Relationship between midweek training measures of testosterone and cortisol concentrations and game outcome in professional rugby union matches.
The aim of this study was to assess the response of salivary-free testosterone and cortisol concentrations across selected midweek skill-based training sessions and their association with subsequent match outcome 3 days later. Twenty-two rugby union players were assessed for salivary-free testosterone and cortisol concentrations before and after a midweek training session over 6 consecutive weeks. The relative percentage change (response) in the testosterone and cortisol concentration and the testosterone to cortisol (T/C) ratio was also determined. Game-day analysis consisted of prematch testosterone concentrations and match outcome. Data were pooled across the winning (n = 3) and losing (n = 3) outcomes. The midweek pretraining T/C ratio was significantly lower (p < 0.01) before a win than a loss and the increase in the pre- to post-T/C ratio before a win was significant (p < 0.001). The increase in the pre- to post-testosterone concentration before a win was also shown to be significant (p < 0.01). However, the relative changes in testosterone before games that were won were not statistically different to that of games lost (p > 0.01). Significant relationships were also demonstrated between game-day pre-testosterone concentrations and the midweek cortisol response (r = -0.90, p = 0.01) and midweek T/C ratio response (r = 0.90, p = 0.01). In conclusion, a midweek measurement of the T/C ratio against a skill-based training session seems to show some potential as an early indicator of subsequent successfully executed performances in competitive rugby union. If this work is subsequently validated, further monitoring of midweek hormone concentrations in response to a mixed psychological-physical training session may assist with assessing competitive readiness leading up to competition.


Intravitreal ranibizumab for subfoveal choroidal neovascularization from age-related macular degeneration with combined severe diabetic retinopathy.
To evaluate the efficacy of intravitreal ranibizumab for subfoveal choroidal neovascularization (CNV) from age-related macular degeneration (AMD) with combined severe diabetic retinopathy (DR). This retrospective, interventional case series included eleven patients (mean age, 70.09 years; range, 54 to 83 years) with at least severe non-proliferative DR and subfoveal CNV secondary to AMD. Each subject was treated with intravitreal injections of 0.5 mg ranibizumab. The primary outcomes included change in best-corrected visual acuity and central subfield thickness (CST) on optical coherence tomography (OCT). The mean follow-up time was 16.7±14 months (range, 6 to 31 months). Mean visual acuity improved from 1.21±0.80 logarithm of the minimum angle of resolution (logMAR) to 1.0±0.6 logMAR (P=0.107), 0.95±0.62 logMAR (P=0.044), 1.10±0.68 logMAR (P=0.296), and 1.13±0.66 logMAR (P=0.838) at 1, 3, 6, and 12 months after injection, respectively. Eight patients (72.7%) gained or maintained vision (mean 0.32 logMAR), whereas three patients (27.3%) lost more than one line of vision (mean 0.51 logMAR). The mean OCT CST was 343.9±134.6 µm at baseline, and the mean CST at 1, 3, 6, 12 months after the injection was 367.8±172.1 (P=0.864), 346.2±246.2 (P=0.857), 342±194.1 (P=0.551), and 294.2±108.3 µm (P=0.621), respectively. Intravitreal ranibizumab injection can be considered to be a therapy for the stabilization of subfoveal CNV secondary to AMD with combined severe DR. However, these patients might exhibit limited visual improvement after treatment.


Ciclesonide and the treatment of asthma.
Asthma is a chronic disease characterized by airway inflammation and hyper-responsiveness. Inhaled corticosteroids (ICSs) constitute the guideline-recommended first-line therapy for persistent asthma. However, concerns regarding ICS-related adverse events may contribute to their underutilization by physicians and patients. The currently available published data on the pharmacokinetic and pharmacodynamic properties, safety and efficacy of the ICS, ciclesonide, is described. Peer-reviewed publications (1996 - 2009) on the pharmacodynamic and pharmacokinetic profile, safety and efficacy of ciclesonide were reviewed. Ciclesonide is delivered as an inactive prodrug, which is cleaved to the active molecule by intracellular esterases located in the lungs. This and other pharmacodynamic and pharmacokinetic properties may limit the amount of active molecule outside the lung and may reduce the incidence of side effects. Randomized placebo-controlled studies found that ciclesonide can initiate and maintain disease control in subjects with persistent asthma of all disease severities. Moreover, studies have found that ciclesonide is as effective as other ICSs in establishing and controlling disease symptoms. Controlled clinical trials also showed that ciclesonide is associated with minimal systemic and local treatment-related adverse events. Published findings indicate that ciclesonide is effective at initiating and maintaining asthma control and is well tolerated, with a positive safety profile.


Biological therapy in IBD. Anti-tumor necrosis factor-alpha and others.
Currently used standard treatment in IBD is effective and sufficient for the majority of patients. Published numbers regarding therapy refractoriness are probably related to referral centers and not representative. Pharmacological optimization of available drugs improves the standard situation further. Biological therapies in a larger meaning are studied intensively, but obviously hopes are to some extent not real. Biological and for some principles clinical effects (i.e. TNF antibodies, CD4 antibodies) are proven, the effects are, however, limited and long-term risks and results are not clarified. Numerous approaches are not clinically relevantly effective which is, in particular, true for those inhibiting single mediators. A number of alternative concepts such as hormones and growth factors could be effective and will be studied further. In particular probiotics may be a development of the future and they belong to the 'biologic treatments' in the true sense.


Existence of an orientational electric dipolar response in c60 single crystals.
The dielectric constant in and conductivity sigma of undoped C(60) single crystals have been measured as a function of temperature, 10 K < T < 330 K, and frequency, 0.2 kilohertz < f < 100 kilohertz. On cooling below the first-order structural phase transition at 260 K, a Debye-like relaxational contribution to the dielectric response is observed, which requires the presence of permanent electric dipoles. The relaxation rate is thermally activated with a broad distribution of energies centered at 270 millielectron volts. The existence of a dipole moment in C(60) is unexpected, because it is precluded by symmetry for the pure ordered cubic phase. These data suggest that the high degree of frozen-in orientational disorder of the C(60) molecules is responsible for the existence of electric dipolar activity.


Single-stage, multimodality treatment of soft-tissue sarcoma of the extremity.
The present study describes the techniques available for single-stage sarcoma resection, soft-tissue reconstruction, and radiotherapy for limb preservation in patients who are unable to undergo primary wound closure after a complete soft-tissue resection of their primary sarcoma. From 1989 to 1994, 19 patients (age range, 18-79 years; mean, 51.2 years) underwent radical resection of extremity sarcomas followed by immediate reconstruction. Seven patients had tumors in the upper extremity and 12 patients had tumors in the lower extremity. There were 13 primary tumors and 6 recurrent tumors. Fifteen patients (79%) received radiation therapy, 7 patients by external beam and 8 patients by brachytherapy. Reconstruction included 16 regional flaps in 13 patients and 7 free tissue transfers in 6 patients. Commonly used flaps included the rectus abdominis (N = 5), the latissimus dorsi (N = 4), the anterolateral thigh (N = 4), the reverse-flow radial forearm (N = 2), and the gastrocnemius (N = 2) flaps. Complications included wound breakdown (N = 2), partial skin graft failure (N = 1), hematoma requiring operative evacuation (N = 1), and partial flap necrosis (N = 1). There were no operative mortalities. Eight patients underwent wide local excision, flap closure, and brachytherapy. Mean length of hospital stay for this group was 12.3 days compared with 13.8 days for the remaining 11 patients. There was one complication (13%) in this group and four complications in the remaining patients (4 of 11; 36%). Our study confirms the utility of soft-tissue reconstruction to permit wide local excision with clear margins as well as the delivery of postoperative radiotherapy. It demonstrates the ability of pedicled flaps and free tissue transfers to remain viable and provide sufficient wound coverage in the setting of early postoperative brachytherapy. In addition, this series illustrates the efficacy of a team approach and one-stage therapy for extremity soft-tissue sarcomas that includes excision, reconstruction, and early postoperative brachytherapy in a single hospitalization.


Time-resolved multirotational dynamics of single solution-phase tau proteins reveals details of conformational variation.
Intrinsically disordered proteins (IDPs) are crucial to many cellular processes and have been linked to neurodegenerative diseases. Single molecules of tau, an IDP associated with Alzheimer's disease, are trapped in solution using a microfluidic device, and a time-resolved fluorescence anisotropy decay is recorded for each molecule. Multiple rotational components are resolved and a novel k-means algorithm is used to sort the molecules into two families of conformations. Differences in rotational dynamics suggest a change in the rigidity and steric hindrance surrounding a sequence (306VQIVYK311) which is central to paired helical filament formation. This single-molecule approach can be applied to other IDPs to resolve heterogeneous populations and underlying differences in conformational dynamics.


Visible light photoelectrochemical sensor based on Au nanoparticles and molecularly imprinted poly(o-phenylenediamine)-modified TiO2 nanotubes for specific and sensitive detection chlorpyrifos.
A molecular imprinted polymer thin film for photoelectrochemical (PEC) sensing of chlorpyrifos molecules was first constructed by electropolymerizing the o-phenylenediamine (o-PD) monomer and chlorpyrifos template molecule on gold nanoparticles-modified titanium dioxide nanotubes. The resulting PEC sensors were characterized by scanning electron microscopy, ultraviolet (UV)-vis spectra and electrochemical impedance spectra. Clearly, the imprinted film showed high selectivity to chlorpyrifos in our case. Under visible light irradiation, poly(o-phenylenediamine) (PoPD) can generate the photoelectric transition from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO), delivering the excited electrons to the AuNPs, and then to the conduction band (CB) of the titanium dioxide nanotubes (TiO(2) NTs). Simultaneously, it is believed that a positively charged hole (h(+)) of PoPD that took part in the oxidation process was consumed to promote the amplification of photocurrent response. Under the optimal experimental conditions, the photocurrents were proportional to the concentrations of chlorpyrifos ranging from 0.05 to 10 μmol L(-1) with the detection limit of 0.96 nmol L(-1). The PEC sensor had an excellent specificity and could be successfully applied to the detection of reduced chlorpyrifos in green vegetables, indicating a promising application in PEC sensing.


