Domestic violence and perinatal outcomes - a prospective cohort study from Nepal.
Domestic violence is one of the most common forms of violence against women. Domestic violence during pregnancy is associated with adverse perinatal and maternal outcomes. We aimed to assess whether domestic violence was associated with mode of delivery, low birthweight and preterm birth in two sites in Nepal. In this prospective cohort study we consecutively recruited 2004 pregnant women during antenatal care at two hospitals between June 2015 and September 2016. The Abuse Assessment Screen (modified) was used to assess fear and violence. Having ever experienced either fear or violence was defined as any domestic violence. Obstetric outcomes were obtained from hospital records for 1381 (69%) women, selecting singleton pregnancies only. Mode of delivery was assessed as birth by cesarean section or not. A birthweight of less than 2500 g was defined as low birthweight and preterm birth as birth before completion of 37 weeks gestation. Descriptive and multiple logistic regression analyses were performed to assess associations. Twenty percent of the women reported any domestic violence. Among all 1381 women, 37.6% gave birth by cesarean section. Of those women who delivered by cesarean section, 84.7% had an emergency cesarean section. Less than 10% of the babies were born prematurely and 13.5% were born with low birthweight. We found no significant association between exposure to any domestic violence during pregnancy and risk of a low birthweight baby or birth by cesarean section. However, having experienced both violence and fear was significantly associated with giving birth to a preterm infant [aOR 2.33 (95% CI;1.10-4.73)]. Domestic violence is common in Nepal. This is a potential risk factor for severe morbidity and mortality in newborns. We found that the risk of having a preterm baby was higher for pregnant women who experienced both fear and violence. This should be recognized by the health sector. In this study, no significant differences were found in the rate of cesarean section nor low birthweight for women who had experienced any domestic violence compared to those who did not.


Transition from phase to generalized synchronization in time-delay systems.
The notion of phase synchronization in time-delay systems, exhibiting highly non-phase-coherent attractors, has not been realized yet even though it has been well studied in chaotic dynamical systems without delay. We report the identification of phase synchronization in coupled nonidentical piecewise linear and in coupled Mackey-Glass time-delay systems with highly non-phase-coherent regimes. We show that there is a transition from nonsynchronized behavior to phase and then to generalized synchronization as a function of coupling strength. We have introduced a transformation to capture the phase of the non-phase-coherent attractors, which works equally well for both the time-delay systems. The instantaneous phases of the above coupled systems calculated from the transformed attractors satisfy both the phase and mean frequency locking conditions. These transitions are also characterized in terms of recurrence-based indices, namely generalized autocorrelation function P(t), correlation of probability of recurrence, joint probability of recurrence, and similarity of probability of recurrence. We have quantified the different synchronization regimes in terms of these indices. The existence of phase synchronization is also characterized by typical transitions in the Lyapunov exponents of the coupled time-delay systems.


The specificity of monoclonal fluorescence polarization immunoassay for cyclosporine in recipients of simultaneous pancreas-kidney transplants.
Simultaneous kidney-pancreas transplant (SPK) recipients have a higher rate of acute organ rejection than do recipients of a kidney-alone transplant. The etiology of this increased number of rejection episodes is unknown. Cyclosporine (CsA) monitoring in SPK recipients is an important tool in the care of these patients. Many centers use the monoclonal fluorescence polarization immunoassay (mFPIA) to monitor CsA levels in this group of organ recipients. The reported specificity of the mFPIA for the CsA parent compound has varied in several studies but has not been systematically studied in recipients of an SPK transplant. Twelve recipients of an SPK transplant from 1 month to 3 months after surgery had serial simultaneous whole blood high-performance liquid chromatography (HPLC) and mFPIA CsA concentrations evaluated. A control group of 15 nondiabetic kidney-alone recipients underwent a similar evaluation. The average mFPIA/HPLC ratio in recipients of an SPK was 1.71 +/- 0.05 (r = 0.94), whereas it was 1.56 +/- 0.03 (r = 0.98) in the kidney-alone group (p > 0.01). Interpatient variability (range, 1.41 to 2.13) was very high in the SPK group, whereas intrapatient variability was lower. Seven patients had AUC profiles. The average AUC mFPIA/HPLC ratio was not significantly different from each patient's respective trough ratios. Our study suggests that the mFPIA overestimates CsA parent compound to a greater extent in SPK recipients than in kidney-alone recipients. In addition, the large interpatient variability in the specificity of the mFPIA makes assessing individual patient's levels problematic.


Concurrent generation of subplate and cortical plate neurons in developing trisomy 16 mouse cortex.
During embryonic development of the mammalian cerebral cortex, the generation of the marginal zone (MZ) and subplate (SP) precedes that of the cortical plate (CP). MZ and SP neurons are believed to play a 'pioneering' role in directing the organization of the CP and the specificity of connections between the CP and other brain regions. Here we report that this sequential order of neurogenesis is disrupted in the trisomy 16 (Ts16) mouse, a potential animal model of Down syndrome. Bromodeoxyuridine labeling was used to establish the date of generation of postmitotic SP and CP neurons in the somatosensory cortex. As has been previously reported, most SP neurons in euploid (control) cortex were generated on embryonic day 12.5 (E12.5), and production of CP neurons began a day later. In contrast, in the Ts16 cortex, few SP neurons were born on E12.5 and most were generated on E13.5 and E14.5 when CP neurons were also being produced. Thus, in the Ts16 cortex, many CP neurons are born and arrive at their destinations before the normal complement of SP neurons is present. This disruption of the temporal sequence of SP and CP generation may, therefore, interfere with the pioneering functions of the SP during cortical neurogenesis and may alter the connectivity of the cortex. Indeed, using lipophilic membrane tracers to label axonal projections, we found very little thalamocortical innervation of the Ts16 SP at an age when there is extensive innervation of the euploid SP.


Dengue transmission risk maps of Argentina.
Dengue is an emerging disease that has become important in Argentina because of its vector's presence (Aedes aegypti) and its endemicity in neighbouring countries. Thematic maps were built for Argentina considering four main factors: population susceptibility to dengue virus infection (population density); entrance of the virus from endemic countries (main roads and airports); conditions for the vector (urbanization, altitude, minimum, maximum and mean daily temperatures) and virus extrinsic incubation period (EIP) completion in the mosquito before its death. EIP duration was modelled with a temperature-dependent function and considering life expectancies of 10, 15 and 20 days for the adult mosquito. The results show maximum risk of dengue transmission in the northern and north-eastern part of the country year-round and in the centre during the summer. Although life expectancy of the adult mosquito has a considerable influence on EIP completion, the north-east to south-west decreasing gradient is maintained. Assuming 20-day life expectancy, the EIP would be completed in almost any region of the country; whereas with 15-day life expectancy it would be limited to vector distribution area, and at 10 days it would be restricted to the northern extreme of the country.


Cerebrospinal fluid dynamics in idiopathic intracranial hypertension: a literature review and validation of contemporary findings.
Idiopathic intracranial hypertension (IIH) is a rare disease of unknown aetiology related possibly to disturbed cerebrospinal fluid (CSF) dynamics and characterised by elevated intracranial pressure (ICP) causing optic nerve atrophy if not timely treated. We studied CSF dynamics of the IIH patients based on the available literature and our well-defined cohort. A literature review was performed from PubMed between 1980 and 2020 in compliance with the PRISMA guideline. Our study includes 59 patients with clinical, demographical, neuro-ophthalmological, radiological, outcome data, and lumbar CSF pressure measurements for suspicion of IIH; 39 patients had verified IIH while 20 patients did not according to Friedman's criteria, hence referred to as symptomatic controls. The literature review yielded 19 suitable studies; 452 IIH patients and 264 controls had undergone intraventricular or lumbar CSF pressure measurements. In our study, the mean CSF pressure, pulse amplitudes, power of respiratory waves (RESP), and the pressure constant (P0) were higher in IIH than symptomatic controls (p < 0.01). The mean CSF pressure was higher in IIH patients with psychiatric comorbidity than without (p < 0.05). In IIH patients without acetazolamide treatment, the RAP index and power of slow waves were also higher (p < 0.05). IIH patients with excess CSF around the optic nerves had lower relative pulse pressure coefficient (RPPC) and RESP than those without (p < 0.05). Our literature review revealed increased CSF pressure, resistance to CSF outflow and sagittal sinus pressure (SSP) as key findings in IIH. Our study confirmed significantly higher lumbar CSF pressure and increased CSF pressure waves and RAP index in IIH when excluding patients with acetazolamide treatment. In overall, the findings reflect decreased craniospinal compliance and potentially depleted cerebral autoregulation resulting from the increased CSF pressure in IIH. The increased slow waves in patients without acetazolamide may indicate issues in autoregulation, while increased P0 could reflect the increased SSP.


Multidisciplinary Integrated Metabolic Rehabilitation in Elderly Obese Patients: Effects on Cardiovascular Risk Factors, Fatigue and Muscle Performance.
Obesity is a widespread problem in the elderly, being associated with severe comorbidities negatively influencing life expectancy. Integrated multidisciplinary metabolic rehabilitation aimed to reduce body weight (BW) and fatigue, increase physical autonomy and introduce healthy life style changes has been proposed as a useful intervention to improve the general health status and quality of life of the obese geriatric population. Six hundred-eighty four severely obese subjects (F/M = 592/92; age range: 61-83 years; mean body mass index, BMI ± SD: 42.6 ± 5.6 kg/m2) were admitted to take part in a three-week in-hospital BW reduction program (BWRP), entailing energy restricted diet, psychological counselling, physical rehabilitation and nutritional education. Biochemical parameters, cardiovascular risk factors (throughout the Coronary Heart Disease Risk, CHD-R), fatigue (throughout the Fatigue Severity Scale, FSS) and lower limb muscle performance (throughout the Stair Climbing Test, SCT) were evaluated before and at the end of the BWRP. A 4% BW reduction was achieved at the end of the BWRP. This finding was associated with a significant improvement of the metabolic homeostasis (i.e., decrease in total cholesterol and glucose) and a reduction of systolic blood pressure in both females and males, thus resulting in a reduction of CHD-R in the male group. Total FSS score and SCT time decreased in female and male obese patients. The effects of BWPR were comparable among all age-related subgroups (>60, 60-69 and >70 years), apart from ΔCHD-R, which was higher in male subgroups. Finally, age was negatively correlated with ΔBMI and ΔFSS. Though only a relatively limited number of outcomes were investigated, the present study shows that a 4% BW reduction in severely elderly obese patients is associated with positive multisystemic effects, particularly, muscle-skeletal and cardiometabolic benefits, which can favorably influence their general well-being and improve the autonomy level in performing more common daily activities. The maintenance of a healthy life style, including controlled food intake and regular physical activity, after a BWRP is obviously recommended in all elderly obese patients to further improve their clinical condition.


