Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice.
Genetic risk factors acting during pregnancy or early after birth have been proposed to account for the exponential increase of autism diagnoses in the past 20 years. In particular, a potential link with exposure to environmental mercury has been suggested. Male sex constitutes a second risk factor for autism. A third potential genetic risk factor is decreased Reelin expression. Male heterozygous reeler (rl(+/-)) mice show an autism-like phenotype, including Purkinje cells (PCs) loss and behavioral rigidity. We evaluated the complex interactions between 3 risk factors, i.e. genetic status, sex, and exposure to methylmercury (MeHg), in rl(+/-) mice. Mice were exposed to MeHg during the prenatal and early postnatal period, either at a subtoxic dose (2 ppm in Dams' drinking water), or at a toxic dose (6 ppm Dams' drinking water), based on observations in other rodent species and mice strains. We show that: (a) 2 ppm MeHg does not cause PCs loss in the different animal groups, and does not enhance PCs loss in rl(+/-) males; consistent with a lack of overt neurotoxicity, 2 ppm MeHg per se does not cause behavioral alterations (separation-induced ultrasonic calls in newborns, or sociability and social preference in adults); (b) in stark contrast, 6 ppm MeHg causes a dramatic reduction of PCs number in all groups, irrespective of genotype and sex. Cytochrome C release from mitochondria of PCs is enhanced in 6 ppm MeHg-exposed groups, with a concomitant increase of μ-calpain active subunit. At the behavioral level, 6 ppm MeHg exposure strongly increases ultrasonic vocalizations in all animal groups. Notably, 6 ppm MeHg significantly decreases sociability in rl(+/-) male mice, while the 2 ppm group does not show such as decrease. At a subtoxic dose, MeHg does not enhance the autism-like phenotype of male rl(+/-) mice. At the higher MeHg dose, the scenario is more complex, with some "autism-like" features (loss of sociability, preference for sameness) being evidently affected only in rl(+/-) males, while other neuropathological and behavioral parameters being altered in all groups, independently from genotype and sex. Mitochondrial abnormalities appear to play a crucial role in the observed effects.


Effect of 17 days of bed rest on peak isometric force and unloaded shortening velocity of human soleus fibers.
The purpose of this study was to examine the effect of prolonged bed rest (BR) on the peak isometric force (P0) and unloaded shortening velocity (V0) of single Ca(2+)-activated muscle fibers. Soleus muscle biopsies were obtained from eight adult males before and after 17 days of 6 degrees head-down BR. Chemically permeabilized single fiber segments were mounted between a force transducer and position motor, activated with saturating levels of Ca2+, and subjected to slack length steps. V0 was determined by plotting the time for force redevelopment vs. the slack step distance. Gel electrophoresis revealed that 96% of the pre- and 87% of the post-BR fibers studied expressed only the slow type I myosin heavy chain isoform. Fibers with diameter > 100 microns made up only 14% of this post-BR type I population compared with 33% of the pre-BR type I population. Consequently, the post-BR type I fibers (n = 147) were, on average, 5% smaller in diameter than the pre-BR type I fibers (n = 218) and produced 13% less absolute P0. BR had no overall effect on P0 per fiber cross-sectional area (P0/CSA), even though half of the subjects displayed a decline of 9-12% in P0/CSA after BR. Type I fiber V0 increased by an average of 34% with BR. Although the ratio of myosin light chain 3 to myosin light chain 2 also rose with BR, there was no correlation between this ratio and V0 for either the pre- or post-BR fibers. In separate fibers obtained from the original biopsies, quantitative electron microscopy revealed a 20-24% decrease in thin filament density, with no change in thick filament density. These results raise the possibility that alterations in the geometric relationships between thin and thick filaments may be at least partially responsible for the elevated V0 of the post-BR type I fibers.


Contrast-enhanced fluorodeoxyglucose positron emission tomography/computed tomography in solid pseudopapillary neoplasm of the pancreas.
Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare pancreatic tumor with low malignant potential. It occurs characteristically more often in young women. Radiological and pathological studies have revealed that the tumor is quite different from other pancreatic tumors. Limited information is available in the literature reporting their accumulation of fluorine-(18) fluorodeoxyglucose ((18)F-FDG) in positron emission tomography/computed tomography (PET/CT). Here, we report a case of pancreatic SPN imaged with contrast-enhanced FDG PET/CT. A percutaneous fine needle aspiration from the metabolically active lesion revealed SPN, and it was confirmed with histopathological results. Recurrence or metastasis was not found after 7 months of follow-up.


Congenital bladder diverticulum presenting as bladder outlet obstruction in infants and children.
Congenital primary bladder diverticulum is a rare cause of infra-vesical obstruction. We present a series of 12 cases who presented with urinary retention secondary to a large primary bladder diverticulum. The aim is to high light the diagnostic difficulties and management issues of congenital bladder diverticulae. We reviewed the case sheets of 12 patients with congenital bladder diverticulae who presented as lower tract obstruction with or without infection at a tertiary care centre in the last 10 years. All patients had urine examinations (complete microscopic with culture), serum creatinine, ultrasonography, intravenous urogram, voiding cystourethrogram with or without cystoscopy. The cases were managed by extravesical mobilization of diverticulae, diverticulectomy, and ureteric re-implantation. All patients (aged 1-36 months, mean 16.8 months) presented with retention of urine but 4 of them had symptoms of fever, tachycardia, abdominal distension and vomiting. Serum creatinine was normal in 10 out of 12 cases, but was high in two. Urine cultures grew Escherichia coli in 5 cases. Ultrasonography showed moderate to severe hydronephrosis on the left side in 5 cases, on the right side in 4 cases and bilateral in 3 cases but diverticulae could be located in only 8 cases. Intravenous urogram revealed hydrouretero-nephrosis in 9 cases, a poor functioning kidney with hydrouretero-nephrosis in 3 cases and bilateral hydrouretero-nephrosis in 3 cases. A Voiding Cystourethrogram confirmed the diagnosis in all cases. Vesicoureteric reflux (Grade 4-5) into the ipsilateral ureter was seen in 9 children of which it was bilateral in three cases. All children underwent extravesical diverticulectomy with re-implantation of the ipsilateral ureter in 9 cases, bilateral in 3 cases. All had an uneventful recovery except for one who had a suprapubic leak which healed on conservative treatment. Postoperative ultrasonograms showed mild hydronephrosis in 2 cases and micturating cystourethrograms revealed a grade III V-U reflux in one case which was managed conservatively. Patients are maintaining a sterile urine culture after a follow up of 6-36 months. Primary bladder diverticulum should be kept as a differential diagnosis in cases of bladder outlet obstruction in infants and children. A carefully done voiding cystourethrogram is the hallmark of diagnosis. Good results can be achieved by diverticulectomy and primary definitive repair with ureteric re-implantation even in infants.


Renal artery stent in solitary functioning kidneys: 77% of benefit: A systematic review with meta-analysis.
Solitary functioning kidney (SFK) is tough issue to address in clinical, mostly developed from renal artery stenosis (RAS) in adults. Although renal artery stent is widely used to help SFK patients, the efficacy of the stent is still disputable. This study is aimed at reviewing a series of SFK cases to draw a conclusion about the efficacy of renal artery stent. All related papers published in PubMed, Web of Science, EMBASE, and Cochrane Library were searched. Studies or subsets were included only if they satisfied certain criteria. The benefit rate which equaled the rate of improvement subjoining the rate of stabilization was calculated. All analyses were conducted with Stata version 12.0 (Stata Corporation, College Station, TX). According to 7 papers on the efficacy of renal artery stent, 253 SFK patients were included. The result revealed that the renal artery stent could help SFK patients to improve or stabilize their renal function (RF). The benefit rate was 0.77, with 95% confidence interval between 0.72 and 0.83. With proper patient selection, renal artery stent could benefit SFK patients with a percentage odd of 0.77 to improve or stabilize the RF.


Enrichment of circulating head and neck tumour cells using spiral microfluidic technology.
Whilst locoregional control of head and neck cancers (HNCs) has improved over the last four decades, long-term survival has remained largely unchanged. A possible reason for this is that the rate of distant metastasis has not changed. Such disseminated disease is reflected in measurable levels of cancer cells in the blood of HNC patients, referred to as circulating tumour cells (CTCs). Numerous marker-independent techniques have been developed for CTC isolation and detection. Recently, microfluidics-based platforms have come to the fore to avoid molecular bias. In this pilot, proof of concept study, we evaluated the use of the spiral microfluidic chip for CTC enrichment and subsequent detection in HNC patients. CTCs were detected in 13/24 (54%) HNC patients, representing both early to late stages of disease. Importantly, in 7/13 CTC-positive patients, CTC clusters were observed. This is the first study to use spiral microfluidics technology for CTC enrichment in HNC.


An evaluation of graduated driver licensing effects on fatal crash involvements of young drivers in the United States.
Graduated driver licensing (GDL) systems are designed to reduce the high crash risk of young novice drivers. Almost all states in the United States have some form of a 3-phase GDL system with various restrictions in the intermediate phase. Studies of the effects of GDL in various states show significant reductions in fatal crash involvements of 16- and 17-year-old drivers; however, only a few national studies of GDL effects have been published. The objective of this national panel study was to evaluate the effect of GDL laws on the fatal crash involvements of novice drivers while controlling for possible confounding factors not accounted for in prior studies. The Fatality Analysis Reporting System (FARS) was used to examine 16- and 17-year-old driver involvement in fatal crashes (where GDL laws are applied) relative to 2 young driver age groups (19-20, 21-25) where GDL would not be expected to have an effect. Dates when various GDL laws were adopted in the states between 1990 and 2007 were coded from a variety of sources. Covariates in the longitudinal panel regression analyses conducted included 4 laws that could have an effect on 16- and 17-year-old drivers: primary enforcement seat belt laws, zero-tolerance (ZT) alcohol laws for drivers younger than age 21, lowering the blood alcohol concentration limit for driving to 0.08, and so-called use and lose laws where drivers aged 20 and younger lose their licenses for underage drinking violations. The adoption of a GDL law of average strength was associated with a significant decrease in fatal crash involvements of 16- and 17-year-old drivers relative to fatal crash involvements of one of the 2 comparison groups. GDL laws rated as "good" showed stronger relationships to fatal crash reductions, and laws rated as "less than good" showed no reductions in crash involvements relative to the older driver comparison groups. States that adopt a basic GDL law can expect a decrease of 8 to 14 percent in the proportion of 16- and 17-year-old drivers involved in fatal crashes (relative to 21- to 25-year-old drivers), depending upon their other existing laws that affect novice drivers, such as those used in these analyses. This finding is consistent with recent national studies that used different outcome measures and covariates. The results of this study provide additional support for states to adopt, maintain, and upgrade GDL systems to reduce youthful traffic crash fatalities.


