Satisfaction of General Practice Trainees with the Teaching Skills of Trainers: An Exploratory and Regional Study.
In Portugal, requirements for selection and training of General Practice trainers vary across the different regions of the country. The aim of our study was to assess the satisfaction of general practice trainees with their trainers of the Lisbon and Tagus Valley Regional Health Administration. General Practice trainees were the target population for our cross-sectional, exploratory study. The authors developed a 16-item questionnaire based on the existing literature. The questions covered the following domains: patient safety, learning environment, trainer's feedback, the trainee/trainer relationship, assessment of educational progress and continuous professional development of trainers. Items were scored on a 5-point Likert-type scale. Data was collected at a meeting in October 2018 attended by General Practice trainees. A total of 384 questionnaires were distributed, with a response rate of 59.9%. The majority of respondents were female (79.9%) and all years of specialty training were represented. Our study shows that 60.4% of General Practice trainees from the Lisbon and Tagus Valley Regional Health Administration are very satisfied with the teaching skills of their trainers. However, there was lower satisfaction with trainer's continuous professional development, trainer's feedback, and monitoring of educational progress. The majority (57.4%) of respondents did not give feedback to their supervisors about their teaching performance, mostly because they do not feel comfortable doing so or because they have not considered this. The findings show a high degree of satisfaction of the general practice trainees with their trainers of the Lisbon and Tagus Valley Regional Health Administration. The high response rate attained is one of the strengths of the study. The authors make some suggestions for improvement of domains with lower satisfaction levels. Unfortunately, it is difficult to extrapolate the findings nationwide due to the differences between the training programmes of the different regions. Although there is a high level of satisfaction, there is still potential for improvement, including the expansion of training programmes for trainers.


A Genome-Wide Association Study into the Aetiology of Congenital Solitary Functioning Kidney.
Congenital solitary functioning kidney (CSFK) is a birth defect that occurs in 1:1500 children and predisposes them to kidney injury. Its aetiology is likely multifactorial. In addition to known monogenic causes and environmental risk factors, common genetic variation may contribute to susceptibility to CSFK. We performed a genome-wide association study among 452 patients with CSFK and two control groups of 669 healthy children and 5363 unaffected adults. Variants in two loci reached the genome-wide significance threshold of 5 × 10-8, and variants in 30 loci reached the suggestive significance threshold of 1 × 10-5. Of these, an identified locus with lead single nucleotide variant (SNV) rs140804918 (odds ratio 3.1, p-value = 1.4 × 10-8) on chromosome 7 was most promising due to its close proximity to HGF, a gene known to be involved in kidney development. Based on their known molecular functions, both KCTD20 and STK38 could explain the suggestive significant association with lead SNV rs148413365 on chromosome 6. Our findings need replication in an independent cohort of CSFK patients before they can be established definitively. However, our analysis suggests that common variants play a role in CSFK aetiology. Future research could enhance our understanding of the molecular mechanisms involved.


An evaluation of the completeness of safety reporting in reports of complementary and alternative medicine trials.
Adequate reporting of safety in publications of randomized controlled trials (RCTs) is a pre-requisite for accurate and comprehensive profile evaluation of conventional as well as complementary and alternative medicine (CAM) treatments. Clear and concise information on the definition, frequency, and severity of adverse events (AEs) is necessary for assessing the benefit-harm ratio of any intervention. The objectives of this study are to assess the quality of safety reporting in CAM RCTs; to explore the influence of different trial characteristics on the quality of safety reporting. Survey of safety reporting in RCTs published in 2009 across 15 widely used CAM interventions identified from the Cochrane Collaboration's CAM Field specialized register of trials. Primary outcome measures, the adequacy of reporting of AEs; was defined and categorized according to the CONSORT for harms extension; the percentage of words devoted to the reporting of safety in the entire report and in the results section. Two-hundred and five trials were included in the review. Of these, 15% (31/205) reported that no harms were observed during the trial period. Of the remaining 174 trials reporting any safety information, only 21% (36/174) had adequate safety reporting.For all trials, the median percentage of words devoted to the reporting of safety in the results section was 2.6. Moreover, 69% (n = 141) of all trials devoted a lesser or equal percentage of words to safety compared to author affiliations. Of the predictor variables used in regression analysis, multicenter trials had more words devoted to safety in the results section than single centre trials (P = 0.045). An evaluation of safety reporting in the reports of CAM RCTs across 15 different CAM interventions demonstrated that the reporting of harms was largely inadequate. The quality of reporting safety information in primary reports of CAM randomized trials requires improvement.


