Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products.
The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. This challenge is highlighted by the estimate that 40-45% of drug candidates contain a chiral amine, fueling a demand for broadly applicable synthetic methods that deliver target structures in high yield and enantiomeric excess. Herein we describe the development and application of a "toolbox" of monoamine oxidase variants from Aspergillus niger (MAO-N) which display remarkable substrate scope and tolerance for sterically demanding motifs, including a new variant, which exhibits high activity and enantioselectivity toward substrates containing the aminodiphenylmethane (benzhydrylamine) template. By combining rational structure-guided engineering with high-throughput screening, it has been possible to expand the substrate scope of MAO-N to accommodate amine substrates containing bulky aryl substituents. These engineered MAO-N biocatalysts have been applied in deracemization reactions for the efficient asymmetric synthesis of the generic active pharmaceutical ingredients Solifenacin and Levocetirizine as well as the natural products (R)-coniine, (R)-eleagnine, and (R)-leptaflorine. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.


A systematic review of social support for siblings of children with neurodevelopmental disorders.
Social support is a protective factor for siblings of children with neurodevelopmental disorders. We reviewed studies on social support received by siblings of children with neurodevelopmental disorders. We conducted a pre-registered systematic review (CRD42020207686), searching PsycINFO, MEDLINE, Web of Science, and Scopus. Fifteen articles were eligible for the review, 13 of which used cross-sectional designs. Two studies investigated sibling social support after an intervention. Multiple variables were negatively related to social support (e.g., sibling depression, loneliness, stress). Variables that were positively related to social support included prosocial behavior, competence (academic, social, and activity-related), problem-focused coping, and family quality of life. Potential moderators of the relationship between social support and psychosocial adjustment included the type of disorder of the affected sibling and the type of social support provider. We conclude with an overview of the reliability and validity of the seven social support measurements used across the studies. Lower levels of social support are associated with more negative psychosocial adjustment among siblings of children with neurodevelopmental disorders. We encourage future researchers to further investigate ways to increase social support for siblings to improve outcomes.


Changes in asthma drug therapy costs for patients receiving chronic montelukast therapy in the U.K.
The aim of this study was to assess changes in the costs of asthma drug therapy before and during the use of chronic montelukast treatment in the U.K. A retrospective cohort analysis of a primary care database in the U.K. was carried out. Patients with chronic montelukast use (> or = 140 once-daily doses) were selected for analysis. Benchmarking data were obtained for matched patients with chronic inhaled corticosteroid (ICS) use and patients with chronic salmeterol therapy with concomitant ICS use. The main outcome measures were changes in utilization and monthly cost of asthma therapies costs. Asthma patients experienced significant (P<0.05) reductions in the monthly costs of ICS, short-acting beta-agonists and antibiotics following chronic montelukast therapy. Monthly concomitant drug costs were reduced by Pound Sterling 7.49 per month, which offset 27.5% of the additional cost of montelukast, yielding an increase in total drug costs of Pound Sterling 19.78 per month. Meanwhile, increased total drug costs for matched patients with chronic ICS use, and matched patients with chronic salmeterol therapy and concomitant ICS use, increased by Pound Sterling 5.37 per month and Pound Sterling 44.55 per month respectively. Additionally, patients using chronic montelukast therapy experienced a statistically significant (P<0.05) reduction in the use of short acting beta-agonists, and antibiotics, suggesting improvement in asthma control. Chronic use of montelukast therapy is associated with a reduction of concomitant drug therapy costs.


Prevalence and associated factors with homeopathy use in Brazil: a population-based study.
Despite the controversy about its efficacy, homeopathy is considered a medical practice alternative to the conventional medical model. Prevalence of homeopathy use varies greatly among countries and the literature has conflicting evidence about the relation between sociodemographic factors and health conditions associated with homeopathy use. We aim to estimate the prevalence of homeopathy use and its association with self-perceived health status, depression, and sociodemographic factors. We used data from 90,846 participants in the 2019 Brazilian National Survey of Health (PNS 2019), a population-based study with complex and probabilistic sampling. Sociodemographic and clinical data and information on homeopathy use during the last 12 months were collected. The Patient Health Questionnaire-9 (PHQ-9) was used to assess depression. All variables were categorized. Logistic regression models were built to obtain crude and adjusted odds ratios (OR) and 95% confidence intervals (95%CI). The prevalence of homeopathy use was 0.99% (95%CI: 0.98-1.00). In the adjusted analysis, the following variables were associated with higher use of homeopathy: female gender, age above 51 years, white ethnicity, higher socioeconomic and educational attainment, residence in Southern/Southeastern Brazil, poorer self-reported health status, and depression. Brazil shows increased offer of complementary medicine, including homeopathy. Nevertheless, the use of homeopathy treatment is very low and clearly associated with a higher socioeconomic status, poorer self-reported health status, and depression.


German taxi drivers' experiences and expressions of driving anger: Are the driving anger scale and the driving anger expression inventory valid measures?
The objective of this article was 2-fold: firstly, we wanted to examine whether the original Driving Anger Scale (DAS) and the original Driving Anger Expression Inventory (DAX) apply to German professional taxi drivers because these scales have previously been given to professional and particularly to nonprofessional drivers in different countries. Secondly, we wanted to examine possible differences in driving anger experience and expression between professional German taxi drivers and nonprofessional German drivers. We applied German versions of the DAS, the DAX, and the State-Trait Anger Expression Inventory (STAXI) to a sample of 138 professional German taxi drivers. We then compared their ratings to the ratings of a sample of 1,136 nonprofessional German drivers (Oehl and Brandenburg n.d. ). Regarding our first objective, confirmatory factor analysis shows that the model fit of the DAS is better for nonprofessional drivers than for professional drivers. The DAX applies neither to professional nor to nonprofessional German drivers properly. Consequently, we suggest modified shorter versions of both scales for professional drivers. The STAXI applies to both professional and nonprofessional drivers. With respect to our second objective, we show that professional drivers experience significantly less driving anger than nonprofessional drivers, but they express more driving anger. We conclude that the STAXI can be applied to professional German taxi drivers. In contrast, for the DAS and the DAX we found particular shorter versions for professional taxi drivers. Especially for the DAX, most statements were too strong for German drivers to agree to. They do not show behaviors related to driving anger expression as they are described in the DAX. These problems with the original American DAX items are in line with several other studies in different countries. Future investigations should examine whether (professional) drivers from further countries express their anger as proposed by the DAX. In addition, professional drivers experience less driving anger (DAS) and less general trait anger (STAXI) than nonprofessional drivers, but they report more driving anger expression (DAX) and more current general state anger (STAXI). Subsequent studies should therefore focus on different types of anger within the group of professional drivers.


Distinct alterations in Parkinson's medication-state and disease-state connectivity.
Altered brain connectivity has been described in people with Parkinson's disease and in response to dopaminergic medications. However, it is unclear whether dopaminergic medications primarily 'normalize' disease related connectivity changes or if they induce unique alterations in brain connectivity. Further, it is unclear how these disease- and medication-associated changes in brain connectivity relate differently to specific motor manifestations of disease, such as bradykinesia/rigidity and tremor. In this study, we applied a novel covariance projection approach in combination with a bootstrapped permutation test to resting state functional MRI data from 57 Parkinson's disease and 20 healthy control participants to determine the Parkinson's medication-state and disease-state connectivity changes associated with different motor manifestations of disease. First, we identified brain connections that best classified Parkinson's disease ON versus OFF dopamine and Parkinson's disease versus healthy controls, achieving 96.9 ± 5.9% and 72.7 ± 12.4% classification accuracy, respectively. Second, we investigated the connections that significantly contribute to the classifications. We found that the connections greater in Parkinson's disease OFF compared to ON dopamine are primarily between motor (cerebellum and putamen) and posterior cortical regions, such as the posterior cingulate cortex. By contrast, connections that are greater in ON compared to OFF dopamine are between the right and left medial prefrontal cortex. We also identified the connections that are greater in healthy control compared to Parkinson's disease and found the most significant connections are associated with primary motor regions, such as the striatum and the supplementary motor area. Notably, these are different connections than those identified in Parkinson's disease OFF compared to ON. Third, we determined which of the Parkinson's medication-state and disease-state connections are associated with the severity of different motor symptoms. We found two connections correlate with both bradykinesia/rigidity severity and tremor severity, whereas four connections correlate with only bradykinesia/rigidity severity, and five connections correlate with only tremor severity. Connections that correlate with only tremor severity are anchored by the cerebellum and the supplemental motor area, but only those connections that include the supplemental motor area predict dopaminergic improvement in tremor. Our results suggest that dopaminergic medications do not simply 'normalize' abnormal brain connectivity associated with Parkinson's disease, but rather dopamine drives distinct connectivity changes, only some of which are associated with improved motor symptoms. In addition, the dissociation between of connections related to severity of bradykinesia/rigidity versus tremor highlights the distinct abnormalities in brain circuitry underlying these specific motor symptoms.


Spontaneous subscapular haematoma in a patient using warfarin therapy.
Warfarin is widely used. Spontaneous bleeding is one of the complications of warfarin treatment. A 70-year-old man was admitted to the emergency room with right back pain. There was no history of trauma. He was using warfarin following a bypass graft. The patient's vital signs were stable. On physical examination, swelling at the level of the right scapula was detected. Laboratory findings showed that the international normalised ratio (INR) was ↑↑ (a very high reading) (1.47 1 month previously). There was no melena on rectal examination. A chest CT was performed to differentiate the swelling of the right scapula. Warfarin was stopped and vitamin K was administered. Fresh frozen plasma was initiated and the patient was hospitalised to the cardiovascular surgical service. The fact that use of warfarin in the elderly may increase the risk of spontaneous bleeding should be especially kept in mind.


