Analysis of multiple pesticide residues in tobacco using pressurized liquid extraction, automated solid-phase extraction clean-up and gas chromatography-tandem mass spectrometry.
A new method was developed for the analysis of pesticide residues in tobacco. The objective was to significantly increase the number of samples that can be processed by the laboratory and to enable the extension of the current coverage to additional pesticides. A new analytical approach was therefore defined based on two main axes, the automation of the sample preparation and the selectivity of the analyte detection using tandem mass spectrometry. This latter aspect reduces the stringency of the requirements placed on the clean-up of the extracts and on the chromatographic resolution when less selective detectors are used. The extraction of the analytes from the matrix is performed using the pressurized liquid extraction technique. Tobacco samples are extracted at elevated temperature and pressure (100 C and 100 atm; 1 atm = 101,325 Pa) using acetone as an extraction solvent. The resulting extract is then concentrated using a Vortex evaporator. Three different solid-phase extraction (SPE) procedures, adjusted to the chemical properties of the different active ingredients to be measured, are applied to the concentrated extract, thus leading to three extract fractions. The first fraction contains such main classes of active ingredients as organohalogenated and 2,6-dinitroaniline compounds while the second one collects the organophosphorus and acylalanines residues; these two fractions are analyzed by capillary gas chromatography coupled to tandem mass spectrometry using negative chemical ionization and electron impact ionization in the positive mode, respectively. The third extract fraction gathers the N-methylcarbamates residues which are analyzed by HPLC with post-column derivatization and fluorescence detection. The different sample preparation stages from extraction to SPE clean-up have been automated through the use of recent analytical technologies. In combination with the analysis by tandem mass spectrometry, this provided a potential for a high sample throughput.


How involuntary commitment impacts on the burden of care of the family.
Little research has examined how, or if, involuntary commitment has impacted on the burden experienced by the family. This paper reports a qualitative study which explored how involuntary commitment under the Mental Health Act (MHA) 2000 in Queensland, Australia impacted on families of people with mental illness. Family members of a person with a mental illness, under involuntary commitment at the time or in the previous 12 months, participated in focus groups. Thematic analysis was used to determine the themes. It was apparent from the views of the family that the use of the involuntary commitment was influenced greatly by the pressures experienced by the mental health services (MHS). The MHA did little to assist the family in gaining access to MHS. It was not until after the family made repeated attempts that they were taken seriously. Often the family had few options other than to use deceit and threats to obtain the necessary treatment required. In view of this, the inherit nature of what involuntary commitment implies for persons under it, such as refusing treatment and management difficulties, indicates the family with such an individual experience more hardship in trying to obtain assistance for that person. Thus, the MHA in Queensland has not met its goals of increasing access to MHS. Family members perceive that they were not being listened to and their concerns were not acted upon. The current culture of the MHS appears to serve, to a large degree, to estrange the family from the consumer making relationships difficult and time-consuming to repair. The mental health profession is urged to consider the culture within their workplace and move towards constructive involvement of the family.


Ultrastructural evidence for GABAergic brain stem projections to spinal motoneurons in the rat.
In the present ultrastructural study in the rat, it was determined whether GABA was present in projections descending from the ventromedial reticular formation of the lower brain stem to motoneuronal cell groups in the lumbar spinal cord. For this purpose, the anterograde transport of WGA-HRP was combined with the postembedding immunogold technique for GABA, with the advantage that both markers could be visualized simultaneously in a single terminal. In 4 rats, WGA-HRP was injected in the ventromedial part of the brain stem reticular formation at levels between the rostral inferior olive and the caudal part of the facial nucleus. Vibratome sections were cut from the lumbar spinal cord, reacted for WGA-HRP, and processed for electron microscopy. Ultrathin sections containing the lateral motoneuronal cell groups were cut and treated following the immunogold technique using a polyclonal antibody directed against GABA. It was found that nearly 40% of the terminal profiles that were labeled with WGA-HRP reaction products from the ventromedial brain stem were also labeled for GABA (double labeled). Most of the double-labeled terminals (81%) were F-type (containing many flattened vesicles), 12% were G-type (containing many granular vesicles), and 7% were S-type (containing many spherical vesicles). The majority of the double-labeled terminals contacted proximal dendrites. It is argued that the descending GABAergic projection produces a general inhibitory effect on spinal motoneurons, counteracting the general facilitation produced by the serotonergic projection derived from the same brain stem area.(ABSTRACT TRUNCATED AT 250 WORDS)


Changes in the cellular microRNA profile by the intracellular expression of HIV-1 Tat regulator: A potential mechanism for resistance to apoptosis and impaired proliferation in HIV-1 infected CD4+ T cells.
HIV-1 induces changes in the miRNA expression profile of infected CD4+ T cells that could improve viral replication. HIV-1 regulator Tat modifies the cellular gene expression and has been appointed as an RNA silencing suppressor. Tat is a 101-residue protein codified by two exons that regulates the elongation of viral transcripts. The first exon of Tat (amino acids 1-72) forms the transcriptionally active protein Tat72, but the presence of the second exon (amino acids 73-101) results in a more competent regulatory protein (Tat101) with additional functions. Intracellular, full-length Tat101 induces functional and morphological changes in CD4+ T cells that contribute to HIV-1 pathogenesis such as delay in T-cell proliferation and protection against FasL-mediated apoptosis. But the precise mechanism by which Tat produces these changes remains unknown. We analyzed how the stable expression of intracellular Tat101 and Tat72 modified the miRNA expression profile in Jurkat cells and if this correlated with changes in apoptotic pathways and cell cycle observed in Tat-expressing cells. Specifically, the enhanced expression of hsa-miR-21 and hsa-miR-222 in Jurkat-Tat101 cells was associated with the reduced expression of target mRNAs encoding proteins related to apoptosis and cell cycle such as PTEN, PDCD4 and CDKN1B. We developed Jurkat cells with stable expression of hsa-miR-21 or hsa-miR-222 and observed a similar pattern to Jurkat-Tat101 in resistance to FasL-mediated apoptosis, cell cycle arrest in G2/M and altered cell morphology. Consequently, upregulation of hsa-miR-21 and hsa-miR-222 by Tat may contribute to protect against apoptosis and to anergy observed in HIV-infected CD4+ T cells.


Central amygdala nicotinic and 5-HT1A receptors mediate the reversal effect of nicotine and MDMA on morphine-induced amnesia.
The present study was designed to investigate possible involvement of the central amygdala (CeA) nicotinic acetylcholine (nACh) and 5-hydroxytryptamine 1A (5-HT1A) receptors in the reversal effect of nicotine and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy) on morphine-induced amnesia. Two guide cannulas were stereotaxically implanted in the CeA regions and a step-through passive avoidance task was used for the assessment of memory retrieval in adult male Wistar rats. Our results indicated that post-training s.c. administration of morphine (3-7-mg/kg) impaired memory retrieval. Pre-test administration of nicotine (0.3- and 0.5-mg/kg, s.c.) reversed morphine-induced amnesia. In addition, pre-test intra-CeA injection of MDMA (1-2-μg/rat) with an ineffective dose of nicotine (0.1-mg/kg, s.c.) improved memory retrieval, suggesting the interactive effect of the drugs on memory formation. It should be noted that that pre-test intra-CeA injection of 2-μg/rat of MDMA by itself produced amnesia. Interestingly, pre-test intra-CeA injection of mecamylamine, a nACh receptor antagonist (1-2-μg/rat) or (S)-WAY 100135 (0.25-1-μg/rat), a selective 5-HT1A receptor antagonist inhibited the improvement of morphine-induced amnesia which was produced by pre-test co-injection of nicotine and MDMA. Pre-test intra-CeA injection of the same doses of MDMA, mecamylamine or (S)-WAY 100135 by itself had no effect on morphine-induced amnesia. Moreover, pre-test injection of the same doses of mecamylamine or (S)-WAY 100135 into the CeA alone could not change memory retrieval. Taken together, it can be concluded that there is a functional interaction between morphine, nicotine and MDMA via the CeA nicotinic and serotonergic receptor mechanisms in passive avoidance memory retrieval. Moreover, cross state-dependent memory retrieval may have been induced between the drugs and this probably depends on the rewarding effects of the drugs.


A Deep Learning Framework for Skull Stripping in Brain MRI.
Skull-stripping, an important pre-processing step in neuroimage computing, involves the automated removal of non-brain anatomy (such as the skull, eyes, and ears) from brain images to facilitate brain segmentation and analysis. Manual segmentation is still practiced, but it is time-consuming and highly dependent on the expertise of clinicians or image analysts. Prior studies have developed various skull-stripping algorithms that perform well on brains with mild or no structural abnormalities. Nonetheless, they were not able to address the issue for brains with significant morphological changes, such as those caused by brain tumors, particularly when the tumors are located near the skull's border. In such cases, a portion of the normal brain may be stripped, or the reverse may occur during skull stripping. To address this limitation, we propose to use a novel deep learning framework based on nnUNet for skull stripping in brain MRI. Two publicly available datasets were used to evaluate the proposed method, including a normal brain MRI dataset - The Neurofeedback Skull-stripped Repository (NFBS), and a brain tumor MRI dataset - The Cancer Genome Atlas (TCGA). The method proposed in the study performed better than six other current methods, namely BSE, ROBEX, UNet, SC-UNet, MV-UNet, and 3D U-Net. The proposed method achieved an average Dice coefficient of 0.9960, a sensitivity of 0.9999, and a specificity of 0.9996 on the NFBS dataset, and an average Dice coefficient of 0.9296, a sensitivity of 0.9288, a specificity of 0.9866 and an accuracy of 0.9762 on the TCGA brain tumor dataset.


