Assessment of Pregnancy Status, Malaria Knowledge and Malaria Fever Morbidity among Women of Reproductive Ages in Nigeria.
Malaria is one the major health problem in Nigeria. During pregnancy, it poses serious threat to the survival of both unborn foetus and the mothers. This study determined the effect of adequate malaria knowledge and pregnancy status of women on use of mosquito nets and reported malaria fever morbidity. The data were collected during the Malaria Indicator Survey (MIS) from 4632 women. Data analyses were carried out with descriptive statistics and Seemingly Unrelated Bivariate Probit regression. Results show that 13.19% of the women were pregnant, of which about one-third slept under mosquito nets. Also, 25.26% reported malaria associated fever in the previous two weeks to the time of interview, while 78.28% correctly answered that mosquitoes are responsible for malaria. Knowledge on malaria prevention was low with 55.70% and 14.93% indicating sleeping under mosquito nets and ITN, respectively. Probability of sleeping under mosquito nets significantly increased with knowing that sleeping under mosquito nets and ITN could prevent malaria while it decreased with having fever, age, urban residence and knowing that use of mosquito spray and coil can prevent malaria. The probability of having fever increased significantly with household size, being pregnant and age at first birth but decreased with age, knowing that sleeping under ITN, cutting grasses and closing door/windows would prevent malaria. Use of mosquito nets among the women was low. Also, efforts to enhance their knowledge on malaria prevention and ensuring adequate access to mosquito nets especially for pregnant women would curtail the impact of malaria.


Machete wounds to the head: report of three cases.
Three cases of machete wounds to the head are described. The resulting injuries from this unusual mode of trauma varied in severity and included transection of a previously placed ventriculoperitoneal shunt. Complications of these injuries resulted from delayed and inadequate treatment.


Moving toward Medicare home health coverage for persons with Alzheimer's disease.
Medicare home health care policy does not incorporate research evidence of effective palliative home care interventions for Alzheimer's disease and dementia patients and caregivers. This article examines the dissonance between the needs and burdens of Alzheimer's disease patients and caregivers, research results on medical and palliative care interventions, and medicalized public policy in the Medicare home health benefit. The article asserts existing research establishes a prima facie case exists for the federal government to fund a Medicare Palliative Home Care for Alzheimer's disease demonstration project. The article cites the success of the Medicare Hospice Demonstration project and Hospice Medicare Benefit in reducing costs and improving client quality of life as precedent and a model for Alzheimer's disease. Other research implications are identified.


Postoperative recurrent peptic ulcer: the significance of the Zollinger-Ellison syndrome.
Twenty-four patients with postoperative recurrent peptic ulcer, presenting to a teaching hospital over a six-year period, are reviewed. The diagnosis was confirmed by endoscopy or surgery in all cases. Four patients (16-7%) were shown to have the Zollinger-Ellison syndrome and were treated successfully by total gastrectomy. This is a significantly higher incidence of Zollinger-Ellison syndrome than in previous reports. Six patients were treated medically, with one death. In the remainder, an inadequate initial operation was considered to be the cause of recurrence. Reoperation, usually involving complete vagotomy and antrectomy, was performed. There was no mortality in this group, and no patients have had further recurrence. The importance of serum gastrin studies in all patients with recurrent peptic ulcer is emphasized.


Human platelet heparanase: purification, characterization and catalytic activity.
Heparan sulphate (HS) is an important component of the extracellular matrix (ECM) and the vasculature basal lamina (BL) which functions as a barrier to the extravasation of metastatic and inflammatory cells. Platelet-tumour cell aggregation at the capillary endothelium results in activation and degranulation of platelets. Cleavage of HS by endoglycosidase or heparanase activity produced in relatively large amounts by the platelets and the invading cells may assist in the disassembly of the ECM and BL, and thereby facilitate cell migration. Using a recently published rapid, quantitative assay for heparanase activity towards HS [Freeman, C. and Parish, C.R. (1997), Biochem. J., 325, 229-237], human platelet heparanase has now been purified 1700-fold to homogeneity in 19% yield by a five column procedure, which consists of concanavalin A-Sepharose, Zn2+-chelating-Sepharose, Blue A-agarose, octyl-agarose and gel filtration chromatography. The enzyme, which was shown to be an endoglucuronidase that degrades both heparin and HS, has a native molecular mass of 50 kDa when analysed by gel filtration chromatography and by SDS/PAGE. Platelet heparanase degraded porcine mucosal HS in a stepwise fashion from a number average molecular mass of 18.5 to 13, to 8 and finally to 4.5 kDa fragments as determined by gel filtration analysis. Bovine lung heparin was degraded from 8.9 to 4.8 kDa while porcine mucosal heparin was degraded from 8.1 kDa to 3.8 and finally to 2.9 kDa fragments. Studies of the enzyme's substrate specificity using modified heparin analogues showed that substrate cleavage required the presence of carboxyl groups, but O- and N-sulphation were not essential. Inhibition studies demonstrated an absolute requirement for the presence of O-sulphate groups. Platelet heparanase was inhibited by heparin analogues which also inhibited tumour heparanase, suggesting that sulphated polysaccharides which inhibit tumour metastasis may act to prevent both tumour cell and platelet heparanase degradation of endothelial cell surface HS and the basal laminar.


P300 Event-Related Potentials Mediate the Relationship Between Child Physical Abuse and Externalizing Behavior.
The psychophysiological mechanism linking early childhood experiences to behavior problems remains unclear. This study aimed to examine the association of child physical abuse with P300 event-related potentials (ERP), and to test the mediating effect of P300 amplitude and latency in the relationship between child physical abuse and externalizing behaviors. Cross-sectional secondary data were obtained from 155 children (55.5% boys, mean age: 11.28 ± 0.57 years) who participated in the China Jintan Child Cohort Study. Children self-reported maternal and paternal physical abuse and externalizing behaviors, as well as P300 were obtained in 2013. Additionally, parents and teachers reported child externalizing behaviors in preschool in 2007. P300 were recorded during a standard novel auditory oddball task. Path analysis shows that after controlling for child sex, socioeconomic status, area of residence, IQ, and child externalizing behavior in preschool, children exposed to maternal physical abuse exhibited increased novelty P300 amplitude, which links to more externalizing behavior. Novelty P300 amplitude partially mediated the relationship between maternal physical abuse and externalizing behavior. These findings are the first to document the partial mediating effect of P300 amplitude on the abuse-externalizing relationship and are consistent with the view that physical abuse affects the attention bias to novel cues that likely places them at increased risk for the development and maintenance of externalizing behavior.


Evaluation of a direct motion estimation/correction method in respiratory-gated PET/MRI with motion-adjusted attenuation.
Respiratory motion compensation in PET/CT and PET/MRI is essential as motion is a source of image degradation (motion blur, attenuation artifacts). In previous work, we developed a direct method for joint image reconstruction/motion estimation (JRM) for attenuation-corrected (AC) respiratory-gated PET, which uses a single attenuation-map (μ-map). This approach was successfully implemented for respiratory-gated PET/CT, but since it relied on an accurate μ-map for motion estimation, the question of its applicability in PET/MRI is open. The purpose of this work is to investigate the feasibility of JRM in PET/MRI and to assess the robustness of the motion estimation when a degraded μ-map is used. We performed a series of JRM reconstructions from simulated PET data using a range of simulated Dixon MRI sequence derived μ-maps with wrong attenuation values in the lungs, from -100% (no attenuation) to +100% (double attenuation), as well as truncated arms. We compared the estimated motions with the one obtained from JRM in ideal conditions (no noise, true μ-map as an input). We also applied JRM on 4 patient datasets of the chest, 3 of them containing hot lesions. Patient list-mode data were gated using a principal component analysis method. We compared SUVmax values of the JRM reconstructed activity images and non motion-corrected images. We also assessed the estimated motion fields by comparing the deformed JRM-reconstructed activity with individually non-AC reconstructed gates. Experiments on simulated data showed that JRM-motion estimation is robust to μ-map degradation in the sense that it produces motion fields similar to the ones obtained when using the true μ-map, regardless of the attenuation errors in the lungs (< 0.5% mean absolute difference with the reference motion field). When using a μ-map with truncated arms, JRM estimates a motion field that stretches the μ-map in order to match the projection data. Results on patient datasets showed that using JRM improves the SUVmax values of hot lesions significantly and suppresses motion blur. When the estimated motion fields are applied to the reconstructed activity, the deformed images are geometrically similar to the non-AC individually reconstructed gates. Motion estimation by JRM is robust to variation of the attenuation values in the lungs. JRM successfully compensates for motion when applied to PET/MRI clinical datasets. It provides a potential alternative to existing methods where the motion fields are pre-estimated from separate MRI measurements.


A high fat western diet attenuates phasic dopamine release.
Natural rewards, such as food and social interaction, as well as drugs of abuse elicit increased mesolimbic dopamine release in the nucleus accumbens (NAc). Drugs of abuse, however, increase NAc dopamine release to a greater extent and are known to induce lasting changes on the functioning of the mesolimbic dopamine pathway. Less is known about the long-term effects of diet composition on this reward pathway. In the present study, two diets were compared: a higher-fat diet (Western Diet: WD) and a control diet (standard lab chow) on their effect on the mesolimbic dopamine system. Twenty male C57BL/6 J mice were placed on one of these diets at 7 weeks old. After twelve weeks on the diet, in vivo fixed potential amperometry was used to measure real-time stimulation-evoked dopamine release in the NAc of anesthetized mice before and after an i.p. injection of the dopamine transporter (DAT) inhibitor nomifensine. Results indicated that diet altered mesolimbic dopamine functioning. Mice that consumed the WD demonstrated a hypodopaminergic profile, specifically reduced baseline dopamine release and an attenuated dopaminergic response to DAT inhibition compared to the control diet group. Thus, diet may play a role in mediating dopamine-related behavior, disorders associated with dopamine dysfunction, and pharmacological treatments aimed at altering dopamine transmission.