[Effectiveness of Cooperative Treatment Using Community Medical Systems and Healthcare Services for Second-Line Therapy in Advanced Urothelial Cancer Patients : Impact on Survival].
Chemotherapy and immune-checkpoint inhibitors, used as second-line treatments for advanced urothelial cancer (UC), can have adverse effects in some patients, such as decreased organ function. We investigated the effectiveness of cooperation with medical/welfare services, so-called cooperative medicine, in these cases. A total of 137 UC patients who had undergone second-line therapy were analyzed. Of these 137 patients, 49 were categorized in the "cooperative"treatment group, in which a general practitioner performed blood tests and transfusions ; and, administered medication, while nurses and case workers from a community health care institution provided mental and social support. There were 50 in the "joint" treatment group, who were treated jointly by a urologist and general practitioner ; and, 38 in the "solo" treatment group who were treated by a urologist only. The Short Form Health Survey, SF-36, was used to evaluate quality of life (QoL). We observed that the overall survival after the second-line treatment was significantly longer in the cooperative group than in the other two groups, with multivariate analyses confirming cooperative treatment as a significant factor for better prognosis (P=0.005). The period of second-line treatment in the cooperative group was significantly longer (P=0.003) than that in the solo group, whereas the proportion of patients who subsequently received third-line treatment was higher in the cooperative group, 58. 5%, than in the solo and joint groups, 26. 5% and 25. 5%, respectively. Posttreatment QoL measurements in the joint and solo groups were significantly lower for 3 and 6 items, respectively, whereas there was no appreciable decrease in post-treatment QoL measurements in the cooperative group. Multivariate analysis showed that cooperative treatment was particularly beneficial for female patients ≥75 years of age, and patients with status 2 performance.


Cricoarytenoid arthritis with rheumatoid arthritis and systemic lupus erythematosus.
A 56-year-old woman with rheumatoid arthritis (RA) suddenly developed severe respiratory distress and laryngeal stridor, which required endotracheal intubation. She had had RA for 12 years, which had been controlled well with prednisolone (3 mg/day) at the orthopedic clinic. Laryngoscopy revealed cricoarytenoid arthritis. She was finally diagnosed as having overlap syndrome with RA and systemic lupus erythematosus. She was given high dose corticosteroids that improved her clinical symptoms and laryngoscopic findings. She represents the first patient with overlap syndrome who developed an acute airway obstruction due to cricoarytenoid arthritis.


Cellular and humoral immune response to exercise among gymnasts and untrained girls.
Recent studies reported reduced immunity in athletes following exercise. Physical activity affects both cellular and humoral immune functions. Scant information exists on exercise-induced changes in the immune system among children. The purpose of the present study was to investigate the effect of aerobic exercise on several aspects of cellular and humoral functions among 10-12 year-old highly trained female gymnasts (n = 7) and untrained girls (n = 6). All girls were pre-pubertal. Venous blood samples were drawn before, immediately after and 24 h following 20 min of treadmill running (heart rate 170-180 beats.min-1). White blood cells' number rose significantly following exercise and remained elevated for 24 h. The increase in leukocyte number was due to an increase in granulocytes as well as an increase in lymphocytes and monocytes. While neutrophil count returned to basal values after 24 h, lymphocytes and monocytes number remained elevated 24 h following exercise. Exercise resulted in a significant elevation of T cell lymphocytes, T helpers, T suppressors and natural killer cells. All values returned to normal after 24 h. There were no changes in B cell lymphocytes following exercise. Exercise had no effect on serum IgA, IgM, IgE, IgG and sub-types of IgG (IgG1, IgG2, IgG3 and IgG4). No differences were observed between gymnasts and untrained girls. In summary, the exercise-induced changes in cellular and humoral immune functions among the girls were generally similar to those described in adults. Whether the transitory effects of exercise on the immune system are related to increased susceptibility to illness is still questionable.


Differential responses of sugar, organic acids and anthocyanins to source-sink modulation in Cabernet Sauvignon and Sangiovese grapevines.
Grape berry composition mainly consists of primary and secondary metabolites. Both are sensitive to environment and viticultural management. As a consequence, climate change can affect berry composition and modify wine quality and typicity. Leaf removal techniques can impact berry composition by modulating the source-to-sink balance and, in turn, may mitigate some undesired effects due to climate change. The present study investigated the balance between technological maturity parameters such as sugars and organic acids, and phenolic maturity parameters such as anthocyanins in response to source-sink modulation. Sugar, organic acid, and anthocyanin profiles were compared under two contrasting carbon supply levels in berries of cv. Cabernet Sauvignon and Sangiovese collected at 9 and 14 developmental stages respectively. In addition, whole-canopy net carbon exchange rate was monitored for Sangiovese vines and a mathematic model was used to calculate the balance between carbon fixation and berry sugar accumulation. Carbon limitation affected neither berry size nor the concentration of organic acids at harvest. However, it significantly reduced the accumulation of sugars and total anthocyanins in both cultivars. Most interestingly, carbon limitation decreased total anthocyanin concentration by 84.3% as compared to the non source-limited control, whereas it decreased sugar concentration only by 27.1%. This suggests that carbon limitation led to a strong imbalance between sugars and anthocyanins. Moreover, carbon limitation affected anthocyanin profiles in a cultivar dependent manner. Mathematical analysis of carbon-balance indicated that berries used a higher proportion of fixed carbon for sugar accumulation under carbon limitation (76.9%) than under carbon sufficiency (48%). Thus, under carbon limitation, the grape berry can manage the metabolic fate of carbon in such a way that sugar accumulation is maintained at the expense of secondary metabolites.


High-intensity p38 kinase activity is critical for p21(cip1) induction and the antiproliferative function of G(i) protein-coupled receptors.
G protein-coupled receptors can stimulate the p38 kinase cascade, but the effect this has on cell growth remains poorly characterized. Here we show human somatostatin sst(2) and sst(4) receptors inhibit basic fibroblast growth factor (bFGF)-induced proliferation, via a mechanism that was blocked by the p38 inhibitor PD 169316. The sst(4) receptor could also induce a proliferative activity in the absence of bFGF, which was unaffected by PD 169316. In contrast, the sst(3) receptor had no effect on basal cell growth or on the proliferation evoked by bFGF. The extracellular signal-regulated kinase activity stimulated by the sst(3) receptor was transient in duration compared with a sustained activity induced by the sst(2) and sst(4) receptors and which was critical for the proliferative response of the latter receptor. In addition, activated sst(2) and sst(4) but not sst(3) receptors evoked a prolonged phosphorylation of p38 that was amplified by bFGF. The accumulation of the cell cycle inhibitor p21(cip1) was only apparent after sst(2) and sst(4) receptor activation in the presence of bFGF, which was sensitive to PD 169316 or pertussis toxin. Thus, the contrasting antiproliferative effects evoked by the human sst(2), sst(3), and sst(4) receptors can be accounted for by their differential abilities to activate p38. This activity is critical for p21(cip1) induction, blockade of entry into S phase, as indicated by the lack of retinoblastoma protein phosphorylation, and the associated antiproliferative activity of somatostatin. Furthermore, by changing the intracellular signaling threshold of p38 through cooperative effects of somatostatin and bFGF, the sst(4) receptor can mediate opposing effects on cell proliferation.


Thrombolytic treatment in stroke mimic, inevitable but fortunately safe: An observational study from Iran.
Background: A number of patients with symptoms of acute cerebral ischemia may have other causes called stroke mimics (SM). The prevalence of SM can be as high as 31% in some reports, and these patients are potentially at the risk of intravenous thrombolysis (IVT) therapy and its complications. This study was designed to determine the prevalence of our center's SM (Firoozgar Hospital) among patients who received IVT, their baseline characteristics, final diagnoses, and outcomes. Methods: We reviewed the medical records of all patients who received IVT between June 2015 and May 2018. The following variables were collected: demographic characteristics, past medical history, onset-to-needle (OTN) time, door-to-needle (DTN) time, National Institutes of Health Stroke Scale (NIHSS) score at admission, brain imaging, and all paraclinic findings. Functional outcome at discharge based on modified Rankin Scale (mRS) was also assessed. Results: 10 out of 165 (6.0%) patients including 8 men and 4 women were finally diagnosed with SM. The median age and NIHSS score at presentation were 60 years and 7, respectively. Final diagnoses were seizure (n = 6), hemiplegic migraine (n = 2), conversion (n = 1), and alcohol intoxication (n = 1). All patients were discharged with a mRS score of 0 and 1 without experiencing any thrombolytic adverse effects. Conclusion: None of the patients with SM experienced any adverse effect of tissue plasminogen activator (tPA) including hemorrhage and all of them reached good mRS score. This shows that tPA is generally safe and the risk of treating patients with SM is very low and making a vital treatment decision may outweigh the risk of neglected cases in a time-sensitive setting.


Salmonella Typhimurium Triggers Extracellular Traps Release in Murine Macrophages.
Salmonella comprises two species and more than 2500 serovars with marked differences in host specificity, and is responsible for a wide spectrum of diseases, ranging from localized gastroenteritis to severe life-threatening invasive disease. The initiation of the host inflammatory response, triggered by many Pathogen-Associated Molecular Patterns (PAMPs) that Salmonella possesses, recruits innate immune cells in order to restrain the infection at the local site. Neutrophils are known for killing bacteria through oxidative burst, amid other mechanisms. Amongst those mechanisms for controlling bacteria, the release of Extracellular Traps (ETs) represents a newly described pathway of programmed cell death known as ETosis. Particularly, Neutrophil Extracellular Traps (NETs) were first described in 2004 and since then, a number of reports have demonstrated their role as a novel defense mechanism against different pathogens. This released net-like material is composed of cellular DNA decorated with histones and cellular proteins. These structures have shown ability to trap, neutralize and kill different kinds of microorganisms, ranging from viruses and bacteria to fungi and parasites. Salmonella was one of the first microorganisms that were reported to be killed by NETs and several studies have confirmed the observation and deepened into its variants. Nevertheless, much less is known about their counterparts in other immune cells, e.g. Macrophage Extracellular Traps (METs) and Salmonella-induced MET release has never been reported so far. In this work, we observed the production of METs induced by Salmonella enterica serovar Typhimurium and recorded their effect on bacteria, showing for the first time that macrophages can also release extracellular DNA traps upon encounter with Salmonella Typhimurium. Additionally we show that METs effectively immobilize and reduce Salmonella survival in a few minutes, suggesting METs as a novel immune-mediated defense mechanism against Salmonella infection. Of note, this phenomenon was confirmed in primary macrophages, since MET release was also observed in bone marrow-derived macrophages infected with Salmonella. The evidence of this peculiar mechanism provides new incipient insights into macrophages´ role against Salmonella infection and can help to design new strategies for the clinical control of this transcendental pathogen.