Intracellular fluorescent staining with carboxyfluorescein: a rapid and reliable method for quantifying dye-coupling in mammalian central nervous system.
Previous studies investigating electrotonic coupling in mammalian central nervous system have used the fluorescent marker Lucifer Yellow as an indicator of the presence of intercellular junctions between neurons. The fluorescent dye 5,6-carboxyfluorescein is known to have approximately 5 times the fluorescent yield of Lucifer Yellow. We have investigated the use of this dye as a potential alternative fluorescent marker on two types of neurons in the rat hippocampus in vitro. Unfixed hippocampal slices were mounted in a mixture of n-propyl gallate in glycerol and viewed with epifluorescence optics. Injections of small, brief hyperpolarizing currents through carboxyfluorescein-filled glass pipettes reliably produced neuronal fills of good quality. Both dendritic spines and axonal arborizations (including the thin mossy fibers of the dentate gyrus) were frequently observable. In addition to single cell fills, clusters consisting of 2-6 neurons were observed. No correlation was found between the number of cells per cluster and the ejection time. In addition, even cells exhibiting poor electrophysiological characteristics, or cells impaled only briefly, frequently exhibited good quality dye filling. This method will be particularly useful when large sample sizes are necessary to compare regional variations in the extent of electrotonic coupling in the mammalian brain.


Bright light therapy for sleep problems in adults aged 60+.
The prevalence of sleep problems in adulthood increases with age. While not all sleep changes are pathological in later life, severe disturbances may lead to depression, cognitive impairments, deterioration of quality of life, significant stresses for carers and increased healthcare costs. The most common treatment for sleep disorders (particularly insomnia) is pharmacological. The efficacy of non-drug interventions has been suggested to be slower than pharmacological methods, but with no risk of drug-related tolerance or dependency. Bright light treatment involves participants sitting in front of a "light box" which emits very high (typically 10,000 lux) fluorescent light for periods of around two hours daily. The timing of this light treatment will depend on the irregular timing of the participant's sleep pattern. To assess the efficacy of bright light therapy in improving sleep quality (sleep timing in particular) amongst adults aged 60 and above. The following databases were searched: MEDLINE (1966 - January 2001); EMBASE (1980 - January 2001), CINAHL ( 1982 - January 2001; PsychINFO 1970 to 2001; The Cochrane Library (Issue 1, 2001); National Research Register (NRR [2001]). Bibliographies of existing reviews in the area, as well as of all trial reports obtained, were searched. Experts in the field were consulted. Randomised controlled trials of bright light therapy for primary sleep problems where 80% or more of participants were over 60. Participants must have been screened to exclude those with dementia and/or depression. Abstracts of studies identified in searches of electronic databases were read and assessed to determine whether they might meet the inclusion criteria. Reviewers found no trials on which to base conclusions for the effectiveness of this treatment. When the possible side-effects of standard treatment (hypnotics) are considered, there is a reasonable argument to be made for clinical use of non-pharmacological treatments. In view of the promising results of bright light therapy in other populations with problems of sleep timing, further research into their effectiveness with older adults would seem justifiable.