Influence of Electrical and Ionic Conductivities of Organic Electronic Ion Pump on Acetylcholine Exchange Performance.
By using an easy and effective method of depositing conjugated polymers (PEDOT:PSS) on flexible substrates, a new design for organic bioelectronic devices has been developed. The purpose was to build up a system that mimics the motion of neurotransmitters in the synaptic cleft by obtaining an electrical to chemical signal transport. Fourier transform infrared (FTIR) spectroscopy and Raman measurements have demonstrated that electrochemical overoxidation region which separates the pristine PEDOT:PSS electrodes and allows ionic conduction has been achieved successfully. The influence of both electrical and ionic conductivities on organic electronic ion pump (OEIP) performances has been studied. The ultimate goal was to achieve the highest equilibrium current density at the lowest applied voltage via enhancing the electrical conductivity of PEDOT:PSS and ionic conductivity of electrochemically overoxidized region. The highest equilibrium current density, which corresponds to 4.81 × 1017 number of ions of acetylcholine was about 41 μA cm-2 observed for the OEIP with the electrical conductivities of 54 S cm-1. This was a threshold electrical conductivity beyond which the OEIP performances were not changed much. Once Nafion™ has been applied for enhancing the ionic conductivity, the equilibrium current density increased about ten times and reached up to 408 μA cm-2. Therefore, it has been demonstrated that the OEIP performance mainly scales with the ionic conductivity. A straightforward method of producing organic bioelectronics is proposed here may provide a clue for their effortless mass production in the near future.


[Campylobacter enteritis and related organisms. Clinical microbiology and antibiotic resistance].
The Authors underline the importance to always and correctly investigate also for Campylobacters and related organisms (Clo's) in faeces of humans with enteritis, because prevalent like Salmonella and for surveillance antibiotic resistances; in fact for campylobacteriosis specific therapy is often necessary. Between 2001 and 2005 248 strains of Campylobacter and Clo's were isolated: 225 were C. jejuni (90.7%) and 16 C. coli (6.5%). The recommended antibiotics to use for therapy, for preventing secondary effects too, are erythromycin, ciprofloxacin and tetracycline. Among C. jejuni, resistances towards erithromycine were 6.8% during 2001-02, 6.8% during 2003 and 4.8% during 2004-05; the resistances towards ciprofloxacin were 52.9% during 2001-02, 53.8% during 2003 and 42.9% during 2004-05; the resistances towards tetracycline were 39.2% during 2001-02, 46.2% during 2003 and 50.0% during 2004-05. The strains of C. coli showed less resistances, also in respect of previous our data too. No relevant differences were observed in antibacterial resistances among strains isolated from children and strains isolated from adults.


Neuroglobin in the rat brain: localization.
Neuroglobin (Ngb) is a neuronal hemeprotein similar to myoglobin and hemoglobin and shares their capability for oxygen binding. It has thus been proposed that Ngb acts as an oxygen reservoir or combats reactive oxygen species. In the present study, we investigated the Ngb expression pattern in the rat brain using immunohistochemistry, in situ hybridization, and quantitative real-time PCR (qRT-PCR). This revealed the interesting finding that Ngb expression is restricted to a few neurone populations, many of which are involved in the sleep-wake cycle, circadian regulation or food regulation. In the forebrain we found intense Ngb expression in neurones in the piriform cortex, the central and medial amygdala, the medial preoptic area, the suprachiasmatic nucleus (SCN), the hypothalamic paraventricular nucleus, the perifornical nucleus, the lateral hypothalamus. Within the mid- and hindbrain Ngb expressing neurones were found in the laterodorsal tegmental nucleus, the pedunculo pontine tegmental nucleus, the locus coeruleus, and the lateral parabrachial nucleus. In the medulla oblongata Ngb expressing neurones were found in the nucleus of the solitary tract. The qRT-PCR data showed a diurnal variation of Ngb mRNA in the SCN, having a peak in the day time (light-period) and nadir during night (dark-period).


Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial.
REACH evaluated ramucirumab in the second-line treatment of patients with advanced hepatocellular carcinoma. In the intent-to-treat population (n = 565), a significant improvement in overall survival (OS) was not observed. In patients with an elevated baseline α-fetoprotein (AFP) level (400 ng/mL or greater), an improvement in OS was demonstrated. An analysis of the Japanese patients in REACH was performed. An analysis was performed with the subset of the intent-to-treat population enrolled in Japan (n = 93). The median OS was 12.9 months for the ramucirumab arm (n = 45) and 8.0 months for the placebo arm (n = 48) [hazard ratio (HR) 0.621 (95 % confidence interval (CI) 0.391-0.986); P = 0.0416]. The median progression-free survival was 4.1 months for the ramucirumab arm and 1.7 months for the placebo arm [HR 0.449 (95 % CI 0.285-0.706); P = 0.0004]. The objective response rates were 11 % for the ramucirumab arm and 2 % for the placebo arm (P = 0.0817). The grade 3 or higher treatment-emergent adverse events occurring in more than 5 % of patients with a higher incidence for the ramucirumab arm (n = 44) than for the placebo arm (n = 47) were ascites (7% vs 2 %), hypertension (7 % vs 2 %), and cholangitis (7 % vs 0 %). In patients with a baseline AFP level of 400 ng/mL or greater, the median OS was 12.9 months for the ramucirumab arm (n = 20) and 4.3 months for the placebo arm (n = 22) [HR 0.464 (95 % CI 0.232-0.926); P = 0.0263]. In the Japanese patients in REACH, ramucirumab treatment improved OS, including in patients with a baseline AFP level of 400 ng/mL or greater; improvements in progression-free survival and objective response rate were also demonstrated. The safety profile of ramucirumab was acceptable and well tolerated in Japanese patients. ClinicalTrials.gov identifier NCT01140347.


Striatal dopamine modulates basal ganglia output and regulates social context-dependent behavioral variability through D1 receptors.
Cortico-basal ganglia (BG) circuits are thought to promote the acquisition of motor skills through reinforcement learning. In songbirds, a specialized portion of the BG is responsible for song learning and plasticity. This circuit generates song variability that underlies vocal experimentation in young birds and modulates song variability depending on the social context in adult birds. When male birds sing in the presence of a female, a social context associated with decreased BG-induced song variability, the extracellular dopamine (DA) level is increased in the avian BG nucleus Area X. These results suggest that DA could trigger song variability changes through its action in Area X. Consistent with this hypothesis, we report that DA delivered to Area X weakens the output signal of the avian cortico-BG circuit. Acting through D(1) receptors, DA reduced responses in Area X to song playback and to electrical stimulation of its afferent cortical nucleus HVC (used as a proper name). Specifically, DA reduced the response to direct excitatory input and decreased firing variability in Area X pallidal neurons, which provide the output to the thalamus. As a consequence, DA delivery in Area X also decreased responses to song playback in the cortical output nucleus of the BG loop, the lateral magnocellular nucleus of the anterior nidopallium. Further, interfering with D(1) receptor transmission in Area X abolished social context-related changes in song variability. In conclusion, we propose that DA acts on D(1) receptors in Area X to modulate the BG output signal and trigger changes in song variability.


Computational Analysis of SARS-CoV-2 and SARS-Like Coronavirus Diversity in Human, Bat and Pangolin Populations.
In 2019, a novel coronavirus, SARS-CoV-2/nCoV-19, emerged in Wuhan, China, and has been responsible for the current COVID-19 pandemic. The evolutionary origins of the virus remain elusive and understanding its complex mutational signatures could guide vaccine design and development. As part of the international "CoronaHack" in April 2020, we employed a collection of contemporary methodologies to compare the genomic sequences of coronaviruses isolated from human (SARS-CoV-2; n = 163), bat (bat-CoV; n = 215) and pangolin (pangolin-CoV; n = 7) available in public repositories. We have also noted the pangolin-CoV isolate MP789 to bare stronger resemblance to SARS-CoV-2 than other pangolin-CoV. Following de novo gene annotation prediction, analyses of gene-gene similarity network, codon usage bias and variant discovery were undertaken. Strong host-associated divergences were noted in ORF3a, ORF6, ORF7a, ORF8 and S, and in codon usage bias profiles. Last, we have characterised several high impact variants (in-frame insertion/deletion or stop gain) in bat-CoV and pangolin-CoV populations, some of which are found in the same amino acid position and may be highlighting loci of potential functional relevance.


Half-pin skeletal fixation in children.
In children, 20-mm threaded sockets can be used to attach half pins to an Ilizarov frame. Applications to the humerus and femur are described.


Study of optimal extraction conditions for achieving high yield and antioxidant activity of tomato seed oil.
Value of tomato seed has not been fully recognized. The objectives of this research were to establish suitable processing conditions for extracting oil from tomato seed by using solvent, determine the impact of processing conditions on yield and antioxidant activity of extracted oil, and elucidate kinetics of the oil extraction process. Four processing parameters, including time, temperature, solvent-to-solid ratio and particle size were studied. A second order model was established to describe the oil extraction process. Based on the results, increasing temperature, solvent-to-solid ratio, and extraction time increased oil yield. In contrast, larger particle size reduced the oil yield. The recommended oil extraction conditions were 8 min of extraction time at temperature of 25 °C, solvent-to-solids ratio of 5/1 (v/w) and particle size of 0.38 mm, which gave oil yield of 20.32% with recovery rate of 78.56%. The DPPH scavenging activity of extracted oil was not significantly affected by the extraction parameters. The inhibitory concentration (IC(50) ) of tomato seed oil was 8.67 mg/mL which was notably low compared to most vegetable oils. A 2nd order model successfully described the kinetics of tomato oil extraction process and parameters of extraction kinetics including initial extraction rate (h), equilibrium concentration of oil (C(s) ), and the extraction rate constant (k) could be precisely predicted with R(2) of at least 0.957. The study revealed that tomato seed which is typically treated as a low value byproduct of tomato processing has great potential in producing oil with high antioxidant capability. The impact of processing conditions including time, temperature, solvent-to-solid ratio and particle size on yield, and antioxidant activity of extracted tomato seed oil are reported. Optimal conditions and models which describe the extraction process are recommended. The information is vital for determining the extraction processing conditions for industrial production of high quality tomato seed oil.


The lifetime prevalence of mental disorders: estimation, uses and limitations.
The age-specific lifetime prevalence rate of a disease is the proportion of persons surviving to a given age who have experienced the disease at any time during their lives. This measure of morbidity has been used to report findings in many of the epidemiological surveys of mental disorders of the last 30 years. This paper presents a life-table method for estimating age-specific lifetime prevalence rates from incidence and mortality data. The method is applied to Monroe County, New York, case register data on the incidence of schizophrenia. Using this method, we estimate that at least 3% of the White population surviving to age 55 have experienced an episode of schizophrenia at some time during their lives. The difficulties of producing valid estimates of lifetime prevalence and the difficulties in interpreting differences reported in such rates make this morbidity measure of secondary importance to incidence and point-prevalence data.


Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance.
Intervention to reduce abdominal aortic aneurysm (AAA) expansion and optimization of screening intervals would improve current surveillance programs. The aim of this study was to characterize AAA growth in a national cohort of patients with AAA both overall and by cardiovascular risk factors. In this study, 1743 patients were monitored for changes in AAA diameter by ultrasonography over a mean follow-up of 1.9 years. Mean initial AAA diameter and growth rate were 43 mm (range 28 to 85 mm) and 2.6 mm/year (95% range, -1.0 to 6.1 mm/year), respectively. Baseline diameter was strongly associated with growth, suggesting that AAA growth accelerates as the aneurysm enlarges. AAA growth rate was lower in those with low ankle/brachial pressure index and diabetes but higher for current smokers (all P<0.001). No other factor (including lipids and blood pressure) was associated with AAA growth. Intervals of 36, 24, 12, and 3 months for aneurysms of 35, 40, 45, and 50 mm, respectively, would restrict the probability of breaching the 55-mm limit at rescreening to below 1%. Annual, or less frequent, surveillance intervals are safe for all AAAs < or =45 mm in diameter. Smoking increases AAA growth, but atherosclerosis plays a minor role.


The effect of leukocyte-platelet-rich fibrin on bone morphogenetic protein-2 and insulin-like growth factor-1 levels in patients with chronic periodontitis: a randomized split mouth clinical trail.
The present study evaluates the effects of leukocyte-platelet-rich fibrin (L-PRF) combined with open flap debridement (OFD) on clinical parameters and growth factors levels (GFL) in chronic periodontitis (CP) patients. This trial was registered at clinicaltrials.gov as NCT02594605. 16 patients (32 sites) with chronic periodontitis who had at least two areas of horizontal bone loss, were treated with OFD alone or L-PRF with OFD (OFD + L-PRF). GFL in gingival crevicular fluid (GCF) were analyzed at baseline, 1 week, 2 weeks and 4 weeks after operation. Probing depth (PD) and clinical attachment level (CAL) were measured at baseline and 6 months postoperatively. PD reduction and CAL gain were significantly higher in the OFD + L-PRF sites than in OFD sites. OFD + L-PRF group showed significantly increased bone morphogenetic protein-2 and insulin-like growth factor-1 at 2 weeks compared with baseline. L-PRF combined with OFD significantly increases GFL and thus, it enhances the periodontal healing on CP patients.


Intracellular clusterin interacts with brain isoforms of the bridging integrator 1 and with the microtubule-associated protein Tau in Alzheimer's disease.
Sporadic or late-onset Alzheimer's disease (AD) is expected to affect 50% of individuals reaching 85 years of age. The most significant genetic risk factor for late-onset AD is the e4 allele of APOE gene encoding apolipoprotein E, a lipid carrier shown to modulate brain amyloid burden. Recent genome-wide association studies have uncovered additional single nucleotide polymorphisms (SNPs) linked to AD susceptibility, including those in the CLU and BIN1 genes encoding for clusterin (CLU) and the bridging integrator 1 (BIN1) proteins, respectively. Because CLU has been implicated in brain amyloid-β (Aβ) clearance in mouse models of amyloid deposition, we sought to investigate whether an AD-linked SNP in the CLU gene altered Aβ42 biomarker levels in the cerebrospinal fluid (CSF). Instead, we found that the CLU rs11136000 SNP modified CSF levels of the microtubule-associated protein Tau in AD patients. We also found that an intracellular form of CLU (iCLU) was upregulated in the brain of Tau overexpressing Tg4510 mice, but not in Tg2576 amyloid mouse model. By overexpressing iCLU and Tau in cell culture systems we discovered that iCLU was a Tau-interacting protein and that iCLU associated with brain-specific isoforms of BIN1, also recently identified as a Tau-binding protein. Through expression analysis of CLU and BIN1 variants, we found that CLU and BIN1 interacted via their coiled-coil motifs. In co-immunoprecipitation studies using human brain tissue, we showed that iCLU and the major BIN1 isoform expressed in neurons were associated with modified Tau species found in AD. Finally, we showed that expression of certain coding CLU variants linked to AD risk led to increased levels of iCLU. Together, our findings suggest that iCLU and BIN1 interaction might impact Tau function in neurons and uncover potential new mechanisms underlying the etiology of Tau pathology in AD.


The Greeks in the West: genetic signatures of the Hellenic colonisation in southern Italy and Sicily.
Greek colonisation of South Italy and Sicily (Magna Graecia) was a defining event in European cultural history, although the demographic processes and genetic impacts involved have not been systematically investigated. Here, we combine high-resolution surveys of the variability at the uni-parentally inherited Y chromosome and mitochondrial DNA in selected samples of putative source and recipient populations with forward-in-time simulations of alternative demographic models to detect signatures of that impact. Using a subset of haplotypes chosen to represent historical sources, we recover a clear signature of Greek ancestry in East Sicily compatible with the settlement from Euboea during the Archaic Period (eighth to fifth century BCE). We inferred moderate sex-bias in the numbers of individuals involved in the colonisation: a few thousand breeding men and a few hundred breeding women were the estimated number of migrants. Last, we demonstrate that studies aimed at quantifying Hellenic genetic flow by the proportion of specific lineages surviving in present-day populations may be misleading.


A case-control study of cerebellar tonsillar ectopia (Chiari) and head/neck trauma (whiplash).
Chiari malformation is defined as herniation of the cerebellar tonsils through the foramen magnum, also known as cerebellar tonsillar ectopia (CTE). CTE may become symptomatic following whiplash trauma. The purpose of the present study was to assess the frequency of CTE in traumatic vs non-traumatic populations. Case-control. Cervical MRI scans for 1200 neck pain patients were reviewed; 600 trauma (cases) and 600 non-trauma (controls). Half of the groups were scanned in a recumbent position and half were scanned in an upright position. Two radiologists interpreted the scans for the level of the cerebellar tonsils. A total of 1195 of 1200 scans were read. CTE was found in 5.7% and 5.3% in the recumbent and upright non-trauma groups vs 9.8% and 23.3% in the recumbent and upright trauma groups (p = 0.0001). The results described in the present investigation are first to demonstrate a neuroradiographic difference between neck pain patients with and without a recent history of whiplash trauma. The results of prior research on psychosocial causes of chronic pain following whiplash are likely confounded because of a failure to account for a possible neuropathologic basis for the symptoms.


An Anomaly with Potential as a New Prognostic Marker in CLL with del(13q): Gain of 16p13.3.
Deletion 13q [del(13q)] is a favorable prognostic marker if it is detected as a sole abnormality in chronic lymphocytic leukemia (CLL). However the clinical courses of cases with isolated del(13q) are quite heterogeneous. In our study, we investigated copy number variations (CNVs), loss of heterozygosity (LOH), and the size of del(13q) in 30 CLL patients with isolated del(13q). We used CGH+SNP microarrays in order to understand the cause of this clinical heterogeneity. We detected del(13q) in 28/30 CLL cases. The size of the deletion varied from 0.34 to 28.81 Mb, and there was no clinical effect of the deletion size. We found new prognostic markers, especially the gain of 16p13.3. These markers have statistically significant associations with short time to first treatment and advanced disease stage. Detecting both CNVs and LOH at the same time is an advantageous feature of aCGH+SNP. However, it is very challenging for the array analysis to detect mosaic anomalies. Therefore, it is very important to confirm the results by FISH. In our study, we detected approximately 9% mosaic del(13q) by microarray. In addition, the gain of 16p13.3 may affect the disease prognosis in CLL. However, additional studies with more patients are needed to confirm these results.


Integrated Transcriptomic and Metabolomic analysis reveals a transcriptional regulation network for the biosynthesis of carotenoids and flavonoids in 'Cara cara' navel Orange.
Carotenoids and flavonoids are important secondary metabolites in plants, which exert multiple bioactivities and benefits to human health. Although the genes that encode carotenogenesis and flavonoid biosynthetic enzymes are well characterized, the transcriptional regulatory mechanisms that are related to the pathway genes remain to be investigated. In this study, 'Cara cara' navel orange (CNO) fruit at four development stages were used to identify the key genes and TFs for carotenoids and flavonoids accumulation. In this study, CNO was used to investigate the profiles of carotenoids and flavonoids by a combination of metabolomic and transcriptomic analyses. The important stage for the accumulation of the major carotenoid, lycopene was found to be at 120 days after florescence (DAF). The transcripts of five carotenogenesis genes were highly correlated with lycopene contents, and 16, 40, 48, 24 and 18 transcription factors (TFs) were predicted to potentially bind 1-deoxy-D-xylulose-5-phosphate synthase (DXS1), deoxyxylulose 5-phosphate reductoisomerase (DXR), geranylgeranyl diphosphate synthase (GGPPS2), phytoene synthase (PSY1) and lycopene β-cyclase (LCYB) promoters, respectively. Narirutin was the most abundant flavonoid in the flesh at the early stages, 60 DAF was the most important stage for the accumulation of flavonoids, and 17, 22, 14, 25, 24 and 16 TFs could potentially bind phenylalanine ammonia-lyase (PAL-1 and PAL-4), 4-Coumarate-CoA ligase (4CL-2 and 4CL-5), chalcone synthase (CHS-1) and chalcone isomerase (CHI) promoters, respectively. Furthermore, both sets of 15 candidate TFs might regulate at least three key genes and contribute to carotenoids/flavonoids accumulation in CNO fruit. Finally, a hierarchical model for the regulatory network among the pathway genes and TFs was proposed. Collectively, our results suggest that DXS1, DXR, GGPPS2, PSY1 and LCYB genes were the most important genes for carotenoids accumulation, while PAL-1, PAL-4, 4CL-2, 4CL-5, CHS-1 and CHI for flavonoids biosynthesis. A total of 24 TFs were postulated as co-regulators in both pathways directly, which might play important roles in carotenoids and flavonoids accumulation in CNO fruit.


Guidelines for drug treatment of epilepsy: a critical review.
This article critically reviews the role of evidence-based medicine and its guidelines, from their logistic preparation to their interpretation. The strengths and weaknesses of the methodological points are presented, as well the reasons for the extreme popularity of the guidelines in developed countries. The review discusses the main foundations of the most cited guidelines and some recent large studies. Some of the final conclusions are that clinical experience is always an important factor to consider, even in the face of solid evidence, to achieve the best possible management of any particular patient.


