage, which could be used for breeding of highly antioxidative genotypes of S. officinalis.


Comparison of heuristic dynamic programming and dual heuristic programming adaptive critics for neurocontrol of a turbogenerator.
This paper presents the design of an optimal neurocontroller that replaces the conventional automatic voltage regulator (AVR) and the turbine governor for a turbogenerator connected to the power grid. The neurocontroller design uses a novel technique based on the adaptive critic designs (ACDs), specifically on heuristic dynamic programming (HDP) and dual heuristic programming (DHP). Results show that both neurocontrollers are robust, but that DHP outperforms HDP or conventional controllers, especially when the system conditions and configuration change. This paper also shows how to design optimal neurocontrollers for nonlinear systems, such as turbogenerators, without having to do continually online training of the neural networks, thus avoiding risks of instability.


Food allergy: recent advances in pathophysiology and treatment.
Food allergies, defined as an adverse immune response to food proteins, affect as many as 6% of young children and 3%-4% of adults in westernized countries, and their prevalence appears to be rising. In addition to well-recognized acute allergic reactions and anaphylaxis triggered by IgE antibody-mediated immune responses to food proteins, there is an increasing recognition of cell-mediated disorders such as eosinophilic gastroenteropathies and food protein-induced enterocolitis syndrome. We are gaining an increasing understanding of the pathophysiology of food allergic disorders and are beginning to comprehend how these result from a failure to establish or maintain normal oral tolerance. Many food allergens have been characterized at a molecular level, and this knowledge, combined with an increasing appreciation of the nature of humoral and cellular immune responses resulting in allergy or tolerance, is leading to novel therapeutic approaches. Currently, management of food allergies consists of educating the patient to avoid ingesting the responsible allergen and initiating therapy if ingestion occurs. However, numerous strategies for definitive treatment are being studied, including sublingual/oral immunotherapy, injection of anti-IgE antibodies, cytokine/anticytokine therapies, Chinese herbal therapies, and novel immunotherapies utilizing engineered proteins and strategic immunomodulators.


Parent-adolescent congruency in reports of adolescent sexual behavior and in communications about sexual behavior.
Agreement between mothers' and adolescents' reports of communication about sex, satisfaction with the parent-child relationship, maternal disapproval of adolescent sexual activity, and adolescent sexual behavior was investigated in a sample of 745 African American adolescents (ages 14-17) and their mothers. Congruence between the 2 sets of reports tended to be low. Adolescent perceptions and reports were found to be more predictive of adolescent sexual behavior than maternal reports. Mothers tended to underestimate the sexual activity of their teens and teens tended to underestimate their mother's level of disapproval of their engaging in sexual activity. Reasons for these misperceptions were explored.


Porous polystyrene beads as carriers for self-emulsifying system containing loratadine.
The aim of this study was to formulate a self-emulsifying system (SES) containing a lipophilic drug, loratadine, and to explore the potential of preformed porous polystyrene beads (PPB) to act as carriers for such SES. Isotropic SES was formulated, which comprised Captex 200 (63% wt/wt), Cremophore EL (16% wt/wt), Capmul MCM (16% wt/wt), and loratadine (5% wt/wt). SES was evaluated for droplet size, drug content, and in vitro drug release. SES was loaded into preformed and characterized PPB using solvent evaporation method. SES-loaded PPB were evaluated using scanning electron microscopy (SEM) for density, specific surface area (S(BET)), loading efficiency, drug content, and in vitro drug release. After SES loading, specific surface area reduced drastically, indicating filling of PPB micropores with SES. Loading efficiency was least for small size (SS) and comparable for medium size (MS) and large size (LS) PPB fractions. In vitro drug release was rapid in case of SS beads due to the presence of SES near to surface. LS fraction showed inadequate drug release owing to presence of deeper micropores that resisted outward diffusion of entrapped SES. Leaching of SES from micropores was the rate-limiting step for drug release. Geometrical features such as bead size and pore architecture of PPB were found to govern the loading efficiency and in vitro drug release from SES-loaded PPB.


Periodontitis and osteoporosis.
Today's knowledge and studies show a firm correlation between osteoporosis and periodontitis, particularly in postmenopausal women. This review study deals with epidemiological and etiopathogenetic association between chronic periodontitis and an osteoporosis. A special emphasis is put on explanation of possible relations between a premature tooth loss and decrease of length and density of jaw bones, particularly their alveolar prolongations. The second part of the paper deals with principles of treatment in patients suffering of osteoporosis. Osteoporosis reduces density of jaw bones and decreases a number of teeth in jaws, but it does not affect other clinical signs and markers of periodontitis such as inflammation, bleeding and the depth of periodontal pockets and microbial plaque.


