In-vitro evaluation of the quality of paracetamol and co-trimoxazole tablets used in Malawi based on pharmacopoeial standards.
This study was an in-vitro evaluation of different brands of paracetamol and cotrimoxazole tablets, used or found in Malawi, based on Pharmacopoeia standards, in order to ascertain the existence and extent of substandard medicines in Malawi and to give an overview of their distribution in the public and private sectors. A cross-sectional analytical study was conducted using 11 samples each of paracetamol and cotrimoxazole tablets. Stratified random sampling was used to collect samples. Samples were analyzed using HPLC and Spectrophometric methods as outlined in the BP-2007 and USP-32 at the National Drug Quality Control Laboratory (NDQCL)-Lilongwe (under Pharmacy Medicines and Poisons Board-PMPB) and Orient Pharma Co. Ltd of Taiwan. The results were analyzed using Epi Info. Fifty percent of samples (n=22) were not registered in the country by the PMPB as required by the PMP Act with the majority of those coming from public health facilities. All paracetamol and cotrimoxazole samples complied with identification tests using spectrophotometric and HPLC method. Overall, 27.3% of samples failed to meet the BP-2007 standards for Active Ingredient content, while 22.7% of the samples failed the Friability test. The results from Malawi are similar in magnitude to those within surrounding countries in Africa. This pilot study provides objective evidence to show that substandard and unregistered paracetamol and cotrimoxazole are present and being used in Malawi, and thus posing a considerable hazard to public health in Malawi. PMPB, together with the Ministry of Health, must continue to develop a quality assurance system to ensure that medicines are randomly and routinely checked.


[The sick cilia syndrome].
The incidence of bronchiectasis should decrease because of improved immunization, but certain defects would still cause the malady. Fifteen consecutive patients with bronchiectasis were examined for ciliary defects by examining the nasal mucosae with an electron microscope and measuring the clearance of technetium-99m from the lung with a gamma camera. Three patients were found to have defects. Compound cilia, disorganization of the tubular structure, vacuolization and deficient inner dynein arms were observed. In one patient a loss of cell membranes which returned to normal after 4 months, was observed. Ciliary abnormalitites can either be anatomical or physiological and 'sick cilia' should be considered as a cause of bronchiectasis.


An explicit quality indicator set for measurement of quality of care in patients with cirrhosis.
Cirrhosis is a prevalent and expensive condition. With an increasing emphasis on quality in health care and recognition of inconsistencies in the management of patients with cirrhosis, we established a set of explicit quality indicators (QIs) for their treatment. We organized an 11-member, multidisciplinary expert panel and followed modified Delphi methods to systematically identify a set of QIs for cirrhosis. We provided the panel with a report that summarized the results of a comprehensive literature review of data linking candidate QIs to outcomes. The panel performed independent ratings of each candidate QI by using a standard 9-point RAND appropriateness scale (RAS) (ranging from 1 = not appropriate to 9 = most appropriate). The panel members then met, reviewed the ratings, and voted again by using an iterative process of discussion. The final set of QIs was selected; QIs had a median RAS >7, and panel members agreed on those selected. Among 169 candidate QIs, the panel rated 41 QIs as valid measures of quality care. The selected QIs cover 6 domains of care including ascites (13 QIs), variceal bleeding (18 QIs), hepatic encephalopathy (4 QIs), hepatocellular cancer (1 QI), liver transplantation (2 QIs), and general cirrhosis care (3 QIs). Content coverage included prevention, diagnosis, treatment, timeliness, and follow-up. We developed an explicit set of evidence-based QIs for treatment of cirrhosis. These provide physicians and institutions with a tool to identify processes amenable to quality improvement. This tool is intended to be applicable in any setting where care for patients with cirrhosis is provided.


Decreased cervical cancer cell adhesion on nanotubular titanium for the treatment of cervical cancer.
Cervical cancer can be treated by surgical resection, chemotherapy, and/or radiation. Titanium biomaterials have been suggested as a tool to help in the local delivery of chemotherapeutic agents and/or radiation to cervical cancer sites. However, current titanium medical devices used for treating cervical cancer do not by themselves possess any anticancer properties; such devices act as carriers for pharmaceutical agents or radiation sources and may even allow for the growth of cancer cells. Based on studies, which have demonstrated decreased lung, breast, and bone cancer cell functions on nanostructured compared to nanosmooth polymers, the objective of the present in vitro study was to modify titanium to possess nanotubular surface features and determine cervical cancer cell adhesion after 4 hours. Here, titanium was anodized to possess nanotubular surface features. Results demonstrated the ability to decrease cervical cancer cell adhesion by about a half on nanotubular compared to currently used nanosmooth titanium (without the use of chemotherapeutics or radiation), opening up numerous possibilities for the use of nanotubular titanium in local drug delivery or radiation treatment of cervical cancer.


Upon the photostability of 8-nitro-cGMP and its caging as a 7-dimethylaminocoumarinyl ester.
8-Nitro-cGMP was recently discovered as a second messenger of nitric oxide. We describe here the synthesis and properties of DMACM-modified 8-nitro-cGMP for photochemical uncaging. Owing to the limited photostability of 8-nitro-cGMP care must be taken, but the photorelease of the intact product was readily feasible. Unexpectedly, 8-nitro-cGMP decays under formation of 8-nitrosoguanine when irradiated with light.


Optimizing the MIC breakpoints of amoxicillin and tetracycline for antibiotic selection in the rescue therapy of H. pylori with bismuth quadruple regimen.
H. pylori with triple-drug resistance (TR) to clarithromycin, metronidazole, and levofloxacin limits the success of rescue therapy. We aimed to identify the optimal breakpoints of antibiotic minimal inhibitory concentration (MIC) to predict the success of rescue therapy for TR H. pylori infection. We consecutively enrolled 430 patients with at least one course of failed H. pylori eradications to receive an H. pylori culture for antibiotic MIC test. Seventy-three (17%) had TR H. pylori infection (MIC of clarithromycin > 0.5, levofloxacin > 1, and metronidazole > 8 mg/L, respectively). Sixty-nine cases with TR H. pylori infection received rescue therapy with either ATBP (amoxicillin, tetracycline, bismuth, and PPI) or MTBP (metronidazole, tetracycline, bismuth and PPI) for 7-14 days. Fourteen patients with positive 13C-urea breath test after the first rescue therapy were retreated with a crossover second rescue therapy. The MTBP regimen had higher eradication success than the ATBP regimen as the first rescue therapy for TR H. pylori (intent-to-treat (ITT) analysis, 70.3 vs. 46.9%, p = 0.048; per protocol (PP) analysis, 78.8% vs. 51.7%, p = 0.025). For MTBP regimen, tetracycline MIC ≤ 0.094 mg/L (p < 0.001) with a 14-day treatment duration (p = 0.037) could predict eradication success with 100% accuracy. For the ATBP regimen, amoxicillin MIC selected as ≤ 0.032 mg/L could optimally determine eradication success (72.2 vs. 33.3%, p = 0.025). Optimizing the MIC breakpoints of amoxicillin and tetracycline resistance better predicts the outcome of bismuth quadruple therapy. Further prospective studies using the revised MIC breakpoints to select antibiotics are warranted.


Total hip arthroplasty following failed intertrochanteric hip fracture fixation treated with a cephalomedullary nail.
Cephalomedullary nails (CMNs) are commonly used for the treatment of intertrochanteric hip fractures. Total hip arthroplasty (THA) may be used as a salvage procedure when fixation fails in these patients. The aim of this study was to analyze the complications of THA following failed intertrochanteric hip fracture fixation using a CMN. Patients who underwent THA were identified from the 5% subset of Medicare Parts A/B between 2002 and 2015. A subgroup involving those with an intertrochanteric fracture that was treated using a CMN during the previous five years was identified and compared with the remaining patients who underwent THA. The length of stay (LOS) was compared using both univariate and multivariate analysis. The incidence of infection, dislocation, revision, and re-admission was compared between the two groups, using multivariate analysis adjusted for demographic, hospital, and clinical factors. The Medicare data yielded 56 522 patients who underwent primary THA, of whom 369 had previously been treated with a CMN. The percentage of THAs that were undertaken between 2002 and 2005 in patients who had previously been treated with a CMN (0.346%) more than doubled between 2012 and 2015 (0.781%). The CMN group tended to be older and female, and to have a higher Charlson Comorbidity Index and lower socioeconomic status. The mean LOS was 1.5 days longer (5.3 vs 3.8) in the CMN group (p < 0.0001). The incidence of complications was significantly higher in the CMN group compared with the non-CMN group: infection (6.2% vs 2.6%), dislocation (8.1% vs 4.5%), revision (8.4% vs 4.3%), revision for infection (1.1% vs 0.37%), and revision for dislocation (2.2% vs 0.6%). The incidence of conversion to THA following failed intertrochanteric hip fracture fixation using a CMN continues to increase. This occurs in elderly patients with increased comorbidities. There is a significantly increased risk of infection, dislocation, and LOS in these patients. Patients with failed intertrochanteric hip fracture fixation using a CMN who require THA should be made aware of the increased risk of complications, and steps need to be taken to reduce this risk. Cite this article: Bone Joint J 2019;101-B(6 Supple B):91-96.


Religiosity and adherence to antiretroviral therapy among patients attending a public hospital-based HIV/AIDS clinic in Uganda.
In Uganda, the prevalence of non-adherence to antiretroviral therapy (ART) by HIV/AIDS patients remains high and sometimes this is blamed on patients' religious behavior. A descriptive design was used to examine the relationship between religiosity and ART adherence in a sample of 220 patients attending a HIV/AIDS clinic in a Ugandan public hospital. Participants who self-identified as Pentecostal and Muslim had the highest percentage of members with high religiosity scores and ART adherence. Among Muslim participants (34), 82% reported high religiosity scores and high levels of ART adherence. Of the fifty Pentecostals participants, 96% reported high religiosity scores and 80% reported high levels of ART adherence. Correlation analysis showed a significant relationship between ART adherence and religiosity (r = 0.618, P ≤ 0.01). Therefore, collaboration between religious leaders and HIV/AIDS healthcare providers should be encouraged as one of the strategies for enhancing ART adherence.


Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death.
A specific search for intramyocardial platelet aggregates was made in 90 patients who died suddenly of ischemic heart disease. Platelet aggregates in small intramyocardial vessels were found in 27 (30%). There was a significant difference (p less than .05) in the incidence of platelet aggregates in patients with chest pain of recent onset (unstable angina) before death (16/36, 44.4%) and that in those without it (11/54, 20.4%). Multifocal microscopic necrosis with involvement of the full thickness of the ventricular wall, including the subpericardial zone, was significantly more common (p = less than .005) in the patients with platelet emboli (55.6% vs 12.7%). With one exception, aggregates were confined to the segment of myocardium immediately downstream of a major epicardial coronary artery containing an atheromatous plaque that had undergone fissuring and on which mural thrombus had developed. The results support the view that platelet aggregates in the myocardium represent an embolic phenomenon and are a potential cause of unstable angina. The association of myocardial necrosis with such emboli could precipitate sudden death from ventricular fibrillation.


Gene expression of benthic amphipods (genus: Diporeia) in relation to a circular ssDNA virus across two Laurentian Great Lakes.
Circular rep-encoding ssDNA (CRESS-DNA) viruses are common constituents of invertebrate viral consortia. Despite their ubiquity and sequence diversity, the effects of CRESS-DNA viruses on invertebrate biology and ecology remain largely unknown. This study assessed the relationship between the transcriptional profile of benthic amphipods of genus Diporeia and the presence of the CRESS-DNA virus, LM29173, in the Laurentian Great Lakes to provide potential insight into the influence of these viruses on invertebrate gene expression. Twelve transcriptomes derived from Diporeia were compared, representing organisms from two amphipod haplotype clades (Great Lakes Michigan and Superior, defined by COI barcode sequencing) with varying viral loads (up to 3 × 106 genome copies organism-1). Read recruitment to de novo assembled transcripts revealed 2,208 significantly over or underexpressed contigs in transcriptomes with above average LM29173 load. Of these contigs, 31.5% were assigned a putative function. The greatest proportion of annotated, differentially expressed transcripts were associated with functions including: (1) replication, recombination, and repair, (2) cell structure/biogenesis, and (3) post-translational modification, protein turnover, and chaperones. Contigs putatively associated with innate immunity displayed no consistent pattern of expression, though several transcripts were significantly overexpressed in amphipods with high viral load. Quantitation (RT-qPCR) of target transcripts, non-muscular myosin heavy chain, β-actin, and ubiquitin-conjugating enzyme E2, corroborated transcriptome analysis and indicated that Lake Michigan and Lake Superior amphipods with high LM29173 load exhibit lake-specific trends in gene expression. While this investigation provides the first comparative survey of the transcriptional profile of invertebrates of variable CRESS-DNA viral load, additional inquiry is required to define the scope of host-specific responses to potential infection.


The V angle compliments radiographic assessment of acute acromioclavicular joint dislocations by differentiating between Rockwood types III versus V and by considering dynamic horizontal translation in coronal radiographs.
Acromioclavicular joint (ACJ) dislocations are usually graded radiographically according to Rockwood, but differentiation between Rockwood types III and V may be ambiguous. The potentially clinically relevant horizontal instability is barely addressed in coronal radiographs. It was hypothesized that a new radiologic parameter (V angle) would complement ACJ diagnostics on anteroposterior radiographs by differentiating between cases of Rockwood III and V while also considering the aspect of dynamic horizontal translation (DHT). Ninety-five patients with acute ACJ dislocations (Rockwood types III and V) were included retrospectively between 2017 and 2020. On anteroposterior views (weightbearing: n = 62, non-weight-bearing: n = 33), the coracoclavicular (CC) distance and the newly introduced V angle for assessing scapular orientation were measured bilaterally. This angle is referenced between the spinal column and a line crossing the superior scapular angle and the crossing point between the supraspinatus fossa and the medial base of the coracoid process, reported as the side-comparative difference (non-injured side *minus* injured side). DHT on Alexander views was divided into stable, partially unstable or completely unstable. The V angle on the injured side alone (mean 50.0°; 95% confidence interval (CI), 48.6°-51.3°) showed no correlation with the side-comparative CC distance [%] (r = - 0.040; n.s.). Thus, the V angle on the non-injured side was considered, displaying a normal distribution (n.s.) with a mean of 58.0° (95% CI, 56.6°-59.4°). The side-comparative V angle showed a correlation with the side-comparative CC distance (r = 0.83; p < 0.001) and was able to differentiate between Rockwood types III (4.7°; 95% CI, 3.9°-5.5°; n = 39) and V (10.3°; 95% CI, 9.7°-11.0°; n = 56) (p < 0.001). A cut-off value of 7° had a 94.6% sensitivity and an 82.1% specificity (area under curve, AUC: 0.954; 95% CI, 0.915-0.994). The side-comparative V angle was greater for cases with complete DHT (8.7°; 95% CI, 7.9°-9.5°; n = 78) than for cases with partial DHT (4.8°; 95% CI, 3.3°-6.3°; n = 16) (p < 0.001). A cut-off value of 5° showed a sensitivity of 84.6% and a specificity of 66.7% (AUC 0.824; 95% CI, 0.725-0.924). The scapular-based V angle on anteroposterior radiographs distinguishes between Rockwood types III and V as well as cases with partial or complete DHT. Diagnostic study. Level II.


Pineal vasotocin: release into cat cerebrospinal fluid by melanocyte-stimulating hormone release-inhibiting factor.
The intracarotid injection of both synthetic melanocyte-stimulating hormone release-inhibiting factor (MIF) and purified MIF prepared from bovine hypothalami induces arginine vasotocin release into cerebrospinal fluid of cats and significantly decreases the pineal arginine vasotocin content at 5 minutes after the injection. The present results demonstrate an extrapituitary endocrine effect of synthetic and purified bovine MIF.


Desquamative interstitial pneumonia: a systematic review of its features and outcomes.
Desquamative Interstitial Pneumonia (DIP) is a rare form of idiopathic interstitial pneumonia (IIP). Data on clinical features, aetiology, prognosis and effect of treatment strategies are limited. We aimed to collect all published cases to better characterise DIP. A systematic literature search was performed for all original cases of adult patients with histopathologically-confirmed DIP. Individual patient data were extracted and summarised. We included 68 individual cases and 13 case series reporting on 294 cases. Most common presenting symptoms were dyspnoea and cough. Pulmonary function showed a restrictive pattern (71%) with decreased diffusion capacity. We found a high incidence (81%) of ever smoking in patients with DIP and 22% of patients had other (occupational) exposures. Characteristic features on high-resolution computed tomography (HRCT) scan were bilateral ground-glass opacities with lower lobe predominance (92%). Treatment and duration of treatment widely varied. Initial response to treatment was generally good, but definitely not uniformly so. A significant proportion of patients died (25% of individual cases) or experienced a relapse (18% of individual cases). DIP remains an uncommon disease, frequently but not always related to smoking or other exposures. Furthermore, DIP behaves as a progressive disease more often than generally thought, possibly associated with different underlying aetiology.


Prediction of Nocturnal Hypoglycemia From Continuous Glucose Monitoring Data in People With Type 1 Diabetes: A Proof-of-Concept Study.
Intensive insulin therapy has documented benefits but may also come at the expense of a higher risk of hypoglycemia. Hypoglycemia is associated with higher all-cause mortality and nocturnal hypoglycemia has been associated with the sudden dead-in-bed syndrome. This proof-of-concept study sought to investigate if nocturnal hypoglycemia can be predicted. Continuous glucose monitoring, meal, insulin, and demographics data from 463 people with type 1 diabetes were obtained from a clinical trial. A total of 4721 nights without or with hypoglycemia (429) were available including data from three consecutive days before the night. Thirty-two features were calculated based on these data. Data were split into 20% participants for evaluation and 80% for training. The optimal feature subset was found from forward selection of the 80% participants with linear discriminant analysis as basis for the classifier. The forward selection resulted in a feature subset of four features. The evaluation resulted in an area under the receiver operating characteristics curve (ROC-AUC) of 0.79 leading to a sensitivity and a specificity of, e.g., 75% and 70%. It was possible to predict nocturnal hypoglycemic episodes with a ROC-AUC of 0.79. A warning at bedtime about nocturnal hypoglycemia could be of great help for people with diabetes to enable preventive actions. Further development of the proposed algorithm is needed for implementation in everyday practice.


Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache.
The present study combined molecular and neuroimaging techniques to examine if free radical-mediated damage to barrier function in hypoxia would result in extracellular edema, raise intracranial pressure (ICP) and account for the neurological symptoms typical of high-altitude headache (HAH) also known as acute mountain sickness (AMS). Twenty-two subjects were randomly exposed for 18 h to 12% (hypoxia) and 21% oxygen (O2 (normoxia)) for collection of venous blood (0 h, 8 h, 15 h, 18 h) and CSF (18 h) after lumbar puncture (LP). Electron paramagnetic resonance (EPR) spectroscopy identified a clear increase in the blood and CSF concentration of O2 and carbon-centered free radicals (P<0.05 versus normoxia) subsequently identified as lipid-derived alkoxyl (LO*) and alkyl (LC*) species. Magnetic resonance imaging (MRI) demonstrated a mild increase in brain volume (7.0+/-4.8 mL or 0.6%+/-0.4%, P<0.05 versus normoxia) that resolved within 6 h of normoxic recovery. However, there was no detectable evidence for gross barrier dysfunction, elevated lumbar pressures, T2 prolongation or associated neuronal and astroglial damage. Clinical AMS was diagnosed in 50% of subjects during the hypoxic trial and corresponding headache scores were markedly elevated (P<0.05 versus non-AMS). A greater increase in brain volume was observed, though this was slight, independent of oxidative stress, barrier dysfunction, raised lumbar pressure, vascular damage and measurable evidence of cerebral edema and only apparent in the most severe of cases. These findings suggest that free-radical-mediated vasogenic edema is not an important pathophysiological event that contributes to the mild brain swelling observed in HAH.


[How to teach ballet to a swat?].
There is increasing interest in including humanities subjects in the medical curriculum, as a means of accelerating students' personal development and of helping them in their meeting with patients, in order to counteract a perceived communication deficit in the health care system. Traditionally, medical schools have favoured students who concentrate on what is most relevant for their exams, possibly at the expense of reflection, idealism and empathy. As medical students in the University of Oslo, we do not feel that the situation is as bad as some claim it is. Most medical students have a wide range of ability and show interest and involvement in their own as well as their patients' situation. Humanities subjects are included in the curriculum, but it is tempting to see them as "spice" added for flavour and spread out over the course with no clear logic behind it. We do not necessarily see the need for more humanities courses, but we do see a need for more critical evaluation of what is taught. Humanities in the medical education should aim not just at improving communication skills, they should also include perspectives on how health care professionals can take of themselves, and put medicine into a wider scientific and historical perspective.


