Lipolytic action of a new alpha-2 adrenergic antagonist of the piperazinopyrimidine family: RP 55462.
Recent investigations have demonstrated the in vitro lipid mobilizing effects induced by alpha-2 adrenergic antagonist administration and have focused attention on the putative therapeutic interest of such compounds in the treatment of obesity as adjuvants in caloric restriction programs. We studied the impact of RP 55462 [6-chloro-4-(isopropylamino)-5-(methyl)-2, piperazinopyrimidine], a new alpha-2 adrenergic antagonist compound of the piperazinopyrimidine family, on fat cell function. The alpha-2-blocking properties of this agent, which had been defined initially on the brain were confirmed on adipocytes. RP 55462 competed with [3H]yohimbine binding sites on human fat cell membranes and inhibited the antilipolytic action of alpha-2-agonist compounds (UK 14304, clonidine and epinephrine) in human and hamster fat cells. It was also noticed that RP 55462 alone was able to activate lipolysis in isolated fat cells from various species (man, rat, hamster and dog). Moreover, the lipolytic response induced by isoproterenol or synacthene was largely amplified in the presence of RP 55462 in rat fat cells which are the least alpha-2 adrenergic responsive tested. RP-55462-dependent stimulation of lipolysis was not affected by the presence of other alpha-2 adrenergic antagonists (idazoxan, yohimbine or phentolamine). Intravenous administration of RP 55462 in alert dogs promoted an increment in plasma nonesterified acid concentrations reflecting its lipid mobilizing action. In summary this study focuses attention on a new alpha-2-antagonist compound which exhibits an in vivo lipid mobilizing action which could be attributable to its alpha-2 adrenergic antagonist properties. Inasmuch as the lipolytic activity of RP 55462, revealed in in vitro studies, seems to be independent from its alpha-2 adrenolytic properties; further studies are required to define the mechanism of such a lipolytic effect as well as its possible involvement in in vivo conditions.


Filling the Gap: Simulation-based Crisis Resource Management Training for Emergency Medicine Residents.
In today's team-oriented healthcare environment, high-quality patient care requires physicians to possess not only medical knowledge and technical skills but also crisis resource management (CRM) skills. In emergency medicine (EM), the high acuity and dynamic environment makes CRM skills of physicians particularly critical to healthcare team success. The Accreditation Council of Graduate Medicine Education Core Competencies that guide residency program curriculums include CRM skills; however, EM residency programs are not given specific instructions as to how to teach these skills to their trainees. This article describes a simulation-based CRM course designed specifically for novice EM residents. The CRM course includes an introductory didactic presentation followed by a series of simulation scenarios and structured debriefs. The course is designed to use observational learning within simulation education to decrease the time and resources required for implementation. To assess the effectiveness in improving team CRM skills, two independent raters use a validated CRM global rating scale to measure the CRM skills displayed by teams of EM interns in a pretest and posttest during the course. The CRM course improved leadership, problem solving, communication, situational awareness, teamwork, resource utilization and overall CRM skills displayed by teams of EM interns. While the improvement from pretest to posttest did not reach statistical significance for this pilot study, the large effect sizes suggest that statistical significance may be achieved with a larger sample size. This course can feasibly be incorporated into existing EM residency curriculums to provide EM trainees with basic CRM skills required of successful emergency physicians. We believe integrating CRM training early into existing EM education encourages continued deliberate practice, discussion, and improvement of essential CRM skills.


Rapid evolution and the importance of recombination to the gastroenteric pathogen Campylobacter jejuni.
Responsible for the majority of bacterial gastroenteritis in the developed world, Campylobacter jejuni is a pervasive pathogen of humans and animals, but its evolution is obscure. In this paper, we exploit contemporary genetic diversity and empirical evidence to piece together the evolutionary history of C. jejuni and quantify its evolutionary potential. Our combined population genetics-phylogenetics approach reveals a surprising picture. Campylobacter jejuni is a rapidly evolving species, subject to intense purifying selection that purges 60% of novel variation, but possessing a massive evolutionary potential. The low mutation rate is offset by a large effective population size so that a mutation at any site can occur somewhere in the population within the space of a week. Recombination has a fundamental role, generating diversity at twice the rate of de novo mutation, and facilitating gene flow between C. jejuni and its sister species Campylobacter coli. We attempt to calibrate the rate of molecular evolution in C. jejuni based solely on within-species variation. The rates we obtain are up to 1,000 times faster than conventional estimates, placing the C. jejuni-C. coli split at the time of the Neolithic revolution. We weigh the plausibility of such recent bacterial evolution against alternative explanations and discuss the evidence required to settle the issue.


What factors in early pregnancy indicate that the mother will be hit by her partner during the year after childbirth? A nationwide Swedish survey.
To be hit by one's intimate partner during the first year after childbirth may affect a woman's health and ability to take care of her newborn. The purpose of this study was to document the prevalence and indicators in early pregnancy of a woman being hit by her partner during the year after childbirth. Information was collected by a postal questionnaire in early pregnancy and 12 months after childbirth from the approximately 5,550 women in Sweden who visited an antenatal care clinic for the first time during one of three chosen weeks in 1999 and 2000. Of the 3,266 recruited women, 2,563 returned the follow-up questionnaire. Being hit during the first year after childbirth was reported by 52 of the 2,563 (2%) women: 32 (61%) had been hit by their partner once, 12 (23%) twice, and 8 (15%) three or more times. Risk increased in women who were age 24 years or younger (3.9% had been hit), unmarried (7.1%), born in countries outside Europe (6.8%), with a partner born outside Europe (5.4%), had a low level of education (8.9%), and were unemployed (5.0%). In early pregnancy, women with back pain (4.0%), a chronic illness (4.1%), coital pain (6.1%), frequent depression-related symptoms (8.1%), stomach pain (3.8%), or a urinary tract problem (6.3%) were hit more often than others after childbirth. At least 2 percent of Swedish women giving birth in 2000 were hit by their partner during the year after childbirth. Using identified predictors during antenatal care may increase the likelihood of finding women at risk, thereby enhancing the possibility of interventions to prevent this crime and health hazard.


Systemic blood pressure profile correlates with cardiac 123I-MIBG uptake in patients with Parkinson's disease.
To examine the correlation between the systemic blood pressure profile and cardiac (123)I-metaiodobenzylguanidine (MIBG) uptake in patients with Parkinson's disease (PD), we monitored circadian blood pressure patterns of 37 PD patients of 49 to 85 years of age (mean, 71.8±8.4 years) using a portable blood pressure monitoring device. The duration of PD was 0.5 to 15 years, and the disability level (modified Hoehn and Yahr stage) ranged from 1.0 to 4.0 (mean, 2.7±0.7). There were 37 age- and sex-matched control subjects. Cardiac MIBG scintigraphy was performed for the 37 PD patients. Based on the nocturnal fall in mean arterial blood pressure (MABP), we classified patients into extreme dippers (nocturnal reduction of MABP >20%), dippers (>10% but <20%), nondippers (<10% but >0%), and inverted dippers (<0%). Average 24-hour MABP values revealed reduced BP variability in PD patients. The percentage nocturnal fall in MABP was significantly different between PD patients and control subjects (p<0.05). Significant correlations were found between % MABP reduction and the heart-to-mediastinum (H/M) ratio on early and delayed images (p<0.01). The UPDR motor score, early and delay H/M ratios were also significantly different between patients who were and were not dippers (p<0.05). The present results reported for the first time a significant correlation between the systemic blood pressure profile and cardiac (123)I-MIBG uptake in patients with PD. The degeneration between the brainstem and the postganglionic neurons of myocardial sympathetic nerves may progress in parallel in patients with PD.


Medical resource utilization in dermatomyositis/polymyositis patients treated with repository corticotropin injection, intravenous immunoglobulin, and/or rituximab.
Dermatomyositis and polymyositis (DM/PM) are rare, incurable inflammatory diseases that cause progressive muscle weakness and can be associated with increased medical resource use (MRU). When corticosteroid treatment is unsuccessful, patients may receive intravenous immunoglobulin (IVIg), rituximab, or repository corticotropin injection (RCI). This study compared real-world, non-medication MRU between patients treated with RCI and those treated with IVIg and/or rituximab for DM/PM. Claims of DM/PM patients were analyzed from the combination of three commercial health insurance databases in the United States from July 2009 to June 2014. Patients treated with RCI were propensity score matched to those treated with IVIg, rituximab, and both (IVIg+rituximab) based on demographics, prior clinical characteristics, and prior MRU. Per-patient per-month (PPPM) MRU and costs were compared using Poisson regression and generalized linear modeling, respectively. One-hundred thirty-two RCI, 1,150 IVIg, and 562 rituximab patients had an average age of 52.6, 46.6, and 51.7 years, respectively, and roughly two-thirds were female. After matching, there were no significant differences in demographics or prior clinical characteristics. RCI patients had fewer PPPM hospitalizations (0.09 vs 0.17; P=0.049), shorter length of stay (LOS; 3.24 days vs 4.55 days; P=0.004), PPPM hospital outpatient department (HOPD) visits (0.60 vs 1.39; P<0.001), and PPPM physician office visits (2.01 vs 2.33; P=0.035) than IVIg. RCI had fewer PPPM HOPD visits (0.56 vs 0.92; P<0.001) than rituximab. Patients treated with RCI had shorter LOS (2.18 days vs 5.15; P<0.001) and less PPPM HOPD visits (0.53 vs 1.26; P<0.001) than IVIg+rituximab. Total non-medication PPPM costs were 23%-75% lower for RCI compared to IVIg ($2,126 vs $3,964; P<0.001), rituximab ($2,008 vs $2,607; P=0.018), and IVIg+rituximab ($1,234 vs $4,858; P<0.001). Patients treated with RCI had less PPPM non-medication MRU and costs than those treated with IVIg and/or rituximab, particularly in the hospital setting where significant costs are incurred.


Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection.
Enterotoxigenic Escherichia coli (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge. Although molecular interrogation of the vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination ± dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, vaccine responses to some potentially protective non-canonical antigens including EtpA and the YghJ metalloprotease were diminished or absent. These studies highlight important differences in vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide vaccine antigen selection for these pathogens of global importance.