Genome scan for determinants of serum uric acid variability.
Elevated serum uric acid level is associated with obesity, insulin resistance, diabetes, nephropathy, and hypertension. Epidemiologic studies suggest that serum uric acid levels are heritable. We sought to identify chromosomal regions harboring quantitative trait loci that influence serum uric acid in Mexican Americans using data from 644 participants in the San Antonio Family Heart Study. Serum uric acid was found to exhibit significant heritability (0.42) in this population (P = 2 x 10(-7)) after accounting for covariate effects. In addition, genetic correlations between serum uric acid and other cardiovascular risk factors, such as body mass index, waist circumference, systolic BP, and pulse pressure, were identified, suggesting that the genes associated with uric acid level are also associated with these phenotypes. Multipoint linkage analysis identified quantitative trait loci with measurable effects on serum uric acid variability. The highest multipoint logarithm of odds score of 3.3 was found at 133 cM on chromosome 6q22-23, a region that also contains genes that seem to influence familial IgA nephropathy, obesity, BP, insulin resistance, and type 2 diabetes. Given the relationship between uric acid level and these conditions, future studies should investigate potential candidate susceptibility genes found in this region.


Biochemical characterization of cells transformed via transfection by feline sarcoma virus proviral DNA.
Murine fibroblasts transformed by transfection with DNA from mink cells infected with the Snyder-Theilen strain of feline sarcoma virus and subgroup B feline leukemia virus were analyzed for the presence of integrated proviral DNA and the expression of feline leukemia virus- and feline sarcoma virus-specific proteins. The transformed murine cells harbored at least one intact feline sarcoma virus provirus, but did not contain feline leukemia virus provirus. The transformed murine cells expressed an 85,000-dalton protein that was precipitated by antisera directed against feline leukemia virus p12, p15, and p30 proteins. No feline oncornavirus-associated cell membrane antigen reactivity was detected on the surfaces of the transformed murine cells by indirect membrane immunofluorescence techniques. The 85,000-dalton feline sarcoma virus-specific protein was also found in feline cells transformed by transfection. However, these cells also contained env gene products. The results of this study demonstrate that the feline sarcoma virus genome is sufficient to transform murine cells and that expression of the 85,000-dalton gag-x protein is associated with transformation of both murine and feline cells transformed by transfection.


Clinical application of probiotics in the treatment of Helicobacter pylori infection--a brief review.
The role of probiotics in the treatment of gastrointestinal infections is increasingly being documented as an alternative or complement to antibiotics, with the potential to decrease the use of antibiotics or reduce their side effects. Although antibiotics-based Helicobacter pylori eradication treatment is 90% effective, it is expensive and causes antibiotic resistance associated with other adverse effects. Probiotics have an in vitro inhibitory effect on H. pylori. Animal studies demonstrated that probiotic treatment is effective in reducing H. pylori-associated gastric inflammation. About 12 human studies investigated the efficacy of combinations of antibiotics and probiotics, whereas 16 studies used probiotic alone as an alternative to antibiotics for the treatment of H. pylori infection. Most of the studies showed an improvement of H. pylori gastritis and decrease in H. pylori colonization after administration of probiotics. However, no study could demonstrate complete eradication of H. pylori infection by probiotic treatment. Probiotic combinations can reduce adverse effects induced by H. pylori eradication treatment and, thus, have beneficial effects in H. pylori-infected individuals. Long-term intakes of products containing probiotic strains may have a favorable effect on H. pylori infection in humans, particularly by reducing the risk of developing disorders associated with high degrees of gastric inflammation.