Supernumerary Teeth and Dental Development.
The aims of this study were to compare the radiographic development of permanent teeth in a group of children with and without supernumerary teeth (ST), determine whether using cone-beam computed tomography or panoramic radiography improves the accuracy of dental age (DA) estimation and investigate the effects of factors including the numbers and positions of ST. One hundred fifty dental radiographs of children with and without ST at the ages of 6.0 to 14.9 years were included in this study. The children in both groups were age and sex-matched. The lower left-side 7 permanent teeth were evaluated according to the Demirjian method, DA was determined. The difference between chronological age (CA) and DA (CA-DA) for the children with and without ST and further based on the number and localization of ST were calculated. For all groups, the mean DA values were higher than the mean CA values. The difference between the CA and DA values in the children with ST was higher than the difference in the children without ST. Supernumerary teeth in posterior localization, multiple ST and among boys were observed to increase the differences between the mean CA and DA values. The mean age difference between radiographies in the children with and without ST was similar. Panoramic radiography was found adequate in determination of dental development with the Demirjian method. Dental development was even more advanced in the children with ST in comparison to the control group. Clinicians should keep in mind that the dental developments of children with supernumerary teeth may be advanced.


Mitogen-activated protein kinase activation is not sufficient for stimulation of glucose transport or glycogen synthase in 3T3-L1 adipocytes.
The role of mitogen-activated protein (MAP) kinase in the regulation of glucose metabolism has been investigated by comparing the effects of insulin and epidermal growth factor (EGF) on MAP kinase activation, glucose transport, and glycogen synthase in 3T3-L1 adipocytes. Insulin or EGF treatment for 5 min increased p42mapk and p44mapk activity to the same extent as determined by myelin basic protein kinase activity measurements and phosphotyrosine immunoblotting. The profiles of myelin basic protein kinase activity following MonoQ chromatography of extracts obtained from cells incubated with insulin or EGF were almost identical. Insulin increased glucose transport and GLUT4 translocation to the cell surface by 15- and 7-fold, respectively. EGF had no significant effect on these processes. Insulin increased the glycogen synthase ratio (-Glc-6-P/+Glc-6-P) by 7.5- and 3.5-fold in the presence and absence of glucose, respectively. EGF increased the ratios by only 2- and 1.3-fold, respectively. EGF did not appear to inhibit downstream of MAP kinase, because when adipocytes were incubated with insulin plus EGF, the stimulation of glucose transport and glycogen synthase was similar to that observed with insulin alone. These findings indicate that activation of the MAP kinase isoforms p42mapk and p44mapk is not sufficient for the activation of glucose transport and glycogen synthase in 3T3-L1 adipocytes.


Metagenomics and recovery of enzyme genes from alkaline saline environments.
Enzymes functioning at alkaline pH are widely used in the detergent industry as additives to improve the stain removal properties of domestic and industrial cleaning products. This industry provides by far the major mass market for enzymes. With constantly changing formulations in detergents and concerns over energy demands, new and improved enzymes are constantly in demand. Soda lakes host dense populations of alkali-loving microbes and, as such, provide vast reservoirs of potentially useful enzymes for such an industry. Traditional recovery methods for new enzymes have involved the isolation of microbes, preferably from a compatible chemical environment such as a soda lake, followed by screening of the isolates for useful enzymic activity. At least two commercially significant enzymes originating from soda lake microbes have been marketed following this route. However, the failure to cultivate more than a small percentage of microbes from most environments necessarily markedly reduces the recovery of new enzymes. In recent years, interest has focussed on more comprehensive recovery methods based around detecting appropriate enzyme genes in nucleic acids extracted from potentially useful sites, thus maximizing coverage of the whole genetic resource in a particular biotope. Here we review progress to date in soda lake biotopes and discuss ways the field may develop in the future.


Influence of the salmon mutant of Glossina morsitans morsitans on the susceptibility to infection with Trypanosoma congolense.
Four phenotypes of a sex-linked, maternally influenced semi-lethal eye color mutant of Glossina morsitans morsitans Westwood were fed on Trypanosoma congolense Broden infected guinea pigs. Infection rates were evaluated 25 days later by means of dissection. Procyclic as well as mature infections were significantly more common among females with salmon-colored eyes (sal/sal) than among heterozygous (+/sal, phenotypically wild-type) females. A tendency was found for more mature infections among sal/Y males than among wild-type males. Similarly, females tended to be more infected than males with both procyclic and mature infections. These results indicate that the genotype of the fly, exemplified by the allele salmon, might influence the development of T. congolense in G.m. morsitans. A possible explanation for this phenomenon is discussed.


Effect of progesterone pretreatment on cadmium toxicity in the male Fischer (F344/NCr) rat.
A previous report has indicated that progesterone pretreatment can markedly reduce cadmium toxicity in male NAW mice. Therefore we examined the effects of progesterone pretreatment on cadmium toxicity in male Fischer (F344/NCr) rats. A single sc injection of 20 mumol CdCl2/kg proved nonlethal over 24 hr but caused the typical spectrum of testicular lesions in these rats. However, when rats were pretreated with progesterone (100 mg/kg, sc, -48, -24, and 0 hr) and then given cadmium (20 mumol CdCl2/kg, 0 hr), this dose of cadmium proved very toxic, unexpectedly causing a 53% mortality. Progesterone pretreatment had no effect on cadmium-induced testicular lesions in surviving rats. Significant elevations in serum lactate dehydrogenase (LDH) activity, indicative of hepatotoxicity, were also observed in progesterone-pretreated rats given cadmium as compared to rats given cadmium alone. Progesterone pretreatment had no effect on the distribution of cadmium to liver, kidney, or testes. Progesterone pretreatment also had no effect on the cadmium-induced increases in hepatic or renal metallothionein (MT) or hepatic or testicular MT mRNA levels. In contrast, levels of the testicular cadmium-binding protein (TCBP) in progesterone-pretreated rats were doubled. These results indicate that, contrary to previously reported data for the mouse, progesterone pretreatment increased the lethality of cadmium in male Fischer (F344/NCr) rats and had no effect on cadmium-induced testicular toxicity. The mechanism by which progesterone enhanced cadmium toxicity, especially cadmium-induced hepatotoxicity, deserves further study.


Inhibition of Bacillus subtilis scoC expression by multicopy senS.
The Bacillus subtilis aprE gene, which encodes the extracellular alkaline protease, is regulated by many positive and negative transcriptional regulators. SenS is one such positive regulator consisting of 65 amino acids. We found that the senS gene on a multicopy plasmid, pSEN24, caused an increase in aprE expression in strains carrying the upstream region of aprE up to -340 with respect to the transcription initiation site but not in a strain carrying the region up to -299, which is within the binding site of the negative regulator ScoC (Hpr). Epistatic analysis showed that the pSEN24 effect was lost in a scoC-deleted mutant. In accordance with these results, the scoC transcription level as assayed by a scoC-lacZ fusion and Northern analysis was greatly reduced in the cells carrying pSEN24. From these results we conclude that multicopy senS enhances aprE expression by suppressing the transcription of scoC.


The University of Florida Department of Surgery: building a stronger tomorrow on yesterday's foundation.
Established in 1957, the University of Florida Department of Surgery has a solid foundation on which current faculty are driven to build a stronger tomorrow. The department is focused on promoting patient-centered care, expanding its research portfolio to improve techniques and outcomes, and training the surgical leaders of tomorrow. It fosters an environment where faculty, residents, students, and staff challenge long-held traditions with the goal of improving the health of our patients, the quality of our care, and the vitality of our work environment.


[Retroperitoneal fibrosis].
A 53-year-old man without previous significant illness developed severe backache. Neither physiotherapy nor nonsteroidal anti-inflammatory drugs improved his condition so that he had been regularly taking pain-killing medication. 6 months later elevated retention values were detected and the patient was admitted to hospital. On admission the erythrocyte sedimentation rate (ESR) was markedly elevated in the presence of a normocytic anaemia, serum creatinine concentration of 3.71 mg/dl (blood urea of 112 mg/dl) and haematuria. Sonography demonstrated bilateral hydronephrosis, stage III, and a weekly echogenic para-aortic mass. Abdominal computed tomography showed a half-moon-shaped density anterior to the aorta. The middle segments of both ureters were displaced medially and the proximal parts dilated. Other causes (tumour, drug therapy, inflammation) having been largely excluded, idiopathic retroperitoneal fibrosis was diagnosed. The marked urinary obstruction necessitated the implantation of double-J-stents. Immunosuppressive treatment was started with daily 150 mg azathioprine and, initially, 50 mg prednisone. Within one week the serum creatinine concentration and ESR had fallen and the signs of urinary obstruction regressed.


Phases of alcohol problem prevention research.
We build on precedents from other health research to present a phases model of research for alcohol problem prevention that accommodates the special characteristics of this research. We propose a five-level model, in which research moves along a series of relevant continua: from basic to more and more applied research; from descriptive hypothesis-generating pilot studies to full-fledged, methodologically sophisticated, hypothesis-testing studies; from smaller to larger samples for testing; from greater to lesser control of experimental conditions; from more artificial "laboratory" environments to real-world geographically defined communities; from testing the effects of single prevention strategies to more complex studies of multiple strategies integrated into intervention systems; and from research-driven outcome studies to "demonstration" projects that evaluate the capacity of various types of communities to implement prevention programs based on prior evaluations. The five phases of research are: (1) foundational research to define and determine the prevalence of specific alcohol-involved problems, establish causal factors and processes that yield the specific problems or increase the risk of a problem, and provide the foundations for the development of effective prevention interventions; (2) developmental (preliminary effectiveness) studies to develop and test the likely effectiveness, safety, and costs of new interventions or to assess the effectiveness, safety, and costs of an existing intervention; (3) efficacy studies to determine the effects, safety, and costs of an intervention under optimal conditions of implementation (or availability or enforcement) and acceptance (or adoption at the community, organizational, or group level; or participation, compliance, or adherence at the individual level); (4) effectiveness studies of the real-world effectiveness of preventive interventions with purposeful or natural variation in implementation and acceptance; and (5) demonstration studies of the effects of interventions when widely disseminated. The proposed phases model for alcohol problem prevention research presented herein differs in significant ways from the models established by other National Institutes of Health agencies. Greater emphasis is placed on natural experiments, on methods development along the whole research continuum, on collapsing or combining research phases when appropriate, on recognizing the critical importance of behavioral parameters early as well as late in the research sequence, and on extending the research continuum to embrace diffusion and dissemination (i.e., technology transfer) studies. We also include examples of phased research in existing alcohol studies and a discussion of relevant issues, including cost, special populations, methods, and dissemination. If systematically followed, this model has the potential to contribute to wider testing and dissemination of prevention interventions of known effectiveness.