Determinants of wasting among schoolchildren in a Southwestern state of Nigeria: Implications to strengthen the nutritional component of primary health-care model.
Wasting is linked to about one-third of mortality among school-age children. More studies have centered on stunting among under-five children, with few documented studies exploring comparability and determinants of wasting among school pupils in southwestern Nigeria. This study aimed to investigate the comparability and determinants of wasting among schoolchildren in rural and urban communities of Obafemi-Owode local government area, Ogun State, Nigeria. A cross-sectional study utilizing a quantitative approach was carried out among children both in rural and urban primary schools. Data were collected through interviewer-administered questionnaires. EPI-INFO version 6.03 was used, children were classified as wasted if weight-for-height Z-scores were <2 standard deviations below the National Center for Health Statistics/World Health Organization median. Associations were tested using t-tests and Chi-square test, while predictors were examined with logistic regression at 95% level of significance. Male gender was predominant (54.6%). Significantly more pupils from rural areas lived with grandparents and other guardians (60.3%) compared to their urban counterparts (39.7% P = 0.005). Pupils from rural schools were four times more likely to be wasted compared to those located in urban regions (odds ratio [OR]: 4.2; 95 confidence interval [CI] = 2.24-7.69). Male pupils were twice likely to be wasted compared to the female pupils (OR: 2.08; 95 CI = 1.22-3.55). Conclusively, the study revealed that the prevalence of wasting was higher among children from rural schools than in urban schools. There is an urgent need to implement viable interventions and policies that address nutritional deficiencies in primary school pupils, particularly in rural areas.


Cancer prevention through stealth: science, policy advocacy, and multilevel governance in the establishment of a "National Tobacco Control Regime" in the United States.
The role of the US federal government in developing tobacco control through a cooperative, interactive program with state and local private and public organizations has been underestimated. This article investigates how the government initiated and sustained a program of "capacity building" through the scientific authority of the National Cancer Institute, beginning in the 1980s. There are several major questions to be answered: (1) How did this program manage to be adopted and sustained despite the well-documented hindrances to effective tobacco control policy at the federal level? (2) How did a tobacco control policy program become incorporated into the scientific research agenda of the National Cancer Institute? (3) How have science, social factors, and government at various levels interacted in this capacity-building program? The study emphasizes how the US federal government, blocked by a tobacco-friendly Congress from enacting effective tobacco control legislation, utilized its scientific research role and, with the cooperation of other levels of government and large, private antitobacco organizations, established an ongoing policy effort.


Ultracold fermi gases with resonant dipole-dipole interaction.
The superfluid phases in resonant dipolar Fermi gases are investigated by the standard mean-field theory. In contrast to the crossover from Bose-Einstein condensation (BEC) to Bardeen-Cooper-Schrieffer superfluid in Fermi gases with isotropic interactions, resonant dipolar interaction leads to two completely different BEC phases of the tight-binding Fermi molecules on both sides of the resonance, which are characterized by two order parameters with distinct internal symmetries. We point out that, near the resonances, the two competitive phases can coexist, and an emergent relative phase between the two order parameters spontaneously breaks time-reversal symmetry, which could be observed in momentum resolved rf spectroscopy.


Multi T1-weighted contrast MRI with fluid and white matter suppression at 1.5 T.
The fluid and white matter suppression sequence (FLAWS) provides two T1-weighted co-registered datasets: a white matter (WM) suppressed contrast (FLAWS1) and a cerebrospinal fluid (CSF) suppressed contrast (FLAWS2). FLAWS has the potential to improve the contrast of the subcortical brain regions that are important for Deep Brain Stimulation surgery planning. However, to date FLAWS has not been optimized for 1.5 T. In this study, the FLAWS sequence was optimized for use at 1.5 T. In addition, the contrast-enhancement properties of FLAWS image combinations were investigated using two voxel-wise FLAWS combined images: the division (FLAWS-div) and the high contrast (FLAWS-hc) image. FLAWS sequence parameters were optimized for 1.5 T imaging using an approach based on the use of a profit function under constraints for brain tissue signal and contrast maximization. MR experiments were performed on eleven healthy volunteers (age 18-30). Contrast (CN) and contrast to noise ratio (CNR) between brain tissues were measured in each volunteer. Furthermore, a qualitative assessment was performed to ensure that the separation between the internal globus pallidus (GPi) and the external globus pallidus (GPe) is identifiable in FLAWS1. The optimized set of sequence parameters for FLAWS at 1.5 T provided contrasts similar to those obtained in a previous study at 3 T. The separation between the GPi and the GPe was clearly identified in FLAWS1. The CN of FLAWS-hc was higher than that of FLAWS1 and FLAWS2, but was not different from the CN of FLAWS-div. The CNR of FLAWS-hc was higher than that of FLAWS-div. Both qualitative and quantitative assessments validated the optimization of the FLAWS sequence at 1.5 T. Quantitative assessments also showed that FLAWS-hc provides an enhanced contrast compared to FLAWS1 and FLAWS2, with a higher CNR than FLAWS-div.


Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies.
Dysregulation of Ras-extracellular signal-related kinase (ERK) signaling gives rise to RASopathies, a class of neurodevelopmental syndromes associated with intellectual disability. Recently, much attention has been directed at models bearing mild forms of RASopathies whose behavioral impairments can be attenuated by inhibiting the Ras-ERK cascade in the adult. Little is known about the brain mechanisms in severe forms of these disorders. We performed an extensive characterization of a new brain-specific model of severe forms of RASopathies, the KRAS12V mutant mouse. The KRAS12V mutation results in a severe form of intellectual disability, which parallels mental deficits found in patients bearing mutations in this gene. KRAS12V mice show a severe impairment of both short- and long-term memory in a number of behavioral tasks. At the cellular level, an upregulation of ERK signaling during early phases of postnatal development, but not in the adult state, results in a selective enhancement of synaptogenesis in gamma-aminobutyric acidergic interneurons. The enhancement of ERK activity in interneurons at this critical postnatal time leads to a permanent increase in the inhibitory tone throughout the brain, manifesting in reduced synaptic transmission and long-term plasticity in the hippocampus. In the adult, the behavioral and electrophysiological phenotypes in KRAS12V mice can be temporarily reverted by inhibiting gamma-aminobutyric acid signaling but not by a Ras-ERK blockade. Importantly, the synaptogenesis phenotype can be rescued by a treatment at the developmental stage with Ras-ERK inhibitors. These data demonstrate a novel mechanism underlying inhibitory synaptogenesis and provide new insights in understanding mental dysfunctions associated to RASopathies.


Loop electrostatics modulates the intersubunit interactions in ferritin.
Functional ferritins are 24-mer nanocages that self-assemble with extended contacts between pairs of 4-helix bundle subunits coupled in an antiparallel fashion along the C2 axes. The largest intersubunit interaction surface in the ferritin nanocage involves helices, but contacts also occur between groups of three residues midway in the long, solvent-exposed L-loops of facing subunits. The anchor points between intersubunit L-loop pairs are the salt bridges between the symmetry-related, conserved residues Asp80 and Lys82. The resulting quaternary structure of the cage is highly soluble and thermostable. Substitution of negatively charged Asp80 with a positively charged Lys in homopolymeric M ferritin introduces electrostatic repulsions that inhibit the oligomerization of the ferritin subunits. D80K ferritin was present in inclusion bodies under standard overexpressing conditions in E. coli, contrasting with the wild type protein. Small amounts of fully functional D80K nanocages formed when expression was slowed. The more positively charged surface results in a different solubility profile and D80K crystallized in a crystal form with a low density packing. The 3D structure of D80K variant is the same as wild type except for the side chain orientations of Lys80 and facing Lys82. When three contiguous Lys groups are introduced in D80KI81K ferritin variant the nanocage assembly is further inhibited leading to lower solubility and reduced thermal stability. Here, we demonstrate that the electrostatic pairing at the center of the L-loops has a specific kinetic role in the self-assembly of ferritin nanocages.


Diabetic Bone Fracture Repair: A Progenitor Cell-Based Paradigm.
Long bone fractures in diabetics are slower to heal, have an increased risk of developing non-union and demonstrate greater potential of infection and perioperative complications compared to non-diabetics. The causative aberrant bone mineral density and insufficient bone microstructure of diabetic patients are thought to result from altered osteoblast and osteocyte function, increased bone marrow adiposity, decreased progenitor osteo- and chondral differentiation potential and increased pro-inflammatory cytokine circulation. It is therefore reasonable to hypothesize that the root cause of faulty diabetic bone homeostasis and fracture repair is a reduced population of bone marrow progenitor cells and/or their decreased osteochondral capacity complicated by their repressed neo-vascular potential. The potential of transplanted mesenchymal stem cells with a scaffold to support callus formation through the creation of de novo bone in hyperglycemia has been reported. However, there are minimal supporting pre-clinical and clinical investigations confirming these findings. Clinical trials have instead examined mesenchymal stem cell transplantation to slow disease progression, support .-cell viability and function and restore glucose homeostasis while the direct application of allogenic non-diabetic mesenchymal stem cells at the site of orthopaedic injury remains un-investigated. Here, the literature supporting the application of mesenchymal stem cells in diabetic fracture repair is reviewed including the process of dysfunctional diabetic fracture healing, osteoblast dysregulation and the effect of the hyperglycaemic environment on progenitor cell number and performance with a view to translating the preclinical knowledge base to the administration of mesenchymal stem cells in diabetic fracture repair.


Comparison of subcutaneous and intravenous continuous glucose monitoring accuracy in an operating room and an intensive care unit.
Although we have used an intravenous continuous glucose monitor for blood glucose management, a previous study reported that a subcutaneous continuous glucose monitor was also reliable for use in critically ill patients. The aim of this study was to compare the subcutaneous and intravenous continuous glucose monitors. This was an observational trial (UMIN-CTR, ID:000013338). We included patients who were admitted to our intensive care units (ICU) after hepato-biliary pancreatic surgery. Continuous blood glucose measurement was performed from the beginning of the operation to ICU discharge using the intravenous continuous monitor STG-55 (Nikkiso, Tokyo, Japan) and the subcutaneous continuous monitor iPro2 (Medtronic Japan, Tokyo, Japan). The STG-55 measured the glucose level in real time, and the iPro2 measured this every 5 min. We compared glucose levels obtained using the two devices every 5 min using a Bland-Altman plot and a regression analyses. A total of 3592 comparative samples in 15 cases were analyzed. The mean glucose level measured using the STG-55 was 139 ± 21 mg/dl, and that measured using the iPro2 was 144 ± 31 mg/dl. A linear regression line had the equation of the form y = 0.225x + 106. The coefficient of determination was 0.11, and the F-test significance level was set as p < 0.01. The mean of the differences was -5.2 mg/dl, with a 95 % agreement limit of -67 to + 57 mg/dL. The percent error was 44 %. In conclusion, the current study suggests that subcutaneous and intravenous continuous glucose monitoring was not highly correlated during either surgery or ICU stay.


