A Behavioral-Educational Intervention to Promote Pediatric Sleep During Hospitalization: A Pilot Randomized Controlled Trial.
Hospitalization can contribute to common sleep difficulties in children. Interventions aimed at hospitalized children need to be developed and piloted with rigorous evaluative methods. The primary purpose of this study was to examine the feasibility and acceptability of a behavioral-educational intervention aimed at increasing nighttime sleep for hospitalized children. Hospitalized children aged 4-10 years and their caregivers. A pilot randomized, controlled trial with concealed-group allocation was conducted. Forty-eight hospitalized children (ages 4-10) and their care-givers were randomized to either the Relax to Sleep (RTS) intervention group (n = 24) or the Usual Care (UC) comparison group (n = 24). The RTS intervention was comprised of a one-on-one educational session for the parent that was guided by a standardized booklet containing information on sleep and instructions for training the child in the use of a diaphragmatic breathing exercise. UC participants received no information about sleep or relaxation. Children wore actigraphs for 3 days and nights and completed sleep diaries. Outcome measures included feasibility, acceptability, and sleep outcomes. Parental reports indicated they enjoyed the discussion on sleep, found the information helpful, and their child found diaphragmatic breathing easy to use, and would use it again in the future. Children in the RTS group averaged 50 minutes more nighttime sleep, and had less wake after sleep onset time compared to children in the UC group. Sleep is critically important to children's health and well-being and should be given important consideration during hospitalization. Although the results of this pilot trial seem promising, more interventional studies are needed.


Diabetes mellitus, prediabetes, and incidence of subclinical myocardial damage.
Persons with prediabetes and diabetes mellitus are at high risk for cardiovascular events. However, the relationships of prediabetes and diabetes mellitus to the development of subclinical myocardial damage are unclear. We measured cardiac troponin T with a highly sensitive assay (hs-cTnT) at 2 time points, 6 years apart, among 9051 participants of the community-based Atherosclerosis Risk in Communities Study with no diabetes mellitus, or prediabetes, and without cardiovascular disease including silent myocardial infarction by ECG. First, we examined the incidence of elevated hs-cTnT (≥14 ng/L) at 6 years of follow-up. Second, we examined clinical outcomes during the subsequent ≈14 years of follow-up among persons with and without incident elevations in hs-cTnT. Cumulative probabilities of elevated hs-cTnT at 6 years among persons with no diabetes mellitus, prediabetes, and diabetes mellitus were 3.7%, 6.4%, and 10.8%, respectively. Compared with normoglycemic persons, the adjusted relative risks for incident elevated hs-cTnT were 1.40 (95% CI, 1.08-1.80) for prediabetes and 2.47 (95% CI, 1.78-3.43) for diabetes mellitus. Persons with diabetes mellitus and incident elevations in hs-cTnT were at a substantially higher risk of heart failure (hazard ratio, 6.37 [95% CI, 4.27-9.51]), death (hazard ratio, 4.36 [95% CI, 3.14-6.07]), and coronary heart disease (hazard ratio, 3.84 [95% CI, 2.52-5.84]) compared with persons without diabetes mellitus and no incident elevation in hs-cTnT. Prediabetes and diabetes mellitus were independently associated with the development of subclinical myocardial damage, as assessed by hs-cTnT, and those persons with evidence of subclinical damage were at highest risk for clinical events. These results support a possible deleterious effect of hyperglycemia on the myocardium, possibly reflecting a microvascular cause.


The geographical distribution of tick bites and erythema migrans in general practice in The Netherlands.
Lyme disease is caused by Borrelia burgdorferi which is transmitted in Europe by the tick ixodes ricinus. Erythema migrans is a skin lesion which is pathognomonic of Lyme disease. A retrospective study was carried out to determine the geographical distribution of the occurrence of tick bites and erythema migrans in the Netherlands and to identify ecological risk factors. In April 1995, all general practitioners (GPs) in the Netherlands were asked to complete a postal questionnaire on the number of tick bites and erythema migrans case-patients seen in 1994 and the size of the practice. Reminders were sent to non-responders. Information on ecological risk factors by local government area was obtained from a geographical information system. The response rate was 79.9%. In 1994, GPs reported seeing approximately 33,000 patients with tick bites and 6500 with erythema migrans. The incidence rate of erythema migrans was estimated at 4.3 per 10,000 population. Ecological risk factors for both tick bites and erythema migrans were the proportion of the area covered by woods, sandy soil, dry uncultivated land, the number of tourist-nights per inhabitant and sheep population density. The cattle population density was a risk factor for erythema migrans. Using simple methods, a crude estimate of the incidence rate of erythema migrans was obtained rapidly, and high risk areas were identified. Lyme disease appears to be an important problem in the Netherlands.


The Emergence of Non-communicable Disease in Indonesia.
Based on data from the Indonesian Ministry of Health Information Center, the estimated population of Indonesia in 2016 was approximately 258,704,986 people, consisted of 129,988,690 men and 128,716,296 women. This number of Indonesian population represents young population since the proportion of population aged 0-14 years is more than that aged >14 years. Meanwhile, the proportion of population aged 50 years and above is significantly reduced, which is thought to be due to high mortality rate in the middle-aged population. The mortality rate in Indonesia is dominated by non-communicable diseases (NCD). Alteration in environment, technology and lifestyle have changed the pattern of disease in Indonesia to be dominated by NCD such as DM, heart disease, dyslipidemia, obesity, kidney disease, lung disease, and malignancy.According to the 2014 Indonesian Sample Registration System, the 10 most common diseases were stroke (21.1%), heart disease (12.9%), diabetes mellitus (6.7%), tuberculosis (5.7%), complications of high blood pressure (5.3%), chronic lung disease (4.9%), liver disease (2.7%), traffic accidents (2.6%), pneumonia (2.1%), and combined diarrhea and gastroenteritis due to infection (1.9%). Furthermore, according to Indonesia Basic Health Research 2018, most of NCD such as cancer, stroke, kidney disease, joint disease, DM, heart disease, hypertension, and overweight/ obesity, showed an increasing trend compared to the previous report in 2013.Non-communicable diseases are chronic, often asymptomatic and progressive, thus patients usually did not realize having the disease until the sign and symptoms of its complications occur. This problem drives the need of early screening for high-risk population, early treatment and periodic monitoring. Furthermore, ongoing epidemiological studies are also done to evaluate both established and unknown risk factors, pattern of non-communicable disease development in certain area and the treatment response.


Haemodynamic and endocrinological effects of noninvasive mechanical ventilation in respiratory failure.
The aim of this study was to investigate the haemodynamic and endocrinological effects of noninvasive positive pressure ventilation (NIPPV). Eleven patients with oedema and recent hypercapnic and hypoxaemic worsening of a chronic respiratory insufficiency were included. Echocardiography, cardiac radionuclide assessment, blood catecholamines, salt and water handling hormones were measured at admission and discharge (long study (LS)). To discriminate between the action of NIPPV and other treatments, measurements were performed on the fourth day, for 4 h without NIPPV and 4 h with NIPPV (short study (SS)). NIPPV entailed a correction of P(a,CO2) and an increase of P(a,O2) in LS and SS. Oedema disappeared. Body weight decreased (from 85+/-42 to 81+/-40 kg) during LS. Systolic and mean pulmonary arterial pressure decreased in LS and SS. Right ventricular ejection fraction increased in LS. Left ventricular ejection fraction did not change. Cardiac index was normal on admission and then decreased. Natriuretic peptides and catecholamines were increased on admission, whereas plasma renin activity, aldosterone and vasopressin were normal. We suggest that in these patients, oedema can occur independently of renin-angiotensin-aldosterone-vasopressin and with a normal cardiac output. Noninvasive positive pressure ventilation allowed a correction of blood gases, associated with the resolution of oedema, a decrease in pulmonary arterial pressures and an increase in right ventricular ejection fraction.


The peroxin pex3p initiates membrane assembly in peroxisome biogenesis.
Rat cDNA encoding a 372-amino-acid peroxin was isolated, primarily by functional complementation screening, using a peroxisome-deficient Chinese hamster ovary cell mutant, ZPG208, of complementation group 17. The deduced primary sequence showed approximately 25% amino acid identity with the yeast Pex3p, thereby we termed this cDNA rat PEX3 (RnPEX3). Human and Chinese hamster Pex3p showed 96 and 94% identity to rat Pex3p and had 373 amino acids. Pex3p was characterized as an integral membrane protein of peroxisomes, exposing its N- and C-terminal parts to the cytosol. A homozygous, inactivating missense mutation, G to A at position413, in a codon (GGA) for Gly(138) and resulting in a codon (GAA) for Glu was the genetic cause of peroxisome deficiency of complementation group 17 ZPG208. The peroxisome-restoring activity apparently required the full length of Pex3p, whereas its N-terminal part from residues 1 to 40 was sufficient to target a fusion protein to peroxisomes. We also demonstrated that Pex3p binds the farnesylated peroxisomal membrane protein Pex19p. Moreover, upon expression of PEX3 in ZPG208, peroxisomal membrane vesicles were assembled before the import of soluble proteins such as PTS2-tagged green fluorescent protein. Thus, Pex3p assembles membrane vesicles before the matrix proteins are translocated.


Combined influence of visual scene and body tilt on arm pointing movements: gravity matters!
Performing accurate actions such as goal-directed arm movements requires taking into account visual and body orientation cues to localize the target in space and produce appropriate reaching motor commands. We experimentally tilted the body and/or the visual scene to investigate how visual and body orientation cues are combined for the control of unseen arm movements. Subjects were asked to point toward a visual target using an upward movement during slow body and/or visual scene tilts. When the scene was tilted, final pointing errors varied as a function of the direction of the scene tilt (forward or backward). Actual forward body tilt resulted in systematic target undershoots, suggesting that the brain may have overcompensated for the biomechanical movement facilitation arising from body tilt. Combined body and visual scene tilts also affected final pointing errors according to the orientation of the visual scene. The data were further analysed using either a body-centered or a gravity-centered reference frame to encode visual scene orientation with simple additive models (i.e., 'combined' tilts equal to the sum of 'single' tilts). We found that the body-centered model could account only for some of the data regarding kinematic parameters and final errors. In contrast, the gravity-centered modeling in which the body and visual scene orientations were referred to vertical could explain all of these data. Therefore, our findings suggest that the brain uses gravity, thanks to its invariant properties, as a reference for the combination of visual and non-visual cues.