Revealing Molecular Determinants of hERG Blocker and Activator Binding.
The Kv11.1 potassium channel, encoded by the human ether-a-go-go-related gene (hERG), plays an essential role in the cardiac action potential. hERG blockade by small molecules can induce "torsade de pointes" arrhythmias and sudden death; as such, it is an important off-target to avoid during drug discovery. Recently, a cryo-EM structure of the open channel state of hERG was reported, opening the door to in silico docking analyses and interpretation of hERG structure-activity relationships, with a view to avoiding blocking activity. Despite this, docking directly to this cryo-EM structure has been reported to yield binding modes that are unable to explain known mutagenesis data. In this work, we use molecular dynamics simulations to sample a range of channel conformations and run ensemble docking campaigns at the known hERG binding site below the selectivity filter, composed of the central cavity and the four deep hydrophobic pockets. We identify a hERG conformational state allowing discrimination of blockers vs nonblockers from docking; furthermore, the binding pocket agrees with mutagenesis data, and blocker binding modes fit the hERG blocker pharmacophore. We then use the same protocol to identify a binding pocket in the hERG channel pore for hERG activators, again agreeing with the reported mutagenesis. Our approach may be useful in drug discovery campaigns to prioritize candidate compounds based on hERG liability via virtual docking screens.


T cell-associated CD18 but not CD62L, ICAM-1, or PSGL-1 is required for the induction of chronic colitis.
The induction and perpetuation of chronic colitis are thought to involve a complex set of adhesive interactions between T cells and endothelial cells located on the vasculature within secondary lymphoid tissue and the intestine. The objective of this study was to assess the roles of T cell-associated CD18, CD62L (L-selectin), ICAM-1, and P-selectin glycoprotein ligand-1 (PSGL-1) in the induction of chronic colitis in mice. CD4(+)CD25(-) T cells derived from either wild-type (WT), CD18-deficient [CD18 knockout (KO)], CD62L KO, ICAM-1 KO, or PSGL-1 KO mice were adoptively transferred into recombinase activating gene-1 (RAG-1)-deficient mice (RAG KO mice) to assess the potential of these T cells to induce chronic colitis. At 8-10 wk following T cell transfer, we observed moderate to severe colitis as assessed by increases in colon weight-to-length ratios and by blinded histopathological analysis. In contrast, we found that transfer of CD18 KO T cells into RAG KO recipients resulted in the significant attenuation of colonic inflammation in these mice. Furthermore, we observed fewer infiltrating CD4(+) T cells in the colonic lamina propria in the CD18 KO-->RAG KO group compared with the WT-->RAG KO group. Finally, message levels of colonic TNF-alpha, IL-1beta, and IFN-gamma were significantly reduced in CD18 KO-->RAG KO mice compared with colitic control animals. We conclude that T cell-associated CD18, but not CD62L, ICAM-1, or PSGL-1, is required for the development of chronic colitis.


Progressive multifocal leukoencephalopathy secondary to idiopathic CD4 lymphocytopenia treated with pembrolizumab.
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by John Cunningham polyoma virus (JCV) infection. Idiopathic CD4+ T-cell lymphocytopenia (ICL) is a very rare cause of PML. We present an individual with PML secondary to ICL treated with 3 doses of pembrolizumab, a Programmed-Death-1 Immune Checkpoint Inhibitor following with complete resolution of symptoms and conduct a review of the literature. This report illustrates the objective clinical and radiological improvement in a patient with PML due to ICL and suggests further study of immune checkpoint inhibitors as potential treatment for patients with PML.


Myeloperoxidase modulates the phagocytic activity of polymorphonuclear neutrophil leukocytes. Studies with cells from a myeloperoxidase-deficient patient.
Patients lacking the primary granulae enzyme, myeloperoxidase (MPO), do not usually show any increased susceptibility to infection or altered inflammatory response, in contrast to several other biochemical defects in polymorphonuclear neutrophils. We have now evaluated the role of MPO on phagocyte function in a patient with complete MPO deficiency suffering from generalized pustular psoriasis. We found that the MPO-deficient neutrophils showed enhanced phagocytosis (greater than 200% of normal) of IgG- and C3b-opsonized yeast particles and prolonged N-formylmethionyl-leucyl-phenylaline-mediated stimulation of superoxide production. When purified human MPO was added to normal neutrophils during cell adhesion, their Fc- and C3b-mediated phagocytosis was reduced without affecting cell viability. 1 microgram/ml of MPO reduced the Fc and C3b phagocytosis to 47 and 65%, respectively, whereas 10 micrograms/ml reduced the activity to 20 and 54%. Both attachment and ingestion were reduced to a similar extent, indicating that MPO affected the receptor function per se. When MPO was added to the hyperactive MPO-deficient cells, phagocytosis was reduced more rapidly. Catalase, azide, and methionine eliminated the inhibitory effect, and catalase and methionine, in fact, enhanced the phagocytic activity of adherent neutrophils. These data indicate that, apart from being a potent antimicrobial system, the oxidizing activity of the MPO-H2O2-halide system may modulate the inflammatory response by impairing certain receptor-mediated recognition mechanisms of phagocytic cells, which otherwise could elicit inflammatory reactions and tissue injury.


In situ Hearing Tests for the Purpose of a Self-Fit Hearing Aid.
This study investigated the potential and limitations of a self-fit hearing aid. This can be used in the "developing" world or in countries with large distances between the hearing-impaired subjects and the professional. It contains an on-board tone generator for in situ user-controlled, automated audiometry, and other tests for hearing aid fitting. Twenty subjects with mild hearing losses were involved. In situ audiometry showed a test-retest reliability (SD <3.7 dB) that compared well with the precision of diagnostic audiometry using headphones. There was good correspondence (SD <5.2 dB) with traditional pure-tone audiometry. In situ loudness scaling yielded important information about suprathreshold perception, which will have an added value for the selection of compression and the selection of maximum power output to be allowed in hearing aids.


Raloxifene and estradiol benzoate both fully restore hippocampal choline acetyltransferase activity in ovariectomized rats.
Selective estrogen receptor modulators (SERMs) demonstrate tissue-specific estrogen receptor (ER) agonist or antagonist properties. Raloxifene, a prototypical SERM, has ER agonist properties in bone and on cholesterol metabolism but full antagonist properties in the uterus and breast. To characterize the ER agonist/antagonist profile of raloxifene in the brain, we have examined its effect on the activity of a known estrogen-responsive gene product, choline acetyltransferase (ChAT), in the hippocampus and other brain regions of 6-month-old ovariectomized (OVX) Sprague-Dawley rats. Three weeks post-ovariectomy, animals received estradiol benzoate (EB, 0.03 mg or 0.3 mg kg(-1) day(-1) for 3 or 10 days); raloxifene HCl (3.0 mg kg(-1) day(-1) for 3 or 10 days), tamoxifen (3.0 mg kg(-1) day(-1) for 10 days) or vehicle (20% CDX). As previously reported, ChAT activity decreased by approximately 20%-50% in the hippocampus of OVX compared with SHAM-operated control rats with no change in ChAT activity observed in the hypothalamus. Raloxifene or EB reversed the OVX-induced decrease in ChAT activity in the hippocampus but did not change ChAT activity in the hypothalamus. Animals that received combined EB (0.03 mg/kg) plus raloxifene (1 mg/kg) or tamoxifen alone (3.0 or 10 mg/kg) also showed increased hippocampal ChAT activity. Raloxifene failed to increase uterine weight and blocked the estrogen-induced increase in uterine weight, while another SERM, tamoxifen, increased uterine weight. These data demonstrate that raloxifene has estrogen-like properties on hippocampal ChAT activity in vivo, and suggest that benzothiophene SERMs may exert estrogen-like beneficial effects on cholinergic neurotransmission in brain without producing peripheral stimulation of breast or uterine tissue.


Similar survival outcome after endoscopic and open approaches for sinonasal mucosal melanoma.
To describe a cohort of sinonasal mucosal melanoma (SNMM) patients, and to assess if choice of surgical approach (open versus endoscopic) has impact on survival. Adequate data on clinical presentation, treatment, and recurrence pattern were available for 58 consecutive patients treated for SNMM at the Helsinki University Hospital (HUH) between 1983 and 2016. The 5-year disease-specific survival (DSS) was 27% and overall survival 25% for the whole cohort. The 3-year DSS for patients treated with curative intent with endoscopic surgery was comparable to open surgery (56% and 51%, respectively). Patients with tumours arising from the paranasal sinuses and patients with Stage IV disease had significantly worse prognosis compared with other locations and Stage III patients. All patients who had disease persistence at three months after primary treatment succumbed to SNMM. Post-operative radiotherapy did not affect survival significantly, but a trend towards improved local control was observed. Local control after endoscopic surgery was comparable to open surgery. Small tumours without local or locoregional spread had improved prognosis, independent of surgical approach. Disease persistence after treatment with curative intent led to death invariably.


Adaptation of the Modified Mini-Mental State Examination (3MS) and Determination of Its Normative Values in Turkey.
This study aimed to adapt the Modified Mini-Mental State Examination (3MS) and determine its normative values in Turkey. After translation and cultural adaptation processes, a population-based study was conducted between February and June 2016 in Ankara with individuals over the age of 55 years. Subjects with a previous diagnosis of dementia along with neuropsychiatric disorders that might affect cognition were excluded. Data analyses were performed to assess the association of sociodemographic variables with 3MS scores. Two versions of the Turkish 3MS (for educated and minimally educated individuals) were developed. A total of 2,235 participants were included in the field study. After exclusion, the data on the final sample of 1,909 individuals were analyzed, where age, gender, and education accounted for variance in 3MS scores. Younger age and higher educational attainment were associated with better 3MS performance. A widely applicable dementia screening test was adapted to Turkish and its normative values were determined. The test will make it possible to evaluate the cognitive performance of both educated and minimally educated elderly individuals based on their age, gender, and educational level.