Letter: Trophic interactions regulate peatland carbon cycling.
Peatlands are the most efficient natural ecosystems for long-term storage of atmospheric carbon. Our understanding of peatland carbon cycling is based entirely on bottom-up controls regulated by low nutrient availability. Recent studies have shown that top-down controls through predator-prey dynamics can influence ecosystem function, yet this has not been evaluated in peatlands to date. Here, we used a combination of nutrient enrichment and trophic-level manipulation to test the hypothesis that interactions between nutrient availability (bottom-up) and predation (top-down) influence peatland carbon fluxes. Elevated nutrients stimulated bacterial biomass and organic matter decomposition. In the absence of top-down regulation, carbon dioxide (CO2 ) respiration driven by greater decomposition was offset by elevated algal productivity. Herbivores accelerated CO2 emissions by removing algal biomass, while predators indirectly reduced CO2 emissions by muting herbivory in a trophic cascade. This study demonstrates that trophic interactions can mitigate CO2 emissions associated with elevated nutrient levels in northern peatlands.


Recurrent trauma histories of two 'unlucky teeth': 42-month follow-up.
The root fractures occur relatively rarely and account for 0.5-2.5% of all dental injuries. The fracture type, severity of dislocation, mobility of fragments and diastasis have negative influence on the healing process. The aim of this study was to describe the treatment and the 42-month follow-up period of three trauma histories in a 12-year-old patient in 1 year and to emphasize the negative effects of recurrent traumas on the healing pattern and prognosis of root fractures.


Natural Variation in Resistance to Virus Infection in Dipteran Insects.
The power and ease of Drosophila genetics and the medical relevance of mosquito-transmitted viruses have made dipterans important model organisms in antiviral immunology. Studies of virus-host interactions at the molecular and population levels have illuminated determinants of resistance to virus infection. Here, we review the sources and nature of variation in antiviral immunity and virus susceptibility in model dipteran insects, specifically the fruit fly Drosophila melanogaster and vector mosquitoes of the genera Aedes and Culex. We first discuss antiviral immune mechanisms and describe the virus-specificity of these responses. In the following sections, we review genetic and microbiota-dependent variation in antiviral immunity. In the final sections, we explore less well-studied sources of variation, including abiotic factors, sexual dimorphism, infection history, and endogenous viral elements. We borrow from work on other pathogen types and non-dipteran species when it parallels or complements studies in dipterans. Understanding natural variation in virus-host interactions may lead to the identification of novel restriction factors and immune mechanisms and shed light on the molecular determinants of vector competence.


A comparison of readmission and complication rates and charges of inpatient and outpatient multiple-level anterior cervical discectomy and fusion surgeries in the Medicare population.
This study aims to assess the relationship of comorbidities and postoperative complications to rates of readmission for geriatric patients undergoing anterior cervical discectomy and fusion (ACDF) involving more than 2 levels on an inpatient or outpatient basis. With the rising costs of healthcare in the United States, understanding the safety and efficacy of performing common surgical interventions (including ACDF) as outpatient procedures could prove to be of great economic impact.Objective This study aims to assess the effect of comorbidities and postoperative complications on the rates of readmission of geriatric patients undergoing multilevel anterior cervical discectomy and fusion (ACDF) procedures (i.e., ACDF involving 3 or more levels) on an inpatient or outpatient basis. Same-day surgery has been demonstrated to be a safe and cost-effective alternative to the traditional inpatient option for many surgical interventions. With the rising costs of healthcare, understanding the safety and efficacy of performing common surgical interventions as outpatient procedures could prove to be of great economic impact. The study population included total of 2492 patients: 2348 inpatients and 144 outpatients having ACDF procedures involving 3 or more levels in the Medicare Standard Analytical Files database. Age, sex, comorbidities, postoperative complications, readmission rates, and surgical procedure charges were compared between both cohorts. For selected variables, logistic regression was used to model odds ratios for various comorbidities against readmission rates for both inpatient and outpatient cohorts. Chi-square tests were also calculated to compare these comorbidities with readmission in each cohort. Overall complication rates within 30 postoperative days were greater for inpatients than for outpatients (44.2% vs 12.5%, p < 0.001). More inpatients developed postoperative urinary tract infection (7.9% vs 0%, p < 0.001), and the inpatient cohort had increased risk of readmission with comorbidities of anemia (OR 1.52, p < 0.001), smoking (OR 2.12, p < 0.001), and BMI ≥ 30 (OR 1.43, p < 0.001). Outpatients had increased risk of readmission with comorbidities of anemia (OR 2.78, p = 0.047), diabetes mellitus type 1 or 2 (OR 3.25, p = 0.033), and BMI ≥ 30 (OR 3.95, p = 0.008). Inpatients also had increased readmission risk with a postoperative complication of surgical site infection (OR 2.38, p < 0.001). The average charges for inpatient multilevel ACDF were significantly higher than for multilevel ACDF performed on an outpatient basis ($12,734.27 vs $12,152.18, p = 0.0019). This study suggests that ACDF surgery involving 3 or more levels performed as an outpatient procedure in the geriatric population may be associated with lower rates of readmissions, complications, and surgical charges.


Evolution of strategic cooperation.
Group-beneficial behaviors have presented a long-standing challenge for evolutionary theory because, although their benefits are available to all group members, their costs are borne by individuals. Consequently, an individual could benefit from "cheating" their group mates by not paying the costs while still reaping the benefits. There have been many proposed evolutionary mechanisms that could favor cooperation (and disfavor cheating) in particular circumstances. However, if cooperation is still favored in some circumstances, then we might expect evolution to favor strategic cooperation, where the level of contribution toward group-beneficial behavior is varied in response to the social context. To uncover how and why individuals should contribute toward group-beneficial behavior across social contexts, we model strategic cooperation as an evolutionary game where players can quantitatively adjust the amount they contribute toward group-beneficial behavior. We find that the evolutionarily stable strategy (ESS) predicts, unsurprisingly, that players should contribute in relation to their relatedness to the group. However, we surprisingly find that players often contribute to cooperation in such a way that their fitness is inverse to their relatedness to the group such that those that contribute to cooperation end up with the same return from group-beneficial behavior, essentially removing any potential advantage of higher relatedness. These results bring to light a paradox of group-beneficial cooperation: groups do best when they contain highly related individuals, but those with the highest relatedness to the group will often have the lowest fitness within the group.


The potential of human neutrophil peptides in tuberculosis therapy.
The problems of drug resistance and bacterial persistence in tuberculosis have prompted scientists to search for clues from the latest advances in microbiology and immunology. Recent research on human neutrophil peptides (HNPs) has highlighted their bactericidal action against Mycobacterium tuberculosis and suggested that neutrophils may play a more important defensive role in tuberculosis than previously thought. Human neutrophil peptides belong to a family of antimicrobial and cytotoxic peptides known as 'defensins'. Neutrophils use both oxidative and non-oxidative microbicidal mechanisms to provide the host with innate immunity against microbial infections. Defensins are most abundant among an array of oxygen-independent antimicrobial proteins and peptides in neutrophil granules. Defensins are effective against a wide spectrum of microbes including bacteria, viruses, fungi, spirochetes and mycobacteria. In addition to direct antimicrobial activity, HNPs can potentially influence the inflammatory or immune responses by modulating cytokine production or acting like opsonins or chemotactic factors. HNPs are active against M. tuberculosis grown in vitro or within macrophages. HNPs released by neutrophils recruited in the early lesion could attract monocytes to the site and macrophages may in vivo uptake the extracellular HNPs and kill the intracellular pathogens. As such, HNPs are potential therapeutic agents against tuberculosis. HNPs are also cytotoxic against a wide range of normal mammalian cells; however, there is evidence that defensins may not cause significant cytotoxicity at the therapeutic level. Finally, the clinical application of HNPs must be evaluated in the context of possible drug resistance, as some resistance-associated genes have been identified.


A complexity reduction technique for image vector quantization.
A technique for reducing the complexity of spatial-domain image vector quantization (VQ) is proposed. The conventional spatial domain distortion measure is replaced by a transform domain subspace distortion measure. Due to the energy compaction properties of image transforms, the dimensionality of the subspace distortion measure can be reduced drastically without significantly affecting the performance of the new quantizer. A modified LBG algorithm incorporating the new distortion measure is proposed. Unlike conventional transform domain VQ, the codevector dimension is not reduced and a better image quality is guaranteed. The performance and design considerations of a real-time image encoder using the techniques are investigated. Compared with spatial domain a speed up in both codebook design time and search time is obtained for mean residual VQ, and the size of fast RAM is reduced by a factor of four. Degradation of image quality is less than 0.4 dB in PSNR.


The Need for Restructuring the Disordered Science of Amorphous Drug Formulations.
The alarming numbers of poorly soluble discovery compounds have centered the efforts towards finding strategies to improve the solubility. One of the attractive approaches to enhance solubility is via amorphization despite the stability issue associated with it. Although the number of amorphous-based research reports has increased tremendously after year 2000, little is known on the current research practice in designing amorphous formulation and how it has changed after the concept of solid dispersion was first introduced decades ago. In this review we try to answer the following questions: What model compounds and excipients have been used in amorphous-based research? How were these two components selected and prepared? What methods have been used to assess the performance of amorphous formulation? What methodology have evolved and/or been standardized since amorphous-based formulation was first introduced and to what extent have we embraced on new methods? Is the extent of research mirrored in the number of marketed amorphous drug products? We have summarized the history and evolution of amorphous formulation and discuss the current status of amorphous formulation-related research practice. We also explore the potential uses of old experimental methods and how they can be used in tandem with computational tools in designing amorphous formulation more efficiently than the traditional trial-and-error approach.


