[Clinical diagnosis and treatment of multiple level thoracolumbar spinal fractures].
To investigate the clinical characteristics and methods of diagnosis and treatment multiple level thoracolumbar spinal fractures. From March 2002 to March 2006, 17 patients with 35 thoracolumbar spinal fractures were treated, 13 males and 4 females, aged 21-52 years old (36.4 on average), among whom there were 10 cases of traffic accident injury and 7 of high falling injury. One fracture was located at T2, 1 at T3, 1 at T10, 4 at T11, 6 at T12, 5 at L1, at L2, 7 at L3, 5 at L4, and 2 at L15, with a total of 35 segments including 26 segments with unstable fractures and 9 segments with stable compression fractures. According to the Frankel grade, there was 1 case of grade A, 1 of grade B, 2 of grade C, 5 of grade and 8 of grade E. The preoperative height of the anterior border of the vertebral body was (20.8 +/- 3.8) mm and the preoperative kyphosis angle was (16.2 +/- 3.4) degrees. All the unstable fractures were performed operation. Sixteen injured vertebras were treated with long-segment pedicle screw internal fixation; 8 were treated with short-segment pedicle screw internal fixation, and 2 were treated with anterior fusion and fixation. Five injured vertebras with stable compression fractures were not treated and 4 were treated with pedicle screw implantation. The operation time was 1.8-4.2 hours and the amount of blood loss was 300-900 mL. The incisions obtained healing by first intention after the operation. All 17 patients were followed up for 13-41 months (18 months on average), and radiological evaluation showed no failure of the internal fixation. After the operation, Frankel scale assessment showed that 1 patient of grade A improved to grade B, 1 of grade B improved to grade C, 1 of grade improved to grade D, 1 of grade C improved to grade E, 5 of grade D improved to grade E, and 8 of grade E had no improvement. At the final postoperative follow-up, the height of the anterior border of the vertebral body was (31.9 -/+ 3.2) mm and kyphosis angle was (6.8 +/- 3.7) degrees, which were significantly different from those of preoperation (P < 0.01). The treatment of multiple level thoracolumbar spinal fractures should be individualized according to the patients' actual conditions in order to obtain decompression and stability of spines.


Aedes triseriatus and La Crosse virus: similar venereal infection rates in females given the first bloodmeal immediately before mating or several days after mating.
Venereal infection rates of Aedes triseriatus females mated to males transovarially infected with La Crosse virus were determined in 6 cage-mating trials. In trials 1-4, venereal infection rates averaged 46% and 45% in F2 females bloodfed 6-8 hr before and 7 days after exposure, respectively, to transovarially-infected males. These rates were similar to rates previously reported only in mosquitoes receiving a bloodmeal 6-8 days prior to mating. Lower rates (24%-31%) were obtained using F4 and F7 generation mosquitoes in trials 5B and 6. In most trials, oral and transovarial transmission rates by venereally infected females were less than 25%. In trial 5B, however, the transovarial transmission rates reached 60% and 94% in the second and third ovarian cycles, respectively, with filial infection rates of 46% and 65%, respectively. The oral transmission rate in this trial reached 38% after 32 days. LAC virus was not detected in first ovarian cycle progeny. It is concluded that higher venereal infection rates must be found and/or first ovarian cycle progeny shown to become infected, before venereal transmission can be considered to make more than a modest contribution to offsetting the erosion of virus prevalence during TO transmission.


Dialectical Behaviour Therapy and attachment: vehicles for the development of resilience in young people leaving the care system.
It is well recognised that Looked After Children (LAC) and Young People Leaving Care (YPLC) have complex mental health needs and often engage in self-destructive behaviours such as self-harm, drug and alcohol use and suicide attempts. They can experience a high level of instability in relationships and frequently live transient lifestyles. Traditional mental health services for children, young people and adults have been unable to meet the attachment needs of this particular group such that they rarely benefit from therapeutic interventions and remain in a constant state of emotional dysregulation. This article describes the way in which two distinct therapeutic models - Dyadic Developmental Psychotherapy and Dialectical Behaviour Therapy - have been interwoven in order to engage and captivate young people leaving care in a therapeutic relationship. This relationship can then be used to help build skills to increase their resilience as they enter adulthood.


Synchronization and redundancy: implications for robustness of neural learning and decision making.
Learning and decision making in the brain are key processes critical to survival, and yet are processes implemented by nonideal biological building blocks that can impose significant error. We explore quantitatively how the brain might cope with this inherent source of error by taking advantage of two ubiquitous mechanisms, redundancy and synchronization. In particular we consider a neural process whose goal is to learn a decision function by implementing a nonlinear gradient dynamics. The dynamics, however, are assumed to be corrupted by perturbations modeling the error, which might be incurred due to limitations of the biology, intrinsic neuronal noise, and imperfect measurements. We show that error, and the associated uncertainty surrounding a learned solution, can be controlled in large part by trading off synchronization strength among multiple redundant neural systems against the noise amplitude. The impact of the coupling between such redundant systems is quantified by the spectrum of the network Laplacian, and we discuss the role of network topology in synchronization and in reducing the effect of noise. We discuss range of situations in which the mechanisms we model arise in brain science and draw attention to experimental evidence suggesting that cortical circuits capable of implementing the computations of interest here can be found on several scales. Finally, simulations comparing theoretical bounds to the relevant empirical quantities show that the theoretical estimates we derive can be tight.


A survey of adherence to haemophilia therapy in six European countries: results and recommendations.
Very few studies have addressed the question of adherence of haemophiliacs to their treatment. The aim of our study was to compare their levels of adherence to therapy and also to provide recommendations. Professionals of an international research company performed individual interviews with 30 patients in each of six European countries (France, Germany, Italy, Spain, Sweden and UK) resulting in a total of 180 patients. Twenty-eight interviews with haemophilia physicians and specialist nurses were also undertaken. Overall adherence to treatment was high (80-87% in each country). There was a positive correlation between greater adherence and younger age, prophylactic treatment, time spent with a haemophilia treatment centre (HTC) and the quality of the relationship with the haematologist and nurse. The four leading reasons for not using the prescribed amount of clotting factor or skipping the administration interval were reduction, fluctuation or disappearance of symptoms, forgetfulness, lack of time for treatment and convenience. These reasons differed according to the country and the age of the patient. The main suggestions made by patients to improve adherence related to HTC, environment and factor concentrates. Patients considered also that internet and electronic patient diaries were likely to improve adherence. In this selected group of European haemophilia patients, adherence to treatment appears higher than for most patients with other chronic diseases. However, it remains important to be aware of the possibility of non-adherence given the serious implications, particularly when considering a differently selected group of patients.


Application of In-Fusion™ cloning for the parallel construction of E. coli expression vectors.
In-Fusion™ cloning is a flexible DNA ligase-independent cloning technology that has wide-ranging uses in molecular biology. In this chapter we describe the protocols used in the OPPF-UK to design and construct expression vectors using In-Fusion™. Our method for small scale expression screening in Escherichia coli of constructs generated by In-Fusion™ is also outlined.


Gastrointestinal nematodes and anthelmintic resistance in Danish goat herds.
The prevalence of gastrointestinal parasites in Danish goats and the presence of anthelmintic resistance (AR) in 10 selected herds were investigated during April-September 2012. All Danish herds (n = 137) with 10 or more adult goats were invited to participate, and of these 27 herds met the inclusion criterion of more than 10 young kids never treated with anthelmintics. Questionnaire data on management were collected, and faecal samples from 252 kids were analysed by the McMaster technique. From all herds with a mean faecal egg count (FEC) above 300 eggs per g of faeces, pooled samples were stained with peanut agglutinin (PNA) for specific detection of Haemonchus contortus. Strongyle eggs were detected with an individual prevalence of 69%, including Nematodirus battus (3.6%) and other Nematodirus species (15.0%). Eimeria spp. were observed in 99.6% of the kids. H. contortus was found in 11 of 12 (92%) tested herds. Anthelmintics were used in 89% of the herds with mean treatment frequencies of 0.96 and 0.89 treatments per year for kids and adults, respectively. In 2011, new animals were introduced into 44% of the herds of which 25% practised quarantine anthelmintic treatments. In 10 herds the presence of AR was analysed by egg hatch assay and FEC reduction tests using ivermectin (0.3 mg/kg) or fenbendazole (10.0 mg/kg). AR against both fenbendazole and ivermectin was detected in seven herds; AR against fenbendazole in one herd, and AR against ivermectin in another herd. In conclusion, resistance to the most commonly used anthelmintics is widespread in larger goat herds throughout Denmark.


Peripheral blood culture contamination in adults and venepuncture technique: prospective cohort study.
To test the hypothesis that compliance with a hospital protocol on peripheral blood culture (PBC) collection in adults is associated with a reduction in PBC contamination, and to investigate likely contributing factors for contamination. A prospective cohort study was conducted, utilising data collection by participant questionnaire completion, and utilising bacteriology laboratory results on PBCs. Participants were all healthcare workers involved in obtaining PBCs from adults. 1460 PBCs with questionnaires were received. Contamination among the 1460 PBCs as a whole was 8.8%. 766 of the questionnaires were sufficiently complete to allow analysis of blood culture contamination in relation to protocol compliance. Among these, protocol compliance was 30% and contamination was 8.0%. When the protocol was complied with, 2.6% of PBCs were contaminated, but when the protocol was not followed, contamination was significantly higher at 10.3% (OR 4.35, 95% CI 1.84 to 12.54). Univariate analysis on all 1460 PBCs suggested that the site for blood collection, and disinfection of the venepuncture site were important factors in PBC contamination: when no venepuncture site disinfection was performed, contamination was significantly higher than when alcohol was used (5.1% versus 15.8%, OR 3.46, 95% CI 2.01 to 5.97); when a PBC collection site other than a fresh peripheral vein was used, contamination was significantly higher (7.3% versus 12.0%, OR 1.75, 95% CI 1.03 to 2.96). Compliance with a hospital protocol on PBC collection technique in adults significantly reduces blood culture contamination.