Real-world Impact of 3 and 4.5 mg Doses of Dulaglutide on Weight and Hemoglobin A1c in Patients With Type 2 Diabetes Mellitus.
Limited real-world data on the benefits and risks associated with 3 and 4.5 mg doses of dulaglutide currently exists, making it difficult to determine the impact of dose titration for patients currently managed with dulaglutide 1.5 mg weekly. To determine the impact of dulaglutide 3 and 4.5 mg doses on weight and hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM), in clinical practice. Retrospective, observational study of adult T2DM patients receiving dulaglutide 3 or 4.5 mg weekly within a large, university-affiliated, primary care network. The primary outcome was change in weight and HbA1c from baseline to 24 weeks. Secondary outcomes included incremental changes in weight and HbA1c, and describing trends related to dose reductions. Ninety-five patients were included, 62 in the dulaglutide 3 mg group and 33 in the dulaglutide 4.5 mg group. After 24 weeks, the mean changes in weight and HbA1c from baseline were -1.8 kg (P < 0.01) and -0.4% (P < 0.01) in the 3 mg group, and -4.2 kg (P < 0.01) and -0.4% (P = 0.119) in the 4.5 mg group. Incremental change in weight and HbA1c among patients who were titrated from dulaglutide 3 to 4.5 mg weekly were -2.6 kg (P < 0.01) and -0.2% (P = 0.04), respectively. Titration from dulaglutide 1.5 to 3 mg resulted in significant reductions in weight and HbA1c after 24 weeks. Additional, statistically significant, reductions in weight and HbA1c were seen when patients were further titrated to dulaglutide 4.5 mg weekly.


Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury.
Lung injury is associated with increased concentrations of hyaluronan (hyaluronic acid, HA). HA modifies cell behavior through interaction with cell-associated receptors such as receptor for HA-mediated motility (RHAMM, CD168). Using a function blocking anti-RHAMM antibody (R36), we investigated the expression and role of RHAMM in the inflammatory response to intratracheal bleomycin in rats. Immunostaining showed increased expression of RHAMM in macrophages 4-7 d after injury. Surface biotin labeling of cells isolated by lavage confirmed increased surface expression of a 70-kD RHAMM after lung injury, and in situ hybridization demonstrated increased RHAMM mRNA in macrophages responding to injury. Time-lapse cinemicrography demonstrated a 5-fold increase in motility of alveolar macrophages from bleomycin-treated animals that was completely blocked by R36 in vitro. Further, HA-stimulated macrophage chemotaxis was also inhibited by R36. Daily administration of R36 to injured animals resulted in a 40% decrease in macrophage accumulation 7 d after injury. Further, H&E staining of tissue sections showed that bleomycin-mediated changes in lung architecture were improved with R36 treatment. Taken together with previous results showing the inhibitory effects of HA-binding peptide on inflammation and fibrosis, we conclude that the interaction of RHAMM with HA is a critical component of the recruitment of inflammatory cells to the lung after injury.


A research review: involving the African American family in anti-hypertensive medication management.
Research about the role of the family in helping hypertensive individuals manage hypertension using medications is limited. The African American family should be included in whatever future hypertension management research takes place. This review focuses on research conducted using adults and minors as study participants. Theoretical issues about the use of anti-hypertensive medications among hypertensive individuals are presented. Definitions about adherence are critiqued, and future research directions are explored.


Suanzaoren decoction improves depressive-like behaviors by regulating the microbiota-gut-brain axis via inhibiting TLR4/NFκB/NLRP3 inflammation signal pathway.
Depression is a common but serious sickness which causes a considerable burden on individuals and society. Recently, it has been well established that the occurrence of depression was related to the microbiota-gut-brain axis. The toll-like receptor 4 (TLR4)/ nuclear factor kappa-B kinase (NFκB)/ NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway is closely associated with the regulation of microbiota-gut-brain axis. Suanzaoren Decoction (SZRD), which recorded in Jin Gui Yao Lve in Han dynasty, has been used for treating insomnia and depression for a long time. However, the action mechanism of the depression regulation through the TLR4/NFκB/NLRP3 pathway by SZRD was still unclear. In this study, SZRD was firstly performed on a chronic unpredictable mild stress (CUMS) mice model. The results of behavioral tests showed that SZRD treatment could ameliorate the depressive-like behaviors of CUMS mice effectively. According to our previous researches about the components of SZRD in vitro and in vivo, the identification of serum metabolites in depression model rats was further analyzed qualitatively using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. 27 prototypes and 44 metabolites were identified. The main types of metabolic reactions are glucuronization, sulfation, and so on. Then, using immunohistochemistry and western blotting to monitor the difference in activation of TLR4/NFκB/NLRP3 signaling pathway in mice brain and colon. The results showed that SZRD treatment could reduce expression levels of related factors. Additionally, the SZRD treatment could also inhibit the histopathological damage in the path morphology of the hippocampus and colon. The results of 16SrRNA demonstrated that SZRD could reduce the dysbiosis of the intestinal flora of depressive mice. The above results provided important information for studying the action mechanism of SZRD in treating depression by regulating microbiota-gut-brain axis via inhibiting TLR4/NFκB/NLRP3 pathway.


Posttraumatic stress disorder symptoms and attitudes about social support: Does shame matter?
Considerable research has examined the association between posttraumatic stress disorder (PTSD) symptoms and social support. One facet of this relationship that deserves greater attention concerns trauma survivors' negative expectations towards social support, termed negative network orientation. To expand our understanding of negative network orientation, the current study examined shame as a possible mediator in the relationship between PTSD symptoms and negative network orientation, in a sample of 202 female survivors of intimate partner violence (IPV). Additionally, a history of child abuse (CA) was evaluated as a moderator of the association between shame and negative network orientation in this model. Path analyses indicated a significant indirect effect between PTSD symptoms and negative network orientation through shame, indicative of mediation. A history of CA moderated this effect, such that women with a history of CA in addition to IPV showed a significantly stronger relationship between PTSD symptoms and negative network orientation through shame, relative to women who only had a history of IPV. These findings support the relevance of shame in understanding the association between PTSD symptoms and negative beliefs about social support and highlight the role of childhood abuse as a moderator in this process among IPV survivors.


Safety data of injectable nonanimal stabilized hyaluronic acid gel for soft tissue augmentation.
Nonanimal hyaluronic acid gel was recently developed for soft tissue augmentation and volume expansion and has been shown to offer several advantages in comparison to other augmentation materials. There are rare reports of adverse events believed to be secondary to trace amounts of proteins in the hyaluronic acid raw material. To determine the safety profile of nonanimal stabilized hyaluronic acid gel (Restylane, Perlane, Restylane Fine Lines, Q-Med AB, Uppsala, Sweden) for soft tissue augmentation using a retrospective review of all adverse events data from Europe, Canada, Australia, South American, and Asia from 1999 and 2000. Data from an estimated 144,000 patients treated in 1999 indicated the major reaction to injectable hyaluronic acid was localized hypersensitivity reactions, occurring in approximately 1 of every 1400 patients treated. In 1999 there was an adverse event reported for 1 of every 650 patients (0.15%) treated. These were temporary events that included redness, swelling, localized granulomatous reactions, bacterial infection, as well as acneiform and cystic lesions. For 2000 there was an estimated 262,000 patients treated with hyaluronic acid gel. The total number of adverse events was 144, corresponding to one adverse event for every 1800 patients (0.06%) treated. The major adverse event was again hypersensitivity, occurring in 1 of every 5000 patients treated. According to the reported worldwide adverse events data, hypersensitivity to nonanimal hyaluronic acid gel is the major adverse event and is most likely secondary to impurities of bacterial fermentation. According to data from 2000, the incidence of hypersensitivity appears to be declining after the introduction of a more purified hyaluronic acid raw material.


Molecular cloning of the human gastrin gene.
A genomic clone that contains the human gastrin gene was isolated from a human gene library. Restriction endonuclease mapping and DNA sequencing analysis revealed that this gene is about 0.7 kb long, and has an intron. The intron is located at a position that separates the coding region into the peptide region essential for biological activities of gastrin and the non-essential, N-terminal peptide region.


Generalizability of clinical trial results for major depression to community samples: results from the National Epidemiologic Survey on Alcohol and Related Conditions.
Although emerging data indicate that sample composition may influence the effectiveness of mental health interventions, the extent to which subjects in clinical trials represent affected community samples remains unknown. The goal of this study was to assess the proportion of community-dwelling adults with major depressive episode (MDE) who would meet eligibility criteria for a traditional efficacy trial in patients with MDE. We applied a standard set of exclusion criteria used in clinical trials in patients with MDE to the 2001-2002 National Epidemiologic Survey for Alcohol and Related Conditions (NESARC), the largest psychiatric epidemiologic study in the United States to date (N = 43,093). Because individuals who seek treatment for a disorder may systematically differ from those who do not, we applied the criteria first to all individuals with a current diagnosis of MDE (N = 3119) (diagnosed according to DSM-IV) and then to the subsample of individuals who sought treatment (N = 1359). Among the full sample of individuals with MDE, 75.8% were excluded by one or more study eligibility criteria. Approximately two thirds (66.9%) of the subsample of those who sought treatment were excluded. The percentage of subjects excluded by individual study criteria ranged from 2.4% to 47.4% in the overall sample and 0% to 38.4% in the treatment-seeking sample. For both groups, the presence of comorbid, nondepressive, non-substance use Axis I disorders and the duration of the depressive episode excluded the largest percentage of individuals. The design of traditional clinical trials tends to exclude a majority of individuals with MDE. Selection of exclusion criteria may have a powerful influence on the generalizability of study results. Clinical trials should explain the rationale for their exclusion criteria and estimate the impact of eligibility criteria on the generalizability of trial results.


