Preservation of left ventricular mechanical function and energy metabolism in rats after myocardial infarction by the angiotensin-converting enzyme inhibitor quinapril.
We tested whether angiotensin-converting enzyme (ACE) inhibitor therapy with quinapril prevents the deterioration of mechanical function and high-energy phosphate metabolism that occurs in chronically infarcted heart. Rats were subjected to ligation of the left anterior descending coronary artery (LAD) or sham operation. Four groups were studied: sham-operated rats (n = 10), rats with myocardial infarction (MI, n = 9), sham-operated quinapril-treated rats (n = 8), and infarcted quinapril-treated (n = 13) rats. Treated rats received 6 mg/kg/day of the ACE inhibitor quinapril orally, initiated 1 h after MI or sham operation. Eight weeks after LAD ligation or sham operation, hearts were isolated and buffer-perfused isovolumically. High-energy phosphate metabolism and intracellular pH were continuously recorded with 31P-nuclear magnetic resonance (NMR) spectroscopy. Hearts were subjected to 15-min control, 30-min hypoxia (95% N2/5% CO2, and 30-min reoxygenation. Left ventricular developed pressure (LVDP) was reduced in infarcted hearts (58 +/- 10 vs. 98 +/- 9 mm Hg in sham, p < 0.05), and this reduction was partially prevented by quinapril (78 +/- 8 mm Hg). ATP content of residual intact myocardium after sham operation or MI was unchanged. Creatine phosphate was reduced in infarcted hearts (107 +/- 10 vs. 138 +/- 5% of control ATP, p < 0.05), and quinapril prevented this decrease (131 +/- 8%). Therefore, quinapril preserved both function and high-energy phosphate metabolism in the chronically infarcted heart. However, when hearts were subjected to acute hypoxia, susceptibility to acute metabolic stress was substantially increased in both quinapril-treated groups: ATP content at end-hypoxia was reduced to 31 +/- 7 and 37 +/- 6% in sham and infarcted quinapril-treated groups, whereas ATP in untreated sham and infarcted hearts was 66 +/- 6 and 66 +/- 3% of baseline values (p < 0.05 untreated vs. quinapril treated). Likewise, recovery of LVDP during reoxygenation was impaired by quinapril treatment (15 +/- 7 and 15 +/- 4 mm Hg in quinapril-treated sham and MI vs. 73 +/- 9 and 46 +/- 9 mm Hg in untreated sham and MI groups, p < 0.05 untreated vs. quinapril treated). The most likely explanation for the unexpected finding of increased susceptibility to acute metabolic stress in the quinapril-treated groups is reduced wall thickness leading to increased wall stress. The preservation of high-energy phosphate content in residual intact hearts after MI may contribute to the beneficial effects of ACE inhibitors after MI.


Antioxidative and antiproliferative activities of different horsetail (Equisetum arvense L.) extracts.
In this study we investigated antioxidative and antiproliferative activity of different horsetail (Equisetum arvense L.) extracts. The antioxidative activity was measured by the electron spin resonance (ESR) spectroscopy-spin trapping method. The influence of different horsetail extracts during lipid peroxidation of (1) sunflower oil induced by the lipophilic azo-initiator 4,4'-azobis(4-cyanovaleric acid) and (2) soybean phosphatidylcholine liposomes induced by the hydrophilic azo-initiator 2,2'-azobis(2-amidinopropane) dihydrochloride was studied. Antiproliferative activity was measured using the sulforhodamine B colorimetric assay on the human cancer cell lines HeLa, HT-29, and MCF7. The results of ESR analysis confirmed that the extracts investigated suppressed the formation of lipid peroxyl radicals in both systems investigated in a dose-dependent manner. The results indicate that n-butanol, methanol, ethyl acetate, and water extracts had significant peroxyl radical scavenging activity. Extracts inhibited cell growth that was dependent on cell line, type of extract, and extract concentration. Ethyl acetate extract exhibited the most prominent antiproliferative effect, without inducing any cell growth stimulation on human tumor cell lines. The results obtained suggest that the horsetail extracts could be used as an easily accessible source of natural antioxidants and as potential phytochemicals.


Development and technical functionality of an Internet-based intervention for tinnitus in the UK.
Creative approaches to improve access to evidence-based tinnitus treatments are required. The purpose of this study was to develop an Internet-based cognitive behavioural therapy (iCBT) intervention, for those experiencing tinnitus in the United Kingdom (UK). Furthermore, it aimed, through technical functionality testing, to identify specific aspects of the iCBT that require improving. An innovative iCBT intervention for treating tinnitus in the UK has been developed using a cognitive-behavioural theoretical framework. This iCBT was evaluated by two user groups during this developmental phase. Initially, five expert reviews evaluated the intervention, prior to evaluation by a group of 29 adults experiencing significant levels of tinnitus distress. Both groups evaluated iCBT in an independent measures design, using a specifically designed satisfaction outcome measure. Overall, similar ratings were given by the expert reviewers and adults with tinnitus, showing a high level of satisfaction regarding the content, suitability, presentation, usability and exercises provided in the intervention. The iCBT intervention has been refined following technical functionality testing. Rigorous testing of the developed iCBT intervention has been undertaken. These evaluations provide confidence that further clinical trials can commence in the UK, to assess the feasibility and effectiveness of this iCBT intervention for tinnitus.


High-grade gliomas in children and adolescents: is there a role for reoperation?
Tumors of the CNS are the main causes of childhood cancer and have an incidence that exceeds that of leukemia. In addition, they are the leading causes of cancer-related death in childhood. High-grade gliomas account for 11% of such neoplasms and are characterized by aggressive clinical behavior and high morbidity and mortality. There is a lack of studies focusing on the factors that can prolong survival in these patients or guide therapeutic interventions. The authors aimed to investigate the factors related to longer survival durations, with a focus on reoperation for gross-total resection (GTR). In this retrospective cohort study, the authors analyzed 78 patients diagnosed with high-grade gliomas occurring across all CNS locations except diffuse intrinsic pontine gliomas. Patients 0 to < 19 years of age were followed up at the Pediatric Oncology Institute. Overall survival (OS) and progression-free survival (PFS) were analyzed in the context of various prognostic factors, such as age, sex, histology, extent of tumor resection, reoperation for GTR, adjuvant treatment, and treatment initiation from 2010 onward. With a mean age at diagnosis of 8.7 years, 50% of the patients were female and approximately 39% underwent GTR at some point, which was already achieved in approximately 46% of them in the first surgery. The median OS was 17 months, and PFS was 10 months. In terms of median OS, the authors found no significant difference between those with reoperation for GTR and patients without GTR during treatment. Significant differences were observed in the OS in terms of the extent of resection in the first surgery, age, sex, Ki-67 expression, adjuvant treatment, and treatment initiation from 2010 onward. Furthermore, the PFS values significantly differed between those with GTR in the first surgery and Ki-67 expression ≥ 50%. This study demonstrates the importance of GTR for these neoplasms, highlights the role of surgeons in its achievement in the first attempt, and questions the role of reoperation for this purpose. Finally, this study further supports the use of combined adjuvant treatment for the improvement of OS and PFS.


Direct facility funding as a response to user fee reduction: implementation and perceived impact among Kenyan health centres and dispensaries.
There is increasing pressure for reduction of user fees, but this can have adverse effects by decreasing facility-level funds. To address this, direct facility funding (DFF) was piloted in Coast Province, Kenya, with health facility committees (HFCs) responsible for managing the funds. We evaluated the implementation and perceived impact 2.5 years after DFF introduction. Quantitative data collection at 30 public health centres and dispensaries included a structured interview with the in-charge, record reviews and exit interviews. In addition, in-depth interviews were conducted with the in-charge and HFC members at 12 facilities, and with district staff and other stakeholders. DFF procedures were well established: HFCs met regularly and accounting procedures were broadly followed. DFF made an important contribution to facility cash income, accounting for 47% in health centres and 62% in dispensaries. The main items of expenditure were wages for support staff (32%), travel (21%), and construction and maintenance (18%). DFF was perceived to have a highly positive impact through funding support staff such as cleaners and patient attendants, outreach activities, renovations, patient referrals and increasing HFC activity. This was perceived to have improved health worker motivation, utilization and quality of care. A number of problems were identified. HFC training was reportedly inadequate, and no DFF documentation was available at facility level, leading to confusion. Charging user fees above those specified in the national policy remained common, and understanding of DFF among the broader community was very limited. Finally, relationships between HFCs and health workers were sometimes characterized by mistrust and resentment. Relatively small increases in funding may significantly affect facility performance when the funds are managed at the periphery. Kenya plans to scale up DFF nationwide. Our findings indicate this is warranted, but should include improved training and documentation, greater emphasis on community engagement, and insistence on user fee adherence.


Neural Stimulation and Molecular Mechanisms of Plasticity and Regeneration: A Review.
Neural stimulation modulates the depolarization of neurons, thereby triggering activity-associated mechanisms of neuronal plasticity. Activity-associated mechanisms in turn play a major role in post-mitotic structure and function of adult neurons. Our understanding of the interactions between neuronal behavior, patterns of neural activity, and the surrounding environment is evolving at a rapid pace. Brain derived neurotrophic factor is a critical mediator of activity-associated plasticity, while multiple immediate early genes mediate plasticity of neurons following bouts of neural activity. New research has uncovered genetic mechanisms that govern the expression of DNA following changes in neural activity patterns, including RNAPII pause-release and activity-associated double stranded breaks. Discovery of novel mechanisms governing activity-associated plasticity of neurons hints at a layered and complex molecular control of neuronal response to depolarization. Importantly, patterns of depolarization in neurons are shown to be important mediators of genetic expression patterns and molecular responses. More research is needed to fully uncover the molecular response of different types of neurons-to-activity patterns; however, known responses might be leveraged to facilitate recovery after neural damage. Physical rehabilitation through passive or active exercise modulates neurotrophic factor expression in the brain and spinal cord and can initiate cortical plasticity commensurate with functional recovery. Rehabilitation likely relies on activity-associated mechanisms; however, it may be limited in its application. Electrical and magnetic stimulation direct specific activity patterns not accessible through passive or active exercise and work synergistically to improve standing, walking, and forelimb use after injury. Here, we review emerging concepts in the molecular mechanisms of activity-derived plasticity in order to highlight opportunities that could add value to therapeutic protocols for promoting recovery of function after trauma, disease, or age-related functional decline.