A point mutation in the amino terminus of TLR7 abolishes signaling without affecting ligand binding.
TLR7 is the mammalian receptor for ssRNA and some nucleotide-like small molecules. We have generated a mouse by N-nitrose-N'-ethyl urea mutagenesis in which threonine 68 of TLR7 was substituted with isoleucine. Cells bearing this mutant TLR7 lost the sensitivity to the small-molecule TLR7 agonist resiquimod, hence the name TLR7(rsq1). In this work, we report the characterization of this mutant protein. Similar to the wild-type counterpart, TLR7(rsq1) localizes to the endoplasmic reticulum and is expressed at normal levels in both primary cells and reconstituted 293T cells. In addition to small-molecule TLR7 agonists, TLR7(rsq1) fails to be activated by ssRNA. Whole-transcriptome analysis demonstrates that TLR7 is the exclusive and indispensable receptor for both classes of ligands, consistent with the fact that both ligands induce highly similar transcriptional signatures in TLR7(wt/wt) splenocytes. Thus, TLR7(rsq1) is a bona fide phenocopy of the TLR7 null mouse. Because TLR7(rsq1) binds to ssRNA, our studies imply that the N-terminal portion of TLR7 triggers a yet to be identified event on TLR7. TLR7(rsq1) mice might represent a valuable tool to help elucidate novel aspects of TLR7 biology.


The influence of mental fatigue on brain activity: Evidence from a systematic review with meta-analyses.
The occurrence of mental fatigue during tasks like driving a vehicle increases risk of injury or death. Changes in electroencephalographic (EEG) activity associated with mental fatigue has been frequently studied and considered a promising biomarker of mental fatigue. This is despite differences in methodologies and outcomes in prior research. A systematic review with meta-analyses was conducted to establish the influence of mental fatigue on EEG activity spectral bands, and to determine in which regions fatigue-related EEG spectral changes are likely to occur. A high-yield search strategy identified 21 studies meeting inclusion criteria for investigating the change in EEG spectral activity in non-diseased adults engaged in mentally fatiguing tasks. A medium effect size (using Cohen's g) of 0.68 (95%CI: 0.24-1.13) was found for increase in overall EEG activity following mental fatigue. Further examination of individual EEG spectral bands and regions using network meta-analyses indicated large increases in theta (g = 1.03; 95%CI: 0.79-1.60) and alpha bands (g = 0.85; 95%CI: 0.47-1.43), with small to moderate changes found in delta and beta bands. Central regions of the scalp showed largest change (g = 0.80; 95%CI: 0.46-1.21). Sub-group analyses indicated large increases in theta activity in frontal, central and posterior sites (all g > 1), with moderate changes in alpha activity in central and posterior sites. Findings have implications for fatigue monitoring and countermeasures with support for change in theta activity in frontal, central and posterior sites as a robust biomarker of mental fatigue and change in alpha wave activity considered a second line biomarker to account for individual variability.


Bladder regeneration in a canine model using a bladder acellular matrix loaded with a collagen-binding bFGF.
Bladder reconstruction remains challenging for urological surgery due to lack of suitable regenerative scaffolds. In a previous study, we had used a collagen-binding basic fibroblast growth factor (CBD-bFGF) to bind bFGF to the collagen scaffold, which could promote bladder regeneration in rats. However, the limited graft size in rodent models cannot provide enough evidence to demonstrate the repair capabilities of this method for severely damaged bladders in humans or large animals. In this study, the CBD-bFGF was used to activate a bladder acellular matrix (BAM) scaffold, and the CBD-bFGF/BAM functional scaffold was assessed in a canine model with a large segment defect (half of the entire bladder was resected). The results demonstrated that the functional biomaterials could promote bladder smooth muscle, vascular, and nerve regeneration and improve the function of neobladders. Thus, the CBD-bFGF/BAM functional scaffold may be a promising biomaterial for bladder reconstruction.


Demographic properties shape tree size distribution in a Malaysian rain forest.
Different mechanisms have been proposed to explain how vertical and horizontal heterogeneity in light conditions enhances tree species coexistence in forest ecosystems. The foliage partitioning theory proposes that differentiation in vertical foliage distribution, caused by an interspecific variation in mortality-to-growth ratio, promotes stable coexistence. In contrast, successional niche theory posits that horizontal light heterogeneity, caused by gap dynamics, enhances species coexistence through an interspecific trade-off between growth rate and survival. To distinguish between these theories of species coexistence, we analyzed tree inventory data for 370 species from the 50-ha plot in Pasoh Forest Reserve, Malaysia. We used community-wide Bayesian models to quantify size-dependent growth rate and mortality of every species. We compared the observed size distributions and the projected distributions from size-dependent demographic rates. We found that the observed size distributions were not simply correlated with the rate of population increase but were related to demographic properties such as size growth rate and mortality. Species with low relative abundance of juveniles in size distribution showed high growth rate and low mortality at small tree sizes and low per-capita recruitment rate. Overall, our findings were in accordance with those predicted by foliage partitioning theory.


Double-Criteria Active Learning for Multiclass Brain-Computer Interfaces.
Recent technological advances have enabled researchers to collect large amounts of electroencephalography (EEG) signals in labeled and unlabeled datasets. It is expensive and time consuming to collect labeled EEG data for use in brain-computer interface (BCI) systems, however. In this paper, a novel active learning method is proposed to minimize the amount of labeled, subject-specific EEG data required for effective classifier training, by combining measures of uncertainty and representativeness within an extreme learning machine (ELM). Following this approach, an ELM classifier was first used to select a relatively large batch of unlabeled examples, whose uncertainty was measured through the best-versus-second-best (BvSB) strategy. The diversity of each sample was then measured between the limited labeled training data and previously selected unlabeled samples, and similarity is measured among the previously selected samples. Finally, a tradeoff parameter is introduced to control the balance between informative and representative samples, and these samples are then used to construct a powerful ELM classifier. Extensive experiments were conducted using benchmark and multiclass motor imagery EEG datasets to evaluate the efficacy of the proposed method. Experimental results show that the performance of the new algorithm exceeds or matches those of several state-of-the-art active learning algorithms. It is thereby shown that the proposed method improves classifier performance and reduces the need for training samples in BCI applications.


Extending SynBioHub's Functionality with Plugins.
SynBioHub is a repository for synthetic genetic designs represented in the Synthetic Biology Open Language (SBOL). To integrate SynBioHub into more synthetic biology workflows, its data processing capabilities need to be expanded. To this end, a plugin interface has been developed. Plugins can be developed for data submission, visualization, and download. This framework was tested by the development of three example plugins, one of each type as follows: one allowing the submission of SnapGene files, one visualizing the course of different genetic parts, and one preparing plasmid maps for download.


Obesity and diabetes.
Fat mass per se has little effect on the progression of obesity towards diabetes. Predominance of fat in the upper part of the body resulting in android obesity is at least the clinical reflection of factors which lead obesity to progress towards diabetes and atherosclerosis. Therefore this type of obesity may be termed diabetogenic and atherogenic obesity. Insulin and cortisol secretion in obesity are not correlated with body fat but with the predominance of fat in the upper part of the body. Diabetogenic obesity may evolve through 5 stages from initial obesity without diabetes to insulin-dependent diabetes in previously obese subjects. Aside from the characteristics of body fat distribution, the mechanisms which induce or interrupt this progression remain unknown.


Bacterial RNA polymerase inhibitors: an organized overview of their structure, derivatives, biological activity and current clinical development status.
RNA polymerase (RNAP) currently represents an important target for the development of new antibacterial agents. RNAP is a nucleotidyl transferase enzyme able to generate an RNA copy of a DNA or RNA template chain, controlling initiation and termination of transcription. RNAP is found in nature in all eukaryotes, prokaryotes and archaea, as well as in many viruses. Bacterial RNAP is a large molecule (about 400 kDa) and its core structure is composed of four polypeptide subunits: alpha (alpha) required for assembly of the enzyme, beta (beta) involved in chain initiation and elongation, beta' (beta') which binds to the DNA template, and omega (omega) which constrains the beta' subunit and aids its assembly into RNAP, in the stoichiometry alpha2betabeta'omega. The bacterial enzyme differs both from eukaryotic RNAP, which is composed of different subunits and is present in several variants, and from archaeal or viral RNAP. These differences allow to selectively target the bacterial enzyme with appropriately designed inhibitors, excluding interactions with eukaryotic RNAP, accounting for the deep interest developed around these compounds as selective antibacterial agents. In this review the known natural and synthetic inhibitors of RNAP will be described considering their mechanism of action, biological activity, availability of analogues, Structure Activity Relationship (SAR) information and clinical use when already approved or recently entered into clinical trials.


T-cell receptor beta-chain gene rearrangement and expression during human thymic ontogenesis.
T-cell receptor (TCR) beta-chain proteins appear early (approximately 15th week of gestation) during human thymic ontogenesis. These beta-chain proteins, which appear before terminal deoxynucleotidyl transferase (TdT), could be an expression of a fully rearranged (V-D-J), incompletely rearranged (D-J), or germline TCR beta-chain gene. The aims of this study, performed from the 15th week onward, were the following: (1) to investigate whether or not TCR beta gene rearranges at an early stage during human thymic ontogenesis; (2) to investigate whether complete presumptive functional (1.3 kb) TCR beta gene transcript is present at these early stages of development, or if incomplete (1 kb) or germ-line (1.1 kb) transcripts are expressed; (3) to examine the phenotype of TCR beta-chain+ cells with two-color fluorescence using monoclonal antibody (MoAb) beta F1 and MoAbs that recognize CD1, CD2, CD3, CD4, CD8, CD5, and CD7 antigens (rabbit anti-calf TdT antiserum was used to detect TdT); and (4) to demonstrate whether or not beta gene N-diversity regions are detectable as early as the 15th week and whether or not N-nucleotide insertions correlate to TdT expression. Fifteen- to 22-week fetal thymuses and pediatric thymuses were investigated. We demonstrated that TCR beta-chain gene rearranged as early as the 15th week in human thymus and that a complete functional TCR beta gene transcript was expressed at these early stages of human development. No other analyses to date have investigated TCR beta gene expression in early human thymus using molecular biology techniques. No significant differences were detectable between phenotypic analysis of fetal and pediatric samples, except for TdT expression, which appeared after the 20th week. Essentially all mCD3+ (OKT3+) cells were beta-chain+ at the different weeks investigated. A significant percentage of CD1+ cells were beta-chain+, and the percentage increased along with the age of development. After the 20th week, we identified three main populations: TdT+, cCD3+, beta F-(early thymic precursors); TdT+, CD1+, beta F1+ (intermediate maturity cortical thymocytes); and TdT-, mCD3+, beta F1++ (mature medullary thymocytes). Given these values, we may consider beta-chain expression an ordered process. beta gene N-nucleotide insertions were correlated to TdT expression, since N-regions increased considerably after the 20th week. A further increase of N-nucleotide insertions was detected from the 22nd week to the 32nd week.