Methylobacterium sp. 2A Is a Plant Growth-Promoting Rhizobacteria That Has the Potential to Improve Potato Crop Yield Under Adverse Conditions.
A Gram-negative pink-pigmented bacillus (named 2A) was isolated from Solanum tuberosum L. cv. Desirée plants that were strikingly more developed, presented increased root hair density, and higher biomass than other potato lines of the same age. The 16S ribosomal DNA sequence, used for comparative gene sequence analysis, indicated that strain 2A belongs to the genus Methylobacterium. Nucleotide identity between Methylobacterium sp. 2A sequenced genome and the rest of the species that belong to the genus suggested that this species has not been described so far. In vitro, potato plants inoculated with Methylobacterium sp. 2A had a better performance when grown under 50 mM NaCl or when infected with Phytophthora infestans. We inoculated Methylobacterium sp. 2A in Arabidopsis thaliana roots and exposed these plants to salt stress (75 mM NaCl). Methylobacterium sp. 2A-inoculated plants, grown in control or salt stress conditions, displayed a higher density of lateral roots (p < 0.05) compared to noninoculated plants. Moreover, under salt stress, they presented a higher number of leaves and larger rosette diameter. In dual confrontation assays, Methylobacterium sp. 2A displayed biocontrol activity against P. infestans, Botrytis cinerea, and Fusarium graminearum, but not against Rhizoctonia solani, and Pythium dissotocum. In addition, we observed that Methylobacterium sp. 2A diminished the size of necrotic lesions and reduced chlorosis when greenhouse potato plants were infected with P. infestans. Methylobacterium sp. 2A produces indole acetic acid, solubilizes mineral phosphate and is able to grow in a N2 free medium. Whole-genome sequencing revealed metabolic pathways associated with its plant growth promoter capacity. Our results suggest that Methylobacterium sp. 2A is a plant growth-promoting rhizobacteria (PGPR) that can alleviate salt stress, and restricts P. infestans infection in potato plants, emerging as a potential strategy to improve crop management.


A qualitative study examining the impact of multidrug-resistant organism (MDRO) carriage on the daily lives of carriers and parents of carriers with experiences of hospital precautionary measures.
Multidrug-resistant organism (MDRO) carriage may have an adverse impact on the quality of life of carriers, in particular those who have experienced hospital precautionary measures. This study aims to gain a deeper understanding of how MDRO carriage has affected the daily lives of carriers with these experiences. This was a qualitative study based on 15 semi-structured interviews with MDRO carriers or parents of carriers, which were analysed by thematic analysis. Three main themes were identified: (1) Feeling dirty and unworthy portrays the feelings that MDRO carriers often expressed and how these were related to the language usage describing the MDRO, the perceived avoidance by staff and those in their personal networks, and the effects of the precautionary measures implemented in the hospital. (2) MDROs are invisible, but impact is visible covers how the microbe, despite its apparent invisibility, still impacted carriers in their physical and psychological health. MDRO carriage disrupted their lives, by affecting their other unrelated medical conditions at times and by causing varying levels of fear for their own and others' health. (3) Carrying the burden on one's own shoulders describes the lingering questions, uncertainties and confusion that carriers continued to live with and the perceived burden and responsibility that lay on their own shoulders with respect to carrying and preventing the transmission of the MDRO. MDRO carriage can negatively influence the quality of people's lives in various ways. Improved support and sensitivity from health care providers (HCPs) are needed to address feelings of unworthiness among MDRO carriers and the fears that many experience. Clearer information and guidelines are also needed from HCPs to address the many questions and uncertainties that MDRO carriers face outside of the hospital in their daily lives.


Associations between eating frequency, adiposity, diet, and activity in 9-10 year old healthy-weight and centrally obese children.
The rising prevalence of childhood obesity is a key public health issue worldwide. Increased eating frequency (EF) is one aspect of diet that has been beneficially associated with obesity, although the mechanisms are unclear. The aims of the current study were to determine whether increased EF was associated with improved adiposity in children, and if this was due to differences in dietary and activity behaviors. Cross-sectional data from 1,700 children aged 9-10 year were analyzed to examine the associations between EF, as estimated from diet diaries, measures of adiposity, and activity measured by accelerometer. Analyses were stratified by obesity status using waist-to-height ratio to define obesity as it has been shown to be a good predictor of adverse health outcomes. Mean EF was 4.3 occasions/day and after adjustment for underreporting, energy intake (EI), and activity significant relative mean differences of -2.4% for body weight (P = 0.001), -1.0% for BMI (P = 0.020), -33% for BMI z-score (P = 0.014), and -0.6% for waist circumference (P = 0.031) per increase in eating occasion were found in healthy-weight but not centrally obese children. Differences between the extreme quartiles of EF were observed for total fat intake at breakfast (-18%, P < 0.001), fruit and vegetables from snacks (201% healthy-weight and 209% centrally obese children, P < 0.01), and for healthy-weight children, vigorous activity (4%, P = 0.003). Increased EF was favorably associated with adiposity, diet quality, and activity behaviors in healthy-weight but not centrally obese children. Future obesity interventions should consider the mediating role of diet quality and activity in the relationship between EF and adiposity in children.