Unexplained interannual oscillations of cyanobacterial blooms in the Baltic Sea.
Population oscillations in multi-species or even single species systems are well-known but have rarely been detected at the lower trophic levels in marine systems. Nitrogen fixing cyanobacteria are a major component of the Baltic Sea ecosystem and sometimes form huge surface accumulations covering most of the sea surface. By analysing a satellite-derived 39-year (1979-2017) data archive of surface cyanobacteria concentrations we have found evidence of strikingly regular interannual oscillations in cyanobacteria concentrations in the northern Baltic Sea. These oscillations have a period of ~3 years with a high-concentration year generally followed by one or two low-concentration years. Changes in abiotic factors known to influence the growth and survival of cyanobacteria could not provide an explanation for the oscillations. We therefore assume that these oscillations are intrinsic to the marine system, caused by an unknown, probably mainly biological mechanism that may be triggered by a combination of environmental factors. Interactions between different life cycle stages of cyanobacteria as well as between predator-prey or host-parasite are possible candidates for causing the oscillations.


Decreased tuftsin concentrations in patients who have undergone splenectomy.
Serum tuftsin concentrations were measured, using a radioimmunoassay developed in Israel, in normal subjects and in patients who had undergone splenectomy. Concentrations in those who had undergone traumatic and elective splenectomy were much lower. The tuftsin concentration in 38 patients with Hodgkin's disease who had undergone splenectomy during staging laparotomy was not significantly different from the mean concentration in other patients who had had elective splenectomy. In four patients who underwent splenectomy for non-malignant haematological disorders measurements made before and after operation showed that tuftsin concentrations fell significantly in the days after operation. The increased susceptibility to overwhelming infections of patients with Hodgkin's disease and others who have undergone splenectomy may be related to the low tuftsin concentrations. As pre-splenectomy tuftsin concentrations in patients with Hodgkin's disease were normal, the practice of performing staging laparotomy and splenectomy in patients with Hodgkin's disease should perhaps be reconsidered.


Serum insulin-like growth factor type 1 concentrations in healthy dogs and dogs with spontaneous primary hypothyroidism.
Circulating insulin-like growth factor type 1 (IGF-1) concentrations in dogs have been correlated with standard breed bodyweight (SBBW or breed size). Thyroid and somatotropic functions, which have common effects and regulatory mechanisms, were investigated in hypothyroid dogs. IGF-1 was measured in 495 adult healthy dogs (N) and in 220 primary hypothyroid dogs (HOT) with clinical and biological signs of primary hypothyroidism. IGF-1 was determined as a function of SBBW (kg): ≤15 (group A); 15<SBBW≤25 (group B); 25<SBBW≤40 (group C); and >40 (group D). In HOT dogs, median fT4 and c-TSH values were 9pmol/L and 1.5ng/mL, respectively. A significant correlation between bodyweight (BW) and IGF-1 was observed in both HOT and N dogs. The median IGF-1 value (ng/mL) was significantly higher (P<0.01) in HOT dogs compared to N in groups B, C and D (230 vs. 182; 316 vs. 230; 606 vs. 306 respectively). In conclusion, IGF-1 concentration should be interpreted in the context of SBBW in dogs and increases in spontaneous primary hypothyroidism. However, it remains unclear if this association is directly due to hypothyroidism or is the result of the weight gain accompanying hypothyroidism.


Role of reactive oxygen species in cell signalling pathways.
Reactive oxygen species (ROS) were originally thought to only be released by phagocytic cells during their role in host defence. It is now clear that ROS have a cell signalling role in many biological systems, both in animals and in plants. ROS induce programmed cell death or necrosis, induce or suppress the expression of many genes, and activate cell signalling cascades, such as those involving mitogen-activated protein kinases.


Familial leptomeningeal amyloidosis with a transthyretin variant Asp18Gly representing repeated subarachnoid haemorrhages with superficial siderosis.
To report the clinical features of two Japanese brothers with familial leptomeningeal amyloidosis, showing a causative gene abnormality of a transthyretin (TTR) variant Asp18Gly, previously reported only in a Hungarian family. The authors reported on a 42 year old man (patient 1) and his 45 year old brother (patient 2), both suffering from subarachnoid haemorrhage (SAH) without and with hydrocephalus, respectively. DNA sequences of the TTR gene were determined in both patients and the patients' clinical features described. A surgical biopsy of the leptomeninges was performed on patient 1. DNA sequence analyses demonstrated the glycine-for-aspartate substitution at position 18 of the TTR variant. Both patients revealed pyramidal tract signs and cerebellar ataxia. Audiometric studies showed bilateral, mild sensorineural hearing loss in the patients whose cerebrospinal fluid (CSF) protein levels increased. T1 weighted MRI after contrast administration showed diffuse leptomeningeal enhancement along the Sylvian fissures and over the surface of the brainstem, cerebellum, and spinal cord. Gradient echo T2* weighted MRI showed superficial siderosis mainly in the cerebellum. A biopsy of the leptomeninges was obtained from the spinal cord of patient 1. While performing the biopsy, the authors observed the varicose, elongating, and fragile veins on the dorsal surface of the spinal cord. Immunohistochemical study revealed marked deposits of TTR derived amyloid on his leptomeninges. This is the second report of familial leptomeningeal amyloidosis with an Asp18Gly TTR gene mutation, clinically causing only CNS symptoms. Repeated SAH from fragile veins on the dorsal surface of the spinal cord seemed to induce superficial siderosis of the CNS. So far, there have been two reliable hallmarks leading to the diagnosis of leptomeningeal amyloidosis: diffuse leptomeningeal enhancement on contrast MRI and greatly increased CSF protein content. This study has contributed a third hallmark: the presence of superficial siderosis is useful in diagnosing leptomeningeal amyloidosis.


The natural history and long-term follow-up of Scheuermann kyphosis.
Sixty-seven patients who had a diagnosis of Scheuermann kyphosis and a mean angle of kyphosis of 71 degrees were evaluated after an average follow-up of thirty-two years (range, ten to forty-eight years) after the diagnosis. All sixty-seven patients completed a questionnaire; fifty-four had a physical examination and radiographs; fifty-two, pulmonary function testing; and forty-five, strength-testing of the trunk muscles. The results were compared with those in a control group of thirty-four subjects who were matched for age and sex. The patients who had Scheuermann kyphosis had more intense back pain, jobs that tended to have lower requirements for activity, less range of motion of extension of the trunk and less-strong extension of the trunk, and different localization of the pain. No significant differences between the patients and the control subjects were demonstrated for level of education, number of days absent from work because of low-back pain, extent that the pain interfered with activities of daily living, presence of numbness in the lower extremities, self-consciousness, self-esteem, social limitations, use of medication for back pain, or level of recreational activities. Also, the patients reported little preoccupation with their physical appearance. Normal or above-normal averages for pulmonary function were found in patients in whom the kyphosis was less than 100 degrees. Patients in whom the kyphosis was more than 100 degrees and the apex of the curve was in the first to eighth thoracic segments had restrictive lung disease. Five patients had an unexplained, mildly abnormal neurological examination. Mild scoliosis was common; spondylolisthesis was not observed.


Separation of DNA binding from the transcription-activating function of a eukaryotic regulatory protein.
The yeast GAL4 protein (881 amino acids) binds to specific DNA sites upstream of target genes and activates transcription. Derivatives of this protein bearing as few as 74 amino terminal residues bind to these sites but fail to activate transcription. When appropriately positioned in front of a gene these derivatives act as repressors. These and related findings support the idea that GAL4 activates transcription by touching other DNA-bound proteins.


Regional changes in ∆FosB expression in rat brain following MDMA self-administration predict increased sensitivity to effects of locally infused MDMA.
Repeated exposure to drugs produces a plethora of persistent brain changes, some of which underlie the development of drug addiction. An important objective of addiction research is to identify the brain changes that might mediate the transition from drug use to drug misuse. The persistent accumulation of the transcription factor, ∆FosB, following repeated drug exposure provides a means of achieving this objective. Experiments were conducted on sexually mature male Sprague-Dawley rats. The effects of extensive 3,4-methylenedioxymethamphetamine (MDMA) self-administration on immunohistochemical measurements of ∆FosB accumulation in 12 brain regions was compared with a matched, drug-naive, control group. Other groups were pretreated with MDMA (0.0 or 10.0 mg/kg, ip, once daily for 5 days), and the locomotor-activating effect of MDMA (200 μg/side) microinjected bilaterally into brain regions selected on the basis of the ∆FosB results was subsequently determined. MDMA self-administration significantly increased ∆FosB expression in the nucleus accumbens core, ventromedial and dorsomedial caudate-putamen, anterior cingulate, prelimbic, infralimbic, and orbitofrontal cortex, and both the central and basolateral amygdala, but not in the ventrolateral or dorsolateral caudate-putamen. Increases in the nucleus accumbens shell were substantial but were not significant following statistical correction for multiple comparisons. MDMA pretreatment enhanced MDMA-produced hyperactivity only when administered into the nucleus accumbens or the medial, but not the lateral, caudate-putamen, mirroring the ∆FosB results. These data compare favorably to results following repeated exposure to other drugs of abuse and support the idea of common neuroplastic changes following repeated drug exposure.


Effect modification by vitamin C on the relation between gastric cancer and Helicobacter pylori.
A hospital-based case-control study of 295 cases with histologically confirmed gastric cancer and age and sex-matched controls was conducted to evaluate the effect of dietary vitamin C intake upon the relation between Helicobacter pylori infection and gastric cancer in Korea in 1997-1998. Anti-H. pylori IgG was detected by ELISA. A food frequency questionnaire, and a questionnaire on demographic factors, including past medical history, smoking, alcohol consumption, and life style was also administered. The prevalences of H. pylori IgG in cases and controls were 80.7% and 71.2%, respectively, and the odds ratio (OR) of H. pylori for gastric cancer was 1.68 (95% confidence interval (CI): 1.14, 2.44), after adjusting for age, sex, educational level, and a past medical history of gastritis or gastric ulcer. In a stratified analysis, H. pylori seropositivity was found to be a significant risk factor for gastric cancer in the low vitamin C intake group (OR = 4.68; 95% CI: 1.97, 11.1), but not in the high vitamin C intake group (OR = 0.72; 95% CI: 0.32, 1.65). Vitamin C intake was found to modify the relation between H. pylori and gastric cancer.