Amlodipine reduces AngII-induced aortic aneurysms and atherosclerosis in hypercholesterolemic mice.
The purpose of this study was to determine effects of amlodipine, a dihydropyridine calcium channel blocker, on development of angiotensin II (AngII)-induced vascular pathologies. Male LDL receptor -/- mice were infused with vehicle, amlodipine (5 mg/kg/d), AngII (1,000 ng/kg/min), or AngII + amlodipine for 4 weeks through osmotic pumps (n=10/group). Mice were fed a saturated fat-enriched diet for 1 week prior to pump implantation and during 4 weeks of infusion. Infusion of amlodipine resulted in plasma concentrations of 32 ± 2 ng/ml and 27 ± 2 ng/ml for mice in saline + amlodipine and AngII + amlodipine groups, respectively. This infusion rate of amlodipine did not affect AngII-induced increases in systolic blood pressure. Three of 10 (30%) mice infused with AngII died of aortic rupture, while aortic rupture did not occur in mice co-infused with AngII + amlodipine. Suprarenal aortic width and intimal area of ascending aortas were measured to define aortic aneurysms. In the absence of AngII infusion, amlodipine did not change suprarenal aortic width and ascending aortic area. Infusion of AngII led to profound increases of suprarenal aortic width (saline + vehicle versus AngII + vehicle: 0.86 ± 0.02 versus 1.72 ± 0.26 mm; P=0.0006), whereas co-infusion of AngII and amlodipine diminished abdominal dilation (1.02 ± 0.14 mm; P=0.003). As expected, AngII infusion increased mean intimal area of ascending aortas (saline + vehicle versus AngII + vehicle: 8.5 ± 0.3 versus 12.5 ± 1.1 mm(2); P=0.001), while co-infusion of AngII and amlodipine ablated dilation of the ascending aorta (8.6 ± 0.2 mm(2); P=0.03). Co-administration of amlodipine also significantly attenuated AngII-induced atherosclerosis in the thoracic region as quantified by percent lesion area (AngII + vehicle versus AngII + amlodipine: 5.8 ± 2.1 % versus 0.3 ± 0.1%; P=0.05). Amlodipine inhibited AngII-induced aortic aneurysms in both the abdominal and ascending regions, and atherosclerosis in hypercholesterolemic mice.


Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking.
Alzheimer's disease (AD) is characterized by the presence of early intraneuronal deposits of amyloid-beta 42 (Abeta42) that precede extracellular amyloid deposition in vulnerable brain regions. It has been hypothesized that endosomal/lysosomal dysfunction might be associated with the pathological accumulation of intracellular Abeta42 in the brain. Our previous findings suggest that the LDL receptor-related protein 1 (LRP1), a major receptor for apolipoprotein E, facilitates intraneuronal Abeta42 accumulation in mouse brain. However, direct evidence of neuronal endocytosis of Abeta42 through LRP1 is lacking. Here we show that LRP1 endocytic function is required for neuronal Abeta42 uptake. Overexpression of a functional LRP1 minireceptor, mLRP4, increases Abeta42 uptake and accumulation in neuronal lysosomes. Conversely, knockdown of LRP1 expression significantly decreases neuronal Abeta42 uptake. Disruptions of LRP1 endocytic function by either clathrin knockdown or by removal of its cytoplasmic tail decreased both uptake and accumulation of Abeta42 in neurons. Finally, we show that LRP1-mediated neuronal accumulation of Abeta42 is associated with increased cellular toxicity. These results demonstrate that LRP1 endocytic function plays an important role in the uptake and accumulation of Abeta42 in neuronal lysosomes. These findings emphasize the central function of LRP1 in neuronal Abeta metabolism.


Hypertensive crisis in a patient undergoing percutaneous radiofrequency ablation of an adrenal mass under general anesthesia.
Radiofrequency ablation (RFA) is an effective therapeutic intervention for a variety of neoplastic lesions. Many of these procedures are conducted with patients under general anesthesia. Although RFA is associated with infrequent complications, it is not without risk. Injury to adjacent normal structures is a major concern during RFA of cancerous lesions. Unintended injury to normal adrenal tissue during RFA of adrenal tumors can lead to hypertensive crisis, a potentially catastrophic complication. Hemodynamic consequences of RFA of primary or metastatic adrenal masses have not been reported. We report a case of hypertensive crisis (249/140 mm Hg), tachycardia, and ventricular arrhythmia in an 82-yr-old woman undergoing RFA of renal cell carcinoma metastatic to the adrenal gland. Anesthesiologists should be aware of this potentially catastrophic complication. Direct-acting vasodilators and short-acting beta(1)-adrenergic antagonists should be immediately available, and intraarterial blood pressure monitoring should be seriously considered when providing care for patients undergoing RFA of an adrenal mass.


The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a randomized, controlled clinical trial.
Spontaneous bacterial peritonitis (SBP) is a common, life-threatening complication of liver cirrhosis. Third-generation cephalosporins have been considered the first-line treatment of SBP. In 2014, a panel of experts suggested a broader spectrum antibiotic regimen for nosocomial SBP, according to the high rate of bacteria resistant to third-generation cephalosporins found in these patients. However, a broader-spectrum antibiotic regimen has never been compared to third-generation cephalosporins in the treatment of nosocomial SBP. The aim of our study was to compare meropenem plus daptomycin versus ceftazidime in the treatment of nosocomial SBP. Patients with cirrhosis and nosocomial SBP were randomized to receive meropenem (1 g/8 hours) plus daptomycin (6 mg/kg/day) or ceftazidime (2 g/8 hours). A paracentesis was performed after 48 hours of treatment. A reduction in ascitic fluid neutrophil count <25% of pretreatment value was considered a treatment failure. The primary outcome was the efficacy of treatment defined by the resolution of SBP after 7 days of treatment. Thirty-two patients were randomized and 31 were analyzed. The combination of meropenem plus daptomycin was significantly more effective than ceftazidime in the treatment of nosocomial SBP (86.7 vs. 25%; P < 0.001). Ninety-day transplant-free survival (TFS) was not significantly different between the two groups. In the multivariate analysis, ineffective response to first-line treatment (hazard ratio [HR]: 20.6; P = 0.01), development of acute kidney injury during hospitalization (HR: 23.2; P = 0.01), and baseline mean arterial pressure (HR: 0.92; P = 0.01) were found to be independent predictors of 90-day TFS. The combination of meropenem plus daptomycin is more effective than ceftazidime as empirical antibiotic treatment of nosocomial SBP. Efficacy of the empirical antibiotic treatment is a strong predictor of 90-day survival in patients with nosocomial SBP.


Early EEG Features for Outcome Prediction After Cardiac Arrest in Children.
We aimed to determine which early EEG features and feature combinations most accurately predicted short-term neurobehavioral outcomes and survival in children resuscitated after cardiac arrest. This was a prospective, single-center observational study of infants and children resuscitated from cardiac arrest who underwent conventional EEG monitoring with standardized EEG scoring. Logistic regression evaluated the marginal effect of each EEG variable or EEG variable combinations on the outcome. The primary outcome was neurobehavioral outcome (Pediatric Cerebral Performance Category score), and the secondary outcome was mortality. The authors identified the models with the highest areas under the receiver operating characteristic curve (AUC), evaluated the optimal models using a 5-fold cross-validation approach, and calculated test characteristics maximizing specificity. Eighty-nine infants and children were evaluated. Unfavorable neurologic outcome (Pediatric Cerebral Performance Category score 4-6) occurred in 44 subjects (49%), including mortality in 30 subjects (34%). A model incorporating a four-level EEG Background Category (normal, slow-disorganized, discontinuous or burst-suppression, or attenuated-flat), stage 2 Sleep Transients (present or absent), and Reactivity-Variability (present or absent) had the highest AUC. Five-fold cross-validation for the optimal model predicting neurologic outcome indicated a mean AUC of 0.75 (range, 0.70-0.81) and for the optimal model predicting mortality indicated a mean AUC of 0.84 (range, 0.76-0.97). The specificity for unfavorable neurologic outcome and mortality were 95% and 97%, respectively. The positive predictive value for unfavorable neurologic outcome and mortality were both 86%. The specificity of the optimal model using a combination of early EEG features was high for unfavorable neurologic outcome and mortality in critically ill children after cardiac arrest. However, the positive predictive value was only 86% for both outcomes. Therefore, EEG data must be considered in overall clinical context when used for neuroprognostication early after cardiac arrest.


Deep-sea authigenic calcite and dolomite.
Crystals of calcite and, in one case, of dolomite up to 90 microm in size are dispersed in pelagic red clay at several sites on the floor of the South Pacific Ocean. They were analyzed by microscopic, x-ray diffraction, electron x-ray microprobe, and oxygen isotopic techniques. These carbonates are authigenic and were probably precipitated from hydrothermal solutions connected with deep-sea volcanic activity.


Multistation proprioceptive exercise program prevents ankle injuries in basketball.
To investigate the effectiveness of a multistation proprioceptive exercise program for the prevention of ankle injuries in basketball players using a prospective randomized controlled trial in combination with biomechanical tests of neuromuscular performance. A total of 232 players participated in the study and were randomly assigned to a training or control group following the CONSORT statement. The training group performed a multistation proprioceptive exercise program, and the control group continued with their normal workout routines. During one competitive basketball season, the number of ankle injuries was counted and related to the number of sports participation sessions using logistic regression. Additional biomechanical pre–post tests (angle reproduction and postural sway) were performed in both groups to investigate the effects on neuromuscular performance. In the control group, 21 injuries occurred, whereas in the training group, 7 injuries occurred. The risk for sustaining an ankle injury was significantly reduced in the training group by approximately 65%. [corrected] The corresponding number needed to treat was 7. Additional biomechanical tests revealed significant improvements in joint position sense and single-limb stance in the training group. The multistation proprioceptive exercise program effectively prevented ankle injuries in basketball players. Analysis of number needed to treat clearly showed the relatively low prevention effort that is necessary to avoid an ankle injury. Additional biomechanical tests confirmed the neuromuscular effect and confirmed a relationship between injury prevention and altered neuromuscular performance. With this knowledge, proprioceptive training may be optimized to specifically address the demands in various athletic activities.


Characterization of the oncogenic activity of the novel TRIM59 gene in mouse cancer models.
A novel TRIM family member, TRIM59 gene was characterized to be upregulated in SV40 Tag oncogene-directed transgenic and knockout mouse prostate cancer models as a signaling pathway effector. We identified two phosphorylated forms of TRIM59 (p53 and p55) and characterized them using purified TRIM59 proteins from mouse prostate cancer models at different stages with wild-type mice and NIH3T3 cells as controls. p53/p55-TRIM59 proteins possibly represent Ser/Thr and Tyr phosphorylation modifications, respectively. Quantitative measurements by ELISA showed that the p-Ser/Thr TRIM59 correlated with tumorigenesis, whereas the p-Tyr-TRIM59 protein correlated with advanced cancer of the prostate (CaP). The function of TRIM59 was elucidated using short hairpin RNA (shRNA)-mediated knockdown of the gene in human CaP cells, which caused S-phase cell-cycle arrest and cell growth retardation. A hit-and-run effect of TRIM59 shRNA knockdown was observed 24 hours posttransfection. Differential cDNA microarrray analysis was conducted, which showed that the initial and rapid knockdown occurred early in the Ras signaling pathway. To confirm the proto-oncogenic function of TRIM59 in the Ras signaling pathway, we generated a transgenic mouse model using a prostate tissue-specific gene (PSP94) to direct the upregulation of the TRIM59 gene. Restricted TRIM59 gene upregulation in the prostate revealed the full potential for inducing tumorigenesis, similar to the expression of SV40 Tag, and coincided with the upregulation of genes specific to the Ras signaling pathway and bridging genes for SV40 Tag-mediated oncogenesis. The finding of a possible novel oncogene in animal models will implicate a novel strategy for diagnosis, prognosis, and therapy for cancer.