Top-down strategy in rehabilitation of spatial neglect: how about age effect?
The aim of this work is to verify the effectiveness of our treatment in patients with spatial neglect in relation to their age and to the severity of neglect. Lots of studies on rehabilitation were proposed and, in some of them, treatments based upon visual-scanning abilities were described. Our rehabilitation training is aimed to induce patients to find by themselves an adequate strategy to solve spatial problems and, after that, try to let this searching strategy as automatized as possible. In this study, forty-six patients with right brain damage and left visuo-spatial neglect underwent to this specific cognitive treatment. A neuropsychological battery was administered before and after treatment. Repeated measure MANOVA on test performances showed significant main effects of treatments, age, and severity of neglect; an interaction effect between these three variables was found as well. Our results confirm an effectiveness of treatment, in particular for elderly patients. Actually, they seem to show a better recovery of neglect after cerebral stroke, even for those of them affected by a severe neglect. These data could be explained in accordance with recent neurophysiological models that claim compensatory responses to reduce brain plasticity even in terms of reorganization of cognitive functions such as visuo-spatial attention.


The Curtius rearrangement of cyclopropyl and cyclopropenoyl azides. A combined theoretical and experimental mechanistic study.
A combined experimental and theoretical study addresses the concertedness of the thermal Curtius rearrangement. The kinetics of the Curtius rearrangements of methyl 1-azidocarbonyl cycloprop-2-ene-1-carboxylate and methyl 1-azidocarbonyl cyclopropane-1-carboxylate were studied by (1)H NMR spectroscopy, and there is close agreement between calculated and experimental enthalpies and entropies of activation. Density functional theory (DFT) calculations (B3LYP/6-311+G(d,p)) on these same acyl azides suggest gas phase barriers of 27.8 and 25.1 kcal/mol. By comparison, gas phase activation barriers for the rearrangement of acetyl, pivaloyl, and phenyl azides are 27.6, 27.4, and 30.0 kcal/mol, respectively. The barrier for the concerted Curtius reaction of acetyl azide at the CCSD(T)/6-311+G(d,p) level exhibited a comparable activation energy of 26.3 kcal/mol. Intrinsic reaction coordinate (IRC) analyses suggest that all of the rearrangements occur by a concerted pathway with the concomitant loss of N2. The lower activation energy for the rearrangement of methyl 1-azidocarbonyl cycloprop-2-ene-1-carboxylate relative to methyl 1-azidocarbonyl cyclopropane-1-carboxylate was attributed to a weaker bond between the carbonyl carbon and the three-membered ring in the former compound. Calculations on the rearrangement of cycloprop-2-ene-1-oyl azides do not support pi-stabilization of the transition state by the cyclopropene double bond. A comparison of reaction pathways at the CBS-QB3 level for the Curtius rearrangement versus the loss of N2 to form a nitrene intermediate provides strong evidence that the concerted Curtius rearrangement is the dominant process.


Increase in vaccination coverage between subsequent generations of orthodox Protestants in The Netherlands.
The Netherlands experienced several outbreaks of vaccine preventable diseases, largely confined to an orthodox Protestant minority group. Based on religious arguments some orthodox Protestants accept vaccination, while others refuse. Their acceptance of vaccination, however, seems to be changing over time. We estimated vaccination coverage in subsequent generations of orthodox Protestants and identified determinants of the intention to vaccinate their (future) children. In 2013 orthodox Protestants in the age of 18-40 years were invited to fill out an online questionnaire on their own vaccination status, vaccination status of their parents, the vaccination status or vaccination intention for their (future) children, and possible determinants of the intention to vaccinate (future) children. Vaccination coverage of respondents' parents and respondents was compared using chi-square tests. Logistic regression was used to identify determinants associated with vaccination of (future) children. In total, 981 orthodox Protestant respondents were included in the study. Vaccination coverage among the parents of respondents was 40.1% (95% CI 37.8-42.5%), among respondents 55.3% (95% CI 52.2-58.4%). This means an increase of 15.2% in one generation ( P < 0.001). About 65% of respondents vaccinated or intends to vaccinate their (future) children. Multivariate logistic regression showed that strongest predictors for vaccinating (future) children were low or moderate level of religious conservatism (OR 10.4 [95% CI 5.7-18.9] and 4.6 [95% CI 2.9-7.4], respectively), being vaccinated themselves (OR 6.0 [95% CI 4.3-8.5]) and high educational level (OR 2.5 [95% CI 1.6-4.0]). Vaccination coverage among Dutch orthodox Protestants is increasing over time.