Performance of the chromogenic medium CHROMagar Staph Aureus and the Staphychrom coagulase test in the detection and identification of Staphylococcus aureus in clinical specimens.
CHROMagar Staph aureus (CSAM) (CHROMagar Microbiology, Paris, France) is a new chromogenic medium designed to enable detection of colonies of Staphylococcus aureus by their pink color. A total of 775 specimens were cultured in parallel on CHROMagar Staph aureus and conventional media. Among the 267 S. aureus strains recovered on at least one medium, 263 were isolated on CSAM medium (sensitivity, 98.5%), and 245 (sensitivity, 91.8%) were isolated on conventional media. The specificity of presumptive identification of S. aureus on the basis of pink colony color on CSAM medium was 97% (493 of 508). This specificity increased to 100% when coagulase detection with the Staphychrom coagulase test was added and to 98.8% when S. aureus surface components were detected by agglutination in the Pastorex Staph Plus test. Susceptibility testing of 67 S. aureus strains, performed in parallel on pink CSAM colonies and on colonies grown on blood agar, gave similar results. Thus, rapid and accurate recognition and identification of S. aureus isolates were achieved with CSAM as the primary isolation medium, followed by the staphylocoagulase Staphychrom test. Antimicrobial susceptibility testing (disk-diffusion method or ATB STAPH System) can be performed directly on pink CSAM colonies.


An assessment of the potential of the microbial assay for risk assessment (MARA) for ecotoxicological testing.
Rapid microscale toxicity tests make it possible to screen large numbers of compounds and greatly simplify toxicity identification evaluation and other effect directed chemical analyses of effluents or environmental samples. Tests using Vibrio fischeri (such as Microtox®) detect toxicants that cause non-specific narcosis, but are insensitive to other important classes of contaminants. The microbial assay for risk assessment (MARA) is a 24 h multi-species test that seeks to address this problem by using a battery of ten bacteria and a fungus. But there has been little independent evaluation of this test, and there is no published information on its sensitivity to pesticides. Here, we assess the performance of MARA using a range of toxicants including reference chemicals, fungicides and environmental samples. Mean MARA microbial toxic concentrations and IC(20)s (20% Inhibitory concentrations) indicate the toxicant concentrations affecting the more sensitive micro-organisms, while the mean IC(50) (50% Inhibitory concentration) was found to be the concentration that was toxic to most MARA species. For the two fungicides tested, the yeast (Pichia anomalia) was the most sensitive of the ten MARA species, and was more sensitive than the nine other yeasts tested. The test may be particularly valuable for work with fungicides. Mean MARA IC(50)s were comparable to values for nine other yeast species and the lowest individual IC(50)s for each toxicant were comparable to reported IC(50)s for Daphnia magna, Selenastrum capricornutum and Microtox® bioassays. MARA organisms exhibited more variable sensitivities, with the most sensitive organism being different for different samples, enhancing the likelihood of toxicity detection and giving a toxicity "fingerprint" that may help identify toxicants. The test, therefore, has great potential and would be valuable for ecotoxicological testing of pollutants.


Surface thiolation of silicon for antifouling application.
Thiol groups grafted silicon surface was prepared as previously described. 1H,1H,2H,2H-perfluorodecanethiol (PFDT) molecules were then immobilized on such a surface through disulfide bonds formation. To investigate the contribution of PFDT coating to antifouling, the adhesion behaviors of Botryococcus braunii (B. braunii) and Escherichia coli (E. coli) were studied through biofouling assays in the laboratory. The representative microscope images suggest reduced B. braunii and E. coli accumulation densities on PFDT integrated silicon substrate. However, the antifouling performance of PFDT integrated silicon substrate decreased over time. By incubating the aged substrate in 10 mM TCEP·HCl solution for 1 h, the fouled PFDT coating could be removed as the disulfide bonds were cleaved, resulting in reduced absorption of algal cells and exposure of non-fouled silicon substrate surface. Our results indicate that the thiol-terminated substrate can be potentially useful for restoring the fouled surface, as well as maximizing the effective usage of the substrate.


Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study.
Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors. In this open-label, multicenter, phase 1b, dose-escalation trial, HLA-A*02:01-positive patients with mCM received weekly intravenous tebentafusp with increasing monthly doses of durvalumab and/or tremelimumab starting day 15 of each cycle. The primary objective was to identify the maximum tolerated dose (MTD) or recommended phase 2 dose for each combination. Efficacy analyses were performed in all tebentafusp with durvalumab±tremelimumab treated patients with a sensitivity analysis in those who progressed on prior anti-PD(L)1 therapy. 85 patients were assigned to receive tebentafusp in combination with durvalumab (n=43), tremelimumab (n=13), or durvalumab and tremelimumab (n=29). Patients were heavily pretreated with a median of 3 prior lines of therapy, including 76 (89%) who received prior anti-PD(L)1. Maximum target doses of tebentafusp (68 mcg) alone or in combination with durvalumab (20 mg/kg) and tremelimumab (1 mg/kg) were tolerated; MTD was not formally identified for any arm. Adverse event profile was consistent with each individual therapy and there were no new safety signals nor treatment-related deaths. In the efficacy subset (n=72), the response rate was 14%, tumor shrinkage rate was 41% and 1-year OS rate was 76% (95% CI: 70% to 81%). The 1-year OS for triplet combination (79%; 95% CI: 71% to 86%) was similar to tebentafusp plus durvalumab (74%; 95% CI: 67% to 80%). At maximum target doses, the safety of tebentafusp with checkpoint inhibitors was consistent with safety of each individual therapy. Tebentafusp with durvalumab demonstrated promising efficacy in heavily pretreated patients with mCM, including those who progressed on prior anti-PD(L)1. NCT02535078.


Regulating structural dimensionality and emission colors by organic conjugation between SmIII at a fixed distance.
The conjugation of bridging bis(diphenylphosphine oxide) alkane or arene ligands was found to control the structural dimensionality and the emission color of complexes from reactions with SmIII(hfac)3(H2O)2 (hfac- = hexafluoroacetylacetonato) while retaining the SmSm distances. Bis(diphenylphosphine oxide)-1,4-butane (L1) affords a one-dimensional (1D) ribbon {Sm(hfac)3(L1)}∞ (1) that emits red color, while bis(diphenyl-phosphinoyl)-1,4-benzene (L2) results in a two-dimensional (2D) network {Sm(hfac)2(CF3COO)(L2)3}∞ (2) and near-white emission, but bis(diphenyl-phosphinoyl)-9,10-anthracene (L3) forms a zero-dimensional (0D) cyclic structure {Sm(hfac)3(L3)}2 (3) with strong ππ interactions that emit green color. Noticeably, the conjugation change is accompanied by a configurational change of coordination from trans for 1 and 2 to cis for 3. The color change is associated with the superposition of ligand and Sm based electronic band energies and their intensities. Such white light emission by a single compound having contributions from different building components is quite rare.


Effect of selected antimicrobial compounds on the radiosensitization of Salmonella Typhi in ground beef.
In this study, we extended our previous work to determine the efficiency of antimicrobial compounds in increase of relative radiosensitivity of Salmonella Typhi in medium fat ground beef (23% fat) by testing 41 different essential oils (EOs), oleoresins and food sauces. Ground beef samples inoculated with Salmonella Typhi (10(6) CFU g(-1)) were treated with each antimicrobial compound at a concentration of 0.5% (w/w). Then, the samples (25 g each) were packaged under air and irradiated in a (60)Co irradiator at doses from 0 to 1.75 kGy. Radiosensitivity was evaluated by calculating relative radiation sensitivity, defined as the ratio of radiation D(10) value in the absence/presence of antimicrobial compound. Depending on the compound tested, the addition of antimicrobial compound decreased the D(10) value of Salmonella Typhi, resulting in an increase of the radiation sensitivity up to more than four times. Among these antimicrobial compounds, Chinese cinnamon EO, clove EO and trans-cinnamaldehyde were most effective to increase the radiosensitivity of Salmonella Typhi in ground beef. These observations demonstrate that some active compounds can function as radiosensitizers of Salmonella Typhi.


Can Building "Artificially Intelligent Cities" Safeguard Humanity from Natural Disasters, Pandemics, and Other Catastrophes? An Urban Scholar's Perspective.
In recent years, artificial intelligence (AI) has started to manifest itself at an unprecedented pace. With highly sophisticated capabilities, AI has the potential to dramatically change our cities and societies. Despite its growing importance, the urban and social implications of AI are still an understudied area. In order to contribute to the ongoing efforts to address this research gap, this paper introduces the notion of an artificially intelligent city as the potential successor of the popular smart city brand-where the smartness of a city has come to be strongly associated with the use of viable technological solutions, including AI. The study explores whether building artificially intelligent cities can safeguard humanity from natural disasters, pandemics, and other catastrophes. All of the statements in this viewpoint are based on a thorough review of the current status of AI literature, research, developments, trends, and applications. This paper generates insights and identifies prospective research questions by charting the evolution of AI and the potential impacts of the systematic adoption of AI in cities and societies. The generated insights inform urban policymakers, managers, and planners on how to ensure the correct uptake of AI in our cities, and the identified critical questions offer scholars directions for prospective research and development.


The outcomes of idiopathic congenital talipes equinovarus : a core outcome set for research and treatment.
To identify the minimum set of outcomes that should be collected in clinical practice and reported in research related to the care of children with idiopathic congenital talipes equinovarus (CTEV). A list of outcome measurement tools (OMTs) was obtained from the literature through a systematic review. Further outcomes were collected from patients and families through a questionnaire and interview process. The combined list, as well as the appropriate follow-up timepoint, was rated for importance in a two-round Delphi process that included an international group of orthopaedic surgeons, physiotherapists, nurse practitioners, patients, and families. Outcomes that reached no consensus during the Delphi process were further discussed and scored for inclusion/exclusion in a final consensus meeting involving international stakeholder representatives of practitioners, families, and patient charities. In total, 39 OMTs were included from the systematic review. Two additional OMTs were identified from the interviews and questionnaires, and four were added after round one Delphi. Overall, 22 OMTs reached 'consensus in' during the Delphi and two reached 'consensus out'; 21 OMTs reached 'no consensus' and were included in the final consensus meeting. In all, 21 participants attended the consensus meeting, including a wide diversity of clubfoot practitioners, parent/patient representative, and an independent chair. A total of 21 outcomes were discussed and voted upon; six were voted 'in' and 15 were voted 'out'. The final COS document includes nine OMTs and two existing outcome scores with a total of 31 outcome parameters to be collected after a minimum follow-up of five years. It incorporates static and dynamic clinical findings, patient-reported outcome measures, and a definition of CTEV relapse. We have defined a minimum set of outcomes to draw comparisons between centres and studies in the treatment of CTEV. With the use of these outcomes, we hope to allow more meaningful research and a better clinical management of CTEV. Cite this article: Bone Jt Open 2022;3(1):98-106.