Pancreatic excretion of dimethadione and trimethadione by repeated oral administration of trimethadione in dogs.
To examine pancreatic excretion of dimethadione (DMO), a weak organic acid, as well as of its precursor trimethadione (TMO), TMO was given orally to dogs with pancreatic fistulae at a dose of 10-160 mg/kg/day over a period of 14 days. Blood samples were taken once a day during the administration of TMO and for 7 days after discontinuation of the drug. On the 15th day, pancreatic juice was collected under stimulation by secretin (2 Crick-Haper-Raper units/kg/h). DMO concentration in plasma reached a maximal plateau around the 10th day after starting TMO administration, and depended directly on the dose of TMO. Pancreatic excretion of DMO at a steady state closely depended on both the dose of TMO and the DMO concentration in plasma. The pancreatic juice/plasma concentration ratio for DMO exceeded 1.0 at a steady rate and decreased with the increased flow rate. Pancreatic DMO clearance (DMO output/DMO concentration in plasma) increased, depending on the flow rate, the bicarbonate concentration, and pH of pancreatic juice. Pancreatic excretion of TMO was zero or extremely low.


[Effect of hepatocyte growth factor on invasion of ovarian cancer cell line SKOV3 and its signal transduction pathway].
Hepatocyte growth factor (HGF) specifically binds to its receptor c-met, activates a complex set of intracellular pathways, and plays important roles in regulating tumor invasion, metastasis, and angiogenesis. HGF and c-met are overexpressed in ovarian cancer. This study was designed to investigate the role of HGF in ovarian cancer invasion and its signal transduction pathway. HGF-induced invasion of ovarian cancer cell line SKOV3 was analyzed with Boyden chamber invasion assay. The expression changes of c-met and matrix metalloproteinase-9 (MMP-9) in SKOV3 cells before and after treatment with HGF and nuclear factor kappaB (NF-kappaB) inhibitor pyrrolidine dithiocarbamate (PDTC) were measured by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and flow cytometry. The expression of NF-kappaB in SKOV3 cells was evaluated by immunocytochemistry and Western blot. The invasive cells were significantly more in HGF group than in control group and PDTC plus HGF group (343+/-13 vs. 167+/-11 and 241+/-10, P<0.01). HGF promoted the expression of MMP-9 mRNA by 5.66+/-0.10 folds, but had no effect on c-met mRNA expression; PDTC suppressed the HGF-driven expression of MMP-9 mRNA by 2.75+/-0.80 folds. The positive rates of c-met and MMP-9 were significantly higher in HGF-treated cells than in control cells [(96.6+/-2.0)% vs. (73.3+/-2.4)%, P<0.01; (74.6+/-4.4)% vs. (16.0+/-2.9)%, P<0.01]. The protein levels of c-met and MMP-9 were significantly higher in HGF-treated cells than in control cells (2.84+/-0.18 vs. 1.65+/-0.19, P<0.01; 2.94+/-0.13 vs. 0.54+/-0.18, P<0.01). PDTC significantly suppressed the HGF-driven expression of MMP-9 protein: the positive rate and protein level of MMP-9 were (25.8+/-3.7)% and 0.87+/-0.14 (P<0.05). HGF promoted the expression of NF-kappaB protein in a time-dependent manner. The expression peak appeared 1 h after treatment with HGF (from 0.42+/-0.11 to 1.16+/-0.21, P<0.01). PDTC significantly inhibited the HGF-driven expression of NF-kappaB protein (0.38+/-0.12, P<0.01). HGF might stimulate the invasion of SKOV3 cells by up-regulating the expression of MMP-9 via NF-kappaB pathway.


Insulin-like growth factor I and its binding proteins: a study of the binding interface using B-domain analogues.
The biological activity of the insulin-like growth factors (IGF-I and IGF-II) is regulated by six IGF binding proteins (IGFBPs 1-6). To examine the surface of IGF-I that associates with the IGFBPs, we created a series of six IGF-I analogues, [His(4)]-, [Gln(9)]-, [Lys(9)]-, [Ser(16)]-, [Gln(9),Ser(16)]-, and [Lys(9),Ser(16)]IGF-I, that contained substitutions for residues Thr(4), Glu(9), or Phe(16). Substitution of Ser for Phe(16) did not affect secondary structure but significantly decreased the affinity for all IGFBPs by between 14-fold and >330-fold, indicating that Phe(16) is functionally important for IGFBP association. While His(4) or Gln(9) substitutions had little effect on IGFBP affinity, changing the negative charge of Glu(9) to a positive Lys(9) selectively decreased the affinities of IGFBP-2 and -6 by 140- and 30-fold, respectively. Furthermore, the effects of mutations to both residues 9 and 16 appear to be additive. The analogues are biologically active in rat L6 myoblasts and they retain native structure as assessed by their far-UV circular dichroism (CD) profiles. We propose that Phe(16) and adjacent hydrophobic residues (Leu(5) and Leu(54)) form a functional binding pocket for IGFBP association.


A novel inpatient complex pain team: protocol for a mixed-methods evaluation of a single-centre pilot study.
Complex pain is a debilitating condition that is responsible for low quality of life and significant economic impacts. Although best practice in the treatment of complex pain employs a multidisciplinary team, many patients do not have access to this care, leading to poor outcomes. This study evaluates a novel inpatient complex pain team at a large London teaching hospital. A multidisciplinary pain team comprising specialist doctors, nurses, psychologists and physiotherapists was instituted for inpatients with complex pain who will undergo an intense and bespoke evidence-based programme which will then be integrated into the community. A mixed-methods evaluation will take place and patients will be recruited over the course of 1 year. A qualitative arm will interview 15 staff and 15 patients on recruitment and again 6 months later looking to compare and contrast the new pain team with past experiences of pain management. A quantitative arm will assess clinical outcomes using validated scoring tools. An economic evaluation will seek to evaluate the relative cost of the service by comparing healthcare costs before and after the intervention. The study was categorised as a service evaluation, so formal ethical approval was not considered necessary. Participant recruitment began in January 2016 and the 1-year follow-up will end in November 2017. The results of this study will be published in 2018.


RNA interference for multiple myeloma therapy: targeting signal transduction pathways.
Multiple myeloma (MM) is a hematological malignancy characterized by infiltration of malignant plasma cells in the bone marrow (BM) and end-organ damage to the bone, BM, kidney and immune system. Although current treatments have improved the treatment of MM, it still remains an incurable disease. RNA interference (RNAi) effectors such as microRNAs and small interference RNAs have shown potential to selectively downregulate genes implicated in the pathology of a range of diseases. Signaling pathways that facilitate growth, survival and migration of MM cells, provide resistance to conventional therapies, and therefore, target these signaling pathways will prove promising for MM treatment. This review focuses on signaling pathways associated with the development of myeloma cells and how interaction of these cells with the tumor microenvironment impacts disease progression. Together these elements provide potential therapeutic targets for RNAi in the future. Recent advances in oncogenomic studies have revealed the molecular pathogenesis of MM, thus providing new therapeutic targets for RNAi therapy. Pre-clinical evidence suggests that non-viral delivery technology offers the potential to translate this concept into the next generation of RNAi-based therapeutics for MM.


Technical Note: Time-gating to medical linear accelerator pulses: Stray radiation detector.
CCD cameras are employed to image scintillation and Cherenkov radiation in external beam radiotherapy. This is achieved by gating the camera to the linear accelerator (Linac) output. A direct output signal line from the linac is not always accessible and even in cases where such a signal is accessible, a physical wire connected to the output port can potentially alter Linac performance through electrical feedback. A scintillating detector for stray radiation inside the Linac room was developed to remotely time-gate to linac pulses for camera-based dosimetry. A scintillator coupled silicon photomultiplier detector was optimized and systematically tested for location sensitivity and for use with both x rays and electron beams, at different energies and field sizes. Cherenkov radiation emitted due to static photon beams was captured using the remote trigger and compared to the images captured using a wired trigger. The issue of false-positive event detection, due to additional neutron activated products with high energy beams, was addressed. The designed circuit provided voltage >2.5 V even for distances up to 3 m from the isocenter with a 6 MV, 5 × 5 cm beam, using a Ø3 × 20 mm3 Bi4 Ge3 O12 (BGO) crystal. With a larger scintillator size, the detector could be placed even beyond 3 m distance. False-positive triggering was reduced by a coincidence detection scheme. Negligible fluctuations were observed in time-gated imaging of Cherenkov intensity emitted from a water phantom, when comparing directly connected vs this remote triggering approach. The remote detector provides untethered synchronization to linac pulses. It is especially useful for remote Cherenkov imaging or remote scintillator dosimetry imaging during radiotherapeutic procedures when a direct line signal is not accessible.


Vaccinal control of Marek's disease: current challenges, and future strategies to maximize protection.
Marek's disease is an economically important lymphoid neoplasm of chickens, caused by oncogenic strains of Marek's disease herpesvirus. The disease can be successfully controlled by vaccination with attenuated or non-pathogenic MDV strains. However, vaccine failures do occur as field strains continue to evolve towards pathotypes of greater virulence, and this evolution is likely to be driven by the vaccines themselves. Two general strategies can be considered to improve protection by vaccination. Firstly by the development of novel vaccines, and secondly by maximizing the potential of existing vaccines. This second goal requires investigation of optimal timing and vaccine delivery route, and optimal vaccination regimes for different breeds of chick. Accurate quantitation of Marek's disease vaccine virus in vaccinated chicks will contribute significantly to our understanding of vaccinal protection. We recently developed a real-time polymerase chain reaction (PCR) assay for quantitation of CVI988 vaccine virus in the feather tips, a rich source of viral DNA which can easily be sampled in a non-invasive manner. This PCR test is now used commercially to confirm the successful vaccination of chicks. We have also used the PCR to examine various aspects of vaccination in experimental chicks and commercial chicks with a view to determining how vaccine level in feathers correlates with protection against challenge, and for identifying optimal timing and vaccine delivery route, and optimal vaccination regimes for different breeds of chick. In this article we review some aspects of the current vaccinal control of Marek's disease, before highlighting some of the problems associated with current vaccines and vaccination strategies, and the challenges for the future. We go on to discuss the development and use of our real-time PCR feather test, its current applications and potential opportunities in Marek's disease vaccine research.