Control of pulsatile and tonic parathyroid hormone secretion by ionized calcium.
To investigate the effect of changes in ionized calcium on instantaneous PTH secretion, we examined seven young healthy volunteers by 1-min blood sampling under conditions of normo-, hypo-, and hypercalcemia. After a baseline period of 75 min, ambient ionized calcium was either increased or decreased by 0.2 mmol/L for 105 min by clamped infusion of calcium gluconate or sodium citrate. The characteristics of PTH secretion were analyzed by a deconvolution technique, accounting for subject-specific plasma PTH disappearance half-life, as measured during the first 15 min of calcium infusion (range, 2.04-2.93 min). The process regularity of pulsatile PTH secretion was evaluated by an approximate entropy statistic. Under baseline conditions, 32% of total PTH secretion was released in a pulsatile fashion, with a burst frequency of 6.9 +/- 0.8 h-1 and a PTH mass per burst of 2.6 +/- 0.9 pmol/L. The remaining 68% of total secretion was attributed to tonic hormone release. During the initial 30 min of induced hypocalcemia, pulsatile secretion increased by 1140%, whereas tonic secretion did not change. The preferential increase in pulsatile PTH secretion was mediated by a combined rise in burst frequency and mass released per burst. During subsequent steady state hypocalcemia, the tonic secretion rate increased (255% of baseline), whereas burst frequency and burst mass decreased (to 103% and 189% of the baseline values), restoring the baseline ratio of tonic to pulsatile PTH secretion. The regularity of PTH release increased during steady state hypocalcemia. During hypercalcemia, tonic secretion, burst mass, and burst frequency decreased by 75%, 82%, and 32%, respectively, and remained constant throughout the clamp period. We conclude that acute hypocalcemia elicits an immediate pulsatile and a delayed tonic secretory response of the parathyroid gland with increased regularity of PTH release. Acute hypercalcemia suppresses both the pulsatile and the tonic component of PTH secretion.


Monitoring the wild black bear's reaction to human and environmental stressors.
Bears are among the most physiologically remarkable mammals. They spend half their life in an active state and the other half in a state of dormancy without food or water, and without urinating, defecating, or physical activity, yet can rouse and defend themselves when disturbed. Although important data have been obtained in both captive and wild bears, long-term physiological monitoring of bears has not been possible until the recent advancement of implantable devices. Insertable cardiac monitors that were developed for use in human heart patients (Reveal® XT, Medtronic, Inc) were implanted in 15 hibernating bears. Data were recovered from 8, including 2 that were legally shot by hunters. Devices recorded low heart rates (pauses of over 14 seconds) and low respiration rates (1.5 breaths/min) during hibernation, dramatic respiratory sinus arrhythmias in the fall and winter months, and elevated heart rates in summer (up to 214 beats/min (bpm)) and during interactions with hunters (exceeding 250 bpm). The devices documented the first and last day of denning, a period of quiescence in two parturient females after birthing, and extraordinary variation in the amount of activity/day, ranging from 0 (winter) to 1084 minutes (summer). Data showed a transition toward greater nocturnal activity in the fall, preceding hibernation. The data-loggers also provided evidence of the physiological and behavioral responses of bears to our den visits to retrieve the data. Annual variations in heart rate and activity have been documented for the first time in wild black bears. This technique has broad applications to wildlife management and physiological research, enabling the impact of environmental stressors from humans, changing seasons, climate change, social interactions and predation to be directly monitored over multiple years.


Oral treponeme major surface protein: Sequence diversity and distributions within periodontal niches.
Treponema denticola and other species (phylotypes) of oral spirochetes are widely considered to play important etiological roles in periodontitis and other oral infections. The major surface protein (Msp) of T. denticola is directly implicated in several pathological mechanisms. Here, we have analyzed msp sequence diversity across 68 strains of oral phylogroup 1 and 2 treponemes; including reference strains of T. denticola, Treponema putidum, Treponema medium, 'Treponema vincentii', and 'Treponema sinensis'. All encoded Msp proteins contained highly conserved, taxon-specific signal peptides, and shared a predicted 'three-domain' structure. A clone-based strategy employing 'msp-specific' polymerase chain reaction primers was used to analyze msp gene sequence diversity present in subgingival plaque samples collected from a group of individuals with chronic periodontitis (n=10), vs periodontitis-free controls (n=10). We obtained 626 clinical msp gene sequences, which were assigned to 21 distinct 'clinical msp genotypes' (95% sequence identity cut-off). The most frequently detected clinical msp genotype corresponded to T. denticola ATCC 35405T , but this was not correlated to disease status. UniFrac and libshuff analysis revealed that individuals with periodontitis and periodontitis-free controls harbored significantly different communities of treponeme clinical msp genotypes (P<.001). Patients with periodontitis had higher levels of clinical msp genotype diversity than periodontitis-free controls (Mann-Whitney U-test, P<.05). The relative proportions of 'T. vincentii' clinical msp genotypes were significantly higher in the control group than in the periodontitis group (P=.018). In conclusion, our data clearly show that both healthy and diseased individuals commonly harbor a wide diversity of Treponema clinical msp genotypes within their subgingival niches.


Rapid typing of Borrelia burgdorferi sensu lato species in specimens from patients with different manifestations of Lyme borreliosis.
To further investigate the pathogenic potential of different Borrelia burgdorferi genospecies, specimens from 27 patients with different manifestations of Lyme borreliosis were analyzed by PCR and reverse line blotting (RLB). In samples from Lyme arthritis patients, B. burgdorferi sensu stricto was predominantly identified, while in patients with neuroborreliosis or acrodermatitis, Borrelia garinii and Borrelia afzelii, respectively, were exclusively detected. The results demonstrate that PCR-RLB is a valuable tool for epidemiological and pathogenetic studies of Lyme borreliosis.


Estimating the prevalence of fetal alcohol syndrome in Victoria using routinely collected administrative data.
To establish the prevalence of fetal alcohol syndrome (FAS) in Victoria through the Victorian Birth Defects Register (VBDR). A sample of live births from 1995-2002 was selected from the Victorian Perinatal Data Collection and VBDR based on reported microcephaly, FAS or maternal use of alcohol during pregnancy. Following ethics approval, medical records of mother and child were requested for 117 births. One hundred and nine of these were accessed and examined for factors related to FAS. Records were categorised as FAS, possible FAS, unable to categorise, or not FAS. From the VBDR the prevalence was calculated at 0.006 per 1,000 live births. Four additional possible cases of FAS increased this to 0.014 per 1,000 live births. Six cases were defined as 'unable to categorise' as alcohol use was unknown but other features of FAS were evident. Including these cases, plus five where some low-level alcohol use was reported, increased the prevalence to 0.03 per 1,000 live births. Twenty-eight per cent of the audit population and 39% of the microcephalic cases had no information about maternal alcohol use recorded in the antenatal or babies' records. The audit of medical records provided additional information regarding FAS prevalence in Victoria. This prevalence ranges from 0.01 to 0.03 per 1,000 live births. To accurately assess the extent of the problem, there needs to be improved reporting of alcohol use in pregnancy and a system in place to report cases diagnosed during and beyond the perinatal period to the VBDR.


CD46 in innate and adaptive immunity: an update.
CD46 was discovered in 1986 during a search for novel C3b-binding proteins. CD46 is expressed ubiquitously and functions as a co-factor in the factor I-mediated proteolytic cleavage of C3b and C4b. Its vital role in preventing complement deposition on host tissue is underpinned by the fact that deficiency of CD46 is a predisposing factor for numerous disease conditions arising from complement-mediated 'self-attack'. However, in the last 10 years, it has become apparent that CD46 is also heavily involved in a new and somewhat surprising functional aspect of the complement system: the down-modulation of adaptive T helper type 1 (Th1) immune responses by regulating the production of interferon (IFN)-γ versus interleukin (IL)-10 within these cells. Specifically, this latter function of CD46 is a tantalizing discovery - it may not only have delivered the explanation as to why so many pathogens use and abuse CD46 as cell entry receptor but clearly has important clinical implications for the better understanding of Th1-mediated disease states and novel therapeutic approaches for their amelioration. Here, we summarize and discuss the current knowledge about CD46 and its expanding roles in the immune system.


Metabolic differences between obesity-prone and obesity-resistant rats.
We compared, across several physiological variables, rats most and least susceptible to develop obesity when given a high-fat diet. After 4 wk of eating a high-fat diet (60% of calories from fat), rats in the upper (obesity prone, OP) and lower (obesity resistant, OR) quartiles for weight gain were further studied. OP rats ate significantly more than OR rats, but this did not completely explain differences in their susceptibility to dietary obesity. No differences in 24-h energy expenditure were found between groups. OR rats had a significantly lower 24-h respiratory quotient, indicative of a greater relative proportion of fat oxidation and lower plasma levels of free fatty acids (FFA) than OP rats. Thus the ability to avoid dietary obesity produced by a high-fat diet may depend on an ability to increase fat oxidation in response to increased fat intake. Insulin sensitivity, measured by a euglycemic insulin clamp, was significantly higher in OR than OP rats. We cannot determine from these data whether insulin resistance developed as a consequence of elevated FFA levels or whether the ability to oxidize FFA declined as a result of development of insulin resistance. In summary, we propose that rats able to resist becoming obese on a high-fat diet have the ability to adjust the composition of fuel oxidized to the fuel composition of the diet with a minimum increase in body fat. The specific mechanisms by which this occurs are unknown but may be related to effects of diet on insulin sensitivity.


[Predictors of the duration of non-work-related sick leave due to anxiety disorders].
To analyze the duration of non-work-related sick leave due to anxiety disorders and to identify demographic, occupational and clinical variables that may contribute to its prediction. We performed a prospective cohort study of 1,161 workers with an episode of non-work-related sick leave due to an anxiety disorder, belonging to the insured population of a mutual insurance company. We assessed the duration of non-work-related sick leave episodes and the main potentially related demographic, occupational and clinical variables. All non-work-related sick leave processes were followed-up until discharge. Cox regression analyses were conducted to establish the predictors of non-work-related sick leave duration. The median duration of non-work-related sick leave due to anxiety disorders was 83 days. In a multivariate analysis, the following factors were identified as being significantly associated with increases in the duration of sick leave (p <0.05): age of over 35 years, lower educational level (primary school studies, secondary school studies or high-school diploma vs. university degree), and the existence of comorbidity and unemployment occurring during the sick leave. In contrast, being separated or divorced was associated with an earlier return to work (p <0.05). Anxiety disorders are associated with long periods of non-work-related sick leave compared with other disorders and standard time duration. Demographic, occupational and clinical variables collected at the initial assessment of the sick leave episode would help to identify groups with an increased risk of prolonged sick leave, requiring strategies to facilitate return to work.