HPLC and anti-inflammatory studies of the flavonoid rich chloroform extract fraction of Orthosiphon stamineus leaves.
The aim of the present study was to verify the anti-inflammatory activity of Orthosiphon stamineus leaf extracts and to identify the active compound(s) contributing to its anti-inflammatory activity using a developed HPLC method. Active chloroform extract of O. stamineus was fractionated into three fractions using a dry flash column chromatography method. These three fractions were investigated for anti-peritoneal capillary permeability, in vitro nitric oxide scavenging activity, anti-inflammatory and nitric oxide (NO) inhibition using carrageenan-induced hind paw edema method. The flavonoid rich chloroform extract fraction (CF2) [containing sinensetin (2.86% w/w), eupatorin (5.05% w/w) and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (1.101% w/w)], significantly reduced rat hind paw edema, NO and decreased dye leakage to peritoneal cavity at p < 0.05. IC(50) of in vitro NO scavenging of CF2 was 0.3 mg/mL. These results suggest that the anti-inflammatory properties of these CF2 may possibly be due to the presence of flavonoid compounds capable of affecting the NO pathway.


HTRA1 Variants and the Interaction with Smoking Confer the Genetic Susceptibility to Ischemic Stroke.
High temperature requirement protein A1 (HtrA1) was identified as the causative gene of autosomal recessive arteriopathy and associated with lacunar ischemic stroke (IS) in European. This study aimed at evaluating the association of HTRA1 with IS and four tagging single-nucleotide polymorphisms (SNPs) were genotyped in a cohort of 4,098 Chinese. The mRNA level of HTRA1 in 72 IS cases and 72 hypertension controls were measured and compared. In whole population, SNP rs2268350 (C>T) was significantly associated with IS incidence (P=0.034). Stratification analysis observed significant association of rs2268350 in male, smoking and drinking populations, rs2672587 (C>G) in smoking and nonsmoking populations and rs3793917 (C>G) in smoking, nonsmoking and nondrinking populations with stroke respectively (P<0.05). The additive interaction and multiplicative interaction between rs2268350 and smoking were both of significant (P<0.05) after adjustment for the covariates. There was a cumulated risk of IS among genotypes of rs3793917 (P=0.009) and rs2672587 (P=0.047) in smoking population. The mRNA level of HTRA1 in non-smokers with rs2268350 CC was significantly higher than smokers with rs2268350 CT/TT (P=0.046) in IS cases. Our findings support that HTRA1 confers the genetic susceptibility to IS and smoking might modify the genetic effect of HTRA1 on IS by suppressing HTRA1 mRNA expression.


The effect of horizontal forces from a Smart Walker on gait and perceived exertion.
Increasingly, electric motors are being incorporated into wheeled walkers to implement various smart features to better assist their users physically. These modified walkers, known as Smart Walkers, use their electric motors to generate horizontal forces that can be used to reduce the physical load for walking, prevent falls and provide navigation support. However, these forces can also alter gait and may inadvertently increase the exertion of the users. This study aims to describe the effects of assistive and resistive horizontal forces (from -18.47 N to 27.70 N) from a Smart Walker on gait and perceived exertion of its users during steady-state walking. Self-selected comfortable walking speed, cadence, stride length, double support phase and ratings of perceived exertion (RPE) were significantly affected and different effects were found for resistive force, relatively low assistive force and high assistive force. With increasing force from -18.47 N to 0 N, RPE decreased and the users walked with lower double support time. From 0 N to 9.23 N, RPE continued to decrease to its lowest point while gait parameters remained constant. Further increasing force up to 27.70 N increased RPE and led to the users to choose to walk at higher speeds. This study demonstrates that users adapt their gait significantly to the forces applied and relatively high constant forces, whether assistive or resistive, will increase perceived exertion. Hence, these need to be carefully considered when developing Smart Walkers in order to provide safe and effective support to its users.


Perinatal exposure to bisphenol-A impairs spatial memory through upregulation of neurexin1 and neuroligin3 expression in male mouse brain.
Bisphenol-A (BPA), a well known endocrine disruptor, impairs learning and memory in rodents. However, the underlying molecular mechanism of BPA induced impairment in learning and memory is not well known. As synaptic plasticity is the cellular basis of memory, the present study investigated the effect of perinatal exposure to BPA on the expression of synaptic proteins neurexin1 (Nrxn1) and neuroligin3 (Nlgn3), dendritic spine density and spatial memory in postnatal male mice. The pregnant mice were orally administered BPA (50 µg/kgbw/d) from gestation day (GD) 7 to postnatal day (PND) 21 and sesame oil was used as a vehicle control. In Morris water maze (MWM) test, BPA extended the escape latency time to locate the hidden platform in 8 weeks male mice. RT-PCR and Immunoblotting results showed significant upregulation of Nrxn1 and Nlgn3 expression in both cerebral cortex and hippocampus of 3 and 8 weeks male mice. This was further substantiated by in-situ hybridization and immunofluorescence techniques. BPA also significantly increased the density of dendritic spines in both regions, as analyzed by rapid Golgi staining. Thus our data suggest that perinatal exposure to BPA impairs spatial memory through upregulation of expression of synaptic proteins Nrxn1 and Nlgn3 and increased dendritic spine density in cerebral cortex and hippocampus of postnatal male mice.


Identifying contextual determinants of problems in tuberculosis care provision in South Africa: a theory-generating case study.
Despite progress towards End TB Strategy targets for reducing tuberculosis (TB) incidence and deaths by 2035, South Africa remains among the top ten high-burden tuberculosis countries globally. A large challenge lies in how policies to improve detection, diagnosis and treatment completion interact with social and structural drivers of TB. Detailed understanding and theoretical development of the contextual determinants of problems in TB care is required for developing effective interventions. This article reports findings from the pre-implementation phase of a study of TB care in South Africa, contributing to HeAlth System StrEngThening in Sub-Saharan Africa (ASSET)-a five-year research programme developing and evaluating health system strengthening interventions in sub-Saharan Africa. The study aimed to develop hypothetical propositions regarding contextual determinants of problems in TB care to inform intervention development to reduce TB deaths and incidence whilst ensuring the delivery of quality integrated, person-centred care. Theory-building case study design using the Context and Implementation of Complex Interventions (CICI) framework to identify contextual determinants of problems in TB care. Between February and November 2019, we used mixed methods in six public-sector primary healthcare facilities and one public-sector hospital serving impoverished urban and rural communities in the Amajuba District of KwaZulu-Natal Province, South Africa. Qualitative data included stakeholder interviews, observations and documentary analysis. Quantitative data included routine data on sputum testing and TB deaths. Data were inductively analysed and mapped onto the seven CICI contextual domains. Delayed diagnosis was caused by interactions between fragmented healthcare provision; limited resources; verticalised care; poor TB screening, sputum collection and record-keeping. One nurse responsible for TB care, with limited integration of TB with other conditions, and policy focused on treatment adherence contributed to staff stress and limited consideration of patients' psychosocial needs. Patients were lost to follow up due to discontinuity of information, poverty, employment restrictions and limited support for treatment side-effects. Infection control measures appeared to be compromised by efforts to integrate care. Delayed diagnosis, limited psychosocial support for patients and staff, patients lost to follow-up and inadequate infection control are caused by an interaction between multiple interacting contextual determinants. TB policy needs to resolve tensions between treating TB as epidemic and individually-experienced social problem, supporting interventions which strengthen case detection, infection control and treatment, and also promote person-centred support for healthcare professionals and patients.


Tenth International Foamy Virus Conference 2014--achievements and perspectives.
For the past two decades, scientists from around the world, working on different aspects of foamy virus (FV) research, have gathered in different research institutions almost every two years to present their recent results in formal talks, to discuss their ongoing studies informally, and to initiate fruitful collaborations. In this report we review the 2014 anniversary conference to share the meeting summary with the virology community and hope to arouse interest by other researchers to join this exciting field. The topics covered included epidemiology, virus molecular biology, and immunology of FV infection in non-human primates, cattle, and humans with zoonotic FV infections, as well as recent findings on endogenous FVs. Several topics focused on virus replication and interactions between viral and cellular proteins. Use of FV in biomedical research was highlighted with presentations on using FV vectors for gene therapy and FV proteins as scaffold for vaccine antigen presentation. On behalf of the FV community, this report also includes a short tribute to commemorate Prof. Axel Rethwilm, one of the leading experts in the field of retrovirology and foamy viruses, who passed away 29 July 2014.


Diabetes Risk in Childhood Cancer Survivors: A Population-Based Study.
With continued improvements in survival following childhood cancer, the long-term health consequences of cancer treatments are receiving greater focus. Diabetes is emerging as a potential late effect of cancer therapy; however, the magnitude of risk has not been well established. The goal of our study was to evaluate the risk for diabetes in childhood cancer survivors in Ontario using validated population-based databases. We used provincial administrative health databases to compare the rate of diabetes in childhood cancer survivors and controls from the general population. Diabetes was measured using a validated algorithm. We used a cause-specific hazard regression model in which death and development of another cancer were treated as competing risks. We identified 10,438 1-year survivors of childhood cancer that were diagnosed before age 21 between January 1, 1990, and December 31, 2010. The mean follow up was 11.2 years (standard deviation, 6.9). Cancer survivors had a 55% increased rate of developing diabetes compared with matched controls (HR 1.51, 95% CI 1.28 to 1.78) in models adjusted for rurality and income. Individuals treated for cancer between ages 6 and 10 had the highest increased rates of diabetes (HR 3.89, CI 2.26 to 6.68). Among cancer types, leukemia and lymphoma were associated with the greatest increased risk for diabetes. Our study supports evidence of an increased risk for diabetes in survivors of childhood cancer. Future research is warranted for better identification of treatment-related risk factors for diabetes in this population.


