Decorin expression is important for age-related changes in tendon structure and mechanical properties.
The aging population is at an increased risk of tendon injury and tendinopathy. Elucidating the molecular basis of tendon aging is crucial to understanding the age-related changes in structure and function in this vulnerable tissue. In this study, the structural and functional features of tendon aging are investigated. In addition, the roles of decorin and biglycan in the aging process were analyzed using transgenic mice at both mature and aged time points. Our hypothesis is that the increase in tendon injuries in the aging population is the result of altered structural properties that reduce the biomechanical function of the tendon and consequently increase susceptibility to injury. Decorin and biglycan are important regulators of tendon structure and therefore, we further hypothesized that decreased function in aged tendons is partly the result of altered decorin and biglycan expression. Biomechanical analyses of mature (day 150) and aged (day 570) patellar tendons revealed deteriorating viscoelastic properties with age. Histology and polarized light microscopy demonstrated decreased cellularity, alterations in tenocyte shape, and reduced collagen fiber alignment in the aged tendons. Ultrastructural analysis of fibril diameter distributions indicated an altered distribution in aged tendons with an increase of large diameter fibrils. Aged wild type tendons maintained expression of decorin which was associated with the structural and functional changes seen in aged tendons. Aged patellar tendons exhibited altered and generally inferior properties across multiple assays. However, decorin-null tendons exhibited significantly decreased effects of aging compared to the other genotypes. The amelioration of the functional deficits seen in the absence of decorin in aged tendons was associated with altered tendon fibril structure. Fibril diameter distributions in the decorin-null aged tendons were comparable to those observed in the mature wild type tendon with the absence of the subpopulation containing large diameter fibrils. Collectively, our findings provide evidence for age-dependent alterations in tendon architecture and functional activity, and further show that lack of stromal decorin attenuates these changes.


Antipruritic and antiemetic effect of epidural droperidol: comparative study between single and continuous epidural injection.
This study was designed to investigate whether single epidural droperidol or continuous epidural droperidol inhibit pruritus and postoperative nausea and vomiting induced by postoperative continuous epidural fentanyl administration, and to identify the optimal method of administering epidural droperidol. 120 ASA I-II patients undergoing subtotal gastrectomy with general anaesthesia combined with epidural anaesthesia were randomly allocated into three groups: control (no droperidol), single injection (droperidol 2.5 mg) and continuous group (droperidol 2.5 mg 2 day(-1)). Postoperatively the frequency and severity of pruritus and postoperative nausea and vomiting in all groups were compared during 48 h. The frequency and severity of pruritus was significantly lower in both single injection and continuous groups than control group after epidural fentanyl administration (P < 0.05). The frequency and severity of postoperative nausea and vomiting was significantly lower in single injection group than control group after epidural fentanyl administration (P < 0.05). Epidural continuous droperidol is effective for reducing pruritus, and single epidural droperidol injection is effective for reducing pruritus and postoperative nausea and vomiting induced by postoperative continuous epidural fentanyl analgesia.


Donor kidney adapts to body dimensions of recipient: no influence of donor gender on renal function after transplantation.
Female kidneys and kidneys from small donors have been suggested to perform worse after kidney transplantation. Here, we evaluate the impact of gender and body dimensions on posttransplantation GFR in living donor transplantation. Two hundred and ninety-three donor-recipient pairs, who were transplanted at our center were evaluated. All pairs had detailed renal function measurement ((125) I-iothalamate and (131) I-hippuran) 4 months predonation in the donor and 2.5 months posttransplantation in donor and recipient. For 88 pairs, 5 years of recipient follow-up was available. Delta GFR was calculated as (recipient GFR-donor single kidney GFR). Recipients of both male and female kidneys had similar renal function at early and long term after transplantation. Male recipients had higher ERPF, ΔGFR and ΔERPF at both time points. Kidneys of donors smaller than their recipient had higher ΔGFR and ΔERPF than kidneys of larger donors at both time points (p < 0.05). In multivariate analysis, ΔGFR was predicted by donor/recipient BSA-ratio together with transplantation related factors (R(2) 0.19), irrespective of donor and recipient gender. In conclusion, in living donor transplantation, female kidneys perform as well as male donor kidneys. Kidneys adapt to the recipient's body size and demands, independent of gender, without detrimental effects in renal function and outcome up to mid-long term.


Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.
Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p<0·0001), BA.1 (107·3 [86·40-133·2] vs 648·9 [523·5-804·5]; p<0·0001), and BA.4/5 (40·63 [31·99-51·60] vs 223·0 [183·1-271·4]; p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (119 [13·7%; 95% CI 11·5-16·2] of 871) than in those treated with vedolizumab (29 [7·0% [4·8-10·0] of 417; p=0·00040). Cox proportional hazards models of time to breakthrough infection after the third dose of vaccine showed infliximab treatment to be associated with a higher hazard risk than treatment with vedolizumab (hazard ratio [HR] 1·71 [95% CI 1·08-2·71]; p=0·022). Among participants who had a breakthrough infection, we found that higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and, hence, a longer time to breakthrough infection (HR 0·87 [0·79-0·95]; p=0·0028). Our findings underline the importance of continued SARS-CoV-2 vaccination programmes, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy might be reduced, such as those on anti-TNF therapies. Royal Devon University Healthcare NHS Foundation Trust; Hull University Teaching Hospital NHS Trust; NIHR Imperial Biomedical Research Centre; Crohn's and Colitis UK; Guts UK; National Core Studies Immunity Programme, UK Research and Innovation; and unrestricted educational grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos.


Perceived Stress Is Differentially Related to Hippocampal Subfield Volumes among Older Adults.
Chronic exposure to stress has been shown to impact a wide range of health-related outcomes in older adults. Despite extensive animal literature revealing deleterious effects of biological markers of stress on the dentate gyrus subfield of the hippocampus, links between hippocampal subfields and psychological stress have not been studied in humans. This study examined the relationship between perceived stress and hippocampal subfield volumes among racially/ethnically diverse older adults. Between July 2011 and March 2014, 116 nondemented participants were consecutively drawn from the Einstein Aging Study, an ongoing community-based sample of individuals over the age of 70 residing in Bronx, New York. All participants completed the Perceived Stress Scale, Geriatric Depression Scale, and underwent 3.0 T MRI. FreeSurfer was used to derive total hippocampal volume, hippocampal subfield volumes (CA1, CA2/CA3, CA4/Dentate Gyrus (CA4/DG), and subiculum), entorhinal cortex volume, whole brain volume, and total intracranial volume. Linear regression analyses revealed that higher levels of perceived stress were associated with smaller total hippocampal volume (β = -0.20, t = -2.40, p = 0.02), smaller CA2/CA3 volumes (β = -0.18, t = -2.24, p = 0.03) and smaller CA4/DG volumes (β = -0.19, t = -2.28, p = 0.03) after controlling for total intracranial volume, age, gender, and race. These findings remained unchanged after removal of individuals with clinically significant symptoms of depression. Our findings provide evidence of a relationship between a direct indicator of psychological stress and specific hippocampal subfield volumes in elderly individuals. These results highlight the importance of clinical screening for chronic stress in otherwise healthy older adults.


Incident Major Depressive Disorder Predicted by Three Measures of Insulin Resistance: A Dutch Cohort Study.
Major depressive disorder is the leading cause of disability worldwide. Yet, there remain significant challenges in predicting new cases of major depression and devising strategies to prevent the disorder. An important first step in this process is identifying risk factors for the incidence of major depression. There is accumulating biological evidence linking insulin resistance, another highly prevalent condition, and depressive disorders. The objectives of this study were to examine whether three surrogate measures of insulin resistance (high triglyceride-HDL [high-density lipoprotein] ratio; prediabetes, as indicated by fasting plasma glucose level; and high central adiposity, as measured by waist circumference) at the time of study enrollment were associated with an increased rate of incident major depressive disorder over a 9-year follow-up period and to assess whether the new onset of these surrogate measures during the first 2 years after study enrollment was predictive of incident major depressive disorder during the subsequent follow-up period. The Netherlands Study of Depression and Anxiety (NESDA) is a multisite longitudinal study of the course and consequences of depressive and anxiety disorders in adults. The study population comprised 601 NESDA participants (18-65 years old) without a lifetime history of depression or anxiety disorders. The study's outcome was incident major depressive disorder, defined using DSM-IV criteria. Exposure measures included triglyceride-HDL ratio, fasting plasma glucose level, and waist circumference. Fourteen percent of the sample developed major depressive disorder during follow-up. Cox proportional hazards models indicated that higher triglyceride-HDL ratio was positively associated with an increased risk for incident major depression (hazard ratio=1.89, 95% CI=1.15, 3.11), as were higher fasting plasma glucose levels (hazard ratio=1.37, 95% CI=1.05, 1.77) and higher waist circumference (hazard ratio=1.11 95% CI=1.01, 1.21). The development of prediabetes in the 2-year period after study enrollment was positively associated with incident major depressive disorder (hazard ratio=2.66, 95% CI=1.13, 6.27). The development of high triglyceride-HDL ratio and high central adiposity (cut-point ≥100 cm) in the same period was not associated with incident major depression. Three surrogate measures of insulin resistance positively predicted incident major depressive disorder in a 9-year follow-up period among adults with no history of depression or anxiety disorder. In addition, the development of prediabetes between enrollment and the 2-year study visit was positively associated with incident major depressive disorder. These findings may have utility for evaluating the risk for the development of major depression among patients with insulin resistance or metabolic pathology.