Production of inhibitors of lytic activity in the Micrococcaceae.
Eight Staphylococcus xylosus strains lacking lytic activity (LA) were found to excrete agar-diffusible factors inhibiting the LA of LA-positive strains of the same species. The same eight strains, when tested against LA-positive indicator strains from other species of Micrococcaceae, caused marked LA inhibition only of strains of S, saprophyticus and S. cohnii, both species closely related to S. xylosus. Micrococci and planococci, unlike staphylococci, do not normally show LA, yet Micrococcus lylae and M. sedentarius strains produced inhibitors effective against the LA of almost all the indicator strains, and planococci inhibited the LA of a few indicator strains. Micrococcus luteus strains caused LA inhibition of homologous indicators only, i.e. exceptional M. luteus strains exhibiting LA. Thus, a specific and a non-specific type of LA inhibition can be distinguished, and it is suggested that the apparent lack of LA might, in some instances, be explained by the simultaneous production of a specific inhibitor.


Role of transcription factors in fetal lung development and surfactant protein gene expression.
Branching morphogenesis of the lung and differentiation of specialized cell populations is dependent upon reciprocal interactions between epithelial cells derived from endoderm of embryonic foregut and surrounding mesenchymal cells. These interactions are mediated by elaboration and concerted actions of a variety of growth and differentiation factors binding to specific receptors. Such factors include members of the fibroblast growth factor family, sonic hedgehog, members of the transforming growth factor-beta family, epidermal growth factor, and members of the platelet-derived growth factor family. Hormones that increase cyclic AMP formation, glucocorticoids, and retinoids also play important roles in branching morphogenesis, alveolar development, and cellular differentiation. Expression of the genes encoding these morphogens and their receptors is controlled by a variety of transcription factors that also are highly regulated. Several of these transcription factors serve dual roles as regulators of genes involved in early lung development and in specialized functions of differentiated cells. Targeted null mutations of genes encoding many of these morphogens and transcription factors have provided important insight into their function during lung development. In this chapter, the cellular and molecular mechanisms that control lung development are considered, as well as those that regulate expression of the genes encoding the surfactant proteins.


Is the metabolic syndrome a "small baby" syndrome?: the bogalusa heart study.
Metabolic syndrome has been called a "small baby syndrome," but other analyses suggest that postnatal growth is more important than birthweight, or that large babies are also at risk. The aim of this analysis was to examine whether there was a relationship between both low and high birthweight and metabolic syndrome, using multiple definitions of metabolic syndrome, and to determine whether this relationship varied by body size across the life course. Data from the Bogalusa Heart Study, a study of cardiovascular disease in children and young adults, were linked to birth certificate data. Metabolic syndrome was defined by the National Cholesterol Education Program, the International Diabetes Foundation, and the World Health Organization (WHO) definition. Small-for-gestational-age (SGA) was defined as birthweight <10(th) percentile by sex for gestational age and large-for-gestational-age (LGA) as birthweight >90(th) percentile. Birthweight-for-gestational-age was also examined as a continuous predictor. Chi-squared tests and logistic regression were used to examine the relationship between birth size and metabolic syndrome. Higher birthweight-for-gestational-age was associated with a reduced risk of metabolic syndrome, especially by the WHO definition. After adjustment for body mass index (BMI), categorized birthweight was associated with metabolic syndrome, with the protective associations with LGA being stronger than the positive associations with SGA. Among the individual components of metabolic syndrome, higher waist circumference was associated with both SGA and LGA after BMI was controlled for. Effects of SGA and BMI at any age were largely independent rather than interactive. SGA is associated with some, but not all, components of metabolic syndrome. The relationship between SGA and metabolic syndrome is partially confounded by later BMI.


Most large structural variants in cancer genomes can be detected without long reads.
Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure.


Evaluating coverage of maternal syphilis screening and treatment within antenatal care to guide service improvements for prevention of congenital syphilis in Countdown 2030 Countries.
Countdown to 2030 (CD2030) tracks progress in the 81 countries that account for more than 90% of under-five child deaths and 95% of maternal deaths in the world. In 2017, CD2030 identified syphilis screening and treatment during antenatal care (ANC) as priority indicators for monitoring. Country-reported data in the UNAIDS Global AIDS Monitoring System (GAM) system were used to evaluate four key syphilis indicators from CD2030 countries: (1) maternal syphilis screening and (2) treatment coverage during ANC, (3) syphilis seroprevalence among ANC attendees, and (4) national congenital syphilis (CS) case rates. A cascade analysis for CD2030 countries with coverage data for the number of women attending at least 4 antenatal care visits (ANC4), syphilis testing, seroprevalence and treatment was performed to estimate the number of CS cases that were attributable to missed opportunities for syphilis screening and treatment during antenatal care. Of 81 countries, 52 (64%) reported one or more values for CS indicators into the GAM system during 2016-2017; only 53 (65%) had maternal syphilis testing coverage, 41 (51%) had screening positivity, and 40 (49%) had treatment coverage. CS case rates were reported by 13 (16%) countries. During 2016-2017, four countries reported syphilis screening and treatment coverage of ≥95% consistent with World Health Organization (WHO) targets. Sufficient data were available for 40 (49%) of countries to construct a cascade for data years 2016 and 2017. Syphilis screening and treatment service gaps within ANC4 resulted in an estimated total of 103 648 adverse birth outcomes with 41 858 of these occurring as stillbirths among women attending ANC4 (n = 31 914 408). Women not in ANC4 (n = 25 619 784) contributed an additional 67 348 estimated adverse birth outcomes with 27 198 of these occurring as stillbirths for a total of 69 056 preventable stillbirths attributable to syphilis in these 40 countries. These data and findings can serve as an initial baseline evaluation of antenatal syphilis surveillance and service coverage and can be used to guide improvement of delivery and monitoring of syphilis screening and treatment in ANC for these priority countries.


Host life-history traits predict haemosporidian parasite prevalence in tanagers (Aves: Thraupidae).
Vector-borne parasites are important ecological drivers influencing life-history evolution in birds by increasing host mortality or susceptibility to new diseases. Therefore, understanding why vulnerability to infection varies within a host clade is a crucial task for conservation biology and for understanding macroecological life-history patterns. Here, we studied the relationship of avian life-history traits and climate on the prevalence of Plasmodium and Parahaemoproteus parasites. We sampled 3569 individual birds belonging to 53 species of the family Thraupidae. Individuals were captured from 2007 to 2018 at 92 locations. We created 2 phylogenetic generalized least-squares models with Plasmodium and Parahaemoproteus prevalence as our response variables, and with the following predictor variables: climate PC1, climate PC2, body size, mixed-species flock participation, incubation period, migration, nest height, foraging height, forest cover, and diet. We found that Parahaemoproteus and Plasmodium prevalence was higher in species inhabiting open habitats. Tanager species with longer incubation periods had higher Parahaemoproteus prevalence as well, and we hypothesize that these longer incubation periods overlap with maximum vector abundances, resulting in a higher probability of infection among adult hosts during their incubation period and among chicks. Lastly, we found that Plasmodium prevalence was higher in species without migratory behaviour, with mixed-species flock participation, and with an omnivorous or animal-derived diet. We discuss the consequences of higher infection prevalence in relation to life-history traits in tanagers.


Life-Cycle-Dependent Toxicities of Mono- and Bifunctional Alkylating Agents in the 3R-Compliant Model Organism C. elegans.
Caenorhabditis elegans (C. elegans) is gaining recognition and importance as an organismic model for toxicity testing in line with the 3Rs principle (replace, reduce, refine). In this study, we explored the use of C. elegans to examine the toxicities of alkylating sulphur mustard analogues, specifically the monofunctional agent 2-chloroethyl-ethyl sulphide (CEES) and the bifunctional, crosslinking agent mechlorethamine (HN2). We exposed wild-type worms at different life cycle stages (from larvae L1 to adulthood day 10) to CEES or HN2 and scored their viability 24 h later. The susceptibility of C. elegans to CEES and HN2 paralleled that of human cells, with HN2 exhibiting higher toxicity than CEES, reflected in LC50 values in the high µM to low mM range. Importantly, the effects were dependent on the worms' developmental stage as well as organismic age: the highest susceptibility was observed in L1, whereas the lowest was observed in L4 worms. In adult worms, susceptibility to alkylating agents increased with advanced age, especially to HN2. To examine reproductive effects, L4 worms were exposed to CEES and HN2, and both the offspring and the percentage of unhatched eggs were assessed. Moreover, germline apoptosis was assessed by using ced-1p::GFP (MD701) worms. In contrast to concentrations that elicited low toxicities to L4 worms, CEES and HN2 were highly toxic to germline cells, manifesting as increased germline apoptosis as well as reduced offspring number and percentage of eggs hatched. Again, HN2 exhibited stronger effects than CEES. Compound specificity was also evident in toxicities to dopaminergic neurons-HN2 exposure affected expression of dopamine transporter DAT-1 (strain BY200) at lower concentrations than CEES, suggesting a higher neurotoxic effect. Mechanistically, nicotinamide adenine dinucleotide (NAD+) has been linked to mustard agent toxicities. Therefore, the NAD+-dependent system was investigated in the response to CEES and HN2 treatment. Overall NAD+ levels in worm extracts were revealed to be largely resistant to mustard exposure except for high concentrations, which lowered the NAD+ levels in L4 worms 24 h post-treatment. Interestingly, however, mutant worms lacking components of NAD+-dependent pathways involved in genome maintenance, namely pme-2, parg-2, and sirt-2.1 showed a higher and compound-specific susceptibility, indicating an active role of NAD+ in genotoxic stress response. In conclusion, the present results demonstrate that C. elegans represents an attractive model to study the toxicology of alkylating agents, which supports its use in mechanistic as well as intervention studies with major strength in the possibility to analyze toxicities at different life cycle stages.


