Lack of alpha 2-antiplasmin enhances ADP induced platelet micro-aggregation through the presence of excess active plasmin in mice.
The role of alpha2-antiplasmin (alpha2-AP) on platelet aggregation was investigated using mice deficient in alpha2-AP (alpha2-AP(-/-)) or using wild type mice (alpha2-AP(+/+)). Blood samples were taken from each mouse under anesthesia with ether and platelet rich plasma (PRP) was prepared. Platelet aggregation induced by various doses of ADP (0.3-30 microM) was detected using a laser-light scattering (LS) system. Aggregated forms were observed using a scanning electron microscopy (SEM). Dose-dependent platelet aggregation was not different in both types of mice. However, platelet micro-aggregate formation in alpha2-AP(-/-) mice induced by low dose of ADP (1.0 microM) markedly increased compared to the situation in wild type mice. Aggregated form detected by SEM showed supported data from LS analysis. When washed platelets of alpha2-AP(+/+) mice were resuspended in plasma of alpha2-AP(-/-) mice, platelet micro-aggregation was also increased. On the contrary, when washed platelets of alpha2-AP(-/-) mice were suspended in plasma of alpha2-AP(+/+) mice, platelet micro-aggregation did not change. In separate experiments, tPA (1.0 microg/ml) was added to PRP before the stimulation of ADP. tPA had no effect on platelet aggregation in alpha2-AP(+/+) mice, however platelet micro-aggregation in alpha2-AP(-/-) mice was markedly increased by the treatment with tPA. Moreover, the amount of released ATP from stimulated platelets was increased in alpha2-AP(-/-) mice treated with tPA. Lack of alpha2-AP increased platelet micro-aggregation, and plasmin plays an important role in the formation of platelet aggregation when alpha2-AP knockout mice are used. Consequently, the reduction of alpha2-AP could be a risk factor for the activation of platelets resulting in thrombus formation.


Differential immunotoxic effects of the environmental chemical benzo[a]pyrene in young and aged mice.
Young (3-6 months), middle-aged (16-18 months) and aged (23-26 months) mice were exposed in vitro and in vivo to the immunotoxic environmental chemical benzo[a]pyrene. The generation of antibody producing cells to the T-dependent antigens of sheep erythrocytes was observed to be suppressed in all age groups. Significantly, aged mice were shown to exhibit a greater percent suppression of antibody responses than young or middle-aged mice both in vitro and in vivo. The results presented provide the first evidence that the degree of immunological toxicity of environmental chemicals may be partially dependent upon the chronological and immunological age of the animal.


Mutual information detects a decreased interdependence between RR and SAP in orthostatic intolerance after microgravity condition.
Orthostatic intolerance is the most serious symptom of cardiovascular deconditioning induced by microgravity. However, the exact mechanisms underlying these alterations have not been completely clarified. Several methods for studying the time series of systolic arterial pressure and RR interval have been proposed both in the time and in the frequency domain. However, these methods did not produce definitive results. In fact heart rate and arterial pressure show a complex pattern of global variability which is likely due to non linear feedback which involves the autonomic nervous system and to "stochastic" influences. Aim of this study was to evaluate the degree of interdependence between the mechanisms responsible for the variability of SAP and RR signals in subjects exposed to head down (HD). This quantification was achieved by using Mutual Information (MI).


Adolescence as a gateway to adult health outcomes.
Adolescence has long been regarded as a transition from childhood to adulthood. More recently it is become a concern of those wishing to avoid adverse health outcomes during middle and late adulthood. Most of this effort has been focused on behavioural risk factors such as tobacco and excessive alcohol use, physical exercise habits, dietary habits, as well as sexual and injury-related behaviours. The concern is that these habits are established during adolescence, continue into adulthood, and come to constitute ongoing risk factors for adverse health outcomes during middle and late adulthood. There is good reason to criticize this approach. These behaviours are themselves shaped by adolescents' living and working conditions and even then constitute a small proportion of the variance predicting adverse health outcomes during adulthood. More complex models of how adolescence serves as a gateway to adult health outcomes are presented. These are the socio-environmental, public policy, and political economy approaches. The argument is made that adolescence is a period during which public policy plays an especially important role in predicting future health outcomes. Yet, these public policies influence health all across the life span with adolescence providing only one of many important periods during which public policy shapes health prospects during middle and later adulthood. Ultimately one should consider a range of approaches ranging from the behavioural to the political to examine how adolescence serves as a gateway towards future adult prospects. An Adolescent Gateway Towards Adult Health Model is provided to assist in this process.


Physicochemical characterization of a major protein allergen, Der p I, from the house dust mite, Dermatophagoides pteronyssinus. Amino acid analysis and circular dichroism studies.
A major house dust mite allergen, Der p I, was isolated from spent growth medium and physicochemically characterized. These studies show that the allergen is monomeric, contains approximately 216 residues and 4 intra-chain disulphide bonds. The N-terminal amino acid is threonine. Circular dichroism studies show that the allergen contains 10% alpha-helical, 50% beta-pleated sheet and 40% random structures.


Early observations on 31 adults with non-refluxing colon conduits.
A colonic segment with tunneled ureterocolic anastomoses was used for non-refluxing urinary diversion in 31 adults during the last 3 1/2 years. Half of the patients had undergone diversions previously. These pre-existing diversions had been associated with significant urologic complications. The remainder of the patients had a variety of benign and malignant diseases. After the non-refluxing colonic diversion all upper tracts remained stable or improved except in 3 patients in whom 4 ureterocolic anastomoses developed silent stenosis. Of 10 patients who had pre-existing refluxing diversion and episodic acute pyelonephritis 7 had no recurrences. No patient with sterile urine became infected and 18 of 24 patients with persistently infected urine improved. The anatomic versatility of the colon that allows the benefits of a low pressure system and unidirectional urine flow makes the non-refluxing colon conduit an advantageous alternative in adults requiring urinary diversion.


Bacterial shedding and serologic responses following an outbreak of Salmonella Typhi in an endemic cohort.
Salmonella enterica serovar Typhi (Salmonella Typhi) is the cause of typhoid fever. Salmonella Typhi may be transmitted through shedding in the stool, which can continue after recovery from acute illness. Shedding is detected by culturing stool, which is challenging to co-ordinate at scale. We hypothesised that sero-surveillance would direct us to those shedding Salmonella Typhi in stool following a typhoid outbreak. In 2016 a typhoid outbreak affected one in four residents of a Nursing School in Malosa, Malawi. The Department of Health asked for assistance to identify nursing students that might spread the outbreak to other health facilities. We measured IgG antibody titres against Vi capsular polysaccharide (anti-Vi IgG) and IgM / IgG antibodies against H:d flagellin (anti-H:d) three and six months after the outbreak. We selected participants in the highest and lowest deciles for anti-Vi IgG titre (measured at visit one) and obtained stool for Salmonella culture and PCR. All participants reported whether they had experienced fever persisting for three days or more during the outbreak (in keeping with the WHO definitions of 'suspected typhoid'). We tested for salmonellae in the Nursing School environment. We obtained 320 paired serum samples from 407 residents. We cultured stool from 25 residents with high anti-Vi IgG titres and 24 residents with low titres. We did not recover Salmonella Typhi from stool; four stool samples yielded non-typhoidal salmonellae; one sample produced a positive PCR amplification for a Salmonella Typhi target. Median anti-Vi and anti-H:d IgG titres fell among participants who reported persistent fever. There was a smaller fall in anti-H:d IgG titres among participants who did not report persistent fever. Non-typhoidal salmonellae were identified in water sampled at source and from a kitchen tap. High titres of anti-Vi IgG did not identify culture-confirmed shedding of Salmonella Typhi. There was a clear serologic signal of recent typhoid exposure in the cohort, represented by waning IgG antibody titres over time. The presence of non-typhoidal salmonellae in drinking water indicates sub-optimal sanitation. Developing methods to detect and treat shedding remains an important priority to complement typhoid conjugate vaccination in efforts to achieve typhoid elimination.


Early event-related potentials indicate context-specific target processing for eye and hand motor systems.
Concurrent eye and hand movements toward a common visual target require different motor programs based on identical visual input. We used event-related brain potentials (ERP) to determine if and when the processing of the visual target differs for the two motor systems. The N2, an index for target evaluation, was more negative for the target of a hand than of an eye movement in two experiments. A possible interpretation for this finding is different visual target processing. Targets for hand movements require a different weighting of visual information, for example concerning features such as surface structure which are important for hand but not for eye movements. In experiment 2, the early C1-component, which had an average maximum at 67 ms following target onset, was significantly more negative when subjects pointed at the stimuli. Traditionally, the C1 has been regarded as a sensory component, but recent studies have linked it to higher order processing, such as attention and expectations. Thus, the present data indicate that target processing for eye or hand movements is already context-specific during early visual information processing. We suggest that differences in a target's relevance for upcoming movements modify target processing as well as sensory expectations.


Knee varus alters three-dimensional ankle alignment in standing- a study with upright computed tomography.
For knee osteoarthritis (OA) treatment, it is important to correct the lower limb alignment including the foot. However, in the upright position, lower limb alignment is generally assessed from the body surface or radiographs, and it is a challenge to capture the exact characteristics of three-dimensional lower limb alignment. The purpose of the study was to measure lower limb alignment in patients with knee OA using upright computed tomography (CT) and radiography, and to identify features of knee joint deformity. A total of 45 limbs in 25 patients with knee OA were enrolled. The subjects underwent both upright CT and radiography for the whole lower limb in the standing position. The joint angles were calculated on both images. The degree of knee OA was classified according to Kellgren-Lawrence (KL) grade by referring to radiography, which is mainly based on the degree of articular cartilage loss and severity of osteophytes, and the characteristics or correlation between knee and ankle joint in each group was investigated. In KL-I, there was an association between varus of the knee joint and internal rotation of the talocrural joint (r = 0.76, P < 0.05). In KL-II, there was an association between varus of the knee joint and eversion of the subtalar joint (r = 0.63, P < 0.05) and talocrural joint (r = - 0.65, P < 0.05). In KL-III, there was an association between varus of the knee joint and internal rotation of the subtalar joint (r = - 0.62, P < 0.05), and in KL-IV, there was an association between varus of the knee joint and internal rotation of the subtalar joint (r = - 0.58, P < 0.05). The lower limb alignment of patients with knee OA in the standing position was found that as knee OA worsened, it became apparent that compensatory knee joint alignment depended on the ankle joint rather than the subtalar joint. The results may help in the rehabilitation of patients with knee OA, since the ankle joint alignment has a significant impact on the knee joint during coarse movements involving load.