Gut butyrate-producers confer post-infarction cardiac protection.
The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response.


Emotion down-regulation diminishes cognitive control: a neurophysiological investigation.
Traditional models of cognitive control have explained performance monitoring as a "cold" cognitive process, devoid of emotion. In contrast to this dominant view, a growing body of clinical and experimental research indicates that cognitive control and its neural substrates, in particular the error-related negativity (ERN), are moderated by affective and motivational factors, reflecting the aversive experience of response conflict and errors. To add to this growing line of research, here we use the classic emotion regulation paradigm-a manipulation that promotes the cognitive reappraisal of emotion during task performance-to test the extent to which affective variation in the ERN is subject to emotion reappraisal, and also to explore how emotional regulation of the ERN might influence behavioral performance. In a within-subjects design, 41 university students completed 3 identical rounds of a go/no-go task while electroencephalography was recorded. Reappraisal instructions were manipulated so that participants either down-regulated or up-regulated emotional involvement, or completed the task normally, without engaging any reappraisal strategy (control). Results showed attenuated ERN amplitudes when participants down-regulated their emotional experience. In addition, a mediation analysis revealed that the association between reappraisal style and attenuated ERN was mediated by changes in reported emotion ratings. An indirect effects model also revealed that down-regulation predicted sensitivity of error-monitoring processes (difference ERN), which, in turn, predicted poorer task performance. Taken together, these results suggest that the ERN appears to have a strong affective component that is associated with indices of cognitive control and behavioral monitoring.


Metagenomic Analysis Revealing Antibiotic Resistance Genes (ARGs) and Their Genetic Compartments in the Tibetan Environment.
Comprehensive profiles of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) in a minimally impacted environment are essential to understanding the evolution and dissemination of modern antibiotic resistance. Chemical analyses of the samples collected from Tibet demonstrated that the region under investigation was almost devoid of anthropogenic antibiotics. The soils, animal wastes, and sediments were different from each other in terms of bacterial community structures, and in the typical profiles of ARGs and MGEs. Diverse ARGs that encoded resistance to common antibiotics (e.g., beta-lactams, fluoroquinolones, etc.) were found mainly via an efflux mechanism completely distinct from modern antibiotic resistome. In addition, a very small fraction of ARGs in the Tibetan environment were carried by MGEs, indicating the low potential of these ARGs to be transferred among bacteria. In comparison to the ARG profiles in relatively pristine Tibet, contemporary ARGs and MGEs in human-impacted environments have evolved substantially since the broad use of anthropogenic antibiotics.


Hepatitis C virus proteins modulate microRNA expression and chemosensitivity in malignant hepatocytes.
Hepatocellular cancer (HCC) is highly resistant to chemotherapy and is associated with poor prognosis. Chronic hepatitis C virus (HCV) infection is a major cause of HCC. However, the effect of viral proteins in mediating chemosensitivity in tumor cells is unknown. We postulated that HCV viral proteins could modulate therapeutic responses by altering host cell microRNA (miRNA) expression. HepG2 malignant hepatocytes were stably transfected with full-length HCV genome (Hep-394) or an empty vector (Hep-SWX). MiRNA profiling was done by using a custom microarray, and the expression of selected miRNAs was validated by real-time PCR. Protein expression was assessed by Western blotting, whereas caspase activation was assessed by a luminometric assay. The IC(50) to sorafenib was lower in Hep-394 compared with Hep-SWX control cells. Alterations in miRNA expression occurred with 10 miRNAs downregulated >2-fold and 23 miRNAs upregulated >2-fold in Hep-394 cells compared with controls. Of these, miR-193b was overexpressed by 5-fold in Hep-394 cells. miR-193b was predicted to target Mcl-1, an antiapoptotic protein that can modulate the response to sorafenib. The expression of Mcl-1 was decreased, and basal caspase-3/7 activity and poly ADP ribose polymerase cleavage were increased in Hep-394 cells compared with controls. Moreover, transfection with precursors to miR-193b decreased both Mcl-1 expression and the IC(50) to sorafenib. Cellular expression of full-length HCV increases sensitivity to sorafenib by the miRNA-dependent modulation of Mcl-1 and apoptosis. Modulation of miRNA responses may be a useful strategy to enhance response to chemotherapy in HCC.