A Cluster Randomized Trial of a Personalized Multi-Condition Risk Assessment in Primary Care.
Personal risk for multiple conditions should be assessed in primary care. This study evaluated whether collection of risk factors to generate electronic health record (EHR)-linked health risk appraisal (HRA) for coronary heart disease, diabetes, breast cancer, and colorectal cancer was associated with improved patient-provider communication, risk assessment, and plans for breast cancer screening. This pragmatic trial recruited adults with upcoming visits to 11 primary care practices during 2013-2014 (N=3,703). Pre-visit, intervention patients completed a risk factor and perception assessment and received an HRA; coded risk factor data were sent to the EHR. Post-visit, intervention patients reported risk perception. Pre-visit, control patients only completed the risk perception assessment; post-visit they also completed the risk factor assessment and received the HRA. No data were sent to the EHR for controls. Accuracy/improvement of self-perceived risk was assessed by comparing self-perceived to calculated risk. The intervention was associated with improvement of patient-provider communication of changes to improve health (78.5% vs 74.1%, AOR=1.67, 99% CI=1.07, 2.60). There was a similar trend for discussion of risk (54.1% vs 45.5%, AOR=1.34, 95% CI=0.97, 1.85). The intervention was associated with greater improvement in accuracy of self-perceived risk for diabetes (16.0% vs 12.6%, p=0.006) and colorectal cancer (27.9% vs 17.2%, p<0.001) with a similar trend for coronary heart disease and breast cancer. There were no changes in plans for breast cancer screening. Patient-reported risk factors and EHR-linked multi-condition HRAs in primary care can modestly improve communication and promote accuracy of self-perceived risk.


Mediated coupling of surface plasmon polaritons by a moving electron beam.
The mediated coupling of surface plasmon polaritons (SPPs) by a parallel moving electron beam is demonstrated in this paper. The theoretical analysis shows that the electron beam excited spoof surface plasmon polaritons (SSPs) on the grating placed above the metal films play the role as the excitation source in the mediated coupling. The numerical calculations and particle-in-cell simulations demonstrate the significant advantages of the SSPs mediately coupled SPPs in contrast with that coupled by the parallel moving electron beam directly. The photo density of the mediately coupled SPPs reaches up to 106 per cm2 for the electron beam with the charge density 100 nC/cm, which is two orders of magnitude larger than that of the directly coupled SPPs. The tuning band of the mediately coupled SPPs reaches up to 9% for the beam energy ranging from 10 keV to 30 keV, while it almost cannot be tuned for the direct coupling. The lifetime of the mediately coupled SPPs, which reaches up to hundreds of femtoseconds, is also much longer. Accordingly, the mediated coupling may bring great significances for the applications of SPPs.


The effectiveness of papilledema as an indicator of raised intracranial pressure in children with craniosynostosis.
Craniosynostosis management partially depends on the detection and treatment of elevated intracranial pressure (ICP). Examination for papilledema is considered to be the most reliable screening method for identifying raised ICP, but its effectiveness has not been defined. One hundred and twenty-two children with craniosynostosis who underwent funduscopic examinations and then Camino ICP monitoring were studied. All eye examinations were performed by an ophthalmologist after pharmacological pupillary dilation. Fifteen patients (12%) had papilledema. Subsequent ICP monitoring showed that the median ICP was 12.7 mm Hg, with 41 patients (34%) having elevated ICPs (> 15 mm Hg). Those with papilledema had higher ICPs (17.5 +/- 3.2 versus 12.7 +/- 5.5 mm Hg), were older (5.9 +/- 4.7 versus 1.9 +/- 2.6 years), and were more likely to have craniofacial syndromes (73 versus 41%) than those without papilledema (P < 0.05). Patients with both elevated ICPs and papilledema were older (5.9 +/- 4.7 versus 1.6 +/- 1.4 years) and more likely to have multiple-suture synostosis (92 versus 61%) than those with elevated ICPs and no papilledema (P < 0.05). The presence of papilledema was a specific (98%) indicator of raised ICP, but its sensitivity was age-dependent. It was 100% sensitive in children older than 8 years, but it indicated elevated ICP in only 22% of younger patients. These results suggest that ICP monitoring to document elevated ICP is unnecessary in children older than 8 years who have detailed ophthalmological examinations. In the younger child, the presence of papilledema reliably indicates elevated ICP but its absence does not rule out elevated ICP; formal ICP measurement has a greater role in detecting elevated ICP in these patients.


The modified vital index in prehospital emergency care.
Many vital indices and scores have been proposed and used, particularly in relation to trauma. Most were primarily designed for and, within limits, are successful in hospital application. Attempts to use all or part of these in the prehospital context are misguided. There is a major difference between this phase of emergency care and hospital care, and that is the inability to provide a definitive end-point of treatment. A new score is proposed, the modified vital index (MVI) based on vital signs and other parameters important in the prehospital context. The value of the MVI lies in its adaptability to emergency medical care systems at all stages of development. The necessity for the MVI is outlined, as is the detailed working of the system. The hope is expressed that through adaptation of the MVI in different areas a consolidated prehospital scoring system may be achieved.


Expression of interleukin-1beta, interleukin-1 receptor, and interleukin-1 receptor antagonist mRNA in rat carotid artery after balloon angioplasty.
Interleukin-1beta (IL-1beta) is a pleiotropic cytokine capable of inducing smooth muscle activation and leukocyte recruitment in restenosis and atherosclerosis. Our present study investigated the expression of IL-1beta, IL-1 receptor antagonist (IL-1ra), and IL-1 receptor (IL-1RI and IL-1RII) mRNA in carotid artery after balloon angioplasty using semiquantitative reverse transcription/polymerase chain reaction (RT/PCR) and Northern analysis. Time course studies revealed that IL-1beta mRNA was rapidly induced at 6 h (30-fold increase over control, P < 0.001) post balloon injury and diminished to basal levels at 24 h. The increased expression of IL-1ra mRNA was delayed, reaching a peak at 24 h (400-fold increase, P < 0.001) and sustained up to 14 days. The expression of IL-1RII mRNA was remarkably similar to that of IL-1beta, whereas the IL-1RI (the signaling receptor) mRNA expression was delayed (significantly induced at day 1; 14.2-fold increase, P < 0.01) post balloon injury. Immunohistochemical studies revealed a strong induction of IL-1beta in the area with actively proliferating and migrating smooth muscle cells (i.e., in the inner medial layer at day 1 and in neointima at day 14 after balloon injury). The differential but concomitant expression of IL-1beta, IL-1ra, IL-1RI, and IL-1RII mRNAs after balloon angioplasty suggests that each of these IL-1 system components may play a distinct role in neointima formation.


Possible role of cyclooxygenase-2 in schistosomal and non-schistosomal-associated bladder cancer.
Cyclooxygenase (COX) is an angiogenic factor that is strongly related to inflammatory diseases and the development of cancer and metastasis in several cancers. It is overexpressed in a variety of premalignant and malignant conditions, including urinary bladder cancer. Our aim was to investigate and compare the expression of COX-2 enzyme in patients with bladder cancer, chronic cystitis, and normal bladder tissue. The results were correlated to the classic prognostic factors, mainly tumor stage and grade, in a trial to determine the prognostic significance of COX-2 marker. Seventy-five bladder samples were taken, including 50 cases with bladder cancer (31 were schistosomal-associated and 19 non-schistosomal-associated), 20 samples from cases with chronic cystitis (7 were nonschistosomal and 13 were schistosomal cystitis), and 5 samples from normal bladder tissue taken as control. The specimens were stained by streptavidin-biotin immunohistochemistry protocol, with COX-2 monoclonal antibody. Although no notable expression of COX-2 was observed in the normal bladder, it was slightly expressed in chronic cystitis especially in areas of dysplasia and squamous metaplasia, whereas there was a significant increase in COX-2 (P < .001) with moderate-to-strong granular cytoplasmic expression in all malignant histologic types. The COX-2 reactivity was higher in transitional cell carcinoma (TCC) than in squamous cell carcinoma (SqCC) (P < .01). COX-2 expression was significantly higher in schistosomal-associated TCC than in non-schistosomal-associated TCC (P < .01). There was a statistically significant positive correlation between COX-2 expression and tumor grade (P = .0052). COX-2 expression was significantly higher in grade 3 bladder TCC than in grades 1 and 2 bladder TCC (P < .05, P < .01). A correlation between COX-2 expression and progression of bladder TCC also was observed (P = .001). There was a significant difference in COX-2 expression level between the bladder TCCs at different clinical stages (P < .01). COX-2 is overexpressed in schistosomal-associated bladder cancer. COX-2 may be of significance to the development and proliferation of bladder TCC, consistent with a potential role for COX-2 inhibitors in the prevention and management of this disease.