Significance of Lewis phenotyping using saliva and gastric tissue: comparison with the Lewis phenotype inferred from Lewis and secretor genotypes.
Lewis phenotypes using various types of specimen were compared with the Lewis phenotype predicted from Lewis and Secretor genotypes. This is the first logical step in explaining the association between the Lewis expression and Helicobacter pylori. We performed a study of the followings on 209 patients who underwent routine gastroscopy: erythrocyte and saliva Lewis phenotyping, gastric Lewis phenotyping by the tissue array, and the Lewis and Secretor genes genotyping. The results of phenotyping were as follows [Le(a-b-), Le(a+b-), Le(a-b+), and Le(a+b+), respectively, in order]: erythrocyte (12.4%, 25.8%, 61.2%, and 0.5%); saliva (2.4%, 27.3%, 70.3%, and 0.0%); gastric mucosa (8.1%, 6.7%, 45.5%, and 39.7%). The frequency of Le, le (59/508) , le (59/1067) , and le (59) alleles was 74.6%, 21.3%, 3.1%, and 1.0%, respectively, among 418 alleles. The saliva Lewis phenotype was completely consistent with the Lewis phenotype inferred from Lewis and Secretor genotypes, but that of gastric mucosa could not be predicted from genotypes. Lewis phenotyping using erythrocytes is only adequate for transfusion needs. Saliva testing for the Lewis phenotype is a more reliable method for determining the peripheral Lewis phenotype of an individual and the gastric Lewis phenotype must be used for the study on the association between Helicobacter pylori and the Lewis phenotype.


MKBP, a novel member of the small heat shock protein family, binds and activates the myotonic dystrophy protein kinase.
Muscle cells are frequently subjected to severe conditions caused by heat, oxidative, and mechanical stresses. The small heat shock proteins (sHSPs) such as alphaB-crystallin and HSP27, which are highly expressed in muscle cells, have been suggested to play roles in maintaining myofibrillar integrity against such stresses. Here, we identified a novel member of the sHSP family that associates specifically with myotonic dystrophy protein kinase (DMPK). This DMPK-binding protein, MKBP, shows a unique nature compared with other known sHSPs: (a) In muscle cytosol, MKBP exists as an oligomeric complex separate from the complex formed by alphaB-crystallin and HSP27. (b) The expression of MKBP is not induced by heat shock, although it shows the characteristic early response of redistribution to the insoluble fraction like other sHSPs. Immunohistochemical analysis of skeletal muscle cells shows that MKBP localizes to the cross sections of individual myofibrils at the Z-membrane as well as the neuromuscular junction, where DMPK has been suggested to be concentrated. In vitro, MKBP enhances the kinase activity of DMPK and protects it from heat-induced inactivation. These results suggest that MKBP constitutes a novel stress-responsive system independent of other known sHSPs in muscle cells and that DMPK may be involved in this system by being activated by MKBP. Importantly, since the amount of MKBP protein, but not that of other sHSP family member proteins, is selectively upregulated in skeletal muscle from DM patients, an interaction between DMPK and MKBP may be involved in the pathogenesis of DM.


Induction of phagocytic inhibitory activity in cats with chronic Pseudomonas aeruginosa pulmonary infection.
Chronic pulmonary infection has been established in cats by repeated intrapulmonary inoculation of viable Pseudomonas aeruginosa enmeshed in agarose beads. In the serum of all chronically infected animals, a substance(s) developed which inhibited phagocytosis of P. aeruginosa by normal cat alveolar macrophages. Phagocytosis was measured by incubating macrophage monolayers (5 X 10(5) alveolar macrophages) for 20 min in the presence of 3H-labeled bacteria and 5% serum from control or infected animals. Inhibitory activity developed 4 to 16 weeks after initial infection, and inhibition of phagocytosis of P. aeruginosa in the presence of infected cat serum ranged from 30 to 79%. After inhibitory activity developed, it persisted throughout the remainder of the experiment in each animal. The activity was specific for P. aeruginosa of the infecting serotype and did not affect phagocytosis of gram-positive organisms. Inhibitory activity was unchanged by heating serum at 56 degrees C for 30 min. We have previously described a P. aeruginosa-specific, heat-stable, phagocytosis-inhibitory activity in the serum of patients with cystic fibrosis. Since inhibitory activity also develops in cats with chronic P. aeruginosa pulmonary infection, such activity may not be a primary intrinsic abnormality in patients with cystic fibrosis. The animal model described here offers a system for following the development of and for characterization of the P. aeruginosa-specific phagocytosis-inhibitory activity.


Evidence of a functional clitoris in dolphins.
In species that copulate during non-conceptive periods, such as humans and bonobos, sexual intercourse is known to be pleasurable for females. Dolphins also copulate throughout the year, largely to establish and maintain social bonds1. In dolphins, the clitoris is positioned in the anterior aspect of the vaginal entrance2, where physical contact and stimulation during copulation is likely. Clitoral stimulation seems to be important during female-female sexual interactions in common bottlenose dolphins (Tursiops truncatus), which rub each other's clitorises using snouts, flippers, or flukes3. Determining a sexual pleasure response in animals not amenable to neurobehavioral examination is difficult, but investigation of the clitoris may elucidate evidence of functionality. In this study, we assessed macro- and micromorphological features of the clitoris in common bottlenose dolphins to examine functional features, including erectile bodies with lacunae, extensible collagen and/or elastin fibers, and the presence and location of sensory nerves. Our observations suggest the clitoris of dolphins has well-developed erectile spaces, is highly sensitive to tactile stimulation, and is likely functional. VIDEO ABSTRACT.


Muscleblind-like 1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain.
Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by a CTG trinucleotide repeat expansion (CTG(exp)) in the DMPK gene. In skeletal muscle, nuclear sequestration of the alternative splicing factor muscleblind-like 1 (MBNL1) explains the majority of the alternative splicing defects observed in the HSA(LR) transgenic mouse model which expresses a pathogenic range CTG(exp). In the present study, we addressed the possibility that MBNL1 sequestration by CUG(exp) RNA also contributes to splicing defects in the mammalian brain. We examined RNA from the brains of homozygous Mbnl1(ΔE3/ΔE3) knockout mice using splicing-sensitive microarrays. We used RT-PCR to validate a subset of alternative cassette exons identified by microarray analysis with brain tissues from Mbnl1(ΔE3/ΔE3) knockout mice and post-mortem DM1 patients. Surprisingly, splicing-sensitive microarray analysis of Mbnl1(ΔE3/ΔE3) brains yielded only 14 candidates for mis-spliced exons. While we confirmed that several of these splicing events are perturbed in both Mbnl1 knockout and DM1 brains, the extent of splicing mis-regulation in the mouse model was significantly less than observed in DM1. Additionally, several alternative exons, including Grin1 exon 4, App exon 7 and Mapt exons 3 and 9, which have previously been reported to be aberrantly spliced in human DM1 brain, were spliced normally in the Mbnl1 knockout brain. The sequestration of MBNL1 by CUG(exp) RNA results in some of the aberrant splicing events in the DM1 brain. However, we conclude that other factors, possibly other MBNL proteins, likely contribute to splicing mis-regulation in the DM1 brain.


Pulmonary function test quality in the elderly: a comparison with younger adults.
Elderly patients may be at greater risk for misdiagnosis and inappropriate treatment as a consequence of pulmonary function test underutilization and tests being conducted with low quality expectations. This study sought to determine if elderly patients are able to achieve both spirometry and diffusion capacity (DLCO) quality scores comparable to a younger adult population. This was a retrospective review of pulmonary function data over a 22 month period. A list of every subject age ≥ 80 years (elderly group) and ages 40-50 years (control group) tested during the time period was compiled. The quality of spirometry and DLCO testing were examined. Overall, 92.6% (139/150) of the elderly group and 91.5% (163/178) of the control group spirometry tests satisfied all American Thoracic Society/European Respiratory Society acceptability and reproducibility criteria (P = .84), and 84.9% (96/113) of the elderly group and 88.5% (108/122) of the control group DLCO tests satisfied all the acceptability and reproducibility criteria (P = .45). Elderly patients referred to a hospital-based pulmonary function test lab can be expected to achieve spirometry and DLCO quality scores comparable to younger adult patients.


AMPK β1 reduces tumor progression and improves survival in p53 null mice.
The AMP-activated protein kinase (AMPK) is a heterotrimeric protein complex that is an important sensor of cellular energy status. Reduced expression of the AMPK β1 isoform has been linked to reduced survival in different cancers, but whether this accelerates tumor progression and the potential mechanism mediating these effects are not known. Furthermore, it is unknown whether AMPK β1 is implicated in tumorigenesis, and if so, what tissues may be most sensitive. In the current study, we find that in the absence of the tumor suppressor p53, germline genetic deletion of AMPK β1 accelerates the appearance of a T-cell lymphoma that reduces lifespan compared to p53 deficiency alone. This increased tumorigenesis is linked to increases in interleukin-1β (IL1β), reductions in acetyl-CoA carboxylase (ACC) phosphorylation, and elevated lipogenesis. Collectively, these data indicate that reductions in the AMPK β1 subunit accelerate the development of T-cell lymphoma, suggesting that therapies targeting this AMPK subunit or inhibiting lipogenesis may be effective for limiting the proliferation of p53-mutant tumors.


Effects of first trimester binge alcohol exposure on developing white matter in fetal sheep.
Heavy prenatal alcohol exposure is associated with neurodevelopmental abnormalities. Neuropathologic and neuroimaging studies have shown a wide range of structural problems, including abnormal neuronal migration and volume reduction in specific brain regions, including white matter. We identified foci of significant fetal white matter microglia-macrophage immunoreactivity in a "binge" model of early prenatal alcohol exposure in sheep. Ewes of alcohol-exposed fetuses received daily 90 min alcohol (1.5 gm/kg i.v.) infusions at 30-60 d gestation (term = 147 d). Ewes of control fetuses received same volume infusions of normal saline intravenously. Near-term (125 d gestation) fetal brains were labeled with microglia-macrophages using HAM56 antibody. We quantified dense immunoreactive cellular regions across sections and anatomical locations using computer-assisted microscopy and quantitative morphometry. The proportional HAM56-positive area in cortical white matter was greater in the alcohol-exposed fetuses (1.6%) compared with the saline controls (0.7%). The areas were localized to the frontal gyral white matter, temporal gyral white matter, optic radiation, and others (corpus callosum, septum pellucidum, fasciculus subcallosus, and external capsule), with a greater distribution in the gyral white matter. The greater area of macrophage-rich regions in near-term fetal sheep brain suggests a vulnerability of developing white matter that is enhanced by early alcohol exposure.


