Expression of the c-myc proto-oncogene in multiple myeloma and chronic lymphocytic leukemia: an in situ analysis.
The c-myc gene plays a pivotal role in mediating the competence state for cell cycle transversion. This biologic role is in contradiction to reports of elevated expression of the gene in multiple myeloma, a tumor with restricted self-renewal capacity. To more clearly define the role of this gene in plasma cells of myeloma patients, c-myc messenger RNA (mRNA) and/or oncoprotein expression were semiquantitatively analyzed on the single cell level in 19 cases of multiple myeloma, among them 1 biclonal case and 1 case with coexistent chronic lymphocytic leukemia (CLL). Performing anti-sense/mRNA in situ hybridization, mature c-myc gene transcripts were detected in 92% (12 of 13) of cases and could definitely be attributed to the plasma cells by our study. The number of Ki 67-positive plasma cells actively passing the cell cycle was less than 1% and independent of c-myc gene expression. However, because the presence of the 152-c-MYC epitope was correlated to extent of marrow plasmacytosis (r = .64; P = .043) and content of plasmablasts (P = .09), the c-myc gene might serve a function different from proliferative activity, but also associated with tumor cell mass. In CLL cells (21 of 22 cases) and their benign counterparts, ie, bone marrow and peripheral blood lymphocytes, the anti-sense/c-myc mRNA hybridization signals remained below the threshold considered as cutpoint between negative and positive. The low amounts of c-myc transcripts were correlated to neither stage of disease (P = .52) nor lymphocyte counts (P = .24). Because the numbers of peripheral blood lymphoma cells were independent of tumor mass and of c-myc gene transcripts expressed, peripheral blood lymphocytosis might more likely reflect homing processes than proliferative activity in CLL.


Fostering global health policy leadership through World Health Assembly simulations: debating climate change and health.
The South Asian region is predicted to be among the most severely affected by the health impacts of climate change and warrants regional health policy leadership to tackle the same. Model World Health Organization (WHO) simulations offer the academic opportunity to build this leadership. This study describes the conceptualization and conduct of the 'Manipal Model World Health Organization' 2018 debate simulation, where a multi-professional group of students at an Indian university deliberated approaches to address the regional health impacts of climate change in South Asia. We contextualized the Model WHO debate model for a multi-professional classroom. Multi-sectoral stakeholders were engaged to draw participants from health and non-health disciplines. Participants were trained in health research literacy, policy politics, bloc politics, writing and public speaking for Model WHO. Mock sessions provided training in navigating parliamentary procedures. The debate event consisted of 22 participants and a four-member panel from diverse academic disciplines who independently assessed the deliberations. All delegations demonstrated competent written and verbal contributions. Content analysis of resolutions reaffirmed international agreements and addressed the Climate Change Health Risk Framework, and objectives of the WHO Secretariat Action Plan. Besides presenting a stratified typology of academic health policy debate simulations in global, regional, and subnational contexts, we also propose a 'theory of change', illustrating how academic policy discourse platforms can nurture critical thinking, research/policy literacy and leadership skills. Such initiatives help build the health policy leadership required for addressing global health challenges such as climate change.


Digesta kinetics in gazelles in comparison to other ruminants: Evidence for taxon-specific rumen fluid throughput to adjust digesta washing to the natural diet.
Digesta flow plays an important role in ruminant digestive physiology. We measured the mean retention time (MRT) of a solute and a particle marker in the gastrointestinal tract (GIT) and the reticulorumen (RR) of five gazelles and one dikdik species. Species-specific differences were independent from body mass (BM) or food intake. Comparative evaluations (including up to 31 other ruminant species) indicate that MRT GIT relate positively to BM, and are less related to feeding type (the percentage of grass in the natural diet, %grass) than MRT RR. The MRTparticleRR is related to BM and (as a trend) %grass, matching a higher RR capacity with increasing BM in grazers compared to browsers. MRTsoluteRR is neither linked to BM nor to %grass but shows a consistent phylogenetic signal. Selectivity factors (SF; MRTparticle/MRTsolute, proxies for the degree of digesta washing) are positively related to %grass, with a threshold effect, where species with >20% grass have higher SF. These findings suggest that in different ruminant taxa, morphophysiological adaptations controlling MRTsoluteRR evolved to achieve a similar SF RR in relation to a %grass threshold. A high SF could facilitate an increased microbial yield from the forestomach. Reasons for variation in SF above the %grass threshold might represent important drivers of ruminant diversification and await closer investigation.


Human iPSC-Derived 3D Hepatic Organoids in a Miniaturized Dynamic Culture System.
The process of identifying and approving a new drug is a time-consuming and expensive procedure. One of the biggest issues to overcome is the risk of hepatotoxicity, which is one of the main reasons for drug withdrawal from the market. While animal models are the gold standard in preclinical drug testing, the translation of results into therapeutic intervention is often ambiguous due to interspecies differences in hepatic metabolism. The discovery of human induced pluripotent stem cells (hiPSCs) and their derivatives has opened new possibilities for drug testing. We used mesenchymal stem cells and hepatocytes both derived from hiPSCs, together with endothelial cells, to miniaturize the process of generating hepatic organoids. These organoids were then cultivated in vitro using both static and dynamic cultures. Additionally, we tested spheroids solely composed by induced hepatocytes. By miniaturizing the system, we demonstrated the possibility of maintaining the organoids, but not the spheroids, in culture for up to 1 week. This timeframe may be sufficient to carry out a hypothetical pharmacological test or screening. In conclusion, we propose that the hiPSC-derived liver organoid model could complement or, in the near future, replace the pharmacological and toxicological tests conducted on animals.


Lipoprotein(a) and dietary proteins: casein lowers lipoprotein(a) concentrations as compared with soy protein.
Substitution of soy protein for casein in the diet decreases LDL cholesterol and increases HDL cholesterol. How the 2 proteins affect lipoprotein(a) [Lp(a)], an independent risk factor for coronary artery disease, is unknown. We compared the effects of dietary soy protein and casein on plasma Lp(a) concentrations. Nine normolipidemic men were studied initially while consuming their habitual, self-selected diets, and then, in a crossover design, while consuming 2 liquid-formula diets containing either casein or soy protein. The dietary periods lasted 45 d (n = 7) or 33 d (n = 2). Fasting total cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerol, and Lp(a) concentrations were measured throughout. After 30 d of each diet, the mean concentration of Lp(a) was not significantly different after the soy-protein and self-selected diets. However, Lp(a) decreased by an average of 50% (P < 0.001) after the casein diet as compared with concentrations after both the soy-protein and self-selected diets. Two weeks after subjects switched from the self-selected to the soy-protein diet, Lp(a) increased by 20% (P = 0.065), but subsequently decreased to baseline. In contrast, the switch to the casein diet did not cause an increase in Lp(a), but instead a continuing decrease in mean concentrations to 65% below baseline (P < 0.0002). Total cholesterol, LDL cholesterol, and HDL cholesterol were significantly lower > or =30 d after both the casein and soy-protein diets than after the self-selected diet (P < 0.001). HDL cholesterol was 11% higher after the soy-protein diet than after the casein diet (P < 0.002), but LDL cholesterol, total cholesterol, and triacylglycerol were not significantly different after the casein and soy-protein diets. These findings indicate that soy protein may have an Lp(a)-raising effect, potentially detrimental to its use in antiatherogenic diets.


Dynamic-model-based method for selecting significantly expressed genes from time-course expression profiles.
This paper proposes a dynamic-model-based method for selecting significantly expressed (SE) genes from their time-course expression profiles. A gene is considered to be SE if its time-course expression profile is more likely time-dependent than random. The proposed method describes a time-dependent gene expression profile by a nonzero-order autoregressive (AR) model, and a time-independent gene expression profile by a zero-order AR model. Akaike information criterion (AIC) is used to compare the models and subsequently determine whether a time-course gene expression profile is time-independent or time-dependent. The performance of the proposed method is investigated on both a synthetic dataset and a real-life biological dataset in terms of the false discovery rate (FDR) and the false nondiscovery rate (FNR). The results show that the proposed method is valid for selecting SE genes from their time-course expression profiles.


Development of a Model to Measure Emergency Department Staffing Limitations.
The optimal staffing model for emergency departments (EDs) is not known. Improving staffing could lead to more timely, efficient, and effective care. We created a model of staffing to identify times of staffing limitation by provider type. We analyzed data from an academic pediatric ED with 60,000 visits per year. Each 10-minute interval from January 1, 2011, through December 31, 2012, was categorized as nonlimited (no staffing limitation), space limited (≥2 patients in the waiting room with wait times > 30 minutes and ≥ 80% ED bed occupancy), nurse limited (≥2 patients in the waiting room with wait times > 30 min and < 80% ED bed occupancy), or physician limited (≥2 patients in examination rooms who have waited > 30 minutes for a physician) using computer modeling. We calculated the percentage of time each type of limitation was in effect and the median lengths of stay for patients presenting during times of each category of limitation. The ED was space limited 5.0% of the time, nurse limited 16.1% of the time, and physician limited 0.1% of the time. In nonlimited times, length of stay was 201 minutes (interquartile range, 128-301), whereas patients presenting during space-limited, nurse-limited, and physician-limited times had statistically significantly higher LOS of 265 (187-360), 244 (169-337), and 247 (174-334) minutes, respectively. Times identified as space and staffing limited were associated with longer LOS. This computer model could be used to rapidly identify targeted staffing needs and then measure the effect of modifying staffing.


