Thallium-201 myocardial SPECT in a patient with mirror-image dextrocardia and left bundle branch block.
A 53-year-old male patient with a previous diagnosis of situs inversus with mirror-image dextrocardia underwent thallium-201 (Tl-201) stress-redistribution myocardial perfusion single photon emission computed tomography (SPECT). Electrocardiogram (ECG) obtained on right hemithorax revealed constant complete left bundle branch block. Tl-201 stress-redistribution SPECT images revealed abnormal perfusion with reversible ischemia in the anteroseptal, septal and inferoseptal walls. Coronary angiography performed 1 month after SPECT study was normal. This case illustrates that false positive reversible perfusion defects can be seen in patients with mirror-image dextrocardia associated with constant complete left bundle branch block. To our knowledge, this is the first reported case of mirror-image dextrocardia and constant complete left bundle branch block with false positive Tl-201 SPECT findings.


Effect of exercises on quality of life in women with osteoporosis and osteopenia.
Osteoporosis is a disease characterized by decreased bone mass and impaired microarchitecture resulting in bone fragility and an increased risk of fractures. Prevention of osteoporosis and osteoporotic fractures among others include adequate physical activity. Epidemiological studies indicate that fewer fractures in active women, regardless of whether it is a result of direct effects on bone or improve coordination, balance and muscle strength. The aim of research was to examine the impact of exercise program for osteoporosis in the duration of four weeks on health and psychological aspects of patient quality of life using the questionnaire SF-36, used before and after the program. The SF-36 is used for self-assessment of health status and represents the operationalization of two general concept of health such as physical and mental health and consists of 36 particles. The study included 39 participants with osteopenia and osteoporosis. All respondents have implemented a program of exercises for osteoporosis in duration 28 days. The program consisted of exercises for osteoporosis, advice on diet, tips on preventing falls, interviews and examinations performed before and during implementation of the program. Results showed that using a short program of exercises and education leads to significant changes in self-reported quality of life of subjects. The study confirmed a statistically significant reduction in pain using a visual analog scale (VAS) before and after the program.


Early biochemical relapse after radical prostatectomy: which prostate cancer patients may benefit from a restaging 11C-Choline PET/CT scan before salvage radiation therapy?
The aim of the study was to assess which factors may influence (11)C-choline PET/CT detection rate in a population of recurrent prostate cancer (PCa) patients listed for salvage radiation therapy (S-RT) in an early phase of biochemical relapse, to select which patients could obtain the most benefit by performing restaging (11)C-choline PET/CT before S-RT. The study comprised 605 patients, treated with radical prostatectomy (RP) with curative intent for PCa who showed rising PSA levels after primary therapy and listed for S-RT. Prostate-specific antigen (PSA) values were >0.2 ng/mL and <2 ng/mL (mean, 1.05 ng/mL; median, 1.07 ng/mL; range, 0.2-2 ng/m; SD, ±0.59). All patients were classified as N0 after RP. Seventeen of 605 patients received adjuvant RT together with RP, whereas 148 of 605 patients received androgen-deprivation therapy (ADT) at the time of PET/CT. PSA, PSA kinetics, Gleason score, age, time to biochemical relapse, ADT, and initial tumor stage were statistically analyzed to assess which factor could influence PET/CT positivity and the detection of local versus distant relapse. (11)C-choline PET/CT was positive in 28.4% of patients (172/605). Eighty-three of 605 patients were positive in the pelvis (group A), distant metastasis (group B) were detected in 72 of 605 patients, and local and distant sites of relapse were detected in 17 of 605 patients (group C). At multivariate analysis, PSA, PSA doubling time (PSAdt), and ongoing ADT were significant predictors for positive scan results, whereas PSA and PSAdt were significantly related to distant relapse detection (P < 0.05). At the receiver-operating-characteristic analysis, a PSA value of 1.05 ng/mL and PSAdt of 5.95 mo were determined to be the optimal cutoff values in the prediction of a positive (11)C-choline PET/CT scan, with an area under the curve (AUC) of 0.625 for PSA and 0.677 for PSAdt. (11)C-choline PET/CT may be suggested before S-RT during the early phase of biochemical relapse, to select patients who may benefit from this aggressive treatment. Particularly, patients showing fast PSA kinetics or PSA increasing levels despite ongoing ADT should be studied with (11)C-choline PET/CT before S-RT, considering the higher probability to detect positive findings outside the pelvis.


Fiducial marker guided prostate radiotherapy: a review.
Image-guided radiotherapy (IGRT) is an essential tool in the accurate delivery of modern radiotherapy techniques. Prostate radiotherapy positioned using skin marks or bony anatomy may be adequate for delivering a relatively homogeneous whole-pelvic radiotherapy dose, but these surrogates are not reliable when using reduced margins, dose escalation or hypofractionated stereotactic radiotherapy. Fiducial markers (FMs) for prostate IGRT have been in use since the 1990s. They require surgical implantation and provide a surrogate for the position of the prostate gland. A variety of FMs are available and they can be used in a number of ways. This review aimed to establish the evidence for using prostate FMs in terms of feasibility, implantation procedures, types of FMs used, FM migration, imaging modalities used and the clinical impact of FMs. A search strategy was defined and a literature search was carried out in Medline. Inclusion and exclusion criteria were applied, which resulted in 50 articles being included in this review. The evidence demonstrates that FMs provide a more accurate surrogate for the position of the prostate than either external skin marks or bony anatomy. A combination of FM alignment and soft-tissue analysis is currently the most effective and widely available approach to ensuring accuracy in prostate IGRT. FM implantation is safe and well tolerated. FM migration is possible but minimal. Standardization of all techniques and procedures in relation to the use of prostate FMs is required. Finally, a clinical trial investigating a non-surgical alternative to prostate FMs is introduced.


Alteration of JNK-1 signaling in skeletal muscle fails to affect glucose homeostasis and obesity-associated insulin resistance in mice.
Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNK(C)). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNK(C) mice were crossed to Mck-Cre mice yielding JNK(SM-C) mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNK(SM-C) mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance.


Disinfection efficacy of sodium dichloroisocyanurate (NADCC) against common food-borne intestinal protozoa.
The present study was conducted to investigate the efficacy of sodium dichloroisocyanurate (NaDCC) on the infective stages of common food-borne intestinal protozoa; Entamoeba histolytica (E. histolytica), Giardia lamblia (G. lamblia), Cryptosporidium, Cyclospora and Microsporidia; beside its effect on raw green vegetables and fruits. Parasites, isolated from stool of patients with diarrhea or dysentery, were exposed to NaDCC solution (1g/l) for one and two hours. Disinfection effect of NaDCC was assessed by in-vitro viability, using trypan blue stain, and infectivity bioassay in laboratory animals as indicated by fecal and intestinal parasitic counts. Raw vegetables and fruits were dipped in NaDCC solution in the same concentration and exposure time as used for treatment of the parasites. Results revealed statistically significant reductions in viability and infectivity of all examined parasites indicating their susceptibility to NaDCC. Relative variations in susceptibility were revealed; E. histolytica and G. lamblia were most susceptible (100% reduction) followed by Microsporidia then Cryptospridium and Cyclospora. NaDCC did not affect the consistency, color, taste or flavor of raw green vegetables and fruits. The proved efficacy of NaDCC, in cheap and convenient dry tablet form, makes it a promising tool in decontaminating raw vegetables and fruits from food-borne protozoan parasites at household and restaurant levels as well as in catering and fresh produce industry. It is also recommended for disinfection of food preparation surfaces and equipment.


A prospective clinical and pathological examination of injection site reactions with the HIV-1 fusion inhibitor enfuvirtide.
Antiretroviral regimens containing the fusion inhibitor enfuvirtide (ENF) are associated with sustained viral suppression and immunological benefit. However, local injection site reactions (ISR) occur in the majority of patients. The aim of this study was to determine the pathogenesis of ISRs. Injection sites were evaluated prospectively from 30 min up to 15-30 days post-injection in ENF-experienced (Cohort I) and ENF-naive patients (Cohort II) during the first 2 weeks of therapy. Four to five injections were given in rotating abdominal sites by a nurse using a standardized technique and were rigorously evaluated. Reactions were observed in 80-100% of patients; the majority of the reactions were mild to moderate, generally appeared within 24-48 h post-injection, and pain, induration and erythema were the most common clinical signs. Whereas most patients experienced ISRs, the overall prevalence in Cohort II was low (35% maximum). Punch biopsies of injection sites in Cohort I consisted primarily of mixed lymphocytic infiltrates with eosinophils and neutrophils. Injection vehicle (ENF buffer minus ENF) and reduced volume (2 x 0.5 ml ENF [45 mg] versus 1.0 ml [90 mg] ENF) were investigated in Cohort II. Fewer reactions appeared with vehicle and pain was absent with the smaller injection volume. Pathology was indistinguishable between ENF, vehicle and normal tissue in Cohort II patients. These results suggest that injection technique, injection volume and peptide may influence ISR to ENF.


Biweekly administration of low-dose docetaxel in hormone-resistant prostate cancer: pilot study of an effective subtoxic therapy.
Taxane-based chemotherapy has shown activity but also toxicity when administered at standard doses in patients with hormone-resistant prostate cancer (HRPC). In this pilot study, we investigated biweekly low-dose docetaxel in patients with HRPC as a convenient regimen with low toxicity. Sixteen patients with metastatic HRPC entered the study. Median age was 73 years, median performance status (PS) was 2, and median Gleason score was 9. All patients had undergone and failed combined androgen-blockade therapy (luteinizing hormone-releasing hormone analogue plus antiandrogen) for their metastatic disease; 3 had also been treated with mitoxantrone. Treatment consisted of docetaxel 30 mg/m2 administered every 2 weeks. Prostate-specific antigen (PSA) response, characterized by a 50% decrease of PSA level confirmed 4 weeks later, was the primary endpoint. Durations of PSA response and toxicity assessment were secondary endpoints. A total of 136 biweekly docetaxel doses were administered, with a median of 8.5 doses per patient (range, 2-24). Six patients (38%; 95% confidence interval, 25%-43%) fulfilled the criteria of PSA response. Median duration of PSA response was 4.5 months (range, 3-12). Toxicity was negligible: myelotoxicity was practically absent, whereas 3 patients developed grade 1 alopecia and 1 patient developed dacryorrhea. We conclude that our study provides evidence that biweekly docetaxel at 30 mg/m2 can be considered an effective nontoxic therapeutic option for patients with HRPC. Confirmation of these preliminary data in larger-scale trials is justified


In vitro and in vivo antibacterial activities of K-4619, a new semisynthetic aminoglycoside.
The antibacterial activities of K-4619 (3-de-O-methylsporaricin A sulfate) were compared with those of sporaricin A, amikacin, dibekacin, and gentamicin. K-4619 exhibited a high order of activity against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. Its activity against Providencia species and Serratia marcescens was the highest of all drugs tested. K-4619 was highly effective against bacteria that produce various aminoglycoside-inactivating enzymes, except for 3-acetyltransferase I. The bactericidal activity of K-4619 was somewhat greater than that of amikacin. The activity of K-4619 against gram-negative bacteria increased at alkaline pH and was hardly affected by inoculum size, addition of horse serum, and composition of the medium. The in vivo protective effect of K-4619 against infections with Klebsiella pneumoniae, S. marcescens, and P. aeruginosa in mice was greater than that of sporaricin A. K-4619 was also active in mice infected with gentamicin- or amikacin-resistant strains bearing some of the aminoglycoside-inactivating enzymes.