Thoracic cord compression caused by contiguous multilevel ossification of ligamentum flavum in Chinese patients.
To explore the epidemiology, clinical presentation, radiology and surgical treatment outcome in Chinese patients with myelopathy caused by contiguous multilevel ossification of ligamentum flavum. Medical notes and imaging data of 18 Chinese patients (14 males and 4 females, aged 43-72 years, mean: 57 years) with myelopathy caused by contiguous multilevel ossification of ligamentum flavum were studied retrospectively in this article. The diagnosis was based on clinical examination, X-ray films, computerized tomography (CT) and magnetic resonance imaging (MRI) scanning results and pathological results. Sixteen patients were treated by laminectomy and two by laminoplasty. The average follow-up duration was 34 months (range, 28-49 months). The outcome was evaluated by Japanese Orthopaedics Association (JOA) score. The average time for occurring clinical symptoms was 7.5 months (range, 2 days-16 months). All the 18 cases presented with clinical evidences of chronic and progressive thoracic spinal cord compression, which included bilateral leg weakness, spastic gait, numbness in lower limbs, paresthesia in terminal and perineum, and urinary incontinence. Neurological examination revealed severe spastic paraparesis, absence of abdominal reflexes, and reduction of the sensory function below the compression level. The mean JOA score before operation was 3.6 (range, 0-6). MRI and CT scans of the thoracic spine confirmed the presence of contiguous multilevel ossification of the ligamentum flavum. The mean recovery rate after surgery in terms of JOA score was 66.3% (range, 33.3%-100%), with a mean final JOA score of 8.3. Thoracic decompression laminectomy or laminoplasty could result in a good postoperative outcome. Contiguous multilevel ossification of the ligamentum flavum is not a common cause of myelopathy in Chinese population and should be treated as early as possible. MRI and CT scan examinations may diagnose the presence of thoracic ossification of ligamentum flavum (OLF). Posterior decompression, especially with en bloc dissection of the laminae, can obtain satisfactory results.


Levodopa-responsive breathing discomfort in Parkinson's disease patients.
In Parkinson's disease (PD), respiratory disturbances have been reported and the effect of levodopa on respiratory function remains controversial. The objective of this study was to evaluate pulmonary function utilizing spirometric and subjective evaluations in mild to moderated PD. Thirty-four consecutive sporadic PD patients (Hoehn and Yahr scale: 1-3) were prospectively evaluated using clinimetric scales, spirometry and modified Borg scale, all in off- and on-conditions. To check the respiratory function, a follow-up was performed at 4 years in a subgroup of these patients. Spirometric results were normal for all patients in both the on- and off-conditions at baseline. After levodopa administration, in addition to a significant improvement in subjective state of breathing discomfort, the mean forced expiratory volume in 1 s (FEV1), vital capacity (VC), forced vital capacity (FVC) values and their mean percentages predicted values (FEV1%, VC%, FVC%) were significantly increased (p < 0.05). Moreover, residual volume, total lung capacity, and the FEV1/FVC ratio were not significantly different for the ON and OFF conditions. At 4-year follow-up no resulting variations in the baseline values for FEV1%, FVC% or VC% were revealed. The results from this prospective study suggest that PD patients report frequently pulmonary discomfort. Levodopa improves respiratory symptoms. Pulmonary restrictive and obstructive dysfunctions, when not present at baseline, might not be present at 4-year follow-up.


Regulation of expression of human immunodeficiency virus.
Human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS), encodes regulatory factors necessary for its expression. The study of these factors clearly indicates the importance and complexity of post-trascriptional processes in regulating gene expression. Two regulatory proteins, Tat and Rev, are necessary for viral replication. These small nuclear proteins accumulate primarily in the nucleoli and act on HIV via sequence-specific elements found on the viral RNA. Both the Tat responsive element (TAR) and the Rev responsive element (RRE) map within regions of strong RNA secondary structure. While all viral mRNAs contain TAR, only the mRNAs producing HIV structural proteins contain RRE. Tat increases the levels of all viral mRNAs. Its function is complex and involves transcriptional and possibly post-transcriptional steps. Rev promotes the transport of viral mRNAs containing RRE from the nucleus to the cytoplasm and increases the half-life of these viral mRNAs. A third factor, Nef, is a cytoplasmic myristylated protein that has been proposed to down-regulate virus expression. These factors are integrated in a feedback regulatory network that dictates the balanced expression of viral components. The study of HIV expression in human cells will advance our understanding of the mechanisms related to the pathogenicity of HIV. This knowledge may also lead to novel diagnostic and therapeutic approaches to combat AIDS.


Iterative Trajectory Optimization for Physical-Layer Secure Buffer-Aided UAV Mobile Relaying.
With the fast development of commercial unmanned aerial vehicle (UAV) technology, there are increasing research interests on UAV communications. In this work, the mobility and deployment flexibility of UAVs are exploited to form a buffer-aided relaying system assisting terrestrial communication that is blocked. Optimal UAV trajectory design of the UAV-enabled mobile relaying system with a randomly located eavesdropper is investigated from the physical-layer security perspective to improve the overall secrecy rate. Based on the mobility of the UAV relay, a wireless channel model that changes with the trajectory and is exploited for improved secrecy is established. The secrecy rate is maximized by optimizing the discretized trajectory anchor points based on the information causality and UAV mobility constraints. However, the problem is non-convex and therefore difficult to solve. To make the problem tractable, we alternatively optimize the increments of the trajectory anchor points iteratively in a two-dimensional space and decompose the problem into progressive convex approximate problems through the iterative procedure. Convergence of the proposed iterative trajectory optimization technique is proved analytically by the squeeze principle. Simulation results show that finding the optimal trajectory by iteratively updating the displacements is effective and fast converging. It is also shown by the simulation results that the distribution of the eavesdropper location influences the security performance of the system. Specifically, an eavesdropper further away from the destination is beneficial to the system's overall secrecy rate. Furthermore, it is observed that eavesdropper being further away from the destination also results in shorter trajectories, which implies it being energy-efficient as well.


Identification and Analysis of Candidate Genes Associated with Maize Fusarium Cob Resistance Using Next-Generation Sequencing Technology.
The pressure to reduce mineral fertilization and the amount of pesticides used has become a factor limiting production growth, as has the elimination of many crop protection chemicals from the market. A key condition for this to be an effective form of protection is the use of varieties with higher levels of resistance. The most effective and fastest way to assist in the selection and control of pathogens is the conducting of genome-wide association studies. These are useful tools for identifying candidate genes, especially when combined with QTL mapping to map and validate loci for quantitative traits. The aim of this study was to identify new markers coupled to genes that determine maize plant resistance to fusarium head blight through the use of next-generation sequencing, association and physical mapping, and to optimize diagnostic procedures to identify selected molecular markers coupled to plant resistance to this fungal disease. As a result of field experiments and molecular analyses, molecular markers coupled to potential genes for resistance to maize ear fusariosis were selected. The newly selected markers were tested against reference genotypes. As a result of the analyses, it was found that two markers (11801 and 20607) out of the ten that were tested differentiated between susceptible and resistant genotypes. Marker number 11801 proved to be the most effective, with a specious product of 237 bp appearing for genotypes 1, 3, 5, 9 and 10. These genotypes were characterized by a field resistance of 4-6 on the 9° scale (1 being susceptible, 9 being resistant) and for all genotypes except 16 and 20, which were characterized by a field resistance of 9. In the next step, this marker will be tested on a wider population of extreme genotypes in order to use it for the preliminary selection of fusarium-resistant genotypes, and the phosphoenolpyruvate carboxylase kinase 1 gene coupled to it will be subjected to expression analysis.


Sibutramine effects on the reproductive performance of pregnant overweight and non-overweight rats.
It is well established that sibutramine produces weight loss and is used frequently in women of childbearing age. However, the potential adverse consequences attributed to sibutramine use by women who may become pregnant is not known. It was thus of interest to determine the effects of sibutramine on the reproductive performance of pregnant rats. Overweight as well as non-overweight female Wistar rats were treated with sibutramine (6 mg/kg) orally, daily for 15 d and then mated with normal male rats. Pregnancy was confirmed and treatment continued with sibutramine until d 14 of pregnancy. On d 20 of pregnancy all rats were anesthetized for determination of various maternal and fetal parameters. There was a significant maternal weight reduction at the end of pregnancy in the non-overweight drug-treated group compared to the control (non-overweight, no drug). Sibutramine alone and overweight condition alone produced a significant increase in postimplantation loss and placental index. In the overweight with or without sibutramine groups a significant decrease in fetal weight was noted. Data suggest that sibutramine alone or the condition of excess weight in the absence of drugs produced impaired reproductive performance. However, treatment of overweight rats with sibutramine did not further exacerbate fetal loss compared to sibutramine alone or the effects noted with excess weight alone.


Relationship between ankle pain, range of motion, strength and balance in individuals with functional ankle instability: a cross-sectional study.
About 15-60% of individuals with ankle sprains may develop functional ankle instability (FAI), which is characterised by ankle pain, decreased muscle strength, limited range of motion, and impaired balance, causing a decline in social activity and quality of life. However, the relationship between those characters is still unclear. This study aimed to investigate whether a relationship existed between ankle pain, active range of motion (AROM), strength and balance and if ankle pain, AROM and strength can predict balance in individuals with FAI. Seventy-seven subjects (46 males; 31 females) with unilateral FAI participated in this study. Ankle pain was measured by the visual analogue scale (VAS), ankle AROM was measured using a universal goniometer, ankle strength was measured using a handheld dynamometer, the static balance was measured by the Time in Balance Test (TBT) and the dynamic balance was measured by the modified Star Excursion Balance Test (mSEBT). Pearson product-moment correlations were used to determine the correlations between ankle pain, AROM, strength and balance. Multiple linear regressions were used to investigate if ankle pain, AROM and strength can predict balance in individuals with FAI. VAS and AROM-plantarflexion predicted 25.6% of the TBT (f2 = 0.344, P < 0.001). AROM-dorsiflexion predicted 24.6% of the mSEBT-anterior reach (f2 = 0.326, P < 0.001). VAS, AROM-plantarflexion and strength-plantarflexion predicted 33.5% of the mSEBT-posteromedial reach (f2 = 0.504, P < 0.001). AROM-plantarflexion and strength-plantarflexion predicted 28.2% of the mSEBT-posterolateral reach (f2 = 0.393, P < 0.001). This study shows that ankle plantarflexion strength, AROM of dorsiflexion and plantarflexion and pain are predictors of balance in individuals with FAI. These factors could be considered in the rehabilitation of FAI. Trial registration number: ChiCTR2200063532.