Gifted children with learning disabilities: a review of the issues.
Many people have difficulty comprehending that a child can be gifted and also have learning disabilities. As a result, children with special needs that result from both their high abilities and their learning problems are rarely identified and are often poorly served. This article explores the current policies and practices with regard to defining, identifying, and educating this population. Recommendations are included that would help ensure that students who are gifted and have learning disabilities receive the intervention needed to help them achieve their full potential.


Determination of the spectral emission of commercial flashbulbs by emission spectrographic techniques.
The relative energy distributions of the M-2, P-25, AG-1, and M-3 flashbulbs have been determined over the spectral range from 3400 A to 7600 A, using a National Bureau of Standards lamp as a spectral standard, and a Jarrell-Ash Ebert-mount spectrograph as a spectroradiometer. From these data and the blackbody radiation function, values for the color temperature of the flashbulbs have been calculated using a computer to derive a least-squares, best-fit value of color temperature.


The clinical utility of high resolution magnetic resonance imaging in the diagnosis of giant cell arteritis: a critically appraised topic.
Giant cell arteritis (GCA) is a relatively common form of systemic vasculitis, known for its predisposition to affect extracranial branches of the carotid artery and associated potential for causing visual loss and stroke. Neurologists need to be vigilant for this disorder, diagnose it early, and institute effective corticosteroid therapy. The differential diagnosis can be broad. Unfortunately, all clinical and laboratory features of GCA are limited by either low sensitivity or low specificity. Temporal artery biopsy remains the gold standard, but it has its own limitations. Noninvasive imaging techniques, like magnetic resonance imaging (MRI), may be capable of detecting the occurrence of GCA. How useful is high resolution MRI as a diagnostic test in establishing the diagnosis of GCA? We addressed the question through development of a structured critically appraised topic. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarian, and clinical content experts in the field of neuroradiology, rheumatology, and vascular neurology. Participants started with a clinical scenario and a structured question, devised search strategies, located and compiled the best evidence, performed critical appraisals, synthesized the results, summarized the evidence, provided commentary, and declared bottom-line conclusions. A single study which assessed the diagnostic value of MRI against a reference standard in GCA was appraised. For the MRI, the estimated sensitivity was 81% (95% CI 67-95), specificity was 97% (91-100), positive likelihood ratio (LR) was 26.6 (95% CI 3.8-184.8), negative LR was 0.20 (95% CI 0.10-0.41). The study exhibited several methodological weaknesses which interfered with its validity. The specificity and positive LR of high resolution MRI are sufficiently high that a positive MRI combined with other clinical and laboratory data consistent with GCA may be useful in diagnosing GCA. Given the relatively low sensitivity of the test, a negative MRI would not be sufficient to rule out the diagnosis of GCA.


Population genetic structure of savannah elephants in Kenya: conservation and management implications.
We investigated population genetic structure and regional differentiation among African savannah elephants in Kenya using mitochondrial and microsatellite markers. We observed mitochondrial DNA (mtDNA) nucleotide diversity of 1.68% and microsatellite variation in terms of average number of alleles, expected and observed heterozygosities in the total study population of 10.20, 0.75, and 0.69, respectively. Hierarchical analysis of molecular variance of mtDNA variation revealed significant differentiation among the 3 geographical regions studied (F(CT) = 0.264; P < 0.05) and a relatively lower differentiation among populations within regions (F(SC) = 0.218; P < 0.0001). Microsatellite variation significantly differentiated among populations within regions (F(SC) = 0.019; P < 0.0001) but not at the regional levels (F(CT) = 0.000; P > 0.500). We attribute the high differentiation at the mitochondrial genome to the matrilineal social structure of elephant populations, female natal philopatry, and probably ancient vicariance. Lack of significant regional differentiation at the nuclear loci vis-a-vis strong differences at mtDNA loci between regions is likely the effect of subsequent homogenization through male-mediated gene flow. Our results depicting 3 broad regional mtDNA groups and the observed population genetic differentiation as well as connectivity patterns should be incorporated in the planning of future management activities such as translocations.


Actinic reticuloid. A clinical, pathologic, and action spectrum study.
A 54-year-old man suffered from a chronic dermatitis that was more severe on light-exposed areas. Skin biopsy specimens revealed histopathologic findings consistent with those seen in mycosis fungoides. Ultrastructural studies demonstrated the existence of lymphoid cells with hyperconvoluted nuclei, typical of the mycosis fungoides cell or Sézary cell, within the epidermis, dermis, and peripheral blood. Light testing with a monochromator showed abnormal photosensitivity to both short- and long-wave ultraviolet light as well as to the violet, blue, and green wavelengths of visible light. The features of this patient's disease indicate actinic reticuloid.


First Report of Cylindrocladiella parva and C. peruviana Associated with Black-foot Disease of Grapevine in Spain.
From 2007 to 2009, Cylindrocladiella-like isolates were recovered from grapevine (Vitis vinifera L.) roots with symptoms of black-foot disease in Spain, where the causal agents of this disease have been previously reported as Campylocarpon and Cylindrocarpon species (1,2). Three representative isolates were selected to confirm their identity: CPa1 and CPa2 from Asturias (northern Spain), and CPe523 from Cuenca (central Spain). Isolates were incubated on malt extract agar (MEA) and Spezieller Nährstoffarmer Agar (SNA) with carnation leaves (4) at 25°C for 10 days in darkness. On MEA, colonies developed light brown, cottony mycelium. On SNA, all three isolates produced chlamydospores in chains, and conidia were zero-to one-septate, but CPa1 and CPa2 produced longer conidia (10.4 to 18.9 [15.3] × 1.7 to 3.1 [2.4] μm) than CPe523 (6.4 to 12.3 [9.7] × 1.6 to 3.3 [2.4] μm). A fragment of the beta-tubulin gene from all isolates was sequenced with primers T1 and Bt2b (1) and deposited in GenBank (Accession Nos. JQ693133, JQ693134, and JQ693135). CPa1 and CPa2 showed high similarity (99%) to Cylindrocladiella parva (AY793486) and CPe523 showed high similarity (99%) to C. peruviana (AY793500), which is in agreement with the corresponding morphological features of these species (4). Pathogenicity tests were conducted with inoculum produced on wheat (Triticum aestivum L.) seed soaked for 12 h in 300 ml of distilled water and autoclaved three times. Inoculum was prepared by inoculating two fungal disks (8 mm in diameter) of a 2-week-old culture of each isolate grown on potato dextrose agar to wheat seed and incubation at 25°C for 4 weeks. One-month-old grapevine seedlings were planted individually in 220-cc pots filled with a potting medium of sterilized peat moss and 10 g of inoculum, and grown in the greenhouse at 25°C in a completely randomized design. Controls were inoculated with sterile, noninoculated wheat seed. There were six replicate plants per isolate, with an equal number of controls, and the experiment was repeated once. Symptoms developed in all plants by 20 days post-inoculation and consisted of reduced vigor, necrotic root lesions, and occasionally mortality, all of which resembled the symptoms from grapevines in the field from which the isolates were originally recovered. Mean shoot dry weights of inoculated plants (0.25, 0.16, and 0.28 g for CPa1, Cpa2, and CPa523, respectively) were significantly lower (P < 0.05) than that of the controls (0.74 g). Mean root dry weights of inoculated plants (0.28, 0.16, and 0.29 g for CPa1, Cpa2, and CPa523, respectively) were also significantly lower (P < 0.05) than that of the controls (0.68 g). Isolates recovered from the roots of inoculated plants were identical morphologically and molecularly to C. parva and C. peruviana, thereby satisfying Koch's postulates. No symptoms were observed on the control plants. These Cylindrocladiella spp. have been reported from nurseries or vineyards in South Africa and New Zealand (3). To our knowledge, this is the first report of C. parva and C. peruviana associated with black-foot disease of grapevine in Spain, and in Europe. References: (1) S. Alaniz et al. Plant Dis. 91:1187, 2007. (2) S. Alaniz et al. Plant Dis. 95:1028, 2011. (3) E. E. Jones et al. Plant Dis. 96:144, 2012. (4) L. Lombard et al. Mycol. Progress DOI 10.1007/s11557-011-0799-1, 2012.


[Characterization of blood flow in different forms of diabetic foot syndrome].
The lowering of the mean blood flow velocity (Vmean), pulsation index (PI), resistance index (RI) revealed by Doppler ultrasonography is most characteristic of patients with the ischemic form (IF) and mixed form (MF) of diabetic foot syndrome (DFS). The IF is marked by the high degree damping of the pulse wave in limb segments (damping factor). These changes are less significant in the MF of DFS and are in fact lacking in patients with the neuropathic form (NF). In health, the ankle brachial index (ABI) is equal to 1.0. The rise of the index up to 1.1-1.3 is common to patients with the NF of DFS. Occlusion and stenotic lesions of the arteries are associated with the index lowering to 0.7-0.8. The decrease of the index to 0.5 is recorded in critical ischemia. Nevertheless in 10.3% of cases with clinically manifest ischemia, the ABI remains within normal which is determined by arterial wall rigidity in the presence of Menkenberg' s atherosclerosis. Laser Doppler flowmetry provided to patients with the IF of DFS revealed a decrease in the level of the basic and postischemic flow in the feet and legs. The maintenance of the high parameters of the micro-circulatory flow in patients with the NF and MF of DFS is regarded as a consequence of blood shunting in arteriolo-venulat anastomoses. Analysis of thermograms (Thermovision 400, AGEMA) has demonstrated that circulatory deterioration is associated with a decrease in the intensity of infrared irradiation of the legs. Patients with the IF and MF of DFS are characterized by the "amputation" type tomograms This stems from the lowering of the temperature of the distal segments in the presence of ischemia whereas the NF is marked by the "hot feet" symptom. In patients with the IF of DFS, .TcpO2 is 1.3 times lower than in those with the MF and 1.7 times lower in the NF of DFS (p<0.05). In the MF of DFS, the level of oxygenation is 1.3 times lower versus patients with the NF (p<0.05), in which it does not differ from normal. Thus, the hemodynamic parameters in different forms of DFS are significantly different which is especially noticeable in the distal segments of the legs.