Purification and characterization of outer membrane protein P6, a vaccine antigen of non-typeable Haemophilus influenzae.
Outer membrane protein P6 is a promising vaccine antigen with potential to prevent infections caused by non-typeable Haemophilus influenzae. A convenient and reliable method for the purification of P6 and an assessment of the purity, yield, protein structure, antigenicity and immunogenicity of the purified protein are described. The method begins with intact H. influenzae and utilizes a series of incubations and centrifugations using a single buffer to remove all cell components with the exception of the peptidoglycan to which the P6 is associated. P6 is dissociated from the complex with heat and the insoluble peptidoglycan is removed by centrifugation. The procedure yields highly purified P6. Contamination with lipooligosaccharide is less than 0.025 endotoxin U per microgr P6. The yield of P6 is approximately 2 mg of P6 per l H. influenzae culture. The purified P6 retains both the secondary and tertiary structure as measured by circular dichroism and analysis with monoclonal antibodies. The purified P6 is immunogenic in animals. A convenient method for purifying P6 which retains antigenicity and immunogenicity will be an important tool for future studies of the vaccine potential of P6.


Using the Payoff Time in Decision-Analytic Models: A Case Study for Using Statins in Primary Prevention.
The payoff time represents an estimate of when the benefits of an intervention outweigh the costs. It is particularly useful for benefit-harm decision making for interventions that have deferred benefits but upfront harms. The aim of this study was to expand the application of the payoff time and provide an example of its use within a decision-analytic model. Three clinically relevant patient vignettes based on varying levels of estimated 10-year cardiovascular risk (10%, 15%, 20%) were developed. An existing state-transition Markov model taking a health service perspective and a life-time horizon was adapted to include 3 levels of direct treatment disutility (DTD) associated with ongoing statin use: 0.005, 0.01, and 0.015. For each vignette and DTD we calculated a range of outputs including the payoff time inclusive and exclusive of healthcare costs. For a 10% 10-year cardiovascular risk (vignette 1) with low-levels of DTD (0.005), the payoff time was 8.5 years when costs were excluded and 16 years when costs were included. As the baseline risk of cardiovascular increased, the payoff time shortened. For a 15% cardiovascular risk (vignette 2) and for a low-level of DTD, the payoff time was 5.5 years and 9.5 years, respectively. For a 20% cardiovascular risk (vignette 3), the payoff time was 4.2 and 7.2 years, respectively. For higher levels of DTDs for each vignette, the payoff time lengthened, and in some instances the intervention never paid off, leading to an expected net harm for patients. This study has shown how the payoff time can be readily applied to an existing decision-analytic model and be used to complement existing measures to guide healthcare decision making.


Association of nitric oxide production and apoptosis in a model of experimental nephropathy.
In recent studies increased amounts of nitric oxide (NO) and apoptosis have been implicated in various pathological conditions in the kidney. We have studied the role of NO and its association with apoptosis in an experimental model of nephrotic syndrome induced by a single injection of adriamycin (ADR). The alteration in the NO pathway was assessed by measuring nitrite levels in serum/urine and by evaluating the changes in vascular reactivity of the isolated perfused rat kidney (IPRK) system. Rats were stratified into control groups and ADR-induced nephropathy groups. These two groups were then divided into: group 1, animals receiving saline; and group 2, animals receiving aminoguanidine (AG) which is a specific inhibitor of inducible-NO synthase. On day 21, rats were sacrificed after obtaining material for biochemical analysis. Histopathological examination of the kidneys of rats treated with ADR revealed focal areas of mesangial proliferation and mild tubulointerstitial inflammation. They also had significantly higher levels of proteinuria compared with control and treatment groups (P < 0.05). Urine nitrite levels were significantly increased in the ADR-nephropathy group (P < 0.05). In the IPRK phenylephrine and acetylcholine related responses were significantly impaired in the ADR-nephropathy group. Apoptosis was not detected in controls. However, in the ADR-nephropathy group, numerous apoptotic cells were identified in the tubulointerstitial areas. Double staining revealed numerous interstitial apoptotic cells to stain for ED1, a marker for monocytes/macrophages. Treatment with AG prevented the impairment of renal vascular bed responses and reduced both urine nitrite levels and apoptosis to control levels. We suggest that interactions between NO and apoptosis are important in the pathogenesis of the ADR-induced nephrosis.


Assessment of Neurocognitive Functions in 7-Year-Old Children at Familial High Risk for Schizophrenia or Bipolar Disorder: The Danish High Risk and Resilience Study VIA 7.
Children at familial high risk of schizophrenia spectrum disorders (FHR-SZ) or bipolar disorder (FHR-BP) exhibit neurocognitive impairments. Large studies of neurocognition in young children at familial high risk at the same age are important to differentiate the pathophysiology and developmental trajectory of these 2 groups. To characterize neurocognitive functions in 7-year-old children with FHR-SZ or FHR-BP and a control population. This multisite population-based cohort study collected data from January 1, 2013, to January 31, 2016, in the first wave of the Danish High Risk and Resilience Study VIA 7 at 2 university hospital research sites in Copenhagen and Aarhus using Danish registries. Participants (n = 514) included 197 children with FHR-SZ, 118 with FHR-BP, and 199 controls matched with the FHR-SZ group for age, sex, and municipality. Assessors were blinded to risk status. Parents with schizophrenia, bipolar disorder, or neither diagnosis. Neurocognitive functions were measured across 23 tests. Four neurocognitive domains were derived by principal component analysis, including processing speed and working memory, verbal functions, executive and visuospatial functions, and declarative memory and attention. A total of 514 children aged 7 years were included in the analysis (46.3% girls), consisting of 197 children with FHR-SZ (46.2% girls), 118 with FHR-BP (46.6% girls), and 199 controls (46.2% girls). Children with FHR-SZ were significantly impaired compared with controls on processing speed and working memory (Cohen d = 0.50; P < .001), executive and visuospatial functions (Cohen d = 0.28; P = .03), and declarative memory and attention (Cohen d = 0.29; P = .02). Compared with children with FHR-BP, children with FHR-SZ performed significantly poorer in processing speed and working memory (Cohen d = 0.40; P = .002), executive and visuospatial functions (Cohen d = 0.35; P = .008), and declarative memory and attention (Cohen d = 0.31; P = .03). Children with FHR-BP and controls did not differ. Children with FHR-SZ had widespread neurocognitive impairments, supporting the hypothesis of neurocognitive functions as endophenotypes of schizophrenia. The absence of neurocognitive deficits in children with FHR-BP suggests distinct neurodevelopmental manifestations in these familial high-risk groups at this age. Early detection of children with FHR-SZ and cognitive impairments is warranted to investigate associations of neurocognition with transition to psychosis, add to the knowledge of their developmental pathophysiology, and inform early intervention programs.


Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder.
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting via the GABAA receptors. The GABAA receptors are comprised of several different homologous subunits, forming a group of receptors that are both structurally and functionally diverse. Three of the GABAA receptor subunit genes (GABRB3, GABRA5 and GABRG3) form a cluster on chromosome 15q11-q13, in a region that has been genetically associated with autistic disorder (AutD). Based on these data, we examined 16 single nucleotide polymorphisms (SNPs) located within GABRB3, GABRA5 and GABRG3 for linkage disequilibrium (LD) in 226 AutD families (AutD patients and parents). Genotyping was performed using either OLA (oligonucleotide ligation assay), or SSCP (single strand conformation polymorphism) followed by DNA sequencing. We tested for LD using the Pedigree Disequilibrium Test (PDT). PDT results gave significant evidence that AutD is associated with two SNPs located within the GABRG3 gene (exon5_539T/C, p=0.02 and intron5_687T/C, p=0.03), suggesting that the GABRG3 gene or a gene nearby contributes to genetic risk in AutD.


Comparison of Kato-Katz, ethyl-acetate sedimentation, and Midi Parasep® in the diagnosis of hookworm, Ascaris and Trichuris infections in the context of an evaluation of rural sanitation in India.
The Kato-Katz, conventional ethyl-acetate sedimentation, and Midi Parasep(®) methods for diagnosing infection with soil-transmitted helminths were compared. The Kato-Katz technique gave the best overall diagnostic performance with the highest results in all measures (prevalence, faecal egg count, sensitivity) followed by the conventional ethyl-acetate and then the Midi Parasep(®) technique. The Kato-Katz technique showed a significantly higher faecal egg count and sensitivity for both hookworm and Trichuris as compared to the Midi Parasep(®) technique. The conventional ethyl-acetate technique produced smaller pellets and showed lower pellet mobility as compared to the Midi Parasep(®).


HIV epidemics in Shenzhen and Chongqing, China.
Men who have sex with men (MSM) and heterosexuals are the populations with the fastest growing HIV infection rates in China. We characterize the epidemic growth and age patterns between these two routes from 2004 to 2015 in Chongqing and Shenzhen, China. Data were downloaded from the National HIV/ AIDS Comprehensive Response Information Management System. For the new HIV diagnoses of heterosexuals and MSM in both cities, we estimated the growth rates by fitting different sub-exponential models. Heat maps are used to show their age patterns. We used histograms to compare these patterns by birth cohort. The MSM epidemics grew significantly in both cities. Chongqing experienced quadratic growth in HIV reported cases with an estimated growth rate of 0.086 per week and a "deceleration rate" of 0.673. HIV reported cases of MSM in Shenzhen grew even more drastically with a growth rate of 0.033 per week and "deceleration rate" of 0.794. The new infections are mainly affecting the ages of 18 to 30 in Chongqing and ages of 20 to 35 in Shenzhen. They peaked in early 1990's and mid-1990's birth cohorts in Chongqing and Shenzhen respectively. The HIV epidemic among heterosexuals grew rapidly in both cities. The growth rates were estimated as 0.02 and 0.028 in Chongqing and Shenzhen respectively whereas the "deceleration rates" were 0.878 and 0.790 in these two places. It affected mostly aged 18 to 75 in males and 18 to 65 in females in Chongqing and aged 18 to 45 in males and 18 to 50 in females in Shenzhen in 2015. In Chongqing, the heterosexual female epidemics display two peaks in HIV diagnoses in the birth cohorts of early 1950's and early 1980's, with heterosexual male epidemics peaked in early 1940's and early 1960's. The heterosexual male and female epidemics display higher rates in the birth cohort 1940-1960, than the birth cohort 1960-1990. It peaked in birth cohorts of 1950's and 1980's in Shenzhen. We revealed striking differences in epidemic growth and age patterns of the HIV epidemics in these two cities. Our results may be used to inform age-targeted public health policies to curb their epidemic growth.