Plexiform fibromyxoma with cotyledon-like serosal growth: A case report of a rare gastric tumor and review of the literature.
Plexiform fibromyxoma is a rare, benign mesenchymal neoplasm that predilects the gastric antrum and has potential for misdiagnosis as a gastrointestinal stromal tumor (GIST). The histology of the tumor is characterized by interwoven fascicular growth of cytologically bland spindled cells within a variably myxoid stroma. The current study reports the clinicopathological and immunohistochemical findings of a plexiform fibromyxoma resected from a 28-year-old Vietnamese female. The patient presented with acute, severe abdominal pain and worsening anemia. The initial fine-needle aspiration and needle core biopsy of the gastric antral mass led to an initial diagnosis of GIST. The subsequent distal partial gastrectomy revealed a 5.5-cm transmural antral mass that ulcerated the overlying mucosa and grew as variably elongated, myxoedematous, polypoid (cotyledon-like) excrescences from the serosal surface. Microscopically, the tumor demonstrated plexiform and multinodular growth of cytologically bland spindled cells proliferating in an abundant myxocollagenous stroma with a prominent capillary network. Tumor cells immunohistochemically expressed smooth muscle actin and CD10, but did not express CD117, Discovered on GIST-1 or nuclear β-catenin. Follow-up evaluation 23 months post surgery revealed no evidence of residual tumor. A review the cases of this rare entity reported in the English language literature is also provided.


A new probiotic cheese with antioxidative and antimicrobial activity.
The aim of our study was to develop an original probiotic cheese based on the Estonian open-texture, smear-ripened, semisoft cheese "Pikantne." Cheese was produced by two methods using cheese starter cultures (Probat 505) in combination with 0.04% of probiotic Lactobacillus fermentum strain ME-3 (10(9) cfu/mL) with high antimicrobial activity and antioxidative properties. The probiotic Lactobacillus was added into milk simultaneously with starter cultures (cheese A) and into drained curd (cheese B). After addition of probiotic L. fermentum ME-3, the cheese composition, flavor, and aroma were comparable to the control cheese (score values = 4.5, 4.2, and 3.7 for control cheese, cheese A, and cheese B, respectively). Cheese A, which had good sensory properties, was chosen for further testing of viability and probiotic properties. The probiotic strain was found to withstand the technological processing of cheese, surviving and sustaining moderate antimicrobial and high antioxidative activity throughout ripening and storage (the ripened cheese contained approximately 5 x 10(7) cfu/g viable ME-3 cells), although the viability of the ME-3 strain incorporated into the cheese showed a slight decrease between d 24 and 54 after cheese preparation. Semisoft cheese "Pikantne" serves as a suitable carrier of antimicrobial and antioxidative L. fermentum ME-3.


Highly Efficient Framework for Predicting Interactions Between Proteins.
Protein-protein interactions (PPIs) play a central role in many biological processes. Although a large amount of human PPI data has been generated by high-throughput experimental techniques, they are very limited compared to the estimated 130 000 protein interactions in humans. Hence, automatic methods for human PPI-detection are highly desired. This work proposes a novel framework, i.e., Low-rank approximation-kernel Extreme Learning Machine (LELM), for detecting human PPI from a protein's primary sequences automatically. It has three main steps: 1) mapping each protein sequence into a matrix built on all kinds of adjacent amino acids; 2) applying the low-rank approximation model to the obtained matrix to solve its lowest rank representation, which reflects its true subspace structures; and 3) utilizing a powerful kernel extreme learning machine to predict the probability for PPI based on this lowest rank representation. Experimental results on a large-scale human PPI dataset demonstrate that the proposed LELM has significant advantages in accuracy and efficiency over the state-of-art approaches. Hence, this work establishes a new and effective way for the automatic detection of PPI.


Characterization of a gene family encoding SEA (sea-urchin sperm protein, enterokinase and agrin)-domain proteins with lectin-like and heme-binding properties from Schistosoma japonicum.
We previously identified a novel gene family dispersed in the genome of Schistosoma japonicum by retrotransposon-mediated gene duplication mechanism. Although many transcripts were identified, no homolog was readily identifiable from sequence information. Here, we utilized structural homology modeling and biochemical methods to identify remote homologs, and characterized the gene products as SEA (sea-urchin sperm protein, enterokinase and agrin)-domain containing proteins. A common extracellular domain in this family was structurally similar to SEA-domain. SEA-domain is primarily a structural domain, known to assist or regulate binding to glycans. Recombinant proteins from three members of this gene family specifically interacted with glycosaminoglycans with high affinity, with potential implication in ligand acquisition and immune evasion. Similar approach was used to identify a heme-binding site on the SEA-domain. The heme-binding mode showed heme molecule inserted into a hydrophobic pocket, with heme iron putatively coordinated to two histidine axial ligands. Heme-binding properties were confirmed using biochemical assays and UV-visible absorption spectroscopy, which showed high affinity heme-binding (K D = 1.605×10(-6) M) and cognate spectroscopic attributes of hexa-coordinated heme iron. The native proteins were oligomers, antigenic, and are localized on adult worm teguments and gastrodermis; major host-parasite interfaces and site for heme detoxification and acquisition. The results suggest potential role, at least in the nucleation step of heme crystallization (hemozoin formation), and as receptors for heme uptake. Survival strategies exploited by parasites, including heme homeostasis mechanism in hemoparasites, are paramount for successful parasitism. Thus, assessing prospects for application in disease intervention is warranted.


Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption.
Mendelian randomization (MR) is being increasingly used to strengthen causal inference in observational studies. Availability of summary data of genetic associations for a variety of phenotypes from large genome-wide association studies (GWAS) allows straightforward application of MR using summary data methods, typically in a two-sample design. In addition to the conventional inverse variance weighting (IVW) method, recently developed summary data MR methods, such as the MR-Egger and weighted median approaches, allow a relaxation of the instrumental variable assumptions. Here, a new method - the mode-based estimate (MBE) - is proposed to obtain a single causal effect estimate from multiple genetic instruments. The MBE is consistent when the largest number of similar (identical in infinite samples) individual-instrument causal effect estimates comes from valid instruments, even if the majority of instruments are invalid. We evaluate the performance of the method in simulations designed to mimic the two-sample summary data setting, and demonstrate its use by investigating the causal effect of plasma lipid fractions and urate levels on coronary heart disease risk. The MBE presented less bias and lower type-I error rates than other methods under the null in many situations. Its power to detect a causal effect was smaller compared with the IVW and weighted median methods, but was larger than that of MR-Egger regression, with sample size requirements typically smaller than those available from GWAS consortia. The MBE relaxes the instrumental variable assumptions, and should be used in combination with other approaches in sensitivity analyses.


Fluconazole treatment of neonates and infants with severe fungal infections.
A total of 24 neonates and infants, aged from 2 days to 10 months, received treatment with intravenous fluconazole for microbiologically documented or presumed fungal infection. The mean fluconazole dosage was 6 mg/kg/day (range 2-16 mg/kg/day) and the mean duration of therapy was 25 days (range 5-72 days). Efficacy was evaluated in neonates with proven fungal infections, as documented by the presence of pathogen at baseline. A positive clinical response was achieved in 23 of the 24 clinically evaluable patients (96%); eradication of the fungal organism was also achieved in 23 of the 24 evaluable patients (96%). Adverse events occurred in two patients (8%) but therapy was not discontinued in either patient. The present results confirm the efficacy and safety of fluconazole in the treatment of neonates and infants with severe fungal infections.


Diffusion Tensor Imaging of the Kidneys: Influence of b-Value and Number of Encoding Directions on Image Quality and Diffusion Tensor Parameters.
The purpose of this study was to evaluate to which degree investment of acquisition time in more encoding directions leads to better image quality (IQ) and what influence the number of encoding directions and the choice of b-values have on renal diffusion tensor imaging (DTI) parameters. Eight healthy volunteers (32.3 y ± 5.1 y) consented to an examination in a 1.5T whole-body MR scanner. Coronal DTI data sets of the kidneys were acquired with systematic variation of b-values (50, 150, 300, 500, and 700 s/mm(2)) and number of diffusion-encoding directions (6, 15, and 32) using a respiratory-triggered echo-planar sequence (TR/TE 1500 ms/67 ms, matrix size 128 × 128). Additionally, two data sets with more than two b-values were acquired (0, 150, and 300 s/mm(2) and all six b-values). Parametrical maps were calculated on a pixel-by-pixel basis. Image quality was determined with a reader score. Best IQ was visually assessed for images acquired with 15 and 32 encoding directions, whereas images acquired with six directions had significantly lower IQ ratings. Image quality, fractional anisotropy, and mean diffusivity only varied insignificantly for b-values between 300 and 500 s/mm(2). In the renal medulla fractional anisotropy (FA) values between 0.43 and 0.46 and mean diffusivity (MD) values between 1.8-2.1 × 10(-3) mm(2)/s were observed. In the renal cortex, the corresponding ranges were 0.24-0.25 (FA) and 2.2-2.8 × 10(-3) mm(2)/s (MD). Including b-values below 300 s/mm(2), notably higher MD values were observed, while FA remained constant. Susceptibility artifacts were more prominent in FA maps than in MD maps. In DTI of the kidneys at 1.5T, the best compromise between acquisition time and resulting image quality seems the application of 15 encoding directions with b-values between 300 and 500 s/mm(2). Including lower b-values allows for assessment of fast diffusing spin components.