An ultra short episode of sleep is sufficient to promote declarative memory performance.
Various studies have demonstrated that a night of sleep has a beneficial effect on the retention of previously acquired declarative material. In two experiments, we addressed the question of whether this effect extends to daytime naps. In the first experiment we assessed free recall of a list of 30 words after a 60 min retention interval that was either filled with daytime napping or waking activity. Memory performance was significantly enhanced after napping as opposed to waking but was not correlated with time spent in slow wave sleep or total sleep time within the napping condition. The second experiment was designed to clarify the role of total sleep time and therefore included an additional third group, which was allowed to nap for no longer than 6 min on average. In comparing word recall after conditions of no napping (waking), short napping, and long napping, we found superior recall for both nap conditions in contrast to waking as well as for long naps in contrast to short naps. These results demonstrate that even an ultra short period of sleep is sufficient to enhance memory processing. We suggest that the mere onset of sleep may initiate active processes of consolidation which - once triggered - remain effective even if sleep is terminated shortly thereafter.


Dietary steamed wheat bran increases postprandial fat oxidation in association with a reduced blood glucose-dependent insulinotropic polypeptide response in mice.
Obesity is a global epidemic associated with a higher risk of cardiovascular disease and metabolic disorders, such as type 2 diabetes. Previous studies demonstrated that chronic feeding of steamed wheat bran (WB) decreases obesity. To clarify the underlying mechanism and the responsible component for the anti-obesity effects of steamed WB, we investigated the effects of dietary steamed WB and arabinoxylan on postprandial energy metabolism and blood variables. Overnight-fasted male C57BL/6J mice were fed an isocaloric diet with or without steamed WB (30%). Energy metabolism was evaluated using an indirect calorimeter, and plasma glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) levels were measured for 120 min after feeding. We similarly investigated the effect of arabinoxylan, a major component of steamed WB. Mice fed the WB diet had higher postprandial fat oxidation and a lower blood GIP response compared with mice fed the control diet. Mice fed the arabinoxylan diet exhibited a dose-dependent postprandial blood GIP response; increasing the arabinoxylan content in the diet led to a lower postprandial blood GIP response. The arabinoxylan-fed mice also had higher fat oxidation and energy expenditure compared with the control mice. In conclusion, the findings of the present study revealed that dietary steamed WB increases fat oxidation in mice. Increased fat oxidation may have a significant role in the anti-obesity effects of steamed WB. The postprandial effects of steamed WB are due to arabinoxylan, a major component of WB. The reduction of the postprandial blood GIP response may be responsible for the increase in postprandial fat utilization after feeding on a diet containing steamed WB and arabinoxylan.


Ion channel stability and hydrogen bonding. Molecular modelling of channels formed by synthetic alamethicin analogues.
Several analogues of the channel-forming peptaibol alamethicin have been demonstrated to exhibit faster switching between channel substates than does unmodified alamethicin. Molecular modelling studies are used to explore the possible molecular basis of these differences. Models of channels formed by alamethicin analogues were generated by restrained molecular dynamics in vacuo and refined by short molecular dynamics simulations with water molecules within and at either mouth of the channel. A decrease in backbone solvation was found to correlate with a decrease in open channel stability between alamethicin and an analogue in which all alpha-amino-isobutyric acid residues of alamethicin were replaced by leucine. A decrease in the extent of hydrogen-bonding at residue 7 correlates with lower open channel stabilities of analogues in which the glutamine at position 7 was replaced by smaller polar sidechains. These two observations indicate the importance of alamethicin/water H-bonds in stabilizing the open channel.


AGEs inhibit scavenger receptor class B type I gene expression via Smad1 in HUVECs.
Vascular complications are the main cause of morbidity and mortality in diabetic patients, and advanced glycation end products (AGEs) play a critical role in promoting diabetic vascular dysfunction. The human homolog of scavenger receptor class B type I (SR-BI), CD36, and LIMPII analog-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. In endothelial cells, HDL activates endothelial nitric oxide synthase (eNOS) via hSR-BI/CLA-1. In this study, we elucidated the effects of AGEs on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). HSR-BI/CLA-1 expression was examined by real-time PCR, western blot analysis, and reporter gene assay in HUVECs incubated with AGEs. eNOS activity was assessed by detecting the phosphorylation (Ser 1179) of eNOS. Our results showed that AGEs decreased the endogenous expression of hSR-BI/CLA-1. AGEs also inhibited the activity of the hSR-BI/CLA-1 promoter and its mRNA expression via receptor RAGE. We identified the binding site for Smad1 on the hSR-BI/CLA-1 promoter: Smad1 bound to its promoter. AGE treatment stimulated the transcriptional activity of Smad1, and mutation of the Smad1 binding site inhibited the effect of AGEs on the hSR-BI/CLA-1 promoter. HDL-treatment enhanced the phosphorylation of eNOS at Ser 1179, but pretreatment with AGEs inhibited the phosphorylation of eNOS Ser 1179. These results suggested that AGEs downregulate the expression of the endothelial hSR-BI/CLA-1 via the Smad1 pathway, which may be a therapeutic target for diabetic endothelial dysfunction.


Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes.
Linkage of chromosome 11q13 to type 1 diabetes (T1D) was first reported from genome scans (Davies et al. 1994; Hashimoto et al. 1994) resulting in P <2.2 x 10(-5) (Luo et al. 1996) and designated IDDM4 ( insulin dependent diabetes mellitus 4). Association mapping under the linkage peak using 12 polymorphic microsatellite markers suggested some evidence of association with a two-marker haplotype, D11S1917*03-H0570POLYA*02, which was under-transmitted to affected siblings and over-transmitted to unaffected siblings ( P=1.5 x 10(-6)) (Nakagawa et al. 1998). Others have reported evidence for T1D association of the microsatellite marker D11S987, which is approximately 100 kb proximal to D11S1917 (Eckenrode et al. 2000). We have sequenced a 400-kb interval surrounding these loci and identified four genes, including the low-density lipoprotein receptor related protein (LRP5) gene, which has been considered as a functional candidate gene for T1D (Hey et al. 1998; Twells et al. 2001). Consequently, we have developed a comprehensive SNP map of the LRP5 gene region, and identified 95 SNPs encompassing 269 kb of genomic DNA, characterised the LD in the region and haplotypes (Twells et al. 2003). Here, we present our refined linkage curve of the IDDM4 region, comprising 32 microsatellite markers and 12 SNPs, providing a peak MLS=2.58, P=5 x 10(-4), at LRP5 g.17646G>T. The disease association data, largely focused in the LRP5 region with 1,106 T1D families, provided no further evidence for disease association at LRP5 or at D11S987. A second dataset, comprising 1,569 families from Finland, failed to replicate our previous findings at LRP5. The continued search for the variants of the putative IDDM4 locus will greatly benefit from the future development of a haplotype map of the genome.


The emerging low-dose therapy for advanced cancers.
Generally minute doses of drugs have been prescribed in biotherapies, homeopathy, immunization and vaccinations for centuries. Now the use of low doses of drugs is on the rise to combat serious diseases such as advanced cancers around the world. This new therapeutic approach to address solid tumors and other advanced diseases is a departure from the conventional use of maximum dose protocol. A small dose of the prescribed drug is frequently administered in a continuous fashion, at regular intervals, either as a standard treatment or as a maintenance therapy for a long time. However, this new treatment method lacks any standard for drug quantization, dose fractionation, repetition frequency and duration of a treatment course for an individual patient. This paper reviews literature about metronomic therapy and discusses hormesis: both phenomena occur in low dose ranges. Better mathematical models, computer simulations, process optimization and clinical trials are warranted to fully exploit the potential of low dose metronomic therapy to cure chronic and complicated diseases. New protocols to standardize metronomic dosimetry will answer the age old questions related to hormesis and homeopathy. It appears that this new low-dose metronomic therapy will have far reaching effects in curing chronic diseases throughout the world.


Pathological Location of Cranial Nerves in Petroclival Lesions: How to Avoid Their Injury during Anterior Petrosal Approach.
Objectives Numerous surgical approaches have been developed to access the petroclival region. The Kawase approach, through the middle fossa, is a well-described option for addressing cranial base lesions of the petroclival region. Our aim was to gather data about the variation of cranial nerve locations in diverse petroclival pathologies and clarify the most common pathologic variations confirmed during the anterior petrosal approach. Method A retrospective analysis was made of both videos and operative and histologic records of 40 petroclival tumors from January 2009 to September 2013 in which the Kawase approach was used. The anatomical variations of cranial nerves IV-VI related to the tumor were divided into several location categories: superior lateral (SL), inferior lateral (IL), superior medial (SM), inferior medial (IM), and encased (E). These data were then analyzed taking into consideration pathologic subgroups of meningioma, epidermoid, and schwannoma. Results In 41% of meningiomas, the trigeminal nerve is encased by the tumor. In 38% of the meningiomas, the trigeminal nerve is in the SL part of the tumor, and it is in 20% of the IL portion of the tumor. In 38% of the meningiomas, the trochlear nerve is encased by the tumor. The abducens nerve is not always visible (35%). The pathologic nerve pattern differs from that of meningiomas for epidermoid and trigeminal schwannomas. Conclusion The pattern of cranial nerves IV-VI is linked to the type of petroclival tumor. In a meningioma, tumor origin (cavernous, upper clival, tentorial, and petrous apex) is the most important predictor of the location of cranial nerves IV-VI. Classification of four subtypes of petroclival meningiomas using magnetic resonance imaging is very useful to predict the location of deviated cranial nerves IV-VI intraoperatively.