Cell activation via CD44 occurs in advanced stages of squamous cell carcinogenesis.
Squamous cell carcinoma (SCC) derives from dysplastic or metaplastic stratified epithelia. The process of squamous cell carcinogenesis has been investigated for the potential role of the adhesion molecule CD44, whose standard form (CD44s) and isoforms generated by alternative splicing of variant exons are known to display altered expression during tumorigenesis in other systems. We have utilized an in vitro correlate of squamous cell carcinogenesis, in which progression stages from normal squamous epithelium to dysplastic lesions and to SCC are represented by primary cultures of normal keratinocytes, by human papilloma virus-immortalized keratinocytes (UP) and by HPVimmortalized/v-Ha-ras transfected tumorigenic keratinocytes (UPR). We investigated expression of CD44 and of variant isoforms, from mRNA to intracellular and surface protein levels, and found no relationship between expression of CD44 and stages of squamous cell carcinogenesis. However, when the function of CD44 was analyzed as Ca(2+) mobilization ability upon monoclonal antibody binding and crosslinking, signal transduction via CD44 was found only for the neoplastic stage (UPR cells). Ca(2+) mobilization was completely independent of density of surface CD44. We have performed similar analyses in an in vitro model of SCC in which four squamous tumor cell lines and UPR cells were sorted according to increasing resistance to external cytotoxic stimuli, i.e. starving conditions, treatment with the retinoid N-(4-hydroxyphenyl)retinamide and cytolytic activity of effector lymphokine-activated killer cells. No relationship between expression of CD44 and level of cell resistance against external cell death-inducing stimuli was found, while CD44-mediated Ca(2+) mobilization ability was restricted to the highly resistant tumor cell lines. Our results indicate that the role(s) of CD44 in squamous cell proliferative disorders can be evinced from the functional features of the molecule, rather than from its phenotypic repertoire.


Evaluation of two-test serodiagnostic method for early Lyme disease in clinical practice.
The Centers for Disease Control and Prevention (CDC) recommend a two-test approach for the serodiagnosis of Lyme disease (LD), with EIA testing followed by Western immunoblotting (WB) of EIA-equivocal and -positive specimens. This approach was compared with a simplified two-test approach (WB of EIA equivocals only) and WB alone for early LD. Case-patients with erythema migrans (EM) rash >/=5 cm were recruited from three primary-care practices in LD-endemic areas to provide acute- (S1) and convalescent-phase serum specimens (S2). The simplified approach had the highest sensitivity when either S1 or S2 samples were tested, nearly doubling when S2 were tested, while decreasing slightly for the other two approaches. Accordingly, the simplified approach had the lowest negative likelihood ratio for either S1 or S2. For early LD with EM, the simplified approach performed well and was less costly than the other testing approaches since less WB is required.


Zebrafish as a model for the study of the phase II cytosolic sulfotransferases.
Cytosolic sulfotransferases (SULTs) are traditionally known as the Phase II drug-metabolizing or detoxifying enzymes that serve for the detoxification of drugs and other xenobiotics. These enzymes in general catalyze the transfer of a sulfonate group from the active sulfate, 3'-phosphoadenosine 5'-phosphosulfate (PAPS), to low-molecular weight substrate compounds containing hydroxyl or amino group(s). Despite considerable efforts made in recent years, some fundamental aspects of the SULTs, particularly their ontogeny, cell type/tissue/organ-specific distribution, and physiological relevance, particularly their involvement in drug metabolism and detoxification, still remain poorly understood. To better understand these fundamental issues, we have embarked on developing the zebrafish as a model for studies concerning the SULTs. To date, fifteen zebrafish SULTs have been cloned, expressed, purified, and characterized. These zebrafish SULTs, which fall into four major SULT gene families, exhibited differential substrate specificities and distinct patterns of expression at different stages during embryogenesis, through larval development, and on to maturity. The information obtained, as summarized in this review, provides a foundation for further investigation into the physiological and pharmacological involvement of the SULTs using the zebrafish as a model.


Temporal artery flow response during the last minute of a head up tilt test, in relation with orthostatic intolerance after a 60 day head-down bedrest.
Check if the Temporal flow response to Tilt could provide early hemodynamic pattern in the minutes preceding a syncope during the Tilt test performed after a 60-d head down bedrest (HDBR). Twenty-one men divided into 3 groups [Control (Con), Resistive Vibration (RVE) and Chinese Herb (Herb)] underwent a 60 day HDBR. Pre and Post HDBR a 20 min Tilt identified Finishers (F) and Non Finishers (NF). Cerebral (MCA), Temporal (TEMP), Femoral (FEM) flow velocity, were measured by Doppler during the Tilt. Blood pressure (BP) was measured by arm cuff and cardiopress. Four of the 21 subjects were NF at the post HDBR Tilt test (Con gr:2, RVE gr: 1, Herb gr: 1). At 1 min and 10 s before end of Tilt in NF gr, FEM flow decreased less and MCA decreased more at post HDBR Tilt compared to pre (p<0.05), while in the F gr they changed similarly as pre. In NF gr: TEMP flow decreased more at post HDBR Tilt compared to pre, but only at 10 s before the end of Tilt (P<0.05). During the last 10 s a negative TEMP diastolic component appeared which induced a drop in mean velocity until Tilt arrest. The sudden drop in TEMP flow with onset of a negative diastolic flow preceding the decrease in MCA flow confirm that the TEMP vascular resistance respond more directly than the cerebral one to the cardiac output redistribution and that this response occur several seconds before syncope.


Suicide risk in depression and bipolar disorder: Do impulsiveness-aggressiveness and pharmacotherapy predict suicidal intent?
The aims of the present study were to examine clinical, personality, and sociodemographic predictors of suicide risk in a sample of inpatients affected by major affective disorders. The participants were 74 inpatients affected by major depressive disorder or bipolar disorder-I. Patients completed a semi-structured interview, the Beck Hopelessness Scale, the Aggression Questionnaire, the Barratt Impulsiveness Scale, and the Hamilton scales for depression and anxiety. Over 52% of the patients were high suicide risks. Those at risk reported more severe depressive-anxious symptomatology, more impulsivity and more hostility. Impulsivity, the use of antidepressants, anxiety/somatization, and the use of mood stabilizers (a negative predictor) resulted in accurate predicting of suicide intent. Impulsivity and antidepressant use were the strongest predictors even after controlling for several sociodemographic and clinical variables.


Implementation of a Health Impact Assessment (HIA) tool in a regional health organization in Sweden--a feasibility study.
During the last decade, Health Impact Assessment (HIA) has been discussed worldwide as being an important tool for the development of healthy public policy. In Sweden, the Swedish Federation of County Councils and the Swedish Association of Local Authorities have taken the initiative to and are responsible for the development of an HIA tool concerning proposed policy decisions at local and regional levels. The HIA tool was developed as three different templates to be adapted to local conditions and needs: the Health Question, the Health Matrix and the Health Impact Analysis. In this paper we present a feasibility study of the experiences of implementing this HIA tool at regional level in a Health Care District (SWHCD) of Stockholm County Council, based on an inductive approach and on principles of data triangulation. The main findings include the need for continuous revision of the HIA templates during the pilot period. The following factors were instrumental in successfully using the HIA tool in local policy making and management: political consensus, agreement between politicians and public officials on political intentions, a clear- cut decision from management, and offering an opportunity for training. Respondents felt that all public officials should use the HIA as part of their normal work routines. In conclusion, the HIA tool has to be locally adapted and the implementation process has to include close collaboration between politicians and public officials and be followed by continuing education, providing possibilities for a dialogue around the HIA tool, in order to ensure the quality of the instrument. Implications of the study are that the process of developing the tool has worked well but that the possible impacts of its use in this case remain an open question. However, this was not the focus of our study.


Computational study of drug binding to the membrane-bound tetrameric M2 peptide bundle from influenza A virus.
The M2 protein of influenza A virus performs the crucial function of transporting protons to the interior of virions enclosed in the endosome. Adamantane drugs, amantadine (AMN) and rimantidine (RMN), block the proton conduction in some strains, and have been used for the treatment and prophylaxis of influenza A infections. The structures of the transmembrane (TM) region of M2 that have been solved in micelles using NMR (residues 23-60) (Schnell and Chou, 2008) and by X-ray crystallography (residues 22-46) (Stouffer et al., 2008) suggest different drug binding sites: external and internal for RMN and AMN, respectively. We have used molecular dynamics (MD) simulations to investigate the nature of the binding site and binding mode of adamantane drugs on the membrane-bound tetrameric M2-TM peptide bundles using as initial conformations the low-pH AMN-bound crystal structure, a high-pH model derived from the drug-free crystal structure, and the high-pH NMR structure. The MD simulations indicate that under both low- and high-pH conditions, AMN is stable inside the tetrameric bundle, spanning the region between residues Val27 to Gly34. At low pH the polar group of AMN is oriented toward the His37 gate, while under high-pH conditions its orientation exhibits large fluctuations. The present MD simulations also suggest that AMN and RMN molecules do not show strong affinity to the external binding sites.


Screening for Hepatitis C Virus Infection in Adolescents and Adults: US Preventive Services Task Force Recommendation Statement.
Hepatitis C virus (HCV) is the most common chronic blood-borne pathogen in the US and a leading cause of complications from chronic liver disease. HCV is associated with more deaths than the top 60 other reportable infectious diseases combined, including HIV. Cases of acute HCV infection have increased approximately 3.8-fold over the last decade because of increasing injection drug use and improved surveillance. To update its 2013 recommendation, the USPSTF commissioned a review of the evidence on screening for HCV infection in adolescents and adults. This recommendation applies to all asymptomatic adults aged 18 to 79 years without known liver disease. The USPSTF concludes with moderate certainty that screening for HCV infection in adults aged 18 to 79 years has substantial net benefit. The USPSTF recommends screening for HCV infection in adults aged 18 to 79 years. (B recommendation).