Esophageal body motility in people with diabetes: comparison with non-diabetic healthy individuals.
The aim of this study was to compare esophageal motor characteristics between diabetics and healthy individuals. Esophageal manometry was performed in 34 type 2 diabetics and 32 healthy individuals. Waves were evaluated in the 3 thirds of the esophagus (P1=upper, P2=middle, and P3=distal). In diabetics vs. controls, wave distribution was as follows: peristaltic waves, 83.5 ± 22.2% vs. 96.3 ± 4.4%, p<0.002; simultaneous waves, 3.26 ± 5.8% vs. 0.53 ± 1.3%, p<0.01; no transmitted waves, 10.62 ± 20.7% vs. 2.75 ± 3.0%, p<0.002; and retrograde waves, 2.68 ± 4.0% vs. 0.31 ± 1.1%, p<0.03. Wave amplitude was similar between groups. Average upstroke (mmHg/s) in diabetics vs. non-diabetics was P2, 33.8 ± 13.9 vs. 40.2 ± 17.7, p<0.03; and P3, 29.8 ± 15.3 vs. 41.3 ± 14.0, p<0.002. (1) Simultaneous waves, no transmitted waves, and retrograde esophageal waves were significantly more frequent in diabetics. (2) Average upstroke was significantly lower within the middle and distal esophagus of diabetic individuals. (3) Wave amplitude was similar in both groups.


Development of negligible depletion hollow fiber-protected liquid-phase microextraction for sensing freely dissolved triazines.
A new sampling method, termed negligible depletion hollow fiber-protected liquid-phase microextraction, was developed for sensing the freely dissolved concentration (C(free)) and evaluating the availability of atrazine (ATR), desethyl atrazine (DEA), and simazine (SIM) in water. The sampling device was prepared by impregnating 1-octanol to both the pores and the lumen of a piece of polypropylene microporous hollow fiber membrane. After equilibrium and negligible depletion extraction, the 1-octanol in the lumen of the hollow fiber (10 microl) was collected for determination of triazines. Determination of C(free) and the distribution coefficient to 1-octanol (D(ow)) can be performed with this technique. A wide linear working range (1-200 microg/L) and low detection limits (0.1-1 microg/L) were obtained for triazines. Measured log D(ow) values of DEA (1.44 +/- 0.04), SIM (2.06 +/- 0.06), and ATR (2.33 +/- 0.05) agreed well with those reported in the literature. The measured D(ow) values were independent of the chemical concentration and sample pH (pH 3-10) and negligibly affected by the sample salinity (0-500 mM), suggesting that environmentally relevant pH and salinity have no significant effects on the availability of triazines. Although a slight (< or = 31%) increase of C(free) was observed, one-way analysis of variance indicated the C(free) of triazines were not significantly affected by the presence of Aldrich humic acid, Acros humic acid, and bovine albumin V (dissolved organic carbon [DOC], 0-100 mg/L). From 3 to 36% of the spiked triazines, however, were found to associate with the dissolved organic matter (DOM) in surface-water samples (DOC, 32.0-61.9 mg/L), suggesting the origin of the DOM is a key parameter in determining its association with and, thus, the availability of triazines.


[Current status and problems of the entirely subcutaneous ICD (S-ICD®)].
Prevention of sudden cardiac death is one of the most important tasks of cardiology. Transvenous ICD-systems have impressively proven their effectiveness in numerous randomized trials. Transvenous systems have their limitations due to frequent long-term lead complications. Having been available for a few years, the entirely subcutaneous ICD-system (S-ICD®, Boston Scientific, USA, former Cameron Health, USA) seems to be a promising alternative despite the lack of prospective data. The implantation of the SICD® can be performed easily; lead complications are rare because of the totally subcutaneous implantation. The detection and therapy of life-threatening tachyarrhythmias seems to be safe, although inappropriate therapies are a common problem in cases of insufficient ECG screening. S-ICD® is no alternative to the transvenous system due to limited programming options and the lack of stimulation, but it is an interesting supplement of ICD therapy.


New species and records of Pseudacteon Coquillett, 1907 (Diptera, Phoridae), parasitoids of the fire ant Solenopsis geminata group (Hymenoptera, Formicidae).
The genus Pseudacteon Coquillett (Diptera, Phoridae) has a worldwide distribution and comprises parasitic myrmecophilous species that decapitate host ants. Seventy one species are known in the genus, 41 of them occur in the Neotropical Region and are 25 from Brazil. In northeastern Brazil, there are only records for two species, Pseudacteon dentiger Borgmeier and Pseudacteon antiguensis Malloch. In this paper, two new species of the genus are described from female specimens, Pseudacteon pesqueroi new spec. and Pseudacteon plowesi new spec., and also, new records of three Pseudacteon species for the Brazilian Northeast are given.


Percutaneous and surgical treatment of pyogenic liver abscesses: observation over a 21-year period in 148 patients.
Percutaneous drainage of pyogenic liver abscess has become first-line treatment. In the past surgical drainage was preferred in some centres. The aim of this retrospective study was to assess the effectiveness of percutaneous treatments and surgical drainage, in terms of treatment success, hospital stay and costs. Data of 148 patients (90 males; 58 females; mean age, 61 yrs; range, 30-86 yrs) were retrospectively analysed. Patients' outcomes, including the length of hospital stay, procedure-related complications, treatment failure and death, were recorded. Multiple logistic regression model was used for statistical analysis. One hundred and four patients (83 with solitary and 21 with multiple abscesses) were treated percutaneously, either by needle aspiration (91 patients) or catheter drainage (13 patients) depending on the abscess's size, and 44 patients (30 with solitary and 14 with multiple abscesses) were treated surgically. There was no statistically significant difference in patients' demographics or abscess characteristics between groups. Hospital stay was longer, and costs were higher in patients treated surgically (p<0.001). There was statistically significant difference in morbidity rate between groups (p<0.001). No death occurred in both groups. Percutaneous and surgical treatment of pyogenic liver abscesses are both effective, nevertheless percutaneous drainage carries lower morbidity and is cheaper.


Environmental factors and the outcome of rheumatoid arthritis.
The outcome of rheumatoid arthritis (RA) is influenced by both genetic and non-genetic (environmental) factors. Treatment is the most important environmental factor which influences RA outcome. This chapter considers non-treatment environmental influences on the outcome of RA. There is evidence that socio-economic factors (such as level of formal education and area of residence), smoking, diet and psychological factors may affect the levels of pain and physical disability experienced by RA patients. More work is needed in order to understand the mechanisms underlying these associations. Smoking may also adversely affect radiological outcome in the longer term. It is possible that pregnancy may improve the outcome of RA. Contrary to popular lay opinion, there is no evidence that the weather has any influence on RA.


Oral triptans in the preventive management of cluster headache.
Cluster headache is a rare primary neurovascular headache and a severe pain condition with unilateral headache over 15-180 minutes and concomitant unilateral autonomic symptoms. The detailed pathophysiology of the condition is still unclear. Only a few evidence-based therapeutic options for acute therapy and the preventive management of the disease are available. Triptans, in particular sumatriptan 6 mg subcutaneously, are highly effective for acute treatment. This review focuses on the potential use of oral triptans in the prophylaxis of cluster headache.


Individual functions of the HAK and TRK potassium transporters of Schwanniomyces occidentalis.
We have cloned the gene encoding the TRK transporter of the soil yeast Schwanniomyces occidentalis and obtained the HAK1 trk1 delta and the hak1 delta TRK1 mutant strains. Analyses of the transport capacities of these mutants have shown that (i) the HAK1 and the TRK1 potassium transporters are the only transporters operating at low and medium K+ concentrations (< 1 mM); (ii) the HAK1 transporter is functional at low pH but fails at high pH; and (iii) the TRK1 transporter functions at neutral and high pH and fails at low pH. At neutral pH, both transporters are functional, but HAK1 is not expressed, except at very low K+ concentrations (< 50 microM) where HAK1 is very effective. TRK1 is also involved in the control of the membrane potential.


Nitric oxide reduces blood pressure in the nucleus tractus solitarius: a real time electrochemical study.
Increasing evidence has demonstrated that nitric oxide (NO) is involved in central cardiovascular regulation. In this study, we directly measured extracellular NO levels, in real-time, in the nucleus tractus solitarius (NTS) of anesthetized cats using Nafion/Porphyrine/o-Phenylenediamine-coated NO sensors. We found that local application of L-arginine (L-Arg) induced NO overflow in NTS and hypotension. These responses were potentiated in the vagotomized animals. Pretreatment with NO synthase (NOS)/guanylate cyclase inhibitor methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or NO scavenger hemoglobin attenuated L-Arg-induced hypotension, suggesting that exogenous supplement of NO suppressed cardiac functions through the NOS/cyclic guanosine monophosphate mechanism. The role of endogenous NO was examined after local application of N(G)-nitro-L-arginine methyl ester (L-NAME). We found that L-NAME suppressed endogenous NO levels in NTS and elicited hypertension and tachycardia. Taken together, our data suggest that NO is tonically released in the NTS to inhibit blood pressure.


Construction of a simple auditory stimulus polarity indicator.
A device is described which gives a fast, reliable indication of the onset polarity of transient auditory stimuli. The instrument can be inexpensively constructed and is easily calibrated. It greatly simplifies the task of polarity calibration both in new equipment and in existing equipment after modifications have been made. This device will be of use to research laboratories and clinical departments who are currently recording auditory evoked potentials.


Expression of RUNX2 and Osterix in Rat Mesenchymal Stem Cells during Culturing in Osteogenic-Conditioned Medium.
We studied the expression of transcription factors RUNX2 and Osterix after addition of a concentrate of osteogenic-conditioned medium to the culture medium for osteogenic differentiation of mesenchymal stem cells (MSC). The obtained concentrate of osteogenic-conditioned medium containing a complex of bioactive substances with a molecular weight >10 kDa provided MSC differentiation into osteoblasts, which was confirmed by high level of expression of transcription factors RUNX2 and Osterix in comparison with the negative control. The highest expression of transcription factor Osterix was revealed on day 14 of MSC culturing in the presence of osteogenic supplement StemPro (positive control) and the studied concentrate of osteogenic-conditioned medium.