Interactions of monovalent cations with sodium channels in squid axon. I. Modification of physiological inactivation gating.
Inactivation of Na channels has been studied in voltage-clamped, internally perfused squid giant axons during changes in the ionic composition of the intracellular solution. Peak Na currents are reduced when tetramethylammonium ions (TMA+) are substituted for Cs ions internally. The reduction reflects a rapid, voltage-dependent block of a site in the channel by TMA+. The estimated fractional electrical distance for the site is 10% of the channel length from the internal surface. Na tail currents are slowed by TMA+ and exhibit kinetics similar to those seen during certain drug treatments. Steady state INa is simultaneously increased by TMA+, resulting in a "cross-over" of current traces with those in Cs+ and in greatly diminished inactivation at positive membrane potentials. Despite the effect on steady state inactivation, the time constants for entry into and exit from the inactivated state are not significantly different in TMA+ and Cs+. Increasing intracellular Na also reduces steady state inactivation in a dose-dependent manner. Ratios of steady state INa to peak INa vary from approximately 0.14 in Cs+- or K+-perfused axons to approximately 0.4 in TMA+- or Na+-perfused axons. These results are consistent with a scheme in which TMA+ or Na+ can interact with a binding site near the inner channel surface that may also be a binding or coordinating site for a natural inactivation particle. A simple competition between the ions and an inactivation particle is, however, not sufficient to account for the increase in steady state INa, and changes in the inactivation process itself must accompany the interaction of TMA+ and Na+ with the channel.


Policy evaluations of microenterprise business support services in Latin America: A systematic review.
Microenterprises represent 88.4 % of Latin American enterprises, and many countries in the region have developed microenterprise promotion policies in recent years; however, rigorous evaluation remains a pending issue. To shed light on the research done on this topic over the last 20 years and propose a roadmap for the policy evaluation of microenterprise business support services and the development of microenterprise indicators, this work conducts a systematic review, following the PRISMA guidelines, of peer-reviewed journal articles examining the impact of business support services on microenterprise performance in low- and middle-income Latin American countries. We identified 679 studies, and 17 studies met the inclusion criteria. We found that the literature is surprisingly scarce; most studies focus on credits and impacts on financial performance and concentrate on Mexico; and only three articles involve randomised controlled trials. Our results have important implications for policymakers and future research.


Altered cortical activation from the hand after facial botulinum toxin treatment.
Plastic interactions between face and hand cortical tactile circuits occur after severe injuries that affect the hand such as in amputation or spinal cord injury. However, whether loss of facial movements alters the cortical circuits involved in processing tactile inputs from the hand remains unknown. In this prospective observational study we used electroencephalography (EEG) to measure cortical activity evoked by tactile stimulation of the hands before and after botulinum toxin-A-induced facial paralysis. We found a reduction in the tactile event-related potentials (ERPs) 6 weeks after the treatment. This suggests that the limited paralysis of facial muscles induced during cosmetic interventions designed to smooth lines and wrinkles on the face is sufficient to alter the cortical processing of tactile inputs from the hand.


Maternal mental health priorities, help-seeking behaviors, and resources in post-conflict settings: a qualitative study in eastern Uganda.
Limited knowledge exists to inform the selection and introduction of locally relevant, feasible, and effective mental health interventions in diverse socio-cultural contexts and health systems. We examined stakeholders' perspectives on mental health-related priorities, help-seeking behaviors, and existing resources to guide the development of a maternal mental health component for integration into non-specialized care in Soroti, eastern Uganda. We employed rapid ethnographic methods (free listing and ranking; semi-structured interviews; key informant interviews and pile sorting) with community health workers (n = 24), primary health workers (n = 26), perinatal women (n = 24), traditional and religious healers (n = 10), and mental health specialists (n = 9). Interviews were conducted by trained Ateso-speaking interviewers. Two independent teams conducted analyses of interview transcripts following an inductive and thematic approach. Smith's Salience Index was used for analysis of free listing data. When asked about common reasons for visiting health clinics, the most salient responses were malaria, general postnatal care, and husbands being absent. Amongst the free listed items that were identified as mental health problems, the three highest ranked concerns were adeka na aomisio (sickness of thoughts); ipum (epilepsy), and emalaria (malaria). The terms epilepsy and malaria were used in ways that reflected both biomedical and cultural concepts of distress. Sickness of thoughts appeared to overlap substantially with major depression as described in international classification, and was perceived to be caused by unsupportive husbands, intimate partner violence, chronic poverty, and physical illnesses. Reported help-seeking for sickness of thoughts included turning to family and community members for support and consultation, followed by traditional or religious healers and health centers if the problem persisted. Our findings add to existing literature that describes 'thinking too much' idioms as cultural concepts of distress with roots in social adversity. In addition to making feasible and effective treatment available, our findings indicate the importance of prevention strategies that address the social determinants of psychological distress for perinatal women in post-conflict low-resource contexts.


Effect of pheniramine maleate on reperfusion injury in brain tissue.
The aim of this study was to investigate the protective effects of methylprednisolone (Pn), which is a potent anti-inflammatory agent, and pheniramine maleate (Ph), which is an antihistaminic with some anti-inflammatory effects, on reperfusion injury in brain developing after ischemia of the left lower extremity of rats. Twenty-eight randomly selected male Sprague-Dawley rats were divided into 4 groups: Group 1 was the control group, Group 2 was the sham group (I/R), Rats in Group 3 were subjected to I/R and given Ph, and rats in Group 4 were subjected to I/R and given Pn. A tourniquet was applied at the level of left groin region of subjects in the I/R group after induction of anesthesia. One h of ischemia was performed with no drug administration. In the Ph group, half of a total dose of 10 mg/kg Ph was administered intraperitoneally before ischemia and the remaining half before reperfusion. In the Pn group, subjects received a single dose of 50 mg/kg Pn intraperitoneally at the 30th min of ischemia. Brains of all subjects were removed after 24 h for examination. Malondialdehyde (MDA) levels of the prefrontal cortex were significantly lower in the Ph group than in the I/R group (p<0.05). Superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities were found to be significantly higher in the Ph group than in the I/R group (p<0.05). Histological examination demonstrated that Ph had protective effects against I/R injury developing in the brain tissue. Ph has a protective effect against ischemia/reperfusion injury created experimentally in rat brains.


Higher quality of life and lower depression for people on ART in Uganda as compared to a community control group.
Provision of antiretroviral treatment (ART) to people living with HIV (PLWH) has increased globally. Research measuring whether ART restores subjective well-being to "normal" levels is lacking, particularly in resource limited settings. The study objectives are to compare quality of life and depression symptoms for PLWH on ART to a general community population and to explore factors to explain these differences, including socio-economic status and the impact of urban or rural residence. PLWH on ART (n = 263) were recruited from ART delivery sites and participants not on ART (n = 160) were recruited from communities in Wakiso District, Uganda. Participants were interviewed using the translated World Health Organisation Quality of Life brief measure, the Hopkins Symptom Checklist depression section, and questions about socio-economic status, residence as urban or rural and, for PLWH on ART, self-reported adherence and use of HIV counselling. Compared to the community sample and controlling for location of residence, PLWH on ART had significantly higher quality of life (QOL) for physical, psychological and environment domains, but not the social domain. These differences were not due to socio-economic status alone. Depression scores were significantly lower for PLWH on ART. Both comparisons controlled for the effect of location of residence. People on ART self-reported high adherence and the majority had used HIV counselling services. Our findings show better QOL amongst PLWH on ART compared to a general community sample, which cannot be explained solely by differences in socio-economic status nor location of residence. The general community sample results point towards the challenges of life in this setting. Access to health services may underpin this difference and further research should explore this finding, in addition to identification of psychological mechanisms that relate to better QOL. ART provision infrastructure has clear benefits. Further work should consider sustainability and replication for other health conditions.


Occupations on the map: Using a super learner algorithm to downscale labor statistics.
Detailed and accurate labor statistics are fundamental to support social policies that aim to improve the match between labor supply and demand, and support the creation of jobs. Despite overwhelming evidence that labor activities are distributed unevenly across space, detailed statistics on the geographical distribution of labor and work are not readily available. To fill this gap, we demonstrated an approach to create fine-scale gridded occupation maps by means of downscaling district-level labor statistics, informed by remote sensing and other spatial information. We applied a super-learner algorithm that combined the results of different machine learning models to predict the shares of six major occupation categories and the labor force participation rate at a resolution of 30 arc seconds (~1x1 km) in Vietnam. The results were subsequently combined with gridded information on the working-age population to produce maps of the number of workers per occupation. The super learners outperformed (n = 6) or had similar (n = 1) accuracy in comparison to best-performing single machine learning algorithms. A comparison with an independent high-resolution wealth index showed that the shares of the four low-skilled occupation categories (91% of the labor force), were able to explain between 28% and 43% of the spatial variation in wealth in Vietnam, pointing at a strong spatial relationship between work, income and wealth. The proposed approach can also be applied to produce maps of other (labor) statistics, which are only available at aggregated levels.