Identification of the blue light intensity administered to one eye required to suppress bovine plasma melatonin and investigation into effects on milk production in grazing dairy cows.
Long-day photoperiod is known to positively affect milk production in confinement dairy systems, and it has been hypothesized that pineal melatonin (MT) secretion plays a substantial role in this process. Specialized mammalian photoreceptors that regulate MT secretion are optimally stimulated by short wavelength blue light. We investigated the blue light intensity administered to one eye required to suppress MT secretion in nonlactating dairy cows, and subsequently examined effects on milk production in grazing dairy cows. Following a 14-d light-dark 8:16 h environmental conditioning period, 5 nonlactating Holstein-Friesian cows were exposed to treatments of <1, 70, 125, 175, and 225 lx for 8 additional hours using a 5 × 5 Latin square design. Light was administered via headpieces fitted with light-emitting diodes emitting blue light (465 nm) to the right eye. All cows were then exposed to a light-dark 16:8 h cycle for one night via the indoor lighting system (>200 lx white light). Plasma samples collected at regular intervals were assayed for MT. A dose-dependent effect of light treatment on mean circulating MT concentrations (and 95% CI) was observed [9.4 (7.2, 12.3), 5.0 (3.8, 6.6), 4.4 (3.3, 5.7), 3.3 (2.5, 4.3) and 1.7 (1.3, 2.3) pg/mL for treatments of 0, 70, 125, 175, and 225 lx, respectively. Only the 225 lx treatment acutely suppressed plasma melatonin concentration to levels similar to the light-dark 16:8 h treatment [1.9 (1.4, 2.5) pg/mL]. Forty spring-calving cows were blocked on parity, calving date and Economic Breeding Index for milk production and assigned to the control treatment or blue light to a single eye (LT) treatment from calving through 32 wk of lactation. The cows assigned to LT treatment were fitted with headpieces providing 225 lx of blue light to the right eye from 1700 until 0000 h. Mean milk production (and 95% CI) during 32 wk of lactation was not affected by treatment [20.3 (19.3, 21.3) vs. 20.9 (19.8, 22.0) kg/d, control and LT, respectively]. Within multiparous cows, a treatment by week interaction was detected, whereby LT treatment increased milk production during the first 12 wk of lactation [25.8 (24.3, 27.3) vs. 28.0 (26.5, 29.5) kg/d; +8.5%], but had no effect thereafter. Treatment did not affect plasma insulin-like growth factor 1. We identified the blue light intensity to one eye required to acutely suppress MT concentrations. Transient favorable effects on milk production were observed in multiparous cows. It remains unclear how single-eye blue light treatment affects galactopoiesis in grazing dairy cows, and further research is needed to explore whether this modality of light delivery represents a useful means to aid productivity in pasture-based dairy systems.


Rhino-orbital-cerebral mucormycosis with different cerebral involvements: infarct, hemorrhage, and ophthalmoplegia.
Rhino-orbital-cerebral mucormycosis is a rare but often fatal opportunistic necrotizing infection of the sinuses, orbit, and brain caused by saprophytic fungi. It usually develops in patients with diabetes or immune system deficiency. In this study, imaging features in 3 patients with rhino-orbital-cerebral mucormycosis who presented with various symptoms and different cerebral involvements are discussed. Headache, blurred vision, fever, painful ophthalmoplegia, and cranial nerve involvement were among the clinical findings. Computed tomography and magnetic resonance imaging are the best imaging methods for assessing the extent of this disease. Relatively typical but nonspecific characteristics are bone destruction, vascular invasion, and central hypointensity in the paranasal sinuses or an intracranial mass that is revealed by T(2)-weighted magnetic resonance imaging. Imaging findings include cavernous sinus involvement, cerebral infarct, and intracerebral hemorrhage. Because of the invasive and fulminant nature of rhino-orbital-cerebral mucormycosis, successful treatment seems to be based on early diagnosis and on the management of underlying immunologic problems.


Evaluating the effectiveness of intervention in long-term aphasia post-stroke: the experience from CHANT (Communication Hub for Aphasia in North Tyneside).
Despite recognition of the need for increased long-term support for people with aphasia following stroke, there remains limited evidence for effective service-level interventions. To evaluate the outcomes and experiences of people participating in the Communication Hub for Aphasia in North Tyneside (CHANT), a 2-year partnership project between health, local authority and third-sector services, shaped by people with aphasia, which provided a coordinated programme of support and interventions for people with long-term aphasia following stroke. Quantitative and qualitative methods were used in the evaluation. Thirty-nine participants with aphasia were recruited to the 12-month study as they became part of CHANT, with 20 completing all measures at the end of the study. Participants had no other speech and language therapy during the study. Quantitative measures (before and after intervention) were used for quality of life, self-report outcomes and goal attainment. Three of the participants with aphasia and three further people involved in the service (carer, volunteer, public sector worker) each agreed to a series of five semi-structured interviews over a 9-month period. A total of 28 interviews were collected using neutral interviewers; these were transcribed and analysed by a team within NVivo8 software, based on interpretive principles from grounded theory. Thematic analysis of the narratives explored the experience of engaging with CHANT, and the barriers and facilitators affecting quality of life. People with aphasia made significant gains in quality of life (in particular, in communication and psychosocial adjustment to stroke) and self-report measures of change. A total of 82% of real-life goals set as part of intervention were fully or partially achieved at follow-up. Five core themes emerged from the narratives: 'Quality of life', 'Barriers', 'Facilitators', 'Types of CHANT activity' and 'Effectiveness'. The intervention was evaluated through the theme of 'Effectiveness' in relation to the other themes, encapsulating emerging participant views (including the type and timeliness of activity, expectations of outcomes, resources and perceived value). The impact of the intervention was also analysed in terms of identifying barriers and providing facilitators. The quantitative and qualitative (narrative) findings were complementary in demonstrating the effectiveness of the CHANT service delivery model. Moreover, the narratives, through a longitudinal perspective, provided evidence about people's experience of intervention for long-term aphasia. The findings provide foundations for further work into long-term recovery, intervention and adjustment to aphasia post-stroke.


[Selection of surgical treatments for atrial fibrillation].
Radical procedure for elimination of atrial fibrillation (Af) was devised by Cox and named as maze procedure. The concept of maze procedure was interruption of all reentry circuits on both atria. Several modifications of maze procedure were performed. Among them, left atrial maze procedure suggested the mechanism of Af origination and open the door of catheter ablation of pulmonary veins. This article described the surgical procedures and indication of the original Cox maze procedure, left atrial maze procedure and the recent maze IV procedure.


Sperm characteristics and androgens in Acipenser ruthenus after induction of spermiation by carp pituitary extract or GnRHa implants.
Spermiation and changes in androgen (testosterone, T and 11-ketotestosterone, 11-KT) levels were studied in sterlet (Acipenser ruthenus) treated with GnRH agonist implants (DAla(6)-Pro(9)-LHRHa) at 25 and 75 μg kg(-1) b.w. and compared with those males treated with 4 mg kg(-1) b.w. of carp pituitary extract (CPE) and 3 pellets of Ovopel kg(-1) b.w., which contains DAla(6)-Pro(9)NEt-mGnRH and metoclopramide. Sperm quality (sperm mass, spermatozoa concentration and sperm motility and velocity) was evaluated 24, 48 and 72 h after hormonal treatments. Males did not release sperm in the control group injected with physiological solution, while sperm could not be collected 7 days after treatments in all hormonally treated groups. Spermiation rates were 100 % in the CPE and Ovopel groups and 25-50 % in the GnRHa-treated groups. Sperm production was significantly lower in the GnRHa-treated groups than in the CPE and Ovopel groups and decreased 72 h after hormonal treatment. Sperm motility and velocity were higher in the Ovopel and GnRHa (75 μg) groups compared to the CPE and GnRHa (25 μg) groups and decreased 72 h after hormonal treatment. Androgens were only affected in spermiating males and changed in the Ovopel and GnRHa (75 μg) after hormonal treatment. Significant correlations were observed between sperm production, sperm motility and sperm velocity, but not androgens. The present study suggests involvement of dopamine in sturgeon spawning. Additionally, better sperm quality observed in the Ovopel group and particularly sperm motility in the GnRHa (75 μg) suggests enhancement of sperm quality in sturgeon treated with GnRHa. Therefore, further study is needed to induce fully spermiation using GnRHa implants in combination with a dopamine inhibitor.


Technology-Aided Spatial Cues, Instructions, and Preferred Stimulation for Supporting People With Intellectual and Visual Disabilities in Their Occupational Engagement and Mobility: Usability Study.
Persons with severe or profound intellectual disability and visual impairment tend to be passive and sedentary, and technology-aided intervention may be required to improve their condition without excessive demands on staff time. This study aims to extend the assessment of technology-aided interventions for supporting functional occupational engagement and mobility in 7 people with intellectual disability and visual impairment and to use a technology system that is simpler and less expensive than those previously used. The technology system involved a Samsung Galaxy A10, 4 Philips Hue indoor motion sensors, and 4 mini speakers. Within each session, the participants were to collect 18 objects (ie, one at a time) from 3 different areas (stations) located within a large room, bring each of the objects to a central desk, and put away each of those objects there. For each object, the participants received verbal (spatial) cues for guiding them to the area where the object was to be collected, a verbal instruction (ie, request) to take an object, verbal (spatial) cues for guiding them to the central desk, a verbal instruction to put away the object collected, and praise and preferred stimulation. During baseline, the frequency of responses completed correctly (objects collected and put away independently) was 0 or near 0. During the intervention phase (ie, with the support of the technology setup), the frequency increased for all participants, reaching a mean of almost 18 (out of 18 response opportunities) for 6 participants and about 13 for the remaining participant. The mean session duration ranged from 12 to 30 minutes. A program, such as the one used in this study, can be useful in promoting occupational engagement and mobility in persons with intellectual disability and visual impairment.


The effect of alendronate sodium on human erythrocytes.
Alendronate sodium is a medicine, which is commonly used in osteoporosis treatment. Nowadays, this substance is given to patients in tablets, but in future it is planned that it will be administrated into human organisms as intravenous infusions; therefore, significant interactions of this medicine with erythrocytes will be inevitable. It is the reason why we decided to investigate the interaction of alendronate sodium with human erythrocytes. The effect of this medicine on acetylcholinesterase activity, lipid and protein peroxidation, as well as cellular thiol content was examined. Moreover, the effect of alendronate sodium on alterations in erythrocytes morphology was assessed. Human erythrocytes were incubated with alendronate sodium in the concentrations ranging from 0.33 to 100 μM for 1 h and 24 h. No changes have been observed in the parameters examined after 1h of incubation of the erythrocytes with this medicine excluding the carbonyl groups level. Moreover, no alterations in the activity of acetylcholinesterase, the level of thiols as well as in morphology of the erythrocytes incubated with alendronate sodium for 24h have been observed. It was also proven that alendronate sodium increased the level of reactive oxygen species (ROS) but only after 24h of incubation. We have not observed any severe changes in cells studied even at the highest dose of bisphosphonates examined, thus their usage should not be dangerous for the erythrocytes of people treated with these medicines.