Improving the translational hit of experimental treatments in multiple sclerosis.
In other neurological diseases, the failure to translate pre-clinical findings to effective clinical treatments has been partially attributed to bias introduced by shortcomings in the design of animal experiments. Here we evaluate published studies of interventions in animal models of multiple sclerosis for methodological design and quality and to identify candidate interventions with the best evidence of efficacy. A systematic review of the literature describing experiments testing the effectiveness of interventions in animal models of multiple sclerosis was carried out. Data were extracted for reported study quality and design and for neurobehavioural outcome. Weighted mean difference meta-analysis was used to provide summary estimates of the efficacy for drugs where this was reported in five or more publications. The use of a drug in a pre-clinical multiple sclerosis model was reported in 1152 publications, of which 1117 were experimental autoimmune encephalomyelitis (EAE). For 36 interventions analysed in greater detail, neurobehavioural score was improved by 39.6% (95% CI 34.9-44.2%, p < 0.001). However, few studies reported measures to reduce bias, and those reporting randomization or blinding found significantly smaller effect sizes. EAE has proven to be a valuable model in elucidating pathogenesis as well as identifying candidate therapies for multiple sclerosis. However, there is an inconsistent application of measures to limit bias that could be addressed by adopting methodological best practice in study design. Our analysis provides an estimate of sample size required for different levels of power in future studies and suggests a number of interventions for which there are substantial animal data supporting efficacy.


Enhanced expression of podoplanin in oral carcinomas in situ and squamous cell carcinomas.
Podoplanin, a known lymphatic endothelial cell marker, has been reported to be expressed in various types of cancer. To elucidate the expression of podoplanin in precancerous lesions, we examined the immunohistochemical profiles of podoplanin in oral squamous epithelial lesions. We studied a total of 298 foci of squamous cell carcinoma (SCC), carcinoma in situ (CIS), epithelial dysplasia, and hyperplastic and/or normal epithelial lesions by immunohistochemistry using D2-40. There was no positivity for podoplanin in normal or hyperplastic epithelia, while all of the CIS and SCC foci stained positive. Approximately one third of the mild dysplasia foci (10 of 36 foci, 28%) and 80% of moderate dysplasia foci (78/98) showed grade 1 positive reactions (positive only in the 1st layer). Grade 2 reactions (up to 4th layer) were seen in 4 of 98 moderate dysplasia foci (4%), 29 of 74 CIS foci (39%), and 3 of 30 SCC foci (10%). Grade 3 reactions (to more than 5th layer) were found in 35 (47%) CIS foci and 26 (87%) SCC foci. The relationship between the present histological categorization and podoplanin grade was statistically significant. D2-40 expression is considered to be related to the severity of oral precancerous lesions.


Proteome analysis of the moss Physcomitrella patens (Hedw.) B.S.G.
The sequencing of the moss Physcomitrella patens genome has facilitated studies of the plant proteome. To develop a proteome reference map based on the genome sequence, we conducted 2D electrophoreses of proteins extracted from moss protoplasts, protonemata, and gametophores grown under standard conditions on Petri dishes. On silver-stained gels, depending on the developmental stage of the moss, we resolved from 500 to 600 protein spots that were then excised and digested by trypsin, and 212 proteins were identified by PMF-MALDI-TOF. To enhance the proteome coverage, we performed 1D SDS-PAGE with subsequent separation of tryptic peptides derived from digested gel band slices by LC-ESI-MS/MS. The proposed approach allowed us to identify 186 proteins had not been determined by 2D PMF-MALDI-TOF. Proteins identified by both methods were categorized using a system of clusterization of orthologous genes as metabolism (26%), cellular processes and signaling (16%), and information storage and processing (7%). Proteome analysis by differential gel electrophoresis revealed moderate differences between filamentous protonemata and leafy shoots. Surprisingly, protoplasts isolated from protonema filaments displayed significant differences in protein composition compared with both protonemata and gametophores.


Sarecycline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium avium complex: so near and yet so far.
Poor sustained sputum culture conversion rates with the standard-of-care therapy highlight the need for better drugs to treat Mycobacterium avium complex pulmonary disease (MAC-PD). To determine the pharmacokinetics/pharmacodynamics (PK/PD)-optimized exposure of sarecycline and its potential role in treating MAC-PD. We performed MIC studies with MAC ATCC 700898 and 19 clinical isolates and test-tube static concentration-response studies. A dynamic hollow-fibre system model of intracellular MAC (HFS-MAC) study was performed mimicking six human-equivalent sarecycline dose concentration-time profiles to identify the PK/PD optimal exposure of sarecycline for MAC kill. The inhibitory sigmoid maximal effect (Emax) model was used for PK/PD analysis. The sarecycline MIC of MAC ATCC 700898 was 1 mg/L, while the MIC for the 19 clinical strains ranged between 32 and >256 mg/L. The concentration mediating 50% of Emax (EC50) was similar between intracellular and extracellular MAC. In the HFS-MAC, all six sarecycline doses killed intracellular MAC, with an Emax of 1.0 log10 cfu/mL below Day 0 burden (stasis). The sarecycline EC80 (optimal) exposure was identified as AUC0-24/MIC = 139.46. Sarecycline demonstrated anti-MAC Emax in the HFS-MAC model better than ethambutol but worse than omadacycline (>5 log10 cfu/mL below stasis) in HFS-MAC. However, since currently approved highest oral sarecycline dose achieves an AUC0-24 of 48.2 mg·h/L and MAC MICs are >32 mg/L, the target AUC0-24/MIC of 139.46 is unlikely to be achieved in patients.


Low calcium diet increases 4T1 mammary tumor carcinoma cell burden and bone pathology in mice.
Breast cancer metastasizes to bone in the majority of patients with advanced disease. We investigated the effects of inadequate dietary calcium (Ca) on bone turnover, tumor growth, and bone response to tumor in tibia inoculated with 4T1 mammary carcinoma cells. Nine-month-old female Balb/c mice were placed on an adequate Ca (5 g/kg diet, n = 30) or low Ca (80 mg/kg diet, n = 31) diet for 14 days, then injected intratibially with 1,000 4T1 cells (transfected with luciferase for bioluminescence imaging), and sacrificed at 5, 10, or 21 days post-inoculation (n = 7-10 mice/group). Control mice (n = 6/group) were injected with carrier and sacrificed at 10 days post-inoculation. Tibiae with muscle intact were excised and evaluated by microcomputed tomography and histology. In vivo bioluminescent imaging revealed that 4T1 cells metastasized to lung. Therefore, lungs were removed for quantification of tumor. Mice fed low Ca exhibited higher bone turnover and higher tibial lesion scores than mice fed adequate Ca. Lesion severity, manifested as cortical osteolysis and periosteal woven bone formation, and tumor cell infiltration to muscle, increased with time, irrespective of diet. However, for most skeletal endpoints the rates of increase were greater in mice consuming low Ca compared to mice consuming adequate Ca. Infiltration of tumor cells into adjacent muscle, but not metastasis to lung, was also greater in mice consuming low Ca diet. The findings suggest that high bone turnover due to Ca insufficiency results in greater local mammary tumor cell growth, cortical osteolysis, woven bone formation, and invasion to muscle in mice.


Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network.
The Myc/Max/Mad transcription factor network is critically involved in cell behavior; however, there is relatively little information on its genomic binding sites. We have employed the DamID method to carry out global genomic mapping of the Drosophila Myc, Max, and Mad/Mnt proteins. Each protein was tethered to Escherichia coli DNA adenine-methyltransferase (Dam) permitting methylation proximal to in vivo binding sites in Kc cells. Microarray analyses of methylated DNA fragments reveals binding to multiple loci on all major Drosophila chromosomes. This approach also reveals dynamic interactions among network members as we find that increased levels of dMax influence the extent of dMyc, but not dMnt, binding. Computer analysis using the REDUCE algorithm demonstrates that binding regions correlate with the presence of E-boxes, CG repeats, and other sequence motifs. The surprisingly large number of directly bound loci ( approximately 15% of coding regions) suggests that the network interacts widely with the genome. Furthermore, we employ microarray expression analysis to demonstrate that hundreds of DamID-binding loci correspond to genes whose expression is directly regulated by dMyc in larvae. These results suggest that a fundamental aspect of Max network function involves widespread binding and regulation of gene expression.


Laying the foundation for successful team performance trajectories: The roles of team charters and performance strategies.
This study examined the influences of team charters and performance strategies on the performance trajectories of 32 teams of master's of business administration students competing in a business strategy simulation over time. The authors extended existing theory on team development by demonstrating that devoting time to laying a foundation for both teamwork (i.e., team charters) and taskwork (performance strategies) can pay dividends in terms of more effective team performance over time. Using random coefficients growth modeling techniques, they found that teams with high-quality performance strategies outperformed teams with poorer quality strategies. However, a significant interaction between quality of the charters of teams and their performance strategies was found, such that the highest sustained performances were exhibited by teams that were high on both features. (PsycINFO Database Record (c) 2009 APA, all rights reserved).