Coupling of c-fos expression in the spinal cord and amygdala induced by dorsal neck muscles fatigue.
c-fos gene expression in the cervical spinal cord and amygdala was examined in anaesthetized rats following muscle fatigue caused by intermittent high-rate (100 s(-1)) electrical stimulation of the dorsal neck muscles (m. trapezius and m. splenius). Fatigue-related increases in c-fos expression were observed on the stimulated muscle side in the cervical C2-C4 (layers 1, 3-5, 7 and 10) spinal segments, bilaterally in the lumbar L4-L6 (layer 1) segments and in contralateral central (Ce), medial (Me), and basomedial (BM) amygdaloid nuclei. A scarce number of staining cells were found within lateral and basolateral nuclei. The rostro-caudal extent of c-fos expression in the spinal cord supports functional coupling of the cervical and lumbar regions during the neck muscle fatigue development. The distinct c-fos expression in the Ce and Me amygdaloid nuclei suggests that they may contribute to mediating the neck muscle fatigue-related nociception, autonomic and behavioural responses.


The dramatic effect of the annealing temperature and dielectric functionalization on the electron mobility of indene-C60 bis-adduct thin films.
Herein we report on the charge transport properties of spin-coated thin films of an n-type fullerene derivative, i.e. the indene-C60 bis-adduct (ICBA). In particular, the effects of annealing temperature and duration as well as surface functionalization are explored. Electron mobilities approaching 0.1 cm(2) V(-1) s(-1) are reported.


Altered Theory of Mind in Parkinson's Disease and Impact on Caregivers: A Pilot Study.
Mild cognitive impairment (MCI) in Parkinson's disease (PD) includes deficits in theory of mind (ToM). However, associations between ToM and caregiver burden and distress are still unclear. The objective of this pilot study was to preliminarily explore the relation between ToM and caregiver burden and distress in a sample of PD-MCI patients. Twelve PD-MCI patients were evaluated on a ToM task (Faux Pas), whereas their caregivers were assessed on caregiver burden (Zarit Burden Interview-12 items) and distress (Neuropsychiatric Inventory-Distress). Cognitive ToM was significantly associated with caregiver distress, but caregiver burden was associated with the severity of patient psychiatric symptoms.


Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial.
This prospective, multicenter, phase II study investigated the use of four cycles of bortezomib-dexamethasone induction treatment, followed by high-dose melphalan and autologous stem cell transplantation (SCT) in patients with newly diagnosed light chain amyloidosis. The aim of the study was to improve the hematologic complete remission (CR) rate 6 months after SCT from 30% to 50%. Fifty patients were enrolled and 72% had two or more organs involved. The overall hematologic response rate after induction treatment was 80% including 20% CR and 38% very good partial remissions (VGPR). Fifteen patients did not proceed to SCT for various reasons but mostly treatment-related toxicity and disease-related organ damage and death (2 patients). Thirty-one patients received melphalan 200 mg/m2 and four patients a reduced dose because of renal function impairment. There were no deaths related to the transplantation procedure. Hematologic responses improved at 6 months after SCT to 86% with 46% CR and 26% VGPR. However, due to the high treatment discontinuation rate before transplantation the primary endpoint of the study was not met and the CR rate in the intention-to-treat analysis was 32%. Organ responses continued to improve after SCT. We confirm the high efficacy of bortezomib-dexamethasone treatment in patients with AL amyloidosis. However, because of both treatment-related toxicity and disease characteristics, 30% of the patients could not proceed to SCT after induction treatment. (Trial registered at Dutch Trial Register identifier NTR3220).


Hyperbaric oxygen for carbon monoxide poisoning.
Poisoning with carbon monoxide (CO) remains an important cause of accidental and intentional injury worldwide. Several unblinded non-randomized trials have suggested that the use of hyperbaric oxygen (HBO) prevents the development of neurological sequelae. This has led to the widespread use of HBO in the management of patients with carbon monoxide poisoning. To examine randomized trials of the effectiveness of hyperbaric oxygen (HBO) compared to normobaric oxygen (NBO) for the prevention of neurologic sequelae in patients with acute carbon monoxide poisoning. We searched MEDLINE (1966-present), EMBASE (1980-present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognized content experts. All randomized controlled trials involving non-pregnant adults acutely poisoned with carbon monoxide (regardless of severity), with adequate or unclear allocation concealment. Two reviewers independently extracted from each trial information on: the number of randomized patients, types of participants, the dose and duration of the intervention, and the prevalence of neurologic symptoms at follow-up. Seven randomized controlled trials of varying quality were identified; one was excluded because it did not evaluate clinical outcomes. Of the six remaining trials, two represent incomplete publications (one interim analysis, one abstract). Of these six trials, four found no benefit of HBO for the reduction of neurologic sequelae, while two others did. Although pooled analysis does not suggest a benefit from HBOT (OR for neurological deficits 0.78, 95%CI 0.54 to 1.12, p=0.18), significant methodologic and statistical heterogeneity was apparent among the trials, and this result should be interpreted cautiously. Moreover, design or analysis flaws were evident in all trials. Importantly, the conclusions of one positive trial may have been influenced by failure to adjust for multiple hypothesis testing, while interpretation of the other positive trial is hampered by apparent changes in the primary outcome during the course of the trial. Existing randomized trials do not establish whether the administration of HBO to patients with carbon monoxide poisoning reduces the incidence of adverse neurologic outcomes. Additional research is needed to better define the role, if any, of HBO in the treatment of patients with carbon monoxide poisoning. This research question is ideally suited to a multi-center randomized controlled trial.


Medical resource use and expenditure in patients with chronic heart failure: a population-based analysis of 88 195 patients.
Heart failure (HF) is one of the diseases with greater healthcare expenditure. However, little is known about the cost of HF at a population level. Hence, our aim was to study the population-level distribution and predictors of healthcare expenditure in patients with HF. This was a population-based longitudinal study including all prevalent HF cases in Catalonia (Spain) on 31 December 2012 (n = 88 195). We evaluated 1-year healthcare resource use and expenditure using the Health Department (CatSalut) surveillance system that collects detailed information on healthcare usage for the entire population. Mean age was 77.4 (12) years; 55% were women. One-year mortality rate was 14%. All-cause emergency department visits and unplanned hospitalizations were required at least once in 53.4% and 30.8% of patients, respectively. During 2013, a total of €536.2 million were spent in the care of HF patients (7.1% of the total healthcare budget). The main source of expenditure was hospitalization (39% of the total) whereas outpatient care represented 20% of the total expenditure. In the general population, outpatient care and hospitalization were the main expenses. In multivariate analysis, younger age, higher presence of co-morbidities, and a recent HF or all-cause hospitalization were independently associated with higher healthcare expenditure. In Catalonia, a large portion of the annual healthcare budget is devoted to HF patients. Unplanned hospitalization represents the main source of healthcare-related expenditure. The knowledge of how expenditure is distributed in a non-selected HF population might allow health providers to plan the distribution of resources in patients with HF.


Analysis of self-evaluated ethical competence of midwifery students at a selected nursing college in the Free State.
It is imperative to know whether the students who have undergone a specific training perceive themselves as confident and competent in handling ethical dilemmas, in the face of contemporary ethical challenges. Such evaluation is significant especially for nursing and midwifery students who have undergone training that stipulates adherence to a code of ethics and professional norms. At present, such knowledge is limited, and this has an impact for ethics education. The article aims to describe the self-evaluated ethical competence of midwifery students and to contrast the findings to the content of the ethics instruction received. Based on outcomes, the article aims to convey the claim to nursing institutions that current strategies that rely on teaching nursing ethics without appraising the context of a situation are ineffective in fostering ethical competence amongst students. This study made use of a set of self-reflection reports in which the midwifery nursing students narrated their experiences in handling ethical issues. Analysis of the self-reflective reports revealed that one of the three dimensions of ethical competence was limited. There was evidence of moral perception, moral action and substandard moral reasoning. The principles that were mostly referred to within the narratives were autonomy and beneficence. The findings support the argument that teaching principlism and enforcing a code of ethics without contextualising it coerces the student to conform without questioning their beliefs. Thus, ethical competence amongst the midwifery students may be described in terms of compliance to principles with limited reflection on the situation as a whole.


Characteristics of sexual partnerships, not just of individuals, are associated with condom use and recent HIV infection in rural South Africa.
Characteristics of sexual partnerships, as well as those of the individuals involved, might influence the use of condoms and risk of HIV transmission. We set out to identify characteristics of non-spousal sexual partnerships associated with condom use at last sex in the previous year and HIV infection in the previous three years among sexually active young people in rural South Africa. We conducted an analysis of follow-up data (collected in 2004) from a cohort of 14-35-year old men and women recruited to a cluster-randomised trial. Data on 1647 non-spousal sexual partnerships during the previous year were reported in 2004 and analysed alongside new HIV infections over the previous three years among 762 individuals who were HIV-negative in 2001. Structured interviews elicited information on sexual behaviour. HIV serostatus was assessed through oral-fluid ELISA. Condom use at last sex was reported for 615/1647 non-spousal sexual partnerships (37.3%) and was more commonly reported by individuals who were younger, more educated and aware of their HIV status. Condom use was more common in casual partnerships, those where the male partner was younger, where sex was less frequent and where the respondent believed the partner to have other sexual contacts. New HIV infection in the last three years was identified for 87/762 individuals (11.4%) and was more common among females and those out of school. Infection risk was associated with the age of the partners and was less common among individuals reporting less frequent intercourse in the previous year. Characteristics of sexual partnerships, as well as those of individuals, are important determinants of condom use and risk of HIV infection. Male characteristics may be particularly important because of their greater capacity to make decisions about HIV prevention. Established non-spousal sexual partnerships are an increasingly important context for HIV transmission in this setting.