RISK MANAGEMENT FOR CHIROPRACTORS AND OSTEOPATHS: Neck Manipulation & Vertebrobasilar Stroke.
Although rare, vertebrobasilar stroke is the best known of the possible side effects of cervical manipulation. Due to the serious sequelae that may result from cervical manipulation, chiropractors and osteopaths must take the appropriate steps to ensure the risk is minimised. This article outlines how the astute practitioner can minimise this risk. Practitioners must decide on the options for treatment of a patient with neck problems. Practitioners must also advise the patient of these options as part of an appropriate informed consent.


A different route to functional polyolefins: olefin-carbene copolymerisation.
Copolymerisation of carbenes and olefins (ethene), mediated by Rh-based catalyst precursors, is presented as a new, proof-of-concept methodology for the controlled synthesis of functional polymers. The reactions studied show that olefin-carbene polymerisation reactions provide a viable alternative to more traditional olefin polymerization techniques. Rh(III)-catalyst precursors, while active in the homopolymerisation of either olefins or carbenes, proved to be virtually inactive in olefin-carbene copolymerization. Conversely, the use of Rh(I)(cod) catalyst precursors allows the synthesis of high molecular-weight, highly functionalized copolymers. The reactions yield a mixture of copolymers and some carbene homopolymers, which proved to be difficult to separate. Polyethylene was not formed under the applied reaction conditions. The average ethene content in this mixture could be increased up to 11%, although analysis of the mixture revealed that the ethene content in fractions of the copolymer mixture can be as high as 70%. Attempts to increase the ethene content by increasing the ethene pressure unexpectedly led to lower average ethene contents, which is most likely due to changes in the ratio of copolymers vs. carbene homopolymer. This behaviour is most likely a result of the reactivity difference of different active Rh-species formed under the applied reaction conditions. Apparently, higher ethene concentrations slow down the copolymerisation process (mediated by yet unidentified Rh-species) compared to the formation of homopolymers (mediated by different Rh-catalysts; most likely (allyl)Rh(III)-alkyl species), thereby changing the product ratio in favour of the homopolymer. The average ethene content in the copolymer mixture therefore decreases, while the ethene content within the copolymer fraction has likely increased at higher ethene concentrations (but simply less copolymer is formed). The obtained copolymers exhibit a blocky microstructure, with the functional blocks being highly stereoregular. Branching does occur and the functional groups are present in the polymer backbone as well as at the branches. Formation of copolymers was confirmed by Maldi-ToF analysis, which revealed incorporation of several ethene units into the copolymers.


Plummer-Vinson syndrome in a 15-year-old boy.
Plummer-Vinson syndrome presents as a classical triad of dysphagia, iron deficiency anemia and upper esophageal web(s). The syndrome usually occurs in adults, and is rare in childhood. We report a case of this syndrome occurring in a 15-year-old boy. He presented with dysphagia and anemia. Radiological examination showed the presence of webs at the cervical esophagus. The boy was treated with endoscopic balloon dilation and iron supplementation and remains in good general condition six months after the treatment.


Lipid intermediates in the biosynthesis of the wall teichoic acid in Staphylococcus lactis 13.
1. Particulate enzyme systems have been prepared from Staphylococcus lactis I3 which effect the synthesis of wall teichoic acid (a polymer containing a repeating unit in which d-glycerol 1-phosphate is attached to the 4-position on N-acetylglucosamine 1-phosphate) from the nucleotide precursors CDP-glycerol and UDP-N-acetylglucosamine. By using nucleotides labelled with (32)P and (14)C it has been shown that the synthesis proceeds via lipid intermediates. 2. Two intermediates have been found. In one of these N-acetylglucosamine 1-phosphate is present, whereas in the other the repeating unit of the teichoic acid occurs. 3. The simultaneous formation of the teichoic acid, a poly-(N-acetylglucosamine 1-phosphate) and an unidentified lipid, together with the poor ability of most particulate systems to synthesize polymer and the instability of the lipid intermediates themselves, have interfered with pulse-labelling experiments. Nevertheless, the biosynthetic sequence has been elucidated. It is concluded that the intermediates are derivatives of undecaprenol phosphate.