Temperature-sensitive mutants of mouse hepatitis virus strain A59: isolation, characterization and neuropathogenic properties.
Twenty 5-fluorouracil-induced temperature-sensitive (ts) mutants of mouse hepatitis virus strain A59 were isolated from 1284 virus clones. Mutants were preselected on the basis of their inability to induce syncytia in infected cells at the restrictive temperature (40 degrees) vs the permissive temperature (31 degrees). Of these mutants, only those with a relative plating efficiency 40 degrees/31 degrees of 3 x 10(-3) or smaller were kept. Virus yields at 40 degrees compared to 37 degrees and 31 degrees (leakiness) were determined. Most mutants (16) were RNA-, i.e., unable to synthesize virus-specific RNA at the restrictive temperature. The other four were RNA+. No qualitative differences were detected in the virus-specific RNAs in cells infected with RNA+ ts-mutants, both at 31 degrees and 40 degrees. Virus-specific proteins present in cells infected with ts-171 (RNA-) and the RNA+-mutants (ts-43, ts-201, ts-209, and ts-279) were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of immunoprecipitates. No qualitative differences in the pattern of virus-specific cellular proteins were detected among the mutants except for an additional polypeptide of about 46,000 daltons in ts-209-infected cells. Finally, the neuropathogenic properties of eight of the mutants were investigated. Whereas 10(2) PFU of wild-type virus injected intracerebrally killed 50 to 100% of 4-week-old Balc/c mice within 1 week, the mutants were highly attenuated. A dose of 10(5) PFU lead to no or transient disease. However, 4 weeks after infection with ts-342, ts-43, or ts-201 obvious histological changes were observed in brain and spinal cord of clinically healthy mice.


Musculoskeletal fitness and risk of mortality.
To quantify the relationship between musculoskeletal fitness and all-cause mortality in the Canadian population. The sample consisted of 8116 people (3933 men and 4183 women), aged 20-69 yr, who participated in the 1981 Canada Fitness Survey. Measures of musculoskeletal fitness included sit-ups, push-ups, grip strength, and sit-and-reach trunk flexibility. In the 13 yr after the Canada Fitness Survey, there were 238 deaths and a total of 101,685 person-years. Proportional hazards regression was used to estimate the risk of mortality across baseline age- and sex-specific quartiles of the musculoskeletal fitness measures. All models included the effects of age, smoking status, body mass, and estimated VO2max as covariates, and the upper quartile was set as the reference group. There was no pattern of increased risk of mortality across quartiles of trunk flexibility or push-ups; however, there was a significantly higher risk in the lower quartile of sit-ups in both men (relative risk (RR) = 2.72, 95% CI 1.56-4.64) and women (RR = 2.26, 95% CI 1.15-4.43). Grip strength was not predictive of mortality in women, although there was a 49% increased risk of death in the lower quartile of grip strength in males (RR = 1.49, 95% CI 0.86-2.59). The results suggest that some components of musculoskeletal fitness, particularly sit-ups (abdominal muscular endurance), are predictive of mortality in the Canadian population.


Gut microbiota associated with HIV infection is significantly enriched in bacteria tolerant to oxygen.
Gut microbiota modifications occurring during HIV infection have recently been associated with inflammation and microbial translocation. However, discrepancies between studies justified a comprehensive analysis performed on a large sample size. In a case-control study, next-generation sequencing of the 16S rRNA gene was applied to the faecal microbiota of 31 HIV-infected patients, of whom 18 were treated with antiretroviral treatment (ART), compared with 27 healthy controls. 21 sera samples from HIV-infected patients and 7 sera samples from control participants were used to test the presence of 25 markers of inflammation and/or immune activation. Diversity was significantly reduced in HIV individuals when compared with controls and was not restored in the ART group. The relative abundance of several members of Ruminococcaceae such as Faecalibacterium prausnitzii was critically less abundant in the HIV-infected group and inversely correlated with inflammation/immune activation markers. Members of Enterobacteriaceae and Enterococcaceae were found to be enriched and positively correlated with these markers. There were significantly more aerotolerant species enriched in HIV samples (42/52 species, 80.8%) when compared with the control group (14/87 species, 16.1%; χ(2) test, p<10(-5), conditional maximum-likelihood estimate (CMLE) OR=21.9). Imbalance between aerobic and anaerobic flora observed in HIV faecal microbiota could be a consequence of the gut impairment classically observed in HIV infection via the production of oxygen. Overgrowth of proinflammatory aerobic species during HIV infection raises the question of antioxidant supplementation, such as vitamin C, E or N-acetylcysteine.


Streptococcus pneumoniae serotype 19A in hospitalized children with invasive pneumococcal disease after the introduction of conjugated vaccines in Lima, Peru.
The Pneumococcal conjugate vaccine (PCV) has decreased cases of invasive pneumococcal disease (IPD) worldwide. However, the impact of PCVs introduction may be affected by the serotype distribution in a specific context. Cross-sectional multicenter passive surveillance study of IPD cases in pediatric patients hospitalized in Lima, Peru between 2016 and 2019 (after PCV13 introduction) to determine the serotype distribution and antimicrobial resistance of Streptococcus pneumoniae. Serotyping was performed by a sequential multiplex PCR and confirmed by whole genome sequencing. Eighty-five S. pneumoniae isolates were recovered (4.07/100,000 among children <60 months of age). Serotype 19A was the most common (49.4%). Children infected with serotype 19A in comparison with children infected with other serotypes were younger, had a lower rate of meningitis and higher rates of pneumonia, complicated pneumonia and antimicrobial resistance; 28.6% of patients with serotype 19A have received at least one dose of PCV13 vs. 62.8% of patients with other serotypes. Using MIC-breakpoints, 81.2% (56/69) of non-meningitis strains and 31.2% (5/16) of meningitis strains were susceptible to penicillin; 18.8% (3/16) of meningitis strains had intermediate resistance to ceftriaxone. Resistance to azithromycin was 78.8% (67/85). Serotype 19A frequency increased over time in the same study population, from 4.2% (4/96) in 2006-2008, to 8.6% (5/58) in 2009-2011, to 49.4% (42/85) in the current study (2016-2019) (p < 0.001). After PCV13 introduction in Peru, serotype 19A remains the most prevalent; however, the vaccination coverage is still not optimal. Therefore, additonal surveillance studies are needed to determine the remaining IPD burden.


[The influence of kinesiotaping on lumbar spine pain].
Pain in the lumbosacral spine is currently one of the most common pain complaints among the elderly. About 72% of the Polish population younger than 40 years have at least once been treated by a doctor for back pain. Degenerative changes of intervertebral joints, overloads, intervertebral disc diseases, and dysfunction of spinal ligaments are very often responsible for the formation of back pain, which is basically a problem of the elderly, The study was conducted among 60 residents of a Nursing Home in Szczecin with chronic lumbar pain. The age range was 56-85 years. Subjects were randomly divided into two groups of 30 (study group, where KinesioTaping was used, and a control group without KinesioTaping application). To assess the degree of pain experienced by the patient a visual analogue scale (VAS) in the horizontal format from 0-10 was used, on which subjects scored the severity of pain. Flexion, extension, tilt and rotation were measured with a tape to assess spinal and trunk mobility. In all patients, who had a KinesioTaping patch applied on the lumbosacral spine pain measured by VAS reduced (p ≤ 0.001). Considering respondents' sex, the spine mobility in the tilting position improved in men in the study group in terms of tilting to both sides. In all patients, the application of a KinesioTaping patch significantly improved the rotation to the right side (p ≤ 0.05), scores in the "finger-floor" flexion test (p ≤ 0.01), and the extension range (p ≤ 0.01). KinesioTaping is a beneficial method reducing pain and improving the mobility in the lumbosacral spine. The improvement was independent of the sex of the respondents.


The use of the supraceliac aorta for hepatic arterial revascularization in transplantation of the liver.
Thrombosis of the hepatic artery during the early post hepatic transplant period results in massive hepatocyte necrosis, bile duct damage and subsequent graft loss. The incidence of this complication is increased when hepatic arterial reconstruction is possible only by the placement of an interposition infrarenal iliac artery graft. We describe 45 hepatic transplants with difficult arterial reconstruction in which the supraceliac aorta was used for arterial reconstruction. Indications for using the supraceliac aorta as the primary site for arterial reconstruction were inadequate inflow through a narrow recipient common hepatic artery in 51 per cent, previously thrombosed common hepatic artery in 27 per cent, mechanical obstruction of the celiac axis in 13 per cent or intimal dissection in 9 per cent. Direct anastomosis of the donor hepatic artery to the supraceliac aorta was achieved in 22 patients, reducing the need for a graft by 49 per cent. Short segments of iliac artery graft (17 patients) or aortic conduit (six patients) to the supraceliac aortas were required because of insufficient length of the donor artery. The incidence of arterial thrombosis and graft loss were zero per cent in adults and 12.5 per cent in children, both significantly less when compared with the 23.0 to 70.0 per cent thrombosis rate when graft is placed in an infrarenal position. We conclude that routine use of the supraceliac aorta for difficult hepatic arterial reconstruction decreases the need for arterial grafts, the incidence of hepatic arterial thrombosis and loss of hepatic grafts.


Two distant clusters of partially homologous small repeats of Epstein-Barr virus are transcribed upon induction of an abortive or lytic cycle of the virus.
The two regions of the Epstein-Barr virus genome carrying partially homologous clusters of short tandem repeats (DSL and DSR [duplicated sequences, left and right, respectively] ) are transcribed into polyadenylated RNA upon spontaneous or chemical induction of the lytic virus cycle. In Raji, an Epstein-Barr virus genome carrying a nonproducer cell line, transcription of DSL and DSR is only observed upon induction of an abortive life cycle of the virus. In the nonproducer cell line Raji, the polyadenylated transcripts of DSL and DSR are about 2,500 and 2,700 bases, respectively, in length. Four different spontaneous Epstein-Barr virus producer lines, M-ABA, CC34-5, QIMR-WIL, and B95-8, differ in the length of their DSL and/or DSR regions by different numbers of tandem repeats. The size of the RNAs corresponds in all cases to the size of the respective cluster of repeats, indicating that a large part of each RNA species is colinearly transcribed from the entire tandem repeat arrays. Both the DSL and the DSR RNAs have the same polarity proceeding from right to left on the Epstein-Barr virus genome. DNA sequence analysis of the DSR repeat revealed that translation of the RNA would be possible in three open reading frames within the repeat cluster. Short homologies to herpes simplex virus IR-TR sequences and to immunoglobulin switch region sequences (IgH-S) are discussed.