Hexapeptide fragment of carcinoembryonic antigen which acts as an agonist of heterogeneous ribonucleoprotein M.
Colorectal cancers with metastatic potential secrete the glycoprotein carcinoembryonic antigen (CEA). CEA has been implicated in colorectal cancer metastasis by inducing Kupffer cells to produce inflammatory cytokines which, in turn, make the hepatic micro-environment ideal for tumor cell implantation. CEA binds to the heterogeneous ribonucleoprotein M (hnRNP M) which acts as a cell surface receptor in Kupffer cells. The amino acid sequence in CEA, which binds the hnRNP M receptor, is Tyr-Pro-Glu-Leu-Pro-Lys. In this study, the structure of Ac-Tyr-Pro-Glu-Leu-Pro-Lys-NH₂ (YPELPK) was investigated using electronic circular dichroism, vibrational circular dichroism, and molecular dynamics simulations. The binding of the peptide to hnRNP M was also investigated using molecular docking calculations. The biological activity of YPELPK was studied using differentiated human THP-1 cells, which express hnRNP M on their surface and secrete IL-6 when stimulated by CEA. YPELPK forms a stable polyproline-II helix and stimulates IL-6 production of THP-1 cells at micromolar concentrations.


Incidence and Predictors of Complications and Mortality in Cerebrovascular Surgery: National Trends From 2007 to 2012.
Cerebrovascular surgery offers potentially lifesaving treatments for intracranial vascular pathology yet bears substantial risks in the form of perioperative complications and mortality. To better characterize the risks associated with cerebrovascular surgery by broadly investigating the incidence of complications, patient-level predictors of complications, and mortality using the National Surgical Quality Improvement Program database, a prospective, audited, national data set. All cerebrovascular cases were extracted from the National Surgical Quality Improvement Program with the use of Current Procedural Terminology codes. Complication and mortality rates were analyzed with univariate and multivariate statistical analyses. A total of 1141 cases were analyzed. The rate of complications was nearly twice that of previous estimates: Almost one-third of patients (30.9%) experienced at least 1 complication, which was significantly associated with 30-day mortality (odds ratio, 7.76; 95% confidence interval, 4.27-14.10; P < .001). Emergency surgery was associated with higher mortality rates (15.1%) than nonemergency procedures (2.3%). Significant predictors of complications included preoperative ventilator dependence, emergency surgery, bleeding disorders, diabetes mellitus, and alcohol abuse. Significant predictors of mortality included postoperative coma >24 hours, preoperative or postoperative ventilator dependence, black or Asian race, and stroke. The most common complications were ventilator dependence (64.5% in patients ventilated preoperatively, 8.4% in patients not ventilated preoperatively), bleeding requiring transfusion (10.2%), reoperation within 30 days (9.6%), pneumonia (7.3%), and stroke (7.3%). Cerebrovascular surgery is associated with significant risks of morbidity and mortality. Mitigation of these risks requires broader, patient-centered understanding of risk factors and complications specific to cerebrovascular surgery, as presented in this article. These findings pave the way for improving patient safety and outcomes in cerebrovascular surgery. AVM, arteriovenous malformationCI, confidence intervalNSQIP, National Surgical Quality Improvement ProjectOR, odds ratio.


Designing the biomethane production chain from urban wastes at the regional level: An application to the Rome Metropolitan Area.
This paper proposes a methodology to design the biomethane production chain from MSW at the regional level and to assess the environmental and economic performance of the chain. In the design phase, the following parameters are considered: number and production capacity of biomethane plants, localization of plants, waste flows among municipalities and plants. The model is adopted to design the biomethane chain in the Rome Metropolitan Area (Italy). Several structures of production chain are designed and their performances are assessed. The economic factors mostly able to affect the performance of the chain are waste disposal tariff, biomethane selling price, and the economic incentive provided to biomethane producers. Their impacts are discussed through sensitivity analyses. Results show that the structure maximizing the economic performance has the worst environmental performance and vice versa. Hence, a new structure of the economic incentive is proposed, aimed at re-aligning economic and environmental performance.


The binding ability of iron bonded to porphodimethene: structural, magnetic, and electronic relationship to iron porphyrin complexes.
The availability of the parent compound, meso-hexaethylporphodimetheneiron(II), [(Et6N4)Fe] (2), of this report results from a novel synthetic methodology that makes [Et6N4Li2] (1) easily available. The major focus is on how the axial positions, which are the key reactive sites in metalloporphyrins, and the electronic configuration of the metal can be affected by the breakdown of the aromaticity of the porphyrin skeleton and by the nonplanar conformation of the ligand. DFT calculations indicate a 3B1(dz2)1(dyz)1 ground state for 2 versus the 3A2(dxz)1(dyz)1 ground state in the porphyrin analogue. The intermediate-spin state (S = 1) of 2 changed drastically upon addition of one or two axial ligands, as hexacoordination is preferred by iron(II). The hexacoordinate complexes [(Et6N4)Fe(L)(L')] (L = L' = THF, 3; L = L' = Py, 4; L = PhNO, L' = Py, 14) have been isolated and structurally characterized. Strong-field ligands lead to a low-spin diamagnetic state for iron(II), namely for complexes 4-7, 9, and 14, whereas 3 is a typical d6 high-spin complex, as is the pentacoordinate [(Et6N4)Fe(CN)]Bu4N (8). The structural analysis showed common features for 6, 7, 9, and 14: i) a small displacement of the metal from the N4 plane, and ii) an N4 cavity, larger than that in the corresponding porphyrins, affecting the Fe-N bond lengths. The 1H NMR spectrum is quite diagnostic of the two-fold symmetry in the diamagnetic hexacoordinate complexes, revealing either a D2h or a C2v symmetry. The CO stretching frequency (1951 cm(-1)) in complex 6 probes the good electron density at the metal. The one-electron oxidation of 2 led to pentacoordinate iron(III) derivatives [(Et6N4)Fe(Cl)] (10), [(Et6N4)2Fe2(mu-O)] (11), and [(Et6N4)2Fe2(mu-p-OC6H4-O)] (12). Complex 10 is a typical high-spin iron(III) (5.85muB at 298 K), while 11 and 12 behave as antiferromagnetic coupled iron(III) (J = -9.4cm(-1), 12, and J = -115cm(-1), 11). In complexes 10, 11, and 12 iron is sitting in a quite distorted square pyramidal geometry, in which the ligand displays a very distorted roof conformation with different degrees of ruffling. Distinctive structural and magnetic features have been found for the nitrosyl derivative [(Et6N4)Fe-NO], which has a low-spin state (S = 1/2) and the following structural parameters: Fe-N-O, 147.3(2) degrees; Fe-N, 1.708(2) A; N-O, 1.172(3) A. A comparative structural, magnetic, and theoretical analysis of the compounds listed above has been made with the analogous porphyrin derivatives. The detailed structural investigation has been mapped through the X-ray analysis of 2, 7, 8, 9, 11, 13, and 14.


[Influence of institutional experience on results in hip and knee total arthroplasty : An analysis from the German arthroplasty registry (EPRD)].
The German Arthroplasty Registry, EPRD, has the ability to examine early factors influencing the probability of failure of total hip arthroplasty (THA) and knee arthroplasty (TKA). The study analyses the influence of the overall experience of a hospital, as well as the change in supplier on the revision rate. A total of 164,903 cementless THA and 155,577 cemented TKA were in follow-up from 656 hospitals from 2012 to 2019. The number of arthroplasties performed per hospital per year was used as a surrogate parameter for institutional experience. This number was subdivided into 250, 251-500 and more than 500 for hip and knee per year and the overall revision rate was analysed. Additionally, the effects of the change of a major supplier of implant systems to a hospital were analysed. At least 70% of the documented implant components for each calendar quarter were used in that hospital to define the company as a major supplier. The overall revision rate for THA was 3.9% for hospitals with up to 250 arthroplasties per year, 3.3% for hospitals with 251-500 arthroplasties per year and 2.9% for hospitals performing over 500 surgeries per year (p < 0.0001). The revision rate for TKA was also significantly different between the three groups with 3.4, 3.3 and 2.7% (p < 0.0001). Changing the supplier of implant systems also showed a significant increase of the revision rate (p < 0.0001 for THA, p = 0.02 for TKA). The institutional experience significantly influences short-term results in terms of the revision rate of hip and knee arthroplasty. Changing the implant system even in an experienced hospital has a major impact on the early revision rate and, therefore, needs careful transition.


Non-universal tracer diffusion in crowded media of non-inert obstacles.
We study the diffusion of a tracer particle, which moves in continuum space between a lattice of excluded volume, immobile non-inert obstacles. In particular, we analyse how the strength of the tracer-obstacle interactions and the volume occupancy of the crowders alter the diffusive motion of the tracer. From the details of partitioning of the tracer diffusion modes between trapping states when bound to obstacles and bulk diffusion, we examine the degree of localisation of the tracer in the lattice of crowders. We study the properties of the tracer diffusion in terms of the ensemble and time averaged mean squared displacements, the trapping time distributions, the amplitude variation of the time averaged mean squared displacements, and the non-Gaussianity parameter of the diffusing tracer. We conclude that tracer-obstacle adsorption and binding triggers a transient anomalous diffusion. From a very narrow spread of recorded individual time averaged trajectories we exclude continuous type random walk processes as the underlying physical model of the tracer diffusion in our system. For moderate tracer-crowder attraction the motion is found to be fully ergodic, while at stronger attraction strength a transient disparity between ensemble and time averaged mean squared displacements occurs. We also put our results into perspective with findings from experimental single-particle tracking and simulations of the diffusion of tagged tracers in dense crowded suspensions. Our results have implications for the diffusion, transport, and spreading of chemical components in highly crowded environments inside living cells and other structured liquids.