Coronary artery stenoses more often overestimated in older patients: Angiographic stenosis overestimation in elderly.
Angiographic overestimation of coronary artery stenosis severity may result in unnecessary revascularization and is possibly more prevalent with increasing age. To identify whether age is an independent clinical predictor for angiographic overestimation of a coronary artery stenosis. Fractional flow reserve (FFR) of 335 coronary lesions was performed in 260 consecutive patients with stable coronary artery disease (CAD). Overestimation was defined as an angiographically significant stenosis, with normal FFR (>0.80). Age was analysed as both continuous variable and quartiles. The highest age quartile was compared to the remaining quartiles. Multivariable analyses were performed to adjust for differences in baseline variables. Mean age of the total population was 65±10years, overestimation was observed in 11%. Mean age of patients with overestimation was 69±11years, compared to 65±10years in those without overestimation (p=0.01). Overestimation was observed significantly more often in the highest age quartile (22%) in comparison with the younger patients (8.0%) (p<0.001). The adjusted odds ratio for overestimation in the highest quartile group was 3.15 (95% confidence interval: 1.48-6.69). Increasing age is a strong and independent predictor for angiographic overestimation of the severity of a coronary stenosis. Functional measurement of coronary artery stenoses should be considered more often, particularly in elderly to avoid unnecessary revascularization.


Long Survival after Gastrointestinal Bleeding in a New-Onset Heyde's Syndrome Patient Treated with Multiple Endoscopic Hemostatic Procedures and Repeated Transfusions after Aortic Valve Replacement.
Heyde's syndrome, which is caused by aortic stenosis and subsequent acquired von Willebrand factor deficiency, is a gastrointestinal bleeding disease. Gastrointestinal bleeding develops in patients with Heyde's syndrome, which may have a different prognosis from general gastrointestinal bleeding; thus, it is important to understand the clinical course. We report a 76-year-old Japanese female who underwent aortic mechanical valve replacement 1 year ago and presented with recurrent gastrointestinal bleeding in angiodysplasia of the sigmoid colon. Endoscopic interventions achieved hemostasis. However, 6 rebleeding events occurred due to a sigmoid colon ulcer and gastric and jejunal angiodysplasia 7 years after first hemostasis. The patient underwent multiple endoscopic hemostatic procedures (upper, lower, and balloon-assisted endoscopy) and repeated transfusions (total of 394 units of red blood cells). The intensive treatment contributed to the survival time of 10 years. In addition, we performed a literature review of the prognosis of patients with Heyde's syndrome.


Amperometric biosensor involving covalent immobilization of choline oxidase and butyrylcholinesterase on a methacrylate-vinylene carbonate co-polymer.
A two-enzyme sensor for the determination of choline esters was prepared by the covalent co-immobilization of choline oxidase and butyrylcholinesterase on polymer membranes, obtained by radiation-induced co-polymerization of 2-hydroxyethylmethacrylate and vinylene carbonate at low temperature. The enzyme-modified membrane was applied to a platinum electrode and the determination of substrates was based on the electrochemical detection of enzymically generated H2O2. The analytical characteristics of this sensor, including the optimization of immobilization procedures, calibration curves for different substrates, pH and temperature effects and stability, are described.


Arthroscopic posterior subtalar arthrodesis for salvage of posttraumatic arthritis following calcaneal fractures.
Subtalar arthrodesis is a treatment option for pain due to posttraumatic arthritis following calcaneal fractures. The goal of this study is to examine the results of arthroscopic subtalar arthrodesis for posttraumatic arthritis following calcaneal fractures. We performed a retrospective case series reviewing 37 consecutive patients (36 male) treated for posttraumatic arthritis following calcaneal fractures by arthroscopic subtalar arthrodesis. The fractures were due to high-energy injuries in 81% of cases, and 12 fractures (32.4%) had been previously treated with internal fixation. Average follow-up was 57.5 months. Average American Orthopedic Foot and Ankle Society (AOFAS) scores significantly improved from 49.0 ± 10.9 points preoperatively to 76.0 ± 8.0 points at final follow-up. Average time to union was 12.5 weeks. Six patients (16.2%) suffered complications: superficial wound infection (2.7%), symptomatic hardware that warranted removal (5.4%) and nonunion (8.1%) presented nonunion. All three cases had prior internal fixation through an extensile lateral approach, and fused after a repeat surgery. Arthroscopic subtalar arthrodesis offers consistent improvement in cases of posttraumatic arthritis following calcaneal fractures, with a union rate similar to published series of open arthrodesis. We observed more nonunions in patients who had been treated previously with internal fixation. In spite of this, we continue to recommend arthroscopic subtalar arthrodesis, as it preserves the soft tissue envelope better than open techniques.


Investigation of repeated dose (90 day) oral toxicity, reproductive/developmental toxicity and mutagenic potential of 'Calebin A'.
The present work investigated repeated dose and reproductive toxicity of Calebin A in Wistar rats. A study for assessing the mutagenic potential of Calebin A through an AMES test is also described. Calebin A was orally administered to groups of 10 male and/or 10 female Wistar rats each, assigned to three dose levels (20, 50 and 100 mg/kg/body weight) once daily for 90 consecutive days. None of the animals in any of the treatment/control groups exhibited any abnormal clinical signs/behavioral changes, reproductive as well as developmental parameters, or gross and microscopic changes in both male and female rats. Calebin A was also evaluated for its ability to induce reverse mutations at selected loci of Salmonella typhimurium in the presence and absence of Aroclor 1254 induced rat liver S9 cell lines. In conclusion, 100 mg/kg/d of Calebin A is not likely to produce any significant toxic effects in male and female Wistar rats and no reproductive or developmental toxicity was observed at the same dose and hence Calebin A at 100 mg/kg was determined as "No Observed Adverse Effect Level (NOAEL)" under the test conditions.


Effects of losartan and captopril on left ventricular systolic and diastolic function after acute myocardial infarction: results of the Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL) echocardiographic substudy.
Angiotensin-converting enzyme inhibitors have been shown to attenuate adverse remodeling after acute myocardial infarction (AMI), and the same has been suggested for angiotensin II type 1 receptor antagonists in animal models. Therefore the aim of the study was to compare the effects of losartan and captopril on regional systolic, diastolic, and overall left ventricular (LV) function after AMI. Two hundred twenty-five patients aged > or =50 years with documented AMI and heart failure and/or LV dysfunction were randomly assigned treatment with either losartan (50 mg/d) or captopril (50 mg 3 times/d). Echocardiography was performed at randomization and after 3 months; echocardiograms were analyzed blinded at the core laboratory. Main outcome measures were changes in wall motion score index (WMSI), E-wave deceleration time (E-DT), and Tei index of overall LV function. WMSI decreased in both groups (losartan 1.58 +/- 0.23 to 1.52 +/- 0.26, P =.009, captopril 1.60 +/- 0.24 to 1.48 +/- 0.22, P <.001), although the decrease was greater in patients allocated to captopril (captopril -0.12 +/- 0.17 vs losartan -0.05 +/- 0.19, P =.007). In both groups E-DT increased, although the increase was significant only in patients treated with captoril (193 +/- 61 ms to 208 +/- 70 ms, P =.05). The change in E-DT was not different between treatment groups (captopril 14 +/- 74 ms vs losartan 7 +/- 80 ms, P =.52). Tei index decreased in both groups (losartan 0.59 +/- 0.13 to 0.55 +/- 0.15, P =.04, captopril 0.62 +/- 0.15 to 0.55 +/- 0.13, P <.001). However, the reduction was significantly greater in patients treated with captopril (captopril -0.08 +/- 0.14 vs losartan -0.03 +/- 0.14, P =.01). Losartan and captopril improve systolic and overall LV function after AMI, but the benefit is greater for patients treated with captopril.


Neural correlates of the attention network test in schizophrenia.
Attentional deficits are prominent in schizophrenia, affecting nearly all cognitive functions. Human attention comprises three essential components: alerting, orienting and executive control. For the assessment of these functions, the attention network test (ANT) has been proposed and used in healthy controls and patients. In schizophrenia, the ANT has revealed behavioral deficits; however, the corresponding neural correlates have not been examined. In the present study, neural correlates of attention were investigated in 17 schizophrenia patients and 17 healthy controls using the ANT with fMRI. Behavioral deficits emerged in the alertness system with a reduced efficiency for temporal cues. In fMRI, changes were observed for all three domains-alerting, orienting and conflict-and revealed hyper- as well as hypoactivation in patients. Affected regions during alerting comprised a broad fronto-temporo-parieto-occipito-cerebellar network, while differences during orienting mainly tapped fronto-parietal regions and during conflict processing a thalamo-frontal-temporal occipital network including the postcentral regions. In general, hyperactivations were positively correlated with more severe psychopathologial symptoms.


Clinical Implications of Low Absolute Blood Eosinophil Count in the SPIROMICS COPD Cohort.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) considers blood eosinophil counts < 100 cells/μL (BEC≤100) in people with COPD to predict poor inhaled corticosteroid (ICS) responsiveness. However, the BEC≤100 phenotype is inadequately characterized, especially in advanced COPD. Are there differences between GOLD group D patients with high BEC and those with low BEC regarding baseline characteristics and longitudinal outcomes? We used multivariable mixed models and logistic regression to contrast clinical characteristics and outcomes of BEC≤100 vs BEC > 100 (BEC100+) in all subjects with COPD (n = 1,414) and GOLD group D subjects (n = 185) not receiving ICS. We identified n = 485 with BEC≤100 (n = 61 GOLD group D) and n = 929 people with BEC100+ (n = 124 GOLD group D). BEC≤100 status was stable at 6 weeks and approximately 52 weeks (intraclass correlations of 0.78 and 0.71, respectively). Compared with BEC100+, BEC≤100 comprised more women, with greater current smoking, and less frequent childhood asthma. Among all analyzed participants, the two BEC-defined subsets showed similar rates of lung function decline (mean slope, BEC≤100 vs BEC100+, -50 vs -39 mL/y; P = .140), exacerbations (0.40 vs 0.36/y; P = .098), subsequent ICS initiation (2.5% vs 4.4%; P = .071), and mortality (7.8% vs 8.4%; P = .715). However, in GOLD group D, people with BEC≤100 showed higher exacerbation rates within 365 days of enrollment (0.62 vs 0.33/y; P = .002) and total follow-up (1.16 vs 0.83/y; P = .014). They also had greater lung function decline (mean slope of -68 mL/y vs -23 mL/y; P = .036) and had greater emphysema at baseline (voxels < 950 Hounsfield units at total lung capacity of 7.46% vs 4.61%; P = .029). In non-ICS-treated GOLD group D COPD, people with BEC≤100 had more baseline emphysema, prospective exacerbations, and lung function decline. Our analysis has identified a particularly vulnerable subpopulation of people with COPD, suggesting the need for studies focused specifically on their therapeutic treatment. ClinicalTrials.gov; No.: NCT01969344; URL: www. gov.