Moderate baseline vagal tone predicts greater prosociality in children.
Vagal tone is widely believed to be an important physiological aspect of emotion regulation and associated positive behaviors. However, there is inconsistent evidence for relations between children's baseline vagal tone and their helpful or prosocial responses to others (Hastings & Miller, 2014). Recent work in adults suggests a quadratic association (inverted U-shape curve) between baseline vagal tone and prosociality (Kogan et al., 2014). The present research examined whether this nonlinear association was evident in children. The authors found consistent evidence for a quadratic relation between vagal tone and prosociality across 3 samples of children using 6 different measures. Compared to low and high vagal tone, moderate vagal tone in early childhood concurrently predicted greater self-reported prosociality (Study 1), observed empathic concern in response to the distress of others and greater generosity toward less fortunate peers (Study 2), and longitudinally predicted greater self-, mother-, and teacher-reported prosociality 5.5 years later in middle childhood (Study 3). Taken together, the findings suggest that moderate vagal tone at rest represents a physiological preparedness or tendency to engage in different forms of prosociality across different contexts. Early moderate vagal tone may reflect an optimal balance of regulation and arousal that helps prepare children to sympathize, comfort, and share with others. (PsycINFO Database Record


[Parenthood--medical aspects of international adoption].
The unavailability of significant numbers of native-born children for adoption by local families has led to an upsurge in international adoptions throughout the Western world, including Israel. The sudden appearance here of large numbers of babies and young children from countries with a variety of indigenous infectious diseases has focused concern on the issue. It has also induced the Ministry of Health to issue guidelines to protect the well-being of the public at large, as well as to aid adoptive families in maintaining their own, as well as their newly adopted children's health. The great majority of community based primary caregivers are unfamiliar with the health issues surrounding internationally adopted children. These children merit special care and consideration. One possible solution, in addition to educational campaigns, and already implemented abroad, is the specialized training of physicians caring for large numbers of such children. [International Adoption, HIV, Hepatitis B, Hepatitis C, Tuberculosis, Syphilis].


Neuropilin, you gotta let me know: should I stay or should I go?
Neuropilins are highly conserved single pass transmembrane proteins specific to vertebrates. They were originally identified as adhesion molecules in the nervous system, but were subsequently rediscovered as the ligand binding subunit of the class 3 semaphorin receptor in neurons and then as blood vessel receptors for the vascular endothelial growth factor VEGF. More recently they have also been implicated as mediators of the T-cell immune response and as key prognostic markers in several types of cancer. Because neuropilins bind multiple ligands and associate with several different types of co-receptors, they variably promote cell adhesion, repulsion or attraction. Which response they ultimately invoke is decided by the cellular and even subcellular context the neuropilins find themselves in. Here, we review how the developmental functions of the neuropilins are influenced by such different contexts.


Extracorporeal Blood Purification Therapies for Sepsis.
Extracorporeal blood purification is proposed as an adjuvant therapy for sepsis, aiming at controlling the associated dysregulation of the immune system, which is known to induce organ dysfunctions. Different therapies have been developed to address certain steps of the immune dysregulation. Most of the available blood purification devices focus on a single target, such as the endotoxin that triggers the immune cascade, or the cytokine storm that causes organ damages. However, the highly adsorptive membrane named oXiris® is a unique 4-in-1 device that combines cytokine and endotoxin removal properties, renal replacement function, and antithrombogenic properties. More recently, promising treatments that focus on the pathogen itself or the immune cells have been developed and are currently under investigation. In this review, we aim to summarize, according to their target, the different extracorporeal blood purification techniques that are already available for use. We will also briefly introduce the most recent techniques that are still under development. Because of its unique ability to remove both endotoxins and cytokines, we will particularly discuss the highly adsorptive preheparinized oXiris® membrane. We will present its properties, advantages, pitfalls, as well as therapeutic perspectives based on experimental and clinical data. Video Journal Club "Cappuccino with Claudio Ronco" at https://www.karger.com/Journal/ArticleNews/223997?sponsor=52.


Foxo1 Is a T Cell-Intrinsic Inhibitor of the RORγt-Th17 Program.
An uncontrolled exaggerated Th17 response can drive the onset of autoimmune and inflammatory diseases. In this study, we show that, in T cells, Foxo1 is a negative regulator of the Th17 program. Using mixed bone marrow chimeras and Foxo1-deficient mice, we demonstrate that this control is effective in vivo, as well as in vitro during differentiation assays of naive T cells with specific inhibitor of Foxo1 or inhibitors of the PI3K/Akt pathway acting upstream of Foxo1. Consistently, expressing this transcription factor in T cells strongly decreases Th17 generation in vitro as well as transcription of both IL-17A and IL-23R RORγt-target genes. Finally, at the molecular level, we demonstrate that Foxo1 forms a complex with RORγt via its DNA binding domain to inhibit RORγt activity. We conclude that Foxo1 is a direct antagonist of the RORγt-Th17 program acting in a T cell-intrinsic manner.


The effect of experimental male removals on extrapair paternity in the wheatear, Oenanthe oenanthe.
To examine the role of the pair male in ensuring paternity in the wheatear, we removed pair males for 24 h during the fertile period (days 0 to +1 in 1992 and days -5 to -1 in 1993, where day 0=first egg date). Control males were removed during incubation. The frequency and duration of intrusions, and the frequency of extrapair copulations (EPCs), increased during removals in the fertile period, but not during incubation. The frequency of extrapair paternity (EPP) was marginally higher (25%) in experimental than control broods and the presence of the pair male seemed particularly important in ensuring paternity in those days immediately preceding laying. Females were selective over which males they copulated with in the absence of their mate and rejected the majority of attempted EPCs. Only extrapair males in better body condition than the removed pair male eventually gained successful matings. Experimental males in poorer body condition were also more likely to have EPP in their brood than experimental males in better body condition. Female copulatory behaviour was the most important factor in determining patterns of paternity, and mate-guarding behaviours by the pair male appeared to limit the females' opportunities to engage in EPCs by reducing the frequency and duration of intrusions, rather than to control female behaviour directly. Copyright 1999 The Association for the Study of Animal Behaviour.


Asymmetric charge renormalization for nanoparticles in aqueous media.
The effective renormalized charge of nanoparticles in an aqueous electrolyte is essential to determine their solubility. By using a molecular model for the supporting aqueous electrolyte, we find that the effective renormalized charge of the nanoparticles is strongly dependent on the sign of the bare charge. Negatively charged nanoparticles have a lower effective renormalized charge than positively charged nanoparticles. The degree of asymmetry is a nonmonotonic function of the bare charge of the nanoparticle. We show that the effect is due to the asymmetric charge distribution of the water molecules, which we model using a simple three-site molecular structure of point charges.


A contingency management method for 30-days abstinence in non-treatment seeking young adult cannabis users.
Rates of young adult cannabis use are rising, perceived harm is at its historical nadir, and most users do not want to quit. Most studies evaluating effects of cannabis use in young adults are cross-sectional, limiting causal inference. A method to reliably induce abstinence periods in cannabis users would allow assessment of the effects of abstinence and resumption of use on a variety of outcomes in a within-subjects, repeated measures design. We examined the efficacy and feasibility of a voucher-based contingency management procedure for incentivizing one month of continuous cannabis abstinence among young adults who reported at least weekly cannabis use, volunteered to participate in a laboratory study, and did not express a desire to discontinue cannabis use long-term. Continuous cannabis abstinence was reinforced with an escalating incentive schedule, and self-report of abstinence was confirmed by frequent quantitative assays of urine cannabis metabolite (THCCOOH) concentration. New cannabis use during the abstinence period was determined using an established algorithm of change in creatinine-adjusted cannabis metabolite concentrations between study visits. Thirty-eight young adults, aged 18-25 years, enrolled and 34 (89.5%) attained biochemically confirmed 30-day abstinence. Among those who attained abstinence, 93.9% resumed regular use within two-weeks of incentive discontinuation. Findings support the feasibility and efficacy of contingency management to elicit short-term, continuous cannabis abstinence among young adult, non-treatment seeking, regular cannabis users. Further work should test the effectiveness of this contingency management procedure for cannabis abstinence in periods longer than one month, which may be required to evaluate some effects of abstinence.


Impact of HIPAA on confidentiality and privacy issues. Health Insurance Portability and Accountability Act.
All covered entities must comply with new HIPAA regulations governing transaction sets, privacy, and security. The deadline for implementation of new privacy requirements is scheduled for April 14, 2003. Pharmacists should prepare to implement these new requirements as soon as possible. HIPAA rules are complex. Penalties for violations could be severe, so pharmacists are advised to take appropriate measures to avoid liability.


New species of Tomentella (Thelephorales) from the Patagonian Andes forests.
The genus Tomentella forms abundant ectomycorrhizae in coniferous and deciduous forests worldwide. Molecular identification of root tips suggests undescribed species in the Nothofagus forests of Patagonia, Argentina. Tomentella tenuissima, T. pulvinulata and T. patagonica are described here as new to science based on morphological and molecular analyses. Their host range is addressed using available soil sequences. The identity of previous records of T. galzinii and T. radiosa are discussed with morphological and molecular evidence.


[Scarlet fever in Poland in 2008].
The 2008 was another year when the scarlet fever incidence in Poland increased. In total there were 11,179 cases registered and the incidence was 29,3 per 100,000 population ranging from 11.5 in podkarpackie voievodeship to 53.0 in opolskie voievodeship. Cases among children and adolescents of less then 15 years of age accounted for 93.1% of all cases. The incidence peaked among 5 years old children (435.9). Incidence in men (33.9) markedly exceeded the incidence in women (25.1) and incidence in urban areas (32.5) that in rural areas (24.4). Approximately 1.7% of all cases were hospitalized and there were no deaths due to scarlet fever in Poland in 2008.