[Assessment of selected neoplastic markers in women receiving hormone replacement therapy].
The study was performed in order to assess the serum levels of proteins believed to be the markers of neoplastic differentiation (CEA and CA 15.3) and proliferation (TPS) in women receiving hormone replacement therapy. 190 women were included into the study. Women were classified into one of four groups: healthy women receiving hormone replacement therapy (n = 76), women with diagnosed benign breast disease (BBD) receiving HRT (n = 26), women with diagnosed BBD without HRT (n = 48), and control group--age matched, regularly menstruating women without HRT (n = 40). Measurements of serum concentrations of neoplastic markers were performed using radioimmunological method. The results indicate that hormone replacement therapy does not provoke a rise in neoplastic markers concentrations above normal levels in any of assessed groups. Women with BBD using HRT were found to have the lowest TPS and CA 15.3 values and the highest CEA values. The long-term usage of HRT was found to cause a gradual rise of average concentrations of all measured markers in BBD group and in healthy women.


Synthesis, characterization, electronic structure and catalytic performance of bimetallic and trimetallic nanoparticles containing tin.
When anchored on a high-area, siliceous supports, nanoparticle catalysts, consisting of two or three different metals, but totaling no more than twenty atoms in all, exhibit exceptional activities and selectivities in solvent-free, one-step hydrogenation reactions at low temperatures (< 420 K) and much lower pressures (e.g. 30 bar) than those required in current industrial manufacture. The two selective hydrogenations illustrated here are the conversion of (a) cyclododecatriene (CDT) to cyclododecene (CD) and (b) dimethyl terephthalate (DMT) to cyclohexane dimethanol (CHDM); each of these products is extensively used in the polymer industry. All our mixed-metal nanoparticles are derived from an appropriately chosen parent (precursor) mixed-metal carbonyl having phenyl-containing tin ligands, e.g. Ru4(mu4-SnPh)2(CO)12. Various techniques are used to characterize the denuded, anchored cluster catalysts; and it is expected that aberration-corrected high-resolution electron microscopy (and other techniques, which are outlined) will be invaluable in such characterization. Density functional theory has provided important insights into the structures and electronic properties of our catalysts and their precursors.


Quantification of Tafenoquine and 5,6-Orthoquinone Tafenoquine by UHPLC-MS/MS in Blood, Plasma, and Urine, and Application to a Pharmacokinetic Study.
Analytical methods for the quantification of the new 8-aminoquinoline antimalarial tafenoquine (TQ) in human blood, plasma and urine, and the 5,6-orthoquinone tafenoquine metabolite (5,6-OQTQ) in human plasma and urine have been validated. The procedure involved acetonitrile extraction of samples followed by ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Chromatography was performed using a Waters Atlantis T3 column with a gradient of 0.1% formic acid and acetonitrile at a flow rate of 0.5 mL per minute for blood and plasma. Urine analysis was the same but with methanol containing 0.1% formic acid replacing acetonitrile mobile phase. The calibration range for TQ and 5,6-OQTQ in plasma was 1 to 1200 ng/mL, and in urine was 10 to 1000 ng/mL. Blood calibration range for TQ was 1 to 1200 ng/mL. Blood could not be validated for 5,6-OQTQ due to significant signal suppression. The inter-assay precision (coefficient of variation %) was 9.9% for TQ at 1 ng/mL in blood (n = 14) and 8.2% for TQ and 7.1% for 5,6-OQTQ at 1 ng/mL in plasma (n = 14). For urine, the inter-assay precision was 8.2% for TQ and 6.4% for 5,6-OQTQ at 10 ng/mL (n = 14). TQ and 5,6-OQTQ are stable in blood, plasma and urine for at least three months at both -80 °C and -20 °C. Once validated, the analytical methods were applied to samples collected from healthy volunteers who were experimentally infected with Plasmodium falciparum to evaluate the blood stage antimalarial activity of TQ and to determine the therapeutic dose estimates for TQ, the full details of which will be published elsewhere. In this study, the measurement of TQ and 5,6-OQTQ concentrations in samples from one of the four cohorts of participants is reported. Interestingly, TQ urine concentrations were proportional to parasite recrudescence times post dosing To our knowledge, this is the first description of a fully validated method for the measurement of TQ and 5,6-OQTQ quantification in urine.


Randomized trial of informed consent and recruitment for clinical trials in the immediate preoperative period.
The standard process of obtaining informed consent sometimes prevents physicians or patients from participating in clinical trials, partly because they are concerned about eventual treatment allocation or the physician is concerned the patient might harbor some uncertainty about the best treatment. Alternative randomization methods have been advocated that may address these and other concerns. After institutional ethics committee gave its approval, the authors interviewed 770 patients before operation and asked them to consider enrolling in a mock anesthesia trial. Patients were allocated randomly to one of five methods of randomization and consent: one-sided informed consent (the most common approach), prerandomized consent to experimental treatment, prerandomized consent to standard treatment, one-sided physician-modified informed consent, or one-sided patient-modified informed consent. Recruitment rates were compared and sociodemographic and perioperative predictors of recruitment were identified. The randomization method did not result in any significant difference in recruitment rates: one-sided informed consent, 55.6%; prerandomized consent to experimental treatment, 53.3%; prerandomized consent to standard treatment, 53%; one-sided physician-modified informed consent, 60.7%; and one-sided patient-modified informed consent, 56.7% (P = 0.66). Multivariate predictors of recruitment were patient age >45 yr (odds ratio, 1.44; 95% confidence interval [CI], 1.08 to 1.93), English-speaking at home (1.49; 1.0 to 2.21), and male researcher-male patient interaction (1.37; 1.20 to 1.57). No evidence emerged that alternative randomization and consent designs resulted in increased recruitment rates compared with simple one-sided informed consent for a sham anesthesia trial in patients awaiting elective surgery. Older, male patients were more likely to provide consent.


Two differentially expressed genes in normal human prostate tissue and in carcinoma.
Alterations in transcriptional control may contribute directly to carcinogenesis. Using the differential display technique in prostate cancer cells compared to normal prostate epithelial cells, we identified a down-regulated gene and an up-regulated gene in cancer cells. The down-regulated gene encodes human epithelial tropomyosin (TMe1), a member of the family of actin filament-binding proteins. The up-regulated gene encodes cytochrome c oxidase subunit VIc (COSVIc), a protein of the respiration chain in the mitochondrial inner membrane. The differential display pattern was confirmed by Northern hybridization in both prostate tissue and cell lines. In situ hybridization of malignant prostate epithelial tissue using a digoxigenin-labeled antisense riboprobe detected strong staining for mRNA of COSVIc, as opposed to very weak staining in normal prostate epithelium. The expression pattern of COSVIc may be a useful marker for studying the alteration of energy metabolism in cancer cells and for the diagnosis of prostate cancer.


[Method for estimating data of potentiometric titration of membrane fragments by computers].
The flow chart of the computer programme is described for estimation of the quantity and pK values of separate ionogenic sites of the membrane based on the data of potentiometric titration with application of graphic method for calculation of parametres of titration differential curves. Its application makes it possible to reduce the time for calculating the potentiometric curves, to chose minima in the differential curve more objectively for characterization the pK values and to calculate areas of its different plots, which characterize binding capacity for ionogenic groups. The programme was written in the Analytic language for the MIR-2 computer.


Efficient transcription of a protein-coding gene from the RNA polymerase I promoter in transfected cells.
The activity of the mouse ribosomal promoter was examined after fusion to the gene coding for chloramphenicol acetyltransferase (CAT) and transfection into mouse cells. Very little CAT enzyme but high levels of CAT-specific RNA correctly initiated at the ribosomal DNA start site were synthesized. The amount of specific transcripts was neither influenced by long stretches of upstream spacer sequences nor by the insertion of the Moloney murine sarcoma virus enhancer. The deletion mutant pMr delta-39, which has been shown to be fully active in vitro, exhibited a 90% decrease in template activity in vivo. A mutant in which 22 base pairs of ribosomal DNA (between positions -35 and -14) were substituted by foreign DNA sequences proved transcriptionally inactive. The fusion genes were only transcribed in mouse cells, indicating that species-specific transcription factors are involved in ribosomal promoter recognition.


A possible role of adenylate cyclase in the long-tern dietary regulation of insulin secretion from rat islets of Langerhans.
1. Adenylate cyclase activity and patterns of insulin release in response to various concentrations of glucose were determined in islets of Langerhans isolated from starving, fed, or glucose-loaded rats. 2. Basal and glucagon-stimulated activities of adenylate cyclase were lower in islets from starved than from fed rats. The minimum glucose concentration required for stimulation of insulin secretion was higher, whereas the maximum secretory response to glucose was lower, in islets from starved than from fed rats. 3. Adenylate cyclase activity in islets of Langerhans obtained from fed rats loaded with glucose by intermittent intravenous or intraperitoneal injections over 5h was significantly higher than that seen in islets from normal fed rats. Islets obtained from glucose-loaded rats required a lower glucose concentration for stimulation of insulin secretion and attained a higher maximal response to glucose stimulation than those derived from fed rats. 4. Incubation in vitro of islets isolated from normal fed rats, for periods of 1 to 24h in the presence of high concentrations of glucose resulted in an activation of adenylate cyclase that occurred progressively from 2 to 7h and which was maintained during 24h of incubation. The increase of adenylate cyclase activity in isolated islets incubated for 4h in the presence of glucose was not prevented by addition of cycloheximide or actinomycin D. Galactose or 2-deoxyglucose was ineffective in increasing adenylate cyclase activity, and pyruvate (20mm) was less effective than glucose. 5. It is suggested that glucose or a glucose metabolite may exert long-term effects on islet cell adenylate cyclase.


A Study of Malaria Parasite Density in HIV-1 Positive Under-fives in Benin City, Nigeria.
Human immunodeficiency virus (HIV) and malaria are leading causes of morbidity and mortality among under-fives in sub-Saharan Africa. HIV infection could affect development of antimalarial immunity by impaired parasite clearance with predisposition to higher malaria parasitaemia. The objective of this study is to assess asymptomatic malaria parasite density (AMPD) in HIV-1-infected under-fives in a holoendemic zone. HIV-1-positive and -negative children <5 years on follow-up care were recruited and AMPD and CD4 counts were determined. A total of 358 children were studied. Significantly higher malaria parasitaemia was found in HIV-infected individuals (118.7 vs. 87.3 parasite/μl, p = 0.021). Disparity in AMPD was most pronounced at infancy with similar distribution at all age brackets and consistently higher parasitaemia in the subjects. Parasitaemia is higher in HIV-infected than uninfected children. The burden is highest at infancy. Acquisition of antimalarial immunity is similar in both groups. Parasitaemia is not significantly affected by clinical disease stage or worsening immunosuppression.