Multimarker synaptic protein cerebrospinal fluid panels reflect TDP-43 pathology and cognitive performance in a pathological cohort of frontotemporal lobar degeneration.
Synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD). Consequently, a surrogate marker of synapse loss could be used to monitor early pathologic changes in patients with underlying FTLD. The aim of this study was to evaluate the relationship of antemortem cerebrospinal fluid (CSF) levels of 8 synaptic proteins with postmortem global tau and TDP-43 burden and cognitive performance and to assess their diagnostic capacity in a neuropathological FTLD cohort. We included patients with a neuropathological confirmation of FTLD-Tau (n = 24, mean age-at-CSF 67 years ± 11), FTLD-TDP (n = 25, 66 years ± 9) or AD (n = 25, 73 years ± 6) as well as cognitively normal controls (n = 35, 69 years ± 7) from the Penn FTD Center and ADRC. We used a semi-quantitative measure of tau and TDP-43 inclusions to quantify pathological burden across 16 brain regions. Statistical methods included Spearman rank correlations, one-way analysis of covariance, ordinal regression, step-wise multiple linear regression and receiver-operating characteristic curves. CSF calsyntenin-1 and neurexin-2a were correlated in all patient groups (rs = .55 to .88). In FTLD-TDP, we observed low antemortem CSF levels of calsyntenin-1 and neurexin-2a compared to AD (.72-fold, p = .001, .77-fold, p = .04, respectively) and controls (.80-fold, p = .02, .78-fold, p = .02, respectively), which were inversely associated with post-mortem global TDP-43 burden (regression r2 = .56, p = .007 and r2 = .57, p = .006, respectively). A multimarker panel including calsyntenin-1 was associated with TDP-43 burden (r2 = .69, p = .003) and MMSE score (r2 = .19, p = .03) in FTLD. A second multimarker synaptic panel, also including calsyntenin-1, was associated with MMSE score in FTLD-tau (r2 = .49, p = .04) and improved diagnostic performance to discriminate FTLD-Tau and FTLD-TDP neuropathologic subtypes (AUC = .83). These synaptic panels have potential in the differential diagnosis of FTLD neuropathologic subtypes and as surrogate markers of cognitive performance in future clinical trials targeting TDP-43 or tau.


Effect of second language exposure on brain activity for language processing among preschoolers.
We investigated brain activity in 3-5-year-old preschoolers as they listened to connected speech stimuli in Japanese (first language), English (second language), and Chinese (a rarely exposed, foreign language) using near-infrared spectroscopy. Unlike the younger preschoolers who had been exposed to English for almost 1 year, brain activity in the bilateral frontal regions of the older preschoolers who had been exposed to English for almost 2 years was higher for Japanese and English speech stimuli than for Chinese. This tendency seemed to be similar to that observed in adults who had learned English for some years. These results indicate that exposure to a second language affects brain activity to language stimuli among preschoolers.


Competition Among Mental Health Organizations: Environmental Drivers and Strategic Responses.
While mental health system reforms have sought to leverage competition in the private sector to improve service quality and costs, competition among mental health organizations is poorly understood. To inform future studies about the impact of policy and system reforms on mental health organizations and service delivery, this qualitative study explores (1) resources for which organizations compete most intensively, (2) drivers of competition, and (3) leaders' strategic organizational responses. Semi-structured phone interviews were conducted with 15 organizational leaders (CEO's, executive directors) representing about 22% of organizations in the regional mental health market. Interviews covered leaders' perceptions about competition, and their strategic responses. Porter's seminal framework on competition was used to interpret codes and themes. Intensive competition for personnel was driven by workforce shortages, new for-profit organizations, and alternative employment opportunities. In response, organizations have attended to wages/benefits, recruitment, and retention. However, strong community need, expanded insurance coverage, and a history of local strategic responses that created service niches appeared to have minimized competition for financial resources in the region. Competition for funding and clients was expected to intensify under systems reform, and in anticipation, organizations were expanding services. Leaders also feared for the viability of smaller organizations in highly competitive environments. Consistent with theory on competition, mental health organizations compete and respond in ways that might improve services. However, the goals of privatization may have been unrealized because of minimal competition for funding and clients, and intense competition may undermine quality.


Rosacea in children: a review.
Rosacea is a facial inflammatory disorder that shows an increasing incidence with age. While rosacea is common > 60 years of age, pediatric rosacea is uncommon. Diagnostic criteria are based on clinical symptoms. Laboratory investigations and histopathology are only needed to exclude other differential diagnoses. There are several subtypes such as erythemato-telangiectatic, papulo-pustular, periorificial, and granulomatous variants. In contrast to adult rosacea, phymatous subtypes do not belong to pediatric rosacea. A special subtype seen in infants and children is an idiopathic facial aseptic granuloma. Genetic and environmental factors contribute to its pathogenesis. Treatment options are in analogy to adult rosacea classified into topical and systemic drugs. In the case of oral tetracyclines, discoloration of teeth and impairment of enamel are possible adverse events. Pediatric rosacea belongs to the rosacea spectrum but has peculiarities compared to the adult subtype. • Rosacea is a chronic inflammatory disorder different from acne. • Rosacea gets more common with advanced age. • Pediatric rosacea is an uncommon subtype with peculiar clinical presentation. • Demodicosis is very rare in immunocompetent children.


New octahydroquinazoline derivatives: synthesis and hypotensive activity.
Several novel 1-(4-chlorophenyl)-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydro-5-oxo-3-(substitutedphenyl)quinazoline derivatives (2-21) structurally similar to prazosin, were prepared using Mannich reaction of 3-(4-chlorophenylamino)-5,5-dimethyl-2-cyclohexenone (1) with different aromatic amines in the presence of formaline. The structures of the quinazoline derivatives were established using elemental and spectral analyses. Compounds 18, 20 and 21 were found to possess a high hypotensive effect through their expected α(1)-blocking activity like the clinically used drug prazosin but with advantageous of being did not cause reflex tachycardia and having prolonged duration of action when tested in adrenaline-induced hypertension in anaesthetized rats.


Data capture and communication during transfers to definitive care in an inclusive trauma system.
Background trauma survivors in rural areas transferred to urban centers have higher mortality than trauma patients admitted directly to urban centers. Transfer data in trauma registries is important for injury control. Prehospital and early physiologic data may reflect processes of pre-hospital care. British Columbia currently has no standardized process for trauma patient data transfer. We performed a retrospective data analysis for major trauma patients (ISS>15) transferred to a Level I trauma center over a 1year period (n=243). Completion rates of paramedic form and ATLS primary survey variables were extracted. Nominal and interval descriptives were calculated. Documentation rates were considered deficient at <80% and severely deficient <60%. Odds ratios were calculated for primary facility data based on ISS ≥30 vs ISS <30, with 2-sided p-values for confidence intervals RESULTS: Two hundred forty-three patients met inclusion criteria with a mean ISS of 26. Most injured patients were male (79%), the predominant mechanism was blunt (93%) and the average age at injury was 51 years old. Two hundred eighteen patients arrived by Emergency Health Services, and 140 (64%) of EHS pre-hospital forms were transferred with the patient chart. Pre-hospital airway, physiologic data, and GCS completion rates were severely deficient (43-49%). Primary facility data was adequately completed for airway management, systolic blood pressure, and heart rate in (80-83%). Completion rates were deficient for respiratory rate, GCS and temperature (60-77%). An ISS score ≥30 was significantly associated with a lower completion rate for GCS. Overall, documentation for inter-hospital transfer of major trauma patients in BC has significant deficiencies. Physiologic and basic ATLS variables are often omitted in transferred charts. The potential for adverse events is high but performance improvement is achievable. We recommend education, training and a standardized trauma transfer protocol to improve system-wide information transfer.


Characterization and virus susceptibility of a skin cell line from red-spotted grouper (Epinephelus akaara).
A red-spotted grouper Epinephelus akaara skin (RGS) cell line was established and characterized. RGS cells had a normal diploid chromosome number of 2n = 48, the morphology of which was fibroblastic-like in 3 days and epithelial-like over 5 after 16 passages. The cells multiplied well in Dulbecco's modified Eagle's medium supplemented with 10% of fetal bovine serum at 25°C. Susceptibilities of RGS and grass carp ovary (GCO) cells to two viruses were tested, and the results showed that the titer of an iridovirus Rana grylio virus (RGV) in RGS cells was 10³·⁵ TCID₅₀ ml⁻¹, which was much higher than a rhabdovirus spring viremia of carp virus (SVCV) in the cells (10⁰·⁵ TCID₅₀ ml⁻¹). The titers of RGV and SVCV in GCO were 10⁶·⁰ TCID₅₀ ml⁻¹ and 10⁸·⁰ TCID₅₀ ml⁻¹, respectively, which were higher than those in RGS cells. The data may imply that RGS cells could be selectively resistible to some viruses during infection. RT-PCR analysis of RGV-infected RGS cells showed that RGV could replicate in RGS cells. Further study of virus replications in RGS cells was conducted by electron microscopy and immunofluorescence microscopy has shown that virus particles scattered in the cytoplasm and virus protein appeared in both the cytoplasm and nucleus. The results suggested that RGS cells could be used as a potential in vitro model to study the cutaneous barrier function against virus infection.


Improvement of visible light photocatalytic acetaldehyde decomposition of bismuth vanadate/silica nanocomposites by cocatalyst loading.
Photocatalytic activity of bismuth vanadate (BiVO(4)) for acetaldehyde decomposition under visible light irradiation was improved by inclusion of a nanocomposition of silica as an adsorbent material and loading of platinum (Pt) or trivalent iron ion (Fe(3+)) as reduction cocatalysts. Addition of silica enhanced photocatalytic activity due to improvement of adsorption ability, but total decomposition of acetaldehyde was not observed within 24h of visible light irradiation. For further improvement of photocatalytic activity, BiVO(4) with an optimized amount of silica composition were modified with Pt or Fe(3+). Photodeposition of Pt greatly increased photocatalytic activity, and acetaldehyde was totally decomposed within 24h of visible light irradiation.