Global mass spectrometry and transcriptomics array based drug profiling provides novel insight into glucosamine induced endoplasmic reticulum stress.
We investigated the molecular effects of glucosamine supplements, a popular and safe alternative to nonsteroidal anti-inflammatory drugs, for decreasing pain, inflammation, and maintaining healthy joints. Numerous studies have reported an array of molecular effects after glucosamine treatment. We questioned whether the differences in the effects observed in previous studies were associated with the focus on a specific subproteome or with the use of specific cell lines or tissues. To address this question, global mass spectrometry- and transcription array-based glucosamine drug profiling was performed on malignant cell lines from different stages of lymphocyte development. We combined global label-free MS-based protein quantitation with an open search for modifications to obtain the best possible proteome coverage. Our data were largely consistent with previous studies in a variety of cellular models. We mainly observed glucosamine induced O-GlcNAcylation/O-GalNAcylation (O-HexNAcylation); however, we also observed global and local changes in acetylation, methylation, and phosphorylation. For example, our data provides two additional examples of "yin-yang" between phosphorylation and O-HexNAcylation. Furthermore, we mapped novel O-HexNAc sites on GLU2B and calnexin. GLU2B and calnexin are known to be located in the endoplasmic reticulum (ER) and involved in protein folding and quality control. The O-HexNAc sites were regulated by glucosamine treatment and correlated with the up-regulation of the ER stress marker GRP78. The occupancy of O-HexNAc on GLU2B and calnexin sites differed between the cytosolic and nuclear fractions with a higher occupancy in the cytosolic fraction. Based on our data we propose the hypothesis that O-HexNAc either inactivates calnexin and/or targets it to the cytosolic fraction. Further, we hypothesize that O-HexNAcylation induced by glucosamine treatment enhances protein trafficking.


Statins, HMG-CoA Reductase Inhibitors, Improve Neovascularization by Increasing the Expression Density of CXCR4 in Endothelial Progenitor Cells.
Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are used to reduce cholesterol biosynthesis in the liver. Accordingly, statins regulate nitric oxide (NO) and glutamate metabolism, inflammation, angiogenesis, immunity and endothelial progenitor cells (EPCs) functions. The function of EPCs are regulated by stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β), etc. Even though the pharmacologic mechanisms by which statins affect the neovasculogenesis of circulating EPCs, it is still unknown whether statins affect the EPCs function through the regulation of CXCR4, a SDF-1 receptor expression. Therefore, we desired to explore the effects of statins on CXCR4 expression in EPC-mediated neovascularization by in vitro and in vivo analyses. In animal studies, we analyzed the effects of atorvastatin or rosuvastatin treatments in recovery of capillary density and blood flow, the expression of vWF and CXCR4 at ischemia sites in hindlimb ischemia ICR mice. Additionally, we analyzed whether the atorvastatin or rosuvastatin treatments increased the mobilization, homing, and CXCR4 expression of EPCs in hindlimb ischemia ICR mice that underwent bone marrow transplantation. The results indicated that statins treatment led to significantly more CXCR4-positive endothelial progenitor cells incorporated into ischemic sites and in the blood compared with control mice. In vivo, we isolated human EPCs and analyzed the effect of statins treatment on the vasculogenic ability of EPCs and the expression of CXCR4. Compared with the control groups, the neovascularization ability of EPCs was significantly improved in the atorvastatin or rosuvastatin group; this improvement was dependent on CXCR4 up-regulation. The efficacy of statins on improving EPC neovascularization was related to the SDF-1α/CXCR4 axis and might be regulated by the NO. In conclusion, atorvastatin and rosuvastatin improved neovascularization in hindlimb ischemia mice; this effect may have been mediated by increased CXCR4 expression in EPCs.


Expression and hormonal regulation of coactivator and corepressor genes.
Steroid/thyroid/retinoid receptors are members of the nuclear receptor superfamily and ligand-inducible transcription factors. These receptors modulate transcription of various cellular genes, either positively or negatively, by interacting with specific hormone-response elements located in the target gene promoters. Recent data show that nuclear receptors enhance or inhibit transcription by recruiting an array of coactivator and corepressor proteins to the transcription complex. We examined and compared the expression of four coactivator (steroid receptor coactivator-1 and E1A-associated 300-kDa protein) and corepressor (SMRT and N-CoR) genes in a number of tissues including several endocrine glands and cell lines. We also addressed whether their messenger RNA levels are hormonally regulated by studying the effects of thyroid hormone (T3) and estrogen (E2) treatment in rat pituitary cells (GH3) in vitro and in anterior pituitary in vivo. Our studies show that there are distinct tissue-specific expression patterns of these genes. We show that T3 and E2 regulate the expression of steroid receptor coactivator-1 messenger RNA in the anterior pituitary in addition to a gender-related difference. These tissue variations may have physiological implications for heterogeneity of hormone responses that are observed in normal and malignant tissues.


Open-wedge high tibial osteotomy: comparison between manual and computer-assisted techniques.
The purpose of our study was to compare clinical and radiological results of two groups of patients treated for medial compartment osteoarthritis of the knee with either conventional or computer-assisted open-wedge high tibial osteotomy (HTO). Goals of surgical treatment were a correction of the mechanical axis between 2° and 6° of valgus and a modification of posterior tibial slope between -2° and +2°. Twenty-four patients (27 knees) affected by varus knee deformity and operated with HTO were prospectively followed-up. They were randomly divided in two groups, A (11 patients, conventional treatment) and B (13 patients, navigated treatment). The American Knee Society Score and the Modified Cincinnati Rating System Questionnaire were used for clinical assessment. All patients were radiologically evaluated with a comparative lower limb weight-bearing digital radiograph, a standard digital anteroposterior, a latero-lateral radiograph of the knee, and a Rosenberg view. Patients were followed-up at a mean of 39 months. Clinical evaluation showed no statistical difference (n.s.) between the two groups. Radiological results showed an 86% reproducibility in achieving a mechanical axis of 182°-186° in group B compared to a 23% in group A (p = 0.0392); furthermore, in group B, we achieved a modification of posterior tibial slope between -2° and +2° in 100% of patients, while in group A, this goal was achieved only in 24% of cases (p = 0.0021). High tibial osteotomy with navigator is more accurate and reproducible in the correction of the deformity compared to standard technique. Therapeutic study, Level II.


Changes in the prevalence of asthma, eczema and hay fever in pre-pubertal children: a 40-year perspective.
Surveys of primary schools children in Aberdeen carried out in 1964, 1989, 1994 and 1999 suggested a slowing of the increase in parent-reported wheeze between 1994 and 1999. To assess whether this pattern had continued, questionnaires were distributed to 5712 children aged 7-12 years in the same schools in 2004. A total of 3271 (57.3%) completed questionnaires were returned. As in earlier surveys the results were divided into those for younger children (school years 3-4; age 7-9 years) and older children (school years 5-7; age 9-12 years). Compared with 1999, the 2004 results showed a decrease in the proportion of children with wheeze in the last 3 years from 30.1% to 23.3% (P < 0.001) in the younger group and from 27.6% to 25.1% (P = 0.052) in the older group. There was no significant change in the lifetime prevalence of asthma in either the younger or the older group, but the lifetime prevalence of eczema and hay fever increased by around 10% in both the younger and older groups (all P < 0.001). The differences in the time trends for the different conditions suggest that the causal factors for wheeze and asthma differ from those for other allergic diseases of childhood.


Prospective study on the association between harm avoidance and postpartum depressive state in a maternal cohort of Japanese women.
Recent studies have displayed increased interest in examining the relationship between personality traits and the onset, treatment response patterns, and relapse of depression. This study aimed to examine whether or not harm avoidance (HA) was a risk factor for postpartum depression measured by the Edinburgh Postnatal Depression Scale (EPDS) and the state dependency of HA. Pregnant women (n=460; mean age 31.9±4.2 years) who participated in a prenatal program completed the EPDS as a measure of depressive state and the Temperament and Character Inventory (TCI) as a measure of HA during three periods: early pregnancy (T1), late pregnancy (around 36 weeks), and 1 month postpartum (T2). Changes in EPDS and HA scores from T1 to T2 were compared between the non depressive (ND) group and the postpartum depressive (PD) group. There was no significant difference in the level of HA between the ND and PD groups at T1. In the ND group, EPDS and HA scores did not change significantly from T1 to T2. In the PD group, both scores increased significantly from T1 to T2 (EPDS, p<0.0001; HA, p<0.048). In the ND and PD groups, a significant positive correlation was observed in changes in EPDS and HA scores from T1 to T2 (r=0.31, p=0.002). These results suggest that HA cannot be considered a risk factor for the development of postpartum depression measured by EPDS. Furthermore, HA may be state dependent.


Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.
Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10-7) and 15 (chr15:53338796A>G, p = 1.5×10-7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.


Antiviral activity of bone morphogenetic proteins and activins.
Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.


Metal-Based Combinations That Target Protein Synthesis by Fungi.
A wide range of fungicides (or antifungals) are used in agriculture and medicine, with activities against a spectrum of fungal pathogens. Unfortunately, the evolution of fungicide resistance has become a major issue. Therefore, there is an urgent need for new antifungal treatments. Certain metals have been used for decades as efficient fungicides in agriculture. However, concerns over metal toxicity have escalated over this time. Recent studies have revealed that metals like copper and chromate can impair functions required for the fidelity of protein synthesis in fungi. This occurs through different mechanisms, based on targeting of iron-sulphur cluster integrity or competition for uptake with amino acid precursors. Moreover, chromate at least acts synergistically with other agents known to target translation fidelity, like aminoglycoside antibiotics, causing dramatic and selective growth inhibition of several fungal pathogens of humans and plants. As such synergy allows the application of decreased amounts of metals for effective inhibition, it lessens concerns about nonspecific toxicity and opens new possibilities for metal applications in combinatorial fungicides targeting protein synthesis.