The diagnosis and management of neuropathic pain in daily practice in Belgium: an observational study.
This open, multicentre, observational survey investigated how physicians diagnose neuropathic pain (NeP) by applying the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale, and how neuropathic pain conditions are managed in daily practice in Belgium. Physicians were asked to complete the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale for diagnosing NeP, and to fill out a questionnaire regarding the management of NeP, together with a questionnaire evaluating the impact of pain on sleep and daily life. Data on 2,480 pain patients were obtained. A LANSS score > or = 12 (meaning NeP is most probably present) was reported for 1,163 patients. Pathologies typically associated with NeP scored above 12 on the LANSS scale, contrary to pathologies generally considered as being of non-neuropathic origin. Over 90% of the patients with a LANSS score > or = 12 reported that the pain impaired sleep. A high impact on social, family and professional life was also recorded. Additional examinations were performed in 89% of these patients. Most patients were taking multiple drugs, mainly paracetamol and non-steroidal anti-inflammatory drugs, indicating that physicians generally tend to follow treatment guidelines of chronic nociceptive pain, rather than the specific ones for NeP. Specific neuropathic guidelines rather recommend the use of anti-epileptic drugs, tricyclic antidepressants or weak opioids as first-line treatment. In our survey, application of the LANSS scale lead to pronounced treatment simplification with fewer drug combinations. Awareness about NeP as well as its specific treatment recommendations should be raised among healthcare providers. We concluded that the LANSS screening scale is an interesting tool to assist physicians in detecting NeP patients in routine clinical care.


Game-based learning as a vehicle to teach first aid content: a randomized experiment.
Knowledge of first aid (FA), which constitutes lifesaving treatments for injuries or illnesses, is important for every individual. In this study, we have set up a group-randomized controlled trial to assess the effectiveness of a board game for learning FA. Four class groups (120 students) were randomly assigned to 2 conditions, a board game or a traditional lecture method (control condition). The effect of the learning environment on students' achievement was examined through a paper-and-pencil test of FA knowledge. Two months after the intervention, the participants took a retention test and completed a questionnaire assessing enjoyment, interest, and motivation. An analysis of pre- and post-test knowledge scores showed that both conditions produced significant increases in knowledge. The lecture was significantly more effective in increasing knowledge, as compared to the board game. Participants indicated that they liked the game condition more than their fellow participants in the traditional lecture condition. These results suggest that traditional lectures are more effective in increasing student knowledge, whereas educational games are more effective for student enjoyment. From this case study we recommend alteration or a combination of these teaching methods to make learning both effective and enjoyable.


[Granule protein contents of polymorphonuclear leucocytes and serum in 30 cases of myelodysplastic syndromes].
Intracellular contents and serum levels of neutrophilic granule protein components, including myeloperoxidase (MPO), lactoferrin (LF) and lysozyme (LYZ), were investigated in 30 cases of myelodysplastic syndromes (MDS), with 59 healthy adult donors as controls. Both neutrophilic MPO and LF decreased significantly, suggesting the transformation of abnormal clones. Both serum levels of LF and LYZ exhibited a considerable fluctuation which may reflect reflect granulopoiesis in the bone marrow. We are of the opinion that measurement of intracellular MPO, LF, LYZ and their serum levels may aid in the diagnosis and prognosis of MDS and is proved to be of great clinical significance.


Does the type of craniomaxillofacial fracture (CMF) differ between patients with intracranial hemorrhage (ICH) and those with blunt cerebrovascular injury (BCVI)? A retrospective study.
The purpose of the present study was to investigate and compare craniomaxillofacial fracture (CMF) type in patients with intracranial hemorrhage (ICH) versus blunt cerebrovascular injury (BCVI). A retrospective cohort study was performed. The predictor variables were the types of CMF. The primary outcomes variables were ICH and BCVI. Secondary outcomes were death and survival with or without neurological sequelae. Descriptive, bivariate, and multiple logistic regression statistics were computed, and the significance level was set at P ≤ 0.05. The sample was composed of 1440 patients with a mean age of 46.6 years ±24 years, and 71% were men. Pure orbital wall (odds ratio [OR]), 3.62; 95% confidence interval [CI], 1.32-12.69; P < 0.022), Le Fort III (OR, 16.08; 95% CI, 5.89-43.50; P < 0.001), cranial vault (OR, 9.74; 95% CI, 18.104.22.168; P < 0.001), skull base (OR, 9.42; 95% CI, 3.86-24.02; P < 0.001) and cervical fractures (OR, 5.50; 95% CI, 1.65-15.97; P = 0.003) were significantly associated with BCVI. All of the CMFs (P < 0.001), except for Le Fort I (OR, 0.79; 95% CI, 0.18-2.63; P = 0.731), nasal (OR, 1.05; 95% CI, 0.77-1.42; P = 0.758), and mandibular (OR, 0.68; 95% CI, 0.45-1.01; P = 0.066) fractures, were significantly associated with ICH. Secondary outcomes were negatively influenced by ICH and BCVI (P < 0.001). Within the limitations of the study it seems that Le Fort I and nasal fractures could be protective of cerebrovascular injuries, by cushioning impact forces. On the other hand it seems that patients with pure orbital wall, Le Fort III and cranio-cervical fractures are more prone to having concomitant life-threatening cerebrovascular injuries. This category of patients should have an immediate and comprehensive neurological assessment and CT angiography to rule out BCVI and to determine its severity.


Evaluation of a competitive enzyme-linked immunosorbent assay for measurements of soluble HLA-G protein.
The human leukocyte antigen (HLA) class Ib molecule, HLA-G, has gained increased attention because of its assumed important role in immune regulation. The HLA-G protein exists in several soluble isoforms. Most important are the actively secreted HLA-G5 full-length isoform generated by alternative splicing retaining intron 4 with a premature stop codon, and the cleavage of full-length membrane-bound HLA-G1 from the cell surface, so-called soluble HLA-G1 (sHLA-G1). A specific and sensitive immunoassay for measurements of soluble HLA-G is mandatory for conceivable routine testing and research projects. We report a novel method, a competitive immunoassay, for measuring HLA-G5/sHLA-G1 in biological fluids. The sHLA-G immunoassay is based upon a competitive enzyme-linked immunosorbent assay (ELISA) principle. It includes a recombinant sHLA-G1 protein in complex with β2-microglobulin and a peptide as a standard, biotinylated recombinant sHLA-G1 as an indicator, and the MEM-G/9 anti-HLA-G monoclonal antibody (mAb) as the capture antibody. The specificity and sensitivity of the assay were evaluated. Testing with different recombinant HLA class I proteins and different anti-HLA class I mAbs showed that the sHLA-G immunoassay was highly specific. Optimal combinations of competitor sHLA-G1 and capture mAb concentrations were determined. Two versions of the assay were tested. One with a relatively wide dynamic range from 3.1 to 100.0 ng/ml, and another more sensitive version ranging from 1.6 to 12.5 ng/ml. An intra-assay coefficient of variation (CV) of 15.5% at 88 ng/ml and an inter-assay CV of 23.1% at 39 ng/ml were determined. An assay based on the competitive sHLA-G ELISA may be important for measurements of sHLA-G proteins in several conditions: assisted reproduction, organ transplantation, cancer, and certain pregnancy complications, both in research studies and possibly in the future also for clinical routine use.


Pharmacology and stereoselectivity of structurally novel cannabinoids in mice.
The pharmacological effects of three stereoisomeric pairs of structurally novel cannabinoids were tested after i.v. administration in mice for depression of spontaneous activity and the production of hypothermia, antinociception and catalepsy. The (-)-enantiomers were as much as 770 times more potent than delta 9-6a,10a-trans-tetrahydrocannabinol and were 7 to 2000 times more potent than their respective (+)-enantiomers. The order of potency for cannabinoid-induced effects was spontaneous activity greater than antinociception greater than hypothermia greater than or equal to catalepsy. Levonantradol was active between 0.123 to 1.5 mg/kg, whereas dextronantradol, its (+)-enantiomer was inactive. (-)-CP 55,244 and (-)-CP55,940 analogs which lack the dihydropyran ring were 5 to 775 times more potent than delta 9-6a,10a-trans-tetrahydrocannabinol and 30 to 2000 times more potent than their respective (+)-enantiomers. Some separation of effects was demonstrated with (+)-CP 55,243 and (-)-CP 56,667 which were inactive in producing hypothermia and catalepsy but were active in the spontaneous activity and tail-flick procedures. The high degree of enantioselectivity and potency of these nonclassical cannabinoids are indicative of a highly specific mechanism of action such as a receptor.


The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBPα and differentiation in MLL-AF9 leukemia.
Trithorax and polycomb group proteins antagonistically regulate the transcription of many genes, and cancer can result from the disruption of this regulation. Deregulation of trithorax function occurs through chromosomal translocations involving the trithorax gene MLL, leading to the expression of MLL fusion proteins and acute leukemia. It is poorly understood how MLL fusion proteins block differentiation, a hallmark of leukemogenesis. We analyzed the effect of acute depletion of menin, a close partner of MLL that is critical for MLL and MLL-AF9 recruitment to target genes, on MLL-AF9 leukemia cell differentiation using an in vivo model. We performed cDNA microarray analysis of menin-regulated genes from primary leukemia cells to determine menin-regulated pathways involved in suppressing MLL-AF9 leukemia cell differentiation. We found that menin binds the promoter of the polycomb gene Ezh2, and promotes its expression. EZH2 interacts with the differentiation-promoting transcription factor C/EBPα and represses C/EBPα target genes. Menin depletion reduces MLL binding to the Ezh2 locus, EZH2 expression, and EZH2 binding and repressive H3K27 methylation at C/EBPα target genes, thereby inducing the expression of pro-differentiation C/EBPα targets. In conclusion, our results show that in contrast to its classical role antagonizing trithorax function, the polycomb group protein EZH2 collaborates with trithorax-associated menin to block MLL-AF9 leukemia cell differentiation, uncovering a novel mechanism for suppression of C/EBPα and leukemia cell differentiation, through menin-mediated upregulation of EZH2.