Indirect and direct relations between aerobic fitness, physical activity, and academic achievement in elementary school students.
There is evidence to suggest that increasing physical activity (PA) improves academic achievement (AA) in children and that aerobic fitness is associated with both cognitive function and AA. However, it is not known how these variables are interrelated and analyses with adequate control for socioeconomic variables are needed. It was hypothesized that PA would not directly affect AA but would have an indirect effect on AA through its effect on aerobic fitness. The purpose of this study was to test this hypothesized mediation using path analysis. Cross-sectional data including AA, aerobic fitness, and daily PA assessed through accelerometry were collected from a large sample (N = 687) of 2nd and 3rd grade students. Demographic data were assessed via parent self-report. A total of 401 students wore the accelerometer for at least 10 hours on 3 days or more and were included in the final path analysis to evaluate potential relations among PA (predictor), aerobic fitness (mediator), and WIAT-III subtest standard scores (outcomes; i.e., reading, spelling, and mathematics). Findings showed a direct effect of PA on aerobic fitness (b = 0.009, p < 0.001) and an indirect effect (mediation) of PA via fitness on math achievement (b = 0.003, p < 0.01) after controlling for student's grade, gender, body mass index, mother's education level, and household income, as well as intraclass correlations among classes and schools. Neither PA nor aerobic fitness were correlated with WIAT-III reading or spelling scores. Mediation analysis indicated that PA exerted an influence on math achievement through its effects on aerobic fitness but was not associated with reading or spelling achievement scores.


Pathogenesis of aphthoid ulcers in Crohn's disease: correlative findings by magnifying colonoscopy, electron microscopy, and immunohistochemistry.
The mechanism of ulceration in Crohn's disease remains unknown. To clarify the role of the follicle associated epithelium (FAE) of colonic lymphoid nodules in the formation of ulcers in Crohn's disease. After identification of colonic lymphoid nodules and aphthoid lesions by magnifying colonoscopy, 76 biopsy specimens were obtained from 10 patients with Crohn's disease and three patients with colonic lymphoid hyperplasia. This study correlated magnifying colonoscopic, electron microscopic, and immunohistochemical findings of biopsy specimens. In Crohn's disease, scanning electron microscopy of lymphoid nodules surrounded by a red halo without visible erosions by magnifying colonoscopy, showed surface erosions 150-200 microns in size. These lymphoid nodules with red halos had small erosions either light microscopically or electron microscopically in 18 of 21 specimens (86%). Correlation of scanning and transmission electron microscopy showed residues of FAE including M cells at the edges of the erosions. In immunohistochemical studies, HLA-DR antigen was limited in M cells of FAE in the patients with lymphoid hyperplasia without inflammatory bowel disease. In Crohn's disease patients in remission, however, HLA-DR antigen was strongly expressed over the entire FAE of lymphoid nodules with a red halo endoscopically, while the expression was weak and irregular in the mucosa surrounding the lymphoid nodules. HLA-DR was strongly expressed in the entire inflamed colonic mucosa in the active stage. The red halo appearance surrounding lymphoid follicles seems to precede visible aphthoid ulcers and suggests that ulcerations in Crohn's disease originate from FAE, possibly related to its physiological role as a portal of entry for potentially pathogenic agents.


An open-label, rater-blinded, augmentation study of aripiprazole in treatment-resistant depression.
About 30% to 46% of patients with major depressive disorder (MDD) fail to fully respond to initial antidepressants. While treatment-resistant depression commonly refers to nonresponse or partial response to at least 2 adequate trials with antidepressants from different classes, due to variability in terminology, a staging system based on prior treatment response has been suggested. Aripiprazole is a novel atypical antipsychotic with partial agonism at dopamine D(2) and serotonin 5-HT(1A) receptors and antagonism at the 5-HT(2) receptors. The present study evaluated whether augmentation with aripiprazole would be beneficial and tolerable in patients with treatment-resistant MDD who had failed 1 or more trials of antidepressants. In an open-label, rater-blinded study conducted from March 2003 through December 2003, 10 patients with DSM-IV MDD without psychotic features who had failed to respond to an adequate trial of at least 1 antidepressant were prescribed aripiprazole (10-30 mg/day) for 6 weeks. The dose of preexisting antidepressants remained unchanged. Treatment response was defined as a 50% or greater reduction in score on the Hamilton Rating Scale for Depression (HAM-D) from baseline to end of treatment. Secondary efficacy measures included scores on the Clinical Global Impressions-Improvement (CGI-I) and -Severity (CGI-S) scales. Eight of 10 patients had failed 2 or more antidepressant trials. The mean daily dose of aripiprazole was 13.21 mg. Intent-to-treat analysis showed that mean ± SD HAM-D scores reduced significantly from baseline (23.0 ± 8.1) to end of treatment (8.1 ± 6.0) (p < .001). There was a significant reduction in CGI-I (p < .05) and a trend toward decrease in CGI-S (p = .06) score. Seventy percent of the subjects were responders and 30% achieved remission. Common adverse effects were akathisia (20%), nausea (20%), and restlessness (20%). The study indicates the potential utility of aripiprazole as an augmenting agent in treatment-resistant depression, particularly in those who had failed 2 or more antidepressant trials. Adequately powered, randomized controlled trials are necessary to evaluate the role of aripiprazole in treatment-resistant depression.


Control of radiofrequency lesion size by power regulation.
The influence of power and exposure duration on lesion size in radiofrequency catheter ablation was investigated in 15 closed-chest dogs. Radiofrequency energy was delivered to the right ventricular endocardium between the tip of a standard 6F electrode catheter and a large W and durations of 5, 10, 20, 30, and 60 seconds. At necropsy 1 week later, well-demarcated homogeneous lesions were found when power had exceeded a threshold level that decreased from 1.8 W at 5 seconds to 0.7 W at 60 seconds. Lesion size ranged from 0 to 7.5 mm in depth and 0 to 9 mm in diameter. For the 5, 10, and 20 second ablations, lesion size was determined by exposure duration and power level. However, after a 20 second exposure, lesion size had reached maturity and was related to delivered power only. Therefore, a gradual, controlled growth of the lesion can be obtained by a stepwise increase of the radiofrequency power level with ample exposure duration at each level to allow for stabilization. At levels exceeding 7 W, the formation of a thin insulating layer of blood coagulum on the electrode surface caused an abrupt increase of impedance within approximately 30 seconds. Therefore, lesion size is limited to 8.5 mm in radiofrequency ablation with a standard 6F endocardial electrode catheter.


Long-Term Outcome of Non-Sustained Ventricular Tachycardia in Structurally Normal Hearts.
The impact of non-sustained ventricular tachycardia (NSVT) on the risk of thromboembolic event and clinical outcomes in patients without structural heart disease remains undetermined. This study aimed to evaluate the association between NSVT and clinical outcomes. The study population of 5903 patients was culled from the "Registry of 24-hour ECG monitoring at Taipei Veterans General Hospital" (REMOTE database) between January 1, 2002 and December 31, 2004. Of that total, we enrolled 3767 patients without sustained ventricular tachycardia, structural heart disease, and permanent pacemaker. For purposes of this study, NSVT was defined as 3 or more consecutive beats arising below the atrioventricular node with an RR interval of <600 ms (>100 beats/min) and lasting < 30 seconds. There were 776 deaths, 2042 hospitalizations for any reason, 638 cardiovascular (CV)-related hospitalizations, 350 ischemic strokes, 409 transient ischemic accident (TIA), 368 new-onset heart failure (HF), and 260 new-onset atrial fibrillation (AF) with a mean follow-up duration of 10 ± 1 years. In multivariate analysis, the presence of NSVT was independently associated with death (hazard ratio [HR]: 1.362, 95% confidence interval [CI]: 1.071-1.731), CV hospitalization (HR: 1.527, 95% CI: 1.171-1.992), ischemic stroke (HR: 1.436, 95% CI: 1.014-2.032), TIA (HR 1.483, 95% CI: 1.069-2.057), and new-onset HF (HR: 1.716, 95% CI: 1.243-2.368). There was no significant association between the presence of NSVT and all-cause hospitalization or new-onset AF. In patients without structural heart disease, presence of NSVT on 24-hour monitoring was independently associated with death, CV hospitalization, ischemic stroke, TIA, and new onset heart failure.


Clinical potential of resistin as a novel prognostic biomarker for cellulitis.
Cellulitis is an acute, subacute or chronic inflammation of the dermis and subdermal tissues, which is typically caused by bacteria, although other causes are possible. The present study aimed to evaluate the association between resistin levels and the recovery time of patients with cellulitis. In addition, the effect of resistin and insulin resistance on the prognosis of cellulitis was investigated. In total, 52 patients with cellulitis (male, 21; female, 31) and an age-matched group of 42 healthy individuals (male, 18; female, 24) were included in the study. The levels of serum resistin, fasting plasma glucose (FPG), homeostasis model assessment-insulin resistance (HOMA-IR), C-reactive protein (CRP) and other biochemical parameters were compared between the groups. The mean resistin levels in the cellulitis and control groups were 9.4±5.3 and 5.8±3.1 ng/ml, respectively. The levels of resistin, FPG, HOMA-IR and CRP were significantly higher in the cellulitis group compared with the control group (P<0.001). Furthermore, the mean recovery time of the patients with cellulitis was 21.2±5.6 days. Thus, increased levels of resistin (P=0.002) and HOMA-IR (P=0.005) could be used as predictive factors for the recovery time. The enhanced levels of resistin and HOMA-IR were shown to correlate with the high CRP levels in the cellulitis group. Therefore, the results indicated that increased levels of resistin may function as a prognostic marker for cellulitis.