Tolvaptan Add-on Therapy to Overcome Loop Diuretic Resistance in Acute Heart Failure With Renal Dysfunction (DR-AHF): Design and Rationale.
Diuretic Resistance in Acute Heart Failure (DR-AHF) was designed to demonstrate the effectiveness of the early tolvaptan (a vasopressin-2 receptor antagonist) add-on therapy in patients with AHF with renal dysfunction and to provide clinical evidence of loop diuretic resistance. This single-centered, open-labeled, randomized, and controlled trial enrolled 128 patients hospitalized with AHF, as participants. These patients with a wet-warm phenotype, whose estimated glomerular filtration rates are of ≥15 ml/min/1.73 m2 and ≤ 60 ml/min/1.73 m2, with a cumulative urine output of <300 ml 2 h after the first dose of intravenous furosemide, will be randomly assigned 1:1 to receive standard care with an uptitrating intravenous furosemide alone, or a combination therapy with 15 mg of tolvaptan administered once daily for 2 days. The standard furosemide treatment will follow the latest position statements of the Heart Failure Association. The primary endpoint is the cumulative urine output at 48 h. The key secondary endpoints include the improvement of fractional excretion of sodium at 6 h, the total dose of furosemide, and the incidence of worsening renal function (WRF) at 48 h. Although the combination of diuretic treatment has recently gained more attention due to its physiologically synergistic action, its advantages may be outweighed by the substantial risk of electrolyte disturbances and severe WRF. Further, there is no consensus on the time point for early starting of add-on therapy and for the preferred diuretic combination. NCT04331132.


A Direct Comparison between Circadian and Noncircadian Rhythms in Neurospora crassa.
A method has been devised for observing both circadian and noncircadian rhythms in a single wild type strain of Neurospora crassa. This method allows a direct comparison of the properties of the two types of rhythm. The circadian rhythm of conidiation always entrains to a light-dark cycle, damps out in constant light, and has a temperature-compensated period length. The noncircadian rhythm of hyphal branching, expressed by the same strain under different environmental conditions, does not entrain to a light-dark cycle, persists in constant light, and its period length is temperature-dependent. These results suggest that the two rhythms have different underlying mechanisms and demonstrate that the differences in the rhythms previously observed in different strains (patch, band, and clock) are not due to genetic differences between these strains but rather are inherent properties of the rhythms themselves.


Myelomeningocele with hydrocephalus and agenesis of corpus callosum.
A 45-day-old male baby presented with a leaking myelomeningocele and signs of meningitis. A computerised tomographic scan of brain revealed gross supratentorial ventriculomegaly with inflammatory exudates suggestive of intracranial infection. An unexpected association of complete agenesis of corpus callosum was discovered, however it is an incidental finding, a rare combination indeed.


Norcantharidin: a potential antiangiogenic agent for gallbladder cancers in vitro and in vivo.
Our objective was to explore the antiangiogenic activity of norcantharidin (NCTD) as an angiogenic inhibitor for gallbladder cancers. In vitro and in vivo experiments to determine the effects of NCTD on HUVECs, chicken CAM capillaries and gallbladder cancer xenograft angiogenesis in nude mice were respectively done. The MTT method was used to assay the cytotoxicity of NCTD on HUVECs. Immunofluorescence was used to evaluate HUVEC apoptosis. The scraping line method, matrigel invasion assay and tube formation assay were used to detect the migration, invasion and tube formation of HUVECs. A digital camera was used to observe chicken CAM capillaries. Experiments with NCTD in a xenograft model were used to observe the effect of NCTD on xenograft growth and survival of mice with xenografts. CD₃₄ immunohistochemistry, flow cytometry and micro-MRA were used, respectively, to determine MVD, cell apoptosis and hemodynamic analysis of the xenografts. Immunohistochemistry and RT-PCR were used, respectively, to detect the expression of VEGF, Ang-2, TSP, TIMP-2 proteins/mRNAs of the xenografts. The xenograft MVD associated with tumor volume, the PCNA/apoptosis ratio and related-protein expression was evaluated simultaneously. We found that NCTD effectively inhibited the proliferation, migration, invasion and capillary-like tube formation of HUVECs in vitro; it reduced angiogenesis and directly destroyed the formed CAM capillaries in vivo. In the experiments in mice, NCTD not only inhibited significantly xenograft proliferation and growth, prolonged survival time of mice with xenografts, decreased the xenograft MVD and vascular perfusion, but also, similarly to ES, decreased significantly the expression of VEGF or Ang-2 protein/mRNA, increased the expression of TSP or TIMP-2 protein/mRNA. Moreover, the xenograft MVD was positively related with tumor volume, PCNA/apoptosis ratio, and VEGF or Ang-2 expression, respectively (all P<0.05), but negatively correlated with TSP or TIMP-2 expression (both P<0.05). These data showed that NCTD could serve as a potential antiangiogenic agent for gallbladder cancers.


Relationship between functional status and health-related quality-of-life after myocardial infarction.
Despite increasing use in clinical and economic studies, no gold standard exists for the measurement of health-related quality of life (HRQL). One approach to assessing the validity of an HRQL instrument for a particular disease population is to examine the empirical relationship between HRQL patient scores and other accepted measures of health or functional status. In 185 patients (mean age 60 years, 79% male) at six months after myocardial infarction, we examined the relationship between patient responses to the Nottingham Health Profile (NHP), a generic HRQL instrument, and physician classification of patients by two widely used functional status indicators: the New York Heart Association (NYHA) classification and the Karnofsky Performance Status Scale. Analysis of NHP scores by NYHA strata confirms that lower HRQL is associated with poorer cardiac functional status (P < 0.0001) and this gradient is observed over all six NHP domains. Statistically significant (P < 0.001) associations were observed between patients' NYHA class and NHP domain scores for energy (Spearman r = 0.52), physical mobility (r = 0.45) and pain (r = 0.43). NHP scores for patients in NYHA Class I were similar to male population controls. A similarly consistent relationship was found between NHP and Karnofsky. We conclude that the NHP is able to discriminate between patients with differing levels of cardiac functioning as classified by NYHA and patient functioning as classified by Karnofsky. Demonstration of such discriminative properties is one important component in assessing the construct validity of HRQL measures.


Angiotensin-(1-7) potentiates the hypotensive effect of bradykinin in conscious rats.
Treatment with angiotensin-converting enzyme inhibitors increases the angiotensin-(1-7) [Ang-(1-7)] and bradykinin concentrations in plasma and tissue. In this study we evaluated the interaction between these peptides by determining the effect of Ang-(1-7) on the hypotensive action of bradykinin in conscious rats. Administration of Ang-(1-7) (5 nmol) did not change mean arterial pressure or heart rate. However, the hypotensive effect of bradykinin, produced by an intravenous or intra-arterial route, was potentiated by Ang-(1-7) in a dose-dependent manner. The Ang-(1-7) doses necessary to transform the effect of a single dose of bradykinin into that produced by a double dose (potentiating unit) were 2 nmol i.v. and 5 nmol IA. The Ang-(1-7) dose used did not change either the pressor effect of Ang II or the hypotensive effect of sodium nitroprusside. The bradykinin-potentiating Ang-(1-7) activity was significantly attenuated by pretreatment with indomethacin (5 mg/kg IM, n = 4). In an additional group the bradykinin-potentiating activity of Ang-(1-7) was evaluated 30 minutes after treatment with the angiotensin-converting enzyme inhibitor enalaprilat (10 mg/kg i.v., n = 9). Under this condition the bradykinin-potentiating activity of Ang-(1-7) was substantially increased, resulting in a potentiating unit of approximately 0.2 nmol IV. Pretreatment with indomethacin (5 mg/kg IM, n = 7) also attenuated the bradykinin-potentiating activity of Ang-(1-7) in enalaprilat-treated rats. These results show that Ang-(1-7) is a bradykinin-potentiating peptide in vivo. Furthermore, the data obtained with indomethacin suggest that prostaglandins participate in the mechanism of the bradykinin potentiation by Ang-(1-7). More importantly, these data suggest that the interaction between Ang-(1-7) and bradykinin can contribute to the pharmacological effects of angiotensin-converting enzyme inhibitors.


[Abnormal findings of cardiac function in patients with systemic lupus erythematosus (author's transl)].
To find out the rate of cardiac involvement among patients with systemic lupus erythematosus (SLE), 34 patients with SLE were examined by ECG, x-ray of the chest, body plethysmography, one- and two-dimensional echocardiography In addition, in 23 patients with SLE a microcatheterization of the right heart side was undertaken with measuring of the mean pulmonary artery pressure and cardiac index during exercise. Echocardiography revealed moderate abnormal findings in 62% of the patients. In particular, there was a thickening of the interventricular septum (31%), an enlargement of the right ventricle (23%), a diminution of the left ventricular fractional shortening (16%), an augmentation of the left atrium (10%) and of the left ventricle (6%). A small pericardial effusion was observed in 6% and a thickening of the left ventricular posterior wall in 3%. At micro-catheterization in 19 out of 23 patients with SLE, there was an increase of the mean pulmonary artery pressure up to abnormal values. In 5 patients, mean pulmonary pressure rose over 40 mm Hg. Most of the patients also showed an increase of the arterial pressure up to pathological values. Furthermore, most of the patients finished exercise because of muscular insufficiency or dyspnoea. Only 4 of 23 patients with SLE reached 90% of the age-corresponding maximal heart rate. The results indicate that with about 80% of all patients with SLE the cardiac capacity is reduced. In about 20% of the patients with SLE, this diminution of cardiac capacity is severe, and the necessity of medical treatment has to be discussed.


Distinction between cerebral abscesses and high-grade neoplasms by dynamic susceptibility contrast perfusion MRI.
The purpose of the study was to determine whether dynamic susceptibility contrast perfusion MRI allowed distinction of cerebral abscesses from cystic high-grade brain neoplasms. In this small preliminary study, dynamic susceptibility perfusion MRI allowed distinction of cerebral abscesses from rim-enhancing high-grade gliomas. Validation of these results using a prospective large study is warranted.