Food and physical activity behaviours of adults attending a prediabetes education class.
The primary objective of this study was to examine food and physical activity behaviours of adults with prediabetes. For this cross-sectional study, adults (aged >17 years) with prediabetes (n=1228) who attended a prediabetes education class were recruited. Participants self-administered an assessment of food and physical activity behaviours using the Food Behaviour Checklist and the Godin Leisure Time Exercise Questionnaire. Linear regression models were performed to identify significant relationships between food, physical activity, age, body mass index and food access variables. Participants were 35.8% men with a mean age of 57.7 years (SD 11.6) and 64.2% women with a mean age of 55.2 years (13.9). Neither group was consuming adequate fruits and vegetables (17.1% for men and 29.2% for women eating 5 or more servings a day) or meeting physical activity guidelines of 150 minutes (29.5% for men and 26.2% for women). Approximately 29.0% of the entire sample "always" consumed milk or soy products. Men reported higher saturated fat intakes than women. For the entire sample, 83.4% rated their diet quality as needing improvement, and most consumed sweetened beverages (71.1% of men and 50.9% of women). Many participants (88.5%) used nutrition facts panels to choose foods. Food behaviour subscales and physical activity were significantly associated with each other and with age, body mass index and food access (p<0.05). Overall, adults with prediabetes reported less than optimal food and physical activity behaviours. Evaluation of lifestyle behaviours using simple tools like the Food Behaviour Checklist and Godin Leisure Time Exercise Questionnaire can be helpful for program design, evaluation and delivery.


Stem Cells Combined With Platelet-rich Plasma Effectively Treat Corticosteroid-induced Osteonecrosis of the Hip: A Prospective Study.
Randomized trials have shown the benefits of injecting bone marrow-derived mesenchymal stem cells (BmMSCs) after standard hip decompression in patients with osteonecrosis of the femoral head. However, the combination of BmMSCs and platelet-rich plasma (PRP) injected into the femoral head after decompression has not been reported previously. This study reports the results in a preliminary series of patients with osteonecrosis of the femoral head treated with BmMSCs plus PRP. (1) What is the survivorship free from reoperation, hip arthroplasty, and femoral head collapse in a preliminary series of patients with osteonecrosis of the femoral head treated with BmMSCs plus PRP? (2) Is there a change in the degree of femoral head involvement based on modified Kerboul angle? (3) What were the scores observed for pain and function at last followup? (4) Was there a difference in survivorship free from reoperation as a function of in vitro MSC count and viability? Twenty-two consecutive patients (35 hips; 11 men and 11 women) with corticosteroid-induced osteonecrosis who met study inclusion criteria were enrolled; none declined participation, and none was lost to followup, although one patient (two hips) died within a year of the procedure for reasons unrelated to it, and five patients (seven hips) did not undergo MRI at the 1-year followup. All patients had precollapse osteonecrosis, rated either University of Pennsylvania Stage 1 (n = 4) or Stage 2 (n = 31 hips). Mean age and body mass index were 43 years and 31 kg/m, respectively. Patients underwent pre- and postoperative radiographs and MRI to assess femoral head involvement using the modified Kerboul angle. Absolute cell count and colony-forming unit (CFU) assays were used to assess MSC abundance and viability of the bone marrow obtained at the time of surgery. Patients were followed at regular intervals to assess clinical response to treatment with a mean followup of 3 years (range, 2-4 years). The change in femoral head involvement was assessed with the modified Kerboul angle; the Harris hip score was used to assess clinical outcome; and conversion to THA, reoperation, and survivorship free from femoral head collapse were analyzed with the Kaplan-Meier method on a per-hip basis. Survivorship free from THA, any procedure, and femoral head collapse was 84% (95% confidence interval [CI], 75%-93%), 67% (95% CI, 55%-79%), and 93% (95% CI, 76%-98%), respectively, at 3 years postoperatively; two patients (four hips) underwent a second decompression and MSC injection for persistent pain without signs of radiographic collapse. All patients with collapse underwent THA. The mean modified Kerboul angle improved from 205° ± 47° to 172° ± 48° postoperatively (mean change -30° ± 6°, p = 0.01). A greater proportion of patients who underwent an additional procedure had a modified Kerboul grade of 3 or 4 preoperatively (80% [four of five] versus 13% [four of 30 Grade 1 or 2; odds ratio, 26; 95% CI, 2-296; p = 0.005). Preoperatively the mean Harris hip score was 57 ± 12, which improved to 85 ± 15 (mean change 28 ± 3, p < 0.001) at most recent followup. Patients undergoing a reoperation or THA had a lower mean concentration of nucleated cells/mL (5.5 x 10 ± 2.8 x 10 cells/mL versus 2.3 x 10 ± 2.2 x 10 cells/mL, p = 0.02) and lower mean CFUs (13 ± 6 versus 19 ± 7, p = 0.04) compared with those who did not. Core hip decompression with injection of concentrated bone marrow plus PRP improved pain and function; > 90% of hips in this series were without collapse at a minimum of 2 years. In this preliminary study, successful results were seen when nucleated cell count was high and modified Kerboul grade was low. Further randomized studies are needed to determine this procedure's efficacy versus core decompression or nonoperative treatment alone. Level II, therapeutic study.


Experiments with osteoblasts cultured under hypergravity conditions.
To understand further the role of gravity in osteoblast attachment, osteoblasts were subjected to hypergravity conditions in vitro. Scanning electron microscopy of all confluent coverslips from FPA units show that the number of attached osteoblasts was similar among gravitational levels and growth durations (~90 cells/microscopic field). Specifically, confluent 1.0 G control cultures contained an average of 91 +/- 8 cells/field, 3.3 G samples had 88 +/- 8 cells/field, and 4.0 G cultures averaged 90 +/- 7 cells/field. The sparsely plated cultures assessed by immunohistochemistry also had similar numbers of cells at each time point (l.0 G was similar to 3.3 and 4.0 G), but cell number changed from one time point to the next as those cells proliferated. Immunohistochemistry of centrifuged samples showed an increase in number (up to 160% increase) and thickness (up to 49% increase) of actin fibers, a decrease in intensity of fibronectin fluorescence (18-23% decrease) and an increase in number of vinculin bulbs (202-374% increase in number of vinculin bulbs/area). While hypergravity exposure did not alter the number of attached osteoblasts, it did result in altered actin, fibronectin, and vinculin elements, changing some aspects of osteoblast- substrate adhesion.


Pharmacokinetics of glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase and their blood glutamate-lowering activity in naïve rats.
Traumatic brain injury (TBI) and stroke lead to elevated levels of glutamate in the brain that negatively affect the neurological outcomes in both animals and humans. Intravenous administration of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) enzymes can be used to lower the blood glutamate levels and to improve the neurological outcome following TBI and stroke. The objective of this study was to analyze the pharmacokinetics and to determine the glutamate-lowering effects of GOT and GPT enzymes in naïve rats. We determined the time course of serum GOT, GPT, and glutamate levels following a single intravenous administration of two different doses of each one of the studied enzymes. Forty-six male rats were randomly assigned into one of 5 treatment groups: saline (control), human GOT at dose 0.03 and 0.06 mg/kg and porcine GPT at dose 0.6 and 1.2 mg/kg. Blood samples were collected at baseline, 5 min, and 2, 4, 8, 12, and 24 h after the drug injection and GOT, GPT and glutamate levels were determined. The pharmacokinetics of both GOT and GPT followed one-compartment model, and both enzymes exhibited substantial glutamate-lowering effects following intravenous administration. Analysis of the pharmacokinetic data indicated that both enzymes were distributed predominantly in the blood (central circulation) and did not permeate to the peripheral organs and tissues. Several-hour delay was present between the time course of the enzyme levels and the glutamate-lowering effects (leading to clock-wise hysteresis on concentration-effect curves), apparently due to the time that is required to affect the pool of serum glutamate. We conclude that the interaction between the systemically-administered enzymes (GOT and GPT) and the glutamate takes place in the central circulation. Thus, glutamate-lowering effects of GOT and GPT apparently lead to redistribution of the excess glutamate from the brain's extracellular fluid into the blood and can reduce secondary brain injury due to glutamate neurotoxicity. The outcomes of this study regarding the pharmacokinetic and pharmacodynamic properties of the GOT and GPT enzymes will be subsequently verified in clinical studies that can lead to design of effective neuroprotective treatment strategies in patients with traumatic brain diseases and stroke.


Cracking the Endothelial Calcium (Ca2+) Code: A Matter of Timing and Spacing.
A monolayer of endothelial cells lines the innermost surface of all blood vessels, thereby coming into close contact with every region of the body and perceiving signals deriving from both the bloodstream and parenchymal tissues. An increase in intracellular Ca2+ concentration ([Ca2+]i) is the main mechanism whereby vascular endothelial cells integrate the information conveyed by local and circulating cues. Herein, we describe the dynamics and spatial distribution of endothelial Ca2+ signals to understand how an array of spatially restricted (at both the subcellular and cellular levels) Ca2+ signals is exploited by the vascular intima to fulfill this complex task. We then illustrate how local endothelial Ca2+ signals affect the most appropriate vascular function and are integrated to transmit this information to more distant sites to maintain cardiovascular homeostasis. Vasorelaxation and sprouting angiogenesis were selected as an example of functions that are finely tuned by the variable spatio-temporal profile endothelial Ca2+ signals. We further highlighted how distinct Ca2+ signatures regulate the different phases of vasculogenesis, i.e., proliferation and migration, in circulating endothelial precursors.


[Isolation and purification of plant histones].
A fractionation pattern for isolation and identification of histones, allowing to obtain preparative amounts of individual histone fractions, is proposed. The obtained fractions were identified by their solubility, by differential staining and by electrophoresis. The fractionation resulted in all major histone fractions of wheat, rye, cotton, pea and calf thymus. The electrophoretic patterns of all plant histones were identical, differing only in their histone H1 contents. The histone fraction H1 was also found to be heterogeneous, which, with the exception of cotton H1 fraction, was more pronounced than in the case of calf thymus. The data obtained can be interpreted in terms of the functional role of histones in the genetic mechanism of plants and a possible use of individual fractions and components of histones for the study of phylogenetic relationships between the species.