Eukaryotic membrane tethers revisited using magnetic tweezers.
Membrane nanotubes, under physiological conditions, typically form en masse. We employed magnetic tweezers (MTW) to extract tethers from human brain tumor cells and compared their biophysical properties with tethers extracted after disruption of the cytoskeleton and from a strongly differing cell type, Chinese hamster ovary cells. In this method, the constant force produced with the MTW is transduced to cells through super-paramagnetic beads attached to the cell membrane. Multiple sudden jumps in bead velocity were manifest in the recorded bead displacement-time profiles. These discrete events were interpreted as successive ruptures of individual tethers. Observation with scanning electron microscopy supported the simultaneous existence of multiple tethers. The physical characteristics, in particular, the number and viscoelastic properties of the extracted tethers were determined from the analytic fit to bead trajectories, provided by a standard model of viscoelasticity. Comparison of tethers formed with MTW and atomic force microscopy (AFM), a technique where the cantilever-force transducer is moved at constant velocity, revealed significant differences in the two methods of tether formation. Our findings imply that extreme care must be used to interpret the outcome of tether pulling experiments performed with single molecular techniques (MTW, AFM, optical tweezers, etc). First, the different methods may be testing distinct membrane structures with distinct properties. Second, as soon as a true cell membrane (as opposed to that of a vesicle) can attach to a substrate, upon pulling on it, multiple nonspecific membrane tethers may be generated. Therefore, under physiological conditions, distinguishing between tethers formed through specific and nonspecific interactions is highly nontrivial if at all possible.


Geographic variation and acoustic structure of the underwater vocalization of harbor seal (Phoca vitulina) in Norway, Sweden and Scotland.
The male harbor seal (Phoca vitulina) produces broadband nonharmonic vocalizations underwater during the breeding season. In total, 120 vocalizations from six colonies were analyzed to provide a description of the acoustic structure and for the presence of geographic variation. The complex harbor seal vocalizations may be described by how the frequency bandwidth varies over time. An algorithm that identifies the boundaries between noise and signal from digital spectrograms was developed in order to extract a frequency bandwidth contour. The contours were used as inputs for multivariate analysis. The vocalizations' sound types (e.g., pulsed sound, whistle, and broadband nonharmonic sound) were determined by comparing the vocalizations' spectrographic representations with sound waves produced by known sound sources. Comparison between colonies revealed differences in the frequency contours, as well as some geographical variation in use of sound types. The vocal differences may reflect a limited exchange of individuals between the six colonies due to long distances and strong site fidelity. Geographically different vocal repertoires have potential for identifying discrete breeding colonies of harbor seals, but more information is needed on the nature and extent of early movements of young, the degree of learning, and the stability of the vocal repertoire. A characteristic feature of many vocalizations in this study was the presence of tonal-like introductory phrases that fit into the categories pulsed sound and whistles. The functions of these phrases are unknown but may be important in distance perception and localization of the sound source. The potential behavioral consequences of the observed variability may be indicative of adaptations to different environmental properties influencing determination of distance and direction and plausible different male mating tactics.


First Report of Arceuthobium globosum subsp. grandicaule in Honduras.
Large-stemmed dwarf mistletoe (Arceuthobium globosum Hawksw. & Wiens subsp. grandicaule Hawksw. & Wiens-Viscaceae) parasitizes several Pinus spp. in central Mexico and western Guatemala (1). In November 2000 several trees of Pinus hartwegii Lindley were discovered being parasitized by this dwarf mistletoe near the summit of Cerro las Minas, Montana de Celaque (2850 m elevation) approximately 12 km southwest of Gracias, Department Lempira, Honduras. Species identification was based on the size of the plants, which were greater than 50 cm in height, and the dark brown color and size (2.1 to 4.5 cm) of the stem base (1). There was no apparent infection of nearby Pinus ayacahuite Ehrenb., which is known to be immune to the pathogen. Specimens of A. globosum subsp. grandicaule were collected and deposited at the Herbario, Escuela Nacional de Ciencias Forestales, Siguatepeque, Honduras and at the Deaver Herbarium, Northern Arizona University, Flagstaff. To our knowledge, this is the first report of this dwarf mistletoe in Honduras and extends its eastern distribution from west-central Guatemala by approximately 300 km. Reference: (1) F. G. Hawksworth and D. Wiens. 1996. Dwarf Mistletoes: Biology, Pathology, and Systematics. USDA Agric. Handb. 709.


Hypoxic depression of ventilation in humans: alternative models for the chemoreflexes.
The ventilatory responses of 5 volunteers to three protocols were determined. In protocol A, PETCO2 was held at 1-2 Torr above resting; and PETO2 at 100 Torr for 10 min, 50 Torr for 20 min, and 100 Torr again for 10 min. In protocol B, PETCO2 was held at 8 Torr above resting, and PETO2 varied as in protocol A. Protocol C formed a control. Each protocol was repeated at least 6 times on each subject. The data were used to evaluate four different models (models 2-5) for incorporating the depressant effect of hypoxia into a standard model (model 1) of the chemoreflex responses. In model 2, hypoxic depression was incorporated as an additive term independent of the central and peripheral chemoreflexes; in model 3 it affected the central chemoreflex gain; in model 4 it affected the peripheral chemoreflex gain; and in model 5 it affected the gain of both reflexes. From this, it was concluded only model 4 was consistent with the data; all other models were inconsistent.


[Spanish version of the personality diagnostic questionnaire-4+ (PDQ-4+)].
The Personality Diagnostic Questionnaire is one of the most frequently used instruments for diagnosing personality disorders (PD). Its last version (PDQ-4+) combines the easy applicability of a questionnaire with the control of state symptoms interference of an interview. The aim of this paper is to present preliminary results on the Spanish version of the PDQ-4+. 159 psychiatric outpatients were assessed using the questionnaire of PDQ-4+. Among them, a sample of 47 were also evaluated using the short interview of clinical significance that completed the PDQ-4+. Results obtained were very similar to that from previous research, indicating similar psychometric properties of the PDQ-4+ Spanish version, to English, Italian, Chinese and Norway versions. In general, the internal consistency was acceptable; the obsessive-compulsive PD scale showing the lowest Cronbach's alpha. The high prevalence of PD obtained with the PDQ-4+ questionnaire was dramatically reduced when the clinical significance scale was added. These results are in more agreement with previous epidemiological studies. Overall, the PDQ-4+ questionnaire seems a good screening instrument in clinical use. Best results are obtained when the clinical significance scale is also administered.


Fuzzy differential inclusions in atmospheric and medical cybernetics.
Uncertainty management in dynamical systems is receiving attention in artificial intelligence, particularly in the fields of qualitative and model based reasoning. Fuzzy dynamical systems occupy a very important position in the class of uncertain systems. It is well established that the fuzzy dynamical systems represented by a set of fuzzy differential inclusions (FDI) are very convenient tools for modeling and simulation of various uncertain systems. In this paper, we discuss about the mathematical modeling of two very complex natural phenomena by means of FDIs. One of them belongs to the atmospheric cybernetics (the term has been used in a broad sense) of the genesis of a cyclonic storm (cyclogenesis), and the other belongs to the bio-medical cybernetics of the evolution of tumor in a human body. Since a discussion of the former already appears in a previous paper by the first author, here, we present very briefly a theoretical formalism of cyclone formation. On the other hand, we treat the latter system more elaborately. We solve the FDIs with the help of an algorithm developed in this paper to numerically simulate the mathematical models. From the simulation results thus obtained, we have drawn a number of interesting conclusions, which have been verified, and this vindicates the validity of our models.


How did a Housing First intervention improve health and social outcomes among homeless adults with mental illness in Toronto? Two-year outcomes from a randomised trial.
We studied the impact of a Housing First (HF) intervention on housing, contact with the justice system, healthcare usage and health outcomes among At Home/Chez Soi randomised trial participants in Toronto, a city with an extensive service network for social and health services for individuals who are experiencing homelessness and mental illness. Participants identified as high needs were randomised to receive either the intervention which provided them with housing and supports by an assertive community treatment team (HF+ACT) or treatment as usual (TAU). Participants (N=197) had in-person interviews every 3 months for 2 years. The HF+ACT group spent more time stably housed compared to the TAU group with the mean difference between the groups of 45.8% (95% CI 37.1% to 54.4%, p<0.0001). Accounting for baseline differences, HF+ACT group showed significant improvements over TAU group for community functioning, selected quality-of-life subscales and arrests at some time points during follow-up. No differences between HF+ACT and TAU groups over the follow-up were observed for health service usage, community integration and substance use. HF for individuals with high levels of need increased housing stability and selected health and justice outcomes over 2 years in a city with many social and health services. ISRCTN42520374.


Genomic Insights into Zika Virus Emergence and Spread.
The emergence and spread of Zika virus in the Americas continues to challenge our disease surveillance systems. Virus genome sequencing during the epidemic uncovered the timescale of Zika virus transmission and spread. Yet, we are only beginning to explore how genomics can enhance our responses to emerging viruses.


PD-1 Blockade in a Liver Transplant Recipient With Microsatellite Unstable Metastatic Colorectal Cancer and Hepatic Impairment.
Immune checkpoint inhibitors represent a newly established standard of care in patients with refractory metastatic colorectal cancer with mismatch repair deficiency and microsatellite instability. However, the use of immunotherapy is unclear in recipients of liver transplants with or without concurrent liver function abnormalities. Clinical trials investigating immunotherapy have mostly excluded liver transplant recipients and patients with abnormal liver function. This report presents the first case, to our knowledge, of a liver transplant patient with mismatch repair-deficient colon adenocarcinoma with liver metastases and concurrent abnormal liver function who safely responded to immunotherapy. We also review the literature on checkpoint inhibitor use in patients with other metastatic solid tumors after liver transplant and those with baseline liver function abnormalities. An increasing body of evidence supports the safety of checkpoint inhibition in patients with cancer and solid organ transplants, but further prospective studies are warranted. Use of immunotherapy in liver transplant recipients who have metastatic colorectal cancer with microsatellite instability is feasible but should be performed in a multidisciplinary team setting.


Identification of stem cells in small intestine and colon by marker gene Lgr5.
The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.