Optimal Response to Quorum-Sensing Signals Varies in Different Host Environments with Different Pathogen Group Size.
The persistence of genetic variation in master regulators of gene expression, such as quorum-sensing systems, is hard to explain. Here, we investigated two alternative hypotheses for the prevalence of polymorphic quorum sensing in Gram-positive bacteria, i.e., the use of different signal/receptor pairs ('pherotypes') to regulate the same functions. First, social interactions between pherotypes or 'facultative cheating' may favor rare variants that exploit the signals of others. Second, different pherotypes may increase fitness in different environments. We evaluated these hypotheses in the invertebrate pathogen Bacillus thuringiensis, using three pherotypes expressed in a common genetic background. Facultative cheating could occur in well-mixed host homogenates provided there was minimal cross talk between competing pherotypes. However, facultative cheating did not occur when spatial structure was increased in static cultures or in naturalistic oral infections, where common pherotypes had higher fitness. There was clear support for environment-dependent fitness; pherotypes varied in responsiveness to signals and in mean competitive fitness. Notably, competitive fitness varied with group size. In contrast to typical social evolution models of quorum sensing which predict higher response to signal at larger group size, the pherotype with highest responsiveness to signals performed best in smaller hosts where infections have a lower pathogen group size. In this system, low signal abundance appears to limit fitness in hosts, while the optimal level of response to signals varies in different host environments.IMPORTANCE Quorum sensing describes the ability of microbes to alter gene regulation according to their local population size. Some successful theory suggests that this is a form of cooperation, namely, investment in shared products is only worthwhile if there are sufficient bacteria making the same product. This theory can explain the genetic diversity in these signaling systems in Gram-positive bacteria, such as Bacillus and Staphylococcus sp. The possible advantages gained by rare genotypes (which can exploit the products of their more common neighbors) could explain why different genotypes can coexist. We show that while these social interactions can occur in simple laboratory experiments, they do not occur in naturalistic infections using an invertebrate pathogen, Bacillus thuringiensis Instead, our results suggest that different genotypes are adapted to differently sized hosts. Overall, social models are not easily applied to this system, implying that a different explanation for this form of quorum sensing is required.


Recombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase.
The Saccharomyces cerevisiae SGS1 gene encodes a RecQ-like DNA helicase, human homologues of which are implicated in the genetic instability disorders, Bloom syndrome (BS), Rothmund-Thomson syndrome (RTS), and Werner syndrome (WS). Telomerase-negative yeast cells can recover from senescence via two recombinational telomere elongation pathways. The "type I" pathway generates telomeres with large blocks of telomeric and subtelomeric sequences and short terminal repeat tracts. The "type II" pathway generates telomeres with extremely long heterogeneous terminal repeat tracts, reminiscent of the long telomeres observed in telomerase-deficient human tumors and tumor-derived cell lines. Here, we report that telomerase-negative (est2) yeast cells lacking SGS1 senesced more rapidly, experienced a higher rate of telomere erosion, and were delayed in the generation of survivors. The est2 sgs1 survivors that were generated grew poorly, arrested in G(2)/M and possessed exclusively type I telomeres, implying that SGS1 is critical for the type II pathway. The mouse WS gene suppressed the slow growth and G(2)/M arrest phenotype of est2 sgs1 survivors, arguing that the telomeric function of SGS1 is conserved. Reintroduction of SGS1 into est2 sgs1 survivors restored growth rate and extended terminal tracts by approximately 300 bp. Both phenotypes were absolutely dependent on Sgs1 helicase activity. Introduction of an sgs1 carboxyl-terminal truncation allele with helicase activity restored growth rate without extending telomeres in most cases, demonstrating that type II telomeres are not necessary for normal growth in the absence of telomerase.


The feasibility of solo-surgeon living donor nephrectomy: initial experience using video-assisted minilaparotomy surgery.
Today, many kinds of surgery are being conducted without human assistants. Living donor nephrectomy (LDN) using video-assisted minilaparotomy surgery (VAM) has been performed by solo-surgeon using Unitrac® (Aesculap Surgical Instrument, Germany). We examined the results from VAM-solo-surgeon living donor nephrectomy (SLDN) and conventional VAM-human-assisted living donor nephrectomy (HLDN). Between July 2007 and April 2008, 82 cases of VAM-LDN were performed by two surgeons. From these cases, we randomly assigned 35 cases to undergo solo-surgery (group I) and the other 47 cases to undergo surgery with one human assistant (group II). All VAM-LDN procedures were performed in the same manner. Only the roles of a first assistant were substituted by the Unitrac® in group I. We compared the perioperative and postoperative data, including operative time, estimated blood loss, and hospital stay, between the two groups. We also investigated cases that developed complications. There were no significant differences in the patient demographic data between the two groups (P > 0.05). The mean operative time was 201.9 ± 32.9 min in group I and 202.4 ± 48.3 min in group II (P = 0.954), whereas mean blood loss was 209.7 ± 167.3 ml in group I and 179.6 ± 87.8 ml in group II (P = 0.294). Postoperative hospital stay were 5.4 ± 1.1 days in group I and 5.5 ± 1.6 days in group II (P = 0.813). The incidence of perioperative complications was not significantly different between the two groups. Our study demonstrates that VAM-SLDN can be performed safely, is economically beneficial, and is comparable to VAM-HLDN in terms of postoperative outcomes.


In vitro virucidal activity by components of a topical film-forming medication.
This study evaluated the in vitro virucidal activity of soluble components of a topical film-forming medication, Zilactin, against Herpes simplex virus type 1 (HSV-1). Using a standard plaque reduction assay, a 1:10 dilution of the experimental liquid resulted in total destruction of infectious HSV-1. The phenomenon could not be explained by ethanol concentration or lowering of pH, both of which had no effect on control samples. As employed in this assay, Zilactin diluted 1:10 did not demonstrate cyctotoxicity to the cell monolayer system. The implications of these findings on the design and implementation of clinical trials are discussed, with special reference made to the restrictions imposed by the natural history of clinical lesions caused by HSV-1.


The dynamics of membrane structure.
The membranes of living organisms are involved in many aspects of the life, growth and development of all cells. The predominant structural elements of these membranes are lipids and proteins and the basic strucvture of these molecules has been reviewed. The physical properties of the lipid constituents particularly their behavior in aqueous systems has led to the concepts of thermotropic and lyotropic mesomorphism; the interaction between different types of lipid molecules modulate this behavior. Interaction of phospholipids in aqueous systems with cholesterol, ions and drugs have been examined in this context. In addition a variety of model lipid-protein systems have been investigated and the implications of interactions between lipids and different proteins in biological membranes has been evaluated. This leads to a detailed consideration of the way lipids and proteins ae organized in cell membranes and contains an appraisal of the evidence supporting contemporary views of membrane structure. Particular attention has been devoted to the question of how mobile the components are within the structure. Particular attention has been devoted to the question of how mobile the components are within the structure. Finally the biosynthesis, turnover and modulation of the properties of interacting membrane constituents is critically reviewed and possible ways of controlling the behavior of cells and organisms by altering the structural parameters of different membranes has been considered.


Methionine restriction affects oxidative stress and glutathione-related redox pathways in the rat.
Lifelong dietary methionine restriction (MR) is associated with increased longevity and decreased incidence of age-related disorders and diseases in rats and mice. A reduction in the levels of oxidative stress may be a contributing mechanistic factor for the beneficial effects of MR. To examine this, we determined the effects of an 80% dietary restriction of Met on different biomarkers of oxidative stress and antioxidant pathways in blood, liver, kidney and brain in the rat. Male F-344 rats were fed control (0.86% methionine) or MR (0.17% methionine) diets for up to six months. Blood and tissues were analyzed for glutathione (GSH) concentrations, related enzyme activities and biomarkers of oxidative stress. MR was associated with reductions in oxidative stress biomarkers including plasma 8-hydoxydeoxyguanosine (8-OHdG) and 8-isoprostane and erythrocyte protein-bound glutathione after one month with levels remaining low for at least six months (P < 0.05). Levels of free GSH in blood were increased after 1-6 months of MR feeding whereas liver GSH levels were reduced over this time (P < 0.05). In MR rats, GSH peroxidase activity was decreased in liver and increased in kidney compared with controls. No changes in the activities of GSH reductase in liver and kidney and superoxide dismutase in liver were observed as a result of MR feeding. Altogether, these findings indicate that oxidative stress is reduced by MR feeding in rats, but this effect cannot be explained by changes in the activity of antioxidant enzymes.


A model of engagement in reflective writing-based portfolios: Interactions between points of vulnerability and acts of adaptability.
Portfolios are widely used for meeting new accreditation standards in the age of competency-based medicine. However, the method of learning through portfolio has been suggested to be vulnerable. The aim of this study was to explore conditions affecting the experience of teaching and learning from the perspective of both students and mentors in a reflective writing-based portfolio initiative. Using mixed-methods rooted in grounded theory, 139 students and 13 mentors completed questionnaires, 23 students participated in four focus groups and 9 mentors in individual interviews. The overarching theme in our data was student-mentor engagement. Our results confirm previous literature describing portfolio as a vulnerable method of learning, extend this concept by identifying and categorizing specific points of vulnerability, and contribute new knowledge regarding acts of adaptability, which serve to strengthen the student-mentor relationship. Engagement is central to the success of portfolio and is shaped by a dynamic interaction between points of vulnerability and acts of adaptability. We propose a model of engagement in portfolio that can be used for faculty development to optimize student-mentor engagement.


Agricultural health in The Gambia II: A systematic survey of safety and injuries in production agriculture.
This study was undertaken to provide baseline information on the injuries and health and safety conditions in Gambian agriculture. The objective was to produce information to guide the formulation of an agricultural health and safety policy for the country, future investigations, prevention and surveillance of the adverse health effects in agriculture. A cross-sectional survey of 20 farmers, 20 nurses, and 20 agricultural extension workers was conducted in the Central and Upper River Divisions of The Gambia. The survey was implemented by the means of questionnaires, walk-through survey and hazard checklist. Seventy percent of farms reported an injury during the past year. Major sources and contributing factors for the injuries were characterized. Predisposing factors to the injuries were climatic conditions, working in static positions, bending and twisting and carrying heavy objects. Cuts and lacerations were identified as the commonest injury types and the most common sources were hand tools (hand hoe, cutlass, axe and knife) and animal-powered carts. A workshop for the major stake holders in the country's agriculture was also held to identify problems and possible solutions for health promotion of Gambian farmers.


Spatiotemporal variations of "triple-demic" outbreaks of respiratory infections in the United States in the post-COVID-19 era.
The US confronted a "triple-demic" of influenza, respiratory syncytial virus (RSV), and COVID-19 in the winter of 2022, leading to increased respiratory infections and a higher demand for medical supplies. It is urgent to analyze these epidemics and their spatial-temporal co-occurrence, identifying hotspots and informing public health strategies. We employed retrospective and prospective space-time scan statistics to assess the situations of COVID-19, influenza, and RSV in 51 US states from October 2021 to February 2022, and from October 2022 to February 2023, respectively. This enabled monitoring of spatiotemporal variations for each epidemic individually and collectively. Compared to winter 2021, COVID-19 cases decreased while influenza and RSV infections significantly increased in winter 2022. We found a high-risk cluster of influenza and COVID-19 (not all three) in winter 2021. In late November 2022, a large high-risk cluster of triple-demic emerged in the central US. The number of states at high risk for multiple epidemics increased from 15 in October 2022 to 21 in January 2023. Our study offers a novel spatiotemporal approach that combines both univariate and multivariate surveillance, as well as retrospective and prospective analyses. This approach offers a more comprehensive and timely understanding of how the co-occurrence of COVID-19, influenza, and RSV impacts various regions within the United States. Our findings assist in tailor-made strategies to mitigate the effects of these respiratory infections.