Barriers and enablers to achieving clinical procedure competency-based outcomes in a national paediatric training/residency program-a multi-centered qualitative study.
In 2018, the Royal College of Physicians of Ireland revised its paediatric training program to a competency-based medical education (CBME) training/residency curriculum. This included a requirement to achieve competence in a number of core procedural skills to progress within the program. Internationally, simulation-based medical education (SBME) is gaining interest as an effective teaching pedagogy for training procedural skill competency. The objectives of this study were to (1) identify enablers and barriers for paediatric trainees to achieve their required procedural competencies, (2) gain insight on the feasibility of achieving the required procedural skills, and (3) explore what simulation-based resources are used as well as their role in achieving the required procedural skill competencies. A multi-centered qualitative study using semi-structured interviews was performed. Twenty-four paediatric consultants and trainees were recruited from two academic tertiary hospitals using purposive and snowball sampling. Interviews were conducted between March and September 2021, audio recorded, transcribed, and analyzed using thematic analysis. Three main themes regarding enablers for achieving procedural competencies were reported and include having protected training time, routine assessments, and a standardized curriculum. Barriers to achieving procedural competencies focused mainly on limited clinical exposure. The use of SBME was recommended by all participants (n = 24, 100%) to assist in achieving procedural competencies and most (n = 15, 62.5%) reported it is feasible to attain the required procedural skills in the paediatric CBME program. It is feasible to achieve the required procedural competencies for most paediatric trainees, but this can be improved with protected training time, routine assessments, and a standardized curriculum. Barriers to achieving these skills mainly center on limited clinical exposure, which can be remedied by SBME. Further research is warranted to determine the costs and types of SBME tools available as well as teaching pedagogies to support paediatric trainees achieve their required procedural competencies.


Protocols for studying the crayfish plague pathogen, Aphanomyces astaci, and its host-pathogen interactions.
The crayfish plague caused by the pathogen Aphanomyces astaci has decimated the European and Asian populations of freshwater crayfish and represents an important threat to the other highly susceptible crayfish species in the world, such as the Australian, Madagascar, and South American species. The development and application of molecular methods addressed to the identification of A. astaci has increased exponentially during the last decades in contrast to a slow trend of the pathogen biology and host interaction. There is still a need for a better comprehension of the A. astaci-crayfish interactions, specifically the resistance and tolerance immune mechanism. These types of studies required a robust basic knowledge on the developmental biology of the pathogen in order to reproduce life stages and to perform infection experiments. A great piece of work in this area was carried out during the 1960 s to 80 s in University of Uppsala. Thus, the purpose of this work was to update previous protocols as well as to generate new guidelines to reproduce key developmental biology stages of A. astaci, to eventually identify crayfish populations with higher resistance and tolerance to this pathogen. This work also refers to other methodologies and guidelines for the diagnosis of crayfish plague, the pathogen isolation, and the in vitro production of zoospores.


Genetic and economic benefits of foreign sire contributions to a domestic sheep industry; including an Ireland-New Zealand case study.
Importation of foreign genetics is a widely used genetic improvement strategy. However, even if the foreign genetic merit is currently greater than the domestic genetic merit, differences in foreign and domestic trends mean that the long-term competitiveness of an importation strategy cannot be guaranteed. Gene flow models are used to quantify the impact that a specific subpopulation, such as foreign genetics, can have over time on the genetic or economic benefit of a domestic industry. We used a deterministic recursive gene flow model to predict the commercial performance of lambs born across various subpopulations. Numerous breeding strategies were evaluated by varying market share, proportions of rams selected for mating, genetic trend, superiority of foreign genetics over domestic genetics and frequency of importation. Specifically, an Ireland-New Zealand case study was simulated to quantify the potential gain that could be made by using foreign sire contributions (New Zealand) in a domestic sheep industry (Ireland). Genetic and economic gains were generated from alternative breeding strategies. The 'base scenario' (i.e. representing the current industry) predicted an average genetic merit value of €2.51 for lambs born and an annualised cumulative benefit of €45 million (m) after 20 years. Maximum genetic (€9.45 for lambs born) and economic (annualised cumulative benefit of €180 m after 20 years) benefits were achieved by implementing the 'PRO-intense-market scenario' which involved shifting market share away from conservative domestic breeders and reducing the proportion of rams that were selected for mating by progressive domestic breeders from the top 40% to the top 20%, without the use of any foreign genetics. The 'PROFOR scenario', which considered the use of foreign and progressive domestic genetics, predicted an average genetic merit value of €7.37 for lambs born and an annualised cumulative benefit of €144 m, after 20 years. Our results demonstrate that there is opportunity for a domestic industry to increase industry benefits without the use of foreign genetics but through an attempt to shift the market share away from conservative domestic breeders towards progressive domestic breeders. However, the importation and use of progressive foreign genetics may be an effective method to trigger a change in behaviour of conservative domestic breeders towards the use of progressive genetics.


The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages.
Adipose tissue-derived cytokines (adipokines) are associated with the development of inflammation and insulin resistance. However, which adipokine(s) mediate this linkage and the mechanisms involved during obesity is poorly understood. Through proteomics and microarray screening, we recently identified lipocalin 2 (LCN 2) as an adipokine that potentially connects obesity and its related adipose inflammation. Herein we show that the levels of LCN2 mRNA are dramatically increased in adipose tissue and liver of ob/ob mice and primary adipose cells isolated from Zucker obese rats, and thiazolidinedione administration reduces LCN2 expression. Interestingly, addition of LCN2 induces mRNA levels of peroxisome proliferator-activated receptor-gamma (PPARgamma) and adiponectin. Reducing LCN2 gene expression causes decreased expression of PPARgamma and adiponectin, slightly reducing insulin-stimulated Akt2 phosphorylation at Serine 473 in 3T3-L1 adipocytes. LCN2 administration to 3T3-L1 cells attenuated TNFalpha-effect on glucose uptake, expression of PPARgamma, insulin receptor substrate-1, and glucose transporter 4, and secretion of adiponectin and leptin. When added to macrophages, LCN2 suppressed lipopolysaccharide-induced cytokine production. Our data suggest that LCN2, as a novel autocrine and paracrine adipokine, acts as an antagonist to the effect of inflammatory molecules on inflammation and secretion of adipokines.


Omics and Extreme Phenotyping Reveal Longitudinal Association Between Left Atrial Size and Pulmonary Vascular Resistance in Group 2 Pulmonary Hypertension.
Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance-isolated postcapillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH), respectively-has been incompletely defined using unbiased methods. Patients with extremes of IpcPH versus CpcPH were identified from a single-center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction <40% or with potential causes of PH beyond left heart disease were excluded. Medication usage in IpcPH and CpcPH was compared across Anatomical Therapeutic Chemical classes and identified vitamin K antagonists as the only medication with pharmacome-wide significance, being more commonly used in CpcPH and for an indication of atrial fibrillation in ≈90% of instances. Accordingly, atrial fibrillation prevalence was significantly higher in CpcPH in a phenome-wide analysis. Review of echocardiographic data most proximal to right heart catheterization revealed that left atrial diameter indexed to body surface area-known to be associated with atrial fibrillation-was increased in CpcPH regardless of the presence of atrial fibrillation. An independent cohort with serial right heart catheterizations and PH-left heart disease showed a significant positive correlation between change in left atrial diameter indexed to body surface area and change in pulmonary vascular resistance. Guided by pharmacomic and phenomic screens in a rigorously phenotyped cohort, we identify a longitudinal association between left atrial diameter indexed to body surface area and pulmonary vascular resistance with implications for the future development of diagnostic, prognostic, and therapeutic tools.


General practitioners' training for, interest in, and knowledge of sports medicine and its organisations.
To assess the training and interest of a group of general practitioners in the area of sport and exercise medicine, and the organisations representing the specialty. A postal questionnaire using a Likert scale in a previously piloted set of questions. 275 general practitioners registered with the Northampton Regional Health Authority. Responses to questions designed to assess training and interest in sport and exercise medicine. A response rate of 87.6% was achieved. It was found that 72.7% of the responding general practitioners felt inadequately trained to practice sport and exercise medicine. Some 76.0% would welcome more training and 36.4% felt that their undergraduate orthopaedic training was of no use in primary care. Many (63.6%) of the general practitioners believed that the current NHS cannot sustain sport and exercise medicine, and there was uncertainty as to whether it is currently a recognised specialty, although 60.4% felt that it should be. General practitioners listed lack of facilities (53.1%), lack of training (42.9%), and lack of time (38.2%) as the main problems in practicing sport and exercise medicine in primary care within the current NHS. General practitioners feel undertrained in sport and exercise medicine at both undergraduate and post-graduate level; they have a perceived need for more training and show an interest in the subject. There is scope for improving the value of undergraduate orthopaedic training. General practitioners wish to see sport and exercise medicine recognised as an NHS specialty but fear that this is not sustainable under current conditions. There is confusion among general practitioners about the current sport and exercise medicine organisations.


Heat shock response and groEL sequence of Bartonella henselae and Bartonella quintana.
Transmission of Bartonella species from ectoparasites to the mammalian host involves adaptation to thermal and other forms of stress. In order to better understand this process, the heat shock response of Bartonella henselae and Bartonella quintana was studied. Cellular proteins synthesized after shift to higher temperatures were intrinsically labelled with [25S]methionine and analysed by gel electrophoresis and fluorography. The apparent molecular masses of three of the major heat shock proteins produced by the two Bartonella species were virtually identical, migrating at 70, 60 and 10 kDa. A fourth major heat shock protein was larger in B. quintana (20 kDa) than in B. henselae (17 kDa). The maximum heat shock response in B. quintana and B. henselae was observed at 39 degrees C and 42 degrees C, respectively. The groEL genes of both Bartonella species were amplified, sequenced and compared to other known groEL genes. The phylogenetic tree based on the groEL alignment places B. quintana and B. henselae in a monophyletic group with Bartonella bacilliformis. The deduced amino acid sequences of Bartonella GroEL homologues contain signature sequences that are uniquely shared by members of the Gram-negative alpha-purple subdivision of bacteria, which live within eukaryotic cells. Recombinant His6-GroEL fusion proteins were expressed in Escherichia coli to generate specific rabbit antisera. The GroEL antisera were used to confirm the identity of the 60 kDa Bartonella heat shock protein. These studies provide a foundation for evaluating the role of the heat shock response in the pathogenesis of Bartonella infection.