Chiari malformation, cervical spine anomalies, and neurologic deficits in velocardiofacial syndrome.
The purpose of this investigation was to evaluate the prevalence of Chiari malformation, cervical spine anomalies, and neurologic deficits in patients with velocardio-facial syndrome. This study was a prospective evaluation of 41 consecutive patients with velocardiofacial syndrome, documented by fluorescence in situ hybridization, between March of 1994 and September of 1998. The 23 girls and 18 boys ranged in age from 0.5 to 15.2 years, with a mean age of 6.7 years. Nineteen patients were assessed with magnetic resonance imaging, 39 underwent lateral cephalometric radiography, and all patients were examined for neurologic deficits. Eight of 19 patients (42 percent) had anomalies of the craniovertebral junction, including Chiari type I malformations (n = 4), occipitalization of the atlas (n = 3), and narrowing of the foramen magnum (n = 1). One patient with Chiari malformation required suboccipital craniectomy with laminectomy and decompression. Fourteen of 41 patients (34 percent) had demonstrated neurologic deficits; 10 patients (24 percent) had velar paresis (6 unilateral and 4 bilateral). Chiari malformations, cervical spine anomalies, and neurologic deficits are common in velocardiofacial syndrome. Because these findings may influence the outcome of surgical intervention, routine assessment of patients with velocardiofacial syndrome should include careful orofacial examination, lateral cephalometric radiography, and magnetic resonance imaging of the craniovertebral junction.


Age- and sex-related effects on the neuroanatomy of healthy elderly.
Effects of age and sex, and their interaction on the structural brain anatomy of healthy elderly were assessed thanks to a cross-sectional study of a cohort of 662 subjects aged from 63 to 75 years. T1- and T2-weighted MRI scans were acquired in each subject and further processed using a voxel-based approach that was optimized for the identification of the cerebrospinal fluid (CSF) compartment. Analysis of covariance revealed a classical neuroanatomy sexual dimorphism, men exhibiting larger gray matter (GM), white matter (WM), and CSF compartment volumes, together with larger WM and CSF fractions, whereas women showed larger GM fraction. GM and WM were found to significantly decrease with age, while CSF volume significantly increased. Tissue probability map analysis showed that the highest rates of GM atrophy in this age range were localized in primary cortices, the angular and superior parietal gyri, the orbital part of the prefrontal cortex, and in the hippocampal region. There was no significant interaction between "Sex" and "Age" for any of the tissue volumes, as well as for any of the tissue probability maps. These findings indicate that brain atrophy during the seventh and eighth decades of life is ubiquitous and proceeds at a rate that is not modulated by "Sex".


Neonatal triethyltin exposure alters adult electrophysiology in rats.
In adults, triethyltin (TET) produces degeneration of white matter, edema, vacuolization on myelin and histotoxic hypoxia. To determine the functional consequences of perinatal exposure to TET, albino rats were administered either 0, 3, 6, or 9 mg/kg TET on postnatal day 5. Upon reaching adulthood, the rats were implanted with electrodes for recording visual evoked potentials (VEPs) and hippocampal afterdischarges (ADs). In addition to these tests, 17 days of kindling trials were administered to the rats followed by testing with pentylenetetrazol and picrotoxin for seizure susceptibility. TET increased latencies of P2, P3, and N3 of the VEP in a dose dependent fashion. TET also decreases N1P2 amplitudes and produced gender-specific alterations in both P1, N1, and N2 latencies and N2P3 amplitudes. TET produced alterations in duration of the AD recorded from cortex during kindling, but did not produce significant alterations in any of the other variables tested. The results support previous studies, since they show that the adult VEP is sensitive to perinatal toxicant exposure.


Bubble Movement on Inclined Hydrophobic Surfaces.
The movement of a single air bubble on an inclined hydrophobic surface submerged in water, including both the upward- and downward-facing sides of the surface, was investigated. A planar Teflon sheet with an apparent contact angle of a sessile water droplet of 106° was used as a hydrophobic surface. The volume of a bubble and the inclination angle of a Teflon sheet varied in the ranges 5-40 μL and 0-45°, respectively. The effects of the bubble volume on the adhesion and dynamics of the bubble were studied experimentally on the facing-up and facing-down surfaces of the submerged hydrophobic Teflon sheet, respectively, and compared. The result shows that the sliding angle has an inverse relationship with the bubble volume for both the upward- and downward-facing surfaces. However, at the same given volume, the bubble on the downward-facing surface spreads over a larger area of the hydrophobic surface than the upward-facing surface due to the greater hydrostatic pressure acting on the bubble on the downward-facing surface. This makes the lateral adhesion force of the bubble greater and requires a larger inclination angle to result in sliding.


Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations.
Factor H is a regulatory glycoprotein of the complement system. We expressed the three N-terminal complement control protein modules of human factor H (FH1-3) and confirmed FH1-3 to be the minimal unit with cofactor activity for C3b proteolysis by factor I. We reconstructed FH1-3 from NMR-derived structures of FH1-2 and FH2-3 revealing an approximately 105-A-long rod-like arrangement of the modules. In structural comparisons with other C3b-engaging proteins, factor H module 3 most closely resembles factor B module 3, consistent with factor H competing with factor B for binding C3b. Factor H modules 1, 2, and 3 each has a similar backbone structure to first, second, and third modules, respectively, of functional sites in decay accelerating factor and complement receptor type 1; the equivalent intermodular tilt and twist angles are also broadly similar. Resemblance between molecular surfaces is closest for first modules but absent in the case of second modules. Substitution of buried Val-62 with Ile (a factor H single nucleotide polymorphism potentially protective for age-related macular degeneration and dense deposit disease) causes rearrangements within the module 1 core and increases thermal stability but does not disturb the interface with module 2. Replacement of partially exposed (in module 1) Arg-53 by His (an atypical hemolytic uremic syndrome-linked mutation) did not impair structural integrity at 37 degrees C, but this FH1-2 mutant was less stable at higher temperatures; furthermore, chemical shift differences indicated potential for small structural changes at the module 1-2 interface.


Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Hepatitis-HIV Spanish Study Group.
Liver disease secondary to hepatitis C virus (HCV) infection is a rising cause of morbidity and mortality among individuals who have been infected parenterally with human immunodeficiency virus (HIV) such as injection drug users, hemophiliacs, and transfused patients. We analyzed both the efficacy of interferon (IFN) alpha therapy in these patients and the predictors of response to this agent. A total of 119 patients with chronic hepatitis C (90 of whom were infected with HIV and 29 of whom were not) were included in a multicenter, prospective, open, nonrandomized observational study. IFN-alpha was given subcutaneously in a dosage of 5 million units three times a week during a 3-month period; those patients who responded received a dose of 3 million units given subcutaneously three times a week for an additional 9 months. One hundred seven patients completed the study; the level of aminotransferases returned to normal and sera became negative (complete response) for HCV RNA in 26 (32.5%) of 80 HIV-infected patients and 10 (37.0%) of 27 non-HIV-infected patients (P = .666) after completion of the treatment. Two variables were independently associated with a response in HIV-infected patients: a CD4+ T lymphocyte count of > 500 x 10(6)/L and a baseline HCV viremia level of < 10(7) copies/mL. In the 12 months following treatment, relapses occurred in 30.8% of the HIV-infected patients and 12.5% of non-HIV-infected patients (P = .403).


Inhibition of platelet-derived growth factor receptor tyrosine kinase by atrial natriuretic peptide.
Atrial natriuretic peptide (ANP) is known to suppress platelet-derived growth factor (PDGF)-stimulated proliferation of rat cultured vascular smooth muscle cells. The present study examined whether ANP inhibits the PDGF receptor (PDGFR) tyrosine kinase activation, an initial event for PDGF cellular signaling. ANP reduced the in vivo tyrosine phosphorylation of PDGFR stimulated by PDGF in a dose-dependent manner. This effect was not due to the reduction in PDGFR protein as detected by immunoblot analysis. 8-Bromo-cyclic GMP, a membrane-permeable 3',5'-cyclic monophosphate (cGMP) derivative, mimicked the action of ANP. HS-142-1, an antagonist for guanylate cyclase A (GC-A) and B, co-incubated with ANP, restored the PDGF-induced PDGFR autophosphorylation. The effect of ANP was also observed in the presence of a protein tyrosine phosphatase inhibitor, sodium orthovanadate. To confirm that ANP exerts its action by inhibiting protein tyrosine kinase (PTK), an in vitro kinase assay was performed. Cyclic GMP inhibited PTK activity of PDGFR partially purified by lectin affinity chromatography. In contrast, PTK activity in immobilized PDGFR immunocomplexes was not inhibited by cGMP. However, exogenous cGMP dependent protein kinase (PKG) reduced the PTK activity in the presence of cGMP. These results demonstrate that ANP suppresses PDGFR PTK through GC-A probably by activating PKG. This may be an important mechanism by which ANP exerts its anti-proliferative action antagonizing PDGF.


Development of Novel Phase-Change Materials Derived from Methoxy Polyethylene Glycol and Aromatic Acyl Chlorides.
In this research, novel, organic, solid-liquid phase-change materials (PCMs) derived from methoxy polyethylene glycol (MPEG) and aromatic acyl chlorides (ACs) were prepared through a condensation reaction. The MPEGs were used as phase-change functional chains with different molecular weights (350, 550, 750, 2000, and 5000 g/mol). The aromatic ACs, terephthaloyl chloride (TPC) and isophthaloyl chloride (IPC), were employed as bulky linker cores. Solubility tests demonstrated that this family of PCMs is soluble in protic polar solvents such as H2O and MeOH, and insoluble in nonpolar solvents such as n-hexane. Fourier-ransform infrared spectroscopy (FT-IR UATR) and nuclear magnetic resonance (1H, 13C, DEPT 135°, COSY, HMQC, and HMBC NMR) were used to confirm the bonding of MPEG chains to ACs. The crystalline morphology of the synthesized materials was examined using polarized optical microscopy (POM), revealing the formation of spherulites with Maltese-cross-extinction patterns. Furthermore, it was confirmed that PCMs with higher molecular weights were crystalline at room temperature and exhibited an increased average spherulite size compared to their precursors. Thermal stability tests conducted through thermogravimetric analysis (TGA) indicated decomposition temperatures close to 400 °C for all PCMs. The phase-change properties were characterized by differential scanning calorimetry (DSC), revealing that the novel PCMs melted and crystallized between -23.7 and 60.2 °C and -39.9 and 45.9 °C, respectively. Moreover, the heat absorbed and released by the PCMs ranged from 57.9 to 198.8 J/g and 48.6 to 195.6 J/g, respectively. Additionally, the PCMs exhibited thermal stability after undergoing thermal cycles of melting-crystallization, indicating that energy absorption and release occurred at nearly constant temperatures. This study presents a new family of high-performance organic PCMs and demonstrates that the orientation of substituent groups in the phenylene ring influences supercooling, transition temperatures, and thermal energy storage capacity depending on the MPEG molecular weight.