A Critical Review on Clinical Application of Separation Techniques for Selective Recognition of Uracil and 5-Fluorouracil.
The most important objectives that are frequently found in bio-analytical chemistry involve applying tools to relevant medical/biological problems and refining these applications. Developing a reliable sample preparation step, for the medical and biological fields is another primary objective in analytical chemistry, in order to extract and isolate the analytes of interest from complex biological matrices. Since, main inborn errors of metabolism (IEM) diagnosable through uracil analysis and the therapeutic monitoring of toxic 5-fluoruracil (an important anti-cancerous drug) in dihydropyrimidine dehydrogenase deficient patients, require an ultra-sensitive, reproducible, selective, and accurate analytical techniques for their measurements. Therefore, keeping in view, the diagnostic value of uracil and 5-fluoruracil measurements, this article refines several analytical techniques involved in selective recognition and quantification of uracil and 5-fluoruracil from biological and pharmaceutical samples. The prospective study revealed that implementation of molecularly imprinted polymer as a solid-phase material for sample preparation and preconcentration of uracil and 5-fluoruracil had proven to be effective as it could obviates problems related to tedious separation techniques, owing to protein binding and drastic interferences, from the complex matrices in real samples such as blood plasma, serum samples.


The ratio of flow in the superior and inferior caval veins after construction of a bidirectional cavopulmonary anastomosis in children.
In patients who have undergone a superior cavopulmonary anastomosis, the superior caval venous flow provides the only, or the most important, pulmonary blood supply, while the inferior caval venous blood is not oxygenated, being mixed with the pulmonary venous blood before entering the systemic circulation. In healthy children, the contribution of superior caval venous flow to total cardiac output has been shown to decrease during growth. Patients who have undergone a superior cavopulmonary anastomosis, however, often have a higher oxygen saturation than predicted by the age-matched ratio of superior to inferior caval venous flows. This study was designed, therefore, to assess the ratio of flows in the superior and inferior caval veins subsequent to a superior cavopulmonary anastomosis. We carried out 18 magnetic resonance imaging studies with velocity-mapping and heart catheterisations so as to assess the contribution of superior caval venous flow to total cardiac output. Patients were divided into 3 groups according to their age. There were five aged from 8 to 24 months, eight aged from 24 to 48 months, and five older than 48 months. No significant difference could be found in the ratios of superior-to-inferior caval venous flow, nor of superior caval venous-to-systemic flow, between the 3 groups. The ratio of venous flows was 0.89 +/- 0.34 in those aged from 8 to 24 months, 1.09 +/- 0.42 in those from 24 to 48 months, and 1.25 +/- 0.27 in the older patients (F analysis of variance 1.06, p 0.37). The ratio of superior caval venous-to-systemic flow was 0.46 +/- 0.08 in the youngest patients, 0.50 +/- 0.09 in those aged from 24 to 48 months, and 0.55 +/- 0.05 in the older patients (F analysis of variance 0.76, p 0.49). These findings suggest that the hemodynamics of a cavopulmonary anastomosis may affect the normal decrease of superior caval venous flow with age. This could be related to a redistribution of flow, with a proportionally higher flow to the head and upper body after construction of a superior cavopulmonary anastomosis. Since increasing cyanosis and progressive exercise intolerance are the main indications for creation of a total cavopulmonary connection, these findings should be taken into account when determining the timing for completion of the Fontan circulation.


Benign liver masses and lesions in children: 53 cases over 12 years.
Primary liver masses in children may require intervention because of symptoms or concern about malignant transformation. To review the management and outcome of benign liver masses in children. We conducted a retrospective chart review of children with liver masses referred to our institution during the period 1997-2009. Benign liver masses were identified in 53 children. Sixteen of these children (30%) had hemangioma/infantile hepatic hemangioendothelioma (IHH) and 15 (28%) had focal nodular hyperplasia. The remainder had 6 cysts, 4 hamartomas, 3 nodular regenerative hyperplasia, 2 adenomas, 2 vascular malformations, and one each of polyarteritis nodosa, granuloma, hepatic hematoma, lymphangioma, and infarction. Median age at presentation was 6 years, and 30 (57%) were female. Masses were initially noticed on imaging studies performed for unrelated symptoms in 33 children (62%), laboratory abnormalities consistent with liver disease in 11 (21%), and palpable abdominal masses in 9 (17%). Diagnosis was made based on characteristic radiographic findings in 31 (58%), but histopathological examination was required for the remaining 22 (42%). Of the 53 children, 27 (51%) were under observation while 17 (32%) had masses resected. Medications targeting masses were used in 9 (17%) and liver transplantation was performed in 4 (8%). The only death (2%) occurred in a child with multifocal IHH unresponsive to medical management and prior to liver transplant availability. IHH and focal nodular hyperplasia were the most common lesions. The majority of benign lesions were found incidentally and diagnosed radiologically. Expectant management was sufficient in most children after diagnosis, although surgical intervention including liver transplant was occasionally necessary.


Rationale and Design of the Balanced Anesthesia Study: A Prospective Randomized Clinical Trial of Two Levels of Anesthetic Depth on Patient Outcome After Major Surgery.
An association between relatively deep anesthesia, as guided by the bispectral index (BIS), and increased postoperative mortality has been demonstrated in 6 of 8 published observational studies, but association does not necessarily mean causality. Small clinical trials of anesthetic depth have demonstrated increased delirium and postoperative cognitive dysfunction in patients who were relatively deeply anesthetized, but have been inadequately powered to study mortality. A large-scale randomized study is required to determine whether causality exists. The primary hypothesis of our study is that "light" anesthesia, defined as a BIS target of 50, will reduce all-cause mortality within 1 year of surgery in comparison with "deep" anesthesia, defined as a BIS target of 35, in patients aged ≥60 years presenting for major surgery under general anesthesia. The trial is an international multicenter, randomized, parallel-group, double-blind (patients and investigators) prospective, intention-to-treat, safety and efficacy study. The relative reduction in mortality in the light anesthesia group is expected to be 20%, giving an absolute risk reduction from 10% to 8%. Power analysis using a = 0.049 and b = 0.2 indicates that 3250 patients are required in each group. The study is underway, and 1325 patients have been recruited in 40 centers in 5 countries. It is anticipated that the study will be completed in 3 years. This randomized controlled trial should definitively answer the question of whether titrating anesthetic depth makes a difference to patient outcome in a vulnerable patient group.


Late cancer and noncancer risks among Chernobyl emergency workers of Russia.
The presented work summarizes data on estimated radiation risks among Chernobyl emergency workers of the Russian Federation. In 1991-1998, the excess relative risk (ERR) of death from malignant neoplasm was statistically significant: excess relative risk per 1 Gy (ERR/Gy)=2.11 with 95% confidence interval (CI) (1.31-2.92). In 1991-2001, the ERR estimation for incident solid cancers gives a positive, but statistically insignificant value: ERR/Gy=0.34 with 95% CI (-0.39; 1.22). In 1986-2003, radiation risk for leukemia incidence was investigated. During the first 10 y after the Chernobyl accident (1986-1996) the relative risk (RR) of leukemia (excluding chronic lymphocytic leukemia) was statistically significant: RR=2.2 with 95% CI (1.3-3.8) for emergency workers with doses>0.15 Gy in comparison with less exposed workers. In 1986-2000, a statistically significant dose response was observed for incident cerebrovascular diseases: ERR/Gy=0.39, 95% CI=(0.004; 0.77). For doses>0.15 Gy a statistically significant risk of cerebrovascular diseases as a function of mean daily dose was observed: ERR per 0.1 Gy d(-1)=2.17 with 95% CI=(0.64; 3.69). Different but overlapping cohorts of Russian emergency workers were used for these estimations. No adjustments were made for recognized risk factors for cerebrovascular diseases. All results should be considered as preliminary.


Human myiasis caused by the reindeer warble fly, Hypoderma tarandi, case series from Norway, 2011 to 2016.
Hypoderma tarandi causes myiasis in reindeer and caribou (Rangifer tarandus spp.) in most northern hemisphere regions where these animals live. We report a series of 39 human myiasis cases caused by H. tarandi in Norway from 2011 to 2016. Thirty-two were residents of Finnmark, the northernmost county of Norway, one a visitor to Finnmark, and six lived in other counties of Norway where reindeer live. Clinical manifestations involved migratory dermal swellings of the face and head, enlargement of regional lymph nodes, and periorbital oedema, with or without eosinophilia. Most cases of human myiasis are seen in tropical and subtropical countries, and in tourists returning from such areas. Our findings demonstrate that myiasis caused by H. tarandi is more common than previously thought. Healthcare professionals in regions where there is a likelihood of human infestation with H. tarandi (regions populated by reindeer), or treating returning travellers, should be aware of the condition. All clinicians are advised to obtain a detailed travel history when assessing patients with migratory dermal swellings. On clinical suspicion, ivermectin should be given to prevent larval invasion of the eye (ophthalmomyiasis). Since H. tarandi oviposits on hair, we suggest wearing a hat as a prevention measure.


Assessment of the relationship between a written measure of empathy and an independently rated interview of Motivational Interviewing.
Motivational Interviewing (MI) is an evidence-based practice shown to be effective when working with people in treatment for substance use disorders. However, MI is a complex treatment modality optimized by training with feedback. Feedback, assessment and monitoring of treatment fidelity require measurement, which is typically done using audiotaped sessions. The gold standard for such measurement of MI skill has been an audiotaped interview, scored by a rater with a detailed structured instrument such as the Motivational Interviewing Treatment Integrity 2.0 (MITI 2.0) Coding System (Moyers, et al., 2005). The Helpful Responses Questionnaire (HRQ) (Miller, Hedrick, & Orlofsky, 1991) is a pen-and-paper test of empathy (a foundational MI skill) that does not require an audiotaped session. A randomized trial of three different regimens for training counselors in MI (live supervision using Teleconferencing, Tape-based supervision and Workshop only) (Smith et al., 2012) offered the opportunity to evaluate the performance of the HRQ as a measure of MI ability, compared to the several MITI 2.0 global scores and subscales. Participants were counselors (N=97) working at community-based substance use treatment programs, whose MI proficiency was measured at four time points: baseline (before an initial 2-day MI workshop), post-workshop, 8weeks post-workshop (i.e., post-supervision), and 20weeks post-workshop with both MITI 2.0 and HRQ. HRQ total scores correlated significantly with the Reflection to Question Ratio from the MITI 2.0 at post-workshop (r=0.33), week 8 (r=0.34), and week 20 (r=0.38), and with the Spirit (r=0.32) and Empathy (r=0.32) global scores at week 20. Correlations of HRQ with other MITI 2.0 subscales and time points after workshop were small and not significant. As predicted, HRQ scores differed between training conditions (X2(2)=7.88, p=0.02), with counselors assigned to live supervision achieving better HRQ scores than those in Workshop only. In summary, HRQ is a modestly accurate measure, mainly of the Reflection to Question Ratio, considered a core marker of MI skill. It is sensitive to training effects and may help identify counselors needing more intensive supervision. Given its ease of administration and scoring, HRQ may be a useful marker of MI skill during training efforts.