What health records data are required for accurate prediction of suicidal behavior?
The study sought to evaluate how availability of different types of health records data affect the accuracy of machine learning models predicting suicidal behavior. Records from 7 large health systems identified 19 061 056 outpatient visits to mental health specialty or general medical providers between 2009 and 2015. Machine learning models (logistic regression with penalized LASSO [least absolute shrinkage and selection operator] variable selection) were developed to predict suicide death (n = 1240) or probable suicide attempt (n = 24 133) in the following 90 days. Base models were used only historical insurance claims data and were then augmented with data regarding sociodemographic characteristics (race, ethnicity, and neighborhood characteristics), past patient-reported outcome questionnaires from electronic health records, and data (diagnoses and questionnaires) recorded during the visit. For prediction of any attempt following mental health specialty visits, a model limited to historical insurance claims data performed approximately as well (C-statistic 0.843) as a model using all available data (C-statistic 0.850). For prediction of suicide attempt following a general medical visit, addition of data recorded during the visit yielded a meaningful improvement over a model using all data up to the prior day (C-statistic 0.853 vs 0.838). Results may not generalize to setting with less comprehensive data or different patterns of care. Even the poorest-performing models were superior to brief self-report questionnaires or traditional clinical assessment. Implementation of suicide risk prediction models in mental health specialty settings may be less technically demanding than expected. In general medical settings, however, delivery of optimal risk predictions at the point of care may require more sophisticated informatics capability.


Effects of brain atrophy and altered functional connectivity on poststroke cognitive impairment.
Brain atrophy and disrupted functional connectivity are often present in patients with poststroke cognitive impairment (PSCI). This study aimed to explore the relationship between remote brain atrophy, connectional diaschisis and cognitive impairment in ischemic stroke patients to provide valuable information about the mechanisms underlying cognitive function recovery. Forty first-time stroke patients with basal ganglia infarcts and twenty-nine age-matched healthy people were enrolled. All participants underwent T1-weighted and functional MRI scans, comprehensive cognitive function assessments at baseline, and 3-month follow-up. Brain volumes were calculated, and the atrophic regions were regarded as regions of interest in seed-based functional connectivity analyses. Pearson correlation analysis was used to explore the relationships among cognitive performance, brain atrophy, and functional connectivity alterations. Compared with healthy participants, stroke patients had worse cognitive performance at baseline and the 3-month follow-up. Worse cognitive performance was associated with smaller bilateral thalamus, left hippocampus, and left amygdala volumes, as well as lower functional connectivity between the left thalamus and the left medial superior frontal gyrus, between the right thalamus and the left median cingulate and paracingulate gyri, between the right hippocampus and the left medial superior frontal gyrus, and between the left amygdala and the right dorsolateral superior frontal gyrus. In patients with basal ganglia infarction, connectional diaschisis between remote brain atrophy and the prefrontal lobe plays a significant role in PSCI. This finding provides new scientific evidence for understanding the mechanisms of PSCI and indicates that the prefrontal lobe may be a target to improve cognitive function after stroke.


24 mJ Cr+4:forsterite four-stage master-oscillator power-amplifier laser system for high resolution mid-infrared spectroscopy.
We present the design of a Cr:forsterite based single-frequency master-oscillator power-amplifier laser system delivering much higher output energy compared to previous literature reports. The system has four amplifying stages with two-pass configuration each, thus enabling the generation of 24 mJ output energy in the spectral region around 1262 nm. It is demonstrated that the presented Cr:forsterite amplifier preserves high spectral and pulse quality, allowing a straightforward energy scaling. This laser system is a promising tool for tunable nonlinear down-conversion to the mid-infrared spectral range and will be a key building block in a system for high-resolution muonic hydrogen spectroscopy in the 6.8 μm range.


[Cerebral and carotid arterial radiograms in low tension glaucoma].
Cerebral and carotid arterial radiograms were performed for 22 healthy volunteers, 8 patients with primary open angle glaucoma(POAG), and 10 patients with low tension glaucoma (LTG). Analysis of the Time-Radioactivity Curves suggested that insufficient perfusion of the carotid artery, especially the internal carotid artery, might play an important role in the optic nerve damage of some cases of LTG.


Prenatal and Childhood Exposure to Organophosphate Pesticides and Behavior Problems in Adolescents and Young Adults in the CHAMACOS Study.
We previously reported associations of prenatal exposure to organophosphate (OP) pesticides with poorer neurodevelopment in early childhood and at school age, including poorer cognitive function and more behavioral problems, in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a birth cohort study in an agriculture community. We investigated the extent to which early-life exposure to OP pesticides is associated with behavioral problems, including mental health, in youth during adolescence and early adulthood. We measured urinary dialkylphosphates (DAPs), nonspecific OP metabolites, in urine samples collected from mothers twice during pregnancy (13 and 26 wk) and at five different times in their children (ages 6 months to 5 y). We assessed maternal report and youth report of externalizing and internalizing behavior problems using the Behavior Assessment System for Children, 2nd edition (BASC-2), when the youth were ages 14, 16, and 18 y. Because there was evidence of nonlinearity, we estimated associations across quartiles of DAPs and modeled repeated outcome measures using generalized estimating equations. There were 335 youths with prenatal maternal DAP measures and 14-. 16-, or 18-y BASC-2 scores. Prenatal maternal DAP concentrations (specific gravity-adjusted median, Q1-Q3=159.4, 78.7-350.4 nmol/L) were associated with higher T-scores (more behavior problems) from maternal report, including more hyperactivity [fourth vs. first quartile of exposure β=2.32; 95% confidence interval (CI): 0.18, 4.45], aggression (β=1.90; 95% CI: 0.15, 3.66), attention problems (β=2.78; 95% CI: 0.26, 5.30), and depression (β=2.66; 95% CI: 0.08, 5.24). Associations with youth report of externalizing problems were null, and associations with depression were suggestive (fourth vs. first quartile of exposure β=2.15; 95% CI: -0.36, 4.67). Childhood DAP metabolites were not associated with behavioral problems. We found associations of prenatal, but not childhood, urinary DAP concentrations with adolescent/young adult externalizing and internalizing behavior problems. These findings are consistent with prior associations we have reported with neurodevelopmental outcomes measured earlier in childhood in CHAMACOS participants and suggests that prenatal exposure to OP pesticides may have lasting effects on the behavioral health of youth as they mature into adulthood, including their mental health. https://doi.org/10.1289/EHP11380.


Transparent, Hydrophobic Fluorinated Ethylene Propylene Offers Rapid, Robust, and Irreversible Passive Adsorption of Diagnostic Antibodies for Sensitive Optical Biosensing.
Current literature data is scarce and somehow contradictory in respect to the suitability of "nonstick" fluoropolymer surfaces for immobilization of biomolecules. We have previously shown empirically that transparent Teflon fluorinated ethylene propylene (FEP) offers rapid and sensitive optical biosensing of clinically relevant biomarkers. This study shows for the first time a comprehensive experimental analysis of passive adsorption of diagnostic IgG antibodies on actual Teflon FEP microfluidic strips. Full equilibrium isotherms and kinetics for passive adsorption were studied and modeled employing a protein titration method using hundreds of multibore microfluidic strips for a range of temperatures, pH, ionic strengths, and inner diameters, using both polyclonal and monoclonal antibody systems. Results were benchmarked against other plastic hydrophobic and glass hydrophilic capillary surfaces. For the first time, it was shown quantitatively that the hydrophobicity of fluoropolymer surfaces encourages the passive adsorption of diagnostic antibodies for biosensing and is insensitive to the temperature of incubation and to ionic buffer strength. The mass of captured antigen increased with increasing antibody surface coverage up to ∼400 ng/cm2, with an optimal adsorbed antibody activity for 45-69% of full monolayer coverage, matching results of other biosensing surfaces. The equilibrium was reached fast, within 5-10 min, and surprisingly both the kinetics and equilibrium of antibody adsorption were dependent on the inner diameter of microcapillaries. This is a novel and relevant result that will generally impact on the design of miniaturized microfluidic biosensing devices. The antibody surface densities obtained with hydrophobic plastic surfaces were 2- to 4-fold lower than for a hydrophilic, glass surface, however the former presented a monolayered adsorption with a higher level of irreversibility, as shown by the adsorption and desorption rates around 1 order of magnitude smaller than for glass, which is highly desirable for biosensing with surface-coated biomolecules.


Phase retrieval algorithms: a comparison.
Iterative algorithms for phase retrieval from intensity data are compared to gradient search methods. Both the problem of phase retrieval from two intensity measurements (in electron microscopy or wave front sensing) and the problem of phase retrieval from a single intensity measurement plus a non-negativity constraint (in astronomy) are considered, with emphasis on the latter. It is shown that both the error-reduction algorithm for the problem of a single intensity measurement and the Gerchberg-Saxton algorithm for the problem of two intensity measurements converge. The error-reduction algorithm is also shown to be closely related to the steepest-descent method. Other algorithms, including the input-output algorithm and the conjugate-gradient method, are shown to converge in practice much faster than the error-reduction algorithm. Examples are shown.


Learning auditory discriminations from observation is efficient but less robust than learning from experience.
Social learning enables complex societies. However, it is largely unknown how insights obtained from observation compare with insights gained from trial-and-error, in particular in terms of their robustness. Here, we use aversive reinforcement to train "experimenter" zebra finches to discriminate between auditory stimuli in the presence of an "observer" finch. We show that experimenters are slow to successfully discriminate the stimuli, but immediately generalize their ability to a new set of similar stimuli. By contrast, observers subjected to the same task are able to discriminate the initial stimulus set, but require more time for successful generalization. Drawing on concepts from machine learning, we suggest that observer learning has evolved to rapidly absorb sensory statistics without pressure to minimize neural resources, whereas learning from experience is endowed with a form of regularization that enables robust inference.


Hyperemesis gravidarum: implications for home care and infusion therapies.
Nausea and vomiting afflicts up to 80% of pregnancies, with the more severe form, hyperemesis, complicating about 1%. Hyperemesis in pregnancy causes fluid volume deficit, starvational ketoacidosis, and at times, metabolic alkalosis with hypokalemia. Significant weight loss may occur and reflect fluid as well as lean tissue loss. The cause is unknown, and although prognosis is generally good with aggressive fluid replacement and nutritional support, there is potential for decreased birth weight. Management strategies for hyperemesis gravidarum, including hydration, enteral and parenteral nutrition, antiemetic therapies, monitoring needs, and psychosocial concerns are discussed with applications made to the home care setting.