Involvement of Polo-like kinase 1 in MEK1/2-regulated spindle formation during mouse oocyte meiosis.
Our recent studies have shown that MEK1/2 is a critical regulator of microtubule organization and spindle formation during oocyte meiosis. In the present study, we found that Plk1 colocalized with p-MEK1/2 at various meiotic stages after GVBD when microtubule began to organize. Also, Plk1 was able to coimmunoprecipitate with p-MEK1/2 in metaphase I stage mouse oocyte extracts, further confirming their physical interaction. Taxol-treated oocytes exhibited a number of cytoplasmic asters, in which both Plk1 and p-MEK1/2 were present, indicating that they might be complexed to participate in the acentrosomal spindle formation at the MTOCs during oocyte meiosis. Depolymerization of microtubules by nocodazole resulted in the complete disassembly of spindles, but Plk1 remained associated with p-MEK1/2, accumulating in the vicinity of chromosomes. More importantly, when p-MEK1/2 activity was blocked by U0126, Plk1 lost its normal localization at the spindle poles, which might be one of the most vital factors causing the abnormal spindles in MEK1/2-inhibited oocytes. Taken together, these data indicate that Plk1 and MEK1/2 regulate the spindle formation in the same pathway and that Plk1 is involved in MEK1/2-regulated spindle assembly during mouse oocyte meiotic maturation.


RNA quantification using noble metal nanoprobes: simultaneous identification of several different mRNA targets using color multiplexing and application to cancer diagnostics.
Nanotechnology provides new tools for gene expression analysis that allow for sensitive and specific characterization of prognostic signatures related to cancer. Cancer is a multigenic complex disease where multiple gene loci contribute to the phenotype. The ability to simultaneously monitor differential expression originating from each locus allows for a more accurate indication of degree of cancerous activity than either locus alone. Metal nanoparticles have been widely used as labels for in vitro identification and quantification of target sequences. Here we describe the synthesis of nanoparticles with different noble metal compositions in an alloy format that are then functionalized with thiol-modified ssDNA (nanoprobes). We also show how to use such nanoprobes in a non-cross-linking colorimetric method for the direct detection and quantification of specific mRNA targets, without the need for enzymatic amplification or reverse transcription steps. The different metals in the alloy provide for distinct absorption spectra due to their characteristic plasmon resonance peaks. The color multiplexing allows for simultaneous identification of several different mRNA targets involved in cancer development. Comparison of the absorption spectra of the nanoprobes mixtures taken before and after induced aggregation of metal nanoparticles allows to both identify and quantify each mRNA target. We describe the use of gold and gold:silver-alloy nanoprobes for the development of the non-cross-linking method to detect a specific BCR-ABL fusion gene (e.g., e1a2 and e14a2) mRNA target associated with chronic myeloid leukemia (CML) using 10 ng μL(-1) of unamplified total human RNA. This simple methodology takes less than 50 min to complete after total RNA extraction with comparable specificity and sensitivity to the more commonly used methods.


The Center for Computational Biology: resources, achievements, and challenges.
The Center for Computational Biology (CCB) is a multidisciplinary program where biomedical scientists, engineers, and clinicians work jointly to combine modern mathematical and computational techniques, to perform phenotypic and genotypic studies of biological structure, function, and physiology in health and disease. CCB has developed a computational framework built around the Manifold Atlas, an integrated biomedical computing environment that enables statistical inference on biological manifolds. These manifolds model biological structures, features, shapes, and flows, and support sophisticated morphometric and statistical analyses. The Manifold Atlas includes tools, workflows, and services for multimodal population-based modeling and analysis of biological manifolds. The broad spectrum of biomedical topics explored by CCB investigators include the study of normal and pathological brain development, maturation and aging, discovery of associations between neuroimaging and genetic biomarkers, and the modeling, analysis, and visualization of biological shape, form, and size. CCB supports a wide range of short-term and long-term collaborations with outside investigators, which drive the center's computational developments and focus the validation and dissemination of CCB resources to new areas and scientific domains.


[Etiology of missing teeth].
This article gives a brief overview of the causes of tooth loss. Caries is still the most prominent reason for tooth loss. In patients over 40 years, periodontal reasons become more prevalent. However, also in this age category caries is the main reason. In young individuals, missing teeth are most frequently associated with agenesia or trauma. Iatrogenic damage is considered to be a casuistic cause of tooth loss. Nevertheless, some specific areas, such as in the combined treatment 'endodontic treatment--post and core--crown', can be distinguished in which tooth loss is more frequently seen.


Blood brain barrier and infection.
The blood brain barrier (BBB) is a highly dynamic structure and consists of endothelial cells, which are characterized by the presence of tight junctions and relative lack of endocytic vesicles. The tight junctions are reinforced by the foot processes of the astrocytes. The BBB functions through these specialised structures, to maintain the environment of the brain in a steady state by regulating the influx and efflux of substances. The protective effect of the BBB is however, lost during bacterial and viral infections. The primary mechanism operative are an increase in the permeability of the BBB and/or direct invasion of the brain by microorganisms. Since the BBB is relatively impermeable to chemotherapeutic agents the treatment of CNS infections is difficult. This paper aims to examine the various mechanisms by which infection spreads to the brain, and suggest measures for successful drug delivery into the brain during infections.


Urinary long noncoding RNAs in nonmuscle-invasive bladder cancer: new architects in cancer prognostic biomarkers.
Several reports over the last 10 years provided evidence that long noncoding RNAs (lncRNAs) are often altered in bladder cancers. lncRNAs are longer than 200 nucleotides and function as important regulators of gene expression, interacting with the major pathways of cell growth, proliferation, differentiation, and survival. A large number of lncRNAs has oncogenic function and is more expressed in tumor compared with normal tissues. Their overexpression may be associated with tumor formation, progression, and metastasis in a variety of tumors including bladder cancer. Although lncRNAs have been shown to have critical regulatory roles in cancer biology, the biological functions and prognostic values in nonmuscle-invasive bladder cancer remain largely unknown. Nevertheless, a growing body of evidence suggests that several lncRNAs expression profiles in bladder malignancies are associated with poor prognosis, and they can be detected in biological fluids, such as urines. Here, we review current progress in the biology and the implication of lncRNAs associated with bladder cancer, and we discuss their potential use as diagnosis and prognosis biomarkers in bladder malignancies with a focus on their role in high-risk nonmuscle-invasive tumors.


Directional light beaming control by a subwavelength asymmetric surface structure.
We propose a direct experimental set-up to observe the directional beaming effect of surface plasmon. A single diffracted beam from an asymmetric-sided surface corrugation is demonstrated. A single subwavelength slit with an asymmetric structure was fabricated using a focused ion beam (FIB) onto a metal surface with a glass substrate. By means of surface plasmon (SP) diffraction, the directionality of the light can be changed by the period of the metallic gratings. We show corresponding numerical simulations achieved by a Rigorous Coupled-Wave Analysis (RCWA) method and a Finite-Difference Time-Domain (FDTD) method. The simulation results were in agreement with the experimental data.


Aging with HIV: a model of disability.
The purpose of this qualitative study was to develop a theoretical model describing the disability experienced by older adults living with HIV. Forty nine HIV positive men and women over the age of 50 years participated in in-depth qualitative interviews. Transcribed interviews were analyzed using grounded theory techniques. Uncertainty or worrying about the future was at the core of the model. Components of disability including symptoms and impairments, difficulties with day to day activities and challenges to social participation were experienced in the context of extrinsic or environmental factors (social support, stigma) and intrinsic contextual factors (positive living strategies, age). Time was an overarching component of the model. The model suggests areas for interventions to prevent or reduce disability related to the consequences of aging with HIV and improve overall quality of life.


Infectivity of bovine adenovirus type 5 recovered from a polyarthritic calf with weak calf syndrome.
Bovine adenovirus type 5, isolated from newborn calves with a polyarthritic disease known as "weak calf syndrome" caused a mild, self-limiting illness in susceptible calves. The induced illness was characterized by marked pyrexia and occasionally by mild diarrhea. It was concluded that the virus may contribute to morbidity and mortality associated with the weak calf syndrome by adding to the stress and debilitation caused by cold wet weather and by bovine viral diarrhea (BVD) virus, which has also been isolated from tissues of calves affected with weak calf syndrome.


Practical Cluster Models for a Layered β-NiOOH Material.
Due to the high oxygen evolution reaction (OER) activity, stability, and abundance of NiOx materials, they are found to be promising catalysts, competitive with expensive metal oxides such as IrO₂ and RuO₂. From a theoretical point of view, studies reported in the literature so far are mostly based on density functional theory using periodic slab models for the bulk and surface of β-NiOOH, one of the active NiOx phases. However, cluster models are a valid method to investigate many aspects about structure, charge carrier transport properties, and OER activity of β-NiOOH. Hence, here we present new cluster models for the surface of β-NiOOH, where the oxygen atoms are bonded to Mg effective core potentials (ECPs) mimicking neighboring atom cores. This cluster embedding procedure is superior to saturating the cluster with hydrogen atoms, and to using other atomic ECPs for β-NiOOH. We find that layered materials such as β-NiOOH are more vulnerable to geometrical rupture and therefore a cluster approach requires additional care in choosing the embedding approach. We evaluated the models by using them to calculate the energy required for water adsorption and deprotonation, which are essential ingredients for OER. Specifically, our results agree with previous slab models that the first deprotonation reaction step requires a large amount of energy. In addition, we find that water and hydroxyl groups have high adsorption energy and therefore the first deprotonation step is limiting the reaction efficiency.


Unmet needs and health care utilization in young adults with cerebral palsy.
To gain insight into the unmet needs and utilization of health care of young adults with cerebral palsy (CP) and to explore relations between unmet needs, health care utilization and subject characteristics. A cross-sectional study was performed in 29 young adults with CP without severe learning disabilities (IQ > 70). Subject characteristics such as age, gender, limb distribution, level of gross motor functioning, level of education and perceived participation and autonomy were measured. Outcome measures were the Southampton Needs Assessment Questionnaire, Impact on Participation and Autonomy and a questionnaire on health care utilization. Young adults with CP reported unmet needs mostly on information (79%), mobility (66%) and health care (66%). About half of the participants visited a rehabilitation physician (52%) or a physical therapist (55%) in the past year. Participants with lower levels of gross motor functioning were found to have more unmet needs and visited various health care professionals more often than young adults with higher levels of gross motor functioning. However, participants with higher levels of gross motor functioning still reported several unmet needs. Although young adults with CP frequently receive treatment from health care professionals, they indicate unmet needs with respect to several areas such as information on diagnosis, functional mobility and formal health care. In the treatment of young adults with CP, attention should be paid to these aspects.