Structural basis of peptide recognition by the angiotensin-1 converting enzyme homologue AnCE from Drosophila melanogaster.
Human somatic angiotensin-1 converting enzyme (ACE) is a zinc-dependent exopeptidase, that catalyses the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, by removing a C-terminal dipeptide. It is the principal component of the renin-angiotensin-aldosterone system that regulates blood pressure. Hence it is an important therapeutic target for the treatment of hypertension and cardiovascular disorders. Here, we report the structures of an ACE homologue from Drosophila melanogaster (AnCE; a proven structural model for the more complex human ACE) co-crystallized with mammalian peptide substrates (bradykinin, Thr(6) -bradykinin, angiotensin I and a snake venom peptide inhibitor, bradykinin-potentiating peptide-b). The structures determined at 2-Å resolution illustrate that both angiotensin II (the cleaved product of angiotensin I by AnCE) and bradykinin-potentiating peptide-b bind in an analogous fashion at the active site of AnCE, but also exhibit significant differences. In addition, the binding of Arg-Pro-Pro, the cleavage product of bradykinin and Thr(6) - bradykinin, provides additional detail of the general peptide binding in AnCE. Thus the new structures of AnCE complexes presented here improves our understanding of the binding of peptides and the mechanism by which peptides inhibit this family of enzymes. The atomic coordinates and structure factors for AnCE-Ang II (code 4AA1), AnCE-BPPb (code 4AA2), AnCE-BK (code 4ASQ) and AnCE-Thr6-BK (code 4ASR) complexes have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/) • AnCE cleaves Ang I by enzymatic study (View interaction) • Bradykinin and AnCE bind by x-ray crystallography (View interaction) • BPP and AnCE bind by x-ray crystallography (View interaction) • AnCE cleaves Bradykinin by enzymatic study (View interaction) • Ang II and AnCE bind by x-ray crystallography (View interaction).


A systematic review of the effect of dietary interventions on cardiovascular disease risk in adults with spinal cord injury.
Cardiovascular disease is one of the leading causes of mortality in individuals with spinal cord injury (SCI), highlighting the need for targeted risk minimization interventions. To determine the effect of dietary interventions on CVD risk in adults with SCI. A systematic literature review of studies investigating the impact of dietary intervention on CVD risk in SCI individuals was conducted according to the PRISMA statement. CASP checklists were used for critical appraisal, Academy of Nutrition and Dietetics Quality criteria checklist (QCC) for determining risk of bias and the GRADE approach to ascertain the quality of evidence of the outcomes. The results were reported descriptively. A total of eight studies were included from the identified 862 articles. Dietary intervention strategies varied across all studies, as did the outcome measures. Adult learning theories were not considered. The lack of controlled trials (two only) meant that while some interventions proved useful, risk of bias was high. Outcome measures were assessed as low to very low quality again identifying that this area is highly under-researched. Despite documented evidence of the benefits of diet on CVD risk reduction, this review has identified a dearth of research in SCI. Nonetheless, the review emphasizes the potential of diet in conjunction with exercise in minimizing CVD risk in SCI. Further good quality research backed by robust data collection, simple, actionable strategies and knowledge translation techniques are essential to ascertain the effects of dietary intervention in lowering CVD risk in SCI.


Immunohistochemical expression of Bax and Bak in canine non-neoplastic tissues.
Apoptosis is critical for embryonic development, maintenance of tissue homeostasis and protection against malignant transformation. The Bcl-2 family of proteins plays a key role in intrinsic apoptosis by controlling the integrity of the outer mitochondrial membrane, and the multidomain pro-apoptotic Bcl-2 family members Bax and Bak are essential components of this pathway. The aim of this study was to provide data on the expression of these proteins in normal canine tissues. Two antibodies against Bax recognising different conformations of the protein and one antibody against Bak were validated by immunohistochemistry and immunoblotting using canine recombinant proteins and keratinocytes treated with ultraviolet light. The antibodies were used immunohistochemically to label a wide panel of histologically normal tissues assembled on tissue microarrays. In addition, a subset of the tissues was evaluated by Western blot analysis. Immunohistochemical and Western blot analyses revealed that both Bax and Bak are widely expressed in non-neoplastic tissues from adult dogs. Immunohistochemistry showed almost exclusively cytoplasmic labelling and prominent labelling of epithelial cells. In lymph nodes, immunohistochemical labelling was diffuse for both proteins and showed enhanced intensities in the mantle zones for Bax and the germinal centres for Bak. Strong reactivity for the active conformation of Bax was detected only in enterocytes and Leydig cells and in scattered lymphocytes. These data indicate widespread expression of Bax and Bak in normal canine tissues. Knowledge of the expression of Bax and Bak in normal tissues is a prerequisite in assessing the role of these proteins in canine neoplastic disease.


Left ventricular systolic dysfunction in outpatients with peripheral atherosclerotic vascular disease: prevalence and association with location of arterial disease.
We aimed to determine the prevalence of left ventricular systolic dysfunction (LVSD) in outpatients with peripheral atherosclerotic vascular disease (PAVD). Further, the associations of stenotic internal carotid artery disease (SICAD) and lower extremity artery disease (LEAD) with LVSD were evaluated. In the Peripheral Artery Disease in Västmanland study, consecutive outpatients with ultrasonographically identified mild to severe stenosis in the internal carotid artery or symptoms of claudication combined with either ankle brachial index of ≤0.90 or ultrasonographic occlusive findings were included (n = 437). Population-based control subjects were matched to the patients (n = 395). LVSD was defined as echocardiographically determined left ventricular ejection fraction (LVEF) <55%, and moderate or greater LVSD was defined as LVEF <45%. The prevalence of LVSD was significantly greater in patients than in controls (13.7% vs. 6.1%, P < 0.001). The prevalence of moderate or greater LVSD in participants not on treatment with a combination of angiotensin-converting enzyme inhibitor and beta-blocker was 2.3% in patients and 1.3% in controls (P = 0.31). When LEAD and SICAD were analysed together, adjusted for potential confounders, SICAD [odds ratio (OR) 2.54, 95% confidence interval (CI) 1.03-6.32], but not LEAD (OR 1.59, 95% CI 0.80-3.18), was independently associated with LVSD. In outpatients with PAVD, we found a 13.7% prevalence of LVSD. However, the prevalence of at least moderate LVSD in patients not on treatment with angiotensin-converting enzyme inhibitor and a beta-blocker was only 2.3% and not significantly different from controls. Stenotic artery disease in the internal carotid artery, but not in the lower extremities, was independently associated with LVSD.


Rapid onset of true antidepressant action.
Antidepressant medications generally are considered to have a delayed onset of action; however, recent evidence is beginning to challenge this conventional wisdom. Meta-analysis of placebo-controlled, randomized trials reveals that patients with depression are more likely to experience a clinically significant response with antidepressants than with placebo by the end of the first week of treatment. About one third of the total treatment benefit over 6 weeks is evident by the end of the first week. Early response to antidepressants is not necessarily a placebo response.


Corruption in the health care sector: A barrier to access of orthopaedic care and medical devices in Uganda.
Globally, injuries cause approximately as many deaths per year as HIV/AIDS, tuberculosis and malaria combined, and 90% of injury deaths occur in low- and middle- income countries. Given not all injuries kill, the disability burden, particularly from orthopaedic injuries, is much higher but is poorly measured at present. The orthopaedic services and orthopaedic medical devices needed to manage the injury burden are frequently unavailable in these countries. Corruption is known to be a major barrier to access of health care, but its effects on access to orthopaedic services is still unknown. A qualitative case study of 45 open-ended interviews was conducted to investigate the access to orthopaedic health services and orthopaedic medical devices in Uganda. Participants included orthopaedic surgeons, related healthcare professionals, industry and government representatives, and patients. Participants' experiences in accessing orthopaedic medical devices were explored. Thematic analysis was used to analyze and code the transcripts. Analysis of the interview data identified poor leadership in government and corruption as major barriers to access of orthopaedic care and orthopaedic medical devices. Corruption was perceived to occur at the worker, hospital and government levels in the forms of misappropriation of funds, theft of equipment, resale of drugs and medical devices, fraud and absenteeism. Other barriers elicited included insufficient health infrastructure and human resources, and high costs of orthopaedic equipment and poverty. This study identified perceived corruption as a significant barrier to access of orthopaedic care and orthopaedic medical devices in Uganda. As the burden of injury continues to grow, the need to combat corruption and ensure access to orthopaedic services is imperative. Anti-corruption strategies such as transparency and accountability measures, codes of conduct, whistleblower protection, and higher wages and benefits for workers could be important and initial steps in improving access orthopaedic care and OMDs, and managing the global injury burden.


Transient elastography evaluation of hepatic and spleen stiffness in patients with hepatosplenic schistosomiasis.
Hepatosplenic schistosomiasis (HES) has not been evaluated by transient elastography so far and its correlation with ultrasound variables remains to be defined. The aim of this study was to describe the parameters of liver and spleen stiffness in HES assessed by transient elastography in comparison with cirrhotics and controls evaluating its correlation with ultrasonographic data. HES, hepatitis C virus-cirrhotic, and control patients were included in this sectional study. Liver and spleen stiffness were compared among the three groups. The ultrasonographic parameters were compared with transient elastography in HES patients. Thirty HES, 30 hepatitis C virus-cirrhotic patients, and 17 controls were included. Those with HES presented liver stiffness that was significantly higher than the controls and lower than the cirrhotics: 9.7 (3.6-75.0) versus 3.7 (2.8-5.4) versus 27.0 (14.7-61.5) kPa (P<0.001). Spleen stiffness values were comparable between hepatosplenic and cirrhotics: 66.4 (25.7-75.0) versus 69.1 (18.0-75.0) kPa (P=0.78) and were significantly higher than the controls 16.5 kPa (6.3-34.3) (P<0.001). In patients with HES, high spleen stiffness was associated with right liver lobe diameter (P=0.015), splenic artery resistance index (P=0.002), portal vein diameter (P=0.021), portal vein area (P=0.008), portal vein congestion index (P=0.035), splenic vein diameter (P=0.013), and spleen diameter (P=0.021). Liver stiffness may be a useful tool to differentiate portal hypertension related to cirrhosis from that of HES. High spleen stiffness is a potential surrogate marker of portal hypertension in this population.