Calcium binding by alpha-lactalbumin in human milk and bovine milk.
The metal-binding property of alpha-lactalbumin (alpha-LA) in human milk was studied and compared to that of bovine milk alpha-LA. Gel filtration on Sephadex G-75 at physiological pH and ionic strength separated alpha-LA in human and bovine milk from most other proteins. The only metal ion associated with alpha-LA under these conditions was Ca2+. Minor protein contaminants were removed by ion-exchange chromatography, and the ratio of Ca2+:alpha-LA was determined in the isolated protein preparations. Concentrations of alpha-LA in mature human milk were between 1.03 and 1.57 mg/ml; the Ca2+ concentration bound to alpha-LA varied, yielding a molar ratio of Ca2+:alpha-LA of approximately 1:1 (0.82-1.41 mol Ca2+/mol alpha-LA) in mature milk. Gel filtration with excess Ca2+ in the running buffer showed that there is another weaker binding site for Ca2+, but this binding does not occur under physiological conditions. Less Ca2+ was bound to bovine alpha-LA (0.6-0.9 mol Ca2+/mol alpha-LA) than to human alpha-LA. Calcium binding was abolished at pH 3.0 and resulted in a substantial increase in the hydrodynamic radius of alpha-LA. Reconstitution of human alpha-LA with Ca2+ and other divalent cations at native pH (6.8) and ionic strength showed a binding specific for Ca2+. Since only 1% of calcium from human milk and 0.15% from bovine milk is alpha-LA bound, alpha-LA is probably unimportant with respect to calcium nutrition of the infant. However, the metal binding of alpha-LA may have a biological significance through its role in the lactose synthase complex.


An Analysis of Prolonged, Continuous Ketamine Infusions.
Opioids carry high risk of dependence, and patients can rapidly build tolerance after repetitive dosing. Low-dose ketamine is an analgesic agent alternative that provides more hemodynamic stability. We sought to describe the effects of prolonged ketamine use in non-burn patients. We queried the electronic health system at the Brooke Army Medical Center for patient encounters with ketamine infusions lasting >72 hours. We abstracted data describing demographics, vital signs, ketamine infusion dose and duration, and discharge diagnoses potentially relevant to ketamine side effects. We identified 194 subjects who met the study inclusion criteria. The median age was 39 years, most were male (67.0%), and most were primarily admitted for a non-trauma reason (59.2%). The mean ketamine drip strength was 43.9 mg/h (95% CI, 36.7-51.1; range 0.1-341.6) and the mean drip length was 130.8 hours (95% CI, 120.3-141.2; range 71-493). Most subjects underwent mechanical ventilation (56.1%) at some point during the infusion and most survived to hospital discharge (83.5%). On a per-day basis, the average heart rate was 93 beats per minute, systolic blood pressure was 128 mmHg, diastolic blood pressure was 71 mmHg, oxygen saturation was 96%, and respiratory rate was 22 respirations per minute. We demonstrate that continuous ketamine infusions provide a useful adjunct for analgesia and/or sedation. Further development of this adjunct modality may serve as an alternative agent to opioids.


Thermal spectrum of uranus: implications for large helium abundance.
An analysis of the infrared spectrum of Uranus' disk between 7 micrometers and 3 millimeters suggests a volume mixing ratio for helium in the atmosphere of 40 +/- 20 percent, more than for the sun, Jupiter, or Saturn. Alternative explanations require even more extreme assumptions regarding gas abundances or aerosol vertical distribution and spectral properties. The most serious difficulty with a model containing large amounts of helium is devising a credible evolutionary or chemical model explaining the absence or segregation of so much hydrogen.


Stabilization of emulsion and butter like products containing essential fatty acids using kalonji seeds extract and curcuminoids.
Owing to the tendency of essential fatty acids (EFAs) to undergo autoxidation, their storage becomes a key problem. Generally, they are stabilized by synthetic antioxidants like TBHQ that are toxic in nature. Recently many studies were reported where these EFAs are stabilized by natural antioxidants. In the present study, curcuminoids and kalonji seeds ethanol extract (KEE) were used to stabilize these EFAs in refined sunflower oil (RSFO), water-in-oil (w/o) emulsion and butter like products (BLPs). In RSFO, though curcuminoids alone exerted pro-oxidant effect, KEE and curcuminoids showed synergistic antioxidant activity that was comparable to TBHQ. KEE exhibited good antioxidant activity in emulsions and BLPs, providing fine physical properties like slipping point, dropping point and spreadability. EFAs increased the nutritional value of BLPs and antioxidants added for their stabilization provided their medicinal benefits.


Current treatments for Alzheimer's disease: cholinesterase inhibitors.
The current recommended standard of care for the symptomatic treatment of mild to moderate Alzheimer's disease is cholinesterase inhibitors. In short- and long-term studies, the 3 cholinesterase inhibitors most commonly used, donepezil, rivastigmine, and galantamine, have demonstrated efficacy in improving not only cognition but also function and behavior in patients suffering from mild to severe cases of Alzheimer's disease and other forms of dementia. However, the benefits of cholinesterase inhibitors in treating the broad spectrum of symptoms associated with Alzheimer's disease are not sustained indefinitely, and the illness continues to progress even while patients are receiving treatment. Additionally, while temporary stabilization may occur, there is typically only a modest improvement from baseline, and side effects from treatment with cholinesterase inhibitors can be too severe for some patients to tolerate. Therefore, additional therapies for Alzheimer's disease still need to be developed that include more tolerable agents with alternative mechanisms of action and broader efficacy.


A natural chimeric yeast containing genetic material from three species.
The Saccharomyces sp. CID1 isolate (CBS 8614) and several other Saccharomyces sensu stricto yeasts were analysed for their mitochondrial and nuclear genes. The data show that Saccharomyces sp. CID1, found so far only in one location in Europe, is a natural hybrid between three different Saccharomyces yeast species. Two of them, Saccharomyces cerevisiae-like and Saccharomyces bayanus-like, are ubiquitous and contributed parts of the nuclear genome; the third, Saccharomyces sp. IFO 1802-like, which has been found only in Japan, contributed the mitochondrial DNA molecule. These data suggest that the yeast cell is able to accommodate, express and propagate genetic material that originates from different species, and the very existence of the resulting natural hybrids indicates that such hybrids are well adapted to their habitats.


Ultrastructure of Sorubim lima (Teleostei, Siluriformes, Pimelodidae) spermiogenesis.
The spermiogenesis and the spermatozoon ultrastructure of Sorubim lima were studied. Our observations showed that early spermatids are round-shaped cells, have spherical nucleus with diffuse chromatin, small quantity of mitochondria and large amount of vesicles in the cytoplasm. During the differentiation process in the nucleus, chromatin compacts in a progressive and homogeneous way, and the flagellum is formed. In the cytoplasm the vesicles, that have double membranes, aggregate and fuse on the plasma membrane. The spermatozoa of S. lima have no acrosome and show spherical nucleus with homogeneous and highly compacted chromatin, intermediary piece with mitochondria and double wall vesicles contiguous to the plasma membrane, as well as a flagellum formed by a basic axoneme (9 + 2).


Evaluation of Root Canal Cleaning and Shaping Efficacy of Three Engine-driven Instruments: SafeSider, ProTaper Universal and Lightspeed LSX.
To compare the cleaning effectiveness and shaping ability of SafeSider, ProTaper Universal and Lightspeed rotary instruments during the preparation of curved root canals in extracted human teeth. A total of 63 roots with curved root canals were divided into three groups. Canals were prepared using SafeSider, ProTaper Universal or Lightspeed LSX. Using pre- and post-instrumentation radiographs, straightening of the canal curvatures and loss of working length were determined with a computer image analysis program. The amounts of debris at the apical 5 mm were quantified on the basis of a numerical evaluation scale. The data were analyzed statistically using the two-way analysis of variance (ANOVA). There was significantly more transportation among the Lightspeed LSX group compared to the SafeSider and ProTaper Universal groups only at the 4 mm level (p < 0.05). The ProTaper Universal instruments performed significantly faster than other groups. No significant differences were observed between the three engine-driven instruments with regards to debris removal. SafeSider, ProTaper Universal and Lightspeed LSX rotary instruments maintained the original canal curvature well at the apical 3 mm and were safe to use. No difference was found in cleaning efficacy and none rendered the apical part of the canal free of debris. SafeSider, ProTaper Universal and Lightspeed LSX rotary instruments are safe to use in curved root canals.


Insulin-specific human T cells. Epitope specificity, major histocompatibility complex restriction, and alloreactivity to a diabetes-associated haplotype.
T cells from an insulin-treated diabetic (ML, HLA DR1, w6) were stimulated in vitro with insulin, cloned at limiting dilution, and examined for their fine specificity and genetic restriction. T cell lines (TCL) derived from beef insulin stimulation were highly specific for epitopes on beef insulin, whereas pork insulin stimulation generated T cells that recognized determinants shared with beef insulin. Included among TCL reactive with pork insulin is one line (P2/9) that is autoreactive with human insulin. Antigen-presenting cells of known HLA type and monoclonal antibodies directed at class II major histocompatibility complex antigens were used to confirm the role of HLA-DR in restricting the response of insulin immune T cells. No preference or determinant selection within the donor's haplotypes was identified because either DR1 or DRw6 antigen-presenting cells could present the A loop of beef insulin. A TCL that recognized the A loop of beef insulin in association with DR1 was also alloreactive to HLA DR3, or a molecule closely linked to it, in the absence of insulin. A second T cell clone with insulin specificity and alloreactivity was also derived by allo stimulation of the donor's cells with DR3+ cells. When tested with a series of DR3+ stimulator cells, the alloreactivity was directed at diabetes-associated haplotypes. These data show that the T cell repertoire for insulin of a single diabetic donor encompasses that of multiple inbred animal strains and includes fine specificity for one to two amino acids, recognition of autologous insulin, and cross-reactivity with an allogeneic major histocompatibility complex antigen.