Independent and coordinated functions of replication protein A tandem high affinity single-stranded DNA binding domains.
The initial high affinity binding of single-stranded DNA (ssDNA) by replication protein A (RPA) is involved in the tandem domains in the central region of the RPA70 subunit (RPA70AB). However, it was not clear whether the two domains, RPA70A and RPA70B, bind DNA simultaneously or sequentially. Here, using primarily heteronuclear NMR complemented by fluorescence spectroscopy, we have analyzed the binding characteristics of the individual RPA70A and RPA70B domains and compared them with the intact RPA70AB. NMR chemical shift comparisons confirmed that RPA70A and RPA70B tumble independently in solution in the absence of ssDNA. NMR chemical shift perturbations showed that all ssDNA oligomers bind to the same sites as observed in the x-ray crystal structure of RPA70AB complexed to d(C)8. Titrations using a variety of 5'-mer ssDNA oligomers showed that RPA70A has a 5-10-fold higher affinity for ssDNA than RPA70B. Detailed analysis of ssDNA binding to RPA70A revealed that all DNA sequences interact in a similar mode. Fluorescence binding measurements with a variety of 8-10'-mer DNA sequences showed that RPA70AB interacts with DNA with approximately 100-fold higher affinity than the isolated domains. Calculation of the theoretical "linkage effect" from the structure of RPA70AB suggests that the high overall affinity for ssDNA is a byproduct of the covalent attachment of the two domains via a short flexible tether, which increases the effective local concentration. Taken together, our data are consistent with a sequential model of DNA binding by RPA according to which RPA70A binds the majority of DNA first and subsequent loading of RPA70B domain is facilitated by the linkage effect.


Recent advances in understanding the role of glucagon-like peptide 1.
The discovery that glucagon-like peptide 1 (GLP-1) mediates a significant proportion of the incretin effect during the postprandial period and the subsequent observation that GLP-1 bioactivity is retained in type 2 diabetes (T2D) led to new therapeutic strategies being developed for T2D treatment based on GLP-1 action. Although owing to its short half-life exogenous GLP-1 has no use therapeutically, GLP-1 mimetics, which have a much longer half-life than native GLP-1, have proven to be effective for T2D treatment since they prolong the incretin effect in patients. These GLP-1 mimetics are a desirable therapeutic option for T2D since they do not provoke hypoglycaemia or weight gain and have simple modes of administration and monitoring. Additionally, over more recent years, GLP-1 action has been found to mediate systemic physiological beneficial effects and this has high clinical relevance due to the post-diagnosis complications of T2D. Indeed, recent studies have found that certain GLP-1 analogue therapies improve the cardiovascular outcomes for people with diabetes. Furthermore, GLP-1-based therapies may enable new therapeutic strategies for diseases that can also arise independently of the clinical manifestation of T2D, such as dementia and Parkinson's disease. GLP-1 functions by binding to its receptor (GLP-1R), which expresses mainly in pancreatic islet beta cells. A better understanding of the mechanisms and signalling pathways by which acute and chronic GLP-1R activation alleviates disease phenotypes and induces desirable physiological responses during healthy conditions will likely lead to the development of new therapeutic GLP-1 mimetic-based therapies, which improve prognosis to a greater extent than current therapies for an array of diseases.


Genipin Delays Corneal Stromal Enzymatic Digestion.
To evaluate the use of genipin in delaying enzymatic digestion of corneal stroma. Human corneal stromal tissue was treated with genipin, a known chemical crosslinker, and then along with control tissue was subjected to enzymatic digestion with collagenase. The effects of genipin treatment in retarding stromal digestion were analyzed with phase contrast microscopy, a protein quantification assay, second harmonic generation imaging, and transmission electron microscopy. Genipin increased stromal resistance to enzymatic digestion when compared with untreated stroma. A morphologic analysis and protein quantification showed increased stromal resistance to enzymatic digestion once stromal tissue was treated with genipin. Second harmonic generation imaging revealed persistent fibrillar collagen signaling in genipin-treated tissue in contrast with untreated tissue suggesting that genipin retards collagenolysis. Genipin increases stromal resistance to enzymatic digestion in controlled experiments as demonstrated by protein quantification studies and through morphologic imaging. This study explores the novel use of genipin in delaying enzymatic stromal digestion. Delaying stromal melting in the setting of corneal infectious or autoimmune keratitis can potentially decrease clinical morbidity.