The Incidence of Acute Kidney Injury and Associated Hospital Mortality.
Studies from multiple countries have shown that acute kidney injury (AKI) in hospitalized patients is associated with mortality and morbidity. There are no reliable data at present on the incidence and mortality of AKI episodes among hospitalized patients in Germany. The utility of administrative codings of AKI for the identification of AKI episodes is also unclear. In an exploratory approach, we retrospectively analyzed all episodes of AKI over a period of 3.5 years (2014-2017) on the basis of routinely obtained serum creatinine measurements in 103 161 patients whose creatinine had been measured at least twice and who had been in the hospital for at least two days. We used the "Kidney Disease: Improving Global Outcomes" (KDIGO) criteria for AKI. In parallel, we assessed the administrative coding of discharge diagnoses of the same patients with codes from the International Classification of Diseases (ICD-10-GM). Among 185 760 hospitalizations, stage 1 AKI occurred in 25 417 cases (13.7%), stage 2 in 8503 cases (4.6%), and stage 3 in 5881 cases (3.1%). AKI cases were associated with length of hospital stay, renal morbidity, and overall mortality, and this association was stage-dependent. The in-hospital mortality was 5.1% for patients with stage 1 AKI, 13.7% for patients with stage 2 AKI, and 24.8% for patients with stage 3 AKI. An administrative coding for acute kidney injury (N17) was present in only 28.8% (11 481) of the AKI cases that were identified by creatinine criteria. Like the AKI cases overall, those that were identified by creatinine criteria but were not coded as AKI had significantly higher mortality, and this association was stage-dependent. AKI episodes are common among hospitalized patients and are associated with considerable morbidity and mortality, yet they are inadequately documented and probably often escape the attention of the treating physicians.


Comparison of two rapid enzyme immunoassays with standard enzyme immunoassay and latex agglutination for the detection of human rotavirus in stools.
We evaluated the performance of six commercially available immunoassays for their ability to detect rotaviruses in stool specimens. Four of the assays were enzyme-linked immunosorbent assays (ELISA), including two rapid enzyme immunoassays (Testpack, Abbott Laboratories, Chicago and Pinpoint, Cambridge Biomedical, UK), and the remaining two were latex agglutination tests. A total of 100 specimens from children with gastroenteritis were tested with the commercial immunoassays and compared with electron microscopy (EM) and polyacrylamide gel electrophoresis (PAGE) as reference tests for the detection of rotavirus. Discordant results were further evaluated by a standard blocking ELISA. The rapid EIAs were found to be highly sensitive (100% for the Testpack and 97% for the Pinpoint) and more sensitive than the other immunoassays tested. High specificity was also recorded with both rapid EIAs (96% and 100% for Testpack and Pinpoint, respectively). The rapid EIA tests were easy to perform, required no specialized equipment, and could yield a result in less than 15 min. The results show that each of the commercial assays evaluated could accurately detect rotavirus in the stools of children with gastroenteritis, although the suitability of choice of assay will ultimately depend upon the requirements of the individual laboratory.


Lidar system applied in atmospheric pollution monitoring.
A lidar system, incorporating tunable dye lasers and a 25-cm diam Newtonian telescope, has been constructed and applied in atmospheric pollution monitoring. The system, which is fully controlled by a specially designed microcomputer, has been used in several field tests, where stack effluents as well as the ambient air have been monitored. Results from particle, NO(2), and SO(2) measurements are discussed.


Multiplying therapies and reducing toxicity in metastatic melanoma.
Prior to 2011, only 2 systemic treatments were approved for the treatment of melanoma and these had limited efficacy. In the past 4 years, 6 novel agents have received FDA approval. Herein, we will focus on 4 recently published NEJM papers reporting the results of clinical trials, comprising 4 agents targeting the MAPK pathway: the BRAF inhibitors vemurafenib and dabrafenib, and the MEK inhibitors trametinib and cobimetenib. These have been developed in parallel with a class of immunologic mediators often referred to as "immune checkpoint inhibitors." These recent studies represent a marked acceleration of progress in the treatment of metastatic melanoma. While it was hoped that combining BRAF and MEK inhibitors would significantly mitigate drug resistance, such combinations have yielded only modestly better results than monotherapy. However, these combinations were successful in reducing the development of cutaneous squamous cell carcinomas and keratocanthomas. Therefore, combination therapies are clearly warranted. Thus far there are only limited data addressing the value of combinations of immunotherapeutic agents: a phase 1 trial of concurrent nivolumab plus ipilimumab suggested enhanced activity that may not depend on BRAF mutation status. Despite the attention and publicity given to the progress achieved in the therapy of melanoma, the majority of patients with metastatic disease still have a poor prognosis. Even novel combination regiments of BRAF and MEK inhibitors achieve complete response in only 13% of patients and a median PFS of 11.4 months in all patients. Better therapies remain desperately needed, especially for the 30-40% of patients with wild-type BRAF, for whom BRAF/MAPK inhibition offers no benefit. In the latter benefit is expected from emerging immunotherapies either singly or in combinations. The extent to which immunotherapies will add to regimens targeting BRAF remains to be determined.


The relationship between coping strategies, alcohol expectancies, drinking motives and drinking behaviour.
Numerous models have been proposed in an attempt to explain both alcohol use and alcohol abuse. Many of these models propose that drinking behaviour is the result of a complex interplay of cognitive and behavioural variables including coping strategies, alcohol expectancies and motives for drinking. However few studies have explored how these elements may work together to predict drinking. The current study proposed a mediational model of alcohol use in which coping strategies are related to alcohol expectancies, which in turn are related to drinking motives. Drinking motives were then viewed as proximal predictors of drinking behaviour. There were 454 participants (55.78% female) who completed self-report questionnaires assessing the above constructs. Approximately half the participants completed the questionnaires online, while the others completed the paper and pencil versions of the same measures. Findings generally supported the hypothesised model. The relationship between avoidant coping and drinking behaviour was mediated by alcohol expectancies of increased confidence and tension reduction, which in turn were related to drinking motives. As expected, drinking motives were positively related to drinking behaviour. Negative expectancies were also directly related to drinking behaviour. The results are discussed in light of cognitive models of drinking, and implications for prevention and early intervention of alcohol-use problems.


Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation.
Inactivation of beta-catenin in mesenchymal progenitors prevents osteoblast differentiation; inactivation of Lrp5, a gene encoding a likely Wnt coreceptor, results in low bone mass (osteopenia) by decreasing bone formation. These observations indicate that Wnt signaling controls osteoblast differentiation and suggest that it may regulate bone formation in differentiated osteoblasts. Here, we study later events and find that stabilization of beta-catenin in differentiated osteoblasts results in high bone mass, while its deletion from differentiated osteoblasts leads to osteopenia. Surprisingly, histological analysis showed that these mutations primarily affect bone resorption rather than bone formation. Cellular and molecular studies showed that beta-catenin together with TCF proteins regulates osteoblast expression of Osteoprotegerin, a major inhibitor of osteoclast differentiation. These findings demonstrate that beta-catenin, and presumably Wnt signaling, promote the ability of differentiated osteoblasts to inhibit osteoclast differentiation; thus, they broaden our knowledge of the functions Wnt proteins have at various stages of skeletogenesis.


Preliminary Evidence for cue-induced Alcohol Craving Modulated by Serotonin Transporter Gene Polymorphism rs1042173.
We previously have shown that cue-induced alcohol craving and propensity for higher drinking are modulated by allelic differences in SLC6A4 associated with serotonin transporter (5-HTT) expression level alterations. In an independent study, we characterized another polymorphism, SNP rs1042173, in 3'-untranslated region (3'-UTR) of the same gene, which also altered 5-HTT expression levels; the T allele of rs1042173 was associated with lower mRNA and protein levels. In subsequent analyses, the TT genotype was found to be associated with higher drinking intensity in alcohol-dependent (AD) individuals of Caucasian descent. Building upon these findings, we hypothesized that the low-expressing TT genotype associated with intense drinking would predict higher craving for alcohol in AD individuals. In this pilot study, we sought to test our hypothesis by examining 34 Hispanic AD volunteers (mean age, 34.8 years) for rs1042173 genotype-based [i.e., TT versus TG/GG (Gx)] differences in subjective response to alcohol. We employed a human laboratory paradigm and analyzed the data using a linear mixed-effects model (SAS® PROC MIXED) to assess treatment, cue procedures, and genotype main effects as well as the two-way interaction effects between them. On subjective "urge to drink" and "crave for a drink," we found a significant main effect of the cue experiment (p ≤ 0.01) and an interaction effect between genotype and cue effects (p < 0.05). TT genotype was associated with higher urge to drink (p = 0.002) and crave for a drink (p = 0.005) when exposed to alcohol cue. Our results not only support the hypothesis that rs1042173 is a genetic marker for cue-induced alcohol craving among AD males but also are suggestive of a neurobiological mechanism associated with the rs1042173-TT genotype that triggers a disproportionate craving in response to alcohol consumption, which in turn may lead to more intense drinking. Future studies with larger sample sizes are needed to characterize the interactive effects of the serotonin transporter-linked polymorphic region (5'-HTTLPR)-L-allele reported in our previous study and of the rs1042173-TT genotype on cue-induced alcohol craving.