Exploring the Relationship between Adiposity and Fitness in Young Children.
High levels of cardiorespiratory fitness (CRF) may attenuate the association between the excessive adiposity and the risks of cardiovascular and metabolic disease. The purpose of this study was to stratify children according to their body mass index (BMI) and adiposity (body fat percentage [BF%]) and to compare levels of CRF across subgroups. This prospective cohort study comprises a cross-sectional and longitudinal analyses of data collected at baseline (n = 641) and 2 yr later (n = 579) on children (7.4-11.6 yr) attending public school in Denmark. Levels of CRF were measured using the Andersen test, whereas BF% was measured by dual-energy x-ray absorptiometry. There were 560 children (87.4%) classified as normal weight according to BMI at baseline, of which 46 (7.4%) were identified as having excessive BF%. These children had significantly lower CRF (mean [95% confidence interval]: -63.1 m [-100.2 to -25.9]) than children with normal BMI and normal BF%, and the effect of BF% on CRF was significantly worse in boys than girls. Overweight children with high BF% had significantly lower prospective (2 yr) CRF levels (-34.4 m [-58.0 to -10.7]) than children with normal BMI and BF%. However, children who improved their BMI and/or BF% classification during the 2-yr period achieved CRF levels (8.9 m [-30.2 to 47.9]), which were comparable with children with normal BMI and BF% at both measurement time points. The CRF levels in children are affected by BMI and BF%, although BF% appears to play a greater role. This association between BF% and CRF is sex dependent, with CRF levels in boys being affected to a greater extent by BF%. Children identified as "normal weight" by BMI but presenting with excessive BF% had significantly lower CRF than "normal weight" children with low BF%.


Patients' views of causes of aggression by patients and effective interventions.
The authors studied patients' perceptions of the causes of aggression by patients and their recommendations for interventions to prevent assaultive behavior. A total of 92 inpatient and outpatient veterans, the majority of whom had a psychiatric diagnosis and some a medical diagnosis, answered questions in individual interviews about whether they had ever witnessed an assault. Fifty-two participants had witnessed aggression. Participants' answers about the causes of patient-to-patient and patient-to-staff aggression were categorized into internal factors-cognition, feelings, and symptoms-and interpersonal stressors, such as personality conflicts and abrasive words. The majority of causes identified were in the category of interpersonal stressors-67 percent for patient-to-patient aggression and 60 percent for patient-to-staff aggression. The participants' answers about suggested interventions to prevent both types of aggression were categorized as individual patient, cooperative patient-staff, and staff interventions. For patient-to-patient aggression, 52 percent of the interventions suggested were for staff. This proportion was 74 percent for patient-to-staff aggression. For both types of aggression, only 10 percent of the suggested interventions involved patient-staff cooperation. The participants indicated that both patients and staff play important parts in causing and in intervening to prevent violence. This information can be used to help plan programs to prevent and intervene in aggressive behavior.


Domestication and the mitochondrial genome: comparing patterns and rates of molecular evolution in domesticated mammals and birds and their wild relatives.
Studies of domesticated animals have led to the suggestion that domestication could have significant effects on patterns of molecular evolution. In particular, analyses of mitochondrial genome sequences from domestic dogs and yaks have yielded higher ratios of non-synonymous to synonymous substitutions in the domesticated lineages than in their wild relatives. These results are important because they imply that changes to selection or population size operating over a short timescale can cause significant changes to the patterns of mitochondrial molecular evolution. In this study, our aim is to test whether the impact on mitochondrial genome evolution is a general feature of domestication or whether it is specific to particular examples. We test whether domesticated mammals and birds have consistently different patterns of molecular evolution than their wild relatives for 16 phylogenetically independent comparisons of mitochondrial genome sequences. We find no consistent difference in branch lengths or dN/dS between domesticated and wild lineages. We also find no evidence that our failure to detect a consistent pattern is due to the short timescales involved or low genetic distance between domesticated lineages and their wild relatives. However, removing comparisons where the wild relative may also have undergone a bottleneck does reveal a pattern consistent with reduced effective population size in domesticated lineages. Our results suggest that, although some domesticated lineages may have undergone changes to selective regime or effective population size that could have affected mitochondrial evolution, it is not possible to generalize these patterns over all domesticated mammals and birds.


Hazardous drinking is associated with a lower risk of coronary heart disease: results from a national representative sample.
This analysis assesses the 12-month prevalence of coronary heart disease (CHD) in individuals according to their category of alcohol use. The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions study (the NESARC, n = 43,093) identified 16,147 abstinent individuals, 15,884 moderate consumers, 9,578 hazardous drinkers-defined as exceeding sex-specific weekly limits established by the World Health Organization, and 1,484 alcohol-dependent subjects. Diagnoses were generated using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV version. Both moderate and hazardous drinking were associated with decreased odds of CHD when compared with abstinence, whereas odds of CHD were not significantly different between alcohol-dependent and abstinent participants. A moderate or even a hazardous consumption of alcohol is associated with a decreased likelihood of CHD after controlling for sociodemographic, psychiatric, and addictive risk factors. Our study shows that alcohol may have cardioprotective effects not only in moderate drinkers, but also in individuals with patterns of use traditionally considered as hazardous.


A Rare Cause of Hyperinsulinemic Hypoglycemia: Kabuki Syndrome
Kabuki syndrome (KS) is a disease characterized by distinctive facial features, skeletal anomalies and delay in neuromotor development. KS 1 is an autosomal dominant condition caused by mutations in the KMT2D gene, whereas KS 2 is an X-linked disorder caused by mutations in the KDM6A gene. In the majority of KS patients who present with hypoglycemia, KDM6A is the defective gene. A 9-month old girl was admitted to our emergency department due to a seizure. On physical examination, hypotonia, mild facial dysmorphism, brachydactyly of the 5th finger, prominent finger pads and pansystolic murmur were detected. A fasting glucose tolerance test was performed the next day due to her history of hypoglycemia, but she had convulsions at the fifth hour of the test. Her serum glucose was 24 mg/dL, insulin 1.94 mIU/L, C-peptide 0.94 ng/mL, growth hormone 11 ng/mL, anti-insulin antibody 4.2 IU/mL, cortisol 19.8 μg/dL, and adrenocorticotropic hormone 9.3 pg/mL. A diagnosis of hyperinsulinemic hypoglycemia was considered. Given the abnormalities, genetic analysis for congenital hyperinsulinism, including the genes causing KS was performed. A heterozygous frameshift mutation (c.2579del, p.Leu860Argfs*70) was detected in the KMT2D gene. Epilepsy and other neurological symptoms may be seen in KS patients and in some of these the neurological symptoms are the result of hypoglycemia. In such cases, the detection and prevention of hypoglycemia can help prevent the progression of neurological symptoms. We suggest considering the diagnosis of KS for patients with hypoglycemia and dysmorphic features, even if the patient does not manifest all features of KS.


Human fatalities related to a Phaeocystis harmful algal bloom in the North Sea.
On May 11, 2020, five surfers drowned after asphyxiation in a massive foam bank near the Dutch coast. We present a detailed account of the event and an examination of factors that govern local foam events, that are traditionally caused by Phaeocystis globosa (Prymnesiophyceae). The data support the hypothesis that the foam originated from a Phaeocystis bloom which if correct would make this accident the first report of human fatalities due to a harmful algal bloom in The Netherlands, and the first globally due to a Phaeocystis bloom. The rarity of massive foam banks and the absence of local real-time plankton monitoring makes it difficult to accurately predict dangerous situations as in 2020. As a prevention, surfers and other water sportsmen need to apply good seamanship during stormy and foamy conditions.


Elbasvir/grazoprevir is effective and tolerable for the treatment of HCV GT1-infected patients: A real world multicenter observatory study in Taiwan.
Treatment of hepatitis C virus (HCV) by elbasvir/grazoprevir (EBR/GZR) was found to be efficacious and well tolerated in clinical trials. This study aimed to evaluate the effectiveness and tolerability of EBR/GZR in the treatment of HCV genotype 1-infected Taiwanese patients. Chronic hepatitis C patients infected with GT1b or 1a without resistance-associated substitution, and treated with 12-week EBR/GZR were enrolled from 10 hospitals in Taiwan between August 2017 and December 2018. All clinical and virologic data were collected at each participating center. Primary efficacy endpoint was sustained virologic response at week 12 (SVR12) after end of the EBR/GZR therapy, assessed in the per-protocol population, which excluded patients with important deviations from the protocol. Analysis was also performed based on the modified full analysis set, which included all allocated patients receiving at least 4-week medication. Virologic failure was recorded as breakthrough, nonresponse, or relapse. Safety was assessed through collection of adverse events, physical examination, vital signs, and standard laboratory evaluations. Per protocol SVR12 rates were 99.5% (1169/1175) for all HCV genotype 1 patients. Among patients with stage 4 or 5 chronic kidney diseases, 100% (107/107) achieved SVR12. In univariate analyses, variables associated with SVR12 were treatment termination (P < 0.0001) and treatment adherence (P < 0.0001) in the mFAS population. Overall, 22.3% of the patients experienced adverse events during treatment. Seven patients did not complete the treatment, five due to liver-unrelated deaths, one due to adverse event and one due to epilepsy. EBR/GZR treatment was highly effective and well tolerated.


Off-axis digital hologram reconstruction: some practical considerations.
Holographic rendering of off-axis intensity digital holograms is discussed. A review of some of the main numerical processing methods, based either on the Fourier transform interpretation of the propagation integral or on its linear system counterpart, is reported. Less common methods such as adjustable magnification reconstruction schemes and Fresnelet decomposition are presented and applied to the digital treatment of off-axis holograms. The influence of experimental parameters on the classical hologram reconstruction methods is assessed, offering guidelines for optimal image rendering regarding the hologram recording conditions.


Implementation and testing of research infrastructure for practice-based research in hearing and communication disorders.
To describe site capability and experience of the CHEER network (Creating Healthcare Excellence through Education and Research) to rapidly collect descriptive data on patients with tinnitus and dizziness visiting participating CHEER sites. Prospective observational data collection study over 6 months. Twenty one community otology and otolaryngology practices in the United States. As proof of concept, a data collection study was developed for patients with tinnitus and dizziness (presenting with or without associated migraine) through a collaborative effort of the CHEER principal investigator (PI) and co-PIs. The 9-page questionnaire included validated instruments and additional patient- and physician-reported information. Information was captured electronically via REDCap by each site's CHEER research coordinator. Site initiation, data entry rates, and research coordinator feedback were also collected. Of the 21 CHEER sites, 15 participated in the study. Nine sites entered a patient within the first 31 days of study initiation, and all 15 sites were entering patients and corresponding clinical data within 72 days. During the 6-month study, 1044 patients were entered into the REDCap database. Research coordinator engagement was a major driver for success, whereas time and resources were deterrents. Incentives included altruism, professional development, and future financial opportunities. The CHEER research network has significant capability and infrastructure to collect prospective data in a practice-based environment. Research coordinator engagement undergirds network success; however, future efforts will cultivate stronger collaboration of the coordinator and site PI. Central coordination of practice-based research through a hub and spoke concept can be successful.