Fluorescent labelling reveals spatial separation of potyvirus populations in mixed infected Nicotiana benthamiana plants.
The distribution of potyviruses in mixed infected Nicotiana benthamiana plants was investigated by using green and red fluorescent proteins (GFP, DsRed). Full-length cDNA clones of Plum pox virus (PPV-NAT-AgfpS; PPV-NAT-red), Tobacco vein mottling virus (TVMV-gfp; TVMV-red) and Clover yellow vein virus (ClYVV-GFP) expressing fluorescent proteins, referred to here as labelled viruses, were used to characterize the distribution of different potyviral populations (e.g. TVMV-gfp/PPV-NAT-red), as well as populations of identical, but differently labelled potyviruses (e.g. PPV-NAT-AgfpS/PPV-NAT-red) or in mixed infections of potyviruses with labelled Potato virus X (PVX). Plants infected by any of the PVX/potyvirus combinations exhibited synergistic symptoms and large numbers of cells were doubly infected. In contrast, co-infections of differently labelled potyvirus populations appeared non-synergistic and remained predominantly separate in the infected plants, independent of whether different viruses or identical but differently labelled viruses were co-infecting. Contact of differently labelled virus populations that exhibited spatial separation was restricted to a small number of cells at the border of different fluorescent cell clusters.


Investigations into the etiology of elevated serum T3 levels in protein-malnourished rats.
Thyroid function studies and the peripheral metabolism of thyroid hormone were examined in rats fed a low protein diet (9% casein) for 4-8 wk. Compared to animals fed a normal protein diet ad libitum, both the low protein rats and a pair-fed control group weighed less at the end of the study. However, serum total T3 levels were significantly higher only in the protein deficient rats. The elevated serum T3 was not explainable by enhanced peripheral T4 to T3 conversion, as there was no evidence of any change in hepatic or renal 5'-deiodinase activity when homogenates were examined for conversion of T4 to T3, reverse T3 to 3,3'-diiodothyronine, or 3',5'-diiodothyronine to 3'-monoiodothyronine. Neither was there an effect on hepatic T3 receptor maximal binding capacity (204 +/- 24 versus 168 +/- 15 fmol/mg DNA control) or binding affinity (2.07 +/- 0.38 versus 2.49 +/- 0.24 x 10(-10) M control). In two separate experiments the dialyzable fraction of T3 was significantly lower in the low protein group while free T3 concentrations were unchanged or reduced. In contrast, serum total and free T4 were either normal or reduced and dialyzable T4 was unaffected by protein deficiency. We conclude that while serum total T3 is elevated in rats chronically fed a low protein diet, this elevation is not due to enhanced T4 to T3 conversion. Rather, the increased T3 levels can be accounted for by a striking alteration in protein binding to T3. Moreover, the failure to demonstrate similar changes in serum total and dialyzable T4 suggests that in the rat, protein deficiency has different effects on binding to the two major thyroid hormones. Dietary induced changes in serum thyroid hormone binding must be kept in mind in nutrition studies in the rat.


A new species of Philoscirtus (Orthoptera: Phaneropteridae: Mecopodinae) from the West Usambara Mountains of Tanzania and its conservation status.
A new Philoscirtus species, P. viridulus n. sp. from forests of the West Usambara Mountains is described and the genus revised. Both species of the genus are known from few localities only. Their habitats are under pressure due to an increasing human population in the East and West Usambara Mountains. Both taxa should be included thus in the IUCN red list of globally threatened taxa to attract more attention to the importance of small forest patches. The biogeographical distribution of species from West Usambaran forests is discussed indicating on one hand that there must have been isolating mechanisms within the West Usambara Mountains and that part of the observed biodiversity in flightless Orthoptera is due to speciation processes not older than approximately 2 million years.


Epidermal growth factor receptor domain II, IV, and kinase domain mutations in human solid tumors.
Mutations that may predict response to adenosine 5'-triphosphate (ATP)-mimetic epidermal growth factor receptor (EGFR) inhibitors occur in the EGFR kinase domain in lung adenocarcinomas and bronchioloalveolar carcinomas (BACs). Data on the frequency of EGFR mutations are sparse in other human tumors. Apart from the deletion mutant EGFRvIII, little is known about the frequency of mutations that encode for the EGFR extracellular domains II and IV that participate in receptor dimerization and formation of the tethered (autoinhibited) receptor conformation. We investigated 566 human neoplasms consisting of various histological types for mutations in exons 6, 7 (encode domain II), 14, 15 (domain IV), 18, 19, and 21 (the kinase domain) using denaturing high-performance liquid chromatography (DHPLC). Approximately 4,500 EGFR exons were screened for the presence of a mutation, and samples with an abnormal finding in DHPLC were sequenced. Only one mutation was found in the extracellular domain IV (glioblastoma), and none in domain II. Eight (11%) out of the 40 lung adenocarcinomas, or 33 BACs, investigated had exon 19 or 21 mutation in the kinase domain, but no mutations were found in other tumor types. Most of the lung cancers with mutated EGFR had three to six copies of the mutated gene in fluorescence in situ hybridization. We conclude that mutations of the EGFR kinase domain and the cysteine-rich extracellular domains are infrequent in most types of human cancer apart from lung adenocarcinoma. Mutated EGFR is usually not amplified in lung cancer.


A 56-Year-Old Man With Progressive Subacute Hypoxemia.
A 56-year-old man with a medical history of diabetes, no prior lung disease, and no tobacco exposure presented with exhaustion and a nonproductive cough 7 days after working in an old farmhouse in Vermont. His friend who worked with him exhibited similar symptoms. He was treated as an outpatient with doxycycline; however, his clinical condition deteriorated and necessitated hospitalization and subsequent intubation.


N-Acetyl-3-aminopyrazoles block the non-canonical NF-kB cascade by selectively inhibiting NIK.
NF-κB-inducing kinase (NIK), an oncogenic drug target that is associated with various cancers, is a central signalling component of the non-canonical pathway. A blind screening process, which established that amino pyrazole related scaffolds have an effect on IKKbeta, led to a hit-to-lead optimization process that identified the aminopyrazole 3a as a low μM selective NIK inhibitor. Compound 3a effectively inhibited the NIK-dependent activation of the NF-κB pathway in tumour cells, confirming its selective inhibitory profile.


A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders.
Leukotriene B(4) (LTB(4)) is a potent chemoattractant and activator of both granulocytes and macrophages. The actions of LTB(4) appear to be mediated by a specific G protein-coupled receptor (GPCR) BLT1, originally termed BLT (Yokomizo, T., T. Izumi, K. Chang, Y. Takuwa, and T. Shimizu. 1997. Nature. 387:620-624). Here, we report the molecular cloning of a novel GPCR for LTB(4), designated BLT2, which binds LTB(4) with a Kd value of 23 nM compared with 1.1 nM for BLT1, but still efficiently transduces intracellular signaling. BLT2 is highly homologous to BLT1, with an amino acid identity of 45.2%, and its open reading frame is located in the promoter region of the BLT1 gene. BLT2 is expressed ubiquitously, in contrast to BLT1, which is expressed predominantly in leukocytes. Chinese hamster ovary cells expressing BLT2 exhibit LTB(4)-induced chemotaxis, calcium mobilization, and pertussis toxin-insensitive inhibition of adenylyl cyclase. Several BLT1 antagonists, including U 75302, failed to inhibit LTB(4) binding to BLT2. Thus, BLT2 is a pharmacologically distinct receptor for LTB(4), and may mediate cellular functions in tissues other than leukocytes. BLT2 provides a novel target for antiinflammatory therapy and promises to expand our knowledge of LTB(4) function. The location of the gene suggests shared transcriptional regulation of these two receptors.


How do patient feedback systems work in low-income and middle-income countries? Insights from a realist evaluation in Bangladesh.
Well-functioning patient feedback systems can contribute to improved quality of healthcare and systems accountability. We used realist evaluation to examine patient feedback systems at health facilities in Bangladesh, informed by theories of citizenship and principal-agent relationships. We collected and analysed data in two stages, using: document review; secondary analysis of data from publicly available web-portals; in-depth interviews with patients, health workers and managers; non-participant observations of feedback environments; and stakeholder workshops. Stage 1 focused on identifying and articulating the initial programme theory (PT) of patient feedback systems. In stage 2, we iteratively tested and refined this initial theory, through analysing data and grounding emerging findings within substantive theories and empirical literature, to arrive at a refined PT. Multiple patient feedback systems operate in Bangladesh, essentially comprising stages of collection, analysis and actions on feedback. Key contextual enablers include political commitment to accountability, whereas key constraints include limited patient awareness of feedback channels, lack of guidelines and documented processes, local political dynamics and priorities, institutional hierarchies and accountability relationships. Findings highlight that relational trust may be important for many people to exercise citizenship and providing feedback, and that appropriate policy and regulatory frameworks with clear lines of accountability are critical for ensuring effective patient feedback management within frontline healthcare facilities. Theories of citizenship and principal-agent relationships can help understand how feedback systems work through spotlighting the citizenship identity and agency, shared or competing interests, and information asymmetries. We extend the understanding of these theories by highlighting how patients, health workers and managers act as both principals and agents, and how information asymmetry and possible agency loss can be addressed. We highlight the importance of awareness raising and non-threatening environment to provide feedback, adequate support to staff to document and analyse feedback and timely actions on the information.