A Mother in Jeopardy: The Ethics of Pregnancy and Chemotherapy.
JM is a 32-year-old primagravida with polycystic ovary disease. She had extreme difficulty conceiving and was started on clomiphene 6 months ago by her fertility specialist. After doubling the dose on the sixth cycle, she successfully became pregnant. On her second prenatal visit at 12 weeks gestation, an ovarian cyst was detected. Ultrasound showed a complex ovarian mass with nodules on the bowel and abdominal wall. There was mild-to-moderate peritoneal fluid. Cytology showed adenocarcinoma of ovarian origin. Further workup demonstrated advanced stage III epithelial ovarian cancer. JM was referred to GYN-oncology who felt pregnancy-sparing debulking was not an option. The oncologist recommended termination of pregnancy due to the risks of delaying chemotherapy. JM refused, citing her fertility difficulties in the past and her desire to carry the pregnancy to term "even if it kills me." She tells the oncologist she cannot bear the thought of terminating her pregnancy under any circumstances. The oncologist wants to comply with her wishes but feels the patient is making a choice that would result in harm to herself. The oncology team requests an ethics consult.


Foxo3a inhibits cardiomyocyte hypertrophy through transactivating catalase.
The forkhead transcription factor Foxo3a is able to inhibit cardiomyocyte hypertrophy. However, its underlying molecular mechanism remains to be fully understood. Our present study demonstrates that Foxo3a can regulate cardiomyocyte hypertrophy through transactivating catalase. Insulin was able to induce cardiomyocyte hypertrophy with an elevated level of reactive oxygen species (ROS). The antioxidant agents, including catalase and N-acetyl-L-cysteine, could inhibit cardiomyocyte hypertrophy induced by insulin, suggesting that ROS is necessary for insulin to induce hypertrophy. Strikingly, we observed that the levels of catalase were decreased in response to insulin treatment. The transcriptional activity of Foxo3a depends on its phosphorylation status with the nonphosphorylated but not phosphorylated form to be functional. Insulin treatment led to an increase in the phosphorylated levels of Foxo3a. To understand the relationship between Foxo3a and catalase in the hypertrophic pathway, we characterized that catalase was a transcriptional target of Foxo3a. Foxo3a bound to the promoter region of catalase and stimulated its activity. The inhibitory effect of Foxo3a on cardiomyocyte hypertrophy depended on its transcriptional regulation of catalase. Finally, we identified that myocardin was a downstream mediator of ROS in conveying the hypertrophic signal of insulin or insulin-like growth factor-1. Foxo3a could negatively regulate myocardin expression levels through up-regulating catalase and the consequent reduction of ROS levels. Taken together, our results reveal that Foxo3a can inhibit hypertrophy by transcriptionally targeting catalase.


Antibody prophylaxis and therapy against West Nile virus infection in wild-type and immunodeficient mice.
West Nile virus (WNV) is a mosquito-borne Flavivirus that causes encephalitis in a subset of susceptible humans. Current treatment for WNV infections is supportive, and no specific therapy or vaccine is available. In this study, we directly tested the prophylactic and therapeutic efficacy of polyclonal antibodies against WNV. Passive administration of human gamma globulin or mouse serum prior to WNV infection protected congenic wild-type, B-cell-deficient ( micro MT), and T- and B-cell-deficient (RAG1) C57BL/6J mice. Notably, no increased mortality due to immune enhancement was observed. Although immune antibody completely prevented morbidity and mortality in wild-type mice, its effect was not durable in immunocompromised mice: many micro MT and RAG1 mice eventually succumbed to infection. Thus, antibody by itself did not completely eliminate viral reservoirs in host tissues, consistent with an intact cellular immune response being required for viral clearance. In therapeutic postexposure studies, human gamma globulin partially protected against WNV-induced mortality. In micro MT mice, therapy had to be initiated within 2 days of infection to gain a survival benefit, whereas in the wild-type mice, therapy even 5 days after infection reduced mortality. This time point is significant because between days 4 and 5, WNV was detected in the brains of infected mice. Thus, passive transfer of immune antibody improves clinical outcome even after WNV has disseminated into the central nervous system.


An examination of geographic access to outpatient stroke rehabilitation services in Tennessee, a stroke belt state.
While over half of US stroke patients were discharged to home, estimates of geographic access to outpatient stroke rehab facilities are unavailable. The objective of our study was to assess distance and travel time to the nearest outpatient stroke rehab facility in Tennessee, a high stroke prevalence state. We systematically scraped Google Maps with the terms "stroke", "rehabilitation", and "outpatient" to identify Tennessee stroke rehab facilities. We then averaged/aggregated Census block-level travel distance and travel time to determine the mean travel distance/time to a facility for each of the 95 Tennessee counties and the overall state. Comparisons of mean travel time/distance were made between rural and urban counties and between low, medium, and high stroke prevalence counties. We found that 79% of facilities were in urban areas. Significantly higher median of mean travel times and distances (p values both <0.001) were observed in rural (22.0 miles, 31.6 min) versus urban counties (10.5 miles, 18.4 min). High (21.5 miles, 32.5 min) and medium (18.7 miles, 28.3 minutes) stroke prevalence counties, which often overlap with rural counties, had significantly higher median of mean travel times and distance than low stroke prevalence counties (7.3 miles, 14.5 min). Rural Tennessee counties were faced with high stroke prevalence, inadequate facilities, and significantly greater travel distance and time to access care. Additional efforts to address transportation barriers and accelerate telerehabilitation implementation are crucial for improving equal access to stroke aftercare in these areas.


A class of semiparametric tests of treatment effect robust to confounder measurement error.
When assessing the presence of an exposure causal effect on a given outcome, measurement error of a confounder can inflate the type I error rate of a treatment effect in even the simplest of settings. In this paper, we develop a large class of semiparametric test statistics of an exposure causal effect, which are completely robust to additive unbiased measurement error of a subset of confounders. A unique and appealing feature of our proposed methodology is that it requires no external information such as validation data or replicates of error-prone confounders. We present a doubly robust form of this test that requires the exposure mean model to be linear in the mismeasured confounders, and only one of two models involving error-free confounders to be correctly specified for the resulting test statistic to have correct type I error rate. We demonstrate validity within our class of test statistics through simulation studies. We apply the methods to a multi-US-city time-series data set to test for an effect of temperature on mortality while adjusting for atmospheric particulate matter with diameter of 2.5 micrometres or less, which is known to be measured with error.


Acute kidney injury interacts with VKORC1 genotype on initiative warfarin dose among heart surgery recipients: a real-world research.
Patients who receive heart valve surgery need anticoagulation prophylaxis to reduce the risk of thrombosis. Warfarin often is a choice but its dosage varies due to gene and clinical factors. We aim to study, among them, if there is an interaction between acute kidney injury and two gene polymorphisms from this study. We extracted data of heart valve surgery recipients from the electronic health record (EHR) system of a medical center. The primary outcome is about the average daily dose of warfarin, measured as an additive interaction effect (INTadd) between acute kidney injury (AKI) and warfarin-related gene polymorphisms. The confounders, including age, sex, body surface area (BSA), comorbidities (i.e., atrial fibrillation [AF], hypertension [HTN], congestive heart failure [CHF]), serum albumin level, warfarin-relevant gene polymorphism (i.e., CYP2C9, VKORC1), prosthetic valve type (i.e., metal, bio), and warfarin history were controlled via a multivariate-linear regression model. The study included 200 patients, among whom 108 (54.00%) are female. Further, the mean age is 54.45 years, 31 (15.50%) have CHF, and 40 (20.00%) patients were prescribed concomitant amiodarone, which potentially overlays with the warfarin prophylaxis period. During the follow-up, AKI occurred in 30 (15.00%) patients. VKORC1 mutation (1639G>A) occurred in 25 (12.50%) patients and CYPC29 *2 or *3 mutations presented in 20 patients (10.00%). We found a significant additive interaction effect between AKI and VKORC1 (- 1.17, 95% CI - 1.82 to - 0.53, p = 0.0004). This result suggests it is probable that there is an interaction between acute kidney injury and the VKORC1 polymorphism for the warfarin dose during the initial period of anticoagulation prophylaxis.


New approaches to tuberculosis--novel drugs based on drug targets related to toll-like receptors in macrophages.
Tuberculosis (TB) is one of the most important health concerns in the world, causing serious levels of morbidity and mortality, particularly in many developing countries. Unfortunately, the development of new anti-TB drugs with superior chemotherapeutic and prophylactic activity has been very slow. Thus, it is urgently necessary to develop novel kinds of antituberculosis drugs that exert their anti-Mycobacterium tuberculosis (MTB) activity through unique drug targets expressed by MTB organisms. At present, the drug targets of most current anti-TB drugs are primarily bacterial metabolic reactions and cell components that are indispensable to the growth and survival of MTB organisms in extracellular milieus, particularly in culture media. To develop novel and unique anti-TB drugs in the future, it is desirable to highlight the drug targets related to the bacterial ability to survive and replicate in host macrophages by escaping from a macrophage's bacterial killing mechanism during infection inside such phagocytes. For this purpose, it is reasonable to focus our research efforts on mycobacterial virulence factors that cross-talk and interfere with signaling pathways of host macrophages, because such virulence factors will provide intracellular milieus favorable to intramacrophage survival and growth of MTB. In this chapter, based on such a viewpoint and strategy, the present status of worldwide research on novel potential drug targets related to Toll-like receptor in the MTB pathogen will be described.


Alcohol intake and cerebral abnormalities on magnetic resonance imaging in a community-based population of middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) study.
Although the risks associated with heavy drinking for increased stroke and neurodegenerative changes are well established, the effects on the brain of low to moderate alcohol intake are unclear. Subclinical cerebral abnormalities identified on MRI have been associated with neurocognitive decline and incident stroke. We examined the associations of alcohol intake with MRI-defined cerebral abnormalities in a middle-aged, population-based cohort. During 1993-1994, a total of 1909 middle-aged adults (40% men and 49% blacks) from 2 communities in the Atherosclerosis Risk in Communities (ARIC) Study (Forsyth County, North Carolina, and Jackson, Miss) underwent a cerebral MRI examination. Trained neuroradiologists coded the images for the presence of infarction and the extent (10-point scale) of white matter lesions, ventricular size, and sulcal size. In logistic regression analyses, there was no association between alcohol intake and the presence of MRI infarction. In linear regression analyses, alcohol intake was not associated with white matter grade. However, intake of each additional alcoholic drink per week was associated with a 0.01 grade greater ventricular size (P=0.03) and a 0.009 grade greater sulcal size (P=0.02) after adjustment for age, sex, race, body mass index, smoking, income, sports index, and diabetes. The positive associations of alcohol intake with ventricular and sulcal size were consistent across sex and race subgroups. A protective effect of low to moderate alcohol intake on cerebral infarction was not found; moreover, increased alcohol intake was associated with brain atrophy.