Renoprotective effect of human umbilical cord-derived mesenchymal stem cells in immunodeficient mice suffering from acute kidney injury.
It is unknown whether human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) can improve the renal function of patients suffering from acute kidney injury. Moreover, before beginning clinical trials, it is necessary to investigate this renoprotective effect of hUC-MSCs in a xenogeneic model of acute kidney injury. However, no previous studies have examined the application of hUC-MSCs to immunodeficient mice suffering from acute kidney injury. The objectives of this study were to examine whether hUC-MSCs could improve renal function in nonobese diabetic-severe combined immune deficiency (NOD-SCID) mice suffering from acute kidney injury, and to investigate the mechanism(s) for hUC-MSCs to improve renal function in this xenogeneic model. Early (3 hr) and late (12 hr) administrations of hUC-MSCs (10(6) cells) were performed via the external jugular vein into NOD-SCID mice suffering from either folic acid (FA) (250 mg/kg body weight) or vehicle. The results showed that early administration of hUC-MSCs improved the renal function of NOD-SCID mice suffering from FA-induced acute kidney injury, as evidenced by decreased serum urea nitrogen and serum creatinine levels, as well as a reduced tubular injury score. The beneficial effects of hUC-MSCs were through reducing apoptosis and promoting proliferation of renal tubular cells. These benefits were independent of inflammatory cytokine effects and transdifferentiation. Furthermore, this study is the first one to show that the reduced apoptosis of renal tubular cells by hUC-MSCs in this xenogeneic model is mediated through the mitochondrial pathway, and through the increase of Akt phosphorylation.


How local community knowledge about malaria affects insecticide-treated net use in northern Ghana.
Large-scale trials of insecticide-treated nets (ITNs) throughout Sub-Saharan Africa demonstrated that they reduce child mortality in malaria endemic communities. These encouraging results have generated interest in ITNs as a viable malaria control strategy in many malaria endemic countries. However, regular use of ITNs under routine or non-project conditions has been beset with several problems. This paper explores how local community knowledge about malaria acts as a barrier to the use of ITNs in three settings. We employed structured formal observation and a range of interviewing techniques which included informal interviews, focus group discussions, semi-structured in-depth interviews, and structured survey interviewing. People recognize the term 'malaria' but have limited biomedical knowledge of the disease, including its aetiology, the role of the vector, and host response. Convulsions and anaemia are rarely linked to malaria. The people acknowledged a role for ITNs in nuisance reduction, but not for malaria prevention.


A dose- rather than delivery profile-dependent mechanism regulates the "muscle-full" effect in response to oral essential amino acid intake in young men.
The anabolic response of skeletal muscle to essential amino acids (EAAs) is dose dependent, maximal at modest doses, and short lived, even with continued EAA availability, a phenomenon termed "muscle-full." However, the effect of EAA ingestion profile on muscle metabolism remains undefined. We determined the effect of Bolus vs. Spread EAA feeding in young men and hypothesized that muscle-full is regulated by a dose-, not delivery profile-, dependent mechanism. We provided 16 young healthy men with 15 g mixed-EAA, either as a single dose ("Bolus"; n = 8) or in 4 fractions at 45-min intervals ("Spread"; n = 8). Plasma insulin and EAA concentrations were assayed by ELISA and ion-exchange chromatography, respectively. Limb blood flow by was determined by Doppler ultrasound, muscle microvascular flow by Sonovue (Bracco) contrast-enhanced ultrasound, and phosphorylation of mammalian target of rapamycin complex 1 substrates by immunoblotting. Intermittent muscle biopsies were taken to quantify myofibrillar-bound (13)C6-phenylalanine to determine muscle protein synthesis (MPS). Bolus feeding achieved rapid insulinemia (13.6 μIU · mL(-1), 25 min after commencement of feeding), aminoacidemia (∼2500 μM at 45 min), and capillary recruitment (+45% at 45 min), whereas Spread feeding achieved attenuated insulin responses, gradual low-amplitude aminoacidemia (peak: ∼1500 μM at 135 min), and no detectable capillary recruitment (all P < 0.01 vs. Bolus). Despite these differences, identical anabolic responses were observed; fasting fractional synthetic rates of 0.054% · h(-1) (Bolus) and 0.066% · h(-1) (Spread) increased to 0.095% and 0.104% · h(-1) (no difference in increment or final values between regimens). With both Spread and Bolus feeding strategies, a latency of at least 90 min was observed before an upswing in MPS was evident. Similarly with both feeding strategies, MPS returned to fasting rates by 180 min despite elevated circulating EAAs. These data do not support EAA delivery profile as an important determinant of anabolism in young men at rest, nor rapid aminoacidemia/leucinemia as being a key factor in maximizing MPS. This trial was registered at clinicaltrials.gov as NCT01735539.


Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources.
Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. A nested case-control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009-2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13-1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19-0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20-1.07), and for the secondary (OR 0.40; CI 0.05-3.11) and tertiary (OR 0.79; CI 0.50-1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.


Adolescent fertility and family planning in East Asia and the Pacific: a review of DHS reports.
Adolescent pregnancy has significant health and socio-economic consequences for women, their families and communities. Efforts to prevent too-early pregnancy rely on accurate information about adolescents' knowledge, behaviours and access to family planning, however available data are limited in some settings. Demographic and Health Survey (DHS) reports are recognised as providing nationally representative data that are accessible to policymakers and programmers. This paper reviews DHS reports for low and lower middle income countries in East Asia and the Pacific to determine what information regarding adolescent fertility and family planning is available, and summarises key findings. The most recent DHS reports were sought for the 33 low and lower middle income countries in the East Asia and Pacific region as defined by UNICEF and World Bank. Age-disaggregated data for all indicators relevant to fertility and current use, knowledge and access to family planning information and services were sought to identify accessible information. Reported data were analysed using an Excel database to determine outcomes for adolescents and compare with adult women. DHS reports were available for eleven countries: Cambodia, Indonesia, Marshall Islands, Nauru, Papua New Guinea, Philippines, Samoa, Solomon Islands, Timor-Leste, Tuvalu and Vietnam. Twenty seven of 40 relevant DHS indicators reported outcomes for adolescent women aged 15-19 years. There were limited data for unmarried adolescents. A significant proportion of women commence sexual activity and childbearing during adolescence in the context of low contraceptive prevalence and high unmet need for contraception. Adolescent women have lower use of contraception, poorer knowledge of family planning and less access to information and services than adult women. DHS reports provide useful and accessible data, however, they are limited by the failure to report data for unmarried adolescents and report age-disaggregated data for some indicators. Further research is required to better understand the barriers that both married and unmarried adolescents face accessing reproductive health information and services, and their information and service delivery preferences.


Sensory gating deficits in the attenuated psychosis syndrome.
Individuals with an "Attenuated Psychosis Syndrome" (APS) have a 20-40% chance of developing a psychotic disorder within two years; however it is difficult to predict which of them will become ill on the basis of their clinical symptoms alone. We examined whether P50 gating deficits could help to discriminate individuals with APS and also those who are particularly likely to make a transition to psychosis. 36 cases meeting PACE (Personal Assessment and Crisis Evaluation) criteria for the APS, all free of antipsychotics, and 60 controls performed an auditory conditioning-testing experiment while their electroencephalogram was recorded. The P50 ratio and its C-T difference were compared between groups. Subjects received follow-up for up to 2 years to determine their clinical outcome. The P50 ratio was significantly higher and C-T difference lower in the APS group compared to controls. Of the individuals with APS who completed the follow-up (n=36), nine (25%) developed psychosis. P50 ratio and the C-T difference did not significantly differ between those individuals who developed psychosis and those who did not within the APS group. P50 deficits appear to be associated with the pre-clinical phase of psychosis. However, due to the limitations of the study and its sample size, replication in an independent cohort is necessary, to clarify the role of P50 deficits in illness progression and whether this inexpensive and non-invasive EEG marker could be of clinical value in the prediction of psychosis outcomes amongst populations at risk.


Income-related inequality in health and health care utilization in Chile, 2000-2009.
To measure and explain income-related inequalities in health and health care utilization in the period 2000 - 2009 in Chile, while assessing variations within the country and determinants of inequalities. Data from the National Socioeconomic Characterization Survey for 2000, 2003, and 2009 were used to measure inequality in health and health care utilization. Income-related inequality in health care utilization was assessed with standardized concentration indices for the probability and total number of visits to specialized care, generalized care, emergency care, dental care, mental health care, and hospital care. Self-assessed health status and physical limitations were used as proxies for health care need. Standardization was performed with demographic and need variables. The decomposition method was applied to estimate the contribution of each factor used to calculate the concentration index, including ethnicity, employment status, health insurance, and region of residence. In Chile, people in lower-income quintiles report worse health status and more physical limitations than people in higher quintiles. In terms of health service utilization, pro-rich inequities were found for specialized and dental visits with a slight pro-rich utilization for general practitioners and all physician visits. All pro-rich inequities have decreased over time. Emergency room visits and hospitalizations are concentrated among lower-income quintiles and have increased over time. Higher education and private health insurance contribute to a pro-rich inequity in dentist, general practitioner, specialized, and all physician visits. Income contributes to a pro-rich inequity in specialized and dentist visits, whereas urban residence and economic activity contribute to a pro-poor inequity in emergency room visits. The pattern of health care utilization in Chile is consistent with policies implemented in the country and in the intended direction. The significant income inequality in the use of specialized and dental services, which favor the rich, deserves policy makers' attention and further investigation related to the quality of these services.