Congenital pancytopenia and absence of B lymphocytes in a neonate with a mutation in the Ikaros gene.
Congenital pancytopenia is a rare and often lethal condition. Current knowledge of lymphoid and hematopoietic development in mice, as well as understanding regulators of human hematopoiesis, have led to the recent discovery of genetic causes of bone marrow failure disorders. However, in the absence of mutations of specific genes or a distinct clinical phenotype, many cases of aplastic anemia are labeled as idiopathic, while congenital immune deficiencies are described as combined immune deficiency. We describe the case of a 33-week gestation age male with severe polyhydramnios, hydrops, and ascites who was noted to be pancytopenic at birth. Bone marrow examination revealed a hypocellular marrow with absent myelopoiesis. An immune workup demonstrated profound B lymphopenia, near absent NK cells, and normal T cell number. Due to the similarity of the patient's phenotype with the IKAROS knockout mouse, studies were performed on bone marrow and peripheral blood to assess a potential pathogenic role of Ikaros. DNA studies revealed a point mutation in one allele of the IKAROS gene, resulting in an amino acid substitution in the DNA-binding zinc finger domain. Functional studies demonstrated that the observed mutation decreased Ikaros DNA-binding affinity, and immunofluorescence microscopy revealed aberrant Ikaros pericentromeric localization. Our report describes a novel case of congenital pancytopenia associated with mutation of the IKAROS gene. Furthermore, these data suggest a critical role of IKAROS in human hematopoiesis and immune development.


Evolution of atrophied T2 lesion volume in primary-progressive multiple sclerosis: results from the phase 3 ORATORIO study.
Atrophied T2-lesion volume (aT2-LV) is an exploratory imaging marker in multiple sclerosis (MS) reflecting the volume of lesions subsumed into cerebrospinal fluid (CSF). To investigate the effect of ocrelizumab (OCR) versus placebo (PBO) over 120 weeks on the accumulation of aT2-LV in a double-blind placebo-controlled (DBP) phase 3, primary-progressive (PP) MS study (ORATORIO; NCT01194570). This post-hoc, MRI-blinded analysis evaluated 732 PPMS randomised to OCR (488) or PBO (244). Atrophied T2-LV was calculated by overlaying baseline T2-lesion masks on follow-up CSF maps. Clinical data from DBP and open-label extension (OLE) periods were available. Treatment effect was evaluated by a mixed-effect model with repeated measures, while logistic regression explored the association of aT2-LV at week 120 and clinical outcomes in the OLE period. OCR treatment significantly reduced accumulation of aT2-LV compared with PBO (319.4 mm3 vs 366.1 mm3, p=0.015) at 120 weeks. OCR showed superiority over PBO in reducing aT2-LV in patients who developed confirmed disability progression (CDP) during the DBP period at 12 (CDP12) and 24 (CDP24) weeks for the composite of Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test and Timed 25-Foot Walk test. Accumulation of aT2-LV at week 120 was related to CDP12-EDSS (p=0.018) and CDP24-EDSS (p=0.022) in the OLE for the patients who were treated by PBO in the DBP only. OCR showed a significant effect of reducing the accumulation of aT2-LV in PPMS in the DBP period and was related to CDP-EDSS in OLE only in the PBO arm.


[Factors contributing to interindividual variability to chemical toxicity].
Recognising toxicokinetic and toxicodynamic variability is important in the risk assessment of chemicals and may help to explain individual differences in susceptibility in exposed populations. This presentation discusses the influence of age, gender, disease and genetics on toxicokinetic and toxicodynamic processes. Neonates have a reduced capacity for metabolism and elimination of xenobiotics that may enhance chemical toxicity caused by a parent chemical. Furthermore, the brain, reproductive organs and immune system have critical postnatal periods of maturation where they appear highly sensitive to toxic effects that interfere with the maturation process and may lead to permanent structural or functional organ changes. In the elderly, a combination of reduced organ function, disease and use of pharmaceuticals contributes to enhanced chemical sensitivity reflected in an increased incidence of adverse drug reactions in this population. There is a high degree of functional polymorphism in biotransforming enzymes. Such polymorphisms have been shown to contribute to interindividual variability in chemical response. During the last few years, accounts have been given of several polymorphisms in genes with importance for toxicodynamic processes, such as DNA repair genes and receptor genes. However, further information is needed in order to evaluate the functional contribution of these polymorphisms to chemical sensitivity and health risk.


Does Dominant Somatotype Differentiate Performance of Jumping and Sprinting Variables in Young Healthy Adults?
The relationship between an athlete's somatotype three-numeral rating and his or her athletic performance is well known. However, a direct effect of the different dominant somatotype on jumping and sprinting variables has not yet been reported. The aim of this study was to investigate the effects of dominant somatotype on sport-specific explosive variables. One hundred and twelve physically active young adults (mean ± standard deviation age: 21.82 ± 3.18 years) were somatotype-rated using the Heath-Carter method. Participants were classified as balanced ectomorph, balanced mesomorph, central, mesomorph-endomorph, and mesomorphic ectomorph. Vertical jump and linear sprint tests were performed to measure peak lower body performance and sprint variables (time, speed, and momentum), respectively. The analysis revealed that balanced mesomorph had significantly higher vertical jump (effect size (ES) = 1.10, p = 0.005) and power to body mass (ES = 1.04, p = 0.023) than mesomorph-endomorph. In addition, balanced mesomorph showed significantly superior performance in 30-m sprint time and velocity than central and mesomorph-endomorph (ES range = 0.93-1, p < 0.05). Finally, balanced ectomorph (ES = 1.12, p = 0.009) and mesomorphic ectomorph (ES = 1.10, p = 0.017) were lower in sprint momentum compared to balanced mesomorphs. In conclusion, this study has shown the importance of the interaction between subtypes and athletic performance. The knowledge gained may be important in identifying those who tend to perform well in sports with explosive power and in prescribing training programs.


Tuberculosis of the spleen: a case report.
A 40-year old Thai male presented with epigastric discomfort and weight loss without fever for 2 months. On examination, there was no hepatosplenomegaly or lymphadenopathy. His ultrasonogram showed multiple lesions in the spleen with enlarged abdominal lymph nodes. Pathology revealed caseating granulomas of the spleen and lymph nodes. No AFB were seen but PCR was positive for M. tuberculosis complex. The fever resolved within 3 days of surgery and the patient was treated with antituberculous drugs.


Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis.
PTEN is mutated at high frequency in many primary human cancers and several familial cancer predisposition disorders. Activation of AKT is a common event in tumors in which the PTEN gene has been inactivated. We previously showed that deletion of the murine Pten gene in embryonic stem (ES) cells led to increased phosphatidylinositol triphosphate (PIP(3)) accumulation, enhanced entry into S phase, and better cell survival. Since PIP(3) controls multiple signaling molecules, it was not clear to what degree the observed phenotypes were due to deregulated AKT activity. In this study, we mutated Akt-1 in Pten(-/-) ES cells to directly assess the role of AKT-1 in PTEN-controlled cellular processes, such as cell proliferation, cell survival, and tumorigenesis in nude mice. We showed that AKT-1 is one of the major downstream effectors of PTEN in ES cells and that activation of AKT-1 is required for both the cell survival and cell proliferation phenotypes observed in Pten(-/-) ES cells. Deletion of Akt-1 partially reverses the aggressive growth of Pten(-/-) ES cells in vivo, suggesting that AKT-1 plays an essential role in PTEN-controlled tumorigenesis.


Physiology and pathophysiology of CLC-1: mechanisms of a chloride channel disease, myotonia.
The CLC-1 chloride channel, a member of the CLC-channel/transporter family, plays important roles for the physiological functions of skeletal muscles. The opening of this chloride channel is voltage dependent and is also regulated by protons and chloride ions. Mutations of the gene encoding CLC-1 result in a genetic disease, myotonia congenita, which can be inherited as an autosmal dominant (Thomsen type) or an autosomal recessive (Becker type) pattern. These mutations are scattered throughout the entire protein sequence, and no clear relationship exists between the inheritance pattern of the mutation and the location of the mutation in the channel protein. The inheritance pattern of some but not all myotonia mutants can be explained by a working hypothesis that these mutations may exert a "dominant negative" effect on the gating function of the channel. However, other mutations may be due to different pathophysiological mechanisms, such as the defect of protein trafficking to membranes. Thus, the underlying mechanisms of myotonia are likely to be quite diverse, and elucidating the pathophysiology of myotonia mutations will require the understanding of multiple molecular/cellular mechanisms of CLC-1 channels in skeletal muscles, including molecular operation, protein synthesis, and membrane trafficking mechanisms.


MAM-6 antigen, a new serum marker for breast cancer monitoring.
Almost all carcinomas contain a cell surface antigen, MAM-6, which has been defined by several monoclonal antibodies, including 115D8 (Hilkens et al., Int. J. Cancer, 34: 197-206, 1984). A quantitative sandwich radioimmunoassay, using 115D8 as catcher and as tracer antibody, has been developed to detect MAM-6 in serum. To quantitate the MAM-6 level, pooled human milk was used as a standard, and arbitrary units were chosen. Less than 5% of the sera of apparently healthy individuals contained more than 5 units/ml. In sera of patients with benign breast lesions, the same low levels were detected. However, concentrations over 5 units/ml were found in 24, 21, 43, and 79% of the sera of patients with pathological Stages I, II, III, and IV breast cancer, respectively. MAM-6 levels were also increased in almost all sera tested from patients with advanced stages of ovarian carcinoma, but in a low percentage of sera from patients with other advanced cancers. A longitudinal study was carried out to test the MAM-6 assay as clinical marker to monitor the therapeutic response of breast cancer. Increasing or decreasing MAM-6 serum levels correlated in 93% of the cases with breast cancer progression or regression, indicating that the assay can be used to monitor the course of the disease during therapy. In some breast cancer patients, elevated MAM-6 levels were observed prior to any clinical indication of tumor recurrence.


[Insulin requirements of the diabetic woman during pregnancy, labor, delivery and the puerperium (author's transl)].
The author demonstrates - contrary to all existing opinions - that without doubt insulin demand increases very early and relative continually; it stagnates only in the last weeks of pregnancy. Therefore gravid women have a resource of insulin - sufficient to guarantee (for sake of fetus) a constant level of blood-glucose. The author argues, that it may be taken for granted, that above all other hormones human placental lactogen (HPL) is responsible for regulation of carbohydrate metabolism during pregnancy. One of the most important consequences of these results is the necessity, to control the renal insulin demand of pregnant women at brief intervals (not longer than 14 days). That is the most certain way to protect fetus from injury (fetopathia!), caused by anomal high concentration of maternal blood-glucose. Moreover: alteration of insulin demand signal the condition of placenta, thus enabling the physician to act in due time.