Morbidity and mortality amongst infants of diabetic mothers admitted into a special care baby unit in Port Harcourt, Nigeria.
Infants born to diabetic women have certain distinctive characteristics, including large size and high morbidity risks. The neonatal mortality rate is over five times that of infants of non diabetic mothers and is higher at all gestational ages and birth weight for gestational age (GA) categories.The study aimed to determine morbidity and mortality pattern amongst infants of diabetic mothers (IDMS) admitted into the Special Care Baby Unit of University of Port Harcourt Teaching Hospital. This was a study of prevalence of morbidity and mortality among IDMs carried out prospectively over a two year period. All IDMs (pregestational and gestational) admitted into the Unit within the period were recruited into the study.Data on delivery mode, GA, birth weight, other associated morbidities, investigation results, treatment, duration of hospital stay and outcome were collated and compared with those of infants of non diabetic mothers matched for GA and birth weight admitted within the same period. Maternal data were reviewed retrospectively. Data were analyzed using SPSS 16.0. Sixty percent of the IDMs were born to mothers with gestational diabetes, while 40% were born to mothers with pregestational DM. 38 (74.3%) were born by Caesarian section (CS), of which 20 (52.6%) were by emergency CS. There was no significant difference in emergency CS rates, when compared with controls, but non-IDMs were more likely to be delivered vaginally. The mean GA of IDMs was 37.84 weeks ± 1.88. 29 (61.7%) of them were macrosomic. The commonest morbidities were Hypoglycemia (significantly higher in IDMs than non-IDMs) and hyperbilirubinaemia in 30 (63.8%) and 26 (57.4%) respectively.There was no difference in morbidity pattern between infants of pre- gestational and gestational diabetic mothers. Mortality rate was not significantly higher in IDMs The incidence of macrosomia in IDMs was high but high rates of emergency CS was not peculiar to them. Hypoglycaemia and hyperbilirubinaemia were the commonest morbidities in IDMs.Referring women with unstable metabolic control to specialized centers improves pre- and post- natal outcomes. Maternal-Infant centers for management of diabetes in pregnancy are advocated on a national scale to reduce associated morbidity and mortality.


Primary health care physicians' approach toward domestic violence in Tehran, Iran.
Primary health care physicians (PHCPs) are the first in the clinic to detect and help victims of intimate partner violence (IPV). Therefore, their attitude and practice toward domestic violence (DV) are important to manage this problem. The aim of current study was to compare the behavior and attitude of PHCPs about DV versus other health risk factors in Tehran, Iran. A convenience sample of 220 PHCPs was evaluated. The study was carried out in April 2012. Two self-administered questionnaires were used to identify physicians' beliefs and behaviors on screening and intervention of DV and other health risk factors. All analyses were performed using SPSS version 18.0 (SPSS, Inc. Chicago, IL). One hundred and ninety eight questionnaires were analyzed. PHCPs' mean age was 39.06 (±7.5) years. Participants were just reported 10% screening of regular patients for DV compared with 29% to 48% for other health risk factors. Mean age of PHCPs was not associated with their approach toward the DV. Compared to male physicians, females spared more time for DV victims. Major of physicians (96%) believed that DV is not a private problem and is something that needs to be addressed cautiously. The results of this study indicated that DV screening occurs less than that of other health risk factors. Attitude of majority of PHCPs was positive for addressing this problem.


The in vitro sensitivity of leukemic and normal leukocytes to hydrocortisone induced cytolysis.
A marked sensitivity of CLL lymphocytes to hydrocortisone in vitro was demonstrated in each of the 25 patients tested. The sensitivity was manifested by the eventual lysis of the affected cells. Malignant lymphocytes from 8 out of 14 ALL patients were found also to be in vitro sensitive, whereas CML cells, AML cells, normal BM cells, thymocytes, peripheral blood lymphocytes, and polymorphonuclear cells were resistant. Within a tested CLL lymphoid suspension it is proven that the hydrocortisone causes the specific lysis of the malignant cells leaving the normal lymphocytes undamaged. The cytolysis is not an immediate action, but is expressed within 7-8 hr of incubation. However, 30 min incubation with the hormone is sufficient for the cytolytic effect to occur 20 hr later. The possible mechanisms involved in the specific glucocorticoid induced cytolysis are discussed.


Comparability of the thermodilution cardiac output method: proximal injectate versus proximal infusion lumens.
In this study we examined the relationship between cardiac output (CO) measurements obtained from the proximal injectate lumen and the proximal infusion lumen of a thermodilution pulmonary artery catheter. The research was predicated on the belief that a strongly significant relationship would provide the clinician with an alternative lumen for measuring CO. Twenty-one subjects were selected by using a nonprobability convenience sampling method. With ice temperature injectate, four injections were performed into one lumen followed by four injections into the alternate lumen. CO values were computed with installed data management physiologic monitors. A Pearson's Product-Moment Correlation Coefficient was calculated, and the result verified a strong positive correlation between CO values (r = 0.96, p = less than 0.0001). Results of a paired t test demonstrated no statistically significant differences between CO means. These findings lend direction for minimizing the potential risk of catheter contamination associated with the manipulation of intravenous lines containing vasoactive medications. It also may save time for the critical care clinician who is trying to balance tasks such as CO measurements and titration of vasoactive or inotropic medications.


Novel field-portable high-pressure adsorbent tube sampler prototype for the direct in situ preconcentration of trace compounds in gases at their working pressures: application to biomethane.
In Europe, renewable energy gases such as biomethane are aimed at substituting natural gas provided their stringent compliance to natural gas quality standards stipulating maximal levels of several chemical trace compounds (TC). Preconcentration is generally required to detect TC and inasmuch as biomethane is compressed for injection in the natural gas grid, preconcentration is commonly either done by collecting the bulk pressurized gas in a high-pressure cylinder or by first depressurizing it to collect a bulk volume in e.g. a gas sampling bag. Such whole gas samples are then transported to the lab and transferred to a preconcentration unit, entailing contamination and TC loss risks. Therefore, here a novel handy field-portable device for the direct in situ high-pressure preconcentration of TC is presented, enabling to sample gases at pressures up to 200 bara through a self-assembled Tenax®TA + Carbopack™X multibed adsorbent tube. The effect of the gas sampling pressure on the preconcentration of TC on adsorbent tubes was evaluated using a synthetic gas mixture containing 41 halogenated volatile organic compounds each at 1 ppmmol in N2. At given normalized sampled volumes and in the pressure range 5-100 bara handled in French gas transport grids, the pressure had no influence on the preconcentration when the gas circulates through the adsorbent tubes and as long as the adsorbents are not saturated. Next, for the first time, a real biomethane stream was sampled using the novel direct high-pressure preconcentration method on Tenax®TA + Carbopack™X multibed adsorbent tubes, allowing to preconcentrate, in a single sampling run, a wide range of volatile organic TC. More than 26 distinct TC were detected, belonging to seven chemical families: alkenes, aromatics, alkanes (linear, cyclic and polycyclic), sulphur-compounds and terpenes, with linear alkanes (pentane, heptane, octane) and terpenes predominating. Semi-quantification indicated pentane, dimethylcyclopropane, hexane, heptane, octane, α-pinene and camphene are present at a ≤1 ppmmol concentration threshold in the biomethane.


Association of THBS1 rs1478605 T>C in 5'-untranslated regions with the development and progression of gastric cancer.
Thrombospondin 1 (THBS1) plays an important role in angiogenesis and tumor progression. The aim of the present study was to investigate the effects of single-nucleotide polymorphisms (rs1478605 and rs3743125) in the untranslated regions of the THBS1 gene on the development and progression of gastric cancer. In the case-control study, 275 gastric cancer patients and 275 cancer-free controls were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism. The data demonstrated that THBS1 rs1478605 genotypic distributions significantly differed between the patient and control groups (P=0.005). Carriers of the CC genotype exhibited a decreased risk of developing gastric cancer compared to the carriers of the CT and TT genotypes [adjusted odd ratio (OR), 0.56; 95% confidence interval (CI), 0.39-0.79; P=0.001]. The CC genotype of rs1478605 was negatively associated with gastric cancer lymph node metastasis (OR, 0.41; 95% CI, 0.23-0.71; P=0.001) and was associated with a reduced risk of lymph node metastasis in male patients (OR, 0.27; 95% CI, 0.14-0.52; P<0.001). The THBS1 CT haplotype was associated with a reduced risk of developing gastric cancer (OR, 0.56; 95% CI, 0.33-0.93; P=0.02). By contrast, no association was observed between THBS1 rs3743125 and the development and progression of gastric cancer. These results suggest that THBS1 rs1478605 represents a potential molecular marker for gastric cancer.


Statistical Learning and Bilingualism.
Over the last 2 decades, research on statistical learning has demonstrated its importance in supporting language development. Notably, most of the research to date has focused on monolingual populations (or has not reported the language background of participants). Several recent studies, however, have begun to focus on the impact of bilingualism on statistical learning. To date, the results have been quite mixed, with a handful of studies finding differences between monolinguals and bilinguals and several other studies reporting no differences. Thus, the purpose of this manuscript is to review the literature to date on how bilingualism impacts statistical learning abilities. We review the contemporary literature, organized by the age of participants and by task when relevant. We note that there are many discrepant findings within this nascent field, although some trends have emerged. For instance, differences in performance may be attributed to factors such as age of acquisition. However, we note that the state of the field does not yet permit firm clinical recommendations.