Effect of breaking bad news on patients' perceptions of doctors.
The breaking of bad news is a routine but difficult task for many health professionals. There are numerous anecdotes of insensitive practice but the subject has attracted little systematic research. We therefore interviewed 106 patients with advanced cancer (from an original sample of 195) to assess their perceptions of the doctors involved in their care. Aspects of the 'breaking bad news' event were recorded during discussion of the illness history and were subsequently rated. Participants were also asked to nominate doctors under the headings 'most helpful' and 'less helpful', and completed standardized psychological screening questionnaires. In 94 of the 106 cases the bad news had been given by a doctor, usually a surgeon. Of the 13 doctors categorized as 'most helpful' when breaking bad news, 8 were general practitioners; of the 7 categorized as 'less helpful' all were surgeons. 69% of patients were neutral or positive about the bad-news consultation, but 20% were negative and 6% very negative. Doctors in surgical specialties were significantly more likely to be rated poorly than non-surgical specialists or general practitioners. Surgeons were the group of doctors most likely to break bad news, but non-surgical doctors were rated more positively in performance of the task. This finding has implications for training.


Spectroscopic study of fast-neutron-irradiated chromatin.
The effects produced by fast neutrons (0-100 Gy) on chromatin structure were analyzed by (i) [1H]-NMR spectroscopy, (ii) time resolved spectroscopy, and (iii) fluorescence resonance energy transfer (FRET). Two types of chromatin were tested: (i) a chromatin from a normal tissue (liver of Wistar rats) and (ii) a chromatin from a tumoral tissue (Guerin limphotrope epithelioma, a rat solid tumor). The fast-neutron action on chromatin determines greater values of the [1H]-NMR transverse relaxation time, indicating a more injured structure. Time-resolved fluorescence measurements show that the relative contribution of the excited state lifetime of bound ethidium bromide to chromatin DNA diminishes with increasing irradiation doses. This reflects the damage that occurs in DNA structure: production of single- and double-strand breaks due to sugar and base modifications. By the FRET method, the distance between dansyl chloride and acridine orange coupled at chromatin was determined. This distance increases upon fast-neutron action. The radiosensitivity of the tumor tissue chromatin seems higher than that of the normal tissue chromatin, probably because of its higher (loose) euchromatin/(compact) heterochromatin ratio. As the values of the physical parameters analyzed are specific for a determined dose, the establishment of these parameters may constitute a criterion for the microdosimetry of chromatin radiolesions produced by fast neutrons.


How the Child's Gender Matters for Families Having a Child With Congenital Adrenal Hyperplasia.
Children with congenital adrenal hyperplasia (CAH) are exposed to high levels of testosterone in utero often resulting in nontypical genitalia at birth for girls. The purpose of this analysis, which draws on data from a larger study, was to examine, based on the gender of the child, the family experiences of having a child with CAH. Sixteen parents were interviewed, and comparisons were made across all categories coded in the parents' interviews to examine similarities and differences in the experiences of families based on the child's gender. Families having a daughter with CAH experienced additional challenges when compared with families having a son. These include fear of stigmatization, challenging surgical decisions, and concerns regarding disclosure of the condition. Acknowledging this and creating support programs tailored for girls that address surgical procedures and complications resulting from being born with elevated testosterone are critical to promoting a healthy family and child response.


Models of the aging brain structure and individual decline.
The aging brain's structural development constitutes a spatiotemporal process that is accessible by MR-based computational morphometry. Here we introduce basic concepts and analytical approaches to quantify age-related differences and changes in neuroanatomical images of the human brain. The presented models first address the estimation of age trajectories, then we consider inter-individual variations of structural decline, using a repeated measures design. We concentrate our overview on preprocessed neuroanatomical images of the human brain to facilitate practical applications to diverse voxel- and surface-based structural markers. Together these methods afford analysis of aging brain structure in relation to behavioral, health, or cognitive parameters.


Improving R0 Resection Rates With a Posterior-First, 2-Stage Approach for En Bloc Resection of Locally Advanced Primary and Recurrent Anorectal Cancers Involving the Deep Pelvic Sidewall.
Using standard anterior approaches, consistent R0 resection of locally advanced primary and recurrent rectal and anal cancer involving the deep pelvic sidewall may be unattainable. Therefore, to improve R0 resection rates, we have used a posterior-first, then anterior 2-stage approach to resection of tumors in this location. To assess the R0 resection rate and surgical outcomes of the first 10 patients operated on using this approach. We conducted a retrospective case series review of our prospectively maintained surgical pathology and tumor registries. This study was conducted at the Mayo Clinic in Rochester, Minnesota. Ten patients (6 female individuals, median age 53.5 years) with primary or recurrent anal or rectal cancer treated with a posterior-first, then anterior 2-stage approach were identified. The primary outcome measures were the R0 resection rate and surgical outcomes. An R0 resection was achieved in all 10 patients. Nine patients developed 1 or more 30-day Clavien-Dindo grade III complications. Nine patients developed gluteal wound complications ranging from superficial wound dehiscence to flap necrosis. During the follow-up period, 4 patients were found to have metastatic disease and 1 patient had local re-recurrence. Small cohort with heterogeneous tumors and a short follow-up duration. A posterior-first, then anterior 2-stage approach has allowed us to achieve consistent R0 resection margins in locally advanced primary and recurrent rectal and anal cancers involving the deep pelvic sidewall. Poor wound healing of the posterior gluteal incision is a common complication. See Video Abstract. ANTECEDENTES:Utilizando abordajes anteriores estándares, la resección R0 consistente del cáncer de recto y ano primario y recurrente localmente avanzado involucrando la pared lateral pélvica profunda puede ser inalcanzable. Por lo tanto, para mejorar las tasas de resección R0, hemos empleado un abordaje de 2 etapas primero posterior y luego anterior para la resección de tumores en esta ubicación.OBJETIVO:Este estudio tuvo como objetivo evaluar la tasa de resección R0 y los resultados quirúrgicos de los primeros 10 pacientes operados con este abordaje.DISEÑO:Realizamos una revisión retrospectiva de series de casos de nuestros registros de patología quirúrgica y tumores mantenidos prospectivamente.AJUSTE:Este estudio se realizó en la Clínica Mayo en Rochester, Minnesota, EE. UU.PACIENTES:Se identificaron diez pacientes (6 mujeres, mediana de edad 53.5 años) con cáncer anal o rectal primario o recurrente tratados con un abordaje de dos etapas, primero posterior y luego anterior.PRINCIPALES MEDIDAS DE RESULTADO:Las medidas de resultado primarias fueron la tasa de resección R0 y los resultados quirúrgicos.RESULTADOS:Se logró una resección R0 en los 10 pacientes. Nueve pacientes desarrollaron una o más complicaciones de grado III de Clavien-Dindo a los 30 días. Nueve pacientes desarrollaron complicaciones de la herida del glúteo que variaron desde dehiscencia superficial de la herida hasta necrosis del colgajo. Durante el período de seguimiento, se encontró que 4 pacientes tenían enfermedad metastásica y un paciente tuvo recurrencia local.LIMITACIONES:Cohorte pequeño con tumores heterogéneos y corta duración de seguimiento.CONCLUSIÓN:Un abordaje en 2 etapas, primero posterior y luego anterior, nos ha permitido lograr márgenes de resección R0 consistentes en cánceres de recto y anal primarios y recurrentes localmente avanzados que afectan la pared lateral pélvica profunda. La mala cicatrización de la incisión glútea posterior es una complicación común. (Traducción-Dr. Aurian Garcia Gonzalez).


Morusin Inhibits Human Osteosarcoma via the PI3K-AKT Signaling Pathway.
Osteosarcoma is considered as one of the most common types of bone tumors, which occurs among adolescents and children. Current therapy strategies still have limited effectiveness therefore, the development of new therapies is urgent. Morusin is a compound isolated from Morus australis (Moraceae). Many studies have reported its anti-tumor effect on several tumor types. However, its role in osteosarcoma is still unclear. In this study, we determined that morusin significantly suppresses the proliferation and promotes the apoptosis of osteosarcoma cells. Furthermore, the migration and invasion of osteosarcoma were reduced after exposure to morusin. The deep mechanism was determined to be the inhibition of the PI3K/AKT signaling pathway. In conclusion, our study indicates morusin as a potential candidate for osteosarcoma therapy.


[Effect of acute stress on the fatty acid composition of lipids of adrenal and heart mitochondria in rabbits].
A comparative study of changes in the fatty acid composition of rabbit heart and adrenal mitochondria was carried out after acute (1h) immobilization stress. In heart mitochondria the stress induced a decrease in the content of capric, lauric, myristic and pentadecanic acids. A statistically significant reduction of the amount of heptadecanoic, linoleic, arachidonic acids and an increase in the level of palmitic acid was noted in adrenal mitochondria. The acute stress resulted in differently directed shifts in the saturation of fatty acids. An elevation of the sum of unsaturated fatty acids was observed in the heart, and a decrease was detected in the adrenal glands. The above shifts in the fatty acid composition of adrenal and heart mitochondria provide evidence for different directions of lipid metabolism in these organs following stress.


Papillary carcinoma of the thyroid associated with sarcoidosis.
A case of papillary carcinoma of the thyroid occurring in association with systemic sarcoidosis is reported. Although benign thyroid disorders occurring in conjunction with sarcoidosis have previously been documented, a search of the literature found no report of thyroid carcinoma occurring in association with sarcoidosis. Diagnosis and therapeutic management prove difficult when thyroid carcinoma and sarcoidosis co-exist. Transbronchial biopsy of lung lesions is warranted in staging thyroid carcinoma in order to exclude the possibility of unknown co-existent disease. The management of cervical lymphadenopathy in thyroid carcinoma should not be altered because of the presence of sarcoidosis, and should include a neck dissection.