Regulation of mitotic recombination between DNA repeats in centromeres.
Centromeres that are essential for faithful segregation of chromosomes consist of unique DNA repeats in many eukaryotes. Although recombination is under-represented around centromeres during meiosis, little is known about recombination between centromere repeats in mitotic cells. Here, we compared spontaneous recombination that occurs between ade6B/ade6X inverted repeats integrated at centromere 1 (cen1) or at a non-centromeric ura4 locus in fission yeast. Remarkably, distinct mechanisms of homologous recombination (HR) were observed in centromere and non-centromere regions. Rad51-dependent HR that requires Rad51, Rad54 and Rad52 was predominant in the centromere, whereas Rad51-independent HR that requires Rad52 also occurred in the arm region. Crossovers between inverted repeats (i.e. inversions) were under-represented in the centromere as compared to the arm region. While heterochromatin was dispensable, Mhf1/CENP-S, Mhf2/CENP-X histone-fold proteins and Fml1/FANCM helicase were required to suppress crossovers. Furthermore, Mhf1 and Fml1 were found to prevent gross chromosomal rearrangements mediated by centromere repeats. These data for the first time uncovered the regulation of mitotic recombination between DNA repeats in centromeres and its physiological role in maintaining genome integrity.


Fluoride release, recharge and flexural properties of polymethylmethacrylate containing fluoridated glass fillers.
The purpose of this study was to investigate the effect of fluoridated glass fillers on fluoride release, recharge and the flexural properties of modified polymethylmethacrylate (PMMA). Specimens of PMMA denture base material with various loading of fluoridated glass fillers (0%, 1%, 2.5%, 5% and 10% by weight) were prepared. Flexural properties were evaluated on rectangular specimens (n = 10) aged in deionized water after 24 hours, 1 and 3 months. Disc specimens (n = 10) were aged for 43 days in deionized water and lactic acid (pH 4.0) and fluoride release was measured at numerous intervals. After ageing, specimens were recharged and fluoride re-release was recorded at 1, 3 and 7 days after recharge. Samples containing 2.5%, 5% and 10% glass fillers showed significantly (p < 0.05) greater levels of fluoride release compared with the control and 1% glass fillers specimens. All experimental specimens exhibited fluoride release in both media. The flexural strength of specimens decreased in proportion to the percentage filler inclusion with the modulus of elasticity values remaining within ISO Standard 1567. The modified PMMA with fluoridated glass fillers has the ability to release and re-release fluoride ion. Flexural strength decreased as glass filler uploading increased.


Nano-sized solid dispersions based on hydrophobic-hydrophilic conjugates for dissolution enhancement of poorly water-soluble drugs.
The aim of this study was to investigate hydrophilic-hydrophobic conjugates as new carriers for nano-sized solid dispersions (SDs). The amphiphilic conjugates were prepared via an esterification reaction between hydroxypropyl methylcellulose (HPMC) and zein. Four formulations of conjugates were investigated with different ratios of zein to HPMC (1:5, 1:10, 1:20, and 1:40). Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy and particle size analyses were performed to characterize and optimize the formulation for SD. Isradipine and prednisolone were chosen as poorly water-soluble drugs for SD using the conjugate as a carrier. Dissolution tests, particle size analyses, powder X-ray diffraction and FTIR were conducted to determine the dissolution enhancement and its mechanism. The conjugate formed small particles as a self-assembled carrier. Although the SD with isradipine or prednisolone showed a small increase in particle size, the dissolution rate of those drugs in SD increased significantly compared to pure drugs. The interaction between the drug and conjugate was attributed to the formation of small particles and changes to the drug crystallinity. This study demonstrated that the hydrophilic-hydrophobic conjugate is a promising material for SD, with the potential of reducing drug particles to nano size in addition to promoting drug amorphousness or molecular interactions.


A unified graphical models framework for automated mitosis detection in human embryos.
Time lapse microscopy has emerged as an important modality for studying human embryo development, as mitosis events can provide insight into embryo health and fate. Mitosis detection can happen through tracking of embryonic cells (tracking based), or from low level image features and classifiers (tracking free). Tracking based approaches are challenged by high dimensional search space, weak features, outliers, missing data, multiple deformable targets, and weak motion model. Tracking free approaches are data driven and complement tracking based approaches. We pose mitosis detection as augmented simultaneous segmentation and classification in a conditional random field (CRF) framework that combines both approaches. It uses a rich set of discriminative features and their spatiotemporal context. It performs a dual pass approximate inference that addresses the high dimensionality of tracking and combines results from both components. For 312 clinical sequences we measured division events to within 30 min and observed an improvement of 25.6% and a 32.9% improvement over purely tracking based and tracking free approach respectively, and close to an order of magnitude over a traditional particle filter. While our work was motivated by human embryo development, it can be extended to other detection problems in image sequences of evolving cell populations.


Deletion of sphingosine kinase 2 attenuates cigarette smoke-mediated chronic obstructive pulmonary disease-like symptoms by reducing lung inflammation.
Cigarette smoke (CS) is the leading cause of chronic obstructive pulmonary disease (COPD), which is characterized by chronic bronchial inflammation and emphysema. Growing evidence supports the hypothesis that dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is critically involved in the pathogenesis of CS-mediated COPD. However, the underlying mechanism remains unclear. Here, we report that supressed CFTR expression is strongly associated with abnormal phospholipid metabolism and increased pulmonary inflammation. In a CS-exposed mouse model with COPD-like symptoms, we found that pulmonary expression of sphingosine kinase 2 (SphK2) and sphingosine-1-phosphate (S1P) secretion were significantly upregulated. Therefore, we constructed a SphK2 gene knockout (SphK2-/-) mouse. After CS exposure for six months, histological lung section staining showed disorganized alveolar structure, increased pulmonary fibrosis, and emphysema-like symptoms in wild-type (WT) mice, which were less pronounced in SphK2-/- mice. Further, SphK2 deficiency also decreased CS-induced pulmonary inflammation, which was reflected by a remarkable reduction in pulmonary infiltration of CD45+CD11b+ neutrophils subpopulation and low levels of IL-6 and IL-33 in bronchial alveolar lavage fluid. However, treatment with S1P receptor agonist suppressed CFTR expression and increased Nf-κB-p65 expression and its nuclear translocation in CS-exposed SphK2-/-mice, which also aggravated small airways fibrosis and pulmonary inflammation. In contrast, inhibition of S1P signaling with the S1P receptor analogue FTY720 rescued CFTR expression, suppressed Nf-κB-p65 expression and nuclear translocation, and alleviated pulmonary fibrosis and inflammation after CS exposure. Our results demonstrate that SphK2-mediated S1P production plays a crucial role in the pathogenesis of CS-induced COPD-like disease by impairing CFTR activity and promoting pulmonary inflammation and fibrosis.


Correlation between the fluorescent response of microfluidity probes and the water content and viscosity of ionic liquid and water mixtures.
Accurate data on transport properties such as viscosity are essential in plant and process design involving ionic liquids. In this study, we determined the absolute viscosity of the ionic liquid + water system at water mole fractions from 0 to 0.25 for three 1-alkyl-3-methylimidazolium ionic liquids: 1-butyl-3-methylimidazolium hexafluorophosphate, 1-butyl-3-methylimidazolium bis(trifluoromethane sulfonyl)imide and 1-ethyl-3-methylimidazolium bis(trifluoromethane sulfonyl)imide. In each case, the excimer to monomer ratio for 1,m-bis(1-pyrenyl)alkanes (m= 3 or 10) was found to increase linearly with the mole fraction of water. Of the probes studied only PRODAN and rhodamine 6G, both of which have the ability to participate in hydrogen bonding, exhibited Perrin hydrodynamic behavior in the lower viscosity bis(trifluoromethane sulfonyl)imides. As a result, these probes allow for the extrapolation of the absolute viscosity of the ionic liquid mixture from the experimental fluorescence steady-state polarization values.


Polyamines as olfactory stimuli in the goldfish Carassius auratus.
Electrophysiological responses of goldfish olfactory receptor neurons (ORNs) and goldfish behavioral responses to polyamines were investigated in vivo. Electro-olfactogram (EOG) recordings indicated that polyamines (putrescine, cadaverine and spermine) are potent olfactory stimuli for goldfish with estimated electrophysiological thresholds of 10(-8)-10(-7) mol l(-1), similar to that for L-arginine, the most stimulatory amino acid. Although thresholds were similar, the magnitude of the EOG responses to intermediate (10(-5)-10(-4) mol l(-1)) and high (10(-3) mol l(-1)) concentrations of polyamines dwarfed the responses to amino acids and related single amine containing compounds (amylamine and butylamine). The EOG responses to 0.1 mmol l(-1) putrescine, cadaverine and spermine were, respectively, 4.2x, 4.3x and 10.3x the response of the standard, 0.1 mmol l(-1) L-arginine. Electrophysiological cross-adaptation experiments indicated that polyamine receptor sites are independent from those to L-amino acids (alanine, arginine, glutamate, lysine, methionine and ornithine), bile salts (sodium taurocholate and taurolithocholate), the single amine containing compounds (amylamine and butylamine) and ATP. Further, the cross-adaptation experiments revealed the existence of independent receptor sites for the different polyamines tested. Pharmacological experiments suggested that polyamine odorant transduction does not primarily involve the cyclic AMP and IP(3) second messenger pathways. Behavioral assays indicated that polyamines are attractants that elicit feeding behavior similar to that elicited by L-amino acids.


A Qualitative Investigation into Why the Motivation of Massage Therapy Students Changes over the Course of Their Professional Education.
In previous research, the motivation of massage therapy students was observed to change between commencement of their professional studies and entry into practice. The change involved a decrease in intrinsic motivation (associated with altruism) and an increase in extrinsic motivation (associated with the prospect of external rewards). This paper reports on the influences underlying those changes. The research used a qualitative design in which data were collected during a series of individual in-depth semi-structured interviews with massage therapy graduates, just after completion of a 2-year (2200-hour) full-time program. After informed consent was obtained, interviews were taped, transcribed, and analyzed, resulting in identification of a number of themes and subthemes. Previously noted changes in student motivation involved an increase in the influence of extrinsic rewards and a decrease in motivation related to helping and working with people. The findings of the present study suggest that these changes are explained by two main themes, each with a number of subthemes. The first theme, The Reality of Life in Practice, is associated with two subthemes: Debt Load, and Effectiveness in Achieving Positive Health Outcomes. The second theme, An Evolving Self-Image As a Health Care Professional, is associated with three sub-themes: Rigor/Intensity of the Educational Program, Developing Perspective of Massage Therapy As a Career, and Interaction with Faculty. The data suggest that the change in motivation noted in previous work (increased extrinsic motivation and decreased intrinsic motivation) is influenced in different ways by each identified theme. Although schools must be vigilant in ensuring that their programs support the humanistic mission of health care, the present study indicates that the change in motivation noted in earlier work is not sinister. Rather, it appears to be related to the development of a realistic perspective of life as a health care practitioner, which departs from the more naïve expectations of students when they commence their professional studies.