Phase II study of bevacizumab in patients with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy.
Alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti-VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS. Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately. Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T(1)), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/μL. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2). Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients.


Memory for sequences of events impaired in typical aging.
Typical aging is associated with diminished episodic memory performance. To improve our understanding of the fundamental mechanisms underlying this age-related memory deficit, we previously developed an integrated, cross-species approach to link converging evidence from human and animal research. This novel approach focuses on the ability to remember sequences of events, an important feature of episodic memory. Unlike existing paradigms, this task is nonspatial, nonverbal, and can be used to isolate different cognitive processes that may be differentially affected in aging. Here, we used this task to make a comprehensive comparison of sequence memory performance between younger (18-22 yr) and older adults (62-86 yr). Specifically, participants viewed repeated sequences of six colored, fractal images and indicated whether each item was presented "in sequence" or "out of sequence." Several out of sequence probe trials were used to provide a detailed assessment of sequence memory, including: (i) repeating an item from earlier in the sequence ("Repeats"; e.g., AB A: DEF), (ii) skipping ahead in the sequence ("Skips"; e.g., AB D: DEF), and (iii) inserting an item from a different sequence into the same ordinal position ("Ordinal Transfers"; e.g., AB 3: DEF). We found that older adults performed as well as younger controls when tested on well-known and predictable sequences, but were severely impaired when tested using novel sequences. Importantly, overall sequence memory performance in older adults steadily declined with age, a decline not detected with other measures (RAVLT or BPS-O). We further characterized this deficit by showing that performance of older adults was severely impaired on specific probe trials that required detailed knowledge of the sequence (Skips and Ordinal Transfers), and was associated with a shift in their underlying mnemonic representation of the sequences. Collectively, these findings provide unambiguous evidence that the capacity to remember sequences of events is fundamentally affected by typical aging.


Loss of function of the ALS protein SigR1 leads to ER pathology associated with defective autophagy and lipid raft disturbances.
Intracellular accumulations of altered, misfolded proteins in neuronal and other cells are pathological hallmarks shared by many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Mutations in several genes give rise to familial forms of ALS. Mutations in Sigma receptor 1 have been found to cause a juvenile form of ALS and frontotemporal lobar degeneration (FTLD). We recently described altered localization, abnormal modification and loss of function of SigR1 in sporadic ALS. In order to further elucidate the molecular mechanisms underlying SigR1-mediated alterations in sporadic and familial ALS, we extended our previous studies using neuronal SigR1 knockdown cell lines. We found that loss of SigR1 leads to abnormal ER morphology, mitochondrial abnormalities and impaired autophagic degradation. Consistent with these results, we found that endosomal trafficking of EGFR is impaired upon SigR1 knockdown. Furthermore, in SigR1-deficient cells the transport of vesicular stomatitis virus glycoprotein is inhibited, leading to the accumulation of this cargo protein in the Golgi apparatus. Moreover, depletion of SigR1 destabilized lipid rafts and associated calcium mobilization, confirming the crucial role of SigR1 in lipid raft and intracellular calcium homeostasis. Taken together, our results support the notion that loss of SigR1 function contributes to ALS pathology by causing abnormal ER morphology, lipid raft destabilization and defective endolysosomal pathways.


Structural evidence that human acetylcholinesterase inhibited by tabun ages through O-dealkylation.
Tabun is a warfare agent that inhibits human acetylcholinesterase (hAChE) by rapid phosphylation of the catalytic serine. A time-dependent reaction occurs on the tabun adduct, leading to an "aged" enzyme, resistant to oxime reactivators. The aging reaction may proceed via either dealkylation or deamidation, depending on the stereochemistry of the phosphoramidyl adduct. We solved the X-ray structure of aged tabun-hAChE complexed with fasciculin II, and we show that aging proceeds through O-dealkylation, in agreement with the aging mechanism that we determined for tabun-inhibited human butyrylcholinesterase and mouse acetylcholinesterase. Noteworthy, aging and binding of fasciculin II lead to an improved thermostability, resulting from additional stabilizing interactions between the two subdomains that face each other across the active site gorge. This first structure of hAChE inhibited by a nerve agent provides structural insight into the inhibition and aging mechanisms and a structural template for the design of molecules capable of reactivating aged hAChE.


["Interpreter of dreams" and "dreamer" in Homer].
In this essay I examine the figure of the homeric [Greek characters: see text], a term which recurs in two passages of the Iliad (I 63; V 149). It has been explained both with the meaning of "interpreter of dreams" and of "dreamer" using his own gifts in favour of the community. This latter seems to be the most ancient use of the word, as it results in the episode told in the first book of the Iliad (crisis in the Greek army after the plague sent by Apollo). This use has an interesting parallel in some functions of the Spartan ephors and, in the second millennium, in the professional figure of the "dreamer" in the nearby Hittite area. More doubtful is the meaning in the Iliad V 149, since, in this case, there are no sufficient reasons to give the commonly attributed meaning of "interpreter of dreams". The analysis of the word, which is undoubtedly linked to the epic tradition, also offers the occasion to linger on some important homeric dreams (Agamemnon, Penelope) and on the use of the same word in the Stories by Herodotus.


Personality patterns and Smoking behavior among students in Tabriz, Iran.
Psychological factors have always been considered for their role on risk taking behavior such as substance abuse, risky driving and smoking. The aim of this study was to determine the association between smoking behavior and potential personality patterns among high school students in Tabriz, Iran. Through a multistage sampling in a cross-sectional study, 1000 students were enrolled to represent the final grade high school student population of Tabriz, Iran in 2013. The personality patterns along with smoking status and some background information were collected through standard questionnaires along with Millon Clinical Multiaxial Inventory-III (MCMI-III). Fourteen personality patterns and ten clinical syndromes. ANOVA and Kruskal Wallis tests were used to compare numeric scales among the study participants, with respect to their smoking status. Stata version 13 statistical software package was used to analyze the data. Multivariate logistic regression was used to predict likelihood of smoking by personality status. Two logistic models were developed in both of whom male sex was identified as a determinant of regular smoking (1st model) and ever-smoking (2nd model). Depressive personality increased the likelihood of being a regular smoker by 2.8 times (OR=2.8, 95% CI: 1.3-6.1). The second personality disorder included in the model was sadistic personality with an odds ratio of 7.9 (96% CI: 1.2-53%). Histrionic personality increased the likelihood of experiencing smoking by 2.2 times (OR=2.2, 95% CI: 1.6-3.1) followed by borderline personality (OR=2.8, 95% CI: 0.97-8.1). Histrionic and depressive personalities could be considered as strong associates of smoking, followed by borderline and sadistic personalities. A causal relationship couldn't be assumed unless well controlled longitudinal studies reached the same findings using psychiatric interviews.


Broad-spectrum antimicrobial activity of human intestinal defensin 5.
Defensins are antibiotic peptides expressed in human and animal myeloid and epithelial cells. Due to the limited availability of natural peptides, the properties of human epithelial defensins have not been studied. We assayed the microbicidal activity of recombinant human intestinal defensin 5 (rHD-5) in the presence of salt (O to 150 mM NaCl) with varied pH (pH 5.5 to pH 8.5) and trypsin (25 and 250 microg/ml). rHD-5 exhibits microbicidal activity against Listeria monocytogenes, Escherichia coli, and Candida albicans. In contrast to cryptdins, the mouse intestinal defensins, rHD-5 is active against both mouse-virulent wild-type Salmonella typhimurium and its isogenic, mouse-avirulent phoP mutant. In the presence of salt, rHD-5 activity was reduced, and at 100 mM NaCl, activity against S. typhimurium was abolished. However, at all salt concentrations tested, rHD-5 remained bactericidal to L. monocytogenes. Activity against L. monocytogenes was not pH dependent but was diminished at pH 5.5 against wild-type S. typhimurium. This acid-induced resistance may have been mediated by the virulence gene regulator phoP, since the phoP mutant was equally sensitive at pH 5.5 and pH 7.4. In the presence of trypsin, rHD-5 was partially cleaved, but even then, rHD-5 at 100 microg/ml decreased the number of CFU of wild-type S. typhimurium by more than 99%. The persistence of microbicidal activity of rHD-5 under these conditions supports the notion that naturally occurring human intestinal defensin is an effective arm of mucosal host defense.


A comparison of subset selection and analysis of covariance for the adjustment of confounders.
Two common methods for adjusting group comparisons for differences in the distribution of confounders, namely analysis of covariance (ANCOVA) and subset selection, are compared using real examples from neuropsychology, theory, and simulations. ANCOVA has potential pitfalls, but the blanket rejection of the method in some areas of empirical psychology is not justified. Assumptions of the methods are reviewed, with issues of selection bias, nonlinearity, and interaction emphasized. Advantages of ANCOVA include better power, improved ability to detect and estimate interactions, and the availability of extensions to deal with measurement error in the covariates. Forms of ANCOVA are advocated that relax the standard assumption of linearity between the outcome and covariates. Specifically, a version of ANCOVA that models the relationship between the covariate and the outcome through cubic spline with fixed knots outperforms other methods in simulations.


Higher success rate observed in reconstruction techniques of acute posterolateral corner knee injuries as compared to repair: an updated systematic review.
There remains controversy regarding the optimal surgical treatment for acute complete (grade III) posterolateral corner (PLC) injuries. The purpose of this article is to systematically review the contemporary literature regarding surgical options and subsequent outcomes of acute grade III PLC injuries. A systematic review was performed using the following search terms: posterolateral corner knee, posterolateral knee, posterolateral instability, multi-ligament knee, and knee dislocation. Inclusion criteria consisted of studies with level I-IV evidence, reporting on human patients with acute grade III PLC injuries undergoing operative management within 4 weeks from injury, with subjective and/or objective outcomes (including varus stress examinations or varus stress radiographs) reported at a minimum 2-year follow-up. Two investigators independently performed the search by sequentially screening articles. Accepted definitions of varus stability on examination or stress radiographs and revision surgery were used to determine success and failure of treatment. A total of 12 studies, consisting of 288 patients were included. Ten studies reported primary repair, while reconstruction techniques were reported in seven studies. Overall, 43% (n = 125/288) of injuries involved the PLC, ACL and PCL. Staged reconstruction was reported in 25% (n = 3/12) of studies. The Lysholm score was the most commonly reported outcome measure. An overall failure rate of 12.4% (n = 35/282) was observed. Surgical failure was significantly higher in patients undergoing repair (21.9%; n = 21/96) compared to reconstruction (7.1%; n = 6/84) (p = 0.0058). Return to sport was greater in patients undergoing reconstruction (100%; n = 22/22) compared to repair (94%; n = 48/51) (n.s). The most common post-operative complication was arthrofibrosis requiring manipulation under anesthesia (8.7%; n = 25/288). A total of 3.8% (n = 11/288) of patients underwent revision PLC reconstruction. There remains substantial heterogeneity in the surgical techniques of acute, grade III PLC injuries with an overall failure rate of 12.4%. Failure rates were significantly lower, and return to sport rates higher in patients undergoing PLC reconstruction compared to repair. The most common postoperative complication was arthrofibrosis requiring manipulation under anesthesia. Level IV.