Partial left ventriculectomy (Batista procedure) in the treatment of dilated cardiomyopathy: Makati Medical Center Philippine experience.
In the Philippines patients with end-stage heart disease refractory to conventional medical and surgical treatment do not have alternative choices. More than 99% of the population cannot afford cardiac transplantation. Partial left ventriculectomy (PLV) is a surgical procedure that improves cardiac function and refractory congestive heart failure (CHF). Between October 1997 and February 1998 eight patients had PLV at the Makati Medical Center, Philippines. All patients had end-stage dilated cardiomyopathy. Six patients had an idiopathic etiology, one was ischemic and one valvular. Seven of eight operations were done with the heart beating and all had transesophageal echo monitoring. An average of a 2-cm reduction in the left ventricle diameter was achieved and ejection fraction improved in all cases. There were no operative deaths. There were three late deaths. Two patients died of refractory CHF and ventricular arrhythmias and one patient died of massive cerebral hemorrhage with coumadin therapy. The five survivors are all doing well with no CHF. Follow-up two-dimensional echo shows stable left ventricular (LV) size and improved ejection fraction. Our initial experience shows that PLV, at least in the short-term, has beneficial effects in the treatment of end-stage dilated cardiomyopathy and might become an alternative to cardiac transplantation.


Production of heterologous antibodies specific for murine B-cell leukemia (BCL1) immunoglobulin by immunization with synthetic peptides homologous to heavy chain hypervariable regions.
Three peptides homologous to each heavy chain hypervariable region expressed by murine B-cell leukemia, BCL1, were synthesized in vitro by solid phase peptide synthesis. All three synthetic peptides elicited responses in rabbits which were immunized with synthetic peptide or synthetic peptide conjugated to the carrier keyhole limpet hemocyanin. Six individual rabbits were immunized, five of which responded by producing antisera which react specifically in radioimmunoassay with the synthetic peptide used as immunogen. One antiserum has specificity for the peptide homologous to the first hypervariable region, three antisera have specificity for the peptide homologous to the second hypervariable region, and one has specificity for the peptide homologous to the third hypervariable region. The five antisera with high titers of antibody recognizing synthetic peptide also specifically recognize native immunoglobulin M secreted by BCL1 tumor cells as demonstrated by immunoprecipitation followed by sodium dodecyl sulfate: polyacrylamide gel electrophoresis and autoradiography. These five antisera do not show reactivity with immunoglobulin secreted by spleen cells from normal BALB/cAn mice or by B-cells from unrelated tumors and cell lines. However, as determined by absorption experiments, the majority of antibodies in each antiserum are directed against the respective synthetic peptide, and only a small portion are reactive with native immunoglobulin M. Nonetheless, these results indicate use of synthetic peptides as a potential alternative source of immunogen for production of antitumor antibody.


Metastatic cancer stem cells: new molecular targets for cancer therapy.
The cancer stem cell (CSC) hypothesis, predicts that a small subpopulation of cancer cells that possess "stem-like" characteristics, are responsible for initiating and maintaining cancer growth. According to the CSC model the many cell populations found in a tumour might represent diverse stages of differentiation. From the cellular point of view metastasis is considered a highly inefficient process and only a subset of tumour cells is capable of successfully traversing the entire metastatic cascade and eventually re-initiates tumour growth at distant sites. Some similar features of both normal and malignant stem cells suggest that CSCs are not only responsible for tumorigenesis, but also for metastases. The CSC theory proposes that the ability of a tumour to metastasize is an inherent property of a subset of CSCs. The similar biological characteristics shared by normal stem cells (NSCs) and CSCs mainly implicate self-renewal and differentiation potential, survival ability, niche-specific microenvironment requirements and specific homing to metastatic sites and may have important implications in terms of new approaches to cancer therapy in the metastatic setting. There are several agents targeting many of these CSC features that have shown to be effective both in vitro and in vivo. Although clinical trials results are still preliminary and continue under investigation, these new therapies are very promising. The identification of new therapeutic targets and drugs based on CSC model constitutes a great challenge.


Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature.
We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ.


Oral hyperpigmentation as an adverse effect of highly active antiretroviral therapy in HIV patients: A systematic review and pooled prevalence.
Human Immunodeficiency Virus (HIV) infects patients via CD4+ cells which are later be destroyed subsequently causing the deteriotation of immune system. HIV generally manifests in the oral cavity as the first indicating sign and a marker of disease progression. HAART medications are used to reduce the incidence of oral manifestations, however it can also generate adverse effects in the oral cavity including oral hyperpigmentation. This review aimed to estimate the prevalence of oral hyperpigmentation which affect individual quality of life as a side effect of HAART. This systematic review applied Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020. Literature search was performed in ScienceDirect, PubMed, and Scopus by combining terms such as highly active antiretroviral therapy, oral manifestation, epidemiology or prevalence published between January 1998 to March 2022. Of 108 articles, eleven articles were included for systematic review and meta-analysis. The pooled prevalence of oral hyperpigmentation in HAART patients was 25% (95% CI: 11%, 38%; I2: 99%). Subgroup analysis based on geographical location showed varied result may be due to the type and duration of HAART used in study population. The most widely used type of ARV was from the NRTI group (n=7) and the study with the shortest duration showed the lowest oral hyperpigmentation prevalence (n=7). There is an increased prevalence of oral hyperpigmentation by the use of HAART. Future study should investigate the correlation between HAART duration and the degree of oral hyperpigmentation. Key words:HAART, oral hyperpigmentation; pooled prevalence.


Identification of the neural component of torque during manually-applied spasticity assessments in children with cerebral palsy.
Clinical assessment of spasticity is compromised by the difficulty to distinguish neural from non-neural components of increased joint torque. Quantifying the contributions of each of these components is crucial to optimize the selection of anti-spasticity treatments such as botulinum toxin (BTX). The aim of this study was to compare different biomechanical parameters that quantify the neural contribution to ankle joint torque measured during manually-applied passive stretches to the gastrocsoleus in children with spastic cerebral palsy (CP). The gastrocsoleus of 53 children with CP (10.9 ± 3.7 y; females n = 14; bilateral/unilateral involvement n = 28/25; Gross Motor Functional Classification Score I-IV) and 10 age-matched typically developing (TD) children were assessed using a manually-applied, instrumented spasticity assessment. Joint angle characteristics, root mean square electromyography and joint torque were simultaneously recorded during passive stretches at increasing velocities. From the CP cohort, 10 muscles were re-assessed for between-session reliability and 19 muscles were re-assessed 6 weeks post-BTX. A parameter related to mechanical work, containing both neural and non-neural components, was compared to newly developed parameters that were based on the modeling of passive stiffness and viscosity. The difference between modeled and measured response provided a quantification of the neural component. Both types of parameters were reliable (ICC > 0.95) and distinguished TD from spastic muscles (p < 0.001). However, only the newly developed parameters significantly decreased post-BTX (p = 0.012). Identifying the neural and non-neural contributions to increased joint torque allows for the development of individually tailored tone management.


Oral Desogestrel as Endometrial Preparation before Operative Hysteroscopy: A Systematic Review.
The pharmacologic preparation of the endometrium before hysteroscopy may be achieved with the use of various drugs. This systematic review aims to summarize the available evidence regarding the use of desogestrel for endometrial preparation before hysteroscopic procedures. A literature search for suitable articles published in English language from inception of the database until August 2019 was performed using the following databases: PubMed/MEDLINE, EMBASE, the Cochrane Library, and Google Scholar. All original articles concerning desogestrel-only pretreatment before hysteroscopic surgery were considered eligible. Reviews, case reports/series, conference papers, studies including the use of combined hormonal preparation, and articles in languages other than English were excluded from the analysis. The literature search retrieved 3 studies that met all the inclusion criteria. The data demonstrated that desogestrel may be considered as a hormonal pretreatment drug before hysteroscopic procedures. The drug was distinctly effective and assessed as helpful by the operating surgeon in numerous patients who were administered the pretreatment of 75 μg daily. Oral desogestrel is a cheap, easily available, safe, and quite efficient alternative for endometrial preparation before hysteroscopic procedures.