Efficacy and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer: A systematic review and meta-analysis.
The aim of the study was to explore the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with non-small cell lung cancer (NSCLC). Studies that enrolled NSCLC patients treated with two lines of ICIs were included using four databases. The initial line (1L-) and subsequent lines (2L-) of ICIs were defined as 1L-ICI and 2L-ICI, respectively. A total of 17 studies involving 2100 patients were included. The pooled objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) for 2L-ICIs were 10%, 50%, 3.0 months, and 13.1 months, respectively. The 2L-ICI discontinuation rates caused by toxicities ranged from 0% to 23.5%. Original data were extracted from six studies, covering 89 patients. Patients in whom 1L-ICIs were discontinued following clinical decision (the mPFS of 2L-ICIs was not reach) achieved a more prolonged mPFS of 2L-ICIs than those due to toxicity (5.2 months) and progressive disease (2.1 months) (p < 0.0001). Patients' 1L-PFS for more than 2-years had preferable 2L-ORR (35.0% vs. 9.8%, p = 0.03), 2L-DCR (85.0% vs. 49.0%, p = 0.007), and 2L-mPFS (12.4 vs. 3.0 months, p < 0.0001) than those less than 1-year. Patients administered the same drugs achieved a significantly prolonged mPFS compared with the remaining patients (5.4 vs. 2.3 months, p = 0.0004), and those who did not accept antitumor treatments during the intervals of two lines of ICIs achieved a prolonged mPFS compared to those patients who did accept treatments (7.6 vs. 1.9 months, p < 0.0001). ICI rechallenge is a useful therapeutic strategy for NSCLC patients, especially suitable for those who achieve long-term tumor remission for more than 2-years under 1L-ICIs.


Lifetime exposure to traumatic psychological stress is associated with elevated inflammation in the Heart and Soul Study.
Exposure to traumatic psychological stress increases risk for disease events and mortality in patients with cardiovascular disease (CVD). While the biological mechanisms of these effects are not known, inflammation may play a key role as it is both elevated by psychological stress and involved in the development and progression of CVD. In a prospective study of patients with stable CVD (n=979), we examined if higher lifetime trauma exposure was associated with elevated levels of inflammation at baseline and at five-year follow-up, and with greater increases in inflammation over time. Inflammation was indexed by a composite score incorporating the inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and resistin. In follow-up analyses, we adjusted for sociodemographic factors, psychiatric disorders and health behaviors that were significantly associated with trauma exposure. Higher trauma exposure was associated with elevated inflammation at baseline (β=.09, p=.01) and at five-year follow-up (β=.09, p=.03). While levels of inflammation increased from baseline to follow-up in the sample, there was no significant association between trauma exposure and rate of change in inflammation. Findings were robust to adjustments for sociodemographic factors and psychiatric disorders, but health behaviors appeared to contribute to the association between trauma and inflammation at follow-up. This is the first large-scale demonstration of an association between lifetime trauma exposure and inflammation. High lifetime exposure to traumatic stress may contribute to an accelerated rate of CVD progression through elevated inflammation.


Anxiety symptoms and functional impairment: A systematic review of the correlation between the two measures.
Researchers and clinicians assume a strong, positive correlation between anxiety symptoms and functional impairment. That assumption may be well-justified since diagnostic criteria typically include functional impairment. Still, the relationship remains largely unavailable in any systematic review. Our aim with this paper was to provide empirical evidence for this assumed relationship and to document the observed correlations between anxiety symptom measures and functional impairment measures. Correlations existed for symptoms of six anxiety disorders (Panic Disorder, Agoraphobia, Social Anxiety Disorder, Post-Traumatic Stress Disorder, Generalized Anxiety Disorder, Obsessive Compulsive Disorder) across four functional domains (global, social, occupational, and physical). Overall, the mean of 497 correlations across all disorders and functional domains was modest (r=.34); since the variability between disorders and functional domains tended to be rather large, we explored these correlations further. We presented these results and the potential explanations for unexpected findings along with the clinical and research implications.


Chromatinization of Escherichia coli with archaeal histones.
Nucleosomes restrict DNA accessibility throughout eukaryotic genomes, with repercussions for replication, transcription, and other DNA-templated processes. How this globally restrictive organization emerged during evolution remains poorly understood. Here, to better understand the challenges associated with establishing globally restrictive chromatin, we express histones in a naive system that has not evolved to deal with nucleosomal structures: Escherichia coli. We find that histone proteins from the archaeon Methanothermus fervidus assemble on the E. coli chromosome in vivo and protect DNA from micrococcal nuclease digestion, allowing us to map binding footprints genome-wide. We show that higher nucleosome occupancy at promoters is associated with lower transcript levels, consistent with local repressive effects. Surprisingly, however, this sudden enforced chromatinization has only mild repercussions for growth unless cells experience topological stress. Our results suggest that histones can become established as ubiquitous chromatin proteins without interfering critically with key DNA-templated processes.


Human pregnane X receptor: a novel target for anticancer drug development.
Multidrug resistance (MDR), a significant barrier to effective pharmacokinetics and pharmacodynamics of anticancer drugs, is mainly due to the induction potential of anticancer drugs for drug metabolizing enzymes (DMEs) and efflux transporters through nuclear receptors. Human Pregnane X Receptor (hPXR) is master transcription factor for cytochrome P450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1). The hPXR is capable of being activated by structurally diverse ligands. Several studies, like in silico modeling, in vitro assays, and in vivo experimentation have been conducted to identify the structural features of ligand for activation of hPXR. This review highlights hPXR as an appealing target for both the development of novel anticancer drugs and the improvement in preclinical and clinical evaluation of anticancer drugs.


Effects of chronic exercise on myocardial refractoriness: a study on isolated rabbit heart.
To determine whether chronic physical training increases atrial and ventricular refractoriness in isolated rabbit heart. Trained rabbits were submitted to a protocol of treadmill running. The electrophysiological parameters of refractoriness investigated in an isolated heart preparation were: (1) atrial effective refractory period (AERP) and atrial functional refractory period and ventricular effective and functional refractory periods (VERP and VFRP) using the extrastimulus technique at four different pacing cycle lengths; (2) the dominant frequency (DF) of ventricular fibrillation (VF). A multi-electrode plaque containing 256 electrodes and a spectral method were used to obtain the mean, maximum and minimum DF of VF. Sinus cycle length of the isolated hearts was determined as an electrophysiological parameter of training. In vivo heart rate, myocardial heat shock proteins (HSP60) and inducible nitric oxide synthase were also determined in some animals as electrophysiological and biochemical markers of training respectively. VERP and VFRP were longer in the trained group than in the control group. The mean DF of VF was lower in the trained group than in the control group. Despite the fact that training did not significantly modify the AERP, it tended to be longer in the trained group (P = 0.09). Training seems to increase the electrical stability of ventricular myocardium. As the electrophysiological modifications were exhibited in hearts not submitted to extrinsic nervous system or humoral influences, they are, at least in part, intrinsic modifications. These electrophysiological data also suggest that training could protect against reentrant ventricular arrhythmias.


A rare case report of viable ileo-ileal knotting of acute abdomen in adults.
Regardless of the cause, bowel obstruction is described as the absence of abnormal transit of intestinal contents. It may involve only the small intestine, the large intestine, or both. It might be brought on by a bodily impediment or widespread modifications to the metabolism, electrolyte balance, or neuroregulatory systems. In the field of general surgery, there are several well-known causes that can vary between developing and developed nations. In this case report, we describe a case of acute small bowel obstruction secondary to ileo-ileal knotting in 35 years old female patient with a complaint of crampy abdominal pain of 7 hour duration. She had associated frequent vomiting of ingested matter followed by bilious matter. She had also mild abdominal distention. She had history of caesarian section delivery 3 times the last time was 4 months back. Ileoileal knotting is a unique and rare clinical entity in which a loop of proximal ileum wrap around the distal part of ileum. The presentation includes abdominal pain and distension, vomiting, and obstipation. The majority of cases require resection and anastomosis or exteriorization of the affected segment, and management entails a high index of suspicion and emergent investigation. We demonstrate an instance of ileo-ileal knotting to highlight the fact that it is an unusual intraoperative finding and, given the rarity of cases, should be taken into account in the alternative diagnosis of patients exhibiting SBO signs and symptoms.


Flower Development in the Solanaceae.
Flower development is the process leading from a reproductive meristem to a mature flower with fully developed floral organs. This multi-step process is complex and involves thousands of genes in intertwined regulatory pathways; navigating through the FLOR-ID website will give an impression of this complexity and of the astonishing amount of work that has been carried on the topic (Bouché et al., Nucleic Acids Res 44:D1167-D1171, 2016). Our understanding of flower development mostly comes from the model species Arabidopsis thaliana, but numerous other studies outside of Brassicaceae have helped apprehend the conservation of these mechanisms in a large evolutionary context (Moyroud and Glover, Curr Biol 27:R941-R951, 2017; Smyth, New Phytol 220:70-86, 2018; Soltis et al., Ann Bot 100:155-163, 2007). Integrating additional species and families to the research on this topic can only advance our understanding of flower development and its evolution.In this chapter, we review the contribution that the Solanaceae family has made to the comprehension of flower development. While many of the general features of flower development (i.e., the key molecular players involved in flower meristem identity, inflorescence architecture or floral organ development) are similar to Arabidopsis, our main objective in this chapter is to highlight the points of divergence and emphasize specificities of the Solanaceae. We will not discuss the large topics of flowering time regulation, inflorescence architecture and fruit development, and we will restrict ourselves to the mechanisms included in a time window after the floral transition and before the fertilization. Moreover, this review will not be exhaustive of the large amount of work carried on the topic, and the choices that we made to describe in large details some stories from the literature are based on the soundness of the functional work performed, and surely as well on our own preferences and expertise.First, we will give a brief overview of the Solanaceae family and some of its specificities. Then, our focus will be on the molecular mechanisms controlling floral organ identity, for which extended functional work in petunia led to substantial revisions to the famous ABC model. Finally, after reviewing some studies on floral organ initiation and growth, we will discuss floral organ maturation, using the examples of the inflated calyx of the Chinese lantern Physalis and petunia petal pigmentation.