Genotyping sleep disorders patients.
The genetic susceptibility factors underlying sleep disorders might help us predict prognoses and responses to treatment. Several candidate polymorphisms for sleep disorders have been proposed, but there has as yet inadequate replication or validation that the candidates may be useful in the clinical setting. To assess the validity of several candidate associations, we obtained saliva deoxyribonucleic acid (DNA) samples and clinical information from 360 consenting research participants who were undergoing clinical polysomnograms. Ten single nucleotide polymorphisms (SNPs) were genotyped. These were thought to be related to depression, circadian sleep disorders, sleep apnea, restless legs syndrome (RLS), excessive sleepiness, or to slow waves in sleep. With multivariate generalized linear models, the association of TEF rs738499 with depressive symptoms was confirmed. Equivocal statistical evidence of association of rs1801260 (the C3111T SNP in the CLOCK gene) with morningness/eveningness and an association of Apolipoprotein E (APOE) rs429358 with the Epworth Sleepiness Scale (ESS) were obtained, but these associations were not strong enough to be of clinical value by themselves. Predicted association of SNPs with sleep apnea, RLS, and slow wave sleep were not confirmed. The SNPs tested would not, by themselves, be of use for clinical genotyping in a sleep clinic.


Transcriptional analysis of the response of Neurospora crassa to phytosphingosine reveals links to mitochondrial function.
Treatment of Neurospora crassa cells with phytosphingosine (PHS) induces programmed cell death (PCD) by an unknown mechanism. To determine the relationship between PHS treatment and PCD, we determined changes in global gene expression levels in N. crassa during a time-course of PHS treatment. Most genes having differential expression levels compared to untreated samples showed an increase in relative expression level upon PHS exposure. However, genes encoding mitochondrial proteins were highly enriched among approximately 100 genes that showed a relative decrease in expression levels after PHS treatment, suggesting that repression of these genes might be related to the death-inducing effects of PHS. Since mutants in respiratory chain complex I are more resistant to both PHS and hydrogen peroxide (H(2)O(2)) than the wild-type strain, possibly related to the production of reactive oxygen species, we also compared gene expression profiles of a complex I mutant (nuo14) and wild-type in response to H(2)O(2). Genes with higher expression levels in the mutant, in the presence of H(2)O(2), are also significantly enriched in genes encoding mitochondrial proteins. These data suggest that complex I mutants cope better with drug-induced decrease in expression of genes encoding mitochondrial proteins and may explain their increased resistance to both PHS and H(2)O(2). As a way of identifying new components required for PHS-induced death, we analysed the PHS sensitivity of 24 strains carrying deletions in genes that showed a significant alteration in expression pattern when the wild-type was exposed to the sphingolipid. Two additional mutants showing increased resistance to PHS were identified and both encode predicted mitochondrial proteins, further supporting the role of the mitochondria in PHS-induced PCD.


Signal characteristics of spontaneous facial expressions: automatic movement in solitary and social smiles.
The assumption that the smile is an evolved facial display suggests that there may be universal features of smiling in addition to the basic facial configuration. We show that smiles include not only a stable configuration of features, but also temporally consistent movement patterns. In spontaneous smiles from two social contexts, duration of lip corner movement during the onset phase was independent of social context and the presence of other facial movements, including dampening. These additional movements produced variation in both peak and offset duration. Both onsets and offsets had dynamic properties similar to automatically controlled movements, with a consistent relation between maximum velocity and amplitude of lip corner movement in smiles from two distinct contexts. Despite the effects of individual and social factors on facial expression timing overall, consistency in onset and offset phases suggests that portions of the smile display are relatively stereotyped and may be automatically produced.


Comparative Effect of Insulin Sensitizers and Statin on Metabolic Profile and Ultrasonographical Score in Non Alcoholic Fatty Liver Disease.
Non Alcoholic Fatty Liver Disease (NAFLD) is a metabolic disorder involving fat accumulation in the liver. The initial management for patients with NAFLD includes lifestyle modification and weight loss in overweight or obese patients. The present study was conducted to compare the efficacy of insulin sensitizers and statin in the patients of NAFLD. The study included 98 patients diagnosed with NAFLD on USG (Ultrasonography) abdomen, divided into three Groups randomly and administered Metformin (Group I), Rosuvastatin (Group II) or Pioglitazone (Group III) along with dietary intervention and lifestyle modification. Their Body Mass Index (BMI), liver function tests, fasting lipid profile, USG scores for fatty liver were done and followed up at 4 weeks, 12 weeks and 24 week for change in above parameters. Out of the three Groups, Group II showed a maximum improvements in usg scores for NAFLD (p<0.001) and fasting lipid profile. Group II also showed maximum derangement of liver enzymes at 24 weeks though none of the subjects had more than three times elevation of liver enzymes. Rosuvastatin may be an effective therapy as add on treatment to dietary and lifestyle intervention in patients of NAFLD. As an add-on treatment Rosuvastatin was superior to Pioglitazone or Metformin and acute decompensation is unlikely with this drug. Metformin was not effective as add on therapy for NAFLD, rather rapid weight loss in short period of time resulted in worsening of hepatic steatosis.


A parallel open-label trial to evaluate microbial cellulose wound dressing in the treatment of diabetic foot ulcers.
The purpose of this study was to compare the rate of wound healing in diabetic foot ulcers (DFU) using either a microbial cellulose (MC) wound dressing or Xeroform™ Petrolatum gauze. In a parallel, open-label trial in which the primary outcome was the rate of wound healing and the time to wound closure, 15 ulcers in type II diabetic patients received an MC dressing. Wounds in 19 control patients with type II diabetes were treated with a Xeroform gauze dressing. All wounds were non infected, Wagner stage II or III and received standard care including debridement, non weight bearing limb support and weekly wound evaluation. The mean time to heal in the MC (±SE) treated group was 32 days ± 2.5 and for controls it was 48 days ± 4.7 (P < 0.01). The rate of weekly wound closure (mean ± SE) was 1.7 times faster in the MC-treated group (cellulose treated, -5.04% per week ± 0.38 versus control, -2.93% per week ± 0.19), (P < 0.001). Among covariants tested by univariate regression, only the original wound area correlated with the time to wound closure (P < 0.001). In conclusion, with the provision of current standards of care, the application of an MC dressing to a diabetic ulcer may enhance the rate of wound healing and shorten the time course of epithelisation.


New Pharmacological Interventions in Bipolar Disorder.
The biological bases of bipolar disorder include aspects related, among others, to neurohormonal pathways, neurotransmission, signal transduction, regulation of gene expression, oxidative stress, neuroplasticity, and changes in the immune system. There is still a gap in understanding its complex neurobiology and, consequently, developing new treatments. Multiple factors probably interact in this complex equation of pathophysiology of bipolar disorder, such as genetic, biochemical, psychosocial, and environmental stress events, correlating with the development and severity of the bipolar disorder. These mechanisms can interact to exacerbate inflammation, impair neurogenesis, and increase oxidative stress damage, cellular mitochondrial dysfunction, changes in neurotrophins and in epigenetic mechanisms, neuroendocrine dysfunction, activation of neuronal death pathways, and dysfunction in neurotransmission systems. In this review, we explore the up-to-date knowledge of the neurobiological underpinnings of bipolar disorders. The difficulty in developing new drugs for bipolar disorder is very much associated with the lack of knowledge about the precise pathophysiology of this disorder. Pharmacological treatment for bipolar patients is vital; to progress to effective medications, it is essential to understand the neurobiology in bipolar patients better and identify novel therapeutic targets.


Significance of DNA content and proliferative rate of the invasive carcinoma found in the mammographically directed breast biopsy.
During the last few years considerable effort has been made to find genetic and biochemical markers that could be used to predict the behavior of cancers with greater accuracy than that obtained by histologic grading or the assessment of other established morphologic features. Because there is considerable evidence that malignant neoplasms have cytogenetic abnormalities, and because atypical features of the nucleus such as pleomorphism and hyperchromasia are known to be prognostically unfavorable findings, quantitative analysis of nuclear DNA was a prime candidate for evaluation. Also, the rate at which malignant tumor cells replicate, and the fraction of tumor cells participating in the proliferative process, are of considerable interest to oncologists for use in assessing patient prognosis and for guiding decisions on the use of various endocrine and cytotoxic agents for adjuvant endocrine and chemotherapy.


A cell kinetic method for the mitotic selection of treated G2 cells.
G2 cells treated with 150 rad X-radiation were isolated from a monolayer culture of exponentially growing Chinese hamster ovary (CHO) cells by a combination of 125Iododeoxyuridine ([125I]UdR)-induced blockade of S-phase cell progression, treatment and mitotic selection (125I-TMS technique). Once the rate at which cells were selected from a small window in mitosis was established (Schneiderman et al., 1972), the cells were exposed to 10 microCi/ml, carrier-free [125I]UdR for 10 min immediately before treatment with 150 rads X-radiation. After X-irradiation the cells located later in the cell cycle than the X-ray-induced division delay transition point (TPx), at or just prior to prophase, progressed without delay and were selected during the next 50 min (Walters & Petersen, 1968; Schneiderman et al., 1972). The G2- and S-phase cells, located prior to the TPx, sustained a transitory delay and resumed progression into mitosis only after recovery from the radiation insult (Terasima & Tolmach, 1963). However, S-phase cells having incorporated [125I]UdR during the pulse label were prevented from entering mitosis (Schneiderman & Hofer, 1980) and only the X-ray-treated G2 cells resumed progression into mitosis and were selected.