EGFR mutations and AKT phosphorylation are markers for sensitivity to combined MCL-1 and BCL-2/xL inhibition in non-small cell lung cancer.
Lung cancer is among the common and deadly cancers. Although the treatment options for late-stage cancer patients have continued to increase in numbers, the overall survival rates for these patients have not shown significant improvement. This highlights the need for new targets and drugs to more effectively treat lung cancer patients. In this study, we characterize the MCL-1 inhibitor maritoclax alone or in combination with a BCL-2/xL inhibitor in a panel of lung cancer cell lines. BCL-2 family proteins, phosphorylated proteins, and apoptosis were monitored following the treatments. We found that maritoclax was effective at inhibiting growth in these lung cancer cells. We also establish that cell lines with EGFR mutations were most sensitive to the combined inhibition of MCL-1 and BCL-2/xL. In addition, a high level of phosphorylated AKT (S473) was identified as a marker for sensitivity to the combination treatment. This work has defined EGFR mutations and AKT phosphorylation as markers for sensitivity to combined MCL-1 and BCL-2/xL targeted therapy and establishes a rationale to explore multiple BCL-2 family members in patients who are refractory to EGFR inhibitor treatment. Our data support the design of a clinical trial that aims to employ inhibitors of the BCL-2 family of proteins in lung cancer patients.


Localizing overlapping parts by searching the interpretation tree.
This paper discusses how local measurements of positions and surface normals may be used to identify and locate overlapping objects. The objects are modeled as polyhedra (or polygons) having up to six degrees of positional freedom relative to the sensors. The approach operates by examining all hypotheses about pairings between sensed data and object surfaces and efficiently discarding inconsistent ones by using local constraints on: distances between faces, angles between face normals, and angles (relative to the surface normals) of vectors between sensed points. The method described here is an extension of a method for recognition and localization of nonoverlapping parts previously described in [18] and [15].


Fifty years of reproductive biology in Australia: highlights from the 50th Annual Meeting of the Society for Reproductive Biology (SRB).
The 2018 edition of the Society for Reproductive Biology's (SRB) Annual Meeting was a celebration of 50 years of Australian research into reproductive biology. The past 50 years has seen many important contributions to this field, and these advances have led to changes in practice and policy, improvements in the efficiency of animal reproduction and improved health outcomes. This conference review delivers a dedicated summary of the symposia, discussing emerging concepts, raising new questions and proposing directions forward. Notably, the symposia discussed in this review emphasised the impact that reproductive research can have on quality of life and the health trajectories of individuals. The breadth of the research discussed encompasses the central regulation of fertility and cyclicity, life course health and how the environment of gametes and embryos can affect subsequent generations, significant advances in our understanding of placental biology and pregnancy disorders and the implications of assisted reproductive technologies on population health. The importance of a reliable food supply and protection of endangered species is also discussed. The research covered at SRB's 2018 meeting not only recognised the important contributions of its members over the past 50 years, but also highlighted key findings and avenues for innovation moving forward that will enable the SRB to continue making significant contributions for the next 50 years.


The influence of the contralateral knee prior to knee arthroplasty on post-arthroplasty function: the multicenter osteoarthritis study.
Some of the poor functional outcomes of knee arthroplasty may be due to pain in the contralateral, unreplaced knee. We investigated the relationship between the preoperative pain status of the contralateral knee and the risk of a poor postoperative functional outcome in patients who underwent knee arthroplasty. We analyzed data on 271 patients in the Multicenter Osteoarthritis Study who had undergone knee arthroplasty since the time of enrollment. Eighty-six percent of these patients were white, 72% were female, and the mean age was sixty-seven years. The severity of pain in the knee contralateral to the one that was replaced was measured before the knee arthroplasty with use of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale, with the scores being grouped into four categories (0, 1 to 4, 5 to 9, and 10 to 20). Poor post-arthroplasty function six months or more after surgery was determined with use of the Patient Acceptable Symptom State (PASS) outcome tool and a clinical performance measure of walking speed. We evaluated the relationship between contralateral pain severity and the functional outcomes with use of Poisson regression. Seventy-two (27%) of 264 patients demonstrated poor post-arthroplasty function by failing to attain the threshold PASS score, and seventy-six (30%) of 250 subjects had a slow walking speed. As the pre-arthroplasty pain in the contralateral knee increased, there was a steady increase in the proportion with poor post-arthroplasty function (p < 0.0001 for PASS and p = 0.04 for slow walking speed). Compared with patients who had no pre-arthroplasty pain in the contralateral knee, those in the highest category of contralateral pain severity had 4.1 times the risk (95% confidence interval, 1.5 to 11.5) of having poor self-reported post-arthroplasty function. Patients in whom both knees had been replaced at the time of outcome collection were less likely to have poor self-reported function than those in whom only one knee had been replaced. Preoperative pain in the contralateral knee is strongly associated with self-reported post-arthroplasty functional outcome and may therefore be a useful indicator of prognosis or a potential target of perioperative intervention. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


[Responses of soil microbial carbolic metabolism characteristics to home-field advantage of leaf litter decomposition in Liaoheyuan Nature Reserve of northern Hebei Province, China].
Using litter bag method, we studied the responses of soil microbial biomass carbon (MBC), microbial respiration (MR) and microbial metabolic quotient (qCO2) in 0-5 cm, 5-10 cm and 10-20 cm soil layers to home-field advantage of Betula platyphlla and Quercus mongolica leaf litter decomposition in Liaoheyuan Nature Reserve, northern Hebei Province. The results showed that the contents of MBC in Betula platyphila and Quercus mongolica leaf litter treatments in home environment (Bh and Qh treatments) were significant higher than that in B. platyphlla and Q. mongolica leaf litter treatments in non-home environment (Ba and Qa treatments). There was no significant difference in MR between home and non-home environments. Response degree of MBC and MR to home-field advantage of different litter decomposition was inconsistent. The MBC of the different soil layers in Qa treatment fell by 39.6%, 34.9% and 33.5% compared to Qh treatment, respectively, and that in B. platyphlla treatment was decreased by 31.6%, 27.1% and 17.0%, respectively. MR of the different soil layers in Qa treatment accounted for 96.3%, 92.4% and 83.7% of Qh treatment, respectively, while MR in B. platyphila treatment was 99. 4%, 97. 3% and 101.3%, respectively. In contrast to MBC, qCO2 in soil showed a reverse pattern. Our study suggested that rich nutrients in soil enhanced microbial activity and weakened the conflict of nutrient uptake between plants and microorganisms, which led to the result that MBC and qCO2 had an obvious response to home-field advantage of litter decomposition, when litter decomposed in its home environment. There was a weak response between MR and home-field advantage of litter decomposition, because of influence of soil temperature, water content and their interaction. Furthermore, MBC, MR and qCO2 had a higher response degree to home-field advantage of Q. mongolica litter than B. platyphila litter, since lower quality litter exhibited higher home-field advantage of litter decomposition.


Gamma-Fe2O3/II-VI sulfide nanocrystal heterojunctions.
Heterostructure nanocrystals (NCs) of gamma-Fe(2)O(3) and MS (M = Zn, Cd, Hg) are synthesized. The large lattice mismatch between gamma-Fe(2)O(3) and MS NCs leads to noncentrosymmetric structures. Crystallographic planes at the heterojunctions are identified by high-resolution transmission electron microscopy. Preferential formation of trimers and higher oligomers for ZnS and dimers or isolated particles for CdS and HgS with gamma-Fe(2)O(3) NCs are observed and explained by changes in the effective mismatch between the coincidence lattices of the most commonly observed junction planes.


Development and evaluation of nasal formulations of ketorolac.
Ketorolac tromethamine is a potent non-narcotic analgesic with moderate anti-inflammatory activity. Clinical studies indicate that ketorolac has a single dose efficacy greater than morphine for postoperative pain and has excellent applicability in the emergency treatment of pain. Due to incomplete oral absorption of ketorolac, several approaches have been tried to develop a nonoral formulation in addition to injections, especially for the treatment of migraine headache. The aim of our study was to develop a nasal formulation of ketorolac with a dose equivalent to the oral formulation. A series of spray and lyophilized powder formulations of ketorolac were administered into the nasal cavity of rabbits, and their pharmacokinetics profiles were assessed. The spray and powder formulations were compared through their pharmacokinetics parameters and absolute bioavailability. Drug plasma concentration was determined using solid phase extraction, followed by an HPLC analysis. Nasal spray formulations were significantly better absorbed than powder formulations. A nasal spray formulation of ketorolac tromethamine showed the highest absorption with an absolute bioavailability of 91%. Within 30 min of administration, the plasma concentration was comparable to that resulting from an intravenous injection. The absolute bioavailability of a solution of ketorolac acid was 70%. Apparently, the dissolution of ketorolac acid into the mucous layer limits its absorption. There were no significant differences in absorption between different powder formulations. Even the reduction of particle size from 123 microm to 63 microm did not indicate better absorption of ketorolac tromethamine from powder formulations. Interestingly, the absolute bioavailability of ketorolac tromethamine from a powder formulation is only 38%, indicating that the drug may not be totally released from the polymer matrix before it is removed from nasal epithelium by mucociliary clearance.


Comparative study of removal of Cr(VI) with PAC, GAC and adsorbent prepared from tobacco roots.
Tobacco roots activated carbon (TRAC) has been prepared from tobacco roots impregnated with 20% of ZnCl2 and carbonized at 6000 degrees C. Its adsorption capacity has been tested for the treatment of wastewater containing hexavalent chromium. The experiments were carried out in a batch process to study the different system variables such as concentration, adsorbent dosage and contact time. Removal of chromium in the process has been found to increase with increase in adsorbent dosage and contact time. The adsorption isotherm data fitted the Langmuir adsorption isotherm model.