Isolation of the Sex Attractant of the American Cockroach.
The sex attractant of the female American cockroach, Periplaneta americana (L.), has been collected and isolated by a combination of extraction, distillation, and chromatographic procedures. Progress through these procedures has been followed by bioassay and by ultraviolet spectrophotometry. The attractant has been isolated by gas chromatography, and characterization by mass spectrometry is proceeding.


Associations between compulsory community treatment and continuity of care in a three year follow-up of the Oxford Community Treatment Order Trial (OCTET) cohort.
Most studies investigating the effectiveness of Community Treatment Orders (CTOs) use readmission to hospital as the primary outcome. Another aim of introducing CTOs was to improve continuity of care. Our study was a 3-year prospective follow-up which tested for associations between CTOs and continuity of care. Our study sample included 333 patients recruited to the Oxford Community Treatment Order Trial (OCTET). We collected data on continuity of care using eight previously operationalized measures. We analysed the association between CTOs and continuity of care in two ways. First, we tested the association between continuity of care and OCTET randomisation arm (CTO versus voluntary care via Section 17 leave). Second, we analysed continuity of care and CTO exposure independent of randomisation; using any exposure to CTO, number of days on CTO, and proportion of outpatient days on CTO as outcomes. 197 (61%) patients were made subject to CTO during the 36-month follow-up. Randomisation to CTO arm was significantly associated with having a higher proportion of clinical documents copied to the user but no other measures of continuity. Having a higher proportion of outpatient days on CTO (irrespective of randomisation) was associated with fewer 60 day breaks without community contact. A sensitivity analysis found that any exposure to CTO and a higher proportion of outpatient days on CTO were associated with fewer days between community mental health team contacts and 60 day breaks without contact. We found some evidence of an association between CTO use and better engagement with the community team in terms of increased contact and fewer breaks in care. Those with CTO experience had a higher number of inpatient admissions which may have acted as a mediator of this association. We found limited evidence for an association between CTO use and other measures of continuity of care.


An Excimer Laser-Induced Eruptive Sebaceous Hyperplasia.
Sebaceous hyperplasia (SH) is a benign proliferation of the sebaceous glands. Ultraviolet radiation is known to be the cofactor for the pathogenesis of SH. Frequently reported adverse events of 308-nm excimer laser are erythema, burning or pain, and itching sensation. However, the role of excimer laser as an aetiological factor of SH is rarely reported in the literature. A 59-year-old female presented with several elevated, umbilicated papules on the face. Papular eruption appeared abruptly after 11 weeks of treatment for vitiligo which includes 308-nm excimer laser therapy. The distribution of lesion was associated with the treated area. Total cumulative dose was 3,300 mJ/cm² over 16 sessions. Histopathologic findings showed enlarged sebaceous glands composed of numerous lobules around a centrally located, widened sebaceous duct. Chronic sun exposure clinically causes SH was proved in the previous animal studies. Thus, we introduce a rare case of eruptive SH in the patient treated with 308-nm excimer laser.


Inbreeding depression and mating systems in two species of Linanthus (Polemoniaceae).
Theory predicts that, at equilibrium, the magnitude of inbreeding depression caused by recessive alleles should decrease as the level of self-fertilization increases, facilitating the evolution of even higher selfing rates. Data are presented on mating systems and inbreeding depression in multiple populations of two annual species in the genus Linanthus (Polemoniaceae). Outcrossing rates were found to be less than 0.075 in populations of a small-flowered species, L. bicolor, and ranged from 0.104 to 0.300 in populations of a larger-flowered species, L. jepsonii. Inbreeding depression for both species was low for all life history stages, with cumulative inbreeding depression less than 0.23 in all populations. Significant inbreeding depression for pollen fertility was found in L. jepsonii populations and may contribute substantially to total inbreeding depression. A competitive treatment had no significant effect on the expression of inbreeding depression for above-ground dry mass. In accordance with theoretical expectations, the magnitude of inbreeding depression was lower in L. bicolor, the more highly selfing species. The magnitude of inbreeding depression in L. jepsonii, although greater than that of L. bicolor, is not sufficient to prevent evolution of increased selfing rates in this species, according to some theoretical models of mating system evolution.


Melatonin exerts oncostatic capacity and decreases melanogenesis in human MNT-1 melanoma cells.
Melanogenesis is a key parameter of differentiation in melanocytes and melanoma cells; therefore, search for factors regulating this pathway are strongly desired. Herein, we investigated the effects of melatonin, a ubiquitous physiological mediator that is found throughout animals and plants. In mammals, the pineal gland secretes this indoleamine into the blood circulation to exert an extensive repertoire of biological activities. Our in vitro assessment indicates an oncostatic capacity of melatonin in time-dependent manner (24, 48, 72 hours) in highly pigmented MNT-1 melanoma cells. The similar pattern of regulation regarding cell viability was observed in amelanotic Sk-Mel-28 cells. Subsequently, MNT-1 cells were tested for the first time for evaluation of melanin/melatonin interaction. Thus primary, electron paramagnetic resonance (EPR) spectroscopy demonstrated that melatonin reduced melanin content. Artificially induced disturbances of melanogenesis by selected inhibitors (N-phenylthiourea or kojic acid) were slightly antagonized by melatonin. Additionally, analysis using transmission electron microscopy has shown that melatonin, particularly at higher dose of 10-3 mol/L, triggered the appearance of premelanosomes (stage I-II of melanosome) and MNT-1 cells synthesize de novo endogenous melatonin shown by LC-MS. In conclusion, these studies show a melanogenic-like function of melatonin suggesting it as an advantageous agent for treatment of pigmentary disorders.


Lobar flexible fiberoptic lung lavage: therapeutic benefit in severe respiratory failure in pulmonary alveolar proteinosis and influenza A H1N1 pneumonia.
Lobar fiberoptic lung lavage is a well-known procedure used in primary pulmonary alveolar proteinosis (PAP); the use of this procedure has increased in the recent years. This procedure has also been used in other pulmonary diseases such as desquamative interstitial pneumonia with good results. We describe a case of extremely severe respiratory failure due to concurrence of PAP and Influenza A H1N1 virus pneumonia which resolved with the help of this procedure. The patient, a 41-year-old woman, needed less mechanical ventilation after undergoing lobar fiberoptic bronchoscopic lavage. Moreover, a rapid and progressive improvement in the computed tomography of the lungs was observed. Flexibile fiberoptic bronchoscopic lobar lavage is a simple, safe procedure used not only in milder disease, but also in particular severe cases in which the physiological derangement of whole lung lavage would not be tolerated by patient or when extra-corporeal membrane oxygenation is not available.


Reimagining the Value of Brachial-Ankle Pulse Wave Velocity as a Biomarker of Cardiovascular Disease Risk-A Call to Action on Behalf of VascAgeNet.
This review critiques the literature supporting clinical assessment and management of cardiovascular disease and cardiovascular disease risk stratification with brachial-ankle pulse wave velocity (baPWV). First, we outline what baPWV actually measures-arterial stiffness of both large central elastic arteries and medium-sized muscular peripheral arteries of the lower limb. Second, we argue that baPWV is not a surrogate for carotid-femoral pulse wave velocity. While both measures are dependent on the properties of the aorta, baPWV is also strongly dependent on the muscular arteries of the lower extremities. Increased lower-extremity arterial stiffness amplifies and hastens wave reflections at the level of the aorta, widens pulse pressure, increases afterload, and reduces coronary perfusion. Third, we used an established evaluation framework to identify the value of baPWV as an independent vascular biomarker. There is sufficient evidence to support (1) proof of concept; (2) prospective validation; (3) incremental value; and (4) clinical utility. However, there is limited or no evidence to support (5) clinical outcomes; (6) cost-effectiveness; (8) methodological consensus; or (9) reference values. Fourth, we address future research requirements. The majority of the evaluation criteria, (1) proof of concept, (2) prospective validation, (3) incremental value, (4) clinical utility and (9) reference values, can be supported using existing cohort datasets, whereas the (5) clinical outcomes and (6) cost-effectiveness criteria require prospective investigation. The (8) methodological consensus criteria will require an expert consensus statement. Finally, we finish this review by providing an example of a future clinical practice model.


Implementing Value-Added Medical Education: Lessons Learned From the Student-Initiated Stanford Frontline COVID-19 Consult Service.
Value-added medical education (VAME) has been difficult to implement due to student and educator constraints. The COVID-19 pandemic caused mass transitions to online learning, removed students from clinical settings, and underscored students' desires for meaningful VAME opportunities. The authors introduced the Stanford Frontline COVID-19 Consult Service (SFCS), through which off-service medical and physician assistant (PA) students provided assistance to clinicians in the form of rapid research regarding COVID-19 clinical questions. The SFCS, a student-derived VAME initiative, was implemented from March to May 2020 by Stanford University medical students, PA students, and faculty. SFCS aligned with not only the interests of clinicians and students but also national accreditation standards. Students attended weekly editorial meetings, didactic sessions on literature reviews and information management, and they underwent rigorous training on the peer review process. After 2 months, the authors expanded the service to local community clinicians. The SFCS enrolled 16 students, was supported by 13 faculty members, and produced 87 peer-reviewed evidence syntheses. Of the 16 SFCS students, 13 (81%) completed evaluations; of 128 Stanford Primary Care and Population Health clinicians, 48 (38%) completed evaluations. Overall student satisfaction with the SFCS was 4.9/5 (standard deviation [SD] 0.3). Self-assessed achievement of SFCS learning objectives exceeded 90% for all objectives. Overall faculty satisfaction with the SFCS was 4.4/5 (SD 0.8). Most faculty (40/46 [87%]) planned to use the database to answer future COVID-19 questions. The SFCS is a novel, student-initiated VAME curriculum focused on increasing students' meaningful contributions to patient care. The authors will track SFCS students throughout their clerkships to gauge clerkship performance/preparedness, and they will develop training for integrating VAME into preclerkship curricula at other institutions. Given its adaptive, student-driven design, the VAME framework used to develop the SFCS empowers students to create their own personalized, experiential learning.