Direct bonding applied to space maintenance.
Based on the conditions of this study, the following conclusions were reached: A success rate of 70 percent seems to justify further investigation into direct bonded space maintainers. A space maintainer directly bonded to the buccal surfaces seems to be efficient in maintaining single tooth spaces. Primary-to-primary appliances were more successful than the primary-to-permanent appliances, which suggests that incomplete first permanent molar eruption and a posterior location affect appliance durability.


Chemical probes of Escherichia coli uncovered through chemical-chemical interaction profiling with compounds of known biological activity.
While cell-based screens have considerable power in identifying new chemical probes of biological systems and leads for new drugs, a major challenge to the utility of such compounds is in connecting phenotype with a cellular target. Here, we present a systematic study to elucidate the mechanism of action of uncharacterized inhibitors of the growth of Escherichia coli through careful analyses of interactions with compounds of known biological activity. We studied growth inhibition with a collection of 200 antibacterial compounds when systematically combined with a panel of 14 known antibiotics of diverse mechanism and chemical class. Our work revealed a high frequency of synergistic chemical-chemical interactions where the interaction profiles were unique to the various compound pairs. Thus, the work revealed that chemical-chemical interaction data provides a fingerprint of biological activity and testable hypotheses regarding the mechanism of action of the novel bioactive molecules. In the study reported here, we determined the mode of action of an inhibitor of folate biosynthesis and a DNA gyrase inhibitor. Moreover, we identified eight membrane-active compounds, found to be promiscuously synergistic with known bioactives.


HER 2/neu protein expression in gastric cancer is associated with poor survival.
The presence of HER 2/neu has been reported in gastric cancer, but its impact on patient survival remains unclear. The purpose of this study was to investigate the expression of HER 2/neu in gastric cancer. A total of 218 paired resected gastric cancer and corresponding normal specimens were collected. HER 2/neu protein expression was assessed by immunohistochemical staining. The correlation between HER 2/neu expression and patient clinicopathological parameters was evaluated and the prognostic significance of HER 2/neu expression was assessed by univariate and multivariate analyses. Forty-one out of 218 (18.8%) gastric cancer specimens showed HER 2/neu-positive expression. No relationship was found between membranous HER 2/neu expression and clinicopathological parameters. However, HER 2/neu expression was correlated with poorer overall survival (p<0.001). In multivariate analysis, HER 2/neu expression was a significant independent prognostic predictor of gastric cancer (p<0.001), and was associated with poor survival in gastric cancer patients. These data indicate that HER 2/neu may play a major role in the therapeutic management of gastric cancer.


Acetylcholine inhibits positive inotropic effect of cholera toxin in ventricular muscle.
Acetylcholine (ACh, 10(-6) M) had no effect on basal adenylate cyclase activity (3.4 +/- 0.56 pmol cyclic AMP . min-1 . mg wet wt-1), adenosine 3',5'-cyclic monophosphate (cyclic AMP) content (0.88 +/- 0.09 pmol/mg wet wt), or the force of contraction in paced (2.5 Hz) chick embryo right ventricles superfused with Tyrode solution. After 60-180 min of superfusion in the presence of cholera toxin (5 x 10(-6) g/ml), adenylate cyclase activity (1.7 times), cyclic AMP content (2.4 times), and contractility (2.4 times) had increased significantly above basal levels. ACh reversed the positive inotropic effect of cholera toxin but did not change the increased activity of adenylate cyclase and content of cyclic AMP obtained in cholera toxin. Stimulation of adenylate cyclase by isoproterenol (ISO) was inhibited by ACh in the absence and presence of cholera toxin. ACh did not change guanosine 3',5'-cyclic monophosphate (cyclic GMP) content in the absence or presence of cholera toxin. Cholera toxin has actions on chick embryo ventricle similar to those of the beta-adrenergic agonist, ISO, and the phosphodiesterase inhibitor, isobutylmethylxanthine. The ability of ACh to reverse the positive inotropic effect of cholera toxin without preventing the accumulation of cyclic AMP may involve the prevention or reversal of cyclic AMP-dependent phosphorylation. In this regard, reduction of Ca2+ influx through voltage-sensitive membrane channels may be an essential component of muscarinic inhibition.


Potential use of analogs of luteinizing hormone-releasing hormones in the treatment of hormone-sensitive neoplasms.
New approaches to the therapy for some endocrine-dependent tumors with analogs of hypothalamic hormones are being developed on the basis of experimental studies in animal models. Analogs of luteinizing hormone-releasing hormones (LH-RH) may open new vistas for the treatment of some hormone-dependent carcinomas. It has been clearly demonstrated that both agonistic and antagonistic analogs of LH-RH can inhibit the growth of rat prostate tumors. A successful treatment of androgen-dependent prostate cancer with agonistic analogs of D-Trp6-LH-RH, D-Ser(But)6des-Gly-NH2(10)-LH-RH ethylamide, and D-Leu6-des-Gly-NH2(10)-LH-RH ethylamide has been documented in several hundred patients. The data accumulated so far from clinical trials suggest that LH-RH agonists can be used as an effective endocrine therapy for prostate carcinoma, therapy avoiding the side effects of estrogen and the psychologic impact of castration. Experimental animal studies and some clinical trials suggest that LH-RH agonists and/or antagonists might also be useful in the treatment of breast cancer. The results of experiments with various hypothalamic analogs in animal models of chondrosarcomas, osteosarcomas, and other tumors appear to be encouraging, but the potential clinical efficacy of LH-RH analogs in the treatment of human hormone-sensitive cancers other than breast and prostate remains to be investigated. The approach to treatment of hormone-dependent tumors based on analogs of hypothalamic hormones might become a useful addition to conventional methods for cancer therapy.


Development of polarizable models for molecular mechanical calculations II: induced dipole models significantly improve accuracy of intermolecular interaction energies.
In the companion paper, we presented a set of induced dipole interaction models using four types of screening functions, which include the Applequist (no screening), the Thole linear, the Thole exponential model, and the Thole Tinker-like (another form of exponential screening function) functions. In this work, we evaluate the performance of polarizability models using a large set of amino acid analog pairs in conformations that are frequently observed in protein structures as a benchmark. For each amino acid pair, we calculated quantum mechanical interaction energies at the MP2/aug-cc-pVTZ//MP2/6-311++G(d,p) level with the basis set superposition error (BSSE) correction and compared them with molecular mechanics results. Encouragingly, all polarizable models significantly outperform the additive F94 and F03 models (mimicking AMBER ff94/ff99 and ff03 force fields, respectively) in reproducing the BSSE-corrected quantum mechanical interaction energies. In particular, the root-mean-square errors (RMSEs) for three Thole models in Set A (where the 1-2 and 1-3 interactions are turned off and all 1-4 interactions are included) are 1.456, 1.417, and 1.406 kcal/mol for model AL (Thole Linear), model AE (Thole exponential), and model AT (Thole Tinker-like), respectively. In contrast, the RMSEs are 3.729 and 3.433 kcal/mol for F94 and F03 models, respectively. A similar trend was observed for the average unsigned errors (AUEs), which are 1.057, 1.025, 1.011, 2.219, and 2.070 kcal/mol for AL, AE, AT, F94/ff99, and F03, respectively. Analyses based on the trend line slopes indicate that the two fixed charge models substantially underestimate the relative strengths of noncharge-charge interactions by 24 (F03) and 35% (F94), respectively, whereas the four polarizable models overestimate the relative strengths by 5 (AT), 3 (AL, AE), and 13% (AA), respectively. Agreement was further improved by adjusting the van der Waals parameters. Judging from the notably improved accuracy in comparison with the fixed charge models, the polarizable models are expected to form the foundation for the development of high quality polarizable force fields for protein and nucleic acid simulations.


Economic evaluation of a farm-to-Special Supplemental Nutrition Programme for Women, Infants and Children intervention promoting vegetable consumption.
To evaluate the cost and cost-effectiveness of a farm-to-Special Supplemental Nutrition Programme for Women, Infants and Children (WIC) intervention to promote vegetable intake and the redemption of WIC vouchers for produce purchases at farmers' markets. An economic analysis was undertaken using data from a pilot of the intervention. Vegetable intake was assessed with a reflection spectroscopy device (the Veggie Meter® [VM]) and via self-report. Voucher redemption was reported by WIC. Total and per participant intervention costs and cost-effectiveness ratios (expressed as cost per intervention effect) were estimated in 2019 US dollars over a 6-month period from the perspective of the agency implementing the intervention. A large, urban WIC agency. Participants were 297 WIC-enrolled adults. Post-intervention, VM scores, self-reported vegetable intake and voucher redemption were higher in the intervention as compared with the control study group. Over the 6-month period, intervention costs were $31 092 ($194 unit cost per participant). Relative to the control group, the intervention cost $8·10 per increased VM score per participant, $3·85 per increased cup/d of vegetables consumed per participant and $3·29 per increased percentage point in voucher redemption per participant. Intervention costs and cost-effectiveness ratios compared favourably with those reported for other interventions targeting vegetable intake in low-income groups, suggesting that the programme may be cost effective in promoting vegetable purchases and consumption. As there is no benchmark against which to compare cost-effectiveness ratios expressed as cost per unit of effectiveness, conclusions regarding whether this is the case must await further research.


Major histocompatibility complex and microsatellite variation in two populations of wild gorillas.
In comparison to their close relatives the chimpanzees and humans, very little is known concerning the amount and structure of genetic variation in gorillas. Two species of gorillas are recognized and while the western gorillas number in the tens of thousands, only several hundred representatives of the mountain gorilla subspecies of eastern gorillas survive. To analyse the possible effects of these different population sizes, this study compares the variation observed at microsatellite and major histocompatibility complex (MHC) loci in samples of wild western and mountain gorillas, collected using a sampling scheme that targeted multiple social groups within defined geographical areas. Noninvasive samples proved a viable source of DNA for sequence analysis of the second exon of the DRB loci of the MHC. Observed levels of variation at the MHC locus were similar between the two gorilla species and were comparable to those in other primates. Comparison of results from analysis of variation at multiple microsatellite loci found only a slight reduction in heterozygosity for the mountain gorillas despite the relatively smaller population size.