Diabetes mellitus in the 21 years after a pregnancy that was complicated by hypertension: findings from a prospective cohort study.
The purpose of this study was to examine the relationship between hypertensive disorders of pregnancy (HDP) and self-reported diabetes mellitus 21 years after delivery. The Mater-University of Queensland Study is a prospective cohort study of women who received antenatal care at a major public hospital in Brisbane, Australia, between 1981 and 1984; 3639 women who completed the questionnaire at 21 years postpartum were included. Of the women without HDP, 7.4% reported a diagnosis of diabetes mellitus compared with 15.3% of the women with HDP (unadjusted odds ratio [OR], 2.03; 95% CI, 1.42, 2.91). After adjustment for all potentially explanatory variables, only prepregnancy body mass index (BMI) and BMI at 21 years after delivery resulted in attenuation of the association (fully adjusted OR, 1.76; 95% CI, 1.21, 2.56). In a smaller subgroup, waist circumference and BMI at 21 years had similar effects on point estimates (fully adjusted OR with BMI, 1.64 [95% CI, 1.11, 2.42]; fully adjusted OR with waist, 1.60 [95% CI, 1.08, 2.40]). HDP are associated with reported diagnosis of diabetes mellitus 21 years after delivery.


Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes.
Optical measurements of the pigments of the retinal pigment epithelium (RPE) and choroid were made on 38 human autopsy eyes of both blacks and whites, varying in age between 2 wk and 90 yr old. Lipofuscin in melanin-bleached RPE was measured as fluorescence at 470 mm following excitation at 365 nm and was found to be proportional to fluorescence measured at 560 nm in unbleached tissue. Transmission measurements of RPE and choroidal melanin were converted and expressed as optical density units. The choroidal melanin content increased from the periphery to the posterior pole. RPE melanin concentration decreased from the periphery to the posterior pole with an increase in the macula. Conversely, the amount of RPE lipofuscin increased from the periphery to the posterior pole with a consistent dip at the fovea. There was an inverse relationship between RPE lipofuscin concentration and RPE melanin concentration. The RPE melanin content was similar between whites and blacks. Lipofuscin concentration was significantly greater (P = 0.002) in the RPE of whites compared to blacks; whereas blacks had a significantly greater (P = 0.005) choroidal melanin content than whites. The amounts of both choroidal and RPE melanin showed a trend of decreasing content with aging, whereas the amount RPE lipofuscin tended to increase (whites greater than blacks). Per fundus area, the amount of choroidal melanin was always greater than that in the RPE. There was a statistically significant (P = 0.001) increase in RPE height with age, most marked in eyes of whites after age 50 and correlated with the increase in lipofuscin concentration.


[Biotyping and resistotyping for epidemiological tracing of the fecal origin of Klebsiella pneumoniae in urinary infections].
Twenty-four (82.7%) out of 29 patients suffering from hospital acquired urinary infections by Klebsiella pneumoniae had the same species in their faeces. Biotyping of 24 urinary and 219 fecal strains of K. pneumoniae resulted in 50 different biotypes - an average of four biotypes per fecal sample. Ten patients (34.4%) had the same biotype in urine and faeces without any correlation with previous vesical catheterization (p greater than 0.05). Using resistotyping to four chemical compounds selected among 34 tested substances (brilliant green, malachite green, potassium tellurite and mercuric chloride) 16 different resistotypes were found. Fourteen patients (58.3%) presented the same resistotype in urine and faeces but only in five patients was there correlation with simultaneous biotyping identity. Simultaneous occurrence of identical biotypes or resistotypes in faeces and urine occurred in only 54.2% of cases. However, there was a significant association between resistance ot mercuric and tellurite ions in fecal and urinary strains isolated from the same patient (p less than 0.001).


Telemedicine screening of glaucoma.
Glaucoma is a major cause of blindness. More than 80,000 Americans suffer permanent vision loss from the disease. Widespread screening is fundamental in limiting the incidence of glaucoma-associated blindness. This pilot study explored the use of stereo digital images taken at a primary care center for telemedicine review by an off-site specialist as a means of screening for glaucoma. Thirty-two diabetic patients were screened at a family medicine clinic. None had previously been diagnosed with glaucoma. A senior optometry student took stereoscopic digital and 35-mm optic disc photographs with a nonmydriatic retinal camera. The digital images were forwarded to a remote ophthalmologist for review. The conventional color stereo slide pairs of the same eyes were subsequently reviewed for comparison. Agreement on signs of glaucomatous disc changes between the two imaging systems was analyzed. Twenty-six of 32 eyes' digital and 35-mm photographs were analyzed. Six of 32 eyes (18.8%) could not be compared due to lack of matching 35-mm slides or digital images. Out of 26 eyes, lamina cribosa visibility was undeterminable in 8 eyes' digital images and 3 other eyes' 35-mm slides. Agreement among digital images and 35-mm slides of the remaining eyes was: 100%-vertical elongation, barring of vessels, bayoneting of vessels, and drance hemorrhage; 96.2%-focus notching of rim and rim pallor; 93.3%-lamina cribosa visability; 92. 3%-overpass cupping; 88.5%-focal enlargement; 84.6%-parapapillary halo; 80%-nerve fiber visibility; 65.4%-parapapillary atrophy. Parapapillary halo (p = 0.046) and nerve fiber layer visibility (p = 0.18) were detected on some 35-mm slides but not seen on matching digital views. Evaluations of cup-to-disc ratio (C/D) using both methods were in general agreement. However, some digital images were noted as too dark for assessing fine glaucomatous disc changes. Stereo digital images taken with a nonmydriatic camera by nonophthalmic photographers is a promising alternative for glaucoma screening in primary care settings. Telemedicine offers efficient communications with off-site glaucoma specialists. A larger study population is necessary to determine the overall effectiveness of using stereo digital imagery and teleophthalmology for glaucoma screening.


International consensus on the most useful assessments used by physical therapists to evaluate patients with temporomandibular disorders: A Delphi study.
To identify assessment tools used to evaluate patients with temporomandibular disorders (TMD) considered to be clinically most useful by a panel of international experts in TMD physical therapy (PT). A Delphi survey method administered to a panel of international experts in TMD PT was conducted over three rounds from October 2017 to June 2018. The initial contact was made by email. Participation was voluntary. An e-survey, according to the Checklist for Reporting Results of Internet E-Surveys (CHERRIES), was posted using SurveyMonkey for each round. Percentages of responses were analysed for each question from each round of the Delphi survey administrations. Twenty-three experts (completion rate: 23/25) completed all three rounds of the survey for three clinical test categories: 1) questionnaires, 2) pain screening tools and 3) physical examination tests. The following was the consensus-based decision regarding the identification of the clinically most useful assessments. (1) Four of 9 questionnaires were identified: Jaw Functional Limitation (JFL-8), Mandibular Function Impairment Questionnaire (MFIQ), Tampa Scale for Kinesiophobia for Temporomandibular disorders (TSK/TMD) and the neck disability index (NDI). (2) Three of 8 identified pain screening tests: visual analog scale (VAS), numeric pain rating scale (NRS) and pain during mandibular movements. (3) Eight of 18 identified physical examination tests: physiological temporomandibular joint (TMJ) movements, trigger point (TrP) palpation of the masticatory muscles, TrP palpation away from the masticatory system, accessory movements, articular palpation, noise detection during movement, manual screening of the cervical spine and the Neck Flexor Muscle Endurance Test. After three rounds in this Delphi survey, the results of the most used assessment tools by TMD PT experts were established. They proved to be founded on test construct, test psychometric properties (reliability/validity) and expert preference for test clusters. A concordance with the screening tools of the diagnostic criteria of TMD consortium was noted. Findings may be used to guide policymaking purposes and future diagnostic research.


Retinal nerve changes in patients with tremor dominant and akinetic rigid Parkinson's disease.
Parkinson disease is a multisystem neurodegenerative disease which involves not only basal ganglia and extrapyramidal system but also many other neurologic systems such as retinal ganglion cells. Optical coherence tomography (OCT) is a non-invasive method for assessment of retinal nerve fiber layer (RNFL) thickness and its changes in different diseases. To evaluate the RNFL thickness in patients with Parkinson disease (PD), we performed OCT in patients with PD and compared it with a control group. From October 2010 to July 2011, 27 PD patients (54 eyes) and 25 healthy persons (50 eyes) were entered to this analytical cross-sectional study according to the defined criteria. PD patients were categorized into two groups "akinetic rigid (AR) and tremor dominant (TD)". RNFL was divided into four quadrants and was assessed by OCT. Afterwards; the data were analyzed by bivariate and multivariate models. The RNFL thickness in PD was significantly lower than the control group. Also, the thicknesses of inferior and nasal quadrants of RNFL in TD group were significantly more than AR group. According to these findings, OCT can be used as a sensitive and objective marker for assessment of early neurodegenerative changes of PD and early initiation of neuroprotective treatments. Future studies with adequate sample sizes are recommended to investigate interactions between age, distribution of the disease and type of PD as well as the effects of individual factors.


Attenuated virulence and biofilm formation in Staphylococcus aureus following sublethal exposure to triclosan.
Subeffective exposure of Staphylococcus aureus to the biocide triclosan can reportedly induce a small-colony variant (SCV) phenotype. S. aureus SCVs are characterized by low growth rates, reduced pigmentation, and lowered antimicrobial susceptibility. While they may exhibit enhanced intracellular survival, there are conflicting reports regarding their pathogenicity. The current study reports the characteristics of an SCV-like strain of S. aureus created by repeated passage on sublethal triclosan concentrations. S. aureus ATCC 6538 (the passage 0 [P0] strain) was serially exposed 10 times to concentration gradients of triclosan to generate strain P10. This strain was then further passaged 10 times on triclosan-free medium (designated strain ×10). The MICs and minimum bactericidal concentrations of triclosan for P0, P10, and ×10 were determined, and growth rates in biofilm and planktonic cultures were measured. Hemolysin, DNase, and coagulase activities were measured, and virulence was determined using a Galleria mellonella pathogenicity model. Strain P10 exhibited decreased susceptibility to triclosan and characteristics of an SCV phenotype, including a considerably reduced growth rate and the formation of pinpoint colonies. However, this strain also had delayed coagulase production, had impaired hemolysis (P < 0.01), was defective in biofilm formation and DNase activity, and displayed significantly attenuated virulence. Colony size, hemolysis, coagulase activity, and virulence were only partially restored in strain ×10, whereas the planktonic growth rate was fully restored. However, ×10 was at least as defective in biofilm formation and DNase production as P10. These data suggest that although repeated exposure to triclosan may result in an SCV-like phenotype, this is not necessarily associated with increased virulence and adapted bacteria may exhibit other functional deficiencies.