Immunomodulation of murine cytomegalovirus-induced myocarditis in mice treated with lipopolysaccharide and tumor necrosis factor.
Murine cytomegalovirus (MCMV) infection of BALB/c mice produces acute and chronic myocarditis similar to clinical disease in humans. In contrast, MCMV-infected C57BL/6 mice develop only mild acute myocarditis. We have investigated the effect of administration of the immunomodulator lipopolysaccharide (LPS) on the development of postviral myocarditis in mice. LPS exacerbated heart inflammation in both strains of MCMV-infected mice, with normally resistant C57BL/6 mice developing chronic myocarditis. Autoantibodies to cardiac myosin were enhanced with LPS treatment in both MCMV-infected mouse strains. LPS treatment also increased the production of TNF in the sera without affecting virus titers in the spleen, liver, or salivary glands, a target organ most affected during persistent virus infection. In LPS/MCMV-infected BALB/c mice, TNF, IL-6, and IL-10 levels were detected in cultures of heart infiltrating cells but not in splenocytes. Importantly, administration of the bioactive synthetic TNF peptide (amino acids 114-130) increased myocarditis in C57BL/6 mice, similar to that seen with LPS treatment. TNF peptide/MCMV-infected BALB/c and C57BL/6 mice showed distinct differences in the expression pattern of IFN-gamma, IL-10, and TNF. These data show that the disease may be partly regulated by TNF among other select cytokines and autoantibodies to cardiac myosin. The immunopathological nature of MCMV-induced myocarditis is thus highlighted.


Genetic deletion of ABP-120 alters the three-dimensional organization of actin filaments in Dictyostelium pseudopods.
This study extends the observations on the defects in pseudopod formation of ABP-120+ and ABP-120- cells by a detailed morphological and biochemical analysis of the actin based cytoskeleton. Both ABP-120+ and ABP-120- cells polymerize the same amount of F-actin in response to stimulation with cAMP. However, unlike ABP-120+ cells, ABP-120- cells do not incorporate actin into the Triton X-100-insoluble cytoskeleton at 30-50 s, the time when ABP-120 is incorporated into the cytoskeleton and when pseudopods are extended after cAMP stimulation in wild-type cells. By confocal and electron microscopy, pseudopods extended by ABP-120- cells are not as large or thick as those produced by ABP-120+ cells and in the electron microscope, an altered filament network is found in pseudopods of ABP-120- cells when compared to pseudopods of ABP-120+ cells. The actin filaments found in areas of pseudopods in ABP-120+ cells either before or after stimulation were long, straight, and arranged into space filling orthogonal networks. Protrusions of ABP-120- cells are less three-dimensional, denser, and filled with multiple foci of aggregated filaments consistent with collapse of the filament network due to the absence of ABP-120-mediated cross-linking activity. The different organization of actin filaments may account for the diminished size of protrusions observed in living and fixed ABP-120- cells compared to ABP-120+ cells and is consistent with the role of ABP-120 in regulating pseudopod extension through its cross-linking of actin filaments.


Young Doctor Movements: motives for membership among aspiring and young family physicians.
Over the past decade, young doctor movements (YDMs) have gained recognition for their efforts in promoting the discipline of family medicine. With growth and expansion comes the need for an inquiry into the membership motives of current/intending members. This study was aimed at determining the main reasons why young and aspiring family physicians (FPs) joined their regional YDM. It was also concerned with determining the main factors that will make non-members want to join a YDM as well as assessing for differences in the responses within YDM members on the one hand, and between YDM members and non-members on the other. This was a cross-sectional web-based study. Using a list of 11 items generated following a series of discussions and feedback among selected FPs and FP trainees, respondents annotated levels of agreement on reasons for current or desired YDM membership. The Mann-Whitney U test was used to determine the distribution and differences in the mean of rank scores of the responses from YDM and non-YDM members while the Kruskal-Wallis test was used to describe same for the various YDMs. The total number of respondents was 200, out of which 102 (51.0%) were current YDM members, 97 (48.5%) were non-members and 1 (0.5%) respondent did not state his/her membership status. Non-YDM members indicated a predominantly academic/professional motive for membership while YDM members indicated the opportunity to socialise with FPs abroad and in their country as their foremost reasons for membership. A mixture of academic, professional and social motives was observed for respondents from Vasco da Gama; predominantly academic and professional motives for respondents from Spice route. While gaining recognition and improving one's practice may be the ultimate goal of an aspiring FP, socialising within a network of like-minded professionals maybe the young FP's way of coping with demands of the discipline.


Primary hyperoxaluria type 1: strategy for organ transplantation.
Primary hyperoxaluria type 1, the most common form of primary hyperoxaluria, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase. This results in increased synthesis and subsequent urinary excretion of the metabolic end-product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract. As glomerular filtration rate decreases due to progressive renal involvement, oxalate accumulates and results in systemic oxalosis. Diagnosis is still often delayed. It is mainly established on the basis of clinical and sonographic findings, urinary oxalate ± glycolate assessment, and DNA analysis. Following specific conservative measures, the ultimate management is based on organ transplantation. Correction of the enzyme defect by liver transplantation should be planned before systemic oxalosis develops to optimize outcomes and may be either simultaneous (immunological benefit) or sequential (biochemical benefit) liver-kidney transplantation depending on disease staging, facilities, and access to deceased or living donors. Allograft and patient survival currently approaches that of transplant patients with kidney transplantation alone and with other diseases requiring combined liver-kidney transplantation. In addition, this strategy has also provided significant improvement in both quality of life and statural growth.


An operating room scheduling strategy to maximize the use of operating room block time: computer simulation of patient scheduling and survey of patients' preferences for surgical waiting time.
Determining the appropriate amount of block time to allocate to surgeons and selecting the days on which to schedule elective cases can maximize operating room (OR) use. We used computer simulation to model OR scheduling. Inputs in the computer model included different methods to determine when a patient will have surgery (on-line bin-packing algorithms), case durations, lengths of time patients wait for surgery (2 wk is the median longest length of time that the outpatients [n = 367] surveyed considered acceptable), hours of block time each day, and number of blocks each week. For block time to be allocated to maximize OR utilization, two parameters must be specified: the method used to decide on what day a patient will have surgery and the average length of time patients wait to have surgery. OR utilization depends greatly on, and increases as, the average length of time patients wait for surgery increases. Operating room utilization can be maximized by allocating block time for the elective cases based on expected total hours of elective cases, scheduling patients into the first available date provided open block time is available within 4 wk, and otherwise scheduling patients in "overflow" time outside of the block time.


Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents.
A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including (14)C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, beta-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet-fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks +23%, P < 0.05, and 20 weeks +29%, P < 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks +49%, P < 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1alpha, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.


Antiidiotypes against anti-H-2 monoclonal antibodies. V. In vivo antiidiotype treatment induces idiotype-specific helper T cells.
Mice have been treated in vivo with xenogeneic antiidiotypes prepared against a murine monoclonal anti-H-2Kk antibody, 11-4.1. B cell immune responses have been found to be altered by such treatment as evidenced by a modification in the idiotypic repertoire of the humoral response to H-2 antigens. Transfer of purified T cells into nude mice before anti-idiotype treatment showed that T cells are involved in the induction of idiotope-bearing antibodies by xenogeneic antiidiotype. Studies using bone marrow chimeras indicate that the environment in which either T or B cells mature does not appear to alter VH region genetic control of induction of antiidiotype-induced molecules. By adoptive transfer studies, T cells from antiidiotype-treated mice were found capable of modifying the idiotypic repertoire of B cells subsequently exposed to antigen even when the T cells were obtained from antiidiotype-primed mice of inappropriate allotype. Although it still must be determined whether idiotypic or antiidiotypic T cells are involved in such B cell idiotype regulation, these results indicate that some T cell functions are altered by xenogeneic antiidiotypes prepared against B cell products and suggest that T cell immunity to major histocompatibility complex antigens may also be affected by such reagents.


Leukemia inhibitory factor induces leukocyte infiltration and cartilage proteoglycan degradation in goat joints.
Recent studies have implicated leukemia inhibitory factor (LIF) in human joint disease. LIF is produced by cultured synovial cells and articular chondrocytes, stimulates cartilage and bone resorption, and has been detected in inflammatory exudates from arthritic joints. The aim of this study was to evaluate the effect of intraarticular injections of human recombinant LIF in the goat. Endotoxin-free, sterile normal saline containing 1 micrograms recombinant human LIF (rhLIF) was injected into the right radiocarpal joints (RCJs) of eight angora goats. The left RCJs were injected with an equivalent volume of vehicle alone (n = 6) or vehicle containing 1 micrograms human albumin (n = 2). Goat joints were examined for clinical features of inflammation, and synovial fluid (SF) was aspirated on days 0, 2, and 6 postinjection. Leukocyte counts and concentrations of keratan sulfate, IL-1 beta, and TNF-alpha were determined in the SF. Proteoglycan synthesis was determined ex vivo in cartilage explants obtained on day 6 postinjection. A statistically significant increase in joint swelling and effusion volume was observed in LIF-injected joints but not in control joints. In the LIF-injected RCJs, the leukocyte count increased from 82 +/- 9 cells/microliters before injection to 10,300 +/- 3357 cells/microliters at day 2 postinjection (p < 0.005) and declined to 678 +/- 113 cells/microliters at day 6 postinjection. Polymorphonuclear leukocytes and monocyte/macrophages predominated in the infiltrate. No appreciable change in leukocyte counts was observed in control joints.(ABSTRACT TRUNCATED AT 250 WORDS)


SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats.
Parkinson's disease has traditionally been viewed as a motor disorder caused by the loss of dopamine (DA) neurons. However, emotional and cognitive syndromes can precede the onset of the motor deficits and provide an opportunity for therapeutic intervention. Potassium channels have recently emerged as potential new targets in the treatment of Parkinson's disease. The selective blockade of small conductance calcium-activated K+ channels (SK channels) by apamin is known to increase burst firing in midbrain DA neurons and therefore DA release. We thus investigated the effects of systemic administration of apamin on the motor, cognitive deficits and anxiety present after bilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesions in rats. Apamin administration (0.1 or 0.3 mg/kg i.p.) counteracted the depression, anxiety-like behaviors evaluated on sucrose consumption and in the elevated plus maze, social recognition and spatial memory deficits produced by partial 6-OHDA lesions. Apamin also reduced asymmetric motor deficits on circling behavior and postural adjustments in the unilateral extensive 6-OHDA model. The partial 6-OHDA lesions (56% striatal DA depletion) produced 20% decrease of iodinated apamin binding sites in the substantia nigra pars compacta in correlation with the loss of tyrosine hydroxylase positive cells, without modifying apamin binding in brain regions receiving DAergic innervation. Striatal extracellular levels of DA, not detectable after 6-OHDA lesions, were enhanced by apamin treatment as measured by in vivo microdialysis. These results indicate that blocking SK channels may reinstate minimal DA activity in the striatum to alleviate the non-motor symptoms induced by partial striatal DA lesions.