Association between prenatal exposure to metals and neonatal morbidity.
An association between prenatal exposure to (semi-)metals and of neonatal morbidity was assessed by introducing an oxidative stress as a possible intermediate step. An oxidative stress was measured by cell proliferation (CP) ratio in umbilical cord blood cells. Urine samples of 18 out of 58 enrolled women (31%) were positive for (semi-)metals; 25.9% of women were positive for aluminum (Al). The CP ratio was higher (1) in subjects with Al, (2) in mothers to newborns diagnosed as small-for-gestational age (p value = .052), (3) neonates that weighed less (p value = .079), and (4) in women who experienced repeated abortions (p value = .049). Our findings suggest the possibility of metal-induced oxidative stress.


Adjunctive aripiprazole, olanzapine, or quetiapine for major depressive disorder: an analysis of number needed to treat, number needed to harm, and likelihood to be helped or harmed.
To describe the efficacy and safety of adjunctive aripiprazole, olanzapine, and quetiapine for major depressive disorder. Published registration study reports, supplemented by clinical trial synopses as disclosed by manufacturers and product labeling. All available reports of studies were identified. Descriptions of the principal results and calculation of number needed to treat (NNT) for response and remission and number needed to harm (NNH) for relevant dichotomous adverse outcomes were extracted. Likelihood to be helped or harmed (LHH) was subsequently calculated. Three registration studies of adjunctive aripiprazole, 5 for olanzapine-fluoxetine combination, and 2 for quetiapine extended-release reveal NNT for response and remission to range from 7 to 14 and 7 to 13, respectively, for adjunctive antipsychotic versus antidepressant monotherapy, depending on the antipsychotic and/or dose. Adverse event profiles for the 3 different adjunctive antipsychotics are more diverse, with adjunctive aripiprazole more strongly associated with akathisia (NNH, 6), adjunctive olanzapine with weight gain (NNH, 3), and adjunctive quetiapine with somnolence (NNH, 5 for 300 mg/d and NNH, 6 for 150 mg/d). Number needed to treat and NNH can be used to quantify efficacy and tolerability outcomes and help place various therapeutic options into clinical perspective. Likelihood to be helped or harmed can illustrate to the clinician and the patient the trade-offs between obtaining potential benefits versus harms. In the case of the adjunctive second-generation antipsychotics approved for treating major depressive disorder, these trade-offs vary greatly among the choices available and require careful, individualized, patient-centered clinical decision making.


An Improved Genome-Wide Association Procedure Explores Gene-Allele Constitutions and Evolutionary Drives of Growth Period Traits in the Global Soybean Germplasm Population.
In soybeans (Glycine max (L.) Merr.), their growth periods, DSF (days of sowing-to-flowering), and DFM (days of flowering-to-maturity) are determined by their required accumulative day-length (ADL) and active temperature (AAT). A sample of 354 soybean varieties from five world eco-regions was tested in four seasons in Nanjing, China. The ADL and AAT of DSF and DFM were calculated from daily day-lengths and temperatures provided by the Nanjing Meteorological Bureau. The improved restricted two-stage multi-locus genome-wide association study using gene-allele sequences as markers (coded GASM-RTM-GWAS) was performed. (i) For DSF and its related ADLDSF and AATDSF, 130-141 genes with 384-406 alleles were explored, and for DFM and its related ADLDFM and AATDFM, 124-135 genes with 362-384 alleles were explored, in a total of six gene-allele systems. DSF shared more ADL and AAT contributions than DFM. (ii) Comparisons between the eco-region gene-allele submatrices indicated that the genetic adaptation from the origin to the geographic sub-regions was characterized by allele emergence (mutation), while genetic expansion from primary maturity group (MG)-sets to early/late MG-sets featured allele exclusion (selection) without allele emergence in addition to inheritance (migration). (iii) Optimal crosses with transgressive segregations in both directions were predicted and recommended for breeding purposes, indicating that allele recombination in soybean is an important evolutionary drive. (iv) Genes of the six traits were mostly trait-specific involved in four categories of 10 groups of biological functions. GASM-RTM-GWAS showed potential in detecting directly causal genes with their alleles, identifying differential trait evolutionary drives, predicting recombination breeding potentials, and revealing population gene networks.


Applications of Three-Dimensional Cell Cultures in the Early Stages of Drug Discovery, Focusing on Gene Expressions, Drug Metabolism, and Susceptibility.
Three-dimensional (3D) cell cultures represent advances in the way in which cells are grown in vitro, and they are gaining ground for a variety of applications. Advantages of 3D systems include reliable and realistic study endpoints. Cells grown in 3D conditions mimic in vivo conditions to an extent that is not possible with traditional 2D cell-culture methods. One major area in which 3D cell cultures have proven to make a difference is with drug discovery. The facets taken advantage of for drug discovery are the cells' complex microenvironment, including the production of extracellular matrices, altered gene expressions and their protein products, drug metabolism, and susceptibility to drugs when compared to 2D cultures. Altered protein and gene expressions are useful for drug-target identification. The susceptibility of 3D cultured cells for drug-induced effects can be used to obtain realistic data in a dose-dependent manner that can aid in identifying effective drug dosage. This review presents the contributions of 3D cell cultures for drug discovery, taking into consideration gene and protein expressions, drug metabolism, and susceptibility to drugs as the major focus points.


Monitoring mitophagy in yeast.
Cellular degradative processes including proteasomal and vacuolar/lysosomal autophagic degradation, as well as the activity of proteases (both cytosolic and mitochondrial), provide for a continuous turnover of damaged and obsolete macromolecules and organelles. Mitochondria are essential for oxidative energy production in aerobic eukaryotic cells, where they are also required for multiple biosynthetic pathways to take place. Mitochondrial homeostasis also plays a crucial role in aging and programmed cell death, and recent data have suggested that mitochondrial degradation is a strictly regulated process. A recent study has shown that in yeast cells subjected to nitrogen starvation, degradation of mitochondria by autophagy occurs by both a selective process (termed mitophagy) and a nonselective process. This chapter provides an overview of the techniques that enable the study of mitophagy. Fluorescent proteins targeted to mitochondria can be used to follow mitochondrial sequestration within vacuoles. Degradation of mitochondria can be assayed using a mitochondrially targeted alkaline phosphatase (ALP) reporter test in which the delivery of mitochondrial N-terminal truncated Pho8Delta60 to the vacuole results from mitophagy. Degradation of mitochondrial proteins can also be followed by Western immunoblot analyses. Finally, electron microscopy observations permit the discrimination between selective mitophagy and nonselective mitochondrial degradation.


An algorithmic approach to single-probe Cherenkov removal in pulsed x-ray beams.
The removal of Cherenkov light in an optical dosimetry system is an important process to ensure accurate dosimetry without compromising spatial resolution. Many solutions have been presented in the literature, each with advantages and disadvantages. We present a methodology to remove Cherenkov light from a scintillator fiber optic dosimeter in a pulsed megavoltage x-ray beam using the temporal waveform across the pulse. A sample waveform of Cherenkov light can be measured by exposing only the fiber to the beam. By assuming that the Cherenkov waveform closely matches the intensity of incident radiation, this waveform can be convoluted with the instantaneous scintillation response function to generate an expected scintillation signal. By finding the least-squares fit between these two functions and the experimental data, the estimated Cherenkov contribution can be subtracted off the net signal. This can be applied for arbitrarily complex Cherenkov waveforms (within the 2 ns timing resolution of the data acquisition), and in fact, the results suggest more fluctuations in the waveforms provide a better fit to data. Four beam profiles for different field sizes and energies were found with this method. They closely matched references data measured with ionization chamber with average differences across the beam no more than 4%. Noisy waveforms are assumed to be the primary cause of differences between the analyzed scintillator and IC results. We propose methods for improving the results and optimizing the data acquisition and analysis processes. These results demonstrate that it is possible and effective with a single probe to use function fitting of expected data to experimental to remove a complicated Cherenkov signal from the net light signal in pulsed-beam optical dosimetry.


Temporal lobe hypoperfusion in isolated amnesia with slow onset: a single photon emission computer tomography study.
Single photon emission computer tomography (SPECT) applied early in the course of Alzheimer's disease (AD) may identify regions with impaired brain function. Moreover, it may be relevant to characterize SPECT perfusion patterns in patients with mild cognitive impairment (MCI), in particular the subgroup of MCI patients with isolated amnesia, as these patients have been demonstrated to convert to AD in more than half of the cases within 3 years. The primary aim of the present study was to characterize the regional cerebral blood flow (CBF) in patients with neuropsychologically verified isolated amnesia. We examined 32 patients (11 men/21 women) with isolated amnesia according to strict neuropsychological criteria and 15 healthy volunteers (11 men/4 women). All subjects had an SPECT-99mTc-d,l-HMPAO perfusion study and neuropsychological assessments. Cranial MRI or CT was performed in all subjects. Semiquantitative (cerebellar relative) flow values were calculated and statistically compared. Patients with isolated amnesia had significant hypoperfusion in several cortical regions of interest compared to control subjects, most prominently in the left temporal cortex. Additionally, there was a trend towards globally reduced CBF in the patients, although this was not significant. These findings may indicate the presence of a progressive degenerative illness affecting multiple brain regions at its early or preclinical stage.


Prenatal diagnosis and preimplantation genetics testing of 3M syndrome in a Chinese family with novel biallelic variants of CUL7.
3M syndrome is a rare autosomal recessive developmental disorder characterized by pre and postnatal growth deficiency, dysmorphic facial features, and normal intelligence. 3M syndrome should be suspected in a proband with a combination of characteristic or recognizable dysmorphic features. The diagnosis of 3M syndrome could be confirmed by identifying biallelic variants in CUL7, OBSL1, or CCDC8. Whole-exome sequencing (WES) was performed to identify genetic causes. Reverse-transcription polymerase chain reaction (RT-PCR) was performed to detect aberrant splicing events. Haplotypes were constructed using multiplex PCR and sequencing. Variants of the parental haplotype and target likely pathogenic variants were detected by PCR and Sanger sequencing from the embryos. Copy number variant (CNV) detection was performed by next-generation sequencing. We present the case of a nonconsanguineous Chinese couple with one abnormal pregnancy, where the fetus showed 3M phenotypes of shortened long bones. WES identified two novel heterozygous mutations in CUL7: NM_014780.5:c.354del (p.Gln119ArgfsTer52) and NM_014780.5:c.1373-15G>A. RT-PCR from RNA of the mother's peripheral blood leucocytes showed that c.1373-15G>A caused the insertion of a 13-bp extra intron sequence and encoded the mutant p.Leu459ProfsTer25. Both variants were classified as likely pathogenic according to ACMG/AMP guidelines and Clinical Genome Resource specifications. During genetic counseling, the options of prenatal diagnosis through chorionic villus sampling or amniocentesis, adoption, sperm donation, and electing not to reproduce, as well as preimplantation genetic testing for monogenic disorders (PGT-M), were discussed. The couple hopes to conceive a child of their own and refused to accept the 25% risk during the next pregnancy and opted for PGT-M. They finally successfully delivered a healthy baby through PGT-M. This study expanded the mutation spectrum of CUL7, detected the aberrant splicing event of CUL7 via RT-PCR, constructed the haplotype for PGT-M, and demonstrated the successful delivery of a healthy baby using PGT-M.