Impact of the coronavirus disease 2019 (COVID-19) pandemic on the care of patients with acute and chronic aortic conditions.
To evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on acute and elective thoracic and abdominal aortic procedures. Forty departments shared their data on acute and elective thoracic and abdominal aortic procedures between January and May 2020 and January and May 2019 in Europe, Asia and the USA. Admission rates as well as delay from onset of symptoms to referral were compared. No differences in the number of acute thoracic and abdominal aortic procedures were observed between 2020 and the reference period in 2019 [incidence rates ratio (IRR): 0.96, confidence interval (CI) 0.89-1.04; P = 0.39]. Also, no difference in the time interval from acute onset of symptoms to referral was recorded (<12 h 32% vs > 12 h 68% in 2020, < 12 h 34% vs > 12 h 66% in 2019 P = 0.29). Conversely, a decline of 35% in elective procedures was seen (IRR: 0.81, CI 0.76-0.87; P < 0.001) with substantial differences between countries and the most pronounced decline in Italy (-40%, P < 0.001). Interestingly, in Switzerland, an increase in the number of elective cases was observed (+35%, P = 0.02). There was no change in the number of acute thoracic and abdominal aortic cases and procedures during the initial wave of the COVID-19 pandemic, whereas the case load of elective operations and procedures decreased significantly. Patients with acute aortic syndromes presented despite COVID-19 and were managed according to current guidelines. Further analysis is required to prove that deferral of elective cases had no impact on premature mortality.


Physiological and metabolic effects of prophylactic treatment with the osmolytes glycerol and betaine on Bos indicus steers during long duration transportation.
The physiological and metabolic effects of prophylactic treatment with osmolytes were investigated using twenty-four 2.5-yr-old Bos indicus steers. Animals were allocated to 1 of 4 treatment groups: 1) control, feed and water deprived for 48 h (n = 6); 2) transported, transported for 48 h (n = 6); 3) glycerol, dosed with glycerol (2 g/kg of BW) and then transported for 48 h (n = 6); and 4) betaine, dosed with betaine (0.25 g/kg of BW) then transported for 48 h (n = 6). Body water, electrolytes, blood pH and gases, plasma lactate, glucose, albumin, total protein, anion gap, strong ion difference, total weak acids, and BW were determined at the conclusion of 24 and 48 h of transportation. The glycerol group had greater body water volumes than the control (P = 0.05) and transported (P = 0.02) groups. The glycerol, transported, and betaine groups had lower (P = 0.02) plasma Mg concentrations than the control group at 24 h, whereas the glycerol group maintained lower (P = 0.04) plasma concentrations of Ca than the control group. The betaine group had lower (P = 0.04) hematocrit than the control group at 24 and 48 h. Plasma bicarbonate and pCO2 were 13 and 17% greater (P = 0.01 and 0.04, respectively) in the glycerol group at 24 h compared with control and transported groups. However, the ratio of [HCO3]/[CO2] in the glycerol group did not differ from the other groups and thereby maintained pH. The glycerol group maintained a 30% greater (P < 0.001) plasma concentration of glucose than the control group, and 14% greater (P = 0.05) than the transported and betaine groups. In contrast, betaine had little effect on increasing blood glucose compared with glycerol. Glycerol-linked hyperhydration at 24 h may not only help to conserve water loss during long distance transportation, but the increased blood glucose may have an important protein-sparing effect due, in part, to greater insulin concentrations inhibiting the breakdown of muscle proteins, thus, countering the amino-acid mobilizing effect of cortisol after 24 h. Therefore, the osmolyte glycerol shows promise as a prophylactic treatment for attenuating the effects of long distance transportation by maintaining body water, decreasing the energy deficit, and preserving health and muscle quality.


Which factors increase informal care hours and societal costs among caregivers of people with dementia? A systematic review of Resource Utilization in Dementia (RUD).
Nearly 19 million people across OECD countries are living with dementia, and millions of family caregivers are affected by the disease. The costs of informal care are estimated to represent 40-75% of the total dementia cost exceeding formal care time and medical costs. To conduct a systematic review to evaluate the methodological quality and factors associated with high informal care hours per month that increase societal costs, and to identify what type of interventions may alleviate the entire burden of informal and formal caregiving. The systematic review was registered at PROSPERO (15.12.2020). A search in Medline, Embase, PsycINFO, and web of science for observational studies, cost-effectiveness, and cost of illness (COI) analyses on resource utilization in dementia (RUD) was conducted on 1 December 2020. Our inclusion criteria included a requirement that studies had to use the original RUD, RUD-FOCA or RUD lite in terms of hours or days per month, and costs as primary or secondary outcome, OECD countries, within the last 20 years and a sample population comprising persons with dementia (PwD) ≥65 years and their caregivers. We followed the PRISMA, GRADE, PICO guidelines and Drummond criteria to assess the methodology and quality of the studies. Of 307 studies, 26 cross-sectional and 3 longitudinal cohort studies were included in the analyses. Two studies had a randomized controlled trial (RCT) design. The methods and cost categories in each study varied widely. Disease severity, caregiver factors, and behavioural and psychological symptoms of dementia (BPSD) were associated with high informal care hours and societal cost. One RCT found no effect of a non-pharmacological intervention on informal care hours, yet another RCT found a cost-effective impact of an in-home respite care programme reducing informal care burden and costs. The divergent use of the RUD components within included studies encourage more harmonized analyses. There are only two RCTs on RUD, one of which shows a significant treatment effect. Larger sample sizes and longer follow-up periods are required in future RCTs with dedicated focus on cost-enhancing and resource intensive factors such as disease severity and BPSD. Novel interventions must diversify between caregiver and PwD groups. CRD42021226388 .


A new release on life: emerging concepts in proteolysis and parasite invasion.
Cell invasion by apicomplexan pathogens such as the malaria parasite and Toxoplasma is accompanied by extensive proteolysis of zoite surface proteins (ZSPs) required for attachment and penetration. Although there is still little known about the proteases involved, a conceptual framework is emerging for the roles of proteolysis in cell invasion. Primary processing of ZSPs, which includes the trimming of terminal peptides or segmentation into multiple fragments, is proposed to activate these adhesive ligands for tight binding to host receptors. Secondary processing, which occurs during penetration, results in the shedding of ZSPs by one of two mechanistically distinct ways, shaving or capping. Resident surface proteins are typically shaved from the surface whereas adhesive ligands mobilized from intracellular secretory vesicles are capped to the posterior end of the parasite before being shed during the final steps of penetration. Intriguingly, recent studies have revealed that ZSPs can be released either by being cleaved adjacent to the membrane anchor or actually within the membrane itself. Mounting evidence suggests that intramembrane cleavage is catalysed by one or more integral membrane serine proteases of the Rhomboid family and we propose that several malaria adhesive ligands may be potential substrates for these enzymes. We also discuss the evidence that the key reason for ZSP shedding during invasion is to break the connection between parasite surface ligands and host receptors. The sequential proteolytic events associated with invasion by pathogenic protozoa may represent vulnerable pathways for the future development of synergistic anti-protozoal therapies.


Craniocerebral trauma inflicted by television falls.
Accidents and inflicted trauma account for 33% and 5-8% of childhood deaths, respectively. Injuries secondary to falling televisions have been reported in the clinical literature. However, descriptions of such injuries at autopsy are limited. The severity and patterns of injury may mimic those considered ''typical'' of inflicted trauma. Thus, integration of data from clinical, scene investigation, and autopsy is necessary for determination of the cause and manner of death. We present autopsy findings from two cases which illustrate injuries sustained from falling televisions. Findings common to both cases include subscalpular hemorrhages, skull fractures, subdural hemorrhages, brain injuries, and optic nerve sheath hemorrhages. The first case showed postsurgical changes secondary to evacuation of a posterior fossa hematoma; three-dimensional reconstruction of the admission computed tomography scan demonstrated the extent of the preintervention skull fractures. In addition, the second case showed a right epidural hematoma. Only case two showed retinal hemorrhage.


Undesigned selection for replication termination of bacterial chromosomes.
The oriC DNA replication origin in bacterial chromosomes, the location of which appears to be physically identified, is genetically regulated by relevant molecular machinery. In contrast, the location of the terminus remains obscure for many bacterial replicons, except for terC, the proposed and well-studied chromosome termination site in certain bacteria. The terC locus, which is composed of specific sequences for its binding protein, is located at a site opposite from oriC, exhibiting a symmetric structure around the oriC-terC axis. Here, we investigated Bacillus subtilis 168 strains whose axes were hindered and found that the native terC function was robust. However, eradication of terminus region specific binding protein resulted in the natural terC sites not being used for termination; instead, new termini were selected at a location exactly opposite to oriC. We concluded that replication generally terminates at the loci where the two approaching replisomes meet. This site was automatically selected, and two replisomes moving at the same rate supported symmetrical chromosome structures relative to oriC. The rule, which was even validated by artificial chromosomes irrespective of oriC, should be general for replicons administered by two replisomes.


Automatic semantic annotation of real-world web images.
As the number of web images is increasing at a rapid rate, searching them semantically presents a significant challenge. Many raw images are constantly uploaded with little meaningful direct annotations of semantic content, limiting their search and discovery. In this paper, we present a semantic annotation technique based on the use of image parametric dimensions and metadata. Using decision trees and rule induction, we develop a rule-based approach to formulate explicit annotations for images fully automatically, so that by the use of our method, semantic query such as " sunset by the sea in autumn in New York" can be answered and indexed purely by machine. Our system is evaluated quantitatively using more than 100,000 web images. Experimental results indicate that this approach is able to deliver highly competent performance, attaining good recall and precision rates of sometimes over 80%. This approach enables a new degree of semantic richness to be automatically associated with images which previously can only be performed manually.


Effects of Highly Oxygenated Water in a Hyperuricemia Rat Model.
Recent years have seen a rapidly rising number of oxygenated water brands that claim to impart health benefits and increase athletic performance by improving oxygen availability in the body. Drinks with higher dissolved oxygen concentrations have in recent times gained popularity as potential ergogenic aids, despite the lack of evidence regarding their efficacy. The aim of this study was to characterize oxygenated water and assess the improvement in uric acid metabolism while identifying performance enhancements in animals administered oxygenated water. Oxygenated water was characterized by hydrogen and oxygen nuclear magnetic resonance (NMR) spectroscopy. Hyperuricemia in rats was induced by treatment with oxonic acid potassium salt, and the animals were given oxygenated drinking water before, during, or after oxonic acid treatment. Serum uric acid was measured to confirm the effects on uric acid metabolism. Following oxygenation, the full width at half maximum (FWHM) was reduced to 11.56 Hz and 64.16 Hz in the hydrogen and oxygen NMR spectra, respectively. Oxygenated water molecule clusters were reduced in size due to the reduction in FWHM. Oxygen concentration did not vary significantly with increased temperature. However, standing time played a critical role in the amount of oxygen dissolved in the water. The rat studies indicated that oxygenated water reduced serum uric acid levels and their rate of increase and enhanced uric acid metabolism. A significant improvement in uric acid metabolism and rate of increase in serum uric acid concentration was observed in hyperuricemic rats administered oxygenated water compared to that in rats administered regular water. High oxygen concentrations enhanced the rate of oxygen absorption, leading to increased glycolysis and mitochondrial protein synthesis. Therefore, oxygenated water is a potential adjuvant therapy or health food for treatment of hyperuricemia.