Novel open-source electronic medical records system for palliative care in low-resource settings.
The need for palliative care in sub-Saharan Africa is staggering: this region shoulders over 67% of the global burden of HIV/AIDS and cancer. However, provisions for these essential services remain limited and poorly integrated with national health systems in most nations. Moreover, the evidence base for palliative care in the region remains scarce. This study chronicles the development and evaluation of DataPall, an open-source electronic medical records system that can be used to track patients, manage data, and generate reports for palliative care providers in these settings.DataPall was developed using design criteria encompassing both functional and technical objectives articulated by hospital leaders and palliative care staff at a leading palliative care center in Malawi. The database can be used with computers that run Windows XP SP 2 or newer, and does not require an internet connection for use. Subsequent to its development and implementation in two hospitals, DataPall was tested among both trained and untrained hospital staff populations on the basis of its usability with comparison to existing paper records systems as well as on the speed at which users could perform basic database functions. Additionally, all participants evaluated this program on a standard system usability scale. In a study of health professionals in a Malawian hospital, DataPall enabled palliative care providers to find patients' appointments, on average, in less than half the time required to locate the same record in current paper records. Moreover, participants generated customizable reports documenting patient records and comprehensive reports on providers' activities with little training necessary. Participants affirmed this ease of use on the system usability scale. DataPall is a simple, effective electronic medical records system that can assist in developing an evidence base of clinical data for palliative care in low resource settings. The system is available at no cost, is specifically designed to chronicle care in the region, and is catered to meet the technical needs and user specifications of such facilities.


Spore Germination and Emergence of Bacillus megaterium.
Bacillus megaterium spores have a characteristic polar knob and equatorial ridge, or groove. During germination, the spore case appears to split along this ridge, and thus allows the new cell to emerge. Mechanically ground spores also split along this ridge, one part of the spore case being hinged to the other, the ridge being evident along a free edge. The equatorial ridge appears to be an area of suspectibility to mechanical pressures and, perhaps, in normal germination, to enzymic action as well.


Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak.
The outcome is reported of a prospective uncontrolled study based on a stepwise treatment protocol during an outbreak of severe acute respiratory syndrome (SARS) in Hong Kong. One hundred and thirty eight patients were treated with broad spectrum antibiotics, a combination of ribavirin and low dose corticosteroid, and then intravenous high dose methylprednisolone according to responses. Sustained response to treatment was defined as (1) defervescence for > or =4 consecutive days, (2) resolution of lung consolidation by >25%, and (3) oxygen independence by the fourth day without fever. Patients with defervescence who achieved either criterion 2 or 3 were classified as partial responders. Patients who fell short of criteria 2 and 3 were non-responders. Laboratory confirmation of SARS coronavirus infection was established in 132 (95.7%). None responded to antibiotics but 25 (18.1%) responded to ribavirin + low dose corticosteroid. Methylprednisolone was used in 107 patients, of whom 95 (88.8%) responded favourably. Evidence of haemolytic anaemia was observed in 49 (36%). A high level of C-reactive protein at presentation was the only independent predictor for use of methylprednisolone (odds ratio 2.18 per 10 mg/dl increase, 95% confidence interval 1.12 to 4.25, p = 0.02). Thirty seven patients (26.8%) required admission to the intensive care unit and 21 (15.2%) required invasive mechanical ventilation. There were 15 deaths (mortality rate 10.9%), most with significant co-morbidities, whereas 122 (88.4%) had been discharged home 4 months after the outbreak onset. The use of high dose pulse methylprednisolone during the clinical course of a SARS outbreak was associated with clinical improvement, but randomised controlled trials are needed to ascertain its efficacy in this condition.


Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor.
Findings from the National Institute of Mental Health's Sequenced Treatment Alternatives to Relieve Depression trial indicate that approximately 50% of patients with major depressive disorder do not experience a treatment response after adequate first-line treatment with a selective serotonin reuptake inhibitor (SSRI). This study was designed to test the hypothesis that, after treatment failure with an SSRI, switching to venlafaxine extended release (ER) would offer advantages over switching to another SSRI, citalopram. The objectives of this trial were to compare the efficacy and safety of venlafaxine ER and citalopram in the treatment of moderate-to-severe depression in patients who did not experience a treatment response to an SSRI other than citalopram and to investigate the effects of severity of depression by categorizing treatment groups according to baseline severity. This was a 12-week, double-blind, randomized, parallel-group, multicenter study. Participants were adult outpatients who, following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram and had not responded, met the diagnostic criteria for depression as described in the Diagnostic and statistical manual of mental disorders, fourth edition, and had a score > or =20 on the 21-item Hamilton Rating Scale for Depression (HAM-D21). After a 7-day screening period, patients were randomly assigned to receive venlafaxine ER 75 mg/day or citalopram 20 mg/day for the first 2 weeks. Doses could be increased every 2 weeks through week 6. Treatment lasted 12 weeks and was followed by a 1-week tapering period. Maximum dosages were venlafaxine ER 300 mg/day or citalopram 60 mg/day. The primary end point was the final on-therapy total HAM-D21 score. To investigate the treatment effects of the severity of depression on efficacy, a subgroup analysis was performed for baseline HAM-D21 total score < or =31 and >31. The analyses for HAM-D21, Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions - Severity (CGI-S), and Clinical Global Impressions - Improvement scores were based on intent-to-treat (ITT) population, for both the primary analysis and subgroup analysis according to baseline HAM-D21 total scores < or =31 or >31. Safety assessments included the recording of adverse events (AEs). A total of 406 patients (200 venlafaxine ER, 206 citalopram) were randomly assigned and 396 patients were included in the ITT population (194 venlafaxine ER, 202 citalopram). Treatment groups were similar in terms of demographics and baseline psychiatric assessments. Two hundred and eighty-four patients (137 venlafaxine ER, 147 citalopram) were present in the ITT population with a baseline HAM-D21 total score < or =31 and 112 patients (57 venlafaxine ER, 55 citalopram) in the >31 group. In the primary analysis, there was no statistical difference between groups. The group with a baseline HAM-D21 total score of 20-31 did not differ significantly in any efficacy parameters. In the group with a baseline HAM-D21 total score >31, the venlafaxine ER group differed significantly from the citalopram group on the primary end point HAM-D21 total score (P=0.0121). The secondary end point CGI-S score was statistically significant (P=0.0359), although the MADRS total score (P=0.0930) was not. AEs were reported by 57.8 and 63.4% of venlafaxine ER and citalopram patients, respectively. Overall discontinuation rates were 24.5% for venlafaxine ER and 20.9% for citalopram. Discontinuation rates owing to an AE as a primary or secondary reason were 5.5% for venlafaxine ER and 5.3% for citalopram. Overall, venlafaxine ER and citalopram showed similar efficacy in patients who had an inadequate response to an SSRI. In the subset of more severely depressed patients, venlafaxine ER was significantly more effective on a number of efficacy measures. Patients who remain severely depressed following treatment with an SSRI may gain more benefit from the dual-action drug venlafaxine, rather than switching to another SSRI.


Assessment of intratumor immune-microenvironment in colorectal cancers with extranodal extension of nodal metastases.
No data is available on the molecular background of the extra-nodal extension (ENE) of lymph node metastasis (LN) in colorectal cancer (CRC). A series of 22 ENE-positive CRCs was considered and three samples per case were selected (the primary CRC, an ENE-negative and an ENE-positive metastatic LN). Samples (n = 66) were analysed by immunohistochemistry for PD-L1, CD4, CD8, CD68 and CD80. Fifteen out of twenty-two cases were further profiled through a hotspot multigene mutational custom panel, including 164 hotspot regions of AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN and TP53 genes. A significantly higher percentage of CD4-, CD8- and CD68-positive cells was observed at the invasive front of both CRCs and in ENE in contrast with what observed at the core of both CRCs and their matched nodal metastases. ENE was also characterized by a significantly higher number of CD80-positive cells. No significant difference was observed in PD-L1 distribution among the different specimens. Fourteen out of 15 CRCs (93%) showed at least a driver mutation. The most frequently mutated gene was TP53 (n = 8 tumors), followed by APC (n = 6), BRAF (n = 4), KRAS, NRAS and PIK3CA (n = 2). In 11 out of 15 CRCs (73%) the mutational profiling of the primary tumor was consistent with what obtained from the two matched LNs. A heterogeneous intratumor immune-microenvironment has been observed in ENE-positive CRCs, which are characterized by an increased leukocytic infiltration at the ENE invasive front.


Blastomycosis of long bones.
The presentation of blastomycosis clinically and radiographically is nonspecific and often mistaken for a neoplasm. Delay in diagnosis is common. Patients with osseous blastomycosis present with pain and swelling. Radiographs usually show an eccentric lucency in the distal ends of long bones. These patients frequently are referred for a neoplastic workup and a diagnosis is made only after biopsy. We review the cases of five patients diagnosed with a bone tumor who had blastomycosis osteomyelitis. The time to diagnosis from original symptoms was 4.7 months (range, 3-8 months). The average age of the patients was 45.6 years (range, 20-59 years). A Musculoskeletal Tumor Society functional assessment was done. Early radiographs of the current patients ranged from normal to showing faint osteopenia in the involved location. As the disease progressed, the area of lucency appeared with either diffuse or well-marginated borders. Treatment included surgical debridement with antifungals. The mean functional score was 93.3%. All patients are disease-free. Blastomycosis, similar to tuberculosis, often is mistaken for a neoplasm. Blastomycosis osteomyelitis can be treated with excellent results. The key is diagnosis and including endemic fungal infections in the differential diagnosis of bone tumors. In addition, every potential neoplasm should include cultures of specimens obtained at biopsy.