The alkaloid rutaecarpine is a selective inhibitor of cytochrome P450 1A in mouse and human liver microsomes.
Rutaecarpine, evodiamine, and dehydroevodiamine are quinazolinocarboline alkaloids isolated from a traditional Chinese medicine, Evodia rutaecarpa. The in vitro effects of these alkaloids on cytochrome P450 (P450)-catalyzed oxidations were studied using mouse and human liver microsomes. Among these alkaloids, rutaecarpine showed the most potent and selective inhibitory effect on CYP1A-catalyzed 7-methoxyresorufin O-demethylation (MROD) and 7-ethoxyresorufin O-deethylation (EROD) activities in untreated mouse liver microsomes. The IC(50) ratio of EROD to MROD was 6. For MROD activity, rutaecarpine was a noncompetitive inhibitor with a K(i) value of 39 +/- 2 nM. In contrast, rutaecarpine had no effects on benzo[a]pyrene hydroxylation (AHH), aniline hydroxylation, and nifedipine oxidation (NFO) activities. In human liver microsomes, 1 microM rutaecarpine caused 98, 91, and 77% decreases of EROD, MROD, and phenacetin O-deethylation activities, respectively. In contrast, less than 15% inhibition of AHH, tolbutamide hydroxylation, chlorzoxazone hydroxylation, and NFO activities were observed in the presence of 1 microM rutaecarpine. To understand the selectivity of inhibition of CYP1A1 and CYP1A2, inhibitory effects of rutaecarpine were studied using liver microsomes of 3-methylcholanthrene (3-MC)-treated mice and Escherichia coli membrane expressing bicistronic human CYP1A1 and CYP1A2. Similar to the CYP1A2 inhibitor furafylline, rutaecarpine preferentially inhibited MROD more than EROD and had no effect on AHH in 3-MC-treated mouse liver microsomes. For bicistronic human P450s, the IC(50) value of rutaecarpine for EROD activity of CYP1A1 was 15 times higher than the value of CYP1A2. These results indicated that rutaecarpine was a potent inhibitor of CYP1A2 in both mouse and human liver microsomes.


Insula mediates heartbeat related effects on visual consciousness.
Interoceptive signals, such as the heartbeat, are processed in a network of brain regions including the insular cortex. Recent studies have shown that such signals modulate perceptual and cognitive processing, and that they impact visual awareness. For example, visual stimuli presented synchronously to the heartbeat take longer to enter visual awareness than the same stimuli presented asynchronously to the heartbeat, and this is reflected in anterior insular activation. This finding demonstrated a link between the processing of interoceptive and exteroceptive signals as well as visual awareness in the insular cortex. The advantage for visual stimuli which are asynchronous to the heartbeat to enter visual consciousness may indicate a role for the anterior insula in the suppression of the sensory consequences of cardiac signals. Here, we present data from the detailed investigation of two patients with insular lesions (as well as four patients with non-insular lesions and healthy age matched controls) indicating that a lesion of the anterior insular cortex, but not of other regions, abolished this cardio-visual suppression effect. The present data provide causal evidence for the role of the anterior insula in the integration of internal interoceptive and external sensory signals for visual awareness.


Dietary supplements, nutraceuticals and functional foods use after myocardial infarction depend on the age, sex, BMI and professional activity - a pilot study.
To assess dietary supplements, functional foods and nutraceuticals use among the patients after myocardial infarction (MI). The authors prospectively enrolled 100 consecutive patients hospitalized due to MI and remaining under coordinated outpatient care after MI in the authors' cardiology department. The authors showed that patients within median (interquartile range) 12.30 (10.18-14.57) months after MI use dietary supplements, nutraceuticals and functional foods in their everyday diet. Vitamins (53% patients), especially vitamin D (35%), were the most frequently used dietary supplements. In contrary to common usage of dietary supplements (59%), smaller proportion of patients use functional foods (21%) and nutraceuticals (5%), especially phytosterols. The authors found that the use of over-the-counter (OTC) drugs and dietary supplements is associated with age (participants <60 years old vs. participants ≥60 years old: OTC drugs: N = 8 [20.0%] vs. N = 32 [53.3%], p < 0.001; herbals: N = 3 [7.5%] vs. N = 16 [26.7%], p = 0.019), sex of the patients following MI (females vs. males: vitamins: N = 17 [70.8%] vs. N = 36 [47,4%], p = 0.045; vitamin D: N = 13 [54.2%] vs. N = 22 [28.9%], p = 0.024; omega-3 fatty acids: N = 3 [12.5%] vs. N = 1 [1.3%], p = 0.042; herbals: N = 8 [33.3%] vs. N = 11[14.5%], p = 0.040), as well as the BMI of the participants (BMI < 24.9 vs. BMI ≥ 25.0: multivitamin/ multimineral dietary supplements: N = 3 [15.0%] vs. N = 31 [42.5%], p = 0.035; vitamin B6: N = 1 [5.0%] vs. N = 21 [28.8%], p = 0.035). In the study group all participants with the age above retirement age have already withdrawn from professional activity and they more often used OTC drugs (N = 14 [25.9%] before retirement age vs. N = 26 [56.5%] above retirement age, p = 0.002). The patients following MI use supplements, functional foods and nutraceuticals. Their use depends on sex, age, BMI and professional activity. The authors believe that their potential beneficial effects require further evaluation in clinical longitudinal studies. Int J Occup Med Environ Health. 2023;36(6).


Intermittent testicular torsion: diagnostic features and management outcomes.
Intermittent testicular torsion (ITT) is a poorly characterized condition but harbors potentially serious implications with regard to testicular viability. We report better characterization of the diagnostic features of ITT. We performed a retrospective review of all patients 1 to 18 years old seen from 1997 to 2003 at our institution diagnosed with ITT. Patients with acute scrotal pain and spontaneous resolution who underwent bilateral testicular fixation were included in the study. A total of 50 patients meeting the inclusion criteria were identified with mean age at presentation of 12.2 years (range 4 to 17). The mean number of painful episodes before surgery was 4.3 (range 1 to 30). The most common presenting features were severe pain of rapid onset and resolution. Nausea and/or vomiting was reported in a quarter of the patients. Finding of a horizontal lie of the testes on examination was significantly associated (p <0.05) with the existence of the bell-clapper deformity. All patients underwent surgical fixation of the testes. There were no postoperative complications. Of 38 patients (97%) for whom followup was available 37 had complete resolution of symptoms (mean followup 7.9 months). ITT should be a diagnostic consideration in patients who present with recurrent acute scrotal pain with rapid spontaneous resolution. Recurrent severe pain with rapid onset and resolution seems to be highly characteristic. Horizontal lie on examination is highly correlated with the bell-clapper deformity at surgical exploration. Surgery may be recommended in these patients as it appears to result in pain relief in the majority, is likely to prevent future testicular infarction and is associated with low morbidity.


Exposure of pregnant mice to carbon black by intratracheal instillation: toxicogenomic effects in dams and offspring.
Exposure to nanomaterials (NM) during sensitive developmental stages may predispose organisms to diseases later in life. However, direct translocation of NM from mother to fetus through the placenta is limited. The present study tests the hypothesis that pulmonary exposure to NM and NM-induced response, such as inflammation during gestation, leads to secondary effects in the fetus. Time-mated C57BL/6BomTac mice were exposed by intratracheal instillation to vehicle (Nanopure water) or one of three concentrations (2.75, 13.5 or 67 μg in 40 μl Nanopure water) of carbon black Printex 90 (CB) on gestational days 7, 10, 15 and 18, to final cumulative doses of 11, 54 or 268 μg/animal. Samples from a subset of male and female newborns were collected on postnatal day 2 (4 days after the last maternal exposure) and from dams 26 to 27 days post-exposure (post-weaning period). Histopathology, DNA microarrays, pathway-specific RT-PCR arrays, focussed RT-PCR, and tissue protein analysis were employed to characterize pulmonary response in dams exposed to CB during pregnancy. Hepatic gene expression in newborns was interpreted in light of the observed biological responses and gene expression changes arising in the lungs of dams following CB exposure. Although retention of CB particles was observed in dams from both the medium and the high dose groups, neutrophil-marked inflammation and altered expression of several cytokines and chemokines, both at the transcriptional and tissue protein levels, was significant only in the high dose group. Analysis of newborn livers by DNA microarrays revealed that female offspring were more sensitive to maternal exposure than male offspring. Cellular signalling, inflammation, cell cycle and lipid metabolism were among the biological pathways affected in female offspring. Males, however, responded with subtle changes in metabolism-related genes. Further investigation is required to determine the long-term health consequences of the gene expression changes in offspring and response to environmental stresses.