Toxoplasma gondii infection and common mental disorders in the Finnish general population.
We investigated whether T. gondii seropositivity is associated with 12-month depressive, anxiety and alcohol use disorders and current depressive symptoms and whether inflammation, measured by C-reactive protein (CRP) level, explains these associations. Health 2000 study (BRIF8901), conducted in years 2000-2001, is based on a nationally representative sample of Finns aged 30 and above, with 7112 participants and 88.6% response rate. DSM-IV depressive, anxiety and alcohol use disorders were assessed with the Composite International Diagnostic Interview and depressive symptoms with the Beck Depressive Inventory (BDI-21). We used logistic regression to investigate the association of T. gondii seropositivity with mental disorders and linear regression with BDI-21 scores. T. gondii seroprevalence was significantly associated with 12-month generalized anxiety disorder but not with other anxiety, depressive or alcohol use disorders. T. gondii seropositivity was associated with higher BDI-21 scores (beta 0.56, 95% CI 0.12-1.00, P = 0.013) and with having a comorbid depressive and anxiety disorder (OR 1.86, 95% CI 1.16-2.97, P = 0.010). Higher CRP levels were associated with these outcomes and with T. gondii seropositivity, but adjusting for CRP did not change the effect of T. gondii seropositivity. Cross-sectional study design with no information on the timing of T. gondii infection. T. gondii seropositivity is associated with generalized anxiety disorder, depressive symptoms and comorbid depressive and anxiety disorders, which is not mediated by inflammation.


Understanding handwriting difficulties: A comparison of children with and without motor impairment.
The nature of handwriting difficulties have been explored in children with specific developmental disorders. The aim of this study was to investigate the nature of handwriting difficulties in children with dysgraphia, a less studied group who have significant handwriting difficulties in the absence of motor control or cognitive difficulties. The performance of a dysgraphia group aged 8-14 years was compared to a group with Developmental Coordination Disorder and to typically developing (TD) controls. Participants completed two handwriting tasks on a digitizing writing tablet. The amount and accuracy of the handwriting product was measured, plus various temporal and spatial features of the writing process. There were no significant differences in performance between the two groups with handwriting difficulties but both performed more poorly than the TD group. Individual differences in the type and severity of handwriting impairments suggest the need for a range of classroom assessments to tailor intervention appropriately.


Role of Autonomic Nervous System and Orexinergic System on Adipose Tissue.
Adipose tissue, defined as white adipose tissue (WAT) and brown adipose tissue (BAT), is a biological caloric reservoir; in response to over-nutrition it expands and, in response to energy deficit, it releases lipids. The WAT primarily stores energy as triglycerides, whereas BAT dissipates chemical energy as heat. In mammals, the BAT is a key site for heat production and an attractive target to promote weight loss. The autonomic nervous system (ANS) exerts a direct control at the cellular and molecular levels in adiposity. The sympathetic nervous system (SNS) provides a complex homeostatic control to specifically coordinate function and crosstalk of both fat pads, as indicated by the increase of the sympathetic outflow to BAT, in response to cold and high-fat diet, but also by the increase or decrease of the sympathetic outflow to selected WAT depots, in response to different lipolytic requirements of these two conditions. More recently, a role has been attributed to the parasympathetic nervous system (PNS) in modulating both adipose tissue insulin-mediated glucose uptake and fatty free acid (FFA) metabolism in an anabolic way and its endocrine function. The regulation of adipose tissue is unlikely to be limited to the autonomic control, since a number of signaling cytokines and neuropeptides play an important role, as well. In this review, we report some experimental evidences about the role played by both the ANS and orexins into different fat pads, related to food intake and energy expenditure, with a special emphasis on body weight status and fat mass (FM) content.


Acral lentiginous melanoma versus other melanoma: A single-center analysis in Japan.
We summarize herein our 14-year experience of conventional treatment outcomes before the era of molecular-targeted therapy and immunotherapy. Specifically, we conducted a retrospective review of our 252 patients with primary cutaneous melanoma (acral lentiginous melanoma [ALM], n = 121; non-acral lentiginous melanoma [non-ALM], n = 131), and compared the prognostic factors between ALM and non-ALM. Melanoma-specific survival and disease-free survival were estimated using the Kaplan-Meier method. Regarding the results, all patients were Japanese (106 male and 146 female), with a mean age of 60.1 years. Among ALM patients, age was elder and primary tumor size was larger than non-ALM. As for tumor thickness, in situ lesions were more frequently observed in ALM. There was no significant difference in the distribution of tumor thickness between the two groups when excluding the in situ lesions. For treatment of the primary melanoma, 248 patients (98.4%) had undergone curative surgical excision and 120 patients with more than 1 mm or ulcerated melanoma had undergone sentinel lymph node biopsy. Patients with systemic metastasis primarily underwent dacarbazine-based chemotherapy. The Kaplan-Meier survival curves revealed no significant difference in melanoma-specific survival and disease-free survival between those with ALM and non-ALM. The results also showed that both ALM and non-ALM, when they initially metastasize, first affect the regional lymph nodes. Incisional biopsy was not an adverse prognostic factor. These results suggest that ALM does not differ in its biological behavior from non-ALM, so we can consider ALM as being equivalent to non-ALM. The initial treatment for ALM and non-ALM can involve the same strategy.


[General statistical characteristics of the background firing in cat's cortical neurons during slow-wave sleep].
Background activity of 62 neurons in cat cerebral cortex was recorded in the state of slow-wave sleep for evaluation of the firing statistics. In according to their statistical characteristics neurons were subdivided in three groups. In the first group deviation from the Poisson process were comparatively small, and revealed as fragments of increased excitability following immediately after the refractory period. Second group demonstrated positive correlation of the neighbouring interspike intervals what was conditioned by the changes of the mean firing rate. In these neurons the number of spikes included into the bursts reduced after random permutation of the interspike intervals. The third group was characterized by the big number of spikes included into the bursts (> 15%), and number of bursts usually dropped down after random permutation. Some neurons of this group had constant interspike intervals within the bursts while in other units these intervals monotonically increased toward the end of the burst. Only limited number of neurons demonstrated maximums of the autocorrelation function corresponded to the frequency of the EEG delta activity.


Nanocatalysis and prospects of green chemistry.
Designing and developing ideal catalyst paves the way to green chemistry. The fields of catalysis and nanoscience have been inextricably linked to each other for a long time. Thanks to the recent advances in characterization techniques, the old technology has been revisited with a new scope. The last decade has witnessed a flood of research activity in the field of nanocatalysis, with most of the studies focusing on the effect of size on catalytic properties. This led to the development of much greener catalysts with higher activity, selectivity and greater ease of separation from the reaction medium. This Minireview describes the emerging trends in the field of nanocatalysis with implications towards green chemistry and sustainability.


Can Pharmacovigilance Learn From the Oil and Gas Industry, Which Has Been Outsourcing for Over a Century?
Outsourcing in pharmacovigilance has grown in the past decade. However, standards are lacking in this area, both for initiating as well as maintaining an outsource relationship. In this paper, the authors propose that the sector can learn from other industries that have been outsourcing activities for a much longer time, such as the oil and gas industry. The Safety Case is put forward as a body of evidence that facilitates the continuous exchange of data, especially focused on risk management of the relationship between outsourcer and vendor. Finally, the authors will make an attempt to come to a global consensus in this area through the Allliance for Clinical Research Excellence and Safety (ACRES) network.


Recurrence rate in vulvar carcinoma in relation to pathological margin distance.
This paper describes the results of a retrospective study of surgical approaches and recurrence rates relating to patients with squamous cell carcinoma (SCC) of the vulva. The aim of this study was to analyze the histological margins in relation to recurrence rate and survival. A retrospective chart review of 93 cases of vulvar cancer. The data collected included clinicopathological and surgical characteristics and the following potential risk factors: pathological margin distance, less than 8 mm; stromal invasion depth, more than 2.5 mm; tumor size; and presence of benign or premalignant epithelial disorders. Ninety-three patients (median age, 74 years) underwent modified radical vulvectomy, hemi-vulvectomy, or local wide excision for SCC of the vulva from 2000 to 2005. The tumor was radically removed in 80 patients (86%), although the histopathological margin was less than 8 mm in 50 patients (54%). Eighteen patients (23%) developed a local recurrence. The recurrence rate did not differ between patients in whom the margin distance was 8 mm or more and those in whom the margin distance was less than 8 mm, (23% and 22%, respectively). The median follow-up was 31 months (range, 2-90 months). Several studies showed that pathological margin distance of more than 8 mm is an important predictor for local recurrence. This finding was not confirmed in the present study.


Regulatory T cells and vasectomy.
CD4+ CD25+ regulatory T cells (Tregs) strongly influence the early and late autoimmune responses to meiotic germ cell antigens (MGCA) and the gonadal immunopathology in vasectomized mice. This is supported by the published and recently acquired information presented here. Within 24h of unilateral vasectomy (uni-vx) the ipsilateral epididymis undergoes epithelial cell apoptosis followed by necrosis, severe inflammation, and granuloma formation. Unexpectedly, vasectomy alone induced MGCA-specific tolerance. In contrast, uni-vx plus simultaneous Treg depletion resulted in MGCA-specific autoimmune response and bilateral autoimmune orchitis. Both tolerance and autoimmunity were strictly linked to the early epididymal injury. We now discovered that testicular autoimmunity in uni-vx mice did not occur when Treg depletion was delayed by one week. Remarkably, this delayed Treg depletion also prevented tolerance induction. Therefore, tolerance depends on a rapid de novo Treg response to MGCA exposed after vasectomy. Moreover, tolerance was blunted in mice genetically deficient in PD-1 ligand, suggesting the involvement of induced Treg. We conclude that pre-existing natural Treg prevents post-vasectomy autoimmunity, whereas vasectomy-induced Treg maintains post-vasectomy tolerance. We further discovered that vasectomized mice were still resistant to autoimmune orchitis induction for at least 12-16 months; thus, tolerance is long-lasting. Although significant sperm autoantibodies of low titers became detectable in uni-vx mice at 7 months, the antibody titers fluctuated over time, suggesting a dynamic "balance" between the autoimmune and tolerance states. Finally, we observed severe epididymal fibrosis and hypo-spermatogenesis at 12 months after uni-vx: findings of highly critical clinical significance.