Refractive index mediated plasmon hybridization in an array of aluminium nanoparticles.
The arrangement of plasmonic nanoparticles in a non-symmetrical environment can feature far-field and/or near-field interactions depending on the distance between the objects. In this work, we study the hybridization of three intrinsic plasmonic modes (dipolar, quadrupolar and hexapolar modes) sustained by one elliptical aluminium nanocylinder, as well as behavior of the hybridized modes when the nanoparticles are organized in arrays or when the refractive index of the surrounding medium is changed. The position and the intensity of these hybridized modes were shown to be affected by the near-field and far-field interactions between the nanoparticles. In this work, two hybridized modes were tuned in the UV spectral range to spectrally coincide with the intrinsic interband excitation and emission bands of ZnO nanocrystals. The refractive index of the ZnO nanocrystal layer influences the positions of the plasmonic modes and increases the role of the superstrate medium, which in turn results in the appearance of two separate modes in the small spectral region. Hence, the enhancement of ZnO nanocrystal photoluminescence benefits from the simultaneous excitation and emission enhancements.


Procedural skills in flexible sigmoidoscopy and colonoscopy for the family physician.
Procedural skills in flexible sigmoidoscopy and colonoscopy are widely accepted as diagnostic and therapeutic tools that assist physicians as they attempt to understand the biological and behavioral elements of undifferentiated gastrointestinal illness. Data support the ability of family physicians to perform and teach some of these endoscopic skills. Although one major contribution of these procedures is in the prevention of premature colorectal cancer mortality, other important patient care benefits are emerging for the office-based physician. Breadth of care enhances our most important therapeutic tool--the doctor/patient relationship. Unnecessary referral contributes to fragmentation and depersonalization of the health care system. Family physicians are urged to examine and acquire new procedural skills appropriate for their community. The process of privileges is discussed.


An outbreak of methicillin-resistant Staphylococcus aureus (MRSA) infection in dermatology indoor patients.
Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. Indiscriminate and increased use of systemic antibiotics has led to the emergence of MRSA. Infected or colonized ward patients are the main reservoir of infection. Once colonized, the risk of subsequent local and systemic infections is high, especially in the elderly, and in debilitated and immunosuppressed patients. We report an outbreak of MRSA in the dermatology ward of a tertiary care hospital and describe measures taken to control it. Ten patients were found to be MRSA positive over a span of three months while screening swabs from wet lesions in indoor patients. On the basis of risk assessment, they were treated with appropriate systemic and topical therapy. One patient died while the remaining nine patients showed a good response to therapy. All the MRSA isolates were found to be sensitive to vancomycin, teicoplanin and linezolid. This is the first case report of MRSA infection in dermatology indoor patients in India.


Correlation between base-excision repair gene polymorphisms and levels of in-vitro BPDE-induced DNA adducts in cultured peripheral blood lymphocytes.
In vitro benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts in cultured peripheral lymphocytes have been shown to be a phenotypic biomarker of individual's DNA repair phenotype that is associated with cancer risk. In this study, we explored associations between genotypes of base-excision repair genes (PARP1 Val762Ala, APEX1 Asp148Glu, and XRCC1 Arg399Gln) and in vitro BPDE-induced DNA adducts in cultured peripheral blood lymphocytes in 706 cancer-free non-Hispanic white subjects. We found that levels of BPDE-induced DNA adducts were significantly higher in ever smokers than in never smokers and that individuals with the Glu variant genotypes (i.e., Asp/Glu and Glu/Glu) exhibited lower levels of BPDE-induced DNA adducts than did individuals with the common Asp/Asp homozygous genotype (median RAL levels: 32.0 for Asp/Asp, 27.0 for Asp/Glu, and 17.0 for Glu/Glu, respectively; P(trend) = 0.030). Further stratified analysis showed that compared with individuals with the common APEX1-148 homozygous Asp/Asp genotype, individuals with the APEX1-148Asp/Glu genotype or the Glu/Glu genotype had a lower risk of having higher-level adducts (adjusted OR = 0.60, 95% CI: 0.36-0.98 and adjusted OR = 0.47, 95% CI: 0.26-0.86, respectively; P(trend) = 0.012) among smokers. Such an effect was not observed in non-smokers. However, there was no significant interaction between the APEX1 Asp148Glu polymorphism and smoking exposure in this study population (P = 0.512). Additional genotype-phenotype analysis found that the APEX1-148Glu allele had significantly increased expression of APEX1 mRNA in 270 Epstein-Barr virus-transformed lymphoblastoid cell lines, which is likely associated with more active repair activity. Our findings suggest that the functional APEX1-148Glu allele is associated with reduced risk of having high levels of BPDE-induced DNA adducts mediated with high levels of mRNA expression.


Tofacitinib versus Biologic Treatments in Moderate-to-Severe Rheumatoid Arthritis Patients Who Have Had an Inadequate Response to Nonbiologic DMARDs: Systematic Literature Review and Network Meta-Analysis.
Objective. To compare the efficacy and tolerability of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), as monotherapy and combined with disease-modifying antirheumatic drugs (DMARDs) versus biological DMARDs (bDMARDs) and other novel DMARDs for second-line moderate-to-severe rheumatoid arthritis (RA) patients by means of a systematic literature review (SLR) and network meta-analysis (NMA). Methods. MEDLINE®, EMBASE®, and Cochrane Central Register of Controlled Trials were searched to identify randomized clinical trials (RCTs) published between 1990 and March 2015. Efficacy data based on American College of Rheumatology (ACR) response criteria, improvements in the Health Assessment Questionnaire Disability Index (HAQ-DI) at 6 months, and discontinuation rates due to adverse events were analyzed by means of Bayesian NMAs. Results. 45 RCTs were identified, the majority of which demonstrated a low risk of bias. Tofacitinib 5 mg twice daily (BID) and 10 mg BID monotherapy exhibited comparable efficacy and discontinuation rates due to adverse events versus other monotherapies. Tofacitinib 5 mg BID and 10 mg BID + DMARDs or methotrexate (MTX) were mostly comparable to other combination therapies in terms of efficacy and discontinuation due to adverse events. Conclusion. In most cases, tofacitinib had similar efficacy and discontinuation rates due to adverse events compared to biologic DMARDs.


The effect of EMDR on the pathophysiology of PTSD.
The process of understanding Posttraumatic Stress Disorder (PTSD) has been a long and difficult one. It is safe to say our understanding of this disorder in incomplete, and our exploration into its pathophysiology is fairly recent. As with any disorder of the brain, the complexities of PTSD are extensive and require integrating cognitive, functional, and chemical components. Given this complexity, it is no wonder that treating PTSD has also been a challenge. Treating a disorder whose components are not fully understood is similar to shooting in the dark. Some shots have hit their mark and some have missed. More than ten years after its conception, the question of whether Eye Movement Desensitization and Reprocessing (EMDR) is a hit or a miss is still debated. If understanding the pathophysiology of PTSD is still recent, understanding the possible physiology behind EMDR is just beginning. This paper will define PTSD, explain some aspects of its physiology, and present some hypotheses as to why EMDR may be a successful treatment for PTSD.


[Blood alcohol value and responsibility in the jurisdiction of the German Federal Court].
The author shows, what effect as a circumstantial evidence the ascertained or the possible blood alcohol concentration has in the jurisdiction of the Federal Court as far as the responsibility is to be judged on. He thinks, that the dispute, which seemed to be at hand between the decisions of the 1. and 4. penal senate, is not to be noticed. According to his opinion the blood alcohol concentration has an outstanding importance for the jurisdiction on the responsibility.


Cholesterol as a target for toxins.
A mechanism is proposed for the way in which cholesterol facilitates channel formation by polyene antibiotics and bacterial protein toxins. Central elements of the model are: (i) interactions between the ring system of the sterol and rigid elements of the polyene or toxin molecule, and (ii) the specific orientation of cholesterol within the membrane.


In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery.
Fragment-based drug (or lead) discovery (FBDD or FBLD) has developed in the last two decades to become a successful key technology in the pharmaceutical industry for early stage drug discovery and development. The FBDD strategy consists of screening low molecular weight compounds against macromolecular targets (usually proteins) of clinical relevance. These small molecular fragments can bind at one or more sites on the target and act as starting points for the development of lead compounds. In developing the fragments attractive features that can translate into compounds with favorable physical, pharmacokinetics and toxicity (ADMET-absorption, distribution, metabolism, excretion, and toxicity) properties can be integrated. Structure-enabled fragment screening campaigns use a combination of screening by a range of biophysical techniques, such as differential scanning fluorimetry, surface plasmon resonance, and thermophoresis, followed by structural characterization of fragment binding using NMR or X-ray crystallography. Structural characterization is also used in subsequent analysis for growing fragments of selected screening hits. The latest iteration of the FBDD workflow employs a high-throughput methodology of massively parallel screening by X-ray crystallography of individually soaked fragments. In this review we will outline the FBDD strategies and explore a variety of in silico approaches to support the follow-up fragment-to-lead optimization of either: growing, linking, and merging. These fragment expansion strategies include hot spot analysis, druggability prediction, SAR (structure-activity relationships) by catalog methods, application of machine learning/deep learning models for virtual screening and several de novo design methods for proposing synthesizable new compounds. Finally, we will highlight recent case studies in fragment-based drug discovery where in silico methods have successfully contributed to the development of lead compounds.


The contribution of human/non-human animal chimeras to stem cell research.
Chimeric animals are made up of cells from two separate zygotes. Human/non-human animal chimeras have been used for a number of research purposes, including human disease modeling. Pluripotent stem cell (PSC) research has relied upon the chimera approach to examine the developmental potential of stem cells, to determine the efficacy of cell replacement therapies, and to establish a means of producing human organs. Based on ethical issues, this work has faced pushback from various sources including funding agencies. We discuss here the essential role these studies have played, from gaining a better understanding of human biology to providing a stepping stone to human disease treatments. We also consider the major ethical issues, as well as the current status of support for this work in the United States.