Immigrant women's views about care during labor and birth: an Australian study of Vietnamese, Turkish, and Filipino women.
Few studies of immigrant women's views of maternity care in their new homelands have been conducted. In Victoria, Australia, approximately 1 woman in 7 giving birth was born overseas in a non-English speaking country. This paper examines the views of three groups of immigrant women about the care they received in hospital for the birth of their babies and compares the findings with a population-based statewide survey. Mothers in a New Country was a study of 318 Vietnamese, Turkish, and Filipino women interviewed about their maternity care experiences by bicultural interviewers 6 months after giving birth in Melbourne, Australia. The interview schedule was adapted from the 1994 Victorian Survey of Recent Mothers, a population-based postal survey of 1336 women. Of the 3 groups, 27 percent of Vietnamese, 48 percent of Turkish, and 39 percent of Filipino women reported their care during labor and birth as "very good," figures significantly lower than for the statewide survey, in which 61 percent of women experiencing similar models of care described their care as "very good." This significant differential in views about care was also present for many individual aspects of care. In the current study of mothers in a new country, comments about aspects of care with which women were particularly happy and unhappy highlighted their appreciation of care that was safe, kind, supportive, and respectful, and conversely, illustrated how distressed women were when care failed to meet these basic standards. What immigrant women wanted from their maternity care proved to be extremely similar to what Australian-born women--and women the world over--want. Unfortunately, immigrant women were much less likely to experience care that gave them what they wanted.


Relative contributions of archaea and bacteria to aerobic ammonia oxidation in the environment.
Traditionally, organisms responsible for major biogeochemical cycling processes have been determined by physiological characterization of environmental isolates in laboratory culture. Molecular techniques have, however, confirmed the widespread occurrence of abundant bacterial and archaeal groups with no cultivated representative, making it difficult to determine their ecosystem function. Until recently, ammonia oxidation, the first step in the globally important process of nitrification, was thought to be performed almost exclusively by bacteria. Metagenome studies, followed by laboratory isolation, then demonstrated the potential for significant ammonia oxidation by mesophilic crenarchaea, whose ecosystem function was previously unknown. Re-assessment of the role of bacteria in ammonia oxidation is now required and this article reviews the current evidence for the relative importance of bacteria and archaea. Much of this evidence is based on metagenomic analysis and molecular techniques for estimation of gene and gene transcript abundance, changes in ammonia oxidizer community structure during active nitrification and phylogeny of natural communities. These studies have been complemented by physiological characterization of a laboratory isolate and by incorporation of labelled substrates. Data from these studies provide increasingly convincing evidence for the importance of archaeal ammonia oxidizers in the global nitrogen cycle. They also highlight the need to re-assess the importance of ammonia-oxidizing bacteria, the requirement and limitations of molecular techniques in linking specific microbial groups to ecosystem function and the limitations of reliance on laboratory cultures.


L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis.
Hepatic encephalopathy is a common complication of cirrhosis and has high associated morbidity and mortality. The condition is classified as overt if it is clinically apparent or minimal if only evident though psychometric testing. The exact pathogenesis of this syndrome is unknown although ammonia is thought to play a key role. L-ornithine L-aspartate has ammonia-lowering properties and may, therefore, benefit people with cirrhosis and hepatic encephalopathy. To evaluate the beneficial and harmful effects of L-ornithine L-aspartate versus placebo, no intervention, or other active interventions in people with cirrhosis and hepatic encephalopathy. We undertook electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS and Science Citation Index Expanded to December 2017 and manual searches of meetings and conference proceedings; checks of bibliographies; and corresponded with investigators and pharmaceutical companies. We included randomised clinical trials, irrespective of publication status, language, or blinding. We included participants with cirrhosis who had minimal or overt hepatic encephalopathy or who were at risk for developing hepatic encephalopathy. We compared: L-ornithine L-aspartate versus placebo or no intervention; and L-ornithine L-aspartate versus other active agents such as non-absorbable disaccharides, antibiotics, probiotics, or branched-chain amino acids. Two review authors, working independently, retrieved data from published reports and correspondence with investigators and pharmaceutical companies. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented the results as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed bias control using the Cochrane Hepato-Biliary Group domains; we evaluated the risk of publication bias and other small trial effects in regression analyses; conducted subgroup and sensitivity analyses; and performed Trial Sequential Analyses. We determined the quality of the evidence using GRADE. We identified 36 randomised clinical trials, involving at least 2377 registered participants, which fulfilled our inclusion criteria including 10 unpublished randomised clinical trials. However, we were only able to access outcome data from 29 trials involving 1891 participants. Five of the included trials assessed prevention, while 31 trials assessed treatment. Five trials were at low risk of bias in the overall assessment of mortality; one trial was at low risk of bias in the assessment of the remaining outcomes.L-ornithine L-aspartate had a beneficial effect on mortality compared with placebo or no intervention when including all trials (RR 0.42, 95% CI 0.24 to 0.72; I2 = 0%; 19 trials; 1489 participants; very low quality evidence), but not when the analysis was restricted to the trials at low risk of bias (RR 0.47, 95% CI 0.06 to 3.58; 4 trials; 244 participants). It had a beneficial effect on hepatic encephalopathy compared with placebo or no intervention when including all trials (RR 0.70, 95% CI 0.59 to 0.83; 22 trials; 1375 participants; I2 = 62%; very low quality evidence), but not in the one trial at low risk of bias (RR 0.96, 95% CI 0.85 to 1.07; 63 participants). The analysis of serious adverse events showed a potential benefit of L-ornithine L-aspartate when including all randomised clinical trials (RR 0.63, 95% CI 0.45 to 0.90; 1 trial; 1489 participants; I2 = 0%; very low quality evidence), but not in the one trial at low risk of bias for this outcome (RR 0.83, 95% CI 0.15 to 4.65; 63 participants). The Trial Sequential Analyses of mortality, hepatic encephalopathy, and serious adverse events found insufficient evidence to support or refute beneficial effects. Subgroup analyses showed no difference in outcomes in the trials evaluating evaluating the prevention or treatment of either overt or minimal hepatic encephalopathy or trials evaluating oral versus intravenous administration We were unable to undertake a meta-analysis of the three trials involving 288 participants evaluating health-related quality of life. Overall, we found no difference between L-ornithine L-aspartate and placebo or no intervention in non-serious adverse events (RR 1.15, 95% CI 0.75 to 1.77; 14 trials; 1076 participants; I2 = 40%). In comparison with lactulose, L-ornithine L-aspartate had no effect on mortality (RR 0.68, 95% CI 0.11 to 4.17; 4 trials; 175 participants; I2 = 0%); hepatic encephalopathy (RR 1.13, 95% CI 0.81 to 1.57); serious adverse events (RR 0.69, 95% CI 0.22 to 2.11); or non-serious adverse events (RR 0.05, 95% CI 0.01 to 0.18). In comparison with probiotics, L-ornithine L-aspartate had no effect on mortality (RR 1.01, 95% CI 0.11 to 9.51); serious adverse events (RR 1.07, 95% CI 0.23 to 4.88); or changes in blood ammonia concentrations from baseline (RR -2.30 95% CI -6.08 to 1.48), but it had a possible beneficial effect on hepatic encephalopathy (RR 0.71, 95% CI 0.56 to 0.90). Finally, in comparison with rifaximin, L-ornithine L-aspartate had no effect on mortality (RR 0.33, 95% CI 0.04 to 3.03; 2 trials; 105 participants); hepatic encephalopathy (RR 1.06, 95% CI 0.57 to 1.96); serious adverse events (RR 0.32, 95% CI 0.01 to 7.42), or non-serious adverse events (RR 0.32, 95% CI 0.01 to 7.42). The results of this review suggest a possible beneficial effect of L-ornithine L-aspartate on mortality, hepatic encephalopathy, and serious adverse events in comparisons with placebo or no-intervention, but, because the quality of the evidence is very low, we are very uncertain about these findings. There was very low quality evidence of a possible beneficial effect of L-ornithine L-aspartate on hepatic encephalopathy, when compared with probiotics, but no other benefits were demonstrated in comparison with other active agents. Additional access to data from completed, but unpublished trials, and new randomised placebo-controlled, double-blind clinical trials are needed.


Negative entropy of mixing for vanadium-platinum solutions.
The phonon densities of states for pure vanadium and the solid solutions V-6.25% Ni, Pd, Pt were determined from inelastic neutron scattering measurements. The solute atoms caused a large stiffening of the phonons, resulting in large, negative vibrational entropies of mixing. For V-6.25%Pt, the negative vibrational entropy of mixing exceeds the conventional positive chemical entropy of mixing. This negative total entropy of mixing should extend to lower concentrations of Pt, and the effect on the bcc solvus line is discussed. The experimental data were inverted to obtain interatomic force constants by using a Born-von Kármán model with an iterative optimization algorithm. The stiffening of bonds responsible for the decrease of entropy was found to occur mainly in first-nearest-neighbor solute-host bonds, and correlates in part with the solute metallic radius.


The effect of Gu-Sui-Bu (Drynaria fortunei J. Sm) immobilized modified calcium hydrogenphosphate on bone cell activities.
In our previous study, we have validated the efficacy and the safety of Gu-Sui-Bu [Drynaria fortunei (Kunze) J. Sm.] by the bone cells culture. However, a satisfactory delivery system for Gu-Sui-Bu must be developed before it can be used in clinical medicine. In this study, we try to use modified calcium hydrogenphosphate (MCHP) bioceramic as a carrier to transport Gu-Sui-Bu into the bone cell culture system. Toward this goal, we evaluated the effect of a Gu-Sui-Bu-immobilized modified calcium hydrogenphosphate (GI-MCHP) on the bone cells activities. THE CHINESE MEDICINE: Gu-Sui-Bu [Drynaria fortunei (kunze) J. Sm] was extracted and then immobilized on the surface of MCHP. The rat osteoblasts-osteoclasts co-culture system was used as the experimental model. After the cells grew to 80% confluence, different sizes of GI-MCHP particles were tested. The mitochondria activity of the bone cells after exposure was determined by colorimetric assay. Biochemical markers such as lactate dehydrogenase (LDH), alkaline phosphatase (ALP), acid phosphatase (ACP) and prostaglandin E(2) titer were analyzed to evaluate the bone cells activities. Histomorphometric study of osteoclasts activities and the phenotype expression of osteoblasts were also evaluated. There is no detectable titer of LDH secretion into the medium and no significant change in the intracellular ALP content. The ALP titer in the culture medium did increase significantly at 3 days' culture, while there is a significant decrease in the intracellular ACP content and significant increase in the ACP titer in the medium. The concentrations of PGE(2) in tested medium are always significantly higher than that of control medium during the 7 days' culture. At the end of 7 days' culture, the PGE(2) concentrations in the tested medium were still 4.74 times that of the control medium. After GI-MCHP treatment on bone cells, the size of the osteoclasts seems decreased and their cell integrity seems lost, while the osteoblasts phenotype expression was relatively preserved. From this study, we demonstrated that Gu-Sui-Bu [Drynaria fortunei (Kunze) J. Sm.] immobilized MCHP has well preserved the potential beneficial effects of Gu-Sui-Bu on the bone cells culture.