The association between statistical learning and language development during childhood: A scoping review.
The statistical account of language acquisition asserts that language is learned through computations on the statistical regularities present in natural languages. This type of account can predict variability in language development measures as arising from individual differences in extracting this statistical information. Given that statistical learning has been attested across different domains and modalities, a central question is which modality is more tightly yoked with language skills. The results of a scoping review, which aimed for the first time at identifying the evidence of the association between statistical learning skills and language outcomes in typically developing infants and children, provide preliminary support for the statistical learning account of language acquisition, mostly in the domain of lexical outcomes, indicating that typically developing infants and children with stronger auditory and audio-visual statistical learning skills perform better on lexical competence tasks. The results also suggest that the relevance of statistical learning skills for language development is dependent on sensory modality.


Balancing of energy-consuming processes of K 562 cells.
A balance of ATP-consuming processes in human erythroleukemia (K 562) cells by use of the decreased 14CO2 formation from [1-14C]-glutamate following inhibition of energy-requiring processes is presented. This method was tested on Ehrlich mouse ascites tumour cells and was used in suspensions of K 562 cells with a low cell content. More than 90 percent of the ATP produced by oxidative phosphorylation could be accounted for in K 562 cells. Protein synthesis consumed about 35 percent, Na+/K(+)-ATPase about 20 percent and transcription processes 5-10 percent of the total ATP. The share of the Ca(2+)-dependent reactions was notably high at 25 percent in comparison with Ehrlich mouse ascites tumour cells, reticulocytes or hepatocytes. ATP consumption by DNA synthesis was assessed at 5-10 percent. Only less than 10 percent of the consumption of ATP produced oxidatively remained for other cellular reactions. The degree of coupling of K 562 cells was high in comparison with that of other eukaryotic cell types.


Clinical outcome according to timing of cabergoline initiation for prevention of OHSS: a randomized controlled trial.
Cabergoline, a dopamine receptor-2 agonist, is suggested to prevent ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation. The aim of this study was to evaluate the influence of different timing of cabergoline administration on clinical outcome among patients at risk of developing OHSS. Among infertile women undergoing IVF treatment at risk of developing OHSS, 206 were enrolled in this study. The subjects were randomly allocated into two groups, i.e. the study group (n=100) receiving cabergoline beginning on the day of human chorionic gonadotrophin (HCG) injection and the control group (n=100) receiving cabergoline starting on the day of oocyte retrieval. Oocyte metaphase-II rate, fertilization rate, clinical outcome and incidence of severe OHSS were compared between the two groups. There were no significant differences in oocyte metaphase-II rate (0.86 ± 0.16 versus 0.85 ± 0.15) or fertilization rate (0.79 ± 0.22 versus 0.76 ± 0.20) or in the incidence of OHSS between two groups. Similarly, there were no significant differences in implantation or clinical pregnancy rate between the two groups. Cabergoline can be administered as soon as HCG injection to prevent early OHSS, without adverse effects on oocyte maturation, fertilization rate and clinical outcome.


Formulation, optimization and evaluation of transferosomal gel for transdermal insulin delivery.
The present study deals with the development of transferosomal gel containing insulin by reverse phase evaporation method for painless insulin delivery for use in the treatment of insulin dependent diabetes mellitus. The effect of independent process variables like ratio of lipids (soya lecithin:cholesterol), ratio of lipids and surfactants, and ratio of surfactants (Tween 80:sodium deoxycholate) on the in vitro permeation flux (μg/cm(2)/h) of formulated transferosomal gels containing insulin through porcine ear skin was optimized using 2(3) factorial design. The optimal permeation flux was achieved as 13.50 ± 0.22 μg/cm(2)/h with drug entrapment efficiency of 56.55 ± 0.37% and average vesicle diameter range, 625-815 nm. The in vitro insulin permeation through porcine ear skin from these transferosomal gel followed zero-order kinetics (R (2) = 0.9232-0.9989) over a period of 24 h with case-II transport mechanism. The in vitro skin permeation of insulin from optimized transferosomal gel by iontophoretic influence (with 0.5 mA/cm(2) current supply) also provided further enhancement of permeation flux to 17.60 ± 0.03 μg/cm(2)/h. The in vivo study of optimized transferosomal gel in alloxan-induced diabetic rat has demonstrated prolonged hypoglycemic effect in diabetic rats over 24 h after transdermal administration.


Effect of naloxone on microcirculatory behavior during irreversible hemorrhagic shock.
Thirty-six male Sprague-Dawley rats were divided into three groups (n = 12): simple hemorrhagic shock group, saline-treated group, and naloxone-treated group. Synchronous videotape recording with two cameras was used to observe the relationship between the change of blood pressure and that of microcirculation of cremaster muscle. It has been suggested that the temporary plugging of capillaries by WBC may be the explanation for no reflow in microvessels after transfusion and infusion during the irreversible stage of shock. Administration of naloxone (2 mg/kg iv) followed by reinfusion of the shed blood is associated with an increase in blood pressure and pulse pressure. Coincidentally, a pulsatile movement of the blood, impacted on the stationary blood cells in capillaries, eventually dislodges them and leads to reperfusion of capillaries. Thereafter systemic blood pressure and carotid artery red blood cell velocity were increased and remained stable. The 24-hr survival rate was significantly increased in the naloxone-treated group (10/12), as compared with that in the saline-treated group (1/12). The mechanism of naloxone treatment is discussed. The suggestion is advanced that the effects on cardiac and microcirculatory performance may influence each other, and that both contribute to the pathogenesis of irreversible hemorrhagic shock.


Communication of prenatal screening and diagnosis results to primary-care health professionals.
To describe how prenatal screening and diagnostic test results are communicated to primary care health professionals. Postal questionnaire. Primary care practices across London, East Anglia, the Southeast and Southwest of England. 714 community-based health professionals (GPs, midwives and health visitors) identified by 247 women (participants in a study of experiences after a positive prenatal diagnosis) as members of their primary care team. Description of how information about prenatal screening and diagnostic test results is communicated to health professionals working in the primary care team. Participants' views about the timeliness and sufficiency of the information they are given. 131 GPs, 143 midwives and 151 health visitors returned questionnaires, an overall response rate of 60.4%. Sixteen percent of primary care professionals reported that they were not usually informed of high-risk results after serum screening for Down's syndrome. Twenty eight percent were either not usually told about the possibility of abnormalities detected on ultrasound or only heard of such abnormalities from the woman herself. Even when informed, 28% of midwives and GPs did not know what action they were expected to take. Information about confirmed abnormalities is not always communicated to primary care. Only 29% were told soon enough about diagnosed abnormalities and only 17% of health professionals reported that the information they were given was always sufficient to allow them to discuss issues with their patients. The presence of specialist screening coordinators was perceived to be helpful by 76% of health professionals. Improvements in how they were told about abnormalities were suggested and these included the need for systems and protocols that ensured that quality information was communicated quickly. The frequent absence of means of effective communication between primary and secondary care about diagnosed abnormalities, and health professionals' uncertainties about their role has implications for the quality of care given to women who receive positive results after prenatal screening or diagnosis. There is a need for standards to be established concerning the communication of information to the health professionals responsible for the community-based care of pregnant women after a positive test result.


Par3 in chick lens placode development.
The lens originates from a simple cuboidal epithelium, which, on its basal side, contacts the optic vesicle, whilst facing the extraembryonic environment on its apical side. As this epithelium changes into the pseudostratified lens placode, its cells elongate and become narrower at their apical ends. This is due to the formation of an apical actin network, whose appearance is restricted to cells of the placodal region, as a result of region-specific signaling mechanisms that remain largely unknown. Here, we investigated the role of the polarity protein PAR3 and the phosphorylation state of its Threonine 833 (T833) aPKC-binding site in the recruitment of aPKC and in the establishment of actin network in the chick lens placode. Overexpression of wild type PAR3 recruited aPKC and punctate actin clusters to the basolateral membranes of the placodal cells. Recruitment of aPKC depended on the charge of the residue that replaced the T833 residue. In contrast, induction of the ectopic actin spots was independent on the charge of this residue.


HIV-1 Vpu antagonizes BST-2 by interfering mainly with the trafficking of newly synthesized BST-2 to the cell surface.
Bone marrow stromal cell antigen-2 (BST-2) inhibits human immunodeficiency virus type 1 (HIV-1) release by cross-linking nascent virions on infected cell surface. HIV-1 Vpu is thought to antagonize BST-2 by downregulating its surface levels via a mechanism that involves intracellular sequestration and lysosomal degradation. Here, we investigated the functional importance of cell-surface BST-2 downregulation and the BST-2 pools targeted by Vpu using an inducible proviral expression system. Vpu established a surface BST-2 equilibrium at ∼60% of its initial levels within 6 h, a condition that coincided with detection of viral release. Analysis of BST-2 post-endocytic trafficking revealed that the protein is engaged in a late endosomal pathway independent of Vpu. While Vpu moderately enhanced cell-surface BST-2 clearance, it strongly affected the protein resupply to the plasma membrane via newly synthesized proteins. Noticeably, Vpu affected clearance of surface BST-2 more substantially in Jurkat T cells than in HeLa cells, suggesting a cell-dependent impact of Vpu on the pool of surface BST-2. Collectively, our data reveal that Vpu imposes a new BST-2 equilibrium, incompatible with efficient restriction of HIV-1 release, by combining an acceleration of surface BST-2 natural clearance, whose degree might be cell-type dependent, to a severe impairment of the protein resupply to the plasma membrane.


Prediction of Postoperative Mortality in Patients With Organ Failure Following Pancreaticoduodenectomy.
Failure to rescue (FTR) patients with postoperative complications contribute to a significant proportion of postoperative mortality. Our main objective was to determine the risk factors for FTR among patients undergoing pancreaticoduodenectomy who suffered a life-threatening complication requiring intensive care unit (ICU) management. Consecutive patients undergoing pancreaticoduodenectomy from 2011 to 2020 were reviewed retrospectively. Causes of organ failure were described as the one that most commonly contributed to patient's transfer to ICU or death. Two groups were created based on whether patients had FTR and risk factors for FTR were compared. The impact of baseline characteristics, operative characteristics, and risk scoring on FTR was analyzed using multiple logistic regression. There were 19/58 (33%) FTR patients. Baseline, operative characteristics, postoperative complications, and length of hospital and ICU stay were similar between groups. However, a higher proportion of FTR patients experienced a postoperative pancreatic fistula (POPF) (16% vs 2.6%, P = .062). Among patients who experienced a POPF, the FTR group had a trend in delayed time from diagnosis to treatment (7 vs 23 hours, P=.131). Renal complications (OR 6.12, 95% CI, 1.23 to 38.43, P = .035) and time from POPF diagnosis to treatment (OR 1.05, 95% CI, 1.00 to 1.11, P = .036) were independent predictors of FTR by multivariable analysis. The occurrence of certain postoperative complications such as renal complications as well as delayed timing of the management of POPF is predictive of FTR following pancreaticoduodenectomy, especially as delayed timing to treatment is a risk factor for FTR.