In vivo effect of polymyxin B on pertussis vaccine.
Pertussis vaccine contains lipopolysaccharide (endotoxin). Polymyxin B sulfate neutralizes endotoxin activity in vivo and in vitro from Enterobacteriaceae and Salmonella-derived endotoxin. In vitro, polymyxin B eliminates the endotoxin reaction of pertussis vaccine in the Limulus lysate test. In this study, platelet and WBC counts and antibody response were compared in rabbits given either pertussis vaccine alone or pertussis vaccine and polymyxin B intravenously. Pertussis vaccine-induced leukopenia and thrombocytopenia were eliminated in the polymyxin B group. The antibody titers in the animals receiving pertussis vaccine and polymyxin B were somewhat lower and rose more slowly. Since the toxicity of pertussis vaccine is related in part to endotoxin, we suggest that a clinical study using a combination of the vaccine with an endotoxin-neutralizing agent be done to assess both amelioration of side effects caused by the vaccine and any effect on immunogenesis.


Methemoglobinemia: an unusual complication of topical anesthesia.
Allergic reactions tend to be easily recognized and treated, but methemoglobinemia is a rare, life-threatening complication of topical anesthesia of which our staff was unaware until recently. Team work prevented a patient fatality. Directives to alert the staff to suspect methemoglobinemia in patients who develop cyanosis and decreased oxygen saturation levels after administration of topical anesthesia despite administration of oxygen will prevent fatalities in the future.


Progressive resistance training prevents loss of muscle mass and strength in bile duct-ligated rats.
Loss of muscle mass and strength is common in cirrhosis and increases the risk of hyperammonaemia and hepatic encephalopathy. Resistance training optimizes muscle mass and strength in several chronic diseases. However, the beneficial effects of resistance training in cirrhosis remain to be investigated. Bile duct-ligated (BDL) rats develop chronic liver disease, hyperammonaemia, reduced muscle mass and strength. Our aim was to test the effects of resistance training on muscle mass, function and ammonia metabolism in BDL-rats. A group of BDL-rats underwent a progressive resistance training programme and a group of non-exercise BDL-rats served as controls. Resistance training comprised of ladder climbing with a progressive increase in carrying weights attached to the tail. Training was performed 5 days a week during 4 weeks. Muscle strength and body composition were assessed using grip strength and EchoMRI. Weight and circumference of the gastrocnemius muscle (normalized to bodyweight), plasma ammonia and glutamine synthetase protein expression and activity were assessed. BDL + exercise rats had significantly larger gastrocnemius circumference compared to non-exercise BDL-rats: ratio 0.082 vs 0.075 (P < 0.05). Gastrocnemius muscle weight was higher in exercisers than controls: 0.006 vs 0.005 (P < 0.05). A tendency towards a lower plasma ammonia in the exercise group compared to controls was observed (P = 0.10). There were no differences in lean body mass, GS protein expression and activity between the groups. Resistance training in rats with chronic liver disease beneficially effects muscle mass and strength. The effects were followed by non-significant reduction in blood ammonia; however, a tendency was observed.