[Frequency of skin reactivity to food allergens in allergic patients].
Food allergy is deemed to have a worldwide prevalence ranging from 2 to 10 %. To determine the frequency of skin reactivity to food allergens by age groups. Cross-sectional, descriptive, prolective, observational study. Patients aged from 2 to 64 years with symptoms consistent with allergic disease were included. Skin prick tests were carried out with food allergens. Frequencies and percentages were estimated. One-hundred and ninety-one patients were included, out of which 63.4% were females. Mean age was 22.5 years; 19.3 % showed positive skin reactivity to at least one food. Distribution by age group was as follows: preschool children 13.5 %, schoolchildren 24.3 %, adolescents 2.7 % and adults 59.5 %. Diagnoses included allergic rhinitis in 84.3 %, asthma in 19.4 %, urticaria in 14.1 % and atopic dermatitis in 8.4 %. Positive skin reactivity frequency distribution in descending order was: soybeans with 5.2 %, peach with 4.7 %, grapes, orange and apple with 3.6 %, nuts with 3.1 %, pineapple, avocado, tomato and tuna with 2.6 %. The frequency of skin reactivity to food allergens was similar to that reported in the national and Latin American literature, but sensitization to each specific allergen varied for each age group.


Pain and behaviour in cluster headache. A prospective study and review of the literature.
Cluster headache (CH) has also been called "suicide headache" on account of the extremely severe pain that characterizes its attacks. It is indeed well known that CH sufferers exhibit peculiar behaviours during attacks. The purposes of our study were: i) to investigate prospectively prodromes and clinical pain features and behaviour of patients during typical, spontaneous attacks of CH defined according to the International Headache Society classification criteria; and ii) to investigate retrospectively the premonitory signs and symptoms preceding onset of the cluster period. Forty-two episodic CH patients consecutively referred to the University of Parma Headache Centre were asked to fill in a questionnaire soon after a "typical" CH attack. In the questionnaires, the patients were requested: a) to describe in their own words the type of pain experienced during the attack; b) to rate peak pain intensity on a visual analogue scale (VAS); c) to indicate the time elapsing between headache onset and peak pain intensity; d) to report the signs and symptoms preceding the attack (prodromes), choosing them from a 65-item list; and, e) to describe in their own words their behaviour during the attack. Each patient was also requested to report any signs and/or symptoms preceding onset of the cluster period (premonitory symptoms). Data analysis showed that the clinical features of pain were very complex and varied widely among patients. In 85.7% of cases, patients rated their peak pain intensity (reached on average within 8.9 minutes of attack onset) at between 8 and 10 on the VAS. Most (88.1%) exhibited typical signs of pyschomotor agitation (restlessness) during the attack. Prodromes were reported by almost all the patients in our sample (97.6%), and premonitory symptoms by only 40.5%. The results of our study suggest: i) that the pain in CH cannot be described either as vascular- or as neuralgic-type; ii) that a traditional three-item scale (mild, moderate, severe) does not allow adequate categorization of pain intensity, and should be replaced by the VAS in order to reflect a broader spectrum of pain intensity; iii) that restlessness during attacks is so frequent that it should become a CH diagnostic criterion; and, iv) that prompt and accurate reporting of prodromes and/or premonitory symptoms could be helpful in establishing early treatment.


Convective paracellular solute flux. A source of ion-ion interaction in the epithelial transport equations.
An electrolyte model of an epithelium (a cell and a tight junction in parallel, both in series with a lateral interspace basement membrane) is analyzed using the formalism of nonequilibrium thermodynamics. It is shown that if the parallel structures are heteroporous (i.e., reflection coefficients for two ion species differ between the components), then a cross-term will appear in the overall transport equations of the epithelium. Formally, this cross-term represents an ion-ion interaction. With respect to the rat proximal tubule, data indicating epithelial ionic reflection coefficients less than unity, together with the assumption of no transcellular solvent drag, imply the presence of convective paracellular solute flux. This means that a model applicable to a heteroporous structure must be used to represent the tubule, and, in particular, the cross-terms for ion-ion interaction must also be evaluated in permeability determinations. A series of calculations is presented that permits the estimation of the Na-Cl interaction for rat proximal tubule from available experimental data. One consequence of tubule heteroporosity is that an electrical potential may be substantially less effective than an equivalent concentration gradient in driving reabsorptive ion fluxes.


Safety and efficacy of oral flecainide acetate in patients with cardiac arrhythmias.
We retrospectively studied the clinical efficacy and safety of oral flecainide in 38 patients with symptomatic arrhythmias. Patients received 100 to 200 mg daily of flecainide for a mean of 25 months (range 8 to 50 months). All patients had normal cardiac function. Paroxysmal atrial fibrillation (PAF) was observed in 29 patients (76%). Other forms of arrhythmia included paroxysmal atrial flutter, seen in 3 patients (8%); premature atrial contraction and ventricular premature contraction, each seen in 2 patients (5%); and supraventricular tachycardia and ventricular tachycardia, each seen in 1 patient (3%). A complete response was obtained in 15 (52%) of 29 patients with PAF and a partial response in 8 patients (27%). The remaining 6 patients (21%) showed no response. A complete response was also obtained in 7 of 9 patients with other forms of arrhythmia. There were no differences in cardiac function and ECG parameters before and after treatment. Flecainide was withdrawn in 4 patients due to the development of electrocardiographic abnormalities. Three of these patients showed an atrial proarrhythmic effect. Abnormal ST elevations in the precordial leads were observed in 1 patient who received 200 mg of flecainide daily. In conclusion, flecainide was effective treatment for supraventricular and ventricular arrhythmias, but attention must be paid to the drug's potential proarrhythmic adverse effects.


Effects of intrathecal administration of neuropeptides on a spinal nociceptive reflex in the rat: VIP, galanin, CGRP, TRH, somatostatin and angiotensin II.
The present study examines the effects of intrathecal administration of selected peptides on nociceptive responses in the rat. Each peptide was delivered via a chronically implanted catheter to the L5 vertebral level. In the tail flick test, VIP (0.65-6.5 nmoles) produced a dose-dependent decrease in reaction time (RT) from 1 to 6-16 min after injection; 6.5 nmoles decreased RT to 37% of control value at 1 min after injection. Galanin (0.65-6.5 nmoles) produced a dose-dependent increase in reaction time at 1 and 6 min; at high doses, many of the rats failed to flick the tail. CGRP (6.5 nmoles) produced a small, transient decrease in RT to 73% of control values at 1 min; 3.25 nmoles were without effect. CSF and 6.5 nmoles of somatostatin, TRH and angiotensin II were without effect. At high doses of galanin and CGRP, rats vocalized to innocuous touch of the tail, as reported for substance P. Von Frey hairs were thus applied to the tail after 6.5 nmoles of VIP, galanin, CGRP or substance P. Vocalization in response to a previously innocuous pressure stimulus was observed at 30 s after injection in all rats given galanin and some rats given CGRP or substance P; the effect lasted 4-8 min. VIP and CSF had no effect. These results suggest that VIP, galanin, CGRP and substance P may act as excitatory agents in nociceptive pathways and that specific peptides may function in the different types of pain modalities; VIP in thermal, galanin in mechanical and substance P and CGRP in both.


High-resolution impedance mapping using electrically activated quantitative phase imaging.
Retrieving electrical impedance maps at the nanoscale rapidly via nondestructive inspection with a high signal-to-noise ratio is an unmet need, likely to impact various applications from biomedicine to energy conversion. In this study, we develop a multimodal functional imaging instrument that is characterized by the dual capability of impedance mapping and phase quantitation, high spatial resolution, and low temporal noise. To achieve this, we advance a quantitative phase imaging system, referred to as epi-magnified image spatial spectrum microscopy combined with electrical actuation, to provide complementary maps of the optical path and electrical impedance. We demonstrate our system with high-resolution maps of optical path differences and electrical impedance variations that can distinguish nanosized, semi-transparent, structured coatings involving two materials with relatively similar electrical properties. We map heterogeneous interfaces corresponding to an indium tin oxide layer exposed by holes with diameters as small as ~550 nm in a titanium (dioxide) over-layer deposited on a glass support. We show that electrical modulation during the phase imaging of a macro-electrode is decisive for retrieving electrical impedance distributions with submicron spatial resolution and beyond the limitations of electrode-based technologies (surface or scanning technologies). The findings, which are substantiated by a theoretical model that fits the experimental data very well enable achieving electro-optical maps with high spatial and temporal resolutions. The virtues and limitations of the novel optoelectrochemical method that provides grounds for a wider range of electrically modulated optical methods for measuring the electric field locally are critically discussed.


Distinct clonal repertoire of brain CD8+ cells in simian immunodeficiency virus infection.
Infection with simian immunodeficiency virus (SIV), like HIV, can lead to central nervous system (CNS) abnormalities. One of the alterations observed in the brain is the accumulation of highly activated CD8 lymphocytes that, while fighting the infection, may cause tissue damage. In order to determine whether these CD8 cells in the brain comprise a distinct clonal population the expression of T-cell receptor (TCR) genes of two SIV-infected monkeys with CNS abnormalities were analyzed, comparing brain to periphery. RNA from magnetically sorted CD8+ cells obtained from the brain, blood, lymph nodes, and spleen was analyzed for the distribution of 24 Vbeta family genes by reverse transcriptase-polymerase chain reaction followed by Southern blot. The CDR3 region of the most enriched family in each brain was sequenced in all the sites for comparison. The pattern of Vbeta distribution in the brain and the periphery was polyclonal, but an increase in certain Vbeta families was found in the brain, suggesting that regional mechanisms participate in the determination of the local clonal specificities. The sequence of the CDR3 domain of predominant Vbeta families in the brain revealed that approximately one-third of the CD8 cells were not identified in the periphery. CD8 cells in the brain exhibit a distinct clonal repertoire. This distinction may have implications for regional immunity, regulation, or selection of site-specific viral mutants.