The interferon receptors.
Early studies on the mode of action of interferons have indicated that a receptor system on the cell surface is involved in its action. The first direct evidence to a high-affinity binding site was found only after pure interferon was available. Two different receptors, one specific for interferons-alpha and beta, and the other for interferon-gamma were recognized. A correlation between affinity to the receptor and specific activity was established. Cross-linked complexes of labeled interferons with their receptors were visualized on gel electrophoresis and even partially purified. Internalization of interferons after binding to the receptor was reported. The role of gangliosides as helpers of interferon binding was recently investigated. Fragments of interferons which still retained binding capacity were described and helped in elucidating the binding site on the interferon molecule.


Ingestion by men of a combined dose of beta-carotene and lycopene does not affect the absorption of beta-carotene but improves that of lycopene.
A double-blind study was conducted in 10 healthy men to investigate serum beta-carotene and lycopene responses after ingestion of individual and combined doses of beta-carotene (BC) and lycopene. On each dosing day, a baseline blood sample was drawn, followed by an oral dose of 0.11 mmol (60 mg) of either all-trans BC or all-trans lycopene or by a combined oral dose of 0.11 mmol each. Subjects were tested with each of the three doses. The dose type was randomized. Blood (10 mL) was drawn at 1, 3, 5, 7, 9, 12 and 24 h after dosing. At 2 and 4 wk after the first dose, the protocol was repeated with the other doses. After ingestion of the BC dose, serum BC concentrations significantly decreased from baseline at 1 and 3 h followed by a continuous increase from baseline that was significant at 12 and 24 h (P < 0.01). Serum lycopene concentrations significantly increased from baseline at 5 h after the lycopene dose (P < 0.008) and returned to baseline thereafter. Ingestion of a combined dose of BC and lycopene resulted in a significant increase in serum concentrations of both BC and lycopene at 24 h (P < 0.05). The 24-h area under the curve (AUC) for BC was not different when BC was ingested alone or with lycopene, whereas the 24-h AUC for lycopene was significantly greater when lycopene was ingested with BC than when ingested alone (P < 0.05). Our data suggest that ingestion of a combined dose of BC and lycopene has little effect on the absorption of BC but improves that of lycopene in men.


Effects of a Sustained, Isometric Forearm Flexion Task to Failure on Torque and Neuromuscular Responses at 3 Elbow Joint Angles.
Ortega, DG, Housh, TJ, Smith, RW, Arnett, JE, Neltner, TJ, Anders, JPV, Schmidt, RJ, and Johnson, GO. The effects of a sustained, isometric forearm flexion task to failure on torque and neuromuscular responses at 3 elbow joint angles. J Strength Cond Res 38(1): e25-e33, 2024-This study examined the effects of a sustained, isometric forearm flexion task anchored to torque to task failure on maximal voluntary isometric contraction (MVIC) and neuromuscular responses at 3 elbow joint angles. Eleven women (mean ± SD: age = 20.8 ± 2.7 years, height = 169.3 ± 7.4 cm, body mass = 67.7 ± 6.9 kg) performed two 3s forearm flexion MVICs at elbow joint angles (JAs) of 75°, 100°, and 125° before and after a sustained, isometric forearm flexion task to failure at a fatiguing joint angle of 100° anchored to a torque value that corresponded to a rating of perceived exertion of 8 (RPE = 8). The amplitude (AMP) and mean power frequency (MPF) of the electromyographic (EMG) and mechanomyographic (MMG) signals were recorded from the biceps brachii. Repeated-measures ANOVAs were used to compare mean differences for MVIC and neuromuscular parameters. Collapsed across JAs, MVIC (p < 0.001) and EMG MPF (p = 0.006) pretest values were greater than posttest values. Collapsed across time, EMG MPF at JA75 was greater than JA100 (p < 0.001) and JA125 (p < 0.001), and JA100 was greater (p = 0.007) than JA125. For EMG AMP, there was a fatigue-induced decrease at JA75 (p = 0.003). For neuromuscular efficiency (NME = normalized torque/normalized EMG AMP), there were decreases from pretest to posttest at JA100 (p = 0.002) and JA125 (p = 0.008). There were no significant interactions or main effects for MMG AMP and MMG MPF. From these findings, it was hypothesized that the decline in MVICs at JA75, JA100, and JA125 was due to fatigue-induced metabolic perturbations that resulted in JA-specific neuromuscular responses. Thus, neuromuscular parameters may provide insight into the JA-specific mechanisms of fatigue.


Development and regulation of cell-mediated immune responses to the blood stages of malaria: implications for vaccine research.
The immune response to the malaria parasite is complex and poorly understood. Although antibodies and T cells can control parasite growth in model systems, natural immunity to malaria in regions of high endemicity takes several years to develop. Variation and polymorphism of antibody target antigens are known to impede immune responses, but these factors alone cannot account for the slow acquisition of immunity. In human and animal model systems, cell-mediated responses can control parasite growth effectively, but such responses are regulated by parasite load via direct effects on dendritic cells and possibly on T and B cells as well. Furthermore, high parasite load is associated with pathology, and cell-mediated responses may also harm the host. Inflammatory cytokines have been implicated in the pathogenesis of cerebral malaria, anemia, weight loss, and respiratory distress in malaria. Immunity without pathology requires rapid parasite clearance, effective regulation of the inflammatory anti-parasite effects of cellular responses, and the eventual development of a repertoire of antibodies effective against multiple strains. Data suggest that this may be hastened by exposure to malaria antigens in low dose, leading to augmented cellular immunity and rapid parasite clearance.


[Secondary pyomyositis of hip muscles (non-tropical pyomyositis)].
By presenting the results of treatment of secondary pyomyositis of deep hip muscles, to draw attention to the seriousness of this complication occurring in association with pelvic and lumbo-sacral infections. The course of disease was evaluated retrospectively in a group of 13 patients with an average age of 65.8 years treated in the period from April 2004 to June 2007. The imaging methods used included native radiography, ultrasonography (SONO), computed tomography (CT) and magnetic resonance imaging (MRI). Markers of inflammation, i.e., C-creative protein, erythrocyte sedimentation rate and WBC differential count, were used to assess the intensity of inflammation. At stage 1, patients were treated conservatively, with appropriate antibiotic therapy. At stages 2 and 3, surgical procedures were used (incision, abscess evacuation and drainage) or abscess was treated by CT-guided needle puncture and pigtail drain insertion. The evaluation took into account survival of the patients in relation to the stage of their disease, early detection of origin of infection, therapy initiation, and other factors putting patients at risk. Of the 13 patients treated, 10 had stage 3 pyomyositis with beginning or developed multiple-organ failure when they were referred to our institution from outside hospitals; three admitted at stage 2 pyomyositis were in relatively good state. Ten patients were cured, two died due to multiple-organ failure and one due to pulmonary embolism after lower-extremity phlebothrombosis. The success of treatment appeared to be related to early surgical intervention. A good outcome of therapy depends on an early diagnosis and treatment of the underlying infection and pyomyositis. To establish the diagnosis of pyomyositis, repeated clinical, laboratory and bacteriological examinations are necessary, as well as the use of imaging methods, namely SONO, CT and MRI. Treatment may be complicated when small multiple abscesses develop deep in the hip muscles where surgical intervention is difficult. Secondary pyomyositis is a serious, life-threatening complication of the underlying infection. The outcome of the disease depends on early diagnosis, therapy and the patient's overall state. Stage 1 pyomyositis (muscle oedema) is treated conservatively with antibiotics. Stage 2 pyomyositis needs surgical intervention with abscess aspiration and drainage; in some cases CT-guided needle puncture with pigtail drain insertion is sufficient. An appropriate antibiotic course is obligatory. Stage 3 pyomyositis associated with septic shock or multiple-organ failure requires a comprehensive care in an acute medicine department. In polymorbid patients prognosis is poor and treatment is expensive and often unsuccessful.


Canonical WNT pathway inhibition reduces ATP synthesis rates in glioblastoma stem cells.
The conserved stem cell signaling network canonical Wingless (WNT) plays important roles in development and disease. Aberrant activation of this pathway has been linked to tumor progression and resistance to therapy. Industry and academia have substantially invested in developing substances, which can efficiently and specifically block the WNT signaling pathway. However, a clear clinical proof of the efficacy of this approach is still missing. Studies on the metabolomics dysregulation of cancer cells have led to innovations in oncological diagnostics. In addition, modulation of cancer cell metabolome is at the base of promising clinical oncology trials currently underway. While onco-protein activation can have profound metabolic outcomes, the involvement of stem cell signals, such as the WNT pathway, in tumor cell metabolomics is yet insufficiently characterized. We determined live cell metabolism and bioenergetics in pathophysiological relevant, WNT-dependent glioblastoma stem cell (GSC) models. We quantified those parameters in cells with canonical WNT activity and in isogenic cells where WNT activity had been inhibited by short hairpin RNA against β-catenin. Furthermore, we applied computational analysis of RNA sequencing to verify our functional findings in independent GSCs cohorts. The investigated collection of disease models allows the separation in tumors with low, moderate and high base line metabolic activity. Suppression of canonical WNT signaling led to significant reduction of total, mitochondrial, and glycolytic ATP production rates. Elevated canonical WNT transcription signature in GSCs positively correlated with transcription levels of mitochondrial ATP synthesis, whereas non-canonical WNT gene expression signature did not. The applied disease modeling technology allows the recapitulation of inter-tumoral heterogeneous metabolic properties of glioblastoma. Our data show for the first time that inhibition of canonical WNT signaling in alive GSCs functionally correlates with energy inhibition and glucose homeostasis. As this correlation occurs in GSCs from different transcriptional or epigenetic transcriptional subtypes, our results suggest that developing therapies directed against glycolysis/ATP-synthesis may be a promising strategy to overcome therapy resistance due to inter-tumoral heterogeneity and offers starting point to impair downstream signal WNT.