Left Atrial Appendage Closure with Amplatzer Cardiac Plug in Nonvalvular Atrial Fibrillation: Safety and Long-Term Outcome.
Atrial fibrillation (AF) is a cardiac arrhythmia with high risk for thromboembolic events, specially stroke. To assess the safety of left atrial appendage closure (LAAC) with the Amplatzer Cardiac Plug for the prevention of thromboembolic events in patients with nonvalvular AF. This study included 15 patients with nonvalvular AF referred for LAAC, 6 older than 75 years (mean age, 69.4 ± 9.3 years; 60% of the male sex). The mean CHADS2 score was 3.4 ± 0.1, and mean CHA2DS2VASc , 4.8 ± 1.8, evidencing a high risk for thromboembolic events. All patients had a HAS-BLED score > 3 (mean, 4.5 ± 1.2) with a high risk for major bleeding within 1 year. The device was successfully implanted in all patients, with correct positioning in the first attempt in most of them (n = 11; 73.3%). There was no periprocedural complication, such as device migration, pericardial tamponade, vascular complications and major bleeding. All patients had an uneventful in-hospital course, being discharged in 2 days. The echocardiographic assessments at 6 and 12 months showed neither device migration, nor thrombus formation, nor peridevice leak. On clinical assessment at 12 months, no patient had thromboembolic events or bleeding related to the device or risk factors. In this small series, LAAC with Amplatzer Cardiac Plug proved to be safe, with high procedural success rate and favorable outcome at the 12-month follow-up. (Arq Bras Cardiol. 2017; [online].ahead print, PP.0-0).


Management of Biochemical Recurrence after Primary Curative Treatment for Prostate Cancer: A Review.
How to manage patients with prostate cancer (PCa) with biochemical recurrence (BCR) following primary curative treatment is a controversial issue. Importantly, this prostate-specific antigen (PSA)-only recurrence is a surrogate neither of PCa-specific survival nor of overall survival. Physicians are therefore challenged with preventing or delaying the onset of clinical progression in those deemed at risk, while avoiding over-treating patients whose disease may never progress beyond PSA-only recurrence. Adjuvant therapy for radical prostatectomy (RP) or local radiotherapy (RT) has a role in certain at-risk patients, although it is not recommended in low-risk PCa owing to the significant side-effects associated with RT and androgen deprivation therapy (ADT). The recommendations for salvage therapy differ depending on whether BCR occurs after RP or primary RT, and in either case, definitive evidence regarding the best strategy is lacking. Options for treatment of BCR after RP are RT at least to the prostatic bed, complete or intermittent ADT, or observation; for BCR after RT, salvage RP, cryotherapy, complete or intermittent ADT, brachytherapy, high-intensity focused ultrasound (HIFU), or observation can be considered. Many patient- and cancer-specific factors need to be taken into account when deciding on the best strategy, and optimal management depends on the involvement of a multidisciplinary team, consultation with the patient themselves, and the adoption of an individualised approach. Improvements in imaging techniques may enable earlier detection of metastases, which will hopefully refine future management decisions.


What Are the Indications for Spinal Fusion Surgery in Scheuermann Kyphosis?
Surgical indications for Scheuermann kyphosis are variable. We sought to evaluate the characteristics of patients undergoing operative versus nonoperative treatment of Scheuermann kyphosis to better understand current practices and the factors which contribute to the decision for surgical management. Multicenter prospective cohort study. We evaluated consecutive patients presenting with Scheuermann kyphosis. Patients underwent either surgical or nonoperative management according to surgeon and patient discretion. Preoperative patient-reported outcome measures (Scoliosis Research Society and Spinal Appearance Questionnaire scores), demographics, and radiographic characteristics were assessed. Overall, 150 patients with Scheuermann kyphosis were enrolled, with 77 choosing nonoperative treatment and 73 treated operatively. Compared with the nonoperative cohort, patients treated operatively were older (16.3±2.0 vs. 15.1±2.2, P=0.0004), and had higher body mass index (26.3±7.2 vs. 22.7±6.5, P=0.003), had greater T2-T12 kyphosis (71±14 degrees vs. 61±12 degrees, P<0.001), increased pelvic incidence (46 vs. 41 degrees, P=0.03) and pelvic tilt (10 vs. 3 degrees, P=0.03). There was no detected difference in maximal sagittal Cobb angle in the operative versus nonoperative patients (73±11 vs. 70±12 degrees, P=0.11). Functionally, the operative patients had worse Scoliosis Research Society pain scores (3.7±0.9 vs. 4.1±0.7, P=0.0027) and appearance scores (2.9±0.7 vs. 3.4±0.8, P <0.0001). Patients undergoing surgical management of Scheuermann disease were more likely to have large body mass index and worse pain scores. Other factors beyond radiographic measurement likely contribute to the decision for surgical management of Scheuermann kyphosis. Level II.


Coronary artery perforation and regrowth of a side branch occluded by a polytetrafluoroethylene-covered stent implantation.
Stenting of the right coronary artery stenosis caused coronary perforation and profound dye (blood) extravasation in a 69-year-old female patient. Instantaneous balloon inflation followed by implantation of a polytetrafluoroethylene- (PTFE-)covered stent sealed the coronary perforation, restored the blood flow, and perceivably caused acute occlusion of a large side branch (SB). The immediate in situ balloon inflation prevented the development of cardiac tamponade. Surprisingly, followup coronary angiography 4 and 11 months later showed spontaneous recanalization of the SB occluded by PTFE-covered stent. The SB was filled through a channel beginning at the end of the covered stent streaming retrogradely beneath it toward the SB ostium. Up to the best of our knowledge, this is the first described case of late spontaneous recanalization of as SB occluded by a PTFE-covered stent.


Gene editing for cell engineering: trends and applications.
Gene editing with all its own advantages in molecular biology applications has made easy manipulation of various production hosts with the discovery and implementation of modern gene editing tools such as Crispr (Clustered regularly interspaced short palindromic repeats), TALENs (Transcription activator-like effector nucleases) and ZFNs (Zinc finger nucleases). With the advent of these modern tools, it is now possible to manipulate the genome of industrial production hosts such as yeast and mammalian cells which allows developing a potential and cost effective recombinant therapeutic protein. These tools also allow single editing to multiple genes for knocking-in or knocking-out of a host genome quickly in an efficient manner. A recent study on "multiplexed" gene editing revolutionized the knock-out and knock-in events of yeast and CHO, mammalian cells genome for metabolic engineering as well as high, stable, and consistent expression of a transgene encoding complex therapeutic protein such as monoclonal antibody. The gene of interest can either be integrated or deleted at single or multiple loci depending on the strategy and production requirement. This review will give a gist of all the modern tools with a brief description and advances in genetic manipulation using three major tools being implemented for the modification of such hosts with the emphasis on the use of Crispr-Cas9 for the "multiplexing gene-editing approach" for genetic manipulation of yeast and CHO mammalian hosts that ultimately leads to a fast track product development with consistent, improved product yield, quality, and thus affordability for a population at large.


Mefloquine antimalarial prophylaxis in pregnancy: dose finding and pharmacokinetic study.
1. A dose finding pharmacokinetic study was performed in 20 Karen women in the third trimester of pregnancy receiving antimalarial prophylaxis with mefloquine. Ten received 250 mg mefloquine base weekly and ten received identical tablets of 125 mg base/week. 2. Both dose regimens were well tolerated. Malaria was prevented effectively, there were no serious adverse effects, all pregnancies proceeded normally, and there were no abnormalities in the babies followed up to 2 years. 3. The median time from dose administration to peak whole blood mefloquine concentration was 6 (range 3-24) h. Mean (+/- s.d.) peak and trough concentrations in the seventh week were 722 +/- 279 and 488 +/- 155 ng ml-1 with the 250 mg/week dose, and 390 +/- 81 and 185 +/- 53 ng ml-1 with the 125 mg/week dose regimens respectively. These blood concentration values are lower than those reported previously in non-pregnant adults. 4. One and two compartmental models were fitted to the whole blood concentration-time data. Mean (+/- s.d.) clearance (CL/F) was 0.78 +/- 0.27 ml min-1 kg-1, and the apparent terminal elimination half-life (t1/2) was 11.6 +/- 7.9 days. 5. Further studies to determine the oral bioavailability of mefloquine are needed, but these results suggest that clearance may be increased in late pregnancy. These preliminary results of good efficacy without significant toxicity are encouraging, and a more extensive evaluation of mefloquine antimalarial prophylaxis in pregnancy is now warranted.