Insect aerodynamics: vertical sustaining force in near-hovering flight.
The source of vertical sustaining force for large insects capable of near-hovering flight is unclear. Induced velocities of a simulation of the insect Melolontha vulgaris in forward flight were measured with a hot-wire anemometer. The results were negative with respect to the drag concept of vertical force, but provided certain support for the circulation concept. Unsteady effects (the effects of variant air velocity) proved significant.


Dual EGFR/HER2 inhibition sensitizes prostate cancer cells to androgen withdrawal by suppressing ErbB3.
Patients with recurrent prostate cancer are commonly treated with androgen withdrawal therapy (AWT); however, almost all patients eventually progress to castration resistant prostate cancer (CRPC), indicating failure of AWT to eliminate androgen-sensitive prostate cancer. The overall goal of these studies is to determine whether dual inhibition of the receptor tyrosine kinases epidermal growth factor receptor (EGFR) and HER2 would prolong the effectiveness of this treatment in prostate cancer. We used androgen-dependent LNCaP cells and its CRPC sublines LNCaP-AI and C4-2. Additional data were collected in pRNS-1-1 cells stably expressing a mutant androgen receptor (AR-T877A), and in nude mice harboring CWR22 tumors. Studies utilized EGFR inhibitors erlotinib and AG1478, and HER2 inhibitors trastuzumab and AG879. Dual EGFR/HER2 inhibition induced apoptosis selectively in androgen-sensitive prostate cancer cells undergoing AWT, but not in the presence of androgens, or in CRPC cells. We show that AWT alone failed to induce significant apoptosis in androgen-dependent cells, due to AWT-induced increase in HER2 and ErbB3, which promoted survival by increasing Akt phosphorylation. AWT-induced ErbB3 stabilized the AR and stimulated PSA, while it was inactivated only by inhibition of both its dimerization partners EGFR and HER2 (prostate cancer cells do not express ErbB4); but not the inhibition of any one receptor alone, explaining the success of dual EGFR/HER2 inhibition in sensitizing androgen-dependent cells to AWT. The effectiveness of the inhibitors in suppressing growth correlated with its ability to prevent Akt phosphorylation. These studies indicate that dual EGFR/HER2 inhibition, administered together with AWT, sensitize prostate cancer cells to apoptosis during AWT.


[Assessment of the impacts of soil erosion on water environment based on the integration of soil erosion process and landscape pattern].
The integration of the effects of landscape pattern to the assessment of the impacts of soil erosion on eco-environmental is of practical significance in methodological prospect, being able to provide an approach for identifying water body's sediment source area, assessing the potential risks of sediment export of on-site soil erosion to the target water body, and evaluating the capacity of regional landscape pattern in preventing soil loss. In this paper, the RUSLE model was applied to simulate the on-site soil erosion rate. With the consideration of the soil retention potential of vegetation cover and topography, a quantitative assessment was conducted on the impacts of soil erosion in the water source region of the middle route for South-to-North Water Transfer Project on rivers and reservoirs by delineating landscape pattern at point (or cell) scale and sub-watershed level. At point (or grid cell) scale, the index of soil erosion impact intensity (I) was developed as an indicator of the potential risk of sediment export to the water bodies. At sub-watershed level, the landscape leakiness index (LI) was employed to indicate the sediment retention capacity of a given landscape pattern. The results revealed that integrating the information of landscape pattern and the indices of soil erosion process could spatially effectively reflect the impact intensity of in situ soil erosion on water bodies. The LI was significantly exponentially correlated to the mean sediment retention capacity of landscape and the mean vegetation coverage of watershed, and the sediment yield at sub-watershed scale was significantly correlated to the LI in an exponential regression. It could be concluded that the approach of delineating landscape pattern based on soil erosion process and the integration of the information of landscape pattern with its soil retention potential could provide a new approach for the risk evaluation of soil erosion.


The Contribution of Phonological Awareness to Reading Fluency and Its Individual Sub-skills in Readers Aged 9- to 12-years.
Research examining phonological awareness (PA) contributions to reading in established readers of different skill levels is limited. The current study examined the contribution of PA to phonological decoding, visual word recognition, reading rate, and reading comprehension in 124 fourth to sixth grade children (aged 9-12 years). On the basis of scores on the FastaReada measure of reading fluency participants were allocated to one of three reading ability categories: dysfluent (n = 47), moderate (n = 38) and fluent (n = 39). For the dysfluent group, PA contributed significantly to all reading measures except rate, but in the moderate group only to phonological decoding. PA did not influence performances on any of the reading measures examined for the fluent reader group. The results support the notion that fluency is characterized by a shift from conscious decoding to rapid and accurate visual recognition of words. Although PA may be influential in reading development, the results of the current study show that it is not sufficient for fluent reading.


Development of EST-SSR markers in castor bean (Ricinus communis L.) and their utilization for genetic purity testing of hybrids.
Expressed sequence tag (EST) databases offer opportunity for the rapid development of simple sequence repeat (SSR) markers in crops. Sequence assembly and clustering of 57 895 ESTs of castor bean resulted in the identification of 10 960 unigenes (6459 singletons and 4501 contigs) having 7429 SSRs. On an average, the unigenes contained 1 SSR for every 1.23 kb of unigene sequence. The identified SSRs mostly consisted of dinucleotide (62.4%) and trinucleotide (33.5%) repeats. The AG class was the most common among the dinucleotide motifs (68.9%), whereas the AAG class (25.9%) was predominant among the trinucleotide motifs. A total of 611 primer pairs were designed for the SSRs, having repeat length more than or equal to 20 nucleotides, of which a set of 130 markers were tested and 92 of these yielding robust amplicons were analyzed for their utility in genetic purity assessment of castor bean hybrids. Nine markers were able to detect polymorphism between the parental lines of nine commercial castor bean hybrids (DCH-32, DCH-177, DCH-519, GCH-2, GCH-4, GCH-5, GCH-6, GCH-7, and RHC-1), and their utility in genetic purity testing was demonstrated. These novel EST-SSR markers would be a valuable addition to the growing molecular marker resources that could be used in genetic improvement programmes of castor bean.


Ultrasound contrast agents: updated data on safety profile.
Contrast echocardiography represents a major technological advancement in the constantly evolving field of cardiovascular imaging. Over the last twenty years numerous studies have been published, illustrating the incremental value of contrast implementation into a variety of clinical scenarios. However, serious concerns have been raised about contrast safety profile, mainly based on postmarketing observational data and several animal studies. The latter have investigated contrast bio effects under experimental conditions that are not consistent with daily clinical practice. On the other hand, numerous clinical trials with large registries have proven otherwise. Not only contrast agents are efficient, but they also demonstrate a remarkable safety profile. So the question is: should we fear contrast utilization or should we consider them as an adjunctive and indispensable clinical tool for daily bedside practice?


Psychological and psychiatric aspects of psychogenic non-epileptic seizures (PNES): A systematic review.
Psychogenic non-epileptic seizures (PNES) are common in neurological settings and often associated with considerable distress and disability. The psychological mechanisms underlying PNES are poorly understood and there is a lack of well-established, evidence-based treatments. This paper advances our understanding of PNES by providing a comprehensive systematic review of the evidence pertaining to the main theoretical models of this phenomenon. Methodological quality appraisal and effect size calculation were conducted on one hundred forty empirical studies on the following aspects of PNES: life adversity, dissociation, anxiety, suggestibility, attentional dysfunction, family/relationship problems, insecure attachment, defence mechanisms, somatization/conversion, coping, emotion regulation, alexithymia, emotional processing, symptom modelling, learning and expectancy. Although most of the studies were only of low to moderate quality, some findings are sufficiently consistent to warrant tentative conclusions: (i) physical symptom reporting is elevated in patients with PNES; (ii) trait dissociation and exposure to traumatic events are common but not inevitable correlates of PNES; (iii) there is a mismatch between subjective reports of anxiety and physical arousal during PNES; and (iv) inconsistent findings in this area are likely to be attributable to the heterogeneity of patients with PNES. Empirical, theoretical and clinical implications are discussed.


The role of Engrailed in establishing the dorsoventral axis of the chick limb.
Expression and mutation analyses in mice suggest that the homeobox-containing gene Engrailed (En) plays a role in dorsoventral patterning of the limb. During the initial stages of limb bud outgrowth, En-1 mRNA and protein are uniformly distributed throughout the ventral limb bud ectoderm. Limbs of En-1(-/-) mice display a double dorsal phenotype suggesting that normal expression of En-1 in the ventral ectoderm is required to establish and/or maintain ventral limb characteristics. Loss of En-1 function also results in ventral expansion of the apical ectodermal ridge (AER), suggesting that En-1 is also required for proper formation of the AER. To further investigate the role En plays in dorsoventral patterning and AER formation, we have used the replication competent retroviral vector, RCAS, to mis-express mouse En-1 in the early chick limb bud. We show that ectopic En-1 expression in dorsal ectoderm is sufficient to repress the endogenous expression of the dorsal ectodermal marker Wnt7a, with a resultant decrease in Lmx1 expression in underlying dorsal mesenchyme. Furthermore, the AER is disrupted morphologically and the expression patterns of the AER signalling molecules Fgf-8 and Fgf-4 are altered. Consistent with recent evidence that there is a reciprocal interaction between signalling molecules in the dorsal ectoderm, AER, and zone of polarising activity (ZPA), loss of Wnt7a, Fgf-8 and Fgf-4 expression leads to a decrease in expression of the signalling molecule Shh in the ZPA. These results strongly support the idea that, in its normal domain of expression, En-1 represses Wnt7a-mediated dorsal differentiation by limiting the expression of Wnt7a to the dorsal ectoderm. Furthermore, our results provide additional evidence that En-1 is involved in AER formation and suggest that En-1 may act to define ventral ectodermal identity.