Health insurance coverage and the use of preventive services by Mexican adults.
The lack of health insurance coverage could be a potentially important deterrent to the use of preventive health care by older adults with high rates of chronic co-morbidities. We use survey data from 12 100 Mexican adults ages 50 and older who participated in the 2001 Mexican Health and Aging Study (MHAS) to analyze the relation between health insurance coverage and the use of preventive health-care services in Mexico. Uninsured adults were less likely to use preventive screenings for hypertension, high cholesterol, diabetes and (breast, cervical and prostate) cancer than insured adults. After adjusting for other factors affecting preventive care utilization in a logistic regression model, we found that these results still hold for high cholesterol and diabetes screening. Similar results hold for the population not working during the survey week and for adults earning below 200% of the poverty line. Our results suggest that insured adults are in a relatively better position to detect some chronic diseases - and have them treated promptly - than uninsured adults because they have better access to cost-effective preventive screenings. Recent public policy initiatives to increase health insurance coverage rates in Mexico could lead to substantially higher preventive health-care utilization rates and improvements in population health.


The catalytic chain of human complement subcomponent C1r. Purification and N-terminal amino acid sequences of the major cyanogen bromide-cleavage fragments.
1. The a- and b-chains of reduced and alkylated human complement subcomponent C1r were separated by high-pressure gel-permeation chromatography and isolated in good yield and in pure form. 2. CNBr cleavage of C1r b-chain yielded eight major peptides, which were purified by gel filtration and high-pressure reversed-phase chromatography. As determined from the sum of their amino acid compositions, these peptides accounted for a minimum molecular weight of 28 000, close to the value 29 100 calculated from the whole b-chain. 3. N-Terminal sequence determinations of C1r b-chain and its CNBr-cleavage peptides allowed the identification of about two-thirds of the amino acids of C1r b-chain. From our results, and on the basis of homology with other serine proteinases, an alignment of the eight CNBr-cleavage peptides from C1r b-chain is proposed. 4. The residues forming the 'charge-relay' system of the active site of serine proteinases (His-57, Asp-102 and Ser-195 in the chymotrypsinogen numbering) are found in the corresponding regions of C1r b-chain, and the amino acid sequence around these residues has been determined. 5. The N-terminal sequence of C1r b-chain has been extended to residue 60 and reveals that C1r b-chain lacks the 'histidine loop', a disulphide bond that is present in all other known serine proteinases.


High-Throughput Microdissection for Next-Generation Sequencing.
Precision medicine promises to enhance patient treatment through the use of emerging molecular technologies, including genomics, transcriptomics, and proteomics. However, current tools in surgical pathology lack the capability to efficiently isolate specific cell populations in complex tissues/tumors, which can confound molecular results. Expression microdissection (xMD) is an immuno-based cell/subcellular isolation tool that procures targets of interest from a cytological or histological specimen. In this study, we demonstrate the accuracy and precision of xMD by rapidly isolating immunostained targets, including cytokeratin AE1/AE3, p53, and estrogen receptor (ER) positive cells and nuclei from tissue sections. Other targets procured included green fluorescent protein (GFP) expressing fibroblasts, in situ hybridization positive Epstein-Barr virus nuclei, and silver stained fungi. In order to assess the effect on molecular data, xMD was utilized to isolate specific targets from a mixed population of cells where the targets constituted only 5% of the sample. Target enrichment from this admixed cell population prior to next-generation sequencing (NGS) produced a minimum 13-fold increase in mutation allele frequency detection. These data suggest a role for xMD in a wide range of molecular pathology studies, as well as in the clinical workflow for samples where tumor cell enrichment is needed, or for those with a relative paucity of target cells.


[Fosinorm in the treatment of essential hypertension with a metabolic syndrome].
The authors made an open-comparative trial of fosinopril (Fosinorm) efficacy and tolerability in 20 patients (9 males and 11 females) with stage II mild and moderate essential hypertension accompanied with disturbed glucose tolerance and dyslipidemia. Fosinorm was given in a dose 10 - 20 mg/day under 24-h monitoring of blood pressure. Diastolic pressure returned to normal in 19 (95%) patients, one patient showed a good hypotensive response. The mean 24-h fall in the systolic and diastolic pressure was significant and made up for systolic pressure 7.5% (9.2% and 9.2%), respectively. Fosinorm had a minimal effect on carbohydrate metabolism, total cholesterol, serum triglycerides. The conclusion is made that Fosinorm is a highly effective antihypertensive drug positively influencing 24-h profile of blood pressure in the absence of negative action on carbohydrate and lipid metabolism.


Prostate cryotherapy: current status.
Minimally invasive options to treat low-risk prostate cancer are more desirable than radical therapy. Technological improvements in cryotherapy have increased its use, and long-term data on its efficacy are emerging. In this review, we discuss contemporary data on cryotherapy with specific focus on studies using the newest technology. With respect to biochemical recurrence rates, cryotherapy appears to be as effective for low-risk prostate cancer as other treatment modalities. The definition of recurrence remains problematic, though contemporary studies are more consistently using both the American Society for Therapeutic Radiation Oncology and Phoenix criteria. Erectile dysfunction rates are universally high after whole-gland cryoablation, but incontinence and urethrorectal fistula rates appear to be low with third-generation cryo systems. Focal cryotherapy has encouraging short-term efficacy in terms of biochemical disease-free survival rate for unifocal disease, and rates of erectile dysfunction are dramatically lower than those seen with whole-gland cryoablation. Cryosurgery has a promising role in primary and salvage treatment of select prostate cancer patients. Focal cryotherapy for unilateral disease offers the added benefit of minimal adverse effects. Long-term data are emerging to support cryosurgery, and large multicenter databases have been developed to answer questions regarding optimal treatment outcomes and patterns.


Incidence of hepatitis E virus infection among blood donors in a high endemic area of Central Italy.
In Europe, autochthonous hepatitis E virus (HEV) infection is mainly a foodborne zoonosis, but it is also transmitted by blood transfusion. Despite the numerous prevalence surveys, only a few studies have investigated HEV incidence. We aimed to determine HEV incidence and risk factors among blood donors in a hyperendemic area in Central Italy. Of 296 blood donors who had tested HEV negative in two previous seroprevalence surveys in L'Aquila, 198 agreed to undergo at least another blood sampling for estimating HEV incidence nearly 2 years after the prevalence surveys. Ten newly acquired infections were detected, yielding an overall incidence of 2.1/100 person-years (95%CI: 1.0-3.9), with an estimated participant's cumulative probability of becoming HEV infected of 6.5% (95%CI: 3.5-12.0) at 4 years after enrolment. Seven newly infected blood donors were IgG positive only, two were IgM positive (one also IgG positive) and one was HEV RNA positive only, harbouring subtype 3c. Incident infection was most strongly associated with eating game meat, raw-dried pork liver sausage and raw-dried wild boar sausage. None of these exposures was statistically significant, even if eating raw-dried wild boar sausage approached significance (P = 0.06). The HEV incidence we found was considerable compared with other similar studies. The nearly significant association of incident infection with wild boar and other game meat consumption was in agreement with the 3c subtype isolation in the viremic donor. However, beyond eating habits, also other exposure sources are likely important in hyperendemic areas, where incidence and risk exposure studies need to be undertaken for effectively preventing HEV transmission.


Upper extremity injuries in the National Football League: part II: elbow, forearm, and wrist injuries.
Very little information is available regarding the incidence, causative mechanisms, and expected duration of time lost following upper extremity injuries in professional American football players. (1) Upper extremity injuries in professional American football players are a common cause of missed time from practice and game participation. (2) The effect of upper extremity injuries differs as a function of the site involved and the athlete's position. Descriptive epidemiologic study. A retrospective review of all documented injuries to the elbow, forearm, and wrist sustained by all players in the National Football League over a 10-year period (1996-2005) was performed using the League's injury surveillance database. An injury was considered significant if it resulted in premature cessation of (or absence from) at least 1 practice, game, or training event. The data were analyzed from multiple perspectives, with emphasis on the type of injury, athlete position, and activity at the time of injury. There were 859 total injuries over the 10-year period: 58% involved the elbow, 30% involved the wrist, and 12% involved the forearm. Ligamentous injuries were the most common diagnosis in the elbow and wrist, with wrist sprains the most common of all diagnoses. Fractures were the most common injury occurring in the forearm. For all 3 anatomic locations, game injuries were much more common than practice injuries by a factor of 2.8 to 1. Forearm injuries led to a mean of 42 days lost, wrist injuries led to a mean of 27 days lost, and elbow injuries led to an average of 22 days lost. Fractures and dislocations led to the greatest amount of time lost (47 days and 53 days, respectively). Tackling was the activity most often (24%) implicated as causing injuries to the elbow, forearm, and wrist. Offensive and defensive linemen were most commonly injured. Elbow injuries were the most common at these positions, constituting approximately 75% of all injuries. Defensive backs sustained the greatest number of forearm injuries, approximately double the total number at any other position. Upper extremity trauma is a significant issue for professional football players. In particular, the high incidence rates of elbow injuries in linemen and forearm injuries in defensive backs warrant further scrutiny.


Self-retaining retractor and handrest system for neurosurgery.
A system for self-retaining retraction that has also been used as part of a technique of dissection in microneurosurgery is described. Small, multiple (i.e., more than two) blades can be used easily with a positioning opportunity of 360 degrees of purchase and without the necessity of another surgeon. Hand tremor, which is not particularly during microsurgery, has been dealt with by the development of a system for stabilization by a handrest. The components of the system, its sequential assembly, and its use are described and illustrated.