Effects of butyrate supplementation in antibiotic-free milk replacer and starter on growth performance in suckling calves.
The aim of this study was to evaluate butyrate supplementation of antibiotic-free milk replacer and starter on growth performance in male Holstein calves. Twenty-nine calves were divided into two groups. Group C (n = 13) was fed antibiotic-free milk replacer without supplementation, and Group B (n = 16) was fed antibiotic-free milk replacer supplemented with butyrate (1.6 % DM of Gustor BP70® ). Starter in Group B contained 0.3 % DM of Gustor BP70® . The intake of milk replacer was lower in group B than in C (p = 0.07 for the treatment x week interaction). Body weight (BW) and heart girth (HG) in group B was higher than in C during the experimental period (p = 0.07 and 0.01 for the treatment × week interaction, respectively). The duration of the weaning period in group B was shorter than in group C (p = 0.02). β-hydroxybutyrate (BHBA) was higher in group B than in C (p = 0.04). Insulin like growth factor-1 (IGF-1) concentrations tended to be higher in group B than in C (p = 0.07 for treatment × week interaction). Our results show that butyrate supplementation in antibiotic-free milk replacer and starter exerted positive effects on growth performance in suckling calves.


Arsenic compounds induce apoptosis by activating the MAPK and caspase pathways in FaDu oral squamous carcinoma cells.
For a number of years, oral cancer has remained in the top ten most common types of cancer, with an incidence rate that is steadily increasing. In total, ~75% oral cancer cases are associated with lifestyle factors, including uncontrolled alcohol consumption, betel and tobacco chewing, and the excessive use of tobacco. Notably, betel chewing is highly associated with oral cancer in Southeast Asia. Arsenic is a key environmental toxicant; however, arsenic trioxide has been used as a medicine for the treatment of acute promyelocytic leukemia, highlighting its anticancer properties. The present study aimed to investigate the role of arsenic compounds in the treatment of cancer, using FaDu oral squamous carcinoma cells treated with sodium arsenite (NaAsO2) and dimethyl arsenic acid (DMA). The results demonstrated that FaDu cells exhibited membrane blebbing phenomena and high levels of apoptosis following treatment with 10 µM NaAsO2 and 1 mM DMA for 24 h. The results of cell viability assay demonstrated that the rate of FaDu cell survival was markedly reduced as the concentration of arsenic compounds increased from 10 to 100 µM NaAsO2, and 1 to 100 mM DMA. Moreover, flow cytometry was carried out to further examine the effects of arsenic compounds on FaDu cell cycle regulation; the results revealed that treatment with NaAsO2 and DMA led to a significant increase in the percentage of FaDu cells in the sub‑G1 and G2/M phases of the cell cycle. An Annexin V/PI double staining assay was subsequently performed to verify the levels of FaDu cell apoptosis following treatment with arsenic compounds. Furthermore, the results of the western blot analyses revealed that the expression levels of caspase‑8, ‑9 and ‑3, and poly ADP‑ribose polymerase, as well the levels of phosphorylated JNK and ERK1/2 were increased following treatment with NaAsO2 and DMA in the FaDu cells. On the whole, the results of the present study revealed that treatment with NaAsO2 and DMA promoted the apoptosis of FaDu oral cancer cells, by activating MAPK pathways, as well as the extrinsic and intrinsic apoptotic pathways.


The effect of educational intervention on decreasing mothers' expressed breast milk bacterial contamination whose infants are admitted to neonatal intensive care unit.
Various reasons accounted for the infection of infants kept at Neonatal Intensive Care Unit (NICU). Expressed breast milk may be regarded as a source of infection in infants. This study investigated the source of bacterial contamination and the impact of educational interventions on the contamination of mothers' expressed breast milk (EBM) level whose infants are hospitalized at NICU. Fifteen mothers used to express breast milking their infants admitted at NICU, involved in this study was conducted during October 2011-March 2012. Samples taken from hands, breast, pumps, breast milk, and milk storage containers and therefore 244 samples were prepared by sterile cotton swab and cultured on Blood Agar and EBM. After presenting enough training to mothers, cultures of the same positions were carried out again. Only those samples proved infected that number of their bacterial colonies exceeded 104 cfu / ml or even there was a growth of pathogenic organism. Before intervention 80% of mothers had infected by at least one sample that reduced to 36% after the intervention. Before intervention 25.4% of samples were contaminated; however after intervention, it reduced to 8.2%. The main source of contamination was milk containers and pumps; moreover, Pseudomonas, E-coli, and Klebsiella were among the most common bacteria of samples' contamination. The possibility of EBM contamination was relatively high but educational interventions might reduce the risk of prevalence.


Right ventricular function in human sepsis: a thermodilution study.
To assess the relations among right ventricular (RV) pressures and volumes in sepsis. Prospective study. ICU. Eighteen patients with sepsis who were in hemodynamically stable condition. Stepwise increases and decreases in RV end-diastolic volume (EDV) as induced by military antishock trousers (MAST) inflation of 0, 15, 30, 50 and then 0 mm Hg over 15-min intervals. RV volumes and pressures were measured using a rapid response thermistor pulmonary arterial catheter based on RV ejection fraction (RVEF) calculations. RV EDV was estimated as stroke volume (SV)/RVEF, while RV end-systolic volume (ESV) was estimated as EDV-SV. Right atrial pressure (Pra) was taken as end-diastolic pressure, and pulmonary artery pressures (Ppa), both mean and end-systolic, were used as RV ejection pressures. MAST inflation to 15 mm Hg had no measurable effects on the measured variables. However, inflation to 30 and 50 mm Hg increased Pra, both mean and end-systolic Ppa, EDV, and ESV, whereas SV and RVEF remained unchanged. The relation between either Pra and EDV (r=0.33) or the change in Pra and EDV, mean or end-systolic Ppa and ESV (r=0.5 and 0.28, respectively), or the change in mean or end-systolic Ppa and ESV for both the group and individual subjects was poor. Furthermore, SV correlated poorly with EDV (r=0.32), while RVEF correlated better with both EDV and ESV (r=-0.41 and -0.69, respectively), although it showed no definable relation to mean or end-systolic Ppa. However, both absolute and relative changes in EDV corresponded closely with respective ESV values (r=0.93). During sepsis, RV EDV and ESV vary independently of changes in Pra and ejection pressure. These data can be explained by assuming that the RV is a highly compliant chamber during filling, such that changes in RV EDV do not alter RV wall stress (preload) or ejection efficiency (RVEF). Thus, changes in RV EDV should proportionally alter RV ESV. Furthermore, the slope of the ESV/EDV relation should be inversely proportional to ejection efficiency.


The accuracy of tuberculin skin tests: self-assessment by adult outpatients.
Tuberculin skin testing is an accurate, inexpensive screening procedure for detecting tuberculosis infection. The return visit needed to interpret the reaction is inconvenient, costly, and may contribute to under-utilization of the test. Although some clinicians ask patients to read their own purified protein derivative (PPD) test results, patient accuracy and the degree of teaching needed to learn this skill are unclear. This study evaluated the accuracy with which 145 outpatients read their own Mantoux skin test (PPD) reactions and reported by postcard after brief training by nurse practitioners. A total of 89 instructed patients returned postcards and also returned for clinician readings; 46 submitted postcards without returning; 7 returned but did not complete postcards; and 3 neither returned postcards nor returned for readings. Ten of 135 postcards were uninterpretable. For 81 subjects with both interpretable tuberculin self-assessment postcards and clinician readings, overall PPD classification agreement was 88 percent; Kappaw = +0.905 (P less than .001). Compared to clinician readings, 1 of 53 patients falsely reported a positive reaction (greater than or equal to 10 mm) and 2 of 25 patients falsely reported negative PPD readings (0-4 mm). There was 100 percent agreement between postcard readings and clinician classifications in a subgroup of patients (N = 26), prospectively identified by nurse practitioners as capable of accurate tuberculin self-assessment. Inter-clinician reading agreement (N = 37) was 89 percent; Kappaw = +0.943 (P less than .001). The brief standardized teaching protocol described can enable most patients to measure and report their PPD results. Study results suggest thatpostcard reports, especially negative ones, from a subgroup of patients selected for their skill in measuring their initial PPD wheal and ability to paraphrase instructions, might be substituted for clinician readings.


Loss of Doc2-Dependent Spontaneous Neurotransmission Augments Glutamatergic Synaptic Strength.
Action potential-evoked vesicle fusion comprises the majority of neurotransmission within chemical synapses, but action potential-independent spontaneous neurotransmission also contributes to the collection of signals sent to the postsynaptic cell. Previous work has implicated spontaneous neurotransmission in homeostatic synaptic scaling, but few studies have selectively manipulated spontaneous neurotransmission without substantial changes in evoked neurotransmission to study this function in detail. Here we used a quadruple knockdown strategy to reduce levels of proteins within the soluble calcium-binding double C2 domain (Doc2)-like protein family to selectively reduce spontaneous neurotransmission in cultured mouse and rat neurons. Activity-evoked responses appear normal while both excitatory and inhibitory spontaneous events exhibit reduced frequency. Excitatory miniature postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs), increase in amplitude after quadruple knockdown. This increase in synaptic efficacy correlates with reduced phosphorylation levels of eukaryotic elongation factor 2 and also requires the presence of elongation factor 2 kinase. Together, these data suggest that spontaneous neurotransmission independently contributes to the regulation of synaptic efficacy, and action potential-evoked and spontaneous neurotransmission can be segregated at least partially on a molecular level.SIGNIFICANCE STATEMENT Action potential-evoked and spontaneous neurotransmission have been observed in nervous system circuits as long as methods have existed to measure them. Despite being well studied, controversy still remains about whether these forms of neurotransmission are regulated independently on a molecular level or whether they are simply a continuum of neurotransmission modes. In this study, members of the Doc2 family of presynaptic proteins were eliminated, which caused a reduction in spontaneous neurotransmission, whereas action potential-evoked neurotransmission remained relatively normal. This protein loss also caused an increase in synaptic strength, suggesting that spontaneous neurotransmission is able to communicate independently with the postsynaptic neuron and trigger downstream signaling cascades that regulate the synaptic state.


[Landau-Kleffner syndrome].
In 1957, Landau and Kleffner reported six cases of a "syndrome of acquired aphasia with convulsive disorder". Since this first report more than 130 cases with acquired language disabilities with EEG-abnormalities have been described. Comprehension of language is primarily affected, spike discharges are predominantly found in temporal regions. Facultative symptoms are epileptic seizures and psychiatric disorders. The paper gives a review of the literature describing the clinical manifestations, the therapeutic procedure, the prognosis and the etiological factors of this syndrome, which is even listed in the last version of the ICD-10 and the International Classification of Epilepsies and Epileptic Syndromes.