Pulsed electromagnetic field affects intrinsic and endoplasmatic reticulum apoptosis induction pathways in MonoMac6 cell line culture.
Current studies were aimed to elucidate influence of pulsed electromagnetic field stimulation on cell viability and apoptosis induction pathways. For the experimental model we have chosen monocytic cell line MonoMac6 and several apoptosis inducers with different mechanism of death induction like puromycin, colchicine, cyclophosphamide, minocycline and hydrogen peroxide. MonoMac6 cell line was grown at density 1x10(5) cells/well in 96-well culture plates. To induce cell death cell cultures were treated with different apoptosis inducers like puromycin, colchicine, cyclophosphamide, minocycline, hydrogen peroxide and at the same time with pulsed electromagnetic field 50 Hz, 45±5 mT (PEMF) for 4 hour per each stimulation, three times, in 24 hours intervals. Afterwards, cells were harvested for flow cytometry analysis of cell viability measured by annexin V-APC labeled and propidium iodide staining. Expression of apoptosis related genes was evaluated by semi quantitative reverse transcription (RT)-PCR assay. NuPAGE Novex Western blot analysis was carried out for apoptosis inducing factor (AIF) abundance in cytosolic and nuclear extracts of MonoMac6 cells. Puromycin, colchicine and minocycline activated cells and simultaneously treated with PEMF have shown out diminished percentage of annexinV positive (AnV+) cells comparing to controls without PEMF stimulation. MonaMac6 cells puromycin/colchicyne and PEMF treated were to a higher extent double stained (AnV+,PI+), which means increased late apoptotic as well as necrotic (PI+) cells, than non-stimulated controls. On the other hand, minocycline activated cells prior to PEMF treatment showed diminished amount of apoptotic and necrotic (annexin V, annexin V and propidium iodide, propidium iodide positive staining) cells. The opposite effect of PEMF on the percentage of annexin V positively stained cells has been achieved after treatment of MonoMac6 culture with cyclophoshamide and hydrogen peroxide. PEMF enhanced early phase of apoptosis induced by both apoptosis inducing agents. The analysis of expression of the apoptosis related genes in MonoMac6 cultures treated with puromycin and exposed to PEMF performed in reverse transcription of polymerase chain reaction (PCR) assay has shown changes in mRNA of genes engaged in intrinsic apoptotic pathway and pathway with AIF abundance. The most influenced was expression of gene belonging to pro-apoptotic family of Bcl-2 and AIF agent. Examination of immunoblots developed with anti-AIF antibody showed that cytosol content of AIF protein was diminished after puromycin and PEMF treatment of MonoMac6 cells. The obtained results indicate that PEMF affects induction of apoptosis in MonoMac6 cells stimulated to death with inducing agents to a different extent. Main finding of the current results is that, PEMF stimulation of MonoMac6 cells simultaneously treated with puromycin caused changes in the Bcl-family genes expression as well as in caspase independent pathway of apoptosis inducing factor (AIF).


Naturopathic management of rheumatoid arthritis.
Complementary and alternative medicines (CAM) are widely used by those with pain and/or musculoskeletal problems, and previous research has shown that high proportions of individuals with rheumatoid arthritis have used these therapies. One of the largest CAM modalities is that of naturopathy, which combines nutritional, herbal, and other complementary practices to treat such conditions. In this review, evidence is examined in relation to those factors which naturopaths believe are significant contributors to rheumatoid arthritis, and are hence the main focus of therapeutic management. These factors include food allergy, increased gut permeability, increased circulating immune complexes, excessive inflammatory processes, and increased oxidative stress. Naturopathic treatment attempts to alleviate symptoms by altering these factors through dietary modification, manipulation of dietary fats, and use of antioxidants and proteolytic enzymes. An understanding of the rationale for these treatments and evaluation of the evidence from their use in clinical settings will assist with the integration of complementary and conventional practices in the treatment of rheumatoid arthritis.


Acute Effects of Two Types of Dumbbell Exercise on Oxygenated Hemodynamic Concentration of Cerebral Activation in Healthy Young Male Adults: A Functional Near-Infrared Spectroscopy Study.
Purpose: To examine cerebral cortical activation differences in the frontal cortex and parietal lobe during the performance of two types of dumbbell exercise. Methods: A total of 22 young healthy male adults (mean age, 23.8 ± 2.05 years; height, 1.75 ± 0.06 m; weight, 71.4 ± 8.80 kg) participated in a crossover design study that involved two experimental exercise conditions: momentum dumbbell and conventional dumbbell. Performance tasks included 10, 10-s sets of single-arm dumbbell exercise, with a rest interval of 60 s between sets and a 5-min washout period between conditions. The primary outcome was the cerebral concentrations of oxygenated hemoglobin (HbO2) in the frontal cortex and parietal lobe assessed during performance of both exercises using functional near-infrared spectroscopy (fNIRS). The secondary outcome was upper-limb muscle activation measured using surface electromyography (sEMG). Outcome data were ascertained during exercise. Results: A significant between-condition difference in HbO2 was observed in the frontal and parietal regions with an increase in HbO2 during momentum, relative to conventional, dumbbell exercise (p < 0.05). Compared to conventional dumbbell exercise, performing a momentum dumbbell exercise led to a higher level of muscle activation in the anterior and posterior deltoids of the upper arm and in the flexor carpi radialis and extensor carpi radialis longus of the forearm (p < 0.05). However, no between-condition differences were found in the biceps and triceps brachii (p > 0.05). Conclusion: Dynamic, compared with conventional, dumbbell exercise resulted in higher hemodynamic responses and greater upper-limb muscle activation in young healthy adults. The findings of this study showed differential cortical hemodynamic responses during performance of the two types of dumbbell exercise with a higher activation level produced during momentum-based dumbbell exercise.


Occupational asthma caused by chloramines in indoor swimming-pool air.
The first series of three workers who developed occupational asthma following exposure to airborne chloramines in indoor chlorinated swimming pools is reported. Health problems of swimmers in indoor pools have traditionally been attributed to the chlorine in the water. Chlorine reacts with bodily proteins to form chloramines; the most volatile and prevalent in the air above swimming pools is nitrogen trichloride. Two lifeguards and one swimming teacher with symptoms suggestive of occupational asthma kept 2-hourly measurements of peak expiratory flow at home and at work, analysed using the occupational asthma system (OASYS) plotter, and/or had specific bronchial challenge testing to nitrogen trichloride, or a workplace challenge. Air measurement in one of the pools showed the nitrogen trichloride levels to be 0.1-0.57 mg x m(-3), which was similar to other studies. Two workers had peak expiratory flow measurements showing occupational asthma (OASYS-2 scores 2.88 and 3.8), both had a positive specific challenge to nitrogen trichloride at 0.5 mg x m(-3) with negative challenges to chlorine released from sodium hypochlorite. The third worker had a positive workplace challenge. Swimming-pool asthma due to airborne nitrogen trichloride can occur in workers who do not enter the water because of this chloramine. The air above indoor swimming pools therefore needs to be assessed and managed as carefully as the water.


An Insight into the Effect of Exercises on the Prevention of Osteoporosis and Associated Fractures in High-risk Individuals.
The purpose of this review was to investigate what type of exercises can potentially prevent osteoporosis (OP) and its associated fractures in high-risk populations. MEDLINE was searched for work relevant to various types of exercises used to prevent osteoporotic fractures in high-risk population, from the year 1995 onwards. Twelve articles were identified, and, from them, four were deemed suitable to the objective. The studies reviewed show that various types of exercise are effective and safe in preventing the onset of OP. For example, high-intensity progressive resistance training (HiPRT) has been shown to increase vertebral height and femoral neck bone mineral density (BMD), in addition to improving functional performance. Additional studies reviewed suggested that bone reabsorption levels may be positively impacted by low-impact exercise, such as walking. This review provides insight into the effectiveness of various types of exercise to combat and possibly prevent OP for high-risk individuals, which include postmenstrual Caucasian females, people with multiple comorbidities, individuals who smoke or consume alcohol, and the frail elderly population. The prevention of OP should reduce both the social (emotional) and economic burdens faced by patients, caregivers, and health-care systems. Moving forward, research that identifies and bridges pharmaceutical treatment and exercise should be conducted, in addition to the comparison of passive versus active forms of exercise to determine which treatment best prevents OP in high-risk populations.


Thresholds of resistance to CSF outflow in predicting shunt responsiveness.
Disturbances in cerebrospinal fluid (CSF) absorption capacity represent one of the primary causes of normal pressure hydrocephalus (NPH). The resistance to CSF outflow (Rout) may reflect the severity of this disturbance and has been used as a supplementary parameter to predict shunt responsiveness. However, there is no widely accepted threshold of Rout in this scenario. This study aimed to determine the most appropriate threshold through meta-analyses. A total of four previously reported cutoff values of Rout (10, 12, 15, and 18 mmHg/ml/minutes) were selected as potential thresholds. A systematic review of existing studies involving NPH, shunt surgeries, and Rout was conducted. The pooled results from retrieved articles were subjected to statistical analyses. A total of nine studies were included in the meta-analyses based on the available preoperative Rout and postoperative improvement of subjects. The odds ratios of the four thresholds were 2·82, 3·58, 2·72, and 2·38 for 10, 12, 15, and 18 mmHg/ml/minutes of Rout, respectively. The Rout of 12 mmHg/ml/minutes yielded high accuracy (72·95%), high sensitivity (80·26%), and moderate specificity (46·79%). The presented study conducted meta-analyses and revealed that a Rout of 12 mmHg/ml/minutes is the most suitable threshold for predicting shunt responsiveness in NPH patients.