Best practice nursing care for ICU patients with incontinence-associated dermatitis and skin complications resulting from faecal incontinence and diarrhoea.
Incontinence-associated dermatitis (IAD), resulting from diarrhoea and/or faecal incontinence, is a common problem in intensive care, occurring in 7-50% of the patients, with an estimated 10 million dollars spent annually on continence skin care. This project aimed to evaluate and improve the staff knowledge on IAD and also improve practice in the identification, prevention and treatment of IAD in the ICU. A pre/post-audit framework was used to implement the best practice recommendations between August 2013 and March 2014. Nursing staff were surveyed and a chart review was conducted to audit baselines of knowledge and nursing practice regarding IAD. Education and product standardization were used to implement the best practice recommendations and a post-audit was conducted to evaluate changes in knowledge and practice. Thirty-one (pre-implementation) and 27 (post-implementation) nurses were surveyed to evaluate knowledge on IAD identification, care and documentation practices. No IAD policy or IAD-specific skin assessment tool for use existed in the ICU. After implementation, there was a 40% increase in the ability of the staff to distinguish between IAD and pressure injuries, an increase from 87% to 100% in the use of skin-protectant and an improvement from 25 to 66% in the correct application of skin-protectants. An encouraging 70% of the nurses were using a single standard skin-protectant after implementation as opposed to audit 1, where 100% of the nurses were using multiple products before implementation. There was a 16% increase in the staff surveyed post-audit who said they reported on the perineal skin in patients with IAD. However, IAD documentation in both audit 1 and audit 2, as evidenced by chart review, remained poor. The project had created an awareness of IAD in the ICU. There was clear knowledge improvement and nursing staff were able to differentiate IAD from pressure injuries. The skin cleansing and protection regime is now more clear and consistent, and a single standardized product is being used to prevent and treat IAD. There was a small improvement in consistently documenting the condition of the perineal skin of patients with IAD; however, it was beyond the scope of this project to develop a policy and implement an IAD-specific skin assessment tool in the ICU, as this would have improved documentation of IAD in the ICU.


Potential of (99m)Tc-MIBI for detecting bone marrow metastases.
In this study, we evaluated the potential of (99m)Tc-hexakis-2-methoxyisobutylisonitrile (MIBI) for detecting bone metastases in comparison with a conventional bone tracer. (99m)Tc-MIBI and (99m)Tc-hydroxymethylene diphosphonate (HMDP) scans were obtained from 99 patients with proven malignant diseases and suspected bone metastases. We compared 373 lesions that showed abnormal uptake on (99m)Tc-MIBI scans or (99m)Tc-HMDP scans (or both). Bone metastases were confirmed in 334 of 373 lesions. Thirty-nine lesions on (99m)Tc-HMDP scans had false-positive findings, but only 2 of these lesions had false-positive findings on (99m)Tc-MIBI scans. (99m)Tc-MIBI and (99m)Tc-HMDP scans were equivalent in 168 of 334 lesions (50.3%). (99m)Tc-MIBI scans correctly detected more lesions than (99m)Tc-HMDP scans: 284 lesions (85.0%) versus 218 lesions (65.3%) (P < 0.005), respectively. (99m)Tc-MIBI scans showed a markedly higher sensitivity for detecting metastases in the femur and humerus compared with (99m)Tc-HMDP scans: 97 of 98 lesions (99.0%) versus 35 of 98 lesions (35.7%) (P < 0.005) and 21 of 22 lesions (95.5%) versus 11 of 22 lesions (50.0%) (P < 0.005), respectively. (99m)Tc-HMDP scans of 17 patients showed no abnormal images. However, (99m)Tc-MIBI scans correctly detected bone metastases, and subsequent development of multiple lesions was observed on follow-up (99m)Tc-HMDP scans of 15 patients. (99m)Tc-MIBI scans were superior to (99m)Tc-HMDP scans in the detection of metastases attributed to breast cancer, multiple myeloma, and hepatoma. On the contrary, (99m)Tc-MIBI scans were less sensitive than (99m)Tc-HMDP scans for detecting bone metastases attributed to prostate cancer in the other skeletal sites except for femur and humerus. (99m)Tc-MIBI scans have better sensitivity for detecting bone metastases and provide more specific complementary findings than conventional bone scans. (99m)Tc-MIBI accumulation attributed to bone marrow metastases may occur at an early stage, before the bone remodeling process in the surrounding bone can be detected on conventional bone scans.


[Surgical aspects of periodic disease abdominal paroxysms].
Thorough investigation of abdomenalgia symptoms in 220 patients allowed to reveal a number of peculiarities of the periodic disease (PD) promoting the correct diagnosis. The case history data, pain localization, fever and great potentialities of diagnostic laparoscopy carried on during the acute paroxysm of the abdominal form of PD are of great significance. The differential diagnosis of PD acute paroxysm and urgent pathology of the organs of the abdominal cavity are considered by the author to be possible when using diagnostic laparoscopy in difficult situations.