Effects of chronic excess salt feeding. Enhanced hypertensogenic effect of sea salt over sodium chloride.
Female rats were fed diets containing either excess sea salt or excess sodium chloride for periods up to 14 months. The hypertension produced by sea salt was more pronounced than that caused by sodium chloride alone, although the average amount of sodium chloride contained in the sea salt feeding was slightly less. The ions involved in this incremental effect of sea salt were not identified.


Estrogen receptor β2 induces proliferation and invasiveness of triple negative breast cancer cells: association with regulation of PHD3 and HIF-1α.
The two estrogen receptor (ER) subtypes, ERα and ERβ, belong to the nuclear receptor superfamily. The human ERβ variant ERβ2 is proposed to be expressed at higher levels than ERβ1 in many breast tumors and it has been suggested that ERβ2, in contrast to ERβ1, is associated with aggressive phenotypes of various cancers. However, the role of endogenous ERβ2 in breast cancer cells remains elusive. In this study, we identified that triple negative breast cancer (TNBC) cell lines express endogenous ERβ2, but not ERα or ERβ1. This allows novel studies of endogenous ERβ2 functions independent of ERα and ERβ1. We show that overexpression of ERβ2 in TNBC cells increased whereas knockdown of endogenous ERβ2 decreased cell proliferation and cell invasion. To elucidate the molecular mechanism responsible for these cellular phenotypes, we assayed ERβ2 dependent global gene expression profiles. We show that ERβ2 decreases prolyl hydroxylase 3 (PHD3) gene expression and further show that this is associated with increased hypoxia inducible factor 1α (HIF-1α) protein levels, thus providing a possible mechanism for the invasive phenotype. These results are further supported by analysing the expression of ERβ2 and PHD3 in breast tumor samples where a negative correlation between ERβ2 and PHD3 expression was observed. Together, we demonstrate that ERβ2 has an important role in enhancing cell proliferation and invasion, beyond modulation of ERβ and ERβ1 signalling which might contribute to the invasive characteristics of TNBC. The invasive phenotype could potentially be mediated through transcriptional repression of PHD3 and increased HIF-1α protein levels.


Diclofenac-induced stimulation of SMCT1 (SLC5A8) in a heterologous expression system: a RPE specific phenomenon.
SMCT1 is a Na(+)-coupled monocarboxylate transporter expressed in a variety of tissues including kidney, thyroid, small intestine, colon, brain, and retina. We found recently that several non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the activity of SMCT1. Here we evaluated the effect of diclofenac, also a NSAID, on SMCT1. SMCT1 cDNA was expressed heterologously in the human retinal pigment epithelial cell lines HRPE and ARPE-19, the human mammary epithelial cell line MCF7, and in Xenopus laevis oocytes. Transport was monitored by substrate uptake and substrate-induced currents. Na(+)-dependent uptake/current was considered as SMCT1 activity. The effect of diclofenac was evaluated for specificity, dose-response, and influence on transport kinetics. To study the specificity of the diclofenac effect, we evaluated the influence of this NSAID on the activity of several other cloned transporters in mammalian cells under identical conditions. In contrast to several NSAIDs that inhibited SMCT1, diclofenac stimulated SMCT1 when expressed in HRPE and ARPE-19 cells. The stimulation was marked, ranging from 2- to 5-fold depending on the concentration of diclofenac. The stimulation was associated with an increase in the maximal velocity of the transport system as well as with an increase in substrate affinity. The observed effect on SMCT1 was selective because the activity of several other cloned transporters, when expressed in HRPE cells and studied under identical conditions, was not affected by diclofenac. Interestingly, the stimulatory effect on SMCT1 observed in HRPE and ARPE-19 cells was not evident in MCF7 cells nor in the X. laevis expression system, indicating that SMCT1 was not the direct target for diclofenac. The RPE-specific effect suggests that the target of diclofenac that mediates the stimulatory effect is expressed in RPE cells but not in MCF7 cells or in X. laevis oocytes. Since SMCT1 is a concentrative transporter for metabolically important compounds such as pyruvate, lactate, beta-hydroxybutyrate, and nicotinate, the stimulation of its activity by diclofenac in RPE cells has biological and clinical significance.


[Giant scrotal lymphedema caused by Milroy's disease].
To report a new case of giant scrotal lymphedema due to Milroy's disease, its treatment and outcome. A 27-year-old man with generalized congenital lymphedema presented with a giant scrotal mass which interfered with his daily activities and physiological necessities. Physical examination showed a scrotal mass 40 x 40 cm in size and a normal penis. CT scan showed a homogeneous mass, thickened vaginal tunica, and bilateral hydrocele. A surgical procedure was performed including mass resection (5.6 kg), and bilateral hydrocelectomy. Skin defect was covered with skin grafts. Several therapeutic alternatives have been suggested for Milroy's disease with genital involvement. Nevertheless, when complications are as severe as in the present case, the only valid therapy is surgery.


U1 snRNA is cleaved by RNase III and processed through an Sm site-dependent pathway.
Core snRNP proteins bind snRNA through the conserved Sm site, PuA(U)n>/=3GPu. While yeast U1 snRNA has three matches to the Sm consensus, the U1 3'-terminal Sm site was found to be both necessary and sufficient for U1 function. Mutation of this site inhibited pre-mRNA splicing, blocked cell division and resulted in the accumulation of two 3'-extended forms of the U1 snRNA. Cells which harbor the Sm site mutation lack mature U1 RNA (U1alpha) but have a minor polyadenylated species, U1gamma, and a prominent, non-polyadenylated species, U1beta. Metabolic depletion of the essential Sm core protein, Smd1p, also resulted in the increased accumulation of U1beta and U1gamma. In vitro, synthetic U1 precursors were cleaved by Rnt1p (RNase III) very near the U1beta 3'-end observed in vivo. We propose that U1beta is an Rnt1p-cleaved intermediate and that U1 maturation to the U1alpha form occurs through an Sm-sensitive step. Interestingly, both U1alpha and a second, much longer RNA, U1straightepsilon, were produced in an rnt1 mutant strain. These results suggest that yeast U1 snRNA processing may progress through Rnt1p-dependent and Rnt1p-independent pathways, both of which require a fun-ctional Sm site for final snRNA maturation.


The structure of human beta-defensin-2 shows evidence of higher order oligomerization.
Defensins are small cationic peptides that are crucial components of innate immunity, serving as both antimicrobial agents and chemoattractant molecules. The specific mechanism of antimicrobial activity involves permeabilization of bacterial membranes. It has been postulated that individual monomers oligomerize to form a pore through anionic membranes, although the evidence is only indirect. Here, we report two high resolution x-ray structures of human beta-defensin-2 (hBD2). The phases were experimentally determined by the multiwavelength anomalous diffraction method, utilizing a novel, rapid method of derivatization with halide ions. Although the shape and charge distribution of the monomer are similar to those of other defensins, an additional alpha-helical region makes this protein topologically distinct from the mammalian alpha- and beta-defensin structures reported previously. hBD2 forms dimers topologically distinct from that of human neutrophil peptide-3. The quaternary octameric arrangement of hBD2 is conserved in two crystal forms. These structures provide the first detailed description of dimerization of beta-defensins, and we postulate that the mode of dimerization of hBD2 is representative of other beta-defensins. The structural and electrostatic properties of the hBD2 octamer support an electrostatic charge-based mechanism of membrane permeabilization by beta-defensins, rather than a mechanism based on formation of bilayer-spanning pores.


Retrospective Study of the Effect of Statins on the Outcome of Lung Cancer Patients, University of Cincinnati Experience.
Objectives: Numerous studies addressed the effect of statin on cancer patients. The aim of this study is to define the effect of statin administration with chemotherapy on the patients' outcomes. Methods: We retrospectively researched the database of the University of Cincinnati cancer to identify lung cancer patients who received statins (S+, n=41) during their treatment in our institute. We also, retrieved data for contemporaneously treated patients who did not receive statins (S-, n=159) as a control arm. Clinico-demographical data and overall survival (OS) were analyzed using Pearson's Chi-square (χ2) test and Kaplan-Meier survival curves with Log-rank test. Adjustment using Cox proportional hazard ratios (HR) were done based on (age, gender, race and stage) to identify effect of statins on their outcomes. Results: The median age for S+ was 64y (IQR; 55-69) and 71.2% of the patients were white. Histopathology was 55.4% and 31.7% for adenocarcinoma and squamous cell carcinoma, respectively. Fifty-six percent were stage IV in each study arm and the median OS was14.9 m. Median OS was insignificantly lower in S–ve arm (13.7 vs 15.6 months; P=0.652, HR=0.91, 95%CI 0.52-1.57). Our results show that after different types of adjustments, S+ did not show survival advantage (P>0.05) compared to the control arm. Conclusion: While showing an increase in overall survival in patients with advanced lung cancer, the results of this study did not reach statistical significance. This could be due for the small sample size of this retrospective study.


Cognitive deficits are associated with functional impairment in severely depressed patients.
Cognitive deficits have been associated with poorer function and quality of life (QOL) in schizophrenia, but no similar findings have been confirmed in persons with major depressive episode (MDE). We investigated whether cognitive deficits were associated with detrimental effects on the QOL of persons with primary MDE. Seventy-seven non-demented adults with MDE underwent evaluations of mood, cognition and QOL. Cognition was assessed with the Mini-Mental State Exam, and delayed recall on the Rey Auditory Verbal Learning Task and the Rey Figure. QOL assessments included instrumental activities of daily living (IADL), activities of daily living (ADL), and satisfaction in role functioning and relationships. Univariate correlation and regression models were used to find those mood and cognitive variables most closely related to each QOL dimension. ADL function and satisfaction with role functioning and relationships were most closely related to depression severity and age. IADL functioning, however, was most closely associated with global cognition. This study did not take into account the physical health of the participants, and all the participants were seriously ill with depression. Thus, the results may not apply to persons with less severe MDE. Antidepressant treatments that preserve or enhance global cognition in addition to relieving core depressive symptoms may lead to the best functional outcomes.