A simplified approach for estimating skin permeation parameters from in vitro finite dose absorption studies.
Historically, percutaneous absorption permeation parameters have been derived from in vitro infinite dose studies, yet there is uncertainty in their accuracy if the applied vehicle saturates or damages the stratum corneum, or when the permeation parameters are inappropriately derived from cumulative absorption data. An approach is provided for determining penetration parameters from in vitro finite dose data. Key variables, and equations for their derivation, are identified from the literature and provide permeation parameters that use only Tmax , AUC, and AUMC from finite dose data. The equations are tested with computer-generated model data and to actual study data. Derived permeation parameters obtained from the computer model data match those used in generating the simulated finite dose data. Parameters obtained from actual study data reasonably and acceptably model the penetration profile kinetics of the study data. From in vitro finite dose absorption data, three parameters can be obtained: the diffusion transit time (td ), which characterizes the diffusion coefficient, the partition volume (Vm P), which characterizes the partition coefficient, and the permeation coefficient (Kp ). These parameters can be obtained from finite dose data without having to know the length of the diffusion pathway through the membrane.


Expression and function of cell cycle proteins in rheumatoid arthritis synovial tissue.
Rheumatoid Arthritis (RA) is a chronic disease characterised by synovial lining hyperplasia and progressive destruction of joint tissues. Experimental data suggests that abnormal alterations in the expression of proteins involved in maintaining homeostatic control of the cell cycle is involved in disease progression in RA. By contributing to the overgrowth of synovial tissue, factors such as dysregulated proliferation or reduced apoptosis of cells can directly influence the pathological outcome of RA.


Activation of the Endoperoxide Ascaridole Modulates Its Sensitizing Capacity.
The monoterpene ascaridole, a fairly stable endoperoxide found in essential oils such as tea tree oil can provoke allergic contact dermatitis which has been evidenced under patch test conditions. However, concomitantly we observed irritative skin reactions that demand further data underlining the sensitization potential of ascaridole. Here, we studied the effects of ascaridole on dendritic cell (DC) activation and protein reactivity, 2 key steps of chemical-induced skin sensitization. Treatment of human monocyte-derived DC with ascaridole found support for full DC maturation, a capability of sensitizers but not irritants. It induced significant upregulation of the expression of the costimulatory molecules CD86, CD80, CD40, and the adhesion molecule CD54 in a time-dependent manner. Maturation was accompanied by release of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, and IL-8. Similar to other chemical skin sensitizers including hydroperoxides, we observed a certain reactivity of ascaridole toward cysteine- but not lysine-containing peptides. During recent years, evidence accumulated for a radical mechanism as trigger for protein reactivity of peroxides. Treatment of the fairly stable endoperoxide ascaridole with iron as radical inducer ("activated ascaridole") resulted in cysteine peptide reactivity exceeding by far that of ascaridole itself. Furthermore, activated ascaridole showed increased potential for induction of the Nrf2 target gene heme oxygenase 1 and upregulation of CD86 and CD54 on THP-1 cells, an established DC surrogate. These results indicate that radical formation could be involved in the steps leading to skin sensitization induced by the endoperoxide ascaridole.


Didanosine plus stavudine with or without hydroxyurea in HIV-1-infected patients: 1 year follow-up. Swiss HIV Cohort Study.
A total of 144 human immunodeficiency virus (HIV)-infected patients (mean CD4 cell count, 367 cells/mm3) were included in a double-blind placebo-controlled trial testing the efficacy on surrogate markers of HIV progression of the combination didanosine (2',3'-dideoxyinosine or DDI) plus stavudine (2',3'-didehydro-2',3'-dideoxythymidine or D4T) with or without hydroxyurea. The primary end point was a reduction of HIV RNA levels to below 200 copies/ml after 12 weeks of treatment. The results showed that the triple combination was associated with a more profound decrease in HIV RNA with an increased proportion of patients with viraemia < 200 copies/ml. This effect persisted for the majority of the patients after a 48 week follow-up. In contrast, the increase in CD4 cell counts was less in patients treated with hydroxyurea because of lymphopenia, and adverse events were more frequent in hydroxyurea-treated patients. In conclusion, the addition of hydroxyurea consistently improved the antiviral activity of the didanosine/stavudine combination over a 48 week follow-up. Increased toxicity and decreased effect on CD4 cell counts might inspire caution.


The [FeFe]-hydrogenase maturase HydF from Clostridium acetobutylicum contains a CO and CN- ligated iron cofactor.
Biosynthesis of the [FeFe] hydrogenases active site (H-cluster) requires three maturation factors whose respective roles are not understood yet. The clostridial maturation enzymes (CaHydE, CaHydF and CaHydG) were homologously overexpressed in their native host Clostridium acetobutylicum. CaHydF was able to activate Chlamydomonas reinhardtii [FeFe] hydrogenase apoprotein (CrHydA1(apo)) to almost 100% compared to the native specific hydrogen evolution activity. Based on electron paramagnetic resonance spectroscopy and Fourier-transform infrared spectroscopy data the existence of a [4Fe4S] cluster and a CO and CN(-) ligand coordinated di-iron cluster is suggested. This study contains the first experimental evidence that the bi-nuclear part of the H-cluster is assembled in HydF.


Topology of Streptococcus pneumoniae CpsC, a polysaccharide copolymerase and bacterial protein tyrosine kinase adaptor protein.
In Gram-positive bacteria, tyrosine kinases are split into two proteins, the cytoplasmic tyrosine kinase and a transmembrane adaptor protein. In Streptococcus pneumoniae, this transmembrane adaptor is CpsC, with the C terminus of CpsC critical for interaction and subsequent tyrosine kinase activity of CpsD. Topology predictions suggest that CpsC has two transmembrane domains, with the N and C termini present in the cytoplasm. In order to investigate CpsC topology, we used a chromosomal hemagglutinin (HA)-tagged Cps2C protein in S. pneumoniae strain D39. Incubation of both protoplasts and membranes with carboxypeptidase B (CP-B) resulted in complete degradation of HA-Cps2C in all cases, indicating that the C terminus of Cps2C was likely extracytoplasmic and hence that the protein's topology was not as predicted. Similar results were seen with membranes from S. pneumoniae strain TIGR4, indicating that Cps4C also showed similar topology. A chromosomally encoded fusion of HA-Cps2C and Cps2D was not degraded by CP-B, suggesting that the fusion fixed the C terminus within the cytoplasm. However, capsule synthesis was unaltered by this fusion. Detection of the CpsC C terminus by flow cytometry indicated that it was extracytoplasmic in approximately 30% of cells. Interestingly, a mutant in the protein tyrosine phosphatase CpsB had a significantly greater proportion of positive cells, although this effect was independent of its phosphatase activity. Our data indicate that CpsC possesses a varied topology, with the C terminus flipping across the cytoplasmic membrane, where it interacts with CpsD in order to regulate tyrosine kinase activity.


Effect of Lactobacillus rhamnosus on Physicochemical Properties of Fermented Plant-Based Raw Materials.
Texture and flavor are currently the main challenges in the development of plant-based dairy alternatives. To overcome them, the potential of microorganisms for fermentation of plant-based raw materials is generating great interest in the food industry. This study examines the effect of Lactobacillus rhamnosus, LGG® (LGG® is a trademark of Chr. Hansen A/S) on the physicochemical properties of fermented soy, oat, and coconut. LGG® was combined with different lactic acid bacteria (LAB) strains and Bifidobacterium, BB-12® (BB-12® is a trademark of Chr. Hansen A/S). Acidification, titratable acidity, and growth of LGG® and BB-12® were evaluated. Oscillation and flow tests were performed to analyze the rheological properties of fermented samples. Acids, carbohydrates, and volatile organic compounds in fermented samples were identified, and a sensory evaluation with a trained panel was conducted. LGG® reduced fermentation time in all three bases. LGG® and BB-12® grew in all fermented raw materials above 107 CFU/g. LGG® had no significant effect on rheological behavior of the samples. Acetoin levels increased and acetaldehyde content decreased in the presence of LGG® in all three bases. Diacetyl levels increased in fermented oat and coconut samples when LGG® was combined with YOFLEX® YF-L01 and NU-TRISH® BY-01 (YOFLEX® and NU-TRISH® are trademarks of Chr. Hansen A/S). In all fermented oat samples, LGG® significantly enhanced fermented flavor notes, such as sourness, lemon, and fruity taste, which in turn led to reduced perception of the attributes related to the base. In fermented coconut samples, gel firmness perception was significantly improved in the presence of LGG®. These findings suggest supplementation of LAB cultures with LGG® to improve fermentation time and sensory perception of fermented plant-based products.


Positrons and 511 keV Radiation as Tracers of Recent Binary Neutron Star Mergers.
Neutron-rich material ejected from neutron star-neutron star (NS-NS) and neutron star-black-hole (NS-BH) binary mergers is heated by nuclear processes to temperatures of a few hundred keV, resulting in a population of electron-positron pairs. Some of the positrons escape from the outer layers of the ejecta. We show that the population of low-energy positrons produced by NS-NS and NS-BH mergers in the Milky Way can account for the observed 511-keV line from the Galactic center (GC). Moreover, we suggest how positrons and the associated 511-keV emission can be used as tracers of recent mergers. Recent discovery of 511-keV emission from the ultrafaint dwarf galaxy Reticulum II, consistent with a rare NS-NS merger event, provides a smoking-gun signature of our proposal.


Synaptonemal complex behavior in asynaptic maize.
Synatonemal complexes were studied in silver-stained spread preparations of microsporocyte complements of asynaptic maize. Complexes were found predominantly in terminal regions of chromosome pairs. These tend to be aggregated in a common portion of the nucleus and to have polar orientation. As many as 19 of the 20 ends were found to be involved in relatively short paired segments. Intercalary regions of cores were not strongly organized and aligned, but some contained completed synaptonemal complex segments. The defect in asynaptic appears to represent stalling of the synaptic process at an early stage of synaptic progression.


A decade of the sperm-washing programme: correlation between markers of HIV and seminal parameters.
The aim of the study was to use a decade of experience of sperm washing to assess the effect of HIV disease on semen parameters and to highlight the continuing importance of risk reduction when some controversially advocate the safety of timed unprotected intercourse for conception in the 'stable' HIV-positive man. Semen parameters of 439 fresh samples used for sperm washing/intrauterine insemination (IUI) were correlated against markers of HIV disease [CD4 cell count, viral load (VL), duration of HIV infection and use of antiretroviral therapy] and the risk of detectable virus in semen was assessed. A significant positive correlation was observed between CD4 cell count and total sperm count, progressive motility, post-preparation/insemination concentration, progressive motility and total motile count inseminated (TMCI), and a significant negative correlation was observed between CD4 cell count and normal sperm morphology (Spearman's correlation; P<0.05). There was no significant difference in any parameter between samples in which VL was detectable and those in which it was undetectable. The use of highly active antiretroviral therapy (HAART) significantly decreased total sperm count, progressive motility, post-preparation count and TMCI and significantly increased proportion of abnormal forms (Mann-Whitney tests; P<0.05). There was a significant negative correlation between duration of HAART use and concentration, total sperm count and post-preparation motility and between years since diagnosis and post-preparation motility. In 9.7% of IUI cycles performed with fresh sperm in men on HAART with undetectable VL, detectable HIV was found in either pre- or post-wash seminal samples. Our data suggest a negative effect of low CD4 cell count and the use of HAART on semen. The significant proportion of 'stable'; men with undetectable serum VL but virus in semen confirms the continued importance of such risk reduction.