Annual appraisal and liege homage: why the British NHS is fundamentally a feudal organisation.
A study of the past can help us understand present-day management structures. Strong parallels can be seen between the present-day British National Health Service (NHS) and English feudal society in the early Middle Ages. Both systems are hierarchical, both show limited mobility between layers in the hierarchies and in both there is a strong element of central control coexisting with significant day-to-day delegation of responsibility. Ceremony plays a key role in relationships, such as through the swearing of liege homage in feudal society and through formal assessment and appraisal in the modern NHS. Although the NHS clearly does not show parallels for every element of feudal society, it is possible to draw practical lessons from the comparison, particularly relating to the ownership of problems, team-working and appraisal.


Beyond the feedforward sweep: feedback computations in the visual cortex.
Visual perception involves the rapid formation of a coarse image representation at the onset of visual processing, which is iteratively refined by late computational processes. These early versus late time windows approximately map onto feedforward and feedback processes, respectively. State-of-the-art convolutional neural networks, the main engine behind recent machine vision successes, are feedforward architectures. Their successes and limitations provide critical information regarding which visual tasks can be solved by purely feedforward processes and which require feedback mechanisms. We provide an overview of recent work in cognitive neuroscience and machine vision that highlights the possible role of feedback processes for both visual recognition and beyond. We conclude by discussing important open questions for future research.


Correction.
In the article by Mozaffarian et al, "Heart Disease and Stroke Statistics—2015 Update: A Report From the American Heart Association," which published online December 17, 2014, and appeared in the January 27, 2015, issue of the journal (Circulation. 2015;131:e29–e322. DOI:10.1161/ CIR.0000000000000152), several corrections were needed. These corrections have been made to the current online version of the article, which is available at http://circ.ahajournals.org/content/131/4/e29.full.


Ureteroscopic laser papillotomy to treat papillary calcifications associated with chronic flank pain.
To evaluate retrospectively the efficacy and durability of a novel approach using ureteroscopic laser papillotomy for the treatment of painful papillary calcifications. Chronic pain due to renal papillary calcifications has not been addressed by current techniques. Ureteroscopic holmium laser lithotripsy and papillotomy were performed on patients with chronic pain and radiographically visible papillary calcifications without free collecting system calculi. The papillary urothelium overlying all cystic dilations and intraductal calcifications was vaporized. Treated patients answered a telephone survey to assess pain scores, duration of response, use of narcotics, and patient satisfaction. We reviewed the medical records to evaluate for procedure-related complications and serum creatinine measurements. Of 20 patients who underwent laser papillotomy and responded to the telephone survey, 7 had bilateral procedures, yielding 27 renal units available for analysis. "Much less pain" was reported after 85% of the procedures, with a durable improvement reported after 59% of the procedures, at a median follow-up of 14.5 months. Significant improvements in the median pain scores were seen at 1 month (1.0, P <0.001), 6 months (2.0, P <0.001), and 1 year (1.5, P <0.001) compared with a median preoperative pain score of 9.0. The mean serum creatinine was unchanged after the procedure. Ureteroscopic laser papillotomy appears to be an effective treatment option for the chronic pain associated with papillary calcifications. Laser papillotomy offers hope to patients who would otherwise have been denied an attempt at treatment because of a lack of free calculi within the collecting system.


Temperature-related mortality in France, a comparison between regions with different climates from the perspective of global warming.
This paper aims to explain the results of an observational population study that was carried out between 1991 and 1995 in six regions (departments) in France. The study was to assess the relationship between temperature and mortality in a few areas of France that offer widely varying climatic conditions and lifestyles, to determine their thermal optimum, defined as a 3 degrees C temperature band with the lowest mortality rate in each area, and then to compare the mortality rates from this baseline band with temperatures above and below the baseline. The study period was selected because it did not include extreme cold or hot events such as a heatwave. Data on daily deaths from each department were first used to examine the entire population and then to examine men, women, various age groups and various causes of death (respiratory disease, stroke, ischaemic heart disease, other disease of the circulatory system, and all other causes excluding violent deaths). Mean temperatures were provided by the National Weather Service. The results depicted an asymmetrical V- or U-shaped relationship between mortality and temperature, with a thermal optimum lower for the elderly, and generally lower for women than for men except in Paris. The relationship was also different depending on the cause of death. In all cases, more evidence was collected showing that cold weather was more deadly than hot weather, and it would now be interesting to enlarge the study to include years with cold spells and heatwaves. Furthermore, the results obtained could be of great use in estimating weather-related mortality as a consequence of future climate-change scenarios.


Daidzein-metabolizing phenotypes in relation to mammographic breast density among premenopausal women in the United States.
Mammographic breast density is an established marker of breast cancer risk, and is hormonally sensitive. Studies suggest that production of the daidzein metabolites equol and O-Desmethylangolensin (ODMA) may be associated with hormones and hormonally mediated factors, but few studies have assessed relationships between the capacity to produce these metabolites and breast density. To evaluate the relationship between equol- and ODMA-producer phenotypes and breast density in premenopausal women in the United States. Two hundred and three women attended a clinic visit and 200 provided a urine sample following a 3 day soy challenge. Samples were analyzed for isoflavones by GC-MS to determine daidzein-metabolizing phenotypes. Percent density on recent (<14 month prior to their clinic visit) mammograms was assessed by one reader using a computer-assisted method. Multiple regression analysis was used to assess relationships between the production of equol and ODMA and breast density. Results 55(27.5%) and 182(91%) women were classed as equol- and ODMA-producers (>87.5 ng/ml urine), respectively. In unadjusted and adjusted analyses, there were no differences in breast density between producers and non-producers of either equol or ODMA (P > 0.05). In this population of low-soy consuming premenopausal women, there were no associations between daidzein-metabolizing phenotypes and breast density, suggesting that these phenotypes per se do not influence premenopausal breast density.


A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains.
Pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains are structurally related regulatory modules that are present in a variety of proteins involved in signal transduction, such as kinases, phospholipases, GTP exchange proteins, and adapter proteins. Initially these domains were shown to mediate protein-protein interactions, but more recently they were also found to bind phosphoinositides. Most studies to date have focused on binding of PH domains to phosphatidylinositol (PtdIns)-4-P and PtdIns-4,5-P2 and have not considered the lipid products of phosphoinositide 3-kinase: PtdIns-3-P, PtdIns-3,4-P2, and PtdIns-3,4,5-P3. Here we have compared the phosphoinositide specificity of six different PH domains and the Shc PTB domain using all five phosphoinositides. We show that the Bruton's tyrosine kinase PH domain binds to PtdIns-3,4, 5-P3 with higher affinity than to PtdIns-4,5-P2, PtdIns-3,4-P2 or inositol 1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4). This selectivity is decreased by the xid mutation (R28C). Selective binding of PtdIns-3,4,5-P3 over PtdIns-4,5-P2 or PtdIns-3,4-P2 was also observed for the amino-terminal PH domain of T lymphoma invasion and metastasis protein (Tiam-1), the PH domains of Son-of-sevenless (Sos) and, to a lesser extent, the PH domain of the beta-adrenergic receptor kinase. The oxysterol binding protein and beta-spectrin PH domains bound PtdIns-3,4,5-P3 and PtdIns-4,5-P2 with similar affinities. PtdIns-3,4,5-P3 and PtdIns-4,5-P2 also bound to the PTB domain of Shc with similar affinities and lipid binding was competed with phosphotyrosine (Tyr(P)-containing peptides. These results indicate that distinct PH domains select for different phosphoinositides.


Use of Force in Somatic Treatment of Adults in Denmark.
The article provides a critical analysis of the new Danish Act on Use of Force in Somatic Treatment of Adults with a Permanently Impaired Ability to Give Consent (FTAC, Act no. 655 of 8 June 2017), which covers adults unable to give an informed consent. The rules in the Act are included in the legal framework governing medical treatment with and without consent in Denmark, and the article draws on international human rights in connection with the subject matter. The aim of the article is also to highlight the grey areas that still exist despite the new rules and to provide legal argumentation for solutions to the issues that can arise in these legal grey areas.


Efficacy of Local Anesthetic With Dexamethasone on the Quality of Recovery Following Total Extraperitoneal Bilateral Inguinal Hernia Repair: A Randomized Clinical Trial.
Quality of recovery (directly associated with patient satisfaction) is an important clinical outcome measurement and a surrogate of anesthetic/surgical care quality. To compare the efficacy of a transversus abdominis plane (TAP) block with dexamethasone sodium phosphate and preperitoneal instillation of local anesthetic (PILA) with dexamethasone vs control on postoperative quality of recovery following a bilateral total extraperitoneal inguinal hernia repair (TEP-IHR) (>24 hours). Secondary objectives included efficacy of this technique on postoperative opioid use, nausea and vomiting, and pain scores. Conducted from November 2013 to August 2015, this randomized, prospective, single-blinded study compared 2 groups (a TAP block and PILA) with a standard anesthetic technique with no regional technique (control) following bilateral TEP-IHR. This study at the Veterans Affairs Medical Center (Indianapolis, Indiana) included patients ages 18 to 80 years with an American Society of Anesthesiologists physical status of 1 to 3 scheduled for an outpatient bilateral TEP-IHR. Nurses assigning pain scores and administrating opioids for pain and staff anesthesiologists administering the Quality of Recovery-40 (QoR-40) questionnaire were blinded. Patients randomized to receive a TAP block with local anesthetics and dexamethasone, PILA with dexamethasone, or no regional technique (3 groups). Patient's response to the QoR-40 questionnaire following a TEP-IHR surgery. The mean (SD) ages in the TAP block (n = 19), PILA (n = 24), and control (n = 23) groups were 58.2 (9.4) years, 62.5 (8.1) years, and 62.9 (7.8) years, respectively. The global QoR-40 scores on postoperative day 1 for the TAP block group (median [interquartile range (IQR)], 178 [173-188]) were comparable with the control group (median [IQR], 174 [150-181]), while the PILA group had better global QoR-40 scores (median [IQR], 184 [175.5-190.75]) (P = .002). The effects of the TAP block and PILA on pain in the postoperative care unit (PACU) (median [IQR], 1 [0-5] and 3.5 [0-6.8], respectively), pain after discharge (median [IQR], 3 [2-5] and 3 [1-5.5], respectively), opiate use after discharge (median [IQR], 6.7 [5-10] and 6.7 [3.3-10], respectively), and incidence of nausea and vomiting in the PACU (4 of 19 [21.1%] and 6 of 24 [25%], respectively) were not significantly different from the control group (median [IQR], 4 [3-6] for pain scores in the PACU; 4 [3-7] for pain scores after discharge; 6.7 [3.3-10] for opioid use after discharge; and 6 of 23 [26.1%] for incidence of nausea/vomiting in the PACU). While there was a significant reduction of opioid use in the PACU in the TAP block group (median [IQR], 0 [0-1.3]) when compared with the control group (median [IQR], 4 [1.3-6.7]) (P = .001), this was not seen in the PILA group (median [IQR], 2 [0-6.4]). This study demonstrates a better quality of recovery in patients' receiving PILA with dexamethasone compared with control for a TEP-IHR surgery. clinicaltrials.gov Identifier: NCT02036983.