The developmental profile and outcome of 325 unselected preterm infants up to two years of age.
A regional birth cohort of 351 preterm infants born between the 1st June, 1981 and the 31st May, 1982 was followed-up during the first two years of life. The follow-up data were obtained from 325 preterm infants. The term, appropriate-for-gestational age low-risk infants born in the region during the same period served as a control population. The follow-up examinations took place at the well-baby clinics run by public health nurses and health centre physicians at 3, 6, 12, 18 and 24 months of conceptional age. A modification of the Denver Developmental Screening Test was applied in the follow-up. In 15 (5%) preterm infants the developmental outcome at two years was doubtful or abnormal. The developmental outcome at two years was doubtful or abnormal. The developmental outcome in preterm infants was associated with gestational age, birthweight, severity of respiratory distress and five-minute Apgar score when analyzed separately. After stepwise logistic regression analysis only five-minute Apgar score significantly predicted the gross motor and fine motor outcomes while the psychosocial outcome was associated with five-minute Apgar score and birthweight. The developmental profiles of the preterm infants differed from those of the control infants by showing higher percentages of unoptimal scores especially in fine motor development at three months and psychosocial development at two years. The prognosis for preterm infants without complications was, however, near that of their term peers.


Management of antithrombotic agents in patients undergoing flexible bronchoscopy.
Bleeding is one of the most feared complications of flexible bronchoscopy. Although infrequent, it can be catastrophic and result in fatal outcomes. Compared to other endoscopic procedures, the risk of morbidity and mortality from the bleeding is increased, as even a small amount of blood can fill the tracheobronchial tree and lead to respiratory failure. Patients using antithrombotic agents (ATAs) have higher bleeding risk. A thorough understanding of the different ATAs is critical to manage patients during the peri-procedural period. A decision to stop an ATA before bronchoscopy should take into account a variety of factors, including indication for its use and the type of procedure. This article serves as a detailed review on the different ATAs, their pharmacokinetics and the pre- and post-bronchoscopy management of patients receiving these medications.


[Characteristics of the reactions to active orthostatic and water loading tests in persons with varying resistance to +Gz loads].
Thirty-seven healthy male test subjects, aged 19-21, with different +Gz acceleration tolerance were examined. Their blood pressure (BP) and heart rate (HR) during 5-min tilt tests and 2% water loading tests were measured 2-3 weeks prior to centrifugation. Quantitative evaluation of orthostatic tolerance using an orthostatic index and BP and HR responses to tilt tests before and after water loading revealed specific features of cardiovascular regulation in the subjects with high and low +Gz acceleration tolerance. The negative predictive indicators include: decreased BP, HR and cardiac index in the supine position in combination with high orthostatic tolerance, as well as decreased orthostatic tolerance in combination with a lower function of vasoconstrictor mechanisms in the upright position and a lower sensitivity of carotid sinus reflexes to blood volume changes during tilt and water loading tests. When examining test subjects with high +Gz tolerance, preference should be given to those who can well tolerate tilt tests and show moderately high BP and HR in the supine position, as well as to those who exhibit a noticeable increment of diastolic BP during 5-min tilt tests.


Concurrent radiochemotherapy in advanced breast cancer.
An initial trial to determine whether the theoretical advantage of concurrent systemic chemotherapeutic protection and local control (by radiation) could be achieved has been applied to 16 patients with breast cancer (Stage 3 and 4). CMFP/CMF combination chemotherapy has been administered with external irradiation (5000 rad breast, 4000-4400 rad nodes). External irradiation was successfully accomplished with tangenital fields to avoid combined modality esophagitis while achieving internal mammary node irradiation. Six patients subsequently received Iridium-192 interstitial implantation. Six patients treated preoperatively (4000 rad, breast) were able to have modified mastectomy within 3-6 weeks of completing radiation therapy without graft requirement or undue morbidity. Acute reactions during therapy included some amplification of epidermitis and myelosuppression. Prolongation of the radiation treatment course occurred in two patients and delay in chemotherapy cycles in four patients. In two patients, the leukocyte count nadir was below 1000 and one was hospitalized with fever. The majority of the patients achieved 75% of the designed chemotherapeutic doses in the ensuing year. Many of the patients with advanced disease were administered an Adriamycin-containing regimen upon completion of the radiation therapy. The current results suggest that it would be feasible to initiate a randomized prospective study using these techniques to compare sequential and concomitant chemo-radiation therapy in primary breast cancer to determine whether there is significant advantage in local control and duration of NED survival in either of the treatment regimens.


Effectiveness of two flavored topical anesthetic agents in reducing injection pain in children: a comparative study.
Topical anesthesia is widely advocated in pediatric dentistry practice to reduce pain and anxiety produced by administration of local anesthesia. There are different combinations of topical anesthetic agents that are marketed worldwide. However, sparse literature reports exist regarding clinical efficacy of these agents. To compare the clinical effectiveness of two strawberry flavored topical anesthetics viz. Precaine (8% Lidocaine + 0.8% Dibucaine) and Precaine B (20% Benzocaine) in children before intra oral local anesthetic injections and for extraction of mobile primary teeth. This triple blind clinical study included sixty children divided equally under three techniques--palatal injections, inferior alveolar nerve block and extraction of mobile primary teeth. Both the products were used alternately using split mouth design in two visits and the child's pain response was assessed using VAS and SEM pain scale. The scores obtained were subjected to statistical analysis. Precaine has shown lower mean scores in all the techniques under both the pain scales, but were statistically insignificant. Gender wise comparison has also shown lower mean scores for Precaine for both males and females, however these were statistically insignificant. On visit wise comparison, Precaine B reported significant lower scores (p < 0.05) in visit 2 compared to visit 1 for inferior alveolar nerve block and extraction of mobile primary teeth under SEM pain scale. Precaine (8% Lidocaine + 0.8% Dibucaine) can be used as effectively as Precaine B (20% Benzocaine).


Mechanical contribution of expiratory muscles to pressure generation during spinal cord stimulation.
Lower thoracic spinal cord stimulation (SCS) results in the generation of large positive airway pressures (Paw) and may be a useful method of restoring cough in patients with spinal cord injury. The purpose of the present study was to assess the mechanical contribution of individual respiratory muscles to pressure generation during SCS. In anesthetized dogs, SCS was applied at different spinal cord levels by using a 15-lead multicontact electrode before and after sequential ablation of the external and internal obliques, transversus abdominis (TA), rectus abdominis, and internal intercostal muscles. Paw was monitored after tracheal occlusion. SCS at the T(9) spinal cord level resulted in maximal changes in Paw (60 +/- 3 cmH(2)O). Section of the oblique muscles resulted in a fall in Paw to 29 +/- 2 cmH(2)O. After subsequent section of the rectus abdominis and TA, Paw fell to 25 +/- 2 and 12 +/- 1 cmH(2)O respectively. There was a small remaining Paw (4 +/- 1 cmH(2)O) after section of the internal intercostal nerves. Stimulation with a two-electrode lead system (T(9) + T(13)) resulted in significantly greater pressure generation compared with a single-electrode lead due to increased contributions from the obliques and transversus muscles. In a separate group of animals, Paw generation was monitored after section of the abdominal muscles and again after section of the external intercostal and levator costae muscles. These studies demonstrated that inspiratory intercostal muscle stimulation resulted in only a small opposing inspiratory action (</=3 cmH(2)O). We conclude that, during SCS, 1) contraction of the obliques and TA muscles makes the largest contribution to changes in Paw, and 2) stimulation with a two-electrode lead system results in more complete abdominal muscle activation and enhanced mechanical actions of the obliques and transversus muscles.


GP claims for completing diabetes 'cycle of care'.
There is a wide variability in the level of claims for diabetes. Service Incentive Payments (SIP) by general practitioners. Cross sectional comparison of the ratio of the number of SIP items claimed between August 2002 and July 2003 to the estimated prevalence of diabetes by divisions of general practice (DGP). Seventy-nine of the 101 DGP with diabetes programs in 2002. The average ratio of diabetes SIP claims to estimated diabetes prevalence (including both diagnosed and undiagnosed cases) for each quarter of the year between August 2002 and July 2003 was 10.1% (standard deviation 3.6). This ratio was higher in DGP with a more disadvantaged population, and more of their GP members in large practices. The provision of IT support in DGP and the proportion of GPs who had patients registered on the division's register were associated with a higher ratio of claims. A multiple regression model with two factors: socioeconomic disadvantage and the proportion of GP members in practices of five or more GPs predicted 41% of the variance. Divisions of general practice appear to be supporting practices serving disadvantaged populations to deliver quality care for patients with chronic disease. The association with practice size and DGP activities suggests that practice organisation and systems are important in the provision of good care for patients with chronic disease.


Is laparoscopic colorectal cancer surgery equal to open surgery? An evidence based perspective.
Laparoscopic colorectal surgery (LCS) is an evolving subject. Recent studies show that LCS can not only offer safe surgery but evidence is growing that this new technique can be superior to classical open procedures. Fewer perioperative complications and faster postoperative recovery are regularly mentioned when studies of LCS are presented. Even though the learning curve of LCS is frequently debated when limitations of laparoscopic surgeries are reviewed, studies show that in experienced hands LCS can be a safe procedure for colorectal cancer treatment. The learning curve however, is associated with high conversion rates and economical aspects such as higher costs and prolonged hospital stay. Nevertheless, laparoscopic colorectal cancer surgery (LCCR) offers several advantages such as less co-morbidity and less postoperative pain in comparison with open procedures. Furthermore, the good exposure of the pelvic cavity by laparoscopy and the magnification of anatomical structures seem to facilitate pelvic dissection laparoscopically. Moreover, recent studies describe no difference in safety and oncological radicalness in LCCR compared to the open total mesorectal excision (TME). The oncological adequacy of LCCR still remains unproven today, because long-term results do not yet exist. To date, only a few studies have described the results of laparoscopic TME combined with preoperative adjuvant treatment for colorectal cancer. The aim of this review is to examine the various areas of development andcontroversy of LCCR in comparison to the conventional open approach.