Molecular epidemiology of tuberculosis: methodology and applications.
The resurgence of tuberculosis around the world has renewed interest in understanding the epidemiology and pathogenesis of this disease. A revolutionary advance in the field of tuberculosis research has been the development of molecular techniques that permit identification and tracking of individual strains of Mycobacterium tuberculosis. With these techniques, molecular epidemiology has been established as a new discipline that adds another dimension to the classical epidemiology of tuberculosis and has increased our understanding of the transmission dynamics of M. tuberculosis. The increased epidemiological knowledge has led to discovery of inadequacies in tuberculosis control programs; this information has helped garner resources for program improvement and has highlighted the need for the continuous surveillance of tuberculosis. Additional genetic methods are being developed based on the knowledge of the genome sequence of M. tuberculosis. These simpler and less costly genotyping techniques promise to expand the application of molecular epidemiology to developing nations (where 90% of the disease burden occurs) in support of national tuberculosis programs. Furthermore, these tools permit ever more effective probes into the dynamics of transmission, the population structure, evolution and pathogenesis of M. tuberculosis.


Metabolic Availability of Lysine in Milk and a Vegetarian Cereal-Legume Meal Determined by the Indicator Amino Acid Oxidation Method in Indian Men.
Lysine rich foods such as milk and legumes serve as important food additions to the lysine deficient cereal-based diets of vegetarian populations in low- and middle-income countries (LMICs) to alleviate the risk of quality corrected dietary protein inadequacy. Dietary protein quality can be determined by estimating the metabolic availability (MA) of lysine. The study aimed to estimate the MA of lysine in spray-dried cow milk powder (SMP), heat-treated spray-dried cow milk powder (HSMP), and a habitually consumed cereal-legume based vegetarian meal (VM), using the indicator amino acid oxidation (IAAO) slope-ratio method. The MA of lysine in SMP, HSMP, and VM was estimated in 7 healthy young men aged 19-24 y with BMI of 21.5 ± 0.5 kg/m2 in a repeated measures design. The IAAO response slopes with 2 graded lysine intakes (10.5 and 15.0 mg·kg-1·d-1) from the SMP and VM were compared with the response slope generated with 3 graded crystalline lysine intakes (6.0, 10.5, and 15.0 mg·kg-1·d-1) at the subrequirement level. To produce HSMP, pasteurized cow milk was heat treated and spray dried. The MA of lysine in HSMP was tested at a single level of lysine intake (15 mg·kg-1·d-1). A total of 8 IAAO experiments were conducted on each participant in randomized order. The IAAO slopes were estimated using a linear mixed-effect regression model. The MA of lysine in SMP, HSMP, and VM was 91.9%, 69.9%, and 86.6% respectively. Heat treatment reduced the MA of lysine by 22% in HSMP compared with SMP in healthy Indian adults. The lysine MA estimates can be used to optimize lysine limited cereal-based diets, with the addition of appropriately processed legumes and milk powder, to meet the protein requirement. This trial was registered at Clinical Trials Registry of India (http://ctri.nic.in) as CTRI/2019/08/020568.


Factors related to short length of stay after carotid endarterectomy.
In the past decade, expected in-hospital length of stay (LOS) after carotid endarterectomy (CEA) has decreased from 4 days to 1. Long LOS is associated with known complications and factors affecting severity of the patient's condition. Factors affecting an intermediate stay of 2 to 4 days need further clarification. The vascular registry at Jobst Vascular Center includes data on manifestation of disease; cardiovascular history; operation and discharge dates; surgeon; surgical details such as patching, shunting, and completion arteriography; and complications. Univariate chi-square and ANOVA and multivariate logistic regression were applied to analyze 635 CEAs performed in 1998, 1999, and 2000. Statistical significance was at a p value less than 0.05 (two-sided). Overall morbidity rate was 8.2% with three (0.5%) in-hospital neurologic complications and one death for a 0.16% mortality rate. Fifty-eight percent of the patients were discharged in 1 day. Patients staying 1 day were 3 years younger. Female gender and prior cerebrovascular accident were factors extending LOS to 2 and 3 days. History of angina, heart failure, valve disease, and vein patch or no patch contributed to LOS of 3 or 4 days. Completion arteriography had an association with LOS of 2 days. The relative percentage of patients with complications increased with LOS. No significant relationship was found for symptoms, smoking, myocardial infarction, atrial fibrillation, cardiac revascularization, or surgeon. Insulin-treated diabetes mellitus, cardiac risk factors, cerebrovascular accident, and vein patch or no patch correlated with prolonged hospitalization. Factors were identified that may alter a clinical pathway designed for discharge 1 day after CEA. Focused management of patients with cardiac and cerebrovascular accident history or requiring vein patch and a better understanding of CEA in women may further increase the percentage of patients discharged 1 day after CEA.


[Pertussis in Poland in 2008].
In 2008, 2 163 cases of pertussis were reported in Poland. The incidence 5.7 per 100 000 was higher, 9% more compared to the last year (5.2). Highest incidence 37.7 per 100 000 population was observed in 10 - 14 age group and among urban areas population in all age groups. Of 2163 cases 870 (40%) were hospitalized. In 2008 one death attributed to pertussis was reported.


Use and perception of hormone therapy following media reports of the Women's Health Initiative: a survey of Australian WISDOM participants.
To investigate the impact of the Women's Health Initiative (WHI) on the use and perception of hormone therapy (HT) in well-informed and altruistic women who had volunteered for a similar long-term study of HT (Women's International Study of long Duration Oestrogen after Menopause, WISDOM). A total of 840 South Australian WISDOM participants were sent questionnaires asking about their source of information about the WHI, interpretation of the 2002 WHI findings, perception of HT as a risk factor for breast cancer, attitudes towards doctors and the media and intent to use HT in the future. Altogether, 618 participants (74%) responded. Written and verbal information provided by WISDOM were rated as the most helpful sources of information about the WHI. Participants were aware of the increase in breast cancer and decrease in fractures seen with combined estrogen/progestogen hormone therapy (EPT) but were less convinced about the other major findings, including cardiovascular disease and dementia. HT was rated as an important risk factor for breast cancer. Participants valued medical research and were more likely to question therapies without evidence. After WHI and WISDOM, most were willing to participate in a subsequent trial and most past HT users resumed therapy. There are sufficient recruits for future long-term HT studies if they are given sufficient quality information and individual counselling. Our study also suggests that women who are appropriately informed may choose to take long-term HT despite a more conservative approach advised by some agencies.


Don't Overweight Weights: Evaluation of Weighting Strategies for Multi-Task Bioactivity Classification Models.
Machine learning models predicting the bioactivity of chemical compounds belong nowadays to the standard tools of cheminformaticians and computational medicinal chemists. Multi-task and federated learning are promising machine learning approaches that allow privacy-preserving usage of large amounts of data from diverse sources, which is crucial for achieving good generalization and high-performance results. Using large, real world data sets from six pharmaceutical companies, here we investigate different strategies for averaging weighted task loss functions to train multi-task bioactivity classification models. The weighting strategies shall be suitable for federated learning and ensure that learning efforts are well distributed even if data are diverse. Comparing several approaches using weights that depend on the number of sub-tasks per assay, task size, and class balance, respectively, we find that a simple sub-task weighting approach leads to robust model performance for all investigated data sets and is especially suited for federated learning.


Durability and rapidity of response to anakinra in patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease that ultimately leads to disability and functional decline. Because patients usually develop RA in mid-life, they may experience its consequences for 20-30 years or longer. Proinflammatory cytokines, notably interleukin (IL)-1 and tumour necrosis factor-alpha, are believed to play significant pathophysiological roles. Clinical trials of biologicals that block these cytokines confirm their importance.Anakinra, a recombinant human IL-1 receptor antagonist, improves clinical signs and symptoms, and slows radiographic progression in patients with active RA. In clinical trials, patients receiving anakinra doses >1 mg/kg, whether administered alone or in combination with methotrexate, were two to three times more likely than patients receiving placebo to achieve a sustained ACR20 (American College of Rheumatology criteria) response. Notably, bone erosion slows to a greater extent and shows accelerated benefit when anakinra treatment is continued for periods beyond 24 weeks. Anakinra has a rapid onset of action, with substantial improvements in biochemical indices (C-reactive protein) seen within 1 week and clinical responses (ACR20 or joint counts) seen within 4 weeks of starting treatment. Anakinra is generally well tolerated, with injection site reactions being the most common adverse event. These reactions are generally mild and typically resolve within 2-3 weeks of treatment. The anakinra product labelling does include a warning regarding an increased risk of infections of 2% in anakinra-treated patients versus <1% in patients receiving placebo.


Lethal pulmonary infection with Francisella novicida is associated with severe sepsis.
The bacterial or host determinants of lethality associated with respiratory Francisella infections are currently unknown. No exo- or endotoxins that contribute to the severity of this disease have been identified. However, a deregulated host immune response upon infection is characterized by an initial 36- to 48-h delay followed by a rapid and excessive inflammatory response prior to death at 72-120 h. Here, we extend these findings by comparing host immune responses between sublethal and lethal respiratory infections of mice with an attenuated transposon mutant (Mut) of F. novicida (F.n.) strain U112 (sublethal) versus the wild-type (WT) strain (lethal). Infection with WT bacteria, but not the Mut, was characterized by sustained bacteremia and systemic dissemination of the pathogen with temporal increases in bacterial burdens in liver and spleen. Severe pathology with large foci of infiltrates associated with extensive tissue damage was evident in WT-infected lungs, and Mut-infected mice displayed much reduced pathology with intact lung architecture. Similar to other experimental models of severe sepsis, WT- but not the Mut-infected mice exhibited a robust increase in numbers of Gr1+ and CD11b+ cells, while displaying a significant depletion of alphabeta T cells. Further, a dramatic up-regulation of multiple cytokines and chemokines was observed only in lethal WT infection. In addition, an earlier and larger increased expression of S100A9, a known mediator of sepsis, was observed in WT-infected mice. Taken together, these results show that a hyperinflammatory host immune response, culminating in severe sepsis, is responsible for the lethal outcome of respiratory tularemia.