Effect of extrinsic incubation temperature on the ability of Aedes taeniorhynchus and Culex pipiens to transmit Rift Valley fever virus.
Studies were conducted to examine the effects of extrinsic incubation (EI) temperature on the vector competence of Egyptian Culex pipiens and North American Aedes taeniorhynchus for Rift Valley fever (RVF) virus. Following per os exposure, infection rates in Ae. taeniorhynchus remained relatively constant at 55%, 56%, and 59% for mosquitoes held at EI temperatures of 13, 26, and 33 degrees C, respectively. In contrast, significantly fewer Cx. pipiens became infected when held at 13 degrees C (38%), than when held at 26 degrees C (75%) or 33 degrees C (91%). In both species, viral dissemination and transmission occurred earlier in mosquitoes held at high temperatures as compared to those held at low temperatures. Following EI at 26 or 33 degrees C, Cx. pipiens were able to transmit virus as early as 1 day after inoculation with RVF virus. However, 3 days were required before the first transmissions by inoculated Ae. taeniorhynchus. Temperature of EI affected these 2 species differently in their ability to transmit RVF virus. Because of the importance of EI temperature on infection and transmission rates, as well the length of the EI period, the role of EI temperature will need to be evaluated for each virus and vector pair.


Fungicidal activity of murine broncho-alveolar macrophages against Blastomyces dermatitidis.
The fungicidal activity of murine broncho-alveolar macrophages (BAM) against the yeast form of a virulent strain of Blastomyces dermatitidis was studied in the small-volume wells of a Terasaki plate. In a 4-h fungicidal assay, significant killing (16-33%) of the fungus by unstimulated BAM was demonstrated with BAM from normal mice and from mice rendered immune to lethal infection with B. dermatitidis. No significant differences between the activity of BAM from these two sources could be identified. Addition of 10% autologous normal or immune serum did not augment the macrophage fungicidal activity. Simultaneous experiments with peritoneal macrophages (PM) also gave reproducible killing of the yeast form in the wells of the Terasaki plate, but in the larger wells of microtitration plates, PM showed no significant fungicidal activity. On the other hand, BAM had similar fungicidal activity against B. dermatitidis in Terasaki and microtitration-plate wells. The modest fungicidal activity of BAM from immune mice against B. dermatitidis suggests that the resistance of immune mice to respiratory challenge is likely to be based on some augmentation of this first line of defence.


Placement of Stimulating Epidural Catheter for a Patient With Large Scapular Sarcoma: A Case Report.
We report the use of continuous electrical stimulation to assist with the preoperative placement of a thoracic epidural which was used to provide postoperative analgesia in a patient undergoing excision of a large scapular sarcoma. The size of the sarcoma and the surrounding area required to maintain a sterile surgical field necessitated that the epidural catheter be inserted several vertebral interspaces caudal to the level of desired catheter tip termination. The use of electrical stimulation allowed for sequential intercostal muscle stimulation during threading, which enabled the placement of the catheter tip at the appropriate spinal level to optimize analgesia.


The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders.
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) is a significant source of disability in the HIV-infected population. Even with stringent adherence to anti-retroviral therapy, >50% of patients living with HIV-1 will develop HAND (Heaton et al., 2010). Because suppression of viral replication alone is not enough to stop HAND progression, there is a need for an adjunctive neuroprotective therapy in this population. To this end, we have developed a small-molecule brain-penetrant inhibitor with activity against mixed-lineage kinase 3 (MLK3), named URMC-099. MLK3 activation is associated with many of the pathologic hallmarks of HAND (Bodner et al., 2002, 2004; Sui et al., 2006) and therefore represents a prime target for adjunctive therapy based on small-molecule kinase inhibition. Here we demonstrate the anti-inflammatory and neuroprotective effects of URMC-099 in multiple murine and rodent models of HAND. In vitro, URMC-099 treatment reduced inflammatory cytokine production by HIV-1 Tat-exposed microglia and prevented destruction and phagocytosis of cultured neuronal axons by these cells. In vivo, URMC-099 treatment reduced inflammatory cytokine production, protected neuronal architecture, and altered the morphologic and ultrastructural response of microglia to HIV-1 Tat exposure. In conclusion, these data provide compelling in vitro and in vivo evidence to investigate the utility of URMC-099 in other models of HAND with the goal of advancement to an adjunctive therapeutic agent.


Presenting the model of risk, disability and hard-to-reach families to inform early intervention services.
Several concepts - risk, resilience, disability and hard-to-reach families in early intervention services - are talked and written about in many ways. Family Stress Theory can be usefully applied to explore these issues systematically. The relationship between risk and disability is complex, and the role of resilience is not fully understood. The idea of "hard-to-reach families" is not well defined, thus presenting challenges to service providers and policy makers. Reflection: This paper presents the Model of Risk, Disability and Hard-to-Reach Families and uses the model to: (1) define the groups of high risk families and families of children with disabilities and explore the concept of resilience within these groups; (2) describe services offered to these groups; and (3) reflect on service use and so-called "hard-to-reach families". Each section includes suggested applications for service providers that may inform the work done with young children and their families who experience risk or disability. Service providers can apply the Model of Risk, Disability and Hard-to-Reach Families to consider each family's unique strengths and challenges, and use those individual elements to influence service recommendations and anticipate service use. Implications for rehabilitation The concepts of risk, resilience, and hard-to-reach families are poorly defined in the literatures, but have important implications with respect to early childhood intervention services. Family Stress Theory can help to identify high-risk families and account for family resilience It is important for clinicians, researchers and policy makers to consider the relationship between disability and risk with respect to services offered to families and the potential barriers to service use. Clinicians and policy makers have a role in promoting accessible early childhood services.


Violence, coping, and consistent medication adherence in HIV-positive couples.
The purpose of this study was to investigate the extent to which intimate partner violence (IPV) influences antiretroviral medication adherence. Furthermore, it was hypothesized that adherence would differ for men and women based on degree of violence and coping strategies employed by each gender. A sample of HIV seroconcordant and serodiscordant heterosexual couples was recruited from the Miami area and assessed on rates of medication adherence, conflict resolution tactics, and coping strategies. Of these, 190 individual participants were prescribed antiretroviral medication. Baseline rates of adherence were 90.29% for men and 87.77% for women. Acts of violence were found to have negative effects on adherence for women but not for men. However, negative coping strategies were predictive of poor adherence for men but not women. Violence was found to be related to poor coping styles for both men and women. This study offers support for the inclusion of partners in conducting interventions. Furthermore, it underlines the importance of recognizing IPV as a barrier to medication adherence.


Microbiology of surgical site infections complicating breast surgery.
Surgical site infection (SSI) rates complicating breast surgery have ranged from 1-26%, but limited data have been provided regarding pathogen identification and in vitro susceptibility results. The aim of this study was to evaluate the results of bacterial cultures of breast SSI sites and antibiotic susceptibility testing to determine the clinical utility of these findings. Medical records were reviewed for SSI in patients who had undergone breast/axillary surgical procedures between June 2003 and June 2006. An SSI was defined by the criteria of the U.S. Centers for Disease Control and Prevention. Clinical data were collected on perioperative prophylactic antibiotics, organisms isolated, and resistance profiles. A total of 832 breast/axillary operations in 683 patients were included. Material was available for culture in 67/144 SSI (47%), but cultures were obtained from only 41 of these sites (61%). There were 25 sites with positive bacterial cultures from which 35 organisms were isolated. Staphylococci were the organisms isolated most commonly (n = 21; 60%); 14 other isolates (40%) included gram-negative bacilli and anaerobes. Susceptibility testing was performed on 16 (76%) of the staphylococcal isolates. Ten (63%) exhibited drug resistance; five were multi-drug resistant. Six of eight non-staphylococcal isolates tested (75%) exhibited antibiotic resistance; two were multi-drug resistant. Although the usual empiric treatment of SSI after breast surgery targets staphylococci, cultures with susceptibility profiles should be obtained because non-staphylococcal bacteria were commonly identified, and drug resistance was seen in more than one-half of the isolates. Further study is needed to define the optimal empiric antibiotic therapy for SSI after breast surgery.


Changes in health expenditures in China in 2000s: has the health system reform improved affordability.
China's health system reform launched in early 2000s has achieved better coverage of health insurance and significantly increased the use of healthcare for vast majority of Chinese population. This study was to examine changes in the structure of total health expenditures in China in 2000-2011, and to investigate the financial burden of healthcare placed on its population, particularly between urban and rural areas and across different socio-economic development regions. Health expenditures data came from the China National Health Accounts study in 1990-2011, and other data used to calculate the financial burden of healthcare were from China Statistical Yearbook and China Population Statistical Yearbook. Total health expenditures were divided into government and social expenditure, and out-of-pocket payment. The financial burden of healthcare was estimated as out-of-pocket payment per capita as a percentage of annual household living consumption expenditure per capita. Between 2000 and 2011, total health expenditures in China increased from Chinese yuan 319 to 1888 (United States dollars 51 to 305), with average annual increase of 17.4%. Government and social health expenditure increased rapidly being 22.9% and 18.8% of average annual growth rate, respectively. The share of out-of-pocket payment in total health expenditure for the urban population declined from 53% in 2005 to 36% in 2011, but had only a slight decrease for the rural population from 53% to 50%. Out-of-pocket payment, as a percentage of annual household living consumption, has continued to rise, particularly in the rural population from the less developed region (6.1% in 2000 to 8.8% in 2011). The rapid increase of public funding to subsidize health insurance in China, as part of the reform strategy, did not mitigate the out-of-pocket payment for healthcare over the past decade. Financial burden of healthcare on the rural population increased. Affordability among the rural households with sick members, particularly in the less developed region, is getting worse. It needs effective measures on cost control including healthcare provider payment reform and well developed health insurance schemes to offer better financial protection for the vulnerable Chinese seeking essential healthcare.