We Are Caregivers: Social Identity Is Associated with Lower Perceived Stress among Rural Informal Caregivers.
ABSTRACTInformal caregivers often experience high stress levels with little support, especially in rural settings. With a mixed-methods approach, this research explored experiences of rural informal caregivers, including how social identification as a caregiver, social interactions, and formal and informal coping support related to perceived stress. Major focus group themes (n = 8) included lacking available services, balancing challenges, unmet practical needs, and strong community identity. Survey data (n = 22) revealed that perceived coping support (e.g., having someone to turn to), social interactions, and caregiver identity (e.g., perceiving the role as important to one's self-concept) were associated with lower life upset stress, but only caregiver identity was associated with managing the personal distress and negative feelings associated with caregiving stress. Results suggest that, although available rural services may fall short, other options might alleviate caregiver stress, including facilitating access to coping support, encouraging social interactions, and enhancing caregiver social identity.


A unique framework in BaGa2Sb2: a new Zintl phase with large tunnels.
BaGa2Sb2 was obtained from a direct element combination reaction in a sealed graphite tube at 950 degrees C, and its structure was determined by single-crystal X-ray diffraction methods. It crystallizes in the orthorhombic space group Pnma (No. 62) with a = 25.454(5) A, b = 4.4421(9) A, c = 10.273(6) A, and Z = 8. The anionic [Ga2Sb6/3]2- framework is assembled by the ethane-like dimeric [Sb3Ga-GaSb3] units sharing Sb atoms, forming parallel tunnels with a 26-membered ring cross section. These tunnels are filled with Ba atoms. The three-dimensional [Ga2Sb6/3]2- framework features a new structure type. The compound satisfies the classical Zintl concept. Band structure calculations indicate that the material is a semiconductor, and this is confirmed by spectroscopic experiments which show E(g) approximately 0.35 eV. The calculations also suggest that the structure is stabilized by strong Ga-Ga covalent bonding interactions. Polycrystalline ingots of BaGa2Sb2 show room-temperature electrical conductivity of approximately 65 S/cm and a Seebeck coefficient of +65 muV/K.


Invited review: A position on the Global Livestock Environmental Assessment Model (GLEAM).
The livestock sector is one of the fastest growing subsectors of the agricultural economy and, while it makes a major contribution to global food supply and economic development, it also consumes significant amounts of natural resources and alters the environment. In order to improve our understanding of the global environmental impact of livestock supply chains, the Food and Agriculture Organization of the United Nations has developed the Global Livestock Environmental Assessment Model (GLEAM). The purpose of this paper is to provide a review of GLEAM. Specifically, it explains the model architecture, methods and functionality, that is the types of analysis that the model can perform. The model focuses primarily on the quantification of greenhouse gases emissions arising from the production of the 11 main livestock commodities. The model inputs and outputs are managed and produced as raster data sets, with spatial resolution of 0.05 decimal degrees. The Global Livestock Environmental Assessment Model v1.0 consists of five distinct modules: (a) the Herd Module; (b) the Manure Module; (c) the Feed Module; (d) the System Module; (e) the Allocation Module. In terms of the modelling approach, GLEAM has several advantages. For example spatial information on livestock distributions and crops yields enables rations to be derived that reflect the local availability of feed resources in developing countries. The Global Livestock Environmental Assessment Model also contains a herd model that enables livestock statistics to be disaggregated and variation in livestock performance and management to be captured. Priorities for future development of GLEAM include: improving data quality and the methods used to perform emissions calculations; extending the scope of the model to include selected additional environmental impacts and to enable predictive modelling; and improving the utility of GLEAM output.


A role for cytochrome b5 in the In vivo disposition of anticancer and cytochrome P450 probe drugs in mice.
The role of microsomal cytochrome b5 (Cyb5) in defining the rate of drug metabolism and disposition has been intensely debated for several decades. Recently we described mouse models involving the hepatic or global deletion of Cyb5, demonstrating its central role in in vivo drug disposition. We have now used the cytochrome b5 complete null (BCN) model to determine the role of Cyb5 in the metabolism of ten pharmaceuticals metabolized by a range of cytochrome P450s, including five anticancer drugs, in vivo and in vitro. The extent to which metabolism was significantly affected by the absence of Cyb5 was substrate-dependent; AUC increased (75-245%) and clearance decreased (35-72%) for phenacetin, metoprolol, and chlorzoxazone. Tolbutamide disposition was not significantly altered by Cyb5 deletion, while for midazolam clearance was decreased by 66%. The absence of Cyb5 had no effect on gefitinib and paclitaxel disposition, while significant changes in the in vivo pharmacokinetics were measured for: cyclophosphamide [maximum plasma concentration (Cmax) and terminal half-life increased 55% and 40%, respectively], tamoxifen (AUClast and Cmax increased 370% and 233%, respectively), and anastrozole (AUC and terminal half-life increased 125% and 62%, respectively; clearance down 80%). These data provide strong evidence that both hepatic and extrahepatic Cyb5 levels are an important determinant of in vivo drug disposition catalyzed by a range of cytochrome P450s, including currently prescribed anticancer agents, and that individuality in Cyb5 expression could be a significant determinant in rates of drug disposition in man.


Cascaded Mach-Zehnder wavelength filters in silicon photonics for low loss and flat pass-band WDM (de-)multiplexing.
We present 1-to-8 wavelength (de-)multiplexer devices based on a binary tree of cascaded Mach-Zehnder-like lattice filters, and manufactured using a 90 nm CMOS-integrated silicon photonics technology. We demonstrate that these devices combine a flat pass-band over more than 50% of the channel spacing with low insertion loss of less than 1.6 dB, and have a small device size of approximately 500 × 400 µm. This makes this type of filters well suited for application as WDM (de-)multiplexer in silicon photonics transceivers for optical data communication in large scale computer systems.


Neurotransmitter regulation of the heart in the nudibranch Archidoris montereyensis.
1. The heart of the nudibranch mollusc Archidoris montereyensis is uniquely responsive to regulation by identifiable cardiac motor neurons. The neurotransmitters mediating the strong excitatory and inhibitory actions of the neurons are unknown. 2. In this study we developed an infused, in vitro preparation of the Archidoris heart to determine which of several cardioactive transmitters described in mollusks could affect changes in the rate, amplitude, or tonus of cardiac contractions. Several neurotransmitters we tested increased the rate and amplitude of heart contractions, including serotonin (threshold < 10 nM), dopamine (100 nM), and the neuropeptides R15 alpha 2 (3 nM), small cardioactive peptide B (10 nM), and FMRFamide (20 microM). Myomodulin also excited the heart (0.8 microM) and potentiated the cardioexcitatory action of serotonin at subthreshold concentrations. 3. Only acetylcholine (10 nM) inhibited the heart, decreasing the rate, amplitude, and tonus of contraction. Glycine and the peptides substance P and R15 alpha 1 had no effect on the heart. 4. Antisera against the active neurotransmitters labeled central neurons and nerves innervating the heart in a pattern consistent with their putative cardioregulatory functions. 5. Thus, despite the simplicity of the cardiac motor circuit in Archidoris, contractile activity of the heart appears to be regulated by several neurotransmitters, each with subtly different modes and thresholds of action.


Combining transcranial magnetic stimulation and electroencephalography may contribute to assess the severity of Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of old age dementia, and mild cognitive impairment (MCI) often precedes AD. In our previous study (Julkunen et al. 2008), we found that the combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) was able to find distinct differences in AD and MCI patients as compared to controls. Here, we reanalyzed the small sample data from our previous study with the aim to test the sensitivity of the TMS-EEG characteristics to discriminate control subjects (n = 4) from MCI (n = 5) and AD (n = 5) subjects. Furthermore, we investigated how the TMS-EEG response characteristics related to the scores of the dementia rating scales used to evaluate the severity of cognitive decline in these subjects. We found that the TMS-EEG response P30 amplitude correlated with cognitive decline and showed good specificity and sensitivity in identifying healthy subjects from those with MCI or AD. Given the small sample size, further studies may be needed to confirm the results.


Progression in the LRRK2-Asssociated Parkinson Disease Population.
Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials. To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation. A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis. Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores. Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08). Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.


Clinical Characteristics and Risk Factors for Rebleeding in Patients with Obscure Gastrointestinal Bleeding.
Objective With the advent of capsule endoscopy (CE) and double-balloon endoscopy (DBE), the diagnosis and treatment of obscure gastrointestinal bleeding (OGIB) have markedly progressed. However, rebleeding sometimes occurs and is difficult to diagnose and treat. The aim of the present study was to investigate the clinical features of OGIB and risk factors for rebleeding in our hospital. Methods A total of 195 patients who underwent CE and/or DBE for OGIB in our hospital from January 2009 to July 2016 were included in the present study. We analyzed 168 cases of small intestinal OGIB, after excluding 27 cases of extra small intestinal bleeding. The clinical characteristics and risk factors related to rebleeding were retrospectively studied. Results Among the 168 patients who were included in the analysis, 95 patients (56.5%) were male. The mean age was 64.5 years (range, 8 to 87 years). Hypertension (31.0%) was the most frequent comorbidity, followed by chronic kidney disease (19.0%). The final diagnoses were ulcerative lesions (n=50, 29.8%), vascular lesions (n=30, 17.9%), tumors (n=7, 4.2%), and diverticula (n=2, 1.2%). The bleeding source was undetermined in the remaining 79 cases (47.0%). Rebleeding was confirmed in 29 cases (17.3%). In a univariate analysis, chronic kidney disease, vascular lesions, and overt previous bleeding were significantly associated with the risk of rebleeding. A multivariate analysis showed that chronic kidney disease, vascular lesion, and overt previous bleeding were significantly associated with the risk of rebleeding. Conclusion Patients with OGIB with overt previous bleeding, vascular lesions, and/or chronic kidney disease had a higher risk of rebleeding.