[Expression of a defect in the respiratory chain in cultured human cells].
Large scale deletions of mitochondrial DNA (mtDNA) or altered inter-genomic regulation in skeletal muscle have been demonstrated in patients with mitochondrial encephalomyopathies due to Cytochrome C oxidase (COx) deficiency. We have analyzed by Southern blotting and Polymerase Chain Reaction (PCR) the mtDNA in primary muscle cultures (myoblast-myotube stages and at clonal densities) and in fibrogenic subclones obtained from 9 patients with partial COx deficiency who had in their muscle biopsy a subpopulation of mtDNA showing deletions of variable size (between 2.1 and 6.5 Kb). Only in the cultures from one patient, southern analysis revealed in myoblasts and myotubes a mtDNA almost identical to that found in the original muscle biopsy and persistence of deletion in muscle cells grown at clonal densities. The deletion was detectable in fibrogenic lineage only by PCR amplification. The deleted mtDNA molecules were detectable in myogenic or fibrogenic cultures from other patients only by PCR amplification. The different amounts of deleted mtDNA in the various tissues could be due either to an unequal distribution of the altered mtDNA during embryogenesis with amplification of deleted molecules in myogenic lineage or could result from negative selection against the altered mtDNA in rapidly proliferating cells, such as fibroblasts.


Novel Electrochemiluminescent Biosensor to Ultrasensitively Detect U94 Gene in Human Herpesvirus 6 Using Metal-Organic Framework-Based Nanoemitters Comprising Iridium(III) Complexes via One-Pot Coordination Reaction Strategy.
The detection of the U94 gene in human herpesvirus 6 is crucial for early diagnosis of HHV-6 infections, which could induce acute febrile illness in infants. In this work, the first ultrasensitive electrochemiluminescence (ECL) biosensor for detecting U94 gene in Human Herpesvirus 6 was successfully designed by utilizing efficient novel metal-organic framework (MOF)-based ECL nanoemitters comprising iridium(III) complexes (Ir-ZIF-8-NH2) synthesized via one-pot coordination reaction strategy as an ECL indicator and a target-catalyzed hairpin assembly (CHA) signal amplification strategy. The as-prepared ECL indicator Ir-ZIF-8-NH2 exhibited an approximately 2.7-fold ECL intensity compared with its small molecular analogue of emissive iridium(III) complex named IrppymIM formed by in situ coordination reaction between iridium(III) solvent complex and imidazole ligands. In addition, a target-catalyzed hairpin assembly (CHA) strategy was employed to further improve the sensitivity of the proposed ECL biosensor, which demonstrated a wide linear range from 1 fM to 1 μM and the limit of detection as low as 0.113 fM (S/N = 3). Significantly, this biosensor was successfully applied to detect U94 gene in plasmids and real virus samples. The recoveries were in the range of 97.0-109.0% for plasmids and 95.7-107.5% for real virus samples with a relative standard deviation (RSD) of 1.87-2.53%. These satisfactory experimental results from the proposed ECL biosensor in this work would inevitably promote the development of new time/cost-effective and sensitive methods to detect HHV-6 with a major global health threat and substantial burden on healthcare in the future.


Effects of Patient Portal Use on Patient Satisfaction: Survey and Partial Least Squares Analysis.
With digital delivery of health care services gaining prominence, patient portals have become a mainstay of many health care organizations. Despite the importance of patient portals, inconclusive data exist regarding the effect of patient portal use on patient satisfaction. The aim of this study is to understand the relationship between the postadoptive use of patient portals and patient satisfaction outcomes. Postadoptive use of patient portals has a positive relationship with the 3 dimensions of patient satisfaction, mediated by gratification, health self-awareness, and health perceptions. A total of 504 valid patient portal user responses were collected, and partial least squares analysis was performed to analyze the data. Patient satisfaction was captured using three dimensions: care team interaction, atmosphere, and instruction effectiveness. The results show that postadoptive use of patient portals has a positive influence on all 3 dimensions of patient satisfaction through the mediating variables of gratification, health self-awareness, and health perceptions. Specifically, postadoptive use had significant positive influence on gratification, health self-awareness, and health perceptions. Each of the 3 patient perceptions had significant positive influence on all 3 dimensions of patient satisfaction: care team interaction, atmosphere, and instruction effectiveness. Specifically, our model explained 31.8% of the care team interaction, 40.6% of the atmosphere, and 39.1% of the instruction effectiveness. Our model shows that patient portal use can influence patient satisfaction through the mediating effects of gratification, health self-awareness, and health perception. Patient satisfaction is an important outcome for health care organizations. Therefore, by promoting effective patient portal use and fostering patient perceptions, health care organizations can improve patient satisfaction.


Development and validation of the Diabetic Peripheral Neuropathic Pain Impact (DPNPI) measure, a patient-reported outcome measure.
Diabetic peripheral neuropathy (DPN) occurs in 26-47 % of diabetes patients and may have negative impacts on physical functioning, sleep, well-being, and quality of life. The Diabetic Peripheral Neuropathic Pain Impact measure (DPNPI) was developed to measure disease impacts and treatment effects. Presented are the DPNPI conceptual development and validation findings. The DPNPI was developed following the FDA Guidance for Industry on patient-reported outcome (PRO) measures. Concept elicitation (CE) included literature review, clinical expert interviews, and patient interviews/focus groups. Qualitative data were analyzed following grounded theory principles, and draft items were cognitively debriefed. The measure underwent psychometric validation, and an a priori statistical analysis plan assessed the measurement model, reliability, and validity. Simultaneous analyses of item functioning were conducted using Rasch measurement theory (RMT). All tests were performed for the total score and each domain. Twenty-five patients and three clinical experts participated in CE which resulted in a 27-item validation ready measure. In the validation study (N = 124), nine draft items were dropped due to high missing data and/or high correlations between items. Factor analysis revealed three domains: physical functioning/mobility, sleep, and daily activities. RMT confirmed adequate item fit and placement within domains. Internal consistency ranged from 0.91 to 0.96 and test-retest from 0.84 to 0.91. All prespecified hypotheses for convergent and discriminant validity were met. CE and psychometric results provide evidence that the final, 18-item DPNPI is a reliable and valid PRO measure of disease impacts and treatment for DPNP. Further validation work should include responsiveness assessment.


New is always better: Novelty modulates oculomotor learning.
Saccadic adaptation aims at keeping saccades accurate to enable precise foveation of objects. It has been believed to be a rather low-level adjustment, responding chiefly to direction and magnitude of postsaccadic position error. However, recent studies have shown that image content can modify saccadic adaptation. Adaptation is more complete for saccades toward socially relevant human figures in comparison to noise when time constraints exist. In the present experiment, we show that saccadic adaptation is also susceptible to the novelty of a stimulus. In a scanning adaptation paradigm, 20 subjects participated in two sessions of forward adaptation to one position at which the same human picture was always displayed versus a position at which a new human figure was presented in every trial. Saccadic adaptation was more complete to the novel-target position. This suggests that novelty can increase oculomotor learning and corroborates the claim that saccadic adaptation includes influences that reflect the target's visual properties.


Sox9 regulates cell state and activity of embryonic mouse mammary progenitor cells.
Embryonic mammary cells are a unique population comprised of undifferentiated, highly plastic progenitor cells that create normal mammary tissues. The mammary gland continues to develop after birth from descendants of embryonic mammary cells. Here, we establish cell lines from mouse mammary organs, immediately after they formed during prenatal development, to facilitate studies of primitive mammary cells, which are difficult to isolate in sufficient quantities for use in functional experiments. We show that some lines can be induced to secrete milk, a distinguishing feature of mammary epithelial cells. Targeted deletion of Sox9, from one clone, decreases the ability to respond to lactogenic stimuli, consistent with a previously identified role for Sox9 in regulating luminal progenitor function. Sox9 ablation also leads to alterations in 3D morphology and downregulation of Zeb1, a key epithelial-mesenchymal transition regulator. Prenatal mammary cell lines are an invaluable resource to study regulation of mammary progenitor cell biology and development.


Castleman's disease as an unusual neck mass: case report.
Castleman's disease is a rare, benign disease of unknown cause that induces reactive lymph node hyperplasia, most commonly in the mediastinum. It has 2 histologic subtypes: hyaline vascular and plasma cellular. A definitive diagnosis necessitates tissue biopsy. A specimen may be even misdiagnosed as lymphoma in frozen section. Surgery is the treatment of choice for the solitary form, whereas chemotherapy, radiotherapy, and steroids are proposed for the multicentric type. A neck mass diagnosed as Castleman's disease in a 48-year-old woman is reported.


Improvement in Creatinine Clearance after Open Heart Surgery in Infants as an Early Indicator of Surgical Success.
Early surgical correction of congenital heart malformations in neonates and small infants may be complicated by acute kidney injury (AKI), which is associated with higher morbidity and mortality rates, especially in patients who require dialysis. Glomerular filtration rate (GFR) is considered the best measurement of renal function which, in neonates and infants, is highly dependent on heart function. To determine whether measurements of creatinine clearance after open heart surgery in neonates and young infants can serve as an early indicator of surgical success or AKI. We conducted a prospective observational study in 19 neonates and small infants (body weight < 5 kg) scheduled for open heart surgery with cardiopulmonary bypass. Urine collection measurement of creatinine clearance and albumin excretion was performed before and during surgery and four times during 48 hours after surgery. Mean creatinine clearance was lowest during surgery (25.2 ± 4. ml/min/1.73 m2) and increased significantly in the first 16 hours post-surgery (45.7 ± 6.3 ml/min/1.73 m2). A similar pattern was noted for urine albumin which was highest during surgery (203 ± 31 µg/min) and lowest (93 ± 20 µg/min) 48 hours post-surgery. AKI occurred in four patients, and two patients even required dialysis. All six showed a decline in creatinine clearance and an increase in urine albumin between 8 and 16 hours post-surgery. In neonates and small infants undergoing open heart surgery, a significant improvement in creatinine clearance in the first 16 hours postoperatively is indicative of a good surgical outcome. This finding has important implications for the early evaluation and treatment of patients in the intensive care unit on the first day post-surgery.


Homozygous deletion of HFE produces a phenotype similar to the HFE p.C282Y/p.C282Y genotype.
Hemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is carried by approximately 1 person in 200 in Northern European populations. However, p.C282Y homozygosity is often characterized by incomplete penetrance. Here, we describe the case of a woman who had a major structural alteration in the HFE gene. Molecular characterization revealed an Alu-mediated recombination leading to the loss of the entire HFE gene sequence. Although homozygous for the HFE deleted allele, the woman had a phenotype similar to that seen in most women homozygous for the common p.C282Y mutation. Contrasting with previously reported results in Hfe knockout and Hfe knockin mice, our report gives further evidence that progression of the disease depends on modifying factors.