Enumeration and characterization of iron(III)-reducing microbial communities from acidic subsurface sediments contaminated with uranium(VI).
Iron(III)-reducing bacteria have been demonstrated to rapidly catalyze the reduction and immobilization of uranium(VI) from contaminated subsurface sediments. Thus, these organisms may aid in the development of bioremediation strategies for uranium contamination, which is prevalent in acidic subsurface sediments at U.S. government facilities. Iron(III)-reducing enrichment cultures were initiated from pristine and contaminated (high in uranium, nitrate; low pH) subsurface sediments at pH 7 and pH 4 to 5. Enumeration of Fe(III)-reducing bacteria yielded cell counts of up to 240 cells ml(-1) for the contaminated and background sediments at both pHs with a range of different carbon sources (glycerol, acetate, lactate, and glucose). In enrichments where nitrate contamination was removed from the sediment by washing, MPN counts of Fe(III)-reducing bacteria increased substantially. Sediments of lower pH typically yielded lower counts of Fe(III)-reducing bacteria in lactate- and acetate-amended enrichments, but higher counts were observed when glucose was used as an electron donor in acidic enrichments. Phylogenetic analysis of 16S rRNA gene sequences extracted from the highest positive MPN dilutions revealed that the predominant members of Fe(III)-reducing consortia from background sediments were closely related to members of the Geobacteraceae family, whereas a recently characterized Fe(III) reducer (Anaeromyxobacter sp.) and organisms not previously shown to reduce Fe(III) (Paenibacillus and Brevibacillus spp.) predominated in the Fe(III)-reducing consortia of contaminated sediments. Analysis of enrichment cultures by terminal restriction fragment length polymorphism (T-RFLP) strongly supported the cloning and sequencing results. Dominant members of the Fe(III)-reducing consortia were observed to be stable over several enrichment culture transfers by T-RFLP in conjunction with measurements of Fe(III) reduction activity and carbon substrate utilization. Enrichment cultures from contaminated sites were also shown to rapidly reduce millimolar amounts of U(VI) in comparison to killed controls. With DNA extracted directly from subsurface sediments, quantitative analysis of 16S rRNA gene sequences with MPN-PCR indicated that Geobacteraceae sequences were more abundant in pristine compared to contaminated environments,whereas Anaeromyxobacter sequences were more abundant in contaminated sediments. Thus, results from a combination of cultivation-based and cultivation-independent approaches indicate that the abundance/community composition of Fe(III)-reducing consortia in subsurface sediments is dependent upon geochemical parameters (pH, nitrate concentration) and that microorganisms capable of producing spores (gram positive) or spore-like bodies (Anaeromyxobacter) were representative of acidic subsurface environments.


Achieving appropriate design for developing world heath care: the case of a low-cost autoclave for primary health clinics.
In developing world health clinics, incidence of surgical site infection is 2 to 10 times higher than in developed world hospitals. This paper identifies lack of availability of appropriately designed, low-cost autoclaves in developing world health clinics as a major contributing factor to the dramatic gap in surgical site infection rates. The paper describes the process of developing a low-cost autoclave that addresses the unique challenges faced by developing world primary health clinics and discusses how appropriateness of design was determined. The resulting pressure cooker-based autoclave design was fabricated and tested against the CDC specifications. Twelve partnering clinics in Nepal trialed these autoclaves from July until December 2012.


[Inpatient management of children and adolescents with psychiatric diseases in Germany].
Employing official statistics from the year 1997 the present article analyses in-patient treatment of children and adolescents with psychological disorders in all 16 German Bundeslaender. Sixty per cent of the children and adolescents who are referred to and treated in a German clinic for psychological disorders on the basis of a psychiatric diagnosis are not given professionally adequate treatment. Furthermore, evidence is presented documenting inpatient treatment of children only 0 to 12 months of age in clinics throughout Germany on the basis of psychiatric diagnoses. A new measure is introduced for future planning of inpatient health care for children and adolescents with psychological disorders in Germany.