A multicentre, randomized study of telmisartan versus carvedilol for prevention of atrial fibrillation recurrence in hypertensive patients.
Atrial remodelling, leading to atrial fibrillation (AF), is mediated by the renin-angiotensin-aldosterone system. Mild hypertensive outpatients (systolic/diastolic blood pressure 140-159/90-99 mmHg) in sinus rhythm who had experienced ≥ 1 electrocardiogram (ECG)-documented AF episode in the previous six months received randomly telmisartan 80 mg/day or carvedilol 25 mg/day. Blood pressure and 24-hour ECG were monitored monthly for one year; patients were asked to report symptomatic AF episodes and to undergo an ECG as early as possible. One hundred and thirty-two patients completed the study (telmisartan, n=70; carvedilol, n=62). Significantly fewer AF episodes were reported with telmisartan versus carvedilol (14.3% vs. 37.1%; p<0.003). Left atrial diameter, assessed by echocardiography, was similar with telmisartan and carvedilol (3.4±2.3 cm vs. 3.6±2.4 cm). At study end, both regimes significantly reduced mean left ventricular mass index, but the reduction obtained with telmisartan was significantly greater than with carvedilol (117.8±10.7 vs. 124.7±14.5; p<0.0001). Mean blood pressure values were not significantly different between the groups (telmisartan 154/97 to 123/75 mmHg; p<0.001; carvedilol 153/94 to 125/78 mmHg; p<0.001). Telmisartan was significantly more effective than carvedilol in preventing recurrent AF episodes in hypertensive AF patients, despite a similar lowering of blood pressure.


Effects of temperature and relative humidity on soil-air partition coefficients of organophosphate flame retardants and polybrominated diphenyl ethers.
The soil-air partition coefficients (KSA) of polybrominated diphenyl ethers (PBDEs) and organophosphate flame retardants (OPFRs) is important for determining their fate in soil and air media. However, KSA values of OPFRs and PBDEs are not available from the current literature, and the effects of environmental factors such as temperature and relative humidity (RH) on KSA values are not clear. In this study, a solid-phase fugacity meter was used to measure the KSA values of PBDEs and OPFRs at different temperatures (25, 30, 35, 40, and 45 °C) and relative humidity (RH) conditions (<3 and 100% RH), the relationships between KSA and octanol-air partition coefficients (KOA) for OPFRs and PBDEs were analyzed. The results showed that an increase in temperature and RH resulted in a decrease of all KSA values for PBDEs and OPFRs. Furthermore, the effects of RH on the soil-air partitioning behavior of PBDEs were larger than that of OPFRs. In addition, a significant correlation (p < 0.0001) was observed between log KSA and log KOA. The experimental KSA values of OPFRs and PBDEs were quite different from the predicted KSA, when calculated with their KOA values. Overall, this study provides a better understanding for predicting the behavior and fate of OPFRs and PBDEs in soil-air systems.


Size-selective attack by parasitic lampreys: consideration of alternate null hypotheses.
The hypothesis that parasitic lampreys actively select larger host fish was tested with previously published laboratory data for Petromyzon marinus and new data for Ichthyomyzon castaneus. Whereas in previous work, expected attack frequencies were proportional to the number of potential hosts in each size group (numbers-dependent null hypothesis), the present study employed a more conservative area-dependent null hypothesis by which expected attack frequencies were adjusted to reflect the surface area of potential hosts in each size group. The balance of the data suggests that lampreys are actively size-selective. It is more difficult to demonstrate size-selectivity in the field because of sampling considerations and the need to account for size-related factors (e.g., swimming speed) that affect host availability. It is unknown if handling times are greater for larger hosts or if the quality of host blood changes with host size, and it is uncertain if lampreys achieve greater energy intake rates on larger hosts, but a larger host survives longer and assures an attacking lamprey of a longer period of feeding.


Degradation 1,2-dimethylbenzene by Corynebacterium strain C125.
In an attempt to obtain bacteria growing on 1,2-dimethylbenzene as sole carbon and energy source two different strains were isolated. One was identified as an Arthrobacter strain, the other as a Corynebacterium strain. Corynebacterium strain C125 was further investigated. The organism was not capable to grow on 1,3- and 1,4-dimethylbenzene. cis-1,2-Dihydroxycyclohexa-3,5-diene oxidoreductase and 3,4-dimethylcatechol-2,3-dioxygenase activity was found in cell extracts. When 3,4-dimethylcatechol was added to cell extract of 1,2-dimethylbenzene-grown cells, first a compound with the spectral properties of 2-hydroxy-5-methyl-6-oxo-2,4-heptadienoate was formed and subsequently acetate was produced. It is proposed that dioxygenases are involved in the initial steps of 1,2-dimethylbenzene degradation, and ring opening proceeds via meta-cleavage.


Pattern of changes over time in myocardial blood flow and microvascular dilator capacity in patients with normally functioning cardiac allografts.
This study tests the hypothesis that myocardial blood flow and coronary microvascular dilator capacity vary as a function of time after orthotopic heart transplantation in humans. Positron emission tomography measurements of myocardial blood flow were obtained at rest and during adenosine in 24 patients between 1 and 86 months after heart transplantation. At the time of the study all patients were clinically well and had angiographically normal epicardial coronary artery vessels. Patients were divided into 3 groups based on time from transplant to positron emission tomography measurement of myocardial blood flow: group 1 to 12 months (n = 9); group 13 to 34 months (n = 8); and group > or = 37 months (n = 7). Basal myocardial blood flow in group 1 to 12 months (1.86+/-1.01 ml/min/g) exceeded (p <0.05) that of group 13 to 34 months (1.17+/-0.73) and group > or = 37 months (0.98+/-0.34). In group 13 to 34 months, basal myocardial blood flow and maximal dilator capacity (minimal coronary vascular resistance with adenosine 36+/-12 mm Hg/ml/min/g) were comparable to that of normal volunteers (1.01+/-0.20 and 37+/-, respectively). In group > or = 37 months, maximal flow response to adenosine was reduced (2.54+/-1.25 vs 3.16+/-0.52, respectively, p = 0.06). Maximal dilator capacity in group > or = 37 months (60+/-34) was impaired versus group 1 to 12 months (36+/-10) and group 13 to 34 months (36+/-12; both p <0.05) as well as normals (37+/-9, p <0.05). During the first year after cardiac transplantation basal myocardial blood flow is elevated out of proportion to external determinants of myocardial oxygen demand, but maximal dilator capacity of the coronary microcirculation is normal. Between 1 and 3 years both basal myocardial blood flow and microvascular function tend to normalize. After 3 years, although basal myocardial blood flow is normal, microvascular dilator capacity is impaired.


Long-term treatment patterns of prophylactic and acute migraine medications and incidence of opioid-related adverse events in patients with migraine.
To describe long-term treatment patterns in migraine patients initiating prophylactic therapy and to evaluate acute medication use and adverse events associated with opioids. This study used the 2005-2014 IBM MarketScan® databases to evaluate migraine patients initiating prophylactic medication. Outcome measures included persistence with prophylactic migraine medications over 2-5 years. Acute medication use and gastrointestinal-related adverse events and opioid abuse following opioid use were evaluated. Cox proportional hazards models were used to evaluate predictors of non-persistence and predictors of gastrointestinal-related AEs and opioid abuse associated with long-term opioid use. In total, 147,832 patients were analyzed. Non-persistence was observed in 90% of patients; 39% switched, 30% restarted, and 31% discontinued treatment. Over the follow-up, 59.9% of patients received triptans, 66.6% non-steroidal anti-inflammatory drugs, 77.4% opioids, and 2.6% ergotamines. Among opioid users, 16.6% experienced nausea/vomiting, 12.2% had constipation, and 10.4% had diarrhea. Opioid abuse was reported in <1% of opioid users. Gastrointestinal-related adverse events increased with increasing number of days' supply of opioids. Non-persistence to prophylactic treatment was frequent among migraine patients. Opioid use was common in migraine patients and the risk of gastrointestinal-related adverse events and opioid abuse increased with long-term use of opioids. These results suggest a need for more effective prophylactic migraine treatments.


Dose Selection of Ropivacaine for Spinal Anesthesia in Elderly Patients with Hip Fracture: An Up-Down Sequential Allocation Study.
The dose selection of ropivacaine for spinal anesthesia in clinical work mainly depends on the experience of the anesthesiologist. In this study, a prospective and modified up-down sequential allocation design was used to provide the optimal dose selection of ropivacaine for spinal anesthesia. This study was divided into two stages, and a total of 164 elderly patients with elective hip fractures were included. In stage I, the dose of ropivacaine was selected using the up-down sequential method of height correction, and the 50% effective dose (ED50) and 95% effective dose (ED95) were obtained. A nomogram for predicting satisfactory anesthesia and a formula for predicting the optimal dose was also given in this stage. In stage II, the dose of ropivacaine was calculated by using the optimal dose prediction formula, so as to evaluate the efficacy and safety of the model. The ED50 and ED95 of the stage I were 7.036 mg (95%CI 6.549-7.585 mg) and 8.709 mg (95%CI 7.902-14.275 mg), respectively. And provided a nomogram predicting satisfactory anesthesia with a C-index of 0.847 (95%CI 0.774-0.92). The optimal dose prediction formula of ropivacaine was calculated, including variables for age, gender, height, and weight. This formula was found to be 90% efficient. It is worth mentioning that the incidence of direct transfer to the ward in the two stages was as high as 86.84% and 93.33%, respectively, and no patients were transferred to the ICU in stage II. The ED50 and ED95 of ropivacaine were 7.036 mg and 8.709 mg, respectively, and the nomograms are sufficiently accurate to predict satisfactory anesthesia. Beyond that, the dose prediction equation provided in this study has high efficacy and safety, and can guide the dose selection of spinal anesthesia in elderly patients with hip fracture in clinical practice. ChiCTR2100046982.