Anticipatory anxiety disrupts neural valuation during risky choice.
Incidental negative emotions unrelated to the current task, such as background anxiety, can strongly influence decisions. This is most evident in psychiatric disorders associated with generalized emotional disturbances. However, the neural mechanisms by which incidental emotions may affect choices remain poorly understood. Here we study the effects of incidental anxiety on human risky decision making, focusing on both behavioral preferences and their underlying neural processes. Although observable choices remained stable across affective contexts with high and low incidental anxiety, we found a clear change in neural valuation signals: during high incidental anxiety, activity in ventromedial prefrontal cortex and ventral striatum showed a marked reduction in (1) neural coding of the expected subjective value (ESV) of risky options, (2) prediction of observed choices, (3) functional coupling with other areas of the valuation system, and (4) baseline activity. At the same time, activity in the anterior insula showed an increase in coding the negative ESV of risky lotteries, and this neural activity predicted whether the risky lotteries would be rejected. This pattern of results suggests that incidental anxiety can shift the focus of neural valuation from possible positive consequences to anticipated negative consequences of choice options. Moreover, our findings show that these changes in neural value coding can occur in the absence of changes in overt behavior. This suggest a possible pathway by which background anxiety may lead to the development of chronic reward desensitization and a maladaptive focus on negative cognitions, as prevalent in affective and anxiety disorders.


Hydrogenophaga crassostreae sp. nov., isolated from a Pacific oyster.
A Gram-negative, motile, rod-shaped, and aerobic bacterial strain, designated LPB0072T, was isolated from a Pacific oyster (Crassostrea gigas). Autotrophic growth with hydrogen gas was not observed. Cells oxidized thiosulfate to sulfate and reduced nitrate to nitrite. The complete genome sequence of strain LPB0072T (CP017476) is 4.94 Mb in length and contains 4459 protein-coding genes, with a G+C content of 61.3 mol%. Analysis of the 16S rRNA gene sequence indicated that strain LPB0072T belongs to the genus Hydrogenophaga, with greatest sequence similarity to the type strain of Hydrogenophaga taeniospiralis (97.5 %). The isoprenoid quinone (Q-8) and the major cellular fatty acids (C16 : 1ω7c and/or C16 : 1ω6c, C16 : 0 and C17 : 1ω6c) identified were concordant with the chemotaxonomic properties of the genus Hydrogenophaga. The average nucleotide identities with closely related species were below the suggested boundary for species delineation, indicating that the isolate is a novel species. Numerous physiological and biochemical features also distinguished the isolate from other known Hydrogenophaga species. Based on the polyphasic data presented in this study, strain LPB0072T should be classified as a novel species in the genus Hydrogenophaga, and the name Hydrogenophaga crassostreae sp. nov. is proposed. The type strain is LPB0072T (=KACC 18705T=JCM 31188T).


Analysis of nitrate reductase mRNA expression and nitrate reductase activity in response to nitrogen supply.
Nitrate is one of the major sources of nitrogen for the growth of plants. It is taken up by plant roots and transported to the leaves where it is reduced to nitrite in the. The main objective of this research was to investigate stimulatory effects of sodium nitrate, potassium nitrate, ammonia and urea on the production/generation of the nitrate reductase mRNA in Triticum aestivum plants. The plants were grown in standard nutrient solution for 21 days and then starved in a media without nitrate for seven days. Starved plants were stimulated with various concentrations of sodium nitrate, potassium nitrate, ammonia and urea, and the expression of nitrate reductase mRNA was analyzed by real-time PCR. Our results indicated that starvation caused significant decrease in the production of nitrate reductase mRNA in the plant leaf. Sodium and potassium nitrate were capable of restoring the production of nitrate mRNA in a dose-dependent manner, since 50 mM of each produced the highest level of the mRNA. The stimulatory effect of potassium nitrate was higher than sodium nitrate, while ammonia and urea did not show such activity. At low concentrations, sodium nitrate and potassium nitrate caused significant increase in the nitrate/nitrite mRNA production, whereas high concentrations of these salts suppressed the expression of this gene considerably.


First Report of Tomato yellow spot virus Infecting Leonurus sibiricus in Brazil.
In Brazil, serious epidemics of begomovirus diseases have been successively reported since the mid-90s, among them those caused by Tomato yellow spot virus (ToYSV) (1). In July 2009 and October 2010, high incidences (40 to 60%) of plants of the weed Leonurus sibiricus (Lamiaceae) exhibiting symptoms of yellow leaf mosaic were found near soybean (Glycine max) crops within the municipalities of Marechal Cândido Rondon and Tapejara, in the states of Paraná and Rio Grande do Sul. Leaves from 21 symptomatic and seven asymptomatic L. sibiricus plants were collected from both localities and tested for the presence of begomovirus. Total DNA was extracted from each sample using Dneasy Plant Mini Kit (Qiagen) and submitted to PCR using begomovirus universal oligonucleotides PAL1v1978/PAR1c496 (3). One fragment of approximately 1,300 bp comprising the 5'-region of the replication-associated protein (Rep) gene, the entire intergenic region (IR), and the 5'-region of the coat protein (CP) gene was amplified from all symptomatic, but not from asymptomatic samples. Amplified fragments corresponding to all isolates were directly sequenced and nucleotide sequence comparisons indicated 98 to 99% nucleotide identity among themselves, and 93 to 94% identity with the corresponding nucleotide sequences for the DNA-A of the begomovirus ToYSV (GenBank Accession No. DQ336350). To confirm these results, the full genome of ToYSV Mc-7 isolated from Marechal Cândido Rondon was cloned and completely sequenced by primer walking (Macrogen Seoul, Korea). The DNA-A of ToYSV Mc-7 (JX513952) was 2,592 nt long and shared 92 and 91% identity with isolates of ToYSV from Argentina (FJ538207) and Brazil (DQ336350), respectively. The DNA-B of ToYSV Mc-7 (JX513952) was 2,568 nt long and shared 91% identity with DNA-B of a Brazilian isolate of ToYSV (DQ336351). The ToYSV Mc-7 isolate is a new strain named Tomato yellow spot virus (Brazil:Marechal Candido Rondon 7:Leonurus:2009) [ToYSV-(BR:MCR7:Le:09)]. To demonstrate pathogenicity, virus-free adults of Bemisia tabaci biotype B were confined on symptomatic L. sibiricus plants for a 48-h acquisition period. The whiteflies were then transferred to healthy L. sibiricus, bean (Phaseolus vulgaris), soybean, and tomato (Solanum lycopersicum) plants. L. sibiricus plants showed the original symptoms on the leaves (five symptomatic plants, seven inoculated plants), whereas bean (3/7), soybean (4/10), and tomato plants (5/10) exhibited mild yellow leaf mosaic. The infection in these symptomatic plants was confirmed by PCR with oligonucleotides PAL1v1978/PAR1c496 (3) and subsequent direct nucleotide sequencing of the 5'-region of the CP gene, which confirmed the identity of the transmitted virus as ToYSV. ToYSV was first reported infecting tomato plants in Minas Gerais state, Brazil (1). Recently, ToYSV was found infecting bean and soybean plants in northwestern Argentina (2). Because L. sibiricus is a weed widely distributed throughout Brazil, and the ToYSV vector B. tabaci is also common, this weed may become a potential source of inoculun of ToYSV to bean, soybean, and tomato crops. To our knowledge, this is the first report of L. sibiricus as a natural host of ToYSV. References: (1) R. F. Calegario et al. Pesq. Agropec. Bras. 42:1335, 2007. (2) P. E. Rodríguez-Pardina et al. Ann. Appl. Biol. 158:69, 2011. (3) M. R. Rojas et al. Plant Dis. 77:340, 1993.


Clinical practice guidelines for nurse-administered procedural sedation and analgesia in the cardiac catheterization laboratory: a modified Delphi study.
To develop clinical practice guidelines for nurse-administered procedural sedation and analgesia in the cardiac catheterization laboratory. Numerous studies have reported that nurse-administered procedural sedation and analgesia is safe. However, the broad scope of existing guidelines for the administration and monitoring of patients who receive sedation during medical procedures without an anaesthetist present means there is a lack of specific guidance regarding optimal nursing practices for the unique circumstances where nurse-administered procedural sedation and analgesia is used in the cardiac catheterization laboratory. A sequential mixed methods design was used. Initial recommendations were produced from three studies conducted by the authors: an integrative review; a qualitative study; and a cross-sectional survey. The recommendations were revised according to responses from a modified Delphi study. The first Delphi round was completed by nine senior cardiac catheterization laboratory nurses. All but one of the draft recommendations met the predetermined cut-off point for inclusion with 59 responses to the second round. Consensus was reached on all recommendations. The guidelines that were derived from the Delphi study offer 24 recommendations within six domains of nursing practice: Pre-procedural assessment; Pre-procedural patient and family education; Pre-procedural patient comfort; Intra-procedural patient comfort; Intra-procedural patient assessment and monitoring; and Postprocedural patient assessment and monitoring. These guidelines provide an important foundation towards the delivery of safe, consistent and evidence-based nursing care for the many patients who receive sedation in the cardiac catheterization laboratory setting.