A facile method to fabricate functionally integrated devices for oil/water separation.
In this paper, we present a facile method for the fabrication of a functionally integrated device, which has the multi-functions of the oil-containment boom, oil-sorption material, and water/oil-separating film, through a single immersion step in an ethanol solution of stearic acid. During the simple immersion process, the two dominant factors of superhydrophobicity, surface roughness and low-surface-energy coatings, could be accomplished simultaneously. The as-prepared functionally integrated device with superhydrophobicity/superoleophilicity displayed a lower density than that of water, such that it could float on water and act as an oil-containment boom; an efficient oil-absorbing property, which was attributed to the capillary effect caused by micrometer-sized pore structures and could be used as oil-sorption materials; a high oil/water separating efficiency which was suitable for water/oil-separating film. In this way, the functions of oil collection, absorption, and water/oil separation are integrated into a single device, and these functions could work independently, reducing the cost in terms of energy consumption and being versatile for a wide range of applications.


Efficacy of the Nance appliance as an anchorage-reinforcement method.
The Nance appliance is widely considered to be an efficient method of anchorage reinforcement; however, much of the perceived advantage is based on clinical judgment. The aim of this study was to assess the amounts of anchorage loss and desired tooth movement associated with the Nance appliance. The mandibular arches of 7 beagle dogs were used. The first and third premolars were extracted. Reference miniscrews were placed at the first premolar sites as stable references to measure the amounts of anchorage loss and desired tooth movement. Four beagles were fitted with custom-made Nance appliances on the fourth premolars and orthodontic bands on the second premolars (Nance group). Three beagles were fitted with orthodontic bands on the second and fourth premolars with no anchorage reinforcement (control group). The second premolars were retracted over 15 weeks in both groups. The amounts of second premolar movement (desired tooth movement) and fourth premolar movement (anchorage loss) were recorded at 5, 10, and 15 weeks. The percentages of desired tooth movement and anchorage loss to the total space closure were calculated. The mean desired tooth movement was significantly more in the Nance group than in the control group at 10 weeks (P <0.05) but was not significantly different at 5 and 15 weeks. The mean percentages of anchorage loss to the total space closure at 15 weeks were 45.7% in the control group and 28.8% in the Nance group. The Nance group had 16.9% less anchorage loss and 16.6% more desired tooth movement than did the control group at 15 weeks (P <0.05). Most of the anchorage loss (80%) in the Nance group occurred during the first 10 weeks. The Nance appliance did not provide absolute anchorage, but there was significantly less anchorage loss with it than in the control group. The majority of anchorage loss occurred during the first 10 weeks in the Nance group.


Invasive fungal infection caused by Blastobotrys mokoenaii in an immunocompromised patient with acute myeloid leukemia: A case report.
Blastobotrys is a genus of rare yeast that is increasingly recognized as a cause of fungal infections in humans. However, there have been no reports of fungal infections in humans caused by Blastobotrys mokoenaii. We describe a case of invasive fungal infection (IFI) caused by B. mokoenaii in an immunocompromised patient with acute myeloid leukemia (AML). A 46-year-old man with relapsed/refractory AML underwent a second allogeneic peripheral blood hematopoietic stem cell transplantation (allo-PBSCT) during remission. The patient had prolonged neutropenia and received systemic steroid therapy for graft-versus-host disease before the second allo-PBSCT. Uncommon yeast was isolated from the blood cultures obtained on day 4. We initially suspected that the uncommon yeast was Trichosporon spp. based on its morphology. However, unlike Trichosporon spp., in vitro antifungal susceptibility tests showed that this yeast isolate was resistant to micafungin, caspofungin, voriconazole, itraconazole, and fluconazole. We performed DNA sequencing and identified it as B. mokoenaii. B. mokoenaii was persistently isolated from blood cultures taken during combination therapy with liposomal amphotericin B and voriconazole. The patient died of multiorgan failure on day 24. B. mokoenaii can cause severe IFI in immunocompromised patients; however, it may not be correctly identified by routine clinical microbiology testing in a hospital laboratory and DNA sequencing is useful for diagnosis.


Secondary neurogenesis and telencephalic organization in zebrafish and mice: a brief review.
Most zebrafish neurodevelopmental studies have focused on the embryo, which is characterized by primary neurogenesis of mostly transient neurons. Secondary neurogenesis becomes dominant in the hatching larva, when major brain parts are established and begin to differentiate. This developmental period allows for a comparative analysis of zebrafish brain organization with amniotes at equivalent stages of neurogenesis. Within a particular time window, the early forebrains of mice (Embyronic stage [E] 12.5/13.5 days [d]) and zebrafish (3 d) reveal highly comparable expression patterns of genes involved in neurogenesis, for example proneural and other transcription factors (Neurogenin1, NeuroD, Mash1/Zashla and Pax6). Further topological correspondences are seen in the expression of LIM and homeobox genes, such as Lhx6/7, Tbr2 and Dlx2a. When this analysis is extended to gamma-aminobutyric acid/glutamic acid decarboxylase (GABA/GAD) cell patterns during this critical time window, an astonishing degree of similarity between the two species is again seen, for example regarding the presence of GABA/GAD cells in the subpallium, with the pallium only starting to be invaded by such cells from the subpallium. Furthermore, the expression of proneural and other genes correlates with GABA cell patterns (e.g. Mash1/Zash1a gene expression in GABA-positive and Neurogenin1/NeuroD in GABA-negative telencephalic regions) in mice and zebrafish. Data from additional vertebrates, such as Xenopus, are also highly consistent with this analysis. Therefore, the vertebrate forebrain appears to undergo a phylotypic stage of secondary neurogenesis, characterized by regionally separated GABAergic (inhibitory) versus glutamatergic (excitatory) cell production sites, which are obscured later in development by tangential migration. This period is highly advantageous for molecular neuroanatomical cross-species comparisons.


Modeling the behavior of confined colloidal particles under shear flow.
We investigate the behavior of colloidal suspensions with different volume fractions confined between parallel walls under a range of steady shears. We model the particles using molecular dynamics (MD) with full hydrodynamic interactions implemented through the use of a lattice-Boltzmann (LB) fluid. A quasi-2d ordering occurs in systems characterized by a coexistence of coupled layers with different densities, order, and granular temperature. We present a phase diagram in terms of shear and volume fraction for each layer, and demonstrate that particle exchange between layers is required for entering the disordered phase.


Corneal retardation time as an ocular hypertension disease indicator.
Objective.A detailed analysis of the corneal retardation timeτas a highly related parameter to the intraocular pressure (IOP), and its plausible role as an indicator of ocular hypertension disease.Approach.A simple theoretical expression forτis derived within the corneal viscoelastic model of Kelvin-Voigt with 3 elements. This retardation time can be easily calculated from the well-known signal and pressure amplitudes of non-contact tonometers like the Ocular Response Analyzer (ORA). Then, a population-based study was performed where 100 subjects aged from 18 to 30 were analyzed (within this group, about 10% had an elevated IOP with more than 21 mmHg).Main results.A clear relationship between the corneal retardation time and the corneal-compensated intraocular pressure (IOPcc) was found, underlying the risk for ocular hypertensive (OHT) subjects with lowerτvalues to develop hypertension illnesses (due to the inability of poorly viscoelastic corneas to absorb IOP fluctuations, resulting in probable optic nerve damage).Significance.Our results might provide an useful tool to systematically discern which OHT patients (and even those with normal IOP values) are more likely to suffer glaucoma progression and, consequently, ensure an early diagnosis.


[Effect of cardioactive compounds on myocardial actomyosin in the centrifuged rat].
It has been shown that during centrifugation the modulating effect of cardioactive compounds, particularly adrenalin and obsidan, varies in similarity to that of Ca ions. The reactivity of the native actomyosin complex of the heart of white rats to such agents declines during centrifugation. This may be associated with changes in regulatory protein components through which the modulating effect of the above compounds is mediated. Differences in the reactivity to adrenalin and obsidan that persist after 2-month readaptation can be attributed to the heterogeneous recovery of properties of individual subunits of regulatory proteins.


[Nocturnal changes in cortisol, catecholamines, cAMP and histamine in children with nocturnal bronchial asthma and in healthy children].
We analyzed the concentration of plasma epinephrine, norepinephrine, dopamine and C-AMP and urinary cortisol, histamine and creatinine in 28 children over a period from 4 p.m. to 8 a.m. 15 children were suffering from nocturnal asthma, 13 had no asthma problems. The cortisol-levels of both, the asthmatic and the healthy children were almost identical, the minimum cortisol-concentrations were found at 8 p.m. The concentration of plasma epinephrine in the asthmatic children was significantly higher than in the control group. Both groups showed minimum levels at 12 p.m. Plasma norepinephrine showed a continuous course with a raise in the early morning hours in both groups. Children without asthma had a continuous decrease of norepinephrine during the sleeping period and an increase in the early morning. Dopamine was significantly lower in the asthmatics. C-AMP was also on a lower level, but the difference between both groups was not significant. Histamine showed an extreme variability in the asthmatic children and was on higher levels during the whole period compared to the control group. The raised epinephrine levels in children with nocturnal asthma could be understood as compensation to a dysfunction of the receptor-transducer-adenylcyclase-complex of beta 2-receptors. A reduction of beta 2-receptors by anti-asthmatic therapy could also be responsible for these epinephrine levels. The significant difference in dopamine levels between children with and without nocturnal asthma is poorly understood. The increase of epinephrine and the decrease of dopamine could be caused by a modulated synthesis of catecholamines in children suffering from nocturnal asthma.


[Efficiency and safety of rhinoseptoplasty in childhood].
180 children were examined and operated for deformation of the nasal ceptum (NS). By intensity of NS growth, three age groups were distinguished: 5-7 years of age (12.7%), 8-13 years (34.4%), 14-15 years (52.9%). External and constitutional signs, characteristic complex of otorhinolaryngological and general symptoms, concomitant and complicating diseases in such children are described as well as methods of correction and plastic repair of nasal septum deformation in children. A total of 265 operations were made. The operations were effective not only in reestablishment of free nasal breathing but also for improvement of functional nasal indices, sharp reduction of the number of concomitant diseases, general conditioning. In the presence of indications, deformation of the NS should be operated in early childhood with consideration of the age specific features of NS growth, it is not necessary to wait for older age and stopping of face skeleton growth.