A SNP associated with alternative splicing of RPT5b causes unequal redundancy between RPT5a and RPT5b among Arabidopsis thaliana natural variation.
The proteasome subunit RPT5, which is essential for gametophyte development, is encoded by two genes in Arabidopsis thaliana; RPT5a and RPT5b. We showed previously that RPT5a and RPT5b are fully redundant in the Columbia (Col-0) accession, whereas in the Wassilewskia accession (Ws-4), RPT5b does not complement the effect of a strong rpt5a mutation in the male gametophyte, and only partially complements rpt5a mutation in the sporophyte. RPT5bCol-0 and RPT5bWs-4 differ by only two SNPs, one located in the promoter and the other in the seventh intron of the gene. By exploiting natural variation at RPT5b we determined that the SNP located in RPT5b intron seven, rather than the promoter SNP, is the sole basis of this lack of redundancy. In Ws-4 this SNP is predicted to create a new splicing branchpoint sequence that induces a partial mis-splicing of the pre-mRNA, leading to the introduction of a Premature Termination Codon. We characterized 5 accessions carrying this A-to-T substitution in intron seven and observed a complete correlation between this SNP and both a 10 to 20% level of the RPT5b pre-mRNA mis-splicing and the lack of ability to complement an rpt5a mutant phenotype. The accession-dependent unequal redundancy between RPT5a and RPT5b genes illustrates an example of evolutionary drifting between duplicated genes through alternative splicing.


Turpentine-induced inflammation reduces the hepatic expression of the multiple drug resistance gene, the plasma cholesterol concentration and the development of atherosclerosis in apolipoprotein E deficient mice.
We aimed to investigate the effect of turpentine-induced inflammation in an atherosclerosis-prone murine model. We have induced a chronic aseptic inflammation in apolipoprotein E-deficient mice, with or without a dietary supplement of aspirin (n = 10, each), by the injection of a mixture (1:1) of turpentine and olive oil in the hind limb twice weekly for a period of 12 weeks. Control animals were injected with olive oil alone (n = 10). The control mice did show any alteration neither in plasma nor at the site of injection. Turpentine-treated mice showed a significant increase in plasma TNF-alpha and SAA concentrations which indicated a systemic inflammatory response that was not substantially affected by aspirin. Also, turpentine injections significantly reduced the plasma cholesterol concentration, probably decreasing intestinal cholesterol re-absorption, and attenuated the size of atherosclerotic lesion. Both effects were minimally influenced by aspirin. The burden of atherosclerosis correlated with plasma lipid levels but not with plasma inflammatory markers. Finally, there was a concomitant decrease in the expression of the hepatic mdr1b gene that correlated with the decrease in plasma cholesterol concentration. Therefore, we conclude that mdr1 is an additional factor to consider in the complexity of alterations in cholesterol metabolism that occur in this model.


Periconception HIV Risk Behavior Among Men and Women Reporting HIV-Serodiscordant Partners in KwaZulu-Natal, South Africa.
HIV-infected men and women who choose to conceive risk infecting their partners. To inform safer conception programs we surveyed HIV risk behavior prior to recent pregnancy amongst South African, HIV-infected women (N = 209) and men (N = 82) recruited from antenatal and antiretroviral clinics, respectively, and reporting an uninfected or unknown-HIV-serostatus pregnancy partner. All participants knew their HIV-positive serostatus prior to the referent pregnancy. Only 11 % of women and 5 % of men had planned the pregnancy; 40 % of women and 27 % of men reported serostatus disclosure to their partner before conception. Knowledge of safer conception strategies was low. Around two-thirds reported consistent condom use, 41 % of women and 88 % of men reported antiretroviral therapy, and a third of women reported male partner circumcision prior to the referent pregnancy. Seven women (3 %) and two men (