Association between use of warfarin with common sulfonylureas and serious hypoglycemic events: retrospective cohort analysis.
Is warfarin use associated with an increased risk of serious hypoglycemic events among older people treated with the sulfonylureas glipizide and glimepiride? This was a retrospective cohort analysis of pharmacy and medical claims from a 20% random sample of Medicare fee for service beneficiaries aged 65 years or older. It included 465,918 beneficiaries with diabetes who filled a prescription for glipizide or glimepiride between 2006 and 2011 (4,355,418 person quarters); 71,895 (15.4%) patients also filled a prescription for warfarin (416,479 person quarters with warfarin use). The main outcome measure was emergency department visit or hospital admission with a primary diagnosis of hypoglycemia in person quarters with concurrent fills of warfarin and glipizide/glimepiride compared with the rates in quarters with glipizide/glimepiride fills only, Multivariable logistic regression was used to adjust for individual characteristics. Secondary outcomes included fall related fracture and altered consciousness/mental status. In quarters with glipizide/glimepiride use, hospital admissions or emergency department visits for hypoglycemia were more common in person quarters with concurrent warfarin use compared with quarters without warfarin use (294/416,479 v 1903/3,938,939; adjusted odds ratio 1.22, 95% confidence interval 1.05 to 1.42). The risk of hypoglycemia associated with concurrent use was higher among people using warfarin for the first time, as well as in those aged 65-74 years. Concurrent use of warfarin and glipizide/glimepiride was also associated with hospital admission or emergency department visit for fall related fractures (3919/416,479 v 20,759/3,938,939; adjusted odds ratio 1.47, 1.41 to 1.54) and altered consciousness/mental status (2490/416,479 v 14,414/3,938,939; adjusted odds ratio 1.22, 1.16 to 1.29). Unmeasured factors could be correlated with both warfarin use and serious hypoglycemic events, leading to confounding. The findings may not generalize beyond the elderly Medicare population. A substantial positive association was seen between use of warfarin with glipizide/glimepiride and hospital admission/emergency department visits for hypoglycemia and related diagnoses, particularly in patients starting warfarin. The findings suggest the possibility of a significant drug interaction between these medications. JAR and DPG receive support from the National Institute on Aging, the Commonwealth Fund, and the Leonard D. Schaeffer Center for Health Policy and Economics at the University of Southern California. ABJ receives support from the NIH Office of the Director. No additional data are available.


Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism.
Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.


Green tea epigallocatechin-3-gallate alleviates Porphyromonas gingivalis-induced periodontitis in mice.
Porphyromonas gingivalis causes inflammation, and leads to the periodontitis in gingival tissue damage and bone resorption. Epigallocatechin-3-gallate (EGCG) is a major polyphenol extract from green tea with plenty of pharmacological functions. The aim of this study was to determine whether continuous oral intake of EGCG would alleviate P. gingivalis-induced periodontitis. Eight-week BALB/c mice were administered with EGCG (0.02%) or vehicle in drinking water. They were fed normal food and orally infected with P. gingivalis every 2days, up to a total of 20 times, and then sacrificed at 15weeks of age. The P. gingivalis-challenged group markedly increased alveolar bone resorption of the maxillae in BALB/c mice by Micro-CT detection, and administration of EGCG resulted in a significant reduction in bone loss. Inflammation cytokine antibody array and enzyme linked immunosorbent assay revealed that some inflammatory mediators in serum were increased by P. gingivalis infection, but were lowered after EGCG treatment. High positive areas of IL-17 and IL-1β in the gingival tissue were observed in the P. gingivalis-challenged mice, and were reduced by EGCG treatment. Real-time polymerase chain reaction (PCR) analyses also showed the expressions of IL-1β, IL-6, IL-17, IL-23, TNF-α and other mediators in gingival tissue were higher in P. gingivalis-challenged mice, and were down-regulated with EGCG treatment, except IL-23. Our results suggest that EGCG, as a natural healthy substance, probably alleviates P. gingivalis-induced periodontitis by anti-inflammatory effect.


The effect of corticosteroids on visual loss in Cryptococcus neoformans var. gattii meningitis.
In Papua New Guinea visual loss is a frequent sequal to Cryptococcus neoformans var. gattii meningitis in immunocompetent patients. We have previously postulated that visual loss may occur as a result of the immunological response to infection around the optic nerve. This retrospective study set out to explore the effect of corticosteroids on visual outcome. Sixteen patients received varying doses of corticosteroid (mainly 100-250 mg of hydrocortisone daily for the prevention of febrile reactions to amphotericin) and 10 received anticryptococcal therapy alone. Visual deterioration occurred less frequently in those treated with corticosteroids (2/16 [12.5%] vs. 7/10 [70%], P = 0.007), blindness was less frequent (1/16 [5.3%] vs. 5/10 [50%], P = 0.018), and in 3 patients vision improved. Corticosteroids may have a role in preventing or halting visual loss in C. neoformans var. gattii meningitis in immunocompetent patients.


Frog melanophores cultured on fluorescent microbeads: biomimic-based biosensing.
Melanophores are pigmented cells in lower vertebrates capable of quick color changes and thereby suitable as whole cell biosensors. In the frog dermis skin layer, the large and dark pigmented melanophore surrounds a core of other pigmented cells. Upon hormonal stimulation the black-brown pigment organelles will redistribute within the melanophore, and thereby cover or uncover the core, making complex color changes possible in the dermis. Previously, melanophores have only been cultured on flat surfaces. Here we mimic the three dimensional biological geometry in the frog dermis by culturing melanophores on fluorescent plastic microbeads. To demonstrate biosensing we use the hormones melatonin and alpha-melanocyte stimulating hormone (alpha-MSH) as lightening or darkening stimuli, respectively. Cellular responses were successfully demonstrated on single cell level by fluorescence microscopy, and in cell suspension by a fluorescence microplate reader and a previously demonstrated computer screen photo-assisted technique. The demonstrated principle is the first step towards "single well/multiple read-out" biosensor arrays based on suspensions of different selective-responding melanophores, each cultured on microbeads with distinctive spectral characteristics. By applying small amount of a clinical sample, or a candidate substance in early drug screening, to a single well containing combinations of melanophores on beads, multiple parameter read-outs will be possible.


Antibiotics in surgical wards: use or misuse? A newly industrialized country's perspective.
Studies exploring the appropriateness of therapeutic antibiotic use among surgical patients are limited, particularly in developing countries. Therefore, the aim of our study was to determine the appropriateness of antibiotics prescribed in a surgical setting in Malaysia. A prospective observational study was conducted in two surgical wards at a tertiary hospital in Malaysia from November 2012-July 2013. Data was collected using a case report form. The appropriateness of antibiotic therapy was based on compliance with either the Malaysian National Antibiotic Guidelines 2008 or International Clinical Practice Guidelines and determined by an expert panel (consisting of two infectious disease consultants and a pharmacist). Over the study period, a total of 593 antibiotic courses were prescribed for 129 patients (4.6±3.4 antibiotics/patient). Only 34 (26.4%) patients received appropriate antibiotic therapy, whilst 95 (73.6%) patients received at least one course of inappropriate antibiotic therapy. The prevalence of inappropriate antibiotic use was 214 (66.3%) and 55 (42.0%) for prophylactic and therapeutic purposes, respectively. The most common causes of inappropriate prophylactic antibiotics were inappropriate timing 20 (36.4%) and inappropriate duration of prophylaxis 19 (34.5%). In cases of inappropriate timing, 9 (45%) were administered too late while 6 (30%) were too early. In contrast, inappropriate choice of antibiotics (42.1%) and inappropriate indication (40.7%) were the most common reasons encountered for inappropriate therapeutic antibiotics. Our study suggests considerable inappropriate use of both prophylactic and therapeutic antibiotics in the surgical wards; highlighting an urgent need for antibiotic stewardship initiatives in this setting.


Effect of honey in preventing gingivitis and dental caries in patients undergoing orthodontic treatment.
THIS STUDY WAS CONDUCTED TO INVESTIGATE THE FOLLOWING: (1) the effects of chewing honey on plaque formation in orthodontic patients, (2) the effect of chewing honey on dental plaque bacterial counts, (3) determine if honey possesses antibacterial effects on bacteria recovered from plaques. Female orthodontic patients (n = 20, 12-18 years of age) participated in this randomized controlled study. The effects of honey were compared to treatment with either 10% sucrose or 10% sorbitol that served as positive and negative controls, respectively. The pH of plaque was measured using a digital pH meter prior to baseline and at 2, 5, 10, 20, and 30 min after chewing honey or rinsing with control solutions and the numbers of Streptococcus mutans, Lactobacilli, and Prophymonas gingivalis in respective plaques were determined. The antibacterial activity of honey was tested against commonly used antibiotics using the disk diffusion method. Significant differences in pH were observed in the honey and sucrose groups compared to the pH observed in the sorbitol group (p ⩽ 0.001). The maximum pH drop occurred at 5 min in both the honey and sucrose groups; however the pH in the honey group rapidly recovered 10-20 min after exposure and did not drop below the critical decalcification pH of 5.5. On the other hand, the pH following sucrose exposure fell <5.5 and was associated with a 30 min recovery time. The pH observed for the sorbitol group did not change over time. Bacterial counts were significantly reduced in the honey group compared to the other treatment groups (p ⩽ 0.001) and honey significantly inhibited the growth of all studied strains compared to inhibition observed with antibiotics (p ⩽ 0.001). Honey can be used as an alternative to traditional remedies for the prevention of dental caries and gingivitis following orthodontic treatment.