Utilisation and optimisation of beta-adrenergic receptor blockers over a 6-month period among chronic heart failure patients with reduced ejection fraction.
Beta-adrenergic receptor blocker (BARB) drugs are a wide range of medicines that are used in various conditions, including chronic heart failure (HF). Several studies have reported a wide-ranging inappropriate use of evidence-based beta-blockers (EBBBs) in chronic HF in both inpatients and outpatients. To assess the utilisation and optimisation of EBBBs among patients with HF who presented with a reduced ejection fraction (HFrEF). A hospital-based retrospective cross-sectional study was carried out at the Adult University Teaching Hospital (AUTH), in Lusaka, Zambia, where patient medical files for the period of 1 July 2018 to 31 July 2021 were reviewed. Patient information, including file number, age, sex, type of BARB and the dose used, was recorded on the developed and validated checklist. Multivariable regression analysis was performed to identify factors associated with utilisation of BARBs. Of the 173 medical records reviewed, BARBs were utilised in 101 (58.4%) patients. Among the patients who utilised BARBs, 96 (95.0%) were taking EBBBs, while the rest (n=5, 5.0 %) were taking atenolol, which is a non-EBBB. Among the patients who were on EBBBs, none of them received the optimal dose. Age ≥65 years (adjusted odds ratio (aOR) 0.3, 95% confidence interval (CI) 0.17 - 0.64), previous hospitalisation (aOR 0.3, 95% CI 0.13 - 0.51) and furosemide dose ≥40 mg (aOR 0.4, 95% CI 0.21 - 0.64) were significantly associated with lower likelihood of BARB utilisation. New York Heart Association (NYHA) class II (aOR 3.4, 95% CI 1.08 - 10.7), NYHA class III (aOR 4.8, 95% CI 1.65 - 13.7) and patients using at least 5 medications (aOR 5.0, 95% CI 2.91 - 8.77) were independent predictors of BARB utilisation. This study showed that 95.0% of chronic HF patients were utilising EBBBs, and none received the optimal dose as recommended in the guidelines. Pharmacotherapy with EBBBs should be optimised among patients with chronic HfrEF, as these drugs reduce both morbidity and mortality.


Management of Flavobacterium meningitis in the neonates: experience with 18 consecutive cases.
18 neonates with bacteriologically confirmed Flavobacterium meningitis and ventriculitis were treated with various antibiotic regimens, including the use of intraventricular antibiotics. During the course of treatment, four patients died. 8/14 patients developed progressive hydrocephalus which required insertion of ventriculo-peritoneal shunts. The remainder 6/14 patients had normal ventricles or only mild ventriculomegaly. 5/8 patients with progressive hydrocephalus and 5/6 patients with normal or mildly dilated ventricles were followed up for at least 24 months. 4/5 of the patients with progressive hydrocephalus had severe bilateral hearing loss and delayed milestones. All the 5 patients with normal or mildly dilated ventricles had normal hearing although 2 of them had gross motor delay due to spastic paraplegia. Patients with progressive hydrocephalus received effective antibiotic treatment more than 8 days after the onset of infection while those with normal or mildly dilated ventricles within 8 days of infection. Onset of ventricular dilatation was associated with ventriculitis. Daily ultrasound scanning of the ventricles in the early stage helped to determine the need for early instillation of intraventricular antibiotics. Combined use of intravenous rifampicin, moxalactam and piperacillin showed promise as an effective antibiotic regimen in treating patients with normal or mildly dilated ventricles. Once significant ventriculomegaly has occurred, concomitant intravenous and intraventricular administration of antibiotics, to which the organisms were sensitive, was necessary to eradicate the infection.


VCAM-1 activation of endothelial cell protein tyrosine phosphatase 1B.
Lymphocytes migrate from the blood into tissue by binding to and migrating across endothelial cells. One of the endothelial cell adhesion molecules that mediate lymphocyte binding is VCAM-1. We have reported that binding to VCAM-1 activates endothelial cell NADPH oxidase for the generation of reactive oxygen species (ROS). The ROS oxidize and stimulate an increase in protein kinase C (PKC)alpha activity. Furthermore, these signals are required for VCAM-1-dependent lymphocyte migration. In this report, we identify a role for protein tyrosine phosphatase 1B (PTP1B) in the VCAM-1 signaling pathway. In primary cultures of endothelial cells and endothelial cell lines, Ab cross-linking of VCAM-1 stimulated an increase in serine phosphorylation of PTP1B, the active form of PTP1B. Ab cross-linking of VCAM-1 also increased activity of PTP1B. This activation of PTP1B was downstream of NADPH oxidase and PKCalpha in the VCAM-1 signaling pathway as determined with pharmacological inhibitors and antisense approaches. In addition, during VCAM-1 signaling, ROS did not oxidize endothelial cell PTP1B. Instead PTP1B was activated by serine phosphorylation. Importantly, inhibition of PTP1B activity blocked VCAM-1-dependent lymphocyte migration across endothelial cells. In summary, VCAM-1 activates endothelial cell NADPH oxidase to generate ROS, resulting in oxidative activation of PKCalpha and then serine phosphorylation of PTP1B. This PTP1B activity is necessary for VCAM-1-dependent transendothelial lymphocyte migration. These data show, for the first time, a function for PTP1B in VCAM-1-dependent lymphocyte migration.