In vitro fertilization of bovine oocytes in a chemically defined, protein-free medium varying the bicarbonate concentration.
Bovine cumulus-enclosed oocytes were matured in culture, freed from cumulus cells, and inseminated with frozen-thawed spermatozoa in a chemically defined protein-free medium containing 5 mM caffeine and 10 micrograms/ml heparin. No penetration of oocytes was observed in the medium without polyvinyl-alcohol (PVA); but when the medium was supplemented with 0.1-5 mg/ml PVA, penetration rates (9-16%) significantly increased. Sperm motility was also stimulated during incubation for 2 h in the presence of PVA. In the medium with 1 mg/ml PVA, a high penetration rate (24 of 62 = 39%) was observed at a sperm concentration of 10 x 10(6) cells/ml. When the bicarbonate concentration was changed in the fertilization medium containing 1 mg/ml PVA and 10 x 10(6) spermatozoa/ml, a high penetration rate (47 of 67 = 70%) and a high proportion (44 of 47 = 94%) of oocytes in which male and female pronuclei had developed were obtained at 46 mM NaHCO3. However, the penetration rate (58-95%), the incidence of pronuclear formation (64-96%), and the proportion of polyspermy (9-21%) varied according to the animal (five different bulls). Spermatozoa obtained from two bulls started to penetrate oocytes 5 h after insemination in the presence of 46 mM NaHCO3. This is the first report indicating that induction of capacitation of bull spermatozoa and penetration of oocytes matured in culture are possible in a chemically defined, protein-free medium.


Identification of Protein Secretion Systems in Bacterial Genomes Using MacSyFinder.
Protein secretion systems are complex molecular machineries that translocate proteins through the outer membrane, and sometimes through multiple other barriers. They have evolved by co-option of components from other envelope-associated cellular machineries, making them sometimes difficult to identify and discriminate. Here, we describe how to identify protein secretion systems in bacterial genomes using MacSyFinder. This flexible computational tool uses the knowledge stemming from experimental studies to identify homologous systems in genome data. It can be used with a set of predefined models-"TXSScan"-to identify all major secretion systems of diderm bacteria (i.e., with inner and with LPS-containing outer membranes). For this, it identifies and clusters colocalized components of secretion systems using sequence similarity searches with hidden Markov model protein profiles. Finally, it checks whether the genetic content and organization of clusters satisfy the constraints of the model. TXSScan models can be customized to search for variants of known systems. The models can also be built from scratch to identify novel systems. In this chapter, we describe a complete pipeline of analysis, including the identification of a reference set of experimentally studied systems, the identification of components and the construction of their protein profiles, the definition of the models, their optimization, and, finally, their use as tools to search genomic data.


Sex Effects on Smoking Cue Perception in Non-Smokers, Smokers, and Ex-Smokers: A Pilot Study.
Recent neuroimaging research suggests sex-related brain differences in smoking addiction. In the present pilot study, we assessed gender-related differences in brain activation in response to cigarette-related video cues, investigating non-smokers, smokers, and ex-smokers. First, we compared 29 females (28.6 ± 5.3) vs. 23 males (31.5 ± 6.4), regardless of current smoking status to assess global gender-related effects. Second, we performed a post hoc analysis of non-smokers (9 females and 8 males), smokers (10 females and 8 males), and ex-smokers (10 females and 7 males). Participants performed a block-design functional magnetic resonance imaging paradigm contrasting smoking with control cue video exposures. Data analyses included task-related general linear model, voxel-based morphometry of gray matter (GM), and tract-based spatial statistics of white matter (WM). First, the global effect regardless of current smoking status revealed higher activation in the bilateral superior frontal gyrus and anterior cingulate cortex (ACC) for females compared to males. Second, the analysis according to current smoking status demonstrated higher activation in female vs. male smokers vs. non-smokers in the superior frontal gyrus, anterior and posterior cingulate cortex, and precuneus, and higher activation in female vs. male ex-smokers vs. non-smokers in the right precentral gyrus, in the right insula and ACC. No structural differences were found in GM or WM. The current study identifies gender-related brain functional differences in smokers and ex-smokers compared to non-smokers. The current work can be considered as a starting point for future investigations into gender differences in brain responses to cigarette-related cues.


Organ-on-chip to investigate host-pathogens interactions.
Infectious diseases remain the subject of intense research. This topic reaches a new era towards the study of host-pathogen interactions mechanisms at the tissue scale. The past few years have hence witnessed the emergence of new methods. Among them, organ-on-chip, which combines biomaterial technology, microfluidic and tissue engineering to recreate the organ physiology is very promising. This review summarises how this technology recapitulates the architecture, the mechanical stimulation and the interface of a tissue and how this particular microenvironment is critical to study host-pathogen interactions.


Induction of IL21 in Peripheral T Follicular Helper Cells Is an Indicator of Influenza Vaccine Response in a Previously Vaccinated HIV-Infected Pediatric Cohort.
HIV-infected patients of all ages frequently underperform in response to seasonal influenza vaccination, despite virologic control of HIV. The molecular mechanisms governing this impairment, as well as predictive biomarkers for responsiveness, remain unknown. This study was performed in samples obtained prevaccination (T0) from HIV-infected children who received the 2012-2013 seasonal influenza vaccine. Response status was determined based on established criterion for hemagglutination inhibition titer; participants with a hemagglutination titer ≥1:40 plus a ≥4-fold increase over T0 at 3 wk postvaccination were designated as responders. All children had a history of prior influenza vaccinations. At T0, the frequencies of CD4 T cell subsets, including peripheral T follicular helper (pTfh) cells, which provide help to B cells for developing into Ab-secreting cells, were similar between responders and nonresponders. However, in response to in vitro stimulation with influenza A/California/7/2009 (H1N1) Ag, differential gene expression related to pTfh cell function was observed by Fluidigm high-density RT-PCR between responders and nonresponders. In responders, H1N1 stimulation at T0 also resulted in CXCR5 induction (mRNA and protein) in CD4 T cells and IL21 gene induction in pTfh cells that were strongly associated with H1N1-specific B cell responses postvaccination. In contrast, CD4 T cells of nonresponders exhibited increased expression of IL2 and STAT5 genes, which are known to antagonize peripheral Tfh cell function. These results suggest that the quality of pTfh cells at the time of immunization is important for influenza vaccine responses and provide a rationale for targeted, ex vivo Ag-driven molecular profiling of purified immune cells to detect predictive biomarkers of the vaccine response.


Assessing doctors' competencies using multisource feedback: validating a Japanese version of the Sheffield Peer Review Assessment Tool (SPRAT).
To assess the validity and reliability of the Sheffield Peer Review Assessment Tool (SPRAT) Japanese version for evaluating doctors' competencies using multisource feedback. SPRAT, originally developed in the UK, was translated and validated in three phases: (1) an existing Japanese version of SPRAT was back-translated into English; (2) two expert panel meetings were held to develop and assure content validity in a Japanese setting; (3) the newly devised Japanese SPRAT instrument was tested by a multisource feedback survey, validity was tested using principal component factor analysis, and reliability was assessed using generalisability and decision studies based on generalisability theory. 86 doctors who had been practising for between 2 and 33 years participated as assessees and were evaluated with the SPRAT tool. First, the doctors identified 1019 potential assessors who were each sent SPRAT forms (response rate, 81%). The mean number of assessors per doctor was 9.7 (SD=2.5). The decision study showed that 95% CIs of ± 0.5 were achieved with only 5 assessors. 85 of the 86 doctors achieved scores that could be placed with 95% CI above the 4 expected standard. Doctors received lower scores from more senior assessors (p<0.001) and higher scores from those they had known longer (p<0.001). Scores also varied with the job role (p<0.05). Following translation and content validation, the Japanese instrument behaved similarly to the UK tool. Assessor selection remains a primary concern, as the assessment scores are affected by the seniority of the assessor, the length of the assessor-assessee working relationship, and the assessor's job role. Users of the SPRAT tool need to be aware of these limitations when administering the instrument.


Child abuse and neglect among orphaned children and youth living in extended families in sub-Saharan Africa: What have we learned from qualitative inquiry?
Researchers and aid organizations have reported that orphans in sub-Saharan Africa (SSA) are particularly vulnerable to abuse and neglect. This article is a review of qualitative studies that address experiences of maltreatment among orphaned children and youth living in extended families in SSA. It aims to inform policy and programming by providing a better understanding of the types of maltreatment encountered and the perceived risk factors. A literature search was carried out using Google, PubMed, Scholars Portal Search and Scopus. Searches of relevant bibliographies and publications of authors were also undertaken. Studies from peer-reviewed journals and the grey literature were reviewed for relevance and quality. Eligible studies had to include orphans living with extended family in SSA as participants, explore their maltreatment experiences and employ a sound qualitative methodology. Findings were coded, extracted, compared and synthesized. Twenty articles, representing 15 studies, were selected. These studies, from diverse SSAn countries, reported similar forms of maltreatment among orphaned children and youth: experiences of intra-household discrimination; material and educational neglect; excessive child labour; exploitation by family members and psychological, sexual and physical abuse. The perceived risk factors were poverty, living with a non-biological caregiver, stigma and alcohol abuse. The findings of the included studies suggest that awareness, prevention and intervention initiatives aimed to curb child abuse and neglect within communities in SSA are needed and should be coupled with efforts to promote education and reduce poverty and stigma.