Pathogenicity of various adenovirus serotypes in the presence of Escherichia coli in chickens.
Ten strains of adenovirus representing 10 serotypes were administered intratracheally to 3-week-old specific-pathogen-free chickens, which also received 2.9 X 10(5) colony-forming units of a pathogenic Escherichia coli intranasally. One group was given only E. coli, and one was retained as an uninoculated control. Gross pathologic alterations post-mortem were minimal and limited to multiple scattered, pale areas in the lungs of an occasional chicken in various groups. Histopathologic changes in the lungs were those of multifocal, interstitial, and occasionally diffuse pneumonia. Moderate to marked interstitial pneumonia was incited by adenovirus strains 75-1A, B-3 A-2, C-2B, and X-11; Ind-C, Stein, Tipton, J-2, and T-8 caused similar but milder lesions. Strains 75-1A, A-2, C-2B, T-8, and X-11 incited moderate to marked multifocal pneumonia; Ind-C, Stein, Tipton, J-2, and B-3 caused mild multifocal pneumonia. In all groups, the pneumonic lesions were more severe 5 days postinoculation than 12 days postinoculation. Bronchiolitis and tracheitis lesions also varied in severity with serotype. A mild hepatitis was seen with serotypes T-8 and 75-1A. Neither the uninoculated control group nor the group inoculated with only E. coli exhibited gross or histopathologic alterations.


Phase III Prospective Randomized Comparison Trial of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab in Patients With Advanced Carcinoid Tumors: SWOG S0518.
Purpose Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs. Patients and Methods Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. Results A total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFN-α-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio [HR], 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). Conclusion No significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.


Emulating a target trial of antiretroviral therapy regimens started before conception and risk of adverse birth outcomes.
To compare the effect of preconception initiation of zidovudine, lamivudine, nevirapine (ZDV/3TC/NVP) versus tenofovir, emtricitabine, efavirenz (TDF/FTC/EFV) on adverse birth outcomes. Emulation of a hypothetical (target) trial using a birth surveillance study in Botswana during an era of CD4-based antiretroviral therapy (ART) initiation. In women who initiated ART less than 3 years from HIV diagnosis, conceived 0.5-5 years after ART initiation, and delivered at least 24-week gestation, we estimated risk ratios for stillbirth, preterm delivery (<37 weeks), very preterm delivery (<32 weeks), small-for-gestational-age (SGA) (<10 percentile), very SGA (<3 percentile), and any adverse or severe birth outcome for first-line ZDV/3TC/NVP versus TDF/FTC/EFV. We conducted a historical comparison in women who initiated TDF/FTC/EFV in 2012-2015 and ZDV/3TC/NVP in 2004-2011, and a contemporaneous comparison in an era of overlapping use from 2009 to 2013. In the historical comparison, 1108 women initiated TDF/FTC/EFV and 637 initiated ZDV/3TC/NVP. In the contemporaneous comparison, 1052 initiated TDF/FTC/EFV and 298 initiated ZDV/3TC/NVP. TDF/FTC/EFV initiators were younger and more likely to be nulliparous than ZDV/3TC/NVP initiators in both comparisons. In the historical comparison, the adjusted risk ratios (95% confidence interval) comparing ZDV/3TC/NVP with TDF/FTC/EFV were 2.95 (1.76, 4.96) for stillbirth, 1.40 (1.17, 1.67) for preterm delivery, 2.58 (1.70, 3.91) for very preterm delivery, 1.96 (1.64, 2.34) for SGA, 2.32 (1.73, 3.09) for very SGA, 1.54 (1.38, 1.72) for any adverse birth outcome, and 2.20 (1.76, 2.75) for any severe birth outcome, and were similar in the contemporaneous comparison. Preconception initiation of ZDV/3TC/NVP compared with TDF/FTC/EFV may increase the risk of adverse birth outcomes.


[Neuroblastoma. Tumor rupture as an unfavorable prognostic factor].
Since there is little information regarding the possible prognostic significance of tumor rupture in localized neuroblastoma, we have analyzed the clinical courses of 163 children registered from 1979-1990 in 12 italian pediatric oncology Centers participating in the Neuroblastoma Cooperative Group of the A.I.E.O.P. (Italian Association for Paediatric Haematology-Oncology). Ten instances (6%) of tumor rupture were described. Ruptures occurred preoperatively in one child, during the operation in 9; among these 9, two were provoked by the surgeon to allow radical tumor excision, 7 were accidental. Of these 10 children, 7 relapsed at 3-25 months (median, 8 months) from diagnosis. Relapses were local in 5 children (2 of the 5 died), disseminated in one (who died), local + disseminated in one (presently alive with disease). Two local relapses were followed by bony or haematologic spread at 4 and 8 months, respectively. Of the 7 children who relapsed, 2 are alive in complete remission at 29, 100 months, respectively; two are alive with disease at 3 and 65 months, 3 died at 8, 15 and 24 months, respectively. We conclude that rupture of a localized neuroblastoma is a factor predisposing to relapse and may compromise the chance of cure. The surgeon should be aware of the risks connected with this complication and make any effort to avoid it.


Marketing public health nursing services.
I am concerned that public health nursing as many of us have known it may disappear unless we become much more skilled in developing and marketing services that the public--particularly high risk target aggregates--needs and will use, and whose termination they will protest. Use of the marketing concepts and approaches I have described can help us to continue to make a valuable contribution to the public's health and help ensure that public health nurses do not become an endangered species. Thus, our utilization of sound marketing approaches is not only good business, but also good public health.


Cloning of type 8 capsule genes and analysis of gene clusters for the production of different capsular polysaccharides in Staphylococcus aureus.
Eleven serotypes of capsular polysaccharide from Staphylococcus aureus have been reported. We have previously cloned a cluster of type 1 capsule (cap1) genes responsible for type 1 capsular polysaccharide biosynthesis in S. aureus M. To clone the type 8 capsule (cap8) genes, a plasmid library of type 8 strain Becker was screened with a labelled DNA fragment containing the cap1 genes under low-stringency conditions. One recombinant plasmid containing a 14-kb insert was chosen for further study and found to complement 14 of the 18 type 8 capsule-negative (Cap8-) mutants used in the study. Additional library screening, subcloning, and complementation experiments showed that all of the 18 Cap8- mutants were complemented by DNA fragments derived from a 20.5-kb contiguous region of the Becker chromosome. The mutants were mapped into six complementation groups, indicating that the cap8 genes are clustered. By Southern hybridization analyses under high-stringency conditions, we found that DNA fragments containing the cap8 gene cluster show extensive homology with all 17 strains tested, including type 1 strains. By further Southern analyses and cloning of the cap8-related homolog from strain M, we show that strain M carries an additional capsule gene cluster different from the cap1 gene cluster. In addition, by using DNA fragments containing different regions of the cap8 gene cluster as probes to hybridize DNA from different strains, we found that the central region of the cap8 gene cluster hybridizes only to DNAs from certain strains tested whereas the flanking regions hybridize to DNAs of all strains tested. Thus, the cap8 gene clusters and its closely related homologs are likely to have organizations similar to those of the encapsulation genes of other bacterial systems.


Minimally invasive approaches in management of hepatic tumors.
Traditionally, the only curative option for patients with liver tumors has been hepatic resection. Unfortunately, only 10%-20% of patients with liver tumors can undergo surgical resection due to limited hepatic reserve, high surgical risk, or unfavorable tumor location. Ablation of liver tumors is currently the main alternative to formal liver resection. Tumor cell death is achieved through a number of technologies, which may be separated into three categories: chemical (percutaneous ethanol injection), cold-based (cryotherapy), and heat-based (radiofrequency and microwave ablation or laser hyperthermia). Although long-term data are limited, ablation may be curative in some patients with a three- and five-year survival rate approaching that of resection. The main factors to success include proper patient selection, excellent diagnostic and procedural imaging, and careful post-procedure management and follow up. Long-term success following tumor ablation will be most dependent on the underlying tumor biology and the ability to achieve a negative margin. Future directions in ablation will include the use of adjunctive agents such as chemotherapeutics, further advances in energy delivery, improved imaging and lesion targeting, and continued refinements of current technology and technique.


Electrical and pharmacological manipulations of the nucleus accumbens core impair synaptic plasticity in the dentate gyrus of the rat.
The interest on the physiology of the nucleus accumbens (NAcc) has grown in recent years given its relationship to addictive behaviours, and the possibility to treat them by interacting with NAcc function. We have shown that the prior stimulation of the core region blocks induction of long-term potentiation (LTP) at the dentate gyrus in anaesthetized rats, while the shell facilitated it. In the present study we have confirmed and expanded those results testing the effects of core and shell stimulation in freely moving rats, as well as the effect of blocking D1 receptors in the NAcc. Our results show that shell stimulation had no effect on baseline recordings of the field excitatory postsynaptic potential (fEPSP) or the population spike amplitude (PSA) for 24 h. Core stimulation did not modify baseline-fEPSP, but significantly depressed PSA up to 8 h. LTP maintenance was not modified; neither by core nor shell stimulation after its induction, but LTP induction was impaired (both in the fEPSP and PSA) by core stimulation 15 min before induction. Shell stimulation showed a slight facilitating effect. Previous, topical application of a dopaminergic-receptor antagonist (SCH23390) into the NAcc produced a significantly depressed baseline fEPSP and PSA, as well as LTP measured in both components of the evoked potentials. Our results confirm a dual role of stimulation of NAcc sub-regions on hippocampal baseline synaptic transmission, and LTP induction when activated before induction. In contrast, stimulation of the NAcc had no influence on an already ongoing dentate gyrus LTP. A role for dopaminergic innervation to the NAcc, modifying susceptibility for synaptic plasticity outside the NAcc is also suggested by our results.