[A comparative study of efficacy of 2-, 3- and 4-glass tests in patients with chronic prostatitis].
To compare informative value of three tests (2-, 3- and 4-glass) in diagnosis ofprostatitis we examined 177 patients with chronic prostatitis (CP) who were randomized into 4 groups. Group 1 patients (n = 33) were examined with standard 4-glass test (Mearls and Stamey), patients of subgroup 2a (n = 42) were examined with 2-glass test before finger rectal test (FRT), FRT was made in subgroup 2b (n = 45) before urine collection (2 portions), group 3 (n = 57) was examined by an original technique proposed by the authors. While performing the latter test special focus was given to urination continuity, then the secretion obtained at FRT was studied. Efficacy of each of the tests was assessed by comfort of the procedure for the patient and the doctor, a proportion of false-positive results. The 3-glass test proved most informative and significant. Also, it is sensitive in detection of urogenital tuberculosis. The 4-glass test is not comfortable for both the patient and the doctor. The 2-glass test often produced false-positive results.


Growth Hormone With Aromatase Inhibitor May Improve Height in CYP11B1 Congenital Adrenal Hyperplasia.
With an estimated prevalence of 1 in 100 000 births, 11β-hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in CYP11B1 Clinical features include virilization, early gonadotropin-independent precocious puberty, hypertension, and reduced stature. The current mainstay of management is with glucocorticoids to replace deficient steroids and to minimize adrenal sex hormone overproduction, thus preventing virilization and optimizing growth. We report a patient with CAH who had been suboptimally treated and presented to us at 6 years of age with precocious puberty, hypertension, tall stature, advanced bone age, and a predicted final height of 150 cm. Hormonal profiles and genetic analysis confirmed a diagnosis of 11β-hydroxylase deficiency. In addition to glucocorticoid replacement, the patient was commenced on growth hormone and a third-generation aromatase inhibitor, anastrozole, in an attempt to optimize his growth. After the initiation of this treatment, the patient's growth rate improved significantly and bone age advancement slowed. The patient reached a final height of 177.5 cm (0.81 SD score), 11.5 cm above his mid-parental height. This patient is only the second reported case of the use of an aromatase inhibitor in combination with growth hormone to optimize height in 11β-hydroxylase-deficient CAH. This novel treatment proved to be highly efficacious, with no adverse effects. It may therefore provide a promising option to promote growth in exceptional circumstances in individuals with 11β-hydroxylase deficiency presenting late with advanced skeletal maturation and consequent short stature.


Intracranial hemorrhage in acute and chronic childhood immune thrombocytopenic purpura over a ten-year period: an Egyptian multicenter study.
Intracranial hemorrhage (ICH) is a rare but major cause of death in immune thrombocytopenic purpura (ITP). The authors reviewed data of 1,840 patient with ITP, from 5 pediatric hematology centers in Egypt from 1997 to 2007, to study the incidence and risk factors of ICH. Ten cases of ICH were identified with a median age at presentation of 7.5 years; 4 patients had acute ITP, 2 persistent and 4 chronic. The platelet count was <10 x 10(9)/l in 7 cases, and only 1 patient had a history of head trauma. Seven children were on treatment prior to or at the time of occurrence of ICH and all were treated by pharmacotherapy. Two children died shortly afterwards due to late referral to a specialized center. Our results suggest that treatment does not prevent ICH and that it can occur at any time during the course of the disease. Delayed referral can be considered a risk factor for unfavorable outcome of ICH, highlighting the importance of teaching sessions for patients and their parents to minimize subsequent morbidity and mortality of ICH in children with ITP.


Ultrastructural changes in chloroplasts resulting from fluctuations in NaCl concentration: freeze-fracture of thylakoid membranes in Dunaliella salina.
The structure of chloroplasts isolated from Dunaliella salina has been studied with respect to changing concentrations of sodium chloride in the culture medium. Freeze-fracture replicas and thin sections of intact chloroplasts do not exhibit any noticeable changes in structure at concentrations ranging between 3.5 and 25% NaCl. Chloroplasts isolated from algal cells that have been acclimatized to the higher salt concentration show a change in the thylakoid membranes. The thylakoid membranes appear compressed over a major portion of the membrane surface, with only the end of the thylakoid membranes unappressed. The number of particles per unit area on the B face is also altered by the salt concentration. The chloroplasts acclimatized to 25% NaCl have about 3 times the number of particles per unit area on a B face of end-membranes as on a comparable face of thylakoid membranes acclimatized to low (3.5% NaCl) salt concentration. These morphological changes can be reversed if the chloroplasts acclimatized to high or low salt concentrations are returned to a medium of different salt concentration prior to freeze-fracturing.


Enhancing student engagement using the flipped classroom.
The flipped classroom is an innovative pedagogical approach that focuses on learner-centered instruction. The purposes of this report were to illustrate how to implement the flipped classroom and to describe students' perceptions of this approach within 2 undergraduate nutrition courses. The template provided enables faculty to design before, during, and after class activities and assessments based on objectives using all levels of Bloom's taxonomy. The majority of the 142 students completing the evaluation preferred the flipped method compared with traditional pedagogical strategies. The process described in the report was successful for both faculty and students.


Are causes of death predictable?
A random sample of death records of adult males from 1967 to 1970 was chosen from the South Australian Registry of Births, Deaths, and Marriages. The natural parents of these individuals were identified by cross-reference to birth certificates, and an extensive search was made of the death records for these parents. In this manner random families were selected for which, where possible, the cause of death and length of life of each family member were determined. From the information pertaining to the stated cause of death, each individual was assigned to one of five death categories.


The anthropology of health systems: A history and review.
Ethnographies of health systems are a theoretically rich and rapidly growing area within medical anthropology. Critical ethnographic work dating back to the 1950s has taken policymakers and health staff as points of entry into the power structures that run through the global health enterprise. In the last decade, there has been a surge of ethnographic work on health systems. We conceptualize the anthropology of health systems as a field; review the history of this body of knowledge; and outline emergent literatures on policymaking, HIV, hospitals, Community Health Workers, health markets, pharmaceuticals, and metrics. High-quality ethnographic work is an excellent way to understand the complex systems that shape health outcomes, and provides a critical vantage point for thinking about global health policy and systems. As theory in this space develops and deepens, we argue that anthropologists should look beyond the discipline to think through what their work does and why it matters.


Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamate release.
To investigate the possible long-term consequences of gestational exposure to cannabinoids on cognitive functions, pregnant rats were administered with the CB1 receptor agonist WIN 55,212-2 (WIN), at a dose (0.5 mgkg) that causes neither malformations nor overt signs of toxicity. Prenatal WIN exposure induced a disruption of memory retention in 40- and 80-day-old offspring subjected to a passive avoidance task. A hyperactive behavior at the ages of 12 and 40 days was also found. The memory impairment caused by the gestational exposure to WIN was correlated with alterations of hippocampal long-term potentiation (LTP) and glutamate release. LTP induced in CA3-CA1 synapses decayed faster in brain slices of rats born from WIN-treated dams, whereas posttetanic and short-term potentiation were similar to the control group. In line with LTP shortening, in vivo microdialysis showed a significant decrease in basal and K(+)-evoked extracellular glutamate levels in the hippocampus of juvenile and adult rats born from WIN-treated dams. A similar reduction in glutamate outflow was also observed in primary cell cultures of hippocampus obtained from pups born from mothers exposed to WIN. The decrease in hippocampal glutamate outflow appears to be the cause of LTP disruption, which in turn might underlie, at least in part, the long-lasting impairment of cognitive functions caused by the gestational exposure to this cannabinoid agonist. These findings could provide an explanation of cognitive alterations observed in children born from women who use marijuana during pregnancy.


Provider variation in fast track treatment time.
To examine the degree to which fast track (FT) treatment time varies among providers. A retrospective cohort study that included 105,783 FT visits at 3 emergency departments (EDs) during a 3-year period. We calculated the median treatment time for 80 primary providers (physicians and physician extenders) and 109 nurses (2 sites only). We used a hierarchical linear regression model that accounted for the clustering of patient visits to the same provider to estimate each provider's median treatment time controlling for patient, clinical, temporal, and ED demand (ie, number of arrivals) characteristics. Median FT treatment time across the 3 sites ranged from 48 to 134 minutes. Adjusted for other factors, the median FT treatment time of providers at the 90th versus 10th percentiles was 1.4 to 2.6 times longer across the 3 sites. The variation by FT nurses was also large. The median FT treatment time of nurses at the 90th versus 10th percentiles was 1.5 and 1.4 times longer at sites A and C, respectively. At all sites, provider and clinical factors explained more variation in FT treatment time than patient, ED demand, or temporal factors. There were clinically meaningful differences in FT treatment time among the providers at all sites. Given that the providers share the same environment and patient population, understanding why such large provider variation in FT treatment time exists warrants further investigation.


A single point mutation in class III ribonucleotide reductase promoter renders Pseudomonas aeruginosa PAO1 inefficient for anaerobic growth and infection.
Pseudomonas aeruginosa strain PAO1 has become the reference strain in many laboratories. One enzyme that is essential for its cell division is the ribonucleotide reductase (RNR) enzyme that supplies the deoxynucleotides required for DNA synthesis and repair. P. aeruginosa is one of the few microorganisms that encodes three different RNR classes (Ia, II and III) in its genome, enabling it to grow and adapt to diverse environmental conditions, including during infection. In this work, we demonstrate that a lack of RNR activity induces cell elongation in P. aeruginosa PAO1. Moreover, RNR gene expression during anaerobiosis differs among P. aeruginosa strains, with class III highly expressed in P. aeruginosa clinical isolates relative to the laboratory P. aeruginosa PAO1 strain. A single point mutation was identified in the P. aeruginosa PAO1 strain class III RNR promoter region that disrupts its anaerobic transcription by the Dnr regulator. An engineered strain that induces the class III RNR expression allows P. aeruginosa PAO1 anaerobic growth and increases its virulence to resemble that of clinical strains. Our results demonstrate that P. aeruginosa PAO1 is adapted to laboratory conditions and is not the best reference strain for anaerobic or infection studies.