Heterotrophic bacteria and bacterivorous protozoa in oceanic macroaggregates.
Oceanic macroaggregates (marine snow and Rhizosolenia mats) sampled from the Sargasso Sea are associated with bacterial and protozoan populations up to four orders of magnitude greater than those present in samples from the surrounding water. Filamentous, curved, and spiral bacteria constituted a higher proportion of the bacteria associated with the particles than were found among bacteria in the surrounding water. Protozoan populations were dominated numerically by heterotrophic microflagellates, but ciliates and amoebas were also observed. Macroaggregates are highly enriched heterotrophic microenvironments in the oceans and may be significant for the cycling of particulate organic matter in planktonic food chains.


Comparison of different incubation conditions for microbiological environmental monitoring.
Environmental monitoring represents an integral part of the microbiological quality control system of a pharmaceutical manufacturing operation. However, guidance documents differ regarding recommendation of a procedure, particularly regarding incubation time, incubation temperature, or nutrient media. Because of these discrepancies, many manufacturers decide for a particular environmental monitoring sample incubation strategy and support this decision with validation data. Such validations are typically laboratory-based in vitro studies, meaning that these are based on comparing incubation conditions and nutrient media through use of cultured microorganisms. An informal survey of the results of these in vitro studies performed at Novartis or European manufacturing sites of different pharmaceutical companies highlighted that no consensus regarding the optimal incubation conditions for microbial recovery existed. To address this question differently, we collected a significant amount of samples directly from air, inanimate surfaces, and personnel in pharmaceutical production and packaging rooms during manufacturing operation (in situ study). Samples were incubated under different conditions suggested in regulatory guidelines, and recovery of total aerobic microorganisms as well as moulds was assessed. We found the highest recovery of total aerobic count from areas with personnel flow using a general microbiological growth medium incubated at 30-35 °C. The highest recovery of moulds was obtained with mycological medium incubated at 20-25 °C. Single-plate strategies (two-temperature incubation or an intermediate incubation temperature of 25-30 °C) also yielded reasonable recovery of total aerobic count and moulds. However, recovery of moulds was found to be highly inefficient at 30-35 °C compared to lower incubation temperatures. This deficiency could not be rectified by subsequent incubation at 20-25 °C. A laboratory-based in vitro study performed in parallel was inconclusive. We consider our results potentially conferrable to other pharmaceutical manufacturing sites in moderate climate zones and believe that these should represent a valuable reference for definition of the incubation strategy of microbiological environmental monitoring samples. Microbiological environmental monitoring confirms that pharmaceutical cleanrooms are in an appropriate hygienic condition for manufacturing of drug products. Guidance documents from different health authorities or expert groups differ regarding recommendation of the applied incubation time, incubation temperature, or nutrient media. Therefore, many pharmaceutical manufacturers perform studies that aim to identify the optimal incubation setup for environmental monitoring samples. An informal survey of the results of such studies, which had been performed at Novartis or European manufacturing sites of different pharmaceutical companies, highlighted no consensus regarding the optimal incubation conditions for microbial recovery. All these studies had been conducted in the laboratory using selections of cultured microbial strains. We tried to solve this disagreement by collecting a significant amount of real environmental monitoring samples directly from the environment in pharmaceutical production and packaging rooms during manufacturing operation. These samples were then incubated under different conditions suggested in the regulatory guidelines. We believe that the results of our study are more meaningful than laboratory-based experiments because we used environmental samples with microorganisms directly isolated from the manufacturing area. Therefore, we believe that our results should represent a valuable reference for definition of the incubation strategy of microbiological environmental monitoring samples.


Robust tracking of the upper limb for functional stroke assessment.
We present a robust 3-D parts-based (PB) tracking system designed to follow the upper limb of stroke survivors during desktop activities. This system fits a probabilistic model of the arm to sequences of images taken from multiple angles. The arm model defines shapes and colors of limbs and limb configurations that are more or less likely. We demonstrate that the system is 1) robust to cluttered scenes and temporary occlusions, 2) accurate relative to a commercial motion capture device, and 3) capable of capturing kinematics that correlate with concurrent measures of post-stroke limb function. To evaluate the PB system, the functional motion of seven stroke survivors was measured concurrently with the PB system and a commercial motion capture system. In addition, functional motion was assessed by an expert using the Fugl-Meyer Assessment (FMA) and related to recorded kinematics. Standard deviation of differences in measured elbow angles between systems was 5.7°; deviation in hand velocity estimates was 2.6 cm/s. Several statistics, moreover, correlated strongly with FMA scores. Standard deviation in shoulder velocity had a significant correlation coefficient with FMA score below -0.75 when measured with all systems.


Lateral Epicondylitis and Tobacco Use: A Case-Control Study.
Although lateral epicondylitis (LE) is a very common tendinopathy, we understand little about the etiology of the disease. Tobacco use has been associated with other tendinopathies, and the purpose of this study is to determine if there is an association between the incidence of lateral epicondylitis and tobacco use. We performed a retrospective cohort study of adult patients diagnosed with lateral epicondylitis. Patients from a single orthopaedic surgeon's practice with LE were matched to control patients with other common upper extremity conditions based on age, gender, and occupation. A total of 65 case patients and 217 control patients were included in the study. The incidence of smoking in patients with lateral epicondylitis was compared to the incidence of smoking in the control group. Of the LE patients, 30/65 (46.2%) were non-smokers, 23/65 (35.4%) were former smokers, and 12/65 (18.5%) were current smokers. Of the control patients, 121/217 (55.8%) were non-smokers, 45/217 (20.7%) were former smokers, and 51/217 (23.5%) were current smokers. The odds of LE patients being former or current smokers compared to control patients were 1.45 times higher, but this was not statistically significant. Among people who did not smoke at the time of presentation, the odds of being a former smoker were 2.28 times higher in LE patients than in controls, which was statistically significant. The odds of being a former smoker were significantly higher in patients with lateral epicondylitis compared to patients with other upper extremity conditions. Although it did not reach statistical significance, the odds of being former or current smokers were also higher in the LE group. These results suggest a relationship between smoking history and incidence of lateral epicondylitis, though more research is needed to determine the exact nature of the relationship. Prognostic, Level III.


Early evidence of Acheulean settlement in northwestern Europe--la Noira site, a 700,000 year-old occupation in the center of France.
The human settlement of Europe during Pleistocene times was sporadic and several stages have been recognized, both from paleaoanthropological and archaeological records. If the first phase of hominin occupation (as early as 1.4 Ma) seems mainly restricted to the southern part of the continent, the second phase, characterized by specific lithic tools (handaxes), is linked to Acheulean settlements and to the emergence of Homo heidelbergensis, the ancestor of Neanderthals. This phase reached northwestern Europe and is documented in numerous sites in Germany, Great Britain and northern France, generally after 600 ka. At la Noira (Brinay, Central France), the Middle Pleistocene alluvial formation of the Cher River covers an archaeological level associated with a slope deposit (diamicton). The lithic assemblage from this level includes Large Cutting Tools (LCTs), flakes and cores, associated with numerous millstone slabs. The lithic series is classified as Acheulean on the basis of both technological and typological analyses. Cryoturbation features indicate that the slope deposits and associated archaeological level were strongly frozen and disturbed after hominin occupation and before fluvial deposition. Eight sediment samples were dated by the electron spin resonance (ESR) method and the weighted average age obtained for the fluvial sands overlying the slope deposits is 665±55 ka. This age is older than previous chronological data placing the first European Acheulean assemblages north of 45(th) parallel north at around 500 ka and modifies our current vision of the initial peopling of northern Europe. Acheulean settlements are older than previously assumed and the oldest evidences are not only located in southern Europe. La Noira is the oldest evidence of Acheulean presence in north-western Europe and attests to the possibility of pioneering phases of Acheulean settlement which would have taken place on a Mode 1-type substratum as early as 700 ka. The lithic assemblage from la Noira thus provides behavioral and technological data on early Acheulean occupation in Europe and contributes to our understanding of the diffusion of this tradition.


Quantum proteolysis resulting from release of single granules by human neutrophils: a novel, nonoxidative mechanism of extracellular proteolytic activity.
Proteinase inhibitors confine the activity of proteolytic enzymes of inflammatory cells, but fail to protect substrates in the immediate pericellular zone. We report quantitative imaging that demonstrates discrete, evanescent, quantized proteolytic events attributable to the release of single azurophil granules from neutrophils. The images provide information about the dynamics of this nonequilibrium system, which is characterized by overwhelmingly high local concentrations of enzymes that rapidly dissipate. With physiologic concentrations of extracellular human leukocyte elastase inhibitors (32.8 microM), the radii of the unit proteolytic events are 1.32 microm (approximately 8 times the radius of the azurophil granule) and are inversely and nonlinearly related to the concentration of proteinase inhibitor that is present in the bathing medium. We have obtained identical results with alpha1-antitrypsin, alpha2m, recombinant secretory leukocyte proteinase inhibitor, and ICI 200,355, and we have found that phagocyte-derived oxidants are not required for the genesis of this catalytic activity. Our results reveal that the enzyme:inhibitor ratio is the primary delimiter of quantized proteolysis in the local microenvironment.


SNORD76, a box C/D snoRNA, acts as a tumor suppressor in glioblastoma.
Glioblastoma (GBM) is associated with disproportionately high morbidity and mortality, reflecting the need to develop new diagnostic and therapeutic targets for this disease. Recently, accumulating evidence has suggested that small nucleolar RNAs (snoRNAs) are gaining prominence and are more actively involved in tumorigenesis than previously thought. However, no report concerning the implication of snoRNAs in glioma has been published to date. In our study, SNORD76 was first found to be inversely associated with Hox Transcript Antisense Intergenic RNA (HOTAIR) knockdown, and surprisingly, forcibly expressed SNORD76 inhibited proliferation and growth of glioma cells. Moreover, downregulation of SNORD76 led to a more malignant phenotype. The pleiotropy of SNORD76 overexpression could be achieved at least partially through inducing cell cycle arrest at S phase by affecting the Rb-associated cell cycle regulation. Enforced SNORD76 expression in orthotopic tumors resulted in decreased tumor growth and the reduction of tumor volume. Additionally, in surgically resected glioma tissues, SNORD76, not its host gene, was associated with the WHO classification and was selectively downregulated in GBM (WHO grade IV). Collectively, our study adds to a growing body of evidence for the participation of snoRNAs in gliomagenesis and is the first to implicate a snoRNA in glioblastoma.