Electrophysiology, molecular modelling, and functional analysis of the effects of dietary quercetin and flavonoid analogues on Kir6.1 channels in rat stomach fundus smooth muscle.
Flavonoids, ubiquitously distributed in the plant world, are regularly ingested with diets rich in fruit, vegetables, wine, and tea. During digestion, they are partially absorbed in the stomach. The present work aimed to assess the in vitro effects of quercetin and ten structurally related flavonoids on the rat gastric fundus smooth muscle, focussing on ATP-dependent K+ (Kir6.1) channels, which play a central role in the regulation of resting membrane potential, membrane excitability and, consequently, of gastric motility. Whole-cell currents through Kir6.1 channels (IKir6.1) were recorded with the patch-clamp technique and the mechanical activity of gastric fundus smooth muscle strips was studied under isometric conditions. Galangin≈tamarixetin > quercetin > kaempferol > isorhamnetin≈luteolin≈fisetin>(±)-taxifolin inhibited pinacidil-evoked, glibenclamide-sensitive IKir6.1 in a concentration-dependent manner. Morin, rutin, and myricetin were ineffective. The steric hindrance of the molecule and the number and position of hydroxyl groups on the B ring played an important role in the activity of the molecule. Molecular docking simulations revealed a possible binding site for flavonoids in the C-terminal domain of the Kir6.1 channel subunit SUR2B, in a flexible loop formed by residues 251 to 254 of chains C and D. Galangin and tamarixetin, but not rutin relaxed both high K+- and carbachol-induced contraction of fundus strips in a concentration-dependent manner. Furthermore, both flavonoids shifted to the right the concentration-relaxation curves to either pinacidil or L-cysteine constructed in strips pre-contracted by high K+, rutin being ineffective. In conclusion, IKir6.1 inhibition exerted by dietary flavonoids might counterbalance their myorelaxant activity, affect gastric accommodation or, at least, some stages of digestion.


Ward staffing. Safety in numbers.
A model for reviewing ward staffing and quality of care in a district general hospital has led to extra nurses being appointed. The review found correlation between low staffing and a high number of clinical incidents. The results have led to changes in practice and action to tackle sickness absence.


Effects of presumptive test reagents on the ability to obtain restriction fragment length polymorphism (RFLP) patterns from human blood and semen stains.
Some of the commonly used presumptive test reagents for identification of blood and semen could potentially affect the recovery of intact high-molecular-weight deoxyribonucleic acid (DNA) from evidentiary samples. Thus, the capability of performing restriction fragment length polymorphism (RFLP) analysis on evidentiary samples could be compromised. In order to investigate the potential effects of presumptive test reagents on the DNA present in these samples, bloodstains on cotton and glass were exposed directly to luminol, benzidine, phenolphthalein, o-tolidine, and leucomalachite green, while semen stains and vaginal swabs containing semen were exposed directly to bromochloroindolyl phosphate (BCIP) and sodium thymolphthalein monophosphate (STMP) reagents. The yield gels for DNA quality and quantity and RFLP results indicated that bloodstains exposed to luminol, benzidine dissolved in ethanol, and phenolphthalein, as well as semen stains and vaginal swabs exposed to BCIP and STMP yield RFLP patterns consistent with that of the uncontaminated control. Except for the phenolphthalein treatment, the quantity of extractable, high-molecular-weight DNA obtained was comparable with that of untreated stains. Therefore, evidentiary material purposely or inadvertently contaminated with these reagents can be successfully typed. However, stains exposed to benzidine dissolved in glacial acetic acid, leucomalachite green, and o-tolidine failed to yield high-molecular-weight DNA or to produce any RFLP patterns.


Epidemiological Determinants of Patient Non-Conveyance to the Hospital in an Emergency Medical Service Environment.
The increasing prevalence of comorbidities worldwide has spurred the need for time-effective pre-hospital emergency medical services (EMS). Some pre-hospital emergency calls requesting EMS result in patient non-conveyance. Decisions for non-conveyance are sometimes driven by the patient or the clinician, which may jeopardize the patients' healthcare outcomes. This study aimed to explore the distribution and determinants of patient non-conveyance to hospitals in a Middle Eastern national Ambulance Service that promotes the transportation of all emergency call patients and does not adopt clinician-based non-conveyance decision. Using R Language, descriptive, bivariate, and binary logistic regression analyses were conducted for 334,392 multi-national patient non-conveyance emergency calls from June 2018 to July 2022, from a total of 1,030,228 calls to which a response unit was dispatched. After data pre-processing, 237,862 cases of patient non-conveyance to hospital were retained, with a monthly average of 41.96% (n = 8799) of the emergency service demands and a standard deviation of 5.49% (n = 2040.63). They predominantly involved South Asians (29.36%, n = 69,849); 64.50% (n = 153,427) were of the age category from 14 to 44 years; 61.22% (n = 145,610) were male; 74.59% (n = 177,424) from the urban setting; and 71.28% (n = 169,552) had received on-scene treatment. Binary logistic regression with full variables and backward methods identified the final models of the determinants of patient non-conveyance decisions with an Akaike information criterion prediction estimator, respectively, of (250,200) and (250,169), indicating no significant difference between both models (Chi-square test; p-value = 0.63). Despite exercising a cautious protocol by encouraging patient transportation to hospital, patient non-conveyance seems to be a problem in the healthcare system that strains the pre-hospital medical response teams' resources. Policies and regulations should be adopted to encourage individuals to access other primary care centers when required rather than draining emergency services for non-emergency situations.


Evaluation of physical activity measures used in middle-aged women.
To evaluate the reliability and validity of five commonly used physical activity questionnaires (PAQ) in women aged 45-65 yr with varying physical activity (PA) levels. Data were obtained from the Evaluation of Physical Activity Measures in Middle-aged Women (PAW) Study and included 66 women (aged 52.6 +/- 5.4 yr). PAQ evaluated include Modifiable Activity Questionnaire (past week and past month version), Nurses' Health Study PAQ, Active Australia Survey, and Women's Health Initiative PAQ. Intraclass correlation coefficients (ICC) between administrations of the PAQ were used to assess test-retest reliability. Spearman rank-order correlation coefficients were used to examine the associations of PA and physical fitness data with PAQ summary estimates. Accelerometer-determined median (25th, 75th percentiles) times (min.d) spent in moderate-lifestyle [760-1951 counts (ct)], moderate-walk (1952-5724 ct), vigorous (> or =5725 ct), and combined moderate and vigorous PA (MVPA > or = 1952 ct) during the 35 d of observation were 66.0 (51.2, 81.3), 23.1 (14.1, 34.6), 0.4 (0.0, 2.3), and 24.3 (15.9, 41.6) min, respectively. The PAQ were shown to be reproducible and relatively stable over time (ICC = 0.32 to 0.91) and were associated with total counts per day (ct.d, 0.46 to 0.60, all P < 0.001), and most were associated with many facets of physical fitness, including cardiorespiratory fitness (0.36 to 0.46, P < 0.01), body composition (-0.27 to -0.34, P < 0.05), and muscular fatigue (-0.25 to -0.44, P < 0.05). The PAQ evaluated in this study were shown to be reliable and associated with PA and physical fitness measures. Current findings support the utility of these PAQ for PA assessment in research studies of middle-aged women.


Microscopic evaluation of traffic safety at signal coordinated intersections: A before-after study.
This research aims to evaluate the safety impacts of signal coordination on signalized intersections and provide a scientific basis to design and improve signal control and management from a traffic safety perspective. A kernel regression model is adopted to evaluate the safety performance of intersections before and after implementing the signal coordination strategy. By using this statistical method, the authors identify the nonlinear relationship between crash frequency and the crash's spatial location and examine the discrepancy of crash spatial distributions between the coordination and noncoordination conditions at disaggregated levels, such as time of day and crash type. A case study is presented with the use of Michigan crash data (2003-2007). The study finds that the (1) crash distribution on arterials tends to be spatially disperse when the signal coordination is in operation and (2) crash frequency at the approaches of intersections is increased with the use of signal coordination under the following conditions: Nonpeak hours, rear-end and sideswipe crashes, intersections with low speed limits, and both injury and property damage-only crashes. Signal coordination poses safety concerns in addition to its operational benefits for intersections.


The current status of the NNRTI family of antiretrovirals used in the HAART regime against HIV infection.
Acquired immunodeficiency syndrome (AIDS) remains, after 25 years of its discovery, as one of the major threats to human life. Reverse Transcriptase is an essential enzyme for virus replication, and therefore constitutes a major target in HIV-1 therapy. Among the different types of drugs targeting RT, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) act by binding in an induced-fit allosteric pocket. In this review, we explore the several NNRTIs' structures and binding interactions, as well as their mechanisms of action. The conformational changes that they cause in RT and their effects on the topology of the active site are discussed. The emergence of mutant, resistant viruses is analysed, focussing on the mutations responsible for the loss of antiviral efficacy of NNRTIs. Explanations for the role of those mutations are presented. Emergent drugs in the pipeline, together with the underlying strategies for drug development, are also analysed.


Changing nursing student attitudes to consumer participation in mental health services: a survey study of traditional and lived experience-led education.
Mental health policy emphasises the importance of consumer participation in mental health services. To align education with policy and orient future healthcare services to active consumer involvement, the potential of academics with a lived experience of mental illness to impact on student attitudes towards consumer participation needs to be examined. A cohort comparative study was undertaken comparing attitudinal change between undergraduate nursing students undertaking two different mental health courses, one nurse-led (n = 61) and one lived experience-led. Attitudes were measured through the Mental Health Consumer Participation Questionnaire. Within-cohort change was assessed via dependent sample t-tests, and degree of change was observed in each cohort, by comparing effect sizes. For the nurse-led course, attitudes on consumer involvement t (60) = -1.79, p < 0.005 (95% CI: -2.84, -0.74) and consumer as staff t (60) = -4.12, p < 0.005 (95% CI: -3.34, -1.16), positively changed with effect size r of 0.40 and 0.47, respectively. For the lived experience-led course, attitudes on consumer capacity t (109) = -3.63, p < 0.005 (95% CI: -0.48, -1.41) and consumer as staff, t (109) = -5.63, p < 0.005 (95% CI: -0.97, -0.46), positively changed, effect size r of 0.33 and 0.47, respectively. Mental health nursing education has a positive and selective influence on attitudes to consumer participation. Lived experience-led education was more beneficial in changing attitudes to consumer capacity and both types of education had similar positive effects on attitudes to consumers as staff.