β-Glucuronidase, a Regulator of Lyme Arthritis Severity, Modulates Lysosomal Trafficking and MMP-9 Secretion in Response to Inflammatory Stimuli.
The lysosomal enzyme β-glucuronidase (Gusb) is a key regulator of Lyme-associated and K/B×N-induced arthritis severity. The luminal enzymes present in lysosomes provide essential catabolic functions for the homeostatic degradation of a variety of macromolecules. In addition to this essential catabolic function, lysosomes play important roles in the inflammatory response following infection. Secretory lysosomes and related vesicles can participate in the inflammatory response through fusion with the plasma membrane and release of bioactive contents into the extracellular milieu. In this study, we show that GUSB hypomorphism potentiates lysosomal exocytosis following inflammatory stimulation. This leads to elevated secretion of lysosomal contents, including glycosaminoglycans, lysosomal hydrolases, and matrix metalloproteinase 9, a known modulator of Lyme arthritis severity. This mechanistic insight led us to test the efficacy of rapamycin, a drug known to suppress lysosomal exocytosis. Both Lyme and K/B×N-associated arthritis were suppressed by this treatment concurrent with reduced lysosomal release.


An unusual oxidation type on bulb filament after a car crash dive.
A car with two dead bodies trapped inside was discovered in a gravel pit. The main hypothesis of investigators was a traffic accident simulation by night. Examination of a broken light-bulb revealed both a rather unusual oxidation type and small rounded cavities never reported before. Tests were performed and allowed forensic scientists to establish that the lightbulbs were switched on during the crash dive, in contrast with the investigators idea.


Self-Reports in the Field Using Smartwatches: An Open-Source Firmware Solution.
In situ self-reports are a useful tool in the social sciences to supplement laboratory experiments. Smartwatches are a promising form factor to realize these methods. However, to date, no user-friendly, general-purpose solution has been available. This article therefore presents a newly developed, free and open-source firmware that facilitates the Experience Sampling Method and other self-report methods on a commercially-available, programmable smartwatch based on the ESP32 microcontroller. In a small-scale pilot study comparing this smartwatch and firmware to an equivalent design on smartphones, participants using the smartwatch showed increased compliance. The presented project demonstrates a useful tool for complementary tools like smartphones for self-reports.


Influence of opposition on ball velocity in the handball jump throw.
The purpose of the present study was to investigate the influence of different degrees of opposition on ball velocity in the jump throw in elite, amateur and adolescent team handball players. Thus, one hundred and nineteen elite, amateur and under 18 team handball players performed jump throws under three different conditions: 1) without opposition, 2) with the opposition of the goalkeeper and 3) with the opposition of the goalkeeper and a defensive player. The degree of opposition was found to have a negative effect on ball velocity in all three groups (p < 0.001). Furthermore, the level of competition had a positive effect on ball velocity (p < 0.001). However, no interaction was found between the level of competition and the degree of opposition on ball velocity (p = 0.178). The findings of this study indicate that an increase of external stimuli probably influences throwing kinematics and thereby maximal ball velocity. However, experience does not seem to be a factor that can reduce the influence of these external stimuli. Key pointsThe degree of opposition had a negative effect upon ball throwing velocity in elite, amateur and adolescent handball players in the jump throw.It indicated that an increase of external stimuli influences the execution of throwing.Experience does not seem to be a factor that can reduce the influence of these external stimuli.


A Non-Invasive Method for Generating the Cyclic Loading-Induced Intra-Articular Cartilage Lesion Model of the Rat Knee.
The pathophysiology of primary osteoarthritis (OA) remains unclear. However, a specific subclassification of OA in relatively younger age groups is likely correlated with a history of articular cartilage damage and ligament avulsion. Surgical animal models of OA of the knee play an important role in understanding the onset and progression of post-traumatic OA and aid in the development of novel therapies for this disease. However, non-surgical models have been recently considered to avoid traumatic inflammation that could affect the evaluation of the intervention. In this study, an intra-articular cartilage lesion rat model induced by in vivo cyclic compressive loading was developed, which allowed researchers to (1) determine the optimal magnitude, speed, and duration of load that could cause focal cartilage damage; (2) assess post-traumatic spatiotemporal pathological changes in chondrocyte vitality; and (3) evaluate the histological expression of destructive or protective molecules that are involved in the adaptation and repair mechanisms against joint compressive loads. This report describes the experimental protocol for this novel cartilage lesion in a rat model.


Multivariate prediction of in-hospital mortality associated with surgical procedures.
The aims of this prospective multicenter study were to identify variables associated with in-hospital mortality among patients undergoing surgical procedures, to develop a prediction rule, and to statistically validate its reliability. Data from 24,654 consecutive informed patients over 15 years of age were collected from 22 surgical centers between January 1989 and December 1990. Using logistic regression analysis separate models were fit for seven surgical disciplines to predict the risk of 30-day in hospital mortality. Variables used to construct the regression models included age, sex, systolic blood pressure, renal dysfunction, hepatic dysfunction, concomitant diseases, severity of surgery, priority of surgery and duration of anesthesia. The performance of the prediction rule was evaluated by computing sensitivity, specificity and predictive values, analyzing the ROC curve and comparing observed with expected deaths. The significance of the independent variables varied within each model. All models significantly predicted the occurrence of in-hospital mortality. At a 0.5 cuptoint of predicted risk sensitivity of prediction rule was 99.89%, positive predictive value 98.51%, and overall predictive value 98.41%, whereas specificity was 7.92% and negative value slightly higher than 50%. The area under the ROC curve was 0.80 (perfect, 1.0). The correlation between observed and expected deaths was 0.99. This prediction rule, developed using multicenter data, is characterized by the following advantages: includes only nine variables; can be utilized by seven different surgical disciplines; is highly accurate, and is easily available to clinicals with access to a microcomputer or programmable calculator. This validated multivariate prediction rule would be useful both to calculate the risk of mortality for an individual surgical patient and to contrast observed and expected mortality rates for an institution or a particular clinician.


miR-365 targets ADAM10 and suppresses the cell growth and metastasis of hepatocellular carcinoma.
Expression of miR-365 has been reported to be downregulated in hepatocellular carcinoma (HCC). However, the biological function and underlying mechanism of miR-365 in HCC growth and metastasis remain unclear. The aim of the present study was to explore the role of miR-365 in HCC progression. We found that miR-365 expression was downregulated in HCC tissues and cell lines. Further results showed that low expression of miR-365 was significantly associated with tumor-node-metastasis (TNM) stage and lymph node metastasis. Functional assays revealed that overexpression of miR-365 significantly inhibited cell proliferation, colony formation, migration and invasion of HCC cells in vitro, and suppressed tumor growth in vivo. Mechanistic investigations demonstrated that ADAM10 (a disintegrin and metalloproteinase 10) is a target of miR-365 in HCC. In addition, knockdown of ADAM10 in HepG2 cells significantly inhibited cell proliferation, colony formation, migration and invasion, which mimicked the suppressive effects induced by miR-365 overexpression. Restoration of ADAM10 expression partially reversed the suppressive effects mediated by miR-365 overexpression. Taken together, these results indicate that miR-365 functions as a tumor-suppressor in HCC through targeting ADAM10, and may serve as a promising candidate for therapeutic applications in HCC treatment.


Quest of Intelligent Research Tools for Rapid Evaluation of Fish Quality: FTIR Spectroscopy and Multispectral Imaging Versus Microbiological Analysis.
The aim of the present study was to assess the microbiological quality of farmed sea bass (Dicentrarchus labrax) fillets stored under aerobic conditions and modified atmosphere packaging (MAP) (31% CO2, 23% O2, 46% Ν2,) at 0, 4, 8, and 12 °C using Fourier transform infrared (FTIR) spectroscopy and multispectral imaging (MSI) in tandem with data analytics, taking into account the results of conventional microbiological analysis. Fish samples were subjected to microbiological analysis (total viable counts (TVC), Pseudomonas spp., H2S producing bacteria, Brochothrix thermosphacta, lactic acid bacteria (LAB), Enterobacteriaceae, and yeasts) and sensory evaluation, together with FTIR and MSI spectral data acquisition. Pseudomonas spp. and H2S-producing bacteria were enumerated at higher population levels compared to other microorganisms, regardless of storage temperature and packaging condition. The developed partial least squares regression (PLS-R) models based on the FTIR spectra of fish stored aerobically and under MAP exhibited satisfactory performance in the estimation of TVC, with coefficients of determination (R2) at 0.78 and 0.99, respectively. In contrast, the performances of PLS-R models based on MSI spectral data were less accurate, with R2 values of 0.44 and 0.62 for fish samples stored aerobically and under MAP, respectively. FTIR spectroscopy is a promising tool to assess the microbiological quality of sea bass fillets stored in air and under MAP that could be effectively employed in the future as an alternative method to conventional microbiological analysis.


Minimally invasive surgical techniques in the treatment of lung cancer.
Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide. Despite recent advances in molecular characterization, targeted and adjuvant therapies of NSCLC, surgical resection remains the mainstay of curative treatment. Minimally invasive video-assisted thoracic surgery (VATS) techniques, in particular VATS lobectomy, are being increasingly utilized over traditional thoracotomy approaches in the treatment of localized NSCLC for the reported benefits with respect to postoperative recovery and the conviction of oncologic equivalence. This article will review the major VATS procedures, including their development, outcomes, and purported advantages over thoracotomy, as well as highlight new advances, such as robotic-assisted procedures.


Vibrational modes identify soft spots in a sheared disordered packing.
We analyze low-frequency vibrational modes in a two-dimensional, zero-temperature, quasistatically sheared model glass to identify a population of structural "soft spots" where particle rearrangements are initiated. The population of spots evolves slowly compared to the interval between particle rearrangements, and the soft spots are structurally different from the rest of the system. Our results suggest that disordered solids flow via localized rearrangements that tend to occur at soft spots, which are analogous to dislocations in crystalline solids.