Interpreting systematic reviews: are we ready to make our own conclusions? A cross-sectional study.
Independent evaluation of clinical evidence is advocated in evidence-based medicine (EBM). However, authors' conclusions are often appealing for readers who look for quick messages. We assessed how well a group of Malaysian hospital practitioners and medical students derived their own conclusions from systematic reviews (SRs) and to what extent these were influenced by their prior beliefs and the direction of the study results. We conducted two cross-sectional studies: one with hospital practitioners (n = 150) attending an EBM course in June 2008 in a tertiary hospital and one with final-year medical students (n = 35) in November 2008. We showed our participants four Cochrane SR abstracts without the authors' conclusions. For each article, the participants chose a conclusion from among six options comprising different combinations of the direction of effect and the strength of the evidence. We predetermined the single option that best reflected the actual authors' conclusions and labelled this as our best conclusion. We compared the participants' choices with our predetermined best conclusions. Two chosen reviews demonstrated that the intervention was beneficial ("positive"), and two others did not ("negative"). We also asked the participants their prior beliefs about the intervention. Overall, 60.3% correctly identified the direction of effect, and 30.1% chose the best conclusions, having identified both the direction of effect and the strength of evidence. More students (48.2%) than practitioners (22.2%) chose the best conclusions (P < 0.001). Fewer than one-half (47%) correctly identified the direction of effect against their prior beliefs. "Positive" SRs were more likely than "negative" SRs to change the participants' beliefs about the effect of the intervention (relative risk (RR) 1.8, 95% confidence interval 1.3 to 2.6) and "convert" those who were previously unsure by making them choose the appropriate direction of effect (RR 1.9, 95% confidence interval 1.3 to 2.8). The majority of our participants could not generate appropriate conclusions from SRs independently. Judicious direction from the authors' conclusions still appears crucial to guiding our health care practitioners in identifying appropriate messages from research. Authors, editors and reviewers should ensure that the conclusions of a paper accurately reflect the results. Similar studies should be conducted in other settings where awareness and application of EBM are different.


Current medico-psycho-social conditions of patients with West syndrome in Japan.
To unveil current medical and psychosocial conditions of patients with West syndrome in Japan. A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset. For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%. The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.


Brain basis of developmental change in visuospatial working memory.
Although brain changes associated with the acquisition of cognitive abilities in early childhood involve increasing localized specialization, little is known about the brain changes associated with the refinement of existing cognitive abilities that reach maturity in adolescence. The goal of this study was to investigate developmental changes in functional brain circuitry that support improvements in visuospatial working memory from childhood to adulthood. We tested thirty 8- to 47-year-olds in an oculomotor delayed response task. Developmental transitions in brain circuitry included both quantitative changes in the recruitment of necessary working memory regions and qualitative changes in the specific regions recruited into the functional working memory circuitry. Children recruited limited activation from core working memory regions (dorsal lateral prefrontal cortex [DLPFC] and parietal regions) and relied primarily on ventromedial regions (caudate nucleus and anterior insula). With adolescence emerged a more diffuse network (DLPFC, anterior cingulate, posterior parietal, anterior insula) that included the functional integration of premotor response preparation and execution circuitry. Finally, adults recruited the most specialized network of localized regions together with additional performance-enhancing regions, including left-lateralized DLPFC, ventrolateral prefrontal cortex, and supramarginal gyrus. These results suggest that the maturation of adult-level cognition involves a combination of increasing localization within necessary regions and their integration with performance-enhancing regions.


Reversal of diabetes in BB rats by transplantation of encapsulated pancreatic islets.
Prolonged survival of pancreatic islet allografts implanted in diabetic BB rats was achieved by encapsulation of individual islets in a protective biocompatible alginate-polylysine-alginate membrane without immunosuppression. Intraperitoneal transplantation of the encapsulated islets reversed the diabetic state of the recipients within 3 days and maintained normoglycemia for 190 days. Normal body weight and urine volume were maintained during this period, and no cataracts were detected in the transplant recipients. In contrast, control rats receiving transplants of unencapsulated islets experienced normoglycemia for less than 2 wk. These results demonstrated that microencapsulation can protect allografted islets from both graft rejection and autoimmune destruction without immunosuppression in an animal model that mimics human insulin-dependent diabetes.


Specific vocalized complaints in whiplash and minor head injury patients.
Subtle complaints of visual-vestibular mismatch may not be elicited in an initial history-taking. Clinicians must be familiar with the nature of these complaints when assessing whiplash patients because other injuries may predominate and patients do not volunteer these more subtle complaints, which may be persisting and sometimes debilitating. A retrospective case review was performed. The study was conducted at a tertiary/quaternary referral clinic. Patients with whiplash, mild head injury, or both were referred for assessment of symptoms persisting for at least 2 years after their injury. A full history; otolaryngologic examination; including assessment of eye movements, corneal reflexes, and gait; investigation including electronystagmography and computerized dynamic posturography; and history-taking and detailed recording of related complaints were performed immediately before diagnostic workup. Many patients had more subtle complaints, which we now recognize as indicative of vestibular pathology, that have not previously been described in detail in the literature and are often generalized using terms such as "dizziness" or "lightheadedness." It is important to take a detailed history from these patients to delineate their more subtle complaints, because their symptoms frequently do not "fit" into traditional syndromes. Complaints verbalized by patients were tabulated. On more careful analysis, they can be identified as arising from a mismatch between vestibular information and other sensory information used to maintain balance. Many patients with the standard vestibular syndromes have the same subtle complaints (apart from the standard vertiginous complaints) that patients with whiplash and minor head injury verbalize. The similarity of the complaints in the two groups indicate that the subtle symptoms are caused by underlying vestibular disease.


Ferric carboxymaltose: a review of its use in iron-deficiency anaemia.
Ferric carboxymaltose (Ferinject(R)), a novel iron complex that consists of a ferric hydroxide core stabilized by a carbohydrate shell, allows for controlled delivery of iron to target tissues. Administered intravenously, it is effective in the treatment of iron-deficiency anaemia, delivering a replenishment dose of up to 1000 mg of iron during a minimum administration time of </=15 minutes. Results of several randomized trials have shown that intravenously administered ferric carboxymaltose rapidly improves haemoglobin levels and replenishes depleted iron stores in various populations of patients with iron-deficiency anaemia, including those with inflammatory bowel disease, heavy uterine bleeding, postpartum iron-deficiency anaemia or chronic kidney disease. It was well tolerated in clinical trials. Ferric carboxymaltose is, therefore, an effective option in the treatment of iron-deficiency anaemia in patients for whom oral iron preparations are ineffective or cannot be administered. Ferric carboxymaltose is a macromolecular ferric hydroxide carbohydrate complex, which allows for controlled delivery of iron within the cells of the reticuloendothelial system and subsequent delivery to the iron-binding proteins ferritin and transferrin, with minimal risk of release of large amounts of ionic iron in the serum. Intravenous administration of ferric carboxymaltose results in transient elevations in serum iron, serum ferritin and transferrin saturation, and, ultimately, in the correction of haemoglobin levels and replenishment of depleted iron stores. The total iron concentration in the serum increased rapidly in a dose-dependent manner after intravenous administration of ferric carboxymaltose. Ferric carboxymaltose is rapidly cleared from the circulation and is distributed primarily to the bone marrow ( approximately 80%) and also to the liver and spleen. Repeated weekly administration of ferric carboxymaltose does not result in accumulation of transferrin iron in patients with iron-deficiency anaemia. Intravenously administered ferric carboxymaltose was effective in the treatment of iron-deficiency anaemia in several 6- to 12-week, randomized, open-label, controlled, multicentre trials in various patient populations, including those with inflammatory bowel disease, heavy uterine bleeding or postpartum iron-deficiency anaemia, and those with chronic kidney disease not undergoing or undergoing haemodialysis. In most trials, patients received either ferric carboxymaltose equivalent to an iron dose of </=1000 mg (or 15 mg/kg in those weighing <66 kg) administered over </=15 minutes (subsequent doses administered at 1-week intervals) or oral ferrous sulfate at a dose equivalent to 65 mg iron three times daily or 100 mg iron twice daily. In one trial, patients with chronic kidney disease undergoing haemodialysis received 200 mg of iron intravenously either as ferric carboxymaltose or iron sucrose administered into the haemodialysis line two to three times weekly. In all trials, ferric carboxymaltose was administered until each patient had received his or her calculated total iron replacement dose. Haemoglobin-related outcomes improved in patients with iron-deficiency anaemia receiving ferric carboxymaltose. Treatment with ferric carboxymaltose was associated with rapid and sustained increases from baseline in haemoglobin levels. Ferric carboxymaltose was considered to be as least as effective as ferrous sulfate with regard to changes from baseline in haemoglobin levels or the proportion of patients achieving a haematopoietic response at various timepoints. In general, improvements in haemoglobin levels were more rapid with ferric carboxymaltose than with ferrous sulfate. In patients with chronic kidney disease undergoing haemodialysis, ferric carboxymaltose was at least as effective as iron sucrose. Ferric carboxymaltose also replenished depleted iron stores and improved health-related quality-of-life (HR-QOL) in patients with iron-deficiency anaemia. Recipients of ferric carboxymaltose demonstrated improvements from baseline in serum ferritin levels and transferrin saturation, as well as improvements from baseline in HR-QOL assessment scores. Ferric carboxymaltose was at least as effective as ferrous sulfate with regard to endpoints related to serum ferritin levels, transferrin saturation and HR-QOL. Ferric carboxymaltose was well tolerated in clinical trials in patients with iron-deficiency anaemia, with most drug-related adverse events considered to be mild to moderate in severity. Commonly reported drug-related adverse events include headache, dizziness, nausea, abdominal pain, constipation, diarrhoea, rash and injection-site reactions. The incidence of drug-related adverse events in patients receiving intravenous ferric carboxymaltose was generally similar to that in patients receiving oral ferrous sulfate. In general, rash and local injection-site reactions were more common with ferric carboxymaltose, whereas gastrointestinal adverse events were more frequent with ferrous sulfate. In patients with chronic kidney disease undergoing haemodialysis, a lower proportion of ferric carboxymaltose than iron sucrose recipients experienced at least one drug-related adverse event.