Volume regulation in mammalian skeletal muscle: the role of sodium-potassium-chloride cotransporters during exposure to hypertonic solutions.
Controversy exists as to whether mammalian skeletal muscle is capable of volume regulation in response to changes in extracellular osmolarity despite evidence that muscle fibres have the required ion transport mechanisms to transport solute and water in situ. We addressed this issue by studying the ability of skeletal muscle to regulate volume during periods of induced hyperosmotic stress using single, mouse extensor digitorum longus (EDL) muscle fibres and intact muscle (soleus and EDL). Fibres and intact muscles were loaded with the fluorophore, calcein, and the change in muscle fluorescence and width (single fibres only) used as a metric of volume change. We hypothesized that skeletal muscle exposed to increased extracellular osmolarity would elicit initial cellular shrinkage followed by a regulatory volume increase (RVI) with the RVI dependent on the sodium–potassium–chloride cotransporter (NKCC). We found that single fibres exposed to a 35% increase in extracellular osmolarity demonstrated a rapid, initial 27–32% decrease in cell volume followed by a RVI which took 10-20 min and returned cell volume to 90–110% of pre-stimulus values. Within intact muscle, exposure to increased extracellular osmolarity of varying degrees also induced a rapid, initial shrinkage followed by a gradual RVI, with a greater rate of initial cell shrinkage and a longer time for RVI to occur with increasing extracellular tonicities. Furthermore, RVI was significantly faster in slow-twitch soleus than fast-twitch EDL. Pre-treatment of muscle with bumetanide (NKCC inhibitor) or ouabain (Na+,K+-ATPase inhibitor), increased the initial volume loss and impaired the RVI response to increased extracellular osmolarity indicating that the NKCC is a primary contributor to volume regulation in skeletal muscle. It is concluded that mouse skeletal muscle initially loses volume then exhibits a RVI when exposed to increases in extracellular osmolarity. The rate of RVI is dependent on the degree of change in extracellular osmolarity, is muscle specific, and is dependent on the functioning of the NKCC and Na+, K+-ATPase.


Interaction of novel platelet-increasing agent eltrombopag with rosuvastatin via breast cancer resistance protein in humans.
Eltrombopag (ELT), an orally available thrombopoietin receptor agonist, is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1), and coadministration of ELT increases the plasma concentration of rosuvastatin in humans. Since the pharmacokinetic mechanism(s) of the interaction is unknown, the present study aimed to clarify the drug interaction potential of ELT at transporters. The OATP1B1-mediated uptake of ELT was inhibited by several therapeutic agents used to treat lifestyle diseases. Among them, rosuvastatin was a potent inhibitor with an IC(50) of 0.05 µM, which corresponds to one-seventh of the calculated maximum unbound rosuvastatin concentration at the inlet to the liver. Nevertheless, a simulation study using a physiologically based pharmacokinetic model predicted that the effect of rosuvastatin on the pharmacokinetic profile of ELT in vivo would be minimal. On the other hand, ELT potently inhibited uptake of rosuvastatin by OATP1B1 and human hepatocytes, with an IC(50) of 0.1 µM. However, the results of the simulation study indicated that inhibition of OATP1B1 by ELT can only partially explain the clinically observed interaction with rosuvastatin. ELT also inhibited transcellular transport of rosuvastatin in MDCKII cells stably expressing breast cancer resistance protein (BCRP), and was found to be a substrate of BCRP. The interaction of ELT with rosuvastatin can be almost quantitatively explained on the assumption that intestinal secretion of rosuvastatin is essentially completely inhibited by ELT. These results suggest that BCRP in small intestine may be the major target for interaction between ELT and rosuvastatin in humans.


Sequence Type 48 Escherichia coli Carrying the blaCTX-M-1 IncI1/ST3 Plasmid in Drinking Water in France.
Drinking water has rarely been recognized as a source of antimicrobial resistance for humans, and only in low-income countries. Here, a sequence type 48 Escherichia coli isolate carrying the blaCTX-M-1 IncI1/ST3 plasmid was recovered from drinking water in France. This plasmid was similar to other blaCTX-M-1 IncI1/ST3 plasmids found previously in animals and humans. Our findings highlight the possible human transfer of extended-spectrum β-lactamase (ESBL) genes through drinking water in high-income countries.


Transverse process and needles of medial branch block to facet joint as landmarks for ultrasound-guided selective nerve root block.
Selective lumbar nerve root block (SNRB) is generally accepted as an effective treatment method for back pain with sciatica. However, it requires devices producing radioactive materials such as C-arm fluoroscopy. This study evaluated the usefulness of the longitudinal view of transverse process and needles for medial branch block as landmarks under ultrasonography. We performed selective nerve root block for 96 nerve roots in 61 patients under the guidance of ultrasound. A curved probe was used to identify the facet joints and transverse processes. Identifying the lumbar nerve roots under the skin surface and ultrasound landmarks, the cephalad and caudal medial branch blocks were undertaken under the transverse view of sonogram first. A needle for nerve root block was inserted between the two transverse processes under longitudinal view, while estimating the depth with the needle for medial branch block. We then injected 1.0 mL of contrast medium and checked the distribution of the nerve root with C-arm fluoroscopy to evaluate the accuracy. The visual analog scale (VAS) was used to access the clinical results. Seven SNRBs were performed for the L2 nerve root, 15 for L3, 49 for L4, and 25 for L5, respectively. Eighty-six SNRBs (89.5%) showed successful positioning of the needles. We failed in the following cases: 1 case for the L2 nerve root; 2 for L3; 3 for L4; and 4 for L5. The failed needles were positioned at wrong leveled segments in 4 cases and inappropriate place in 6 cases. VAS was improved from 7.6 ± 0.6 to 3.5 ± 1.3 after the procedure. For SNRB in lumbar spine, the transverse processes under longitudinal view as the ultrasound landmark and the needles of medial branch block to the facet joint can be a promising guidance.


Climate services to improve public health.
A high level expert panel discussed how climate and health services could best collaborate to improve public health. This was on the agenda of the recent Third International Climate Services Conference, held in Montego Bay, Jamaica, 4-6 December 2013. Issues and challenges concerning a demand led approach to serve the health sector needs, were identified and analysed. Important recommendations emerged to ensure that innovative collaboration between climate and health services assist decision-making processes and the management of climate-sensitive health risk. Key recommendations included: a move from risk assessment towards risk management; the engagement of the public health community with both the climate sector and development sectors, whose decisions impact on health, particularly the most vulnerable; to increase operational research on the use of policy-relevant climate information to manage climate- sensitive health risks; and to develop in-country capacities to improve local knowledge (including collection of epidemiological, climate and socio-economic data), along with institutional interaction with policy makers.


Blood prefabricated hydroxyapatite/tricalcium phosphate induces ectopic vascularized bone formation via modulating the osteoimmune environment.
Successful bone healing depends significantly on the structure of blood clots and the functional responses of blood cells. Despite the importance of blood clots in osteogenesis, few studies have investigated the effects of blood clots during material-mediated bone regeneration. In this study, we implanted the bone graft substitute hydroxyapatite/tricalcium phosphate (HA/TCP) subcutaneously, with or without blood prefabrication, to evaluate the effects of blood clots on material-mediated bone formation. We observed that blood prefabricated HA/TCP induced ectopic vascularized bone-like structures, implying that blood prefabrication can induce a microenvironment sufficient for HA/TCP-mediated bone formation. The possible mechanisms were related to (1) modification of the fibrin network, which facilitates MSCs recruitment and differentiation, (2) modulation of the early osteoimmune environment with the upregulation of osteogenic factor BMP2, and (3) improved expression of VEGF and the enhancement of angiogenesis. These results demonstrate the multifaceted effects of blood clots in regulating osteogenesis, osteoclastogenesis, immune responses, and angiogenesis. Therefore, blood prefabrication can serve as a valuable strategy to improve the osteogenic capacity of materials, and prefabricating materials with blood clots prior to implantation should be encouraged. New generation bone substitute materials could target the modulation of a favorable blood clot response for improved bone regeneration.


Target-oriented design method for ultrabroadband single-mode triple-clad fibers.
Many inherent troubles from holey fiber technology are avoided according to leakage losses from the endlessly single-mode (ESM) property. The target-oriented design method (TODM) brings the potentialities of triple-clad fibers (TCFs) with arbitrarily available structure and performance into full play in transmission performance, because of the scalar wave equation combined with infinitesimal calculus of fiber performance. TCF with modified total internal reflection guidance optimized by TODM under the tolerance Δh1≤6% has an ultrabroadband single-mode property similar to the ESM property of solid-core microstructured nonzero dispersion shifted fibers without tolerance and optimal structure to avoid higher-order modes and to reduce macro-bending loss.


Effects of recombinant ovine interferon tau, placental lactogen, and growth hormone on the ovine uterus.
Studies were conducted to determine effects of intrauterine administration of recombinant ovine interferon tau (IFNtau), placental lactogen (PL), and growth hormone (GH) on endometrial function. In the first study, administration of IFNtau to cyclic ewes for one period (Days 11-15) resulted in an interestrous interval (IEI) of approximately 30 days, whereas administration for two periods (Days 11-15 and Days 21-25) extended the IEI to greater than 50 days. Administration of IFNtau from Days 11 to 15 and of PL or GH from Days 21 to 25 failed to extend the IEI more than for IFNtau alone. In the second study, effects of IFNtau, PL, and GH on endometrial differentiation and function were determined in ovariectomized ewes receiving ovarian steroid replacement therapy. Endometrial expression of mRNAs for estrogen receptor (ER), progesterone receptor (PR), and oxytocin receptor (OTR) were not affected by PL or GH treatment; however, uterine milk protein mRNA levels and stratum spongiosum gland density were increased by both PL and GH treatments. Collectively, results indicated that 1) PL and GH do not regulate endometrial PR, ER, and OTR expression or affect corpus luteum life span; 2) down-regulation of epithelial PR expression is requisite for progesterone induction of secretory gene expression in uterine glandular epithelium; 3) effects of PL and GH on endometrial function require IFNtau; and 4) PL and GH regulate endometrial gland proliferation and perhaps differentiated function.


Application of principles of steady-state kinetics to the estimation of brain acetylcholine turnover rate: effects of oxotremorine and physostigmine.
We have measured the turnover rate of acetylcholine (ACh) in the brains of mice injected with doses of oxotremorine and physostigmine that cause a prolonged increase of ACh concentration in brain. The method used to measure turnover rate of ACh is an application of principles of steady-state kinetics to the change with time of brain choline (Ch) and ACh specific radioactivities after an intravenous pulse injection of phosphorylcholine. We have found that when the concentration of brain ACh and Ch is increased to a new steady state as a result of oxotremorine and physostigmine injections the turnover rate of brain ACh decreases from 0.34 mumol/g/hr (in saline-treated mice) to 0.12 and 0.061 mumol/g/hr, respectively. The possibility that an increase of brain Ch or ACh concentrations plays a role in the control of brain ACh turnover rate is discussed.