[Terminal renal insufficiency and indication for kidney transplantation].
Terminal renal insufficiency is characterized by the need for renal replacement therapy for survival of the patient. In addition to several types of dialysis treatment, successful renal transplantation offers the best form of renal replacement therapy in terms of long-term patient survival and quality of life. Living donor renal transplantation offers the best conditions concerning quality of organ transplanted and graft survival. The risk of complications associated with renal transplantation are manageable; however, these must be weighed against the potential benefits of successful transplantation.


Incidence of acute respiratory symptoms and COVID-19 infection in children in public schools in Bogotá, Colombia, from July to November, 2020
More than 90% of children infected with COVID-19 worldwide developed mild to moderate disease. In Colombia, during 2020, COVID-19 infections in children stayed below 9.2% of the total cases, with no trends for age group or sex. To estimate the incidence of acute respiratory symptoms and COVID-19 in children from public schools in Bogotá, Colombia during the second semester of 2020. A telephone survey was conducted in over 5,000 scholar children. Antecedents and use of health services were informed. Descriptive statistics were used. A total of 151.470 persons per day accounting for an IR of 157,8 per 100,000 people; almost three times the rate reported by the official surveillance system in the city. A lack of diagnosis and consultation in children was found compared to the general population. Further research is needed to elucidate the true burden of the disease in children.


Microneurographically determined muscle sympathetic nerve activity levels are reproducible in insulin-dependent diabetes mellitus.
Our objective was to determine whether microneurographically determined muscle sympathetic nerve activity (MSNA) levels are equally reproducible in control and insulin-dependent diabetes mellitus (IDDM) subjects. We used a retrospective review of MSNA levels in 14 IDDM and 16 control subjects who had at least two microneurographic studies in the last 8 years in our laboratory. Results showed mean MSNA levels were lower in IDDM (9.2+/-1.2 bursts/min) than in control subjects (16.8+/-1.7 bursts/min) (p<0.002) but mean within individual MSNA coefficients (IDDM: 47+/-8%; controls 30+/-5%) and ranges of variation (IDDM: 6.6+/-1.9; controls: 7.5+/-1.9 bursts/min) did not differ between IDDM and control subjects. Thus, microneurographically determined MSNA levels are equally reproducible in IDDM and controls subjects. These results confirm and substantiate our previous findings of diminished MSNA in IDDM subjects.


Inter- and intraobserver variability in LVH and RVH reporting in pediatric ECGs.
Physicians' diagnoses are often used as the gold standard for evaluating computer electrocardiogram (ECG) interpretation programs. As part of a larger study to evaluate the Glasgow pediatric ECG analysis program, inter- and intraobserver variability in the ECG reporting of two pediatric cardiologists was examined. The ECGs of 984 children were sent for reporting independently by two cardiologists with all identifying information except age and sex removed. Three hundred twenty ECGs had no clinical indication available, and they were thus reported "blind." For 664 ECGs, the clinical indication was known and included with the ECG trace. All ECGs reported as right ventricular hypertrophy (RVH) or left ventricular hypertrophy (LVH) were returned to the cardiologists without their knowledge for reporting a second time "blind" as to the clinical indication. When the cardiologists' reports were compared with each other, the provision of clinical information led to greater agreement between them for the diagnosis of LVH (kappa increased from 0.44 to 0.52) but did not substantially affect their agreement in diagnosing RVH (kappa fell from 0.66 to 0.63). Intraindividual comparisons in 166 ECGs revealed that one cardiologist was more consistent in diagnosing RVH and the other more consistent in diagnosing LVH. This study has demonstrated the difficulties in using cardiologists' diagnoses as the gold standard with which to evaluate pediatric ECGs.


The epidemiology of human listeriosis.
Listeriosis is a serious invasive disease that primarily afflicts pregnant women, neonates and immunocompromised adults. The causative organism, Listeria monocytogenes, is primarily transmitted to humans through contaminated foods. Outbreaks of listeriosis have been reported in North America, Europe and Japan. Soft cheeses made from raw milk and ready-to-eat meats are high risk foods for susceptible individuals. Efforts by food processors and food regulatory agencies to aggressively control L. monocytogenes in the high risk foods have resulted in significant decreases in the incidence of sporadic listeriosis.


Evaluation of uncertainties for parameters in binding studies: the sum-of-squares profile and Monte Carlo estimation.
Methods for characterization and evaluation of uncertainties in the parameter values for binding experiments are presented. A sum-of-squares profile is defined and illustrated. Sum-of-squares profiles give a qualitative description of both the uncertainties and correlation of parameters. The Monte Carlo method is developed as an accurate means of evaluating uncertainties in parameter values for nonlinear models. Examples are given for both actual and synthetic data.


The crosslinking theory of aging--added evidence.
The crosslinking theory of aging has been gaining acceptance at a steady pace, as evidenced by many independent rediscoveries. While several earlier studies were indicative, none seemed conclusive until it was shown, using Differential Scanning Calorimetry (DSC), that protein from young human brains could be made to closely resemble protein from old brains by exposing it to either of two entirely different crosslinking agents (glutaraldehyde and dipotassium diperoxy sulfate). This work has now been repeated with additional brain material, and a statistically more significant number of determinations. It is now shown that a treatment of brain protein with either one or two chemically totally different compounds which have no property in common except that both are crosslinkers, changes young brain protein so that it greatly resembles old, crosslinked protein. This shows that crosslinking reactions are involved in the age related changes in the studied proteins.


Why only areca nut chewing cannot cause oral submucous fibrosis?
Oral submucous fibrosis (OSF) is a potentially malignant disorder of the oral cavity. Most of the affected people are betel quid chewers. Although, betel quid is consumed in various forms, only areca nut chewing habit has become very rare. We came across 34 such cases with 32 showing no evidence of OSF. Therefore, we hypothesize that only areca nut chewing cannot cause OSF and presence of other factors like slaked lime and inflammation is necessary. Keeping in mind the composition of areca nut, hypothesis is comprehensively discussed at molecular level in the present paper with special emphasis on the role of TGF-beta and lysyl oxidase enzyme in OSF. If investigated in the suggested direction, it might provide an important clue about the pathogenesis of OSF and thus can help in the future development of treatment strategies.


Clinical investigations of compounds targeting metabotropic glutamate receptors.
Pharmacological modulation of glutamate has long been considered to be of immense therapeutic utility. The metabotropic glutamate receptors (mGluRs) are potential targets for safely altering glutamate-driven excitation. Data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders. For each of the three mGluR groups, compounds have been constructed that produce either potentiation or functional blockade. PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059. Efficacy with mGlu5R antagonists has been reported in trials with patients with gastroesophageal reflux disease; data from patients with Parkinson's disease or Fragile X syndrome have not been as robust as hoped. Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression. The Group III mGluRs are the least developed of the mGluR receptor targets. The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders.


Multinuclear magnetic resonance studies on serine protease transition state analogues.
31P Nuclear Magnetic Resonance (NMR) studies were performed on mono- and diisopropylphosphoryl derivatives of alpha-chymotrypsin, trypsin, and subtilisin. Questions addressed included the pKa of the active center Asp...His...Ser triad in both species. While the pKa in the diisopropylphosphoryl derivatives is near 7.4 (found in this and other laboratories earlier) and reflects a nearly normal imidazolium titration curve, the apparent pKa in the monoisopropylphosphoryl enzymes (obtained by "aging" of the diisopropylphosphoryl derivatives and monitored by 31P NMR) is between 9.7 and 11.4 depending on the protease. This latter "titration" of the 31P NMR signal is reversible and presumably reflects the interaction of the imidazolium positive charge with the monoanionic phosphodiester. Of the two tetrahedral intermediates, the properties of the monoisopropylphosphoryl enzyme are probably more representative of the tetrahedral oxyanionic intermediate invoked during peptide hydrolysis. The same NMR technique was used to determine the action of PAM (pyridine-2-aldoxime methiodide, a known "antidote" for acetylcholinesterase inactivated by diisopropylfluorophosphate), on the inactivated enzymes. It was clear that the "antidote" could reverse the diisopropylphosphorylation but was ineffective on the monoisopropylphosphoryl ("aged") enzyme. 11B NMR studies were performed on phenylboronic (PBA) acid and 3,5-bis-trifluoromethylphenylboronic acid in the absence and presence of chymotrypsin and subtilisin. At 22 degrees C the former, but not the latter, compound was in fast exchange between the free and enzyme bound states. The relaxation parameters could be calculated for the bound PBA in chymotrypsin and the fluorinated analogue in subtilisin and clearly indicated that the boron nucleus was tetrahedral in the active centers, a good analogue for the tetrahedral oxyanionic intermediate.


Molecular profiling of functional interactions between pre-osteoblastic and breast carcinoma cells.
The relationships between cancer cells and the microenvironment play a critical role in cancer growth and development. The bone stroma consists of mesenchymal stem cells and mature osteoblasts that promote cancer growth. Yet it is not completely understood what are the molecular processes guiding cancer cells progression to the bone. In this study, a coculture assay and subsequent gene profiling arrays were used to compare the gene expression profile of a pre-osteoblastic (PO) cell line (MBA-15) with that of a mammary adenocarcinoma (DA3) cells. After coculture, cells were separated by magnetic beads based on the expression of CD326 antigen. RNA was purified and hybridized on gene expression array. The gene expression pattern changes were followed by qRT-PCR. We demonstrate that cocultured DA3 cells express elevated levels of genes that regulate growth and responses to both hormonal stimulus and wounding, as well as reduced expression of genes related to lipid metabolism. Also, cocultured PO cells showed reduced expression of cell junction genes. The study presents a simplified model system, composed of PO and mammary cancer cells, that potentially mimics the molecular interactions in the tumor microenvironment which contribute to tumor progression.


Psychiatric aspects of bariatric surgery.
While most conventional treatments for individuals with severe obesity have a modest and short lived impact bariatric surgery has been consistently shown to result in long-term marked weight loss and significant improvement in medical comorbidities. Empirical data suggest a high prevalence of mental disorders among bariatric surgery candidates. This article reviews specific areas of psychopathology, problems in using psychopharmacological medications post-surgery, body contouring, and recommendations for pre and post-surgery care. Available research indicates a decrease in psychiatric symptoms post-surgery. However, in some patients the improvement appears to erode over time. Therefore, bariatric surgery patients should be monitored not only before surgery but also following surgery and referred for mental health treatment if problems develop.