Vagotomy increases alcohol intake in female rats in diet dependent manner: Implications for increased alcohol use disorder after roux-en-y gastric bypass surgery.
A variety of weight loss surgeries have been developed to fight the obesity epidemic, with Roux-en-Y gastric bypass (RYGB) being one of the most effective and popular procedures. However, the underlying mechanisms behind its efficacy are still not well understood. Furthermore, growing clinical evidence suggests that RYGB may result in increased risk for development of alcohol use disorder (AUD). The vagus nerve is a potentially critical contributor to increased risk of AUD following RYGB due to the potential for significant damage to the vagus during surgery, which has been confirmed in rodent studies. Studies aiming at the mechanisms underlying development of alcohol or substance use disorders following the surgery have exclusively used male rats, despite the majority of RYGB patients being female. Thus, the current study had two objectives: 1) to investigate the effect of RYGB on ethanol (EtOH) intake in female rats using a protocol previously established in male rats, and 2) to test the effect of vagal damage and high fat diet (HFD) on EtOH intake in female rats. In the first study, 22 female rats were maintained on HFD for four weeks and then split into two surgical groups, RYGB (n = 10) and Sham (n = 12). All rats then underwent a two-bottle choice test of increasing EtOH concentrations: 2%, 4%, 6%, 8%. Rats were then forced to abstain from EtOH for two weeks, after which access to 8% EtOH was reinstated. The RYGB female rats significantly increased their intake for low concentrations of EtOH (2% and 4%) and during the reinstatement period for 8%. These results mirror those seen in male rats, and thus, confirms RYGB in female rats as an equally viable model to males. In the second study, 40 female rats were separated into four groups: HFD/Sham, HFD/Vagotomy, normal diet (ND)/Sham, and ND/Vagotomy. All rats then were subjected to the same two-bottle choice test protocol as in the previous study. Rats in the vagotomy condition had significantly greater preference for 2% and 4% EtOH compared with Sham-operated controls. EtOH intake, either in ml or adjusted for body weight, was greater in rats maintained on ND compared with rats maintained on HFD. These data suggest that vagal damage may, at least in part, contribute to increased preference for EtOH. Furthermore, this increase in EtOH preference is counter to the blunting effect of HFD. In conclusion, the data presented here suggest a role for vagal damage in risk of AUD after weight loss surgery.


Cost Effectiveness of Influenza Vaccine for U.S. Children: Live Attenuated and Inactivated Influenza Vaccine.
Prior studies showed that live attenuated influenza vaccine (LAIV) is more effective than inactivated influenza vaccine (IIV) in children aged 2-8 years, supporting the Centers for Disease Control and Prevention (CDC) recommendations in 2014 for preferential LAIV use in this age group. However, 2014-2015 U.S. effectiveness data indicated relatively poor effectiveness of both vaccines, leading CDC in 2015 to no longer prefer LAIV. An age-structured model of influenza transmission and vaccination was developed, which incorporated both direct and indirect protection induced by vaccination. Based on this model, the cost effectiveness of influenza vaccination strategies in children aged 2-8 years in the U.S. was estimated. The base case assumed a mixed vaccination strategy where 33.3% and 66.7% of vaccinated children aged 2-8 years receive LAIV and IIV, respectively. Analyses were performed in 2014-2015. Using published meta-analysis vaccine effectiveness data (83% LAIV and 64% IIV), exclusive LAIV use would be a cost-effective strategy when vaccinating children aged 2-8 years, whereas IIV would not be preferred. However, when 2014-2015 U.S. effectiveness data (0% LAIV and 15% IIV) were used, IIV was likely to be preferred. The cost effectiveness of influenza vaccination in children aged 2-8 years is highly dependent on vaccine effectiveness; the vaccine type with higher effectiveness is preferred. In general, exclusive IIV use is preferred over LAIV use, as long as vaccine effectiveness is higher for IIV than for LAIV.


Understanding promiscuity: when is seeking additional mates better than guarding an already found one?
Paternity protection and the acquisition of multiple mates select for different traits. The consensus from theoretical work is that mate-guarding intensifies with an increasing male bias in the adult sex ratio (ASR). A male bias can thus lead to male monogamy if guarding takes up the entire male time budget. Given that either female- or male-biased ASRs are possible, why is promiscuity clearly much more common than male monogamy? We address this question with two models, differing in whether males can assess temporal cues of female fertility. Our results confirm the importance of the ASR: guarding durations increase with decreasing female availability and increasing number of male competitors. However, several factors prevent the mating system from switching to male monogamy as soon as the ASR becomes male biased. Inefficient guarding, incomplete last male sperm precedence, any mechanism that allows sperm to fertilize eggs after the male's departure, and (in some cases) the unfeasibility of precopulatory guarding all help explain cases where promiscuity exists on its own or alongside temporally limited mate-guarding. Shortening the window of fertilization shifts guarding time budgets from the postcopulatory to the precopulatory stage.


Human papillomavirus type 11 recombinant L1 capsomeres induce virus-neutralizing antibodies.
The human papillomavirus type 11 (HPV-11) L1 major capsid protein can be trypsinized to generate recombinant capsomeres that retain HPV genotype-restricted capsid antigenicity (M. Li, T. P. Cripe, P. A. Estes, M. K. Lyon, R. C. Rose, and R. L. Garcea, J. Virol. 71:2988-2995, 1997). In the present study, HPV-11 virion-neutralizing monoclonal antibodies H11.F1 and H11.H3, previously characterized as recognizing two distinct HPV-11 capsid-neutralizing antigenic domains (S. W. Ludmerer, D. Benincasa, and G. E. Mark III, J. Virol. 70:4791-4794, 1996), were each found to be highly immunoreactive with trypsin-generated capsomeres in an enzyme-linked immunosorbent assay (ELISA). Capsomeres were used to generate high-titer polyclonal immune sera that demonstrated HPV genotype-restricted reactivity by ELISA. The capsomere antisera were then tested in an in vitro infectivity assay and found to neutralize HPV-11 virions. In this assay, HPV-11 capsomere polyclonal antisera exhibited neutralization titers (10(-5) to 10(-6)) comparable to those obtained with a virion-neutralizing antiserum raised previously against intact HPV-11 VLPs (R. C. Rose, R. C. Reichman, and W. Bonnez, J. Gen. Virol. 75:2075-2079, 1994). These results indicate that highly immunogenic, genotype-restricted HPV capsid-neutralizing antigenic domains are contained entirely within capsomeres. Thus, capsomeres may be viable vaccine candidates for the prevention of HPV disease.


HEALTH AWARENESS AMONG FEMALE UNDERGRADUATE MEDICAL STUDENTS IN SAUDI ARABIA.
This study was conducted to assess the level of health awareness (HA) among students attending three undergraduate programs in the Colleges of Applied Medical Sciences (CAMS) in Riyadh, Saudi Arabia (SA). A modified self-reported survey was utilized to measure HA demonstrating four domains: Nutrition (NU), Personal Health (PH), Physical Exercise (PE), and Body Build (BB). The questionnaire was distributed to 302 female students attending the first semester of the academic year 2014-2015 BS degree in Radiology Sciences (RS), Clinical Laboratory (CL), and Health Education (HE) departments. Bloom's taxonomy was utilized to describe the three cognitive levels. Synthesizing, creating, and evaluating were grouped to represent high level indicators; applying cognitive skills only revealed an intermediate level; while memorizing and listing demonstrated low levels. In a 5-point Likert scale, the overall mean (M) of HA among CAMS students was 3.82 with the highest among students attending HE (M = 3.89). The domain of PH ranked first with a high average (M = 4.30). There were significant differences (α = 0.05), in the level of HA in PH and BB domains, among students in terms of program specialty only, but no such significant differences were found for other characteristics. The study recommended incorporating health promotion concepts within teaching curricula and conducting health and education campaigns by health education institutions.


Arsenic contamination in the food chain and its risk assessment of populations residing in the Mekong River basin of Cambodia.
In the present study, we investigated the potential arsenic exposure of Cambodian residents from their daily food consumption. Environmental and ecological samples such as paddy soils, paddy rice (unhusked), staple rice (uncooked and cooked), fish and vegetables were collected from Kandal, Kratie and Kampong Cham provinces in the Mekong River basin of Cambodia. After acid-digestion, digestates were chemically analyzed by inductively coupled plasma mass spectrometry. Results revealed that the means of total arsenic concentration ([As]tot) in paddy soils and paddy rice from Kandal were significantly higher than those from Kampong Cham province (t-test, p<0.05). Moreover, a significant positive correlation between the [As]tot in paddy soils and paddy rice was found (r(14) = 0.826, p<0.01). Calculations of arsenic intake from food consumption indicated that the upper end of the range of the daily dose of inorganic arsenic for Kandal residents (0.089-8.386 μg d(-1) kg(-1) body wt.) was greater than the lower limits on the benchmark dose for a 0.5% increased incidence of lung cancer (BMDL0.5 is equal to 3.0 μg d(-1) kg(-1) body wt.). The present study suggests that the residents in Kandal are at risk of arsenic intake from their daily food consumption. However, the residents in Kratie and Kampong Cham provinces are less likely to be exposed to arsenic through their daily dietary intake. To the best of our knowledge, this is the first report estimating the daily intake and daily dose of inorganic arsenic from food consumption in the Mekong River basin of Cambodia.


Susceptibility of male white-tailed deer (Odocoileus virginianus) to Brucella ovis infection.
Infection with Brucella ovis was established by conjunctival instillation in 8 male white-tailed deer (Odocoileus virginianus). Infection was transient in young bucks, but persisted in bucks that were mature when inoculated. The deer were euthanatized and necropsied at various intervals after inoculation. Brucella ovis was recovered from a mature buck at necropsy on postinoculation day 429. Four deer had gross lesions and histopathologic changes of the epididymides. A mature noninfected buck confined for 7 months with an infected buck acquired infection and developed epididymal lesions.


Delayed diagnosis of spinal cord injuries in Huntington's disease.
Huntington's disease is a neurodegenerative disorder, characterised by progressive cognitive, motor and psychiatric symptoms. Patients with advanced disease presenting to emergency medical services can pose a diagnostic and management challenge for physicians unfamiliar with the condition. We describe two patients with Huntington's disease in whom the diagnosis of traumatic spinal cord injury was delayed, discuss the role that cognitive bias and other factors played in this delay, and the lessons we can learn.


[Upside-down stomach and hiatal hernia].
Hiatal hernias represent a special variant of diaphragmatic hernia in which there is a transdiaphragmatic migration of the stomach through the esophageal hiatus. There are 4 types admitted--sliding (type I), paraesophageal (type II), mixt-combining elements for both previous types (type III) and complex (type IV) and represents at most 5-15% from all hiatal hernias. Upside-down stomach is a special form of organoaxial volvulus of the entire stomach in a sac of mixt hiatal hernia (type III) or complex (type IV). There are asymptomatic forms, but the majority of the patients present signs of gastroesophageal reflux and up to one third may show complications such as bleeding, acute volvulus with obstruction or perforation. Surgical intervention is the only treatment option for the gastric volvulus and offers a durable resolution. The ideal surgical technique, the gold standard, consists in reduction of the stomach in the gastric lodge, resection of the sac and calibration of the hiatus adding a gastropexy or antireflux procedure.