Age and Gender Differences in Facial Attractiveness, but Not Emotion Resemblance, Contribute to Age and Gender Stereotypes.
Considerable research has shown effects of facial appearance on trait impressions and group stereotypes. We extended those findings in two studies that investigated the contribution of resemblance to emotion expressions and attractiveness to younger adults (YA) and older adults (OA) age and gender stereotypes on the dimensions of warmth and competence. Using connectionist modeling of facial metrics of 240 neutral younger and older faces, Study 1 found that, neutral expression older faces or female faces showed greater structural resemblance to happy expressions and less resemblance to angry expressions than did younger or male faces, respectively. In addition, neutral female faces showed greater resemblance to surprise expressions. In Study 2, YA and OA rated the faces of Study 1 for attractiveness and for 4 traits that we aggregated on the dimensions of competence (competent, healthy) and warmth (trustworthy, not shrewd). We found that YA, but not OA, age stereotypes replicated previous research showing higher perceived warmth and lower perceived competence in older adults. In addition, previously documented gender stereotypes were moderated by face age for both YA and OA. The greater attractiveness of younger than older faces and female than male faces influenced age and gender stereotypes, including these deviations from prior research findings using category labels rather than faces. On the other hand, face age and face sex differences in emotion resemblance did not influence age or gender stereotypes, contrary to prediction. Our results provide a caveat to conclusions about age and gender stereotypes derived from responses to category labels, and they reveal the importance of assessing stereotypes with a methodology that is sensitive to influences of group differences in appearance that can exacerbate or mitigate stereotypes in more ecologically valid contexts. Although the gender differences in attractiveness in the present study may not have generalizability, the age differences likely do, and the fact that they can weaken the attribution of greater warmth and strengthen the attribution of lower competence to older than younger individuals has important practical implications.


Effect of multiple neonatal sevoflurane exposures on hippocampal apolipoprotein E levels and learning and memory abilities.
Sevoflurane anesthesia is widely used in pediatric patients. In this study, we investigated whether early multiple exposures to sevoflurane induced cognitive dysfunction by altering the hippocampal expression of ApoE later in development. Sprague-Dawley rats were exposed to 2.6% sevoflurane at postnatal day 7 (P7), P14, and P21 for 2 h. The ability of learning and memory was assessed using the Morris water maze at P37 and P97. The hippocampal volume was measured by magnetic resonance imaging (MRI) at P37 and P97. The hippocampal expression of ApoE was assessed by immunohistochemical analyses and real-time polymerase chain reaction (PCR). Behavioral testing revealed that the ability of learning and memory in the sevoflurane-exposed rats was decreased compared with the control animals; however, there was no significant difference (P > 0.05). The MRI results showed a significant decrease in the left hippocampal volume, left maximum hippocampal length, and right maximum hippocampal length in the sevoflurane young group compared with the control young group (P < 0.05). The brain volume, left maximum hippocampal length, right hippocampal volume, and maximum brain length were significantly lower in the sevoflurane adult group than in the control adult group (P < 0.05). In young animals, the ApoE expression in the hippocampal CA1 and CA3 regions and the ApoE mRNA level were significantly higher compared with the control group (P < 0.05), but not in the dentate gyrus region (P > 0.05). Among the adult animals, there was no significant difference between the groups in any parameter tested (P > 0.05). Multiple exposures to sevoflurane during the neonatal period decreased the volume of the hippocampus and increased the hippocampal expression of ApoE. The differential expression level of ApoE in different hippocampal subdivisions suggested that the expression of ApoE was regionally specific and reversible.


Immune control of HIV-1 after early treatment of acute infection.
Virus-specific T-helper cells are considered critical for the control of chronic viral infections. Successful treatment of acute HIV-1 infection leads to augmentation of these responses, but whether this enhances immune control has not been determined. We administered one or two supervised treatment interruptions to eight subjects with treated acute infection, with the plan to restart therapy if viral load exceeded 5,000 copies of HIV-1 RNA per millilitre of plasma (the level at which therapy has been typically recommended) for three consecutive weeks, or 50,000 RNA copies per ml at one time. Here we show that, despite rebound in viraemia, all subjects were able to achieve at least a transient steady state off therapy with viral load below 5,000 RNA copies per ml. At present, five out of eight subjects remain off therapy with viral loads of less than 500 RNA copies per ml plasma after a median 6.5 months (range 5-8.7 months). We observed increased virus-specific cytotoxic T lymphocytes and maintained T-helper-cell responses in all. Our data indicate that functional immune responses can be augmented in a chronic viral infection, and provide rationale for immunotherapy in HIV-1 infection.


Long Sleep Duration and Social Jetlag Are Associated Inversely with a Healthy Dietary Pattern in Adults: Results from the UK National Diet and Nutrition Survey Rolling Programme Y1⁻4.
Limited observational studies have described the relationship between sleep duration and overall diet. The present study investigated the association between sleep duration on weekdays or social jetlag and empirically derived dietary patterns in a nationally representative sample of UK adults, aged 19⁻64 years old, participating in the 2008⁻2012 UK National Diet and Nutrition Survey Rolling Programme. Survey members completed between three to four days of dietary records. Sleep duration on weekdays was categorized into tertiles to reflect short, normal, and long sleep duration. Social jetlag was calculated as the difference between sleep duration on weekends and weekdays. The association between sleep duration/social jetlag and dietary patterns, derived by principal components analysis, was assessed by regressing diet on sleep, whilst accounting for the complex survey design and adjusting for relevant confounders. Survey members in the highest tertile of sleep duration had on average a 0.45 (95% Confidence Interval (CI) -0.78, -0.12) lower healthy dietary pattern score, compared to middle tertile (p = 0.007). There was an inverted u-shaped association between social jetlag and the healthy dietary pattern, such that when sleep on weekends exceeded weekday sleep by 1 h 45 min, scores for indicating a healthy dietary pattern declined (p = 0.005). In conclusion, long sleep duration on weekdays and an increased social jetlag are associated with a lower healthy dietary pattern score. Further research is required to address factors influencing dietary patterns in long sleepers.


Obsessive-Compulsive (Anankastic) Personality Disorder in the ICD-11: A Scoping Review.
Introduction: With the shift from a categorical to a dimensional model, ICD-11 has made substantial changes to the diagnosis of personality disorders (PDs), including obsessive-compulsive (anankastic) personality disorder (OCPD). The ICD-11 PD model proposes a single diagnosis of PD with specifications regarding severity and domains. However, a systematic overview of ICD-11 anankastia is lacking. In this review we address the reformulation of the OCPD diagnosis in the ICD-11, and draw comparisons with the DSM-5, with a particular focus on diagnostic validity and clinical utility. We hypothesized that the ICD-11 PD model provides a diagnostically valid and clinically useful approach to OCPD, with specific emphasis on the anankastia domain as the primary trait qualifier. Methods: Literature published from 2010 to 2020 was systematically searched using the PubMed/MEDLINE, PsychInfo, Cochrane, and Web of Sciences search engines, in order to find all articles that addressed ICD-11 anankastia. Relevant articles were collated, and themes of these articles subsequently extracted. Results: Out of the 264 publications identified, 19 articles were included in this review. Four themes were identified, namely (a) overlap of DSM-5 OCPD with the ICD-11 PD model, (b) the factorial structure of the ICD-11 PD model with respect to the anankastia domain, (c) the clinical utility of the ICD-11 PD model, and (d) comparison of the ICD-11 PD model of anankastia with the DSM-5 alternative model for OCPD. Conclusions: The ICD-11 anankastia domain overlaps with DSM-5 OCPD traits, and the factor analyses of the ICD-11 PD model further support the diagnostic validity of this domain. There is some support for the clinical utility of the ICD-11 PD model of anankastia but further studies are needed, including of its relationship to obsessive-compulsive and related disorders.


Geometric mechanics of curved crease origami.
Folding a sheet of paper along a curve can lead to structures seen in decorative art and utilitarian packing boxes. Here we present a theory for the simplest such structure: an annular circular strip that is folded along a central circular curve to form a three-dimensional buckled structure driven by geometrical frustration. We quantify this shape in terms of the radius of the circle, the dihedral angle of the fold, and the mechanical properties of the sheet of paper and the fold itself. When the sheet is isometrically deformed everywhere except along the fold itself, stiff folds result in creases with constant curvature and oscillatory torsion. However, relatively softer folds inherit the broken symmetry of the buckled shape with oscillatory curvature and torsion. Our asymptotic analysis of the isometrically deformed state is corroborated by numerical simulations that allow us to generalize our analysis to study structures with multiple curved creases.


Pulse transit time as a measure of respiratory effort under noninvasive ventilation.
Among the respiratory events that may occur during nocturnal noninvasive ventilation (NIV), differentiating between central and obstructive events requires appropriate indicators of respiratory effort. The aim of the present study was to assess pulse transit time (PTT) as an indicator of respiratory effort under NIV in comparison with oesophageal pressure (P(oes)). During wakefulness, PTT was compared to P(oes) during spontaneous breathing and under NIV with or without induced leaks in 11 healthy individuals. In addition, the contribution of PTT versus P(oes) to differentiation of central from obstructive respiratory events occurring under NIV during sleep was evaluated in 10 patients with obesity hypoventilation syndrome (OHS). From spontaneous breathing to NIV without leaks, respiratory effort decreased significantly whereas, with increasing level of leaks, there was a significant increase in respiratory effort. Changes in PTT accurately reflected changes in P(oes). In OHS patients during nocturnal NIV, intraclass correlation coefficients between P(oes) and PTT were 0.970 for total number of events and 0.970 for percentage of central events. PTT accurately reflects the unloading of respiratory muscles induced by NIV and the increase in respiratory effort during leaks. PTT during sleep is also useful to differentiate central from obstructive respiratory events occurring under NIV.


Giant mesenteric cystic lymphangioma of mesocolic origin in an asymptomatic adult patient.
A 34-year-old patient was scheduled for valve replacement to treat a symptomatic mitral regurgitation. The preoperative work-up incidentally discovered an intra-abdominal cystic tumour extending from the epigastrium to the pelvic region on a computed tomography scan. The patient had no abdominal symptoms by the giant cyst from unkown origin. An open "en bloc" resection disclosed a large cyst in the mesocolon. Pathological examination, including immunohistochemistry, enabled the diagnosis of a mesenteric cystic lymphangioma. Long-term follow-up of 12 months shows no recurrence. Mesenteric cystic lymphangioma, which is extremely rare in adults, is a challenge to diagnose and needs complete resection to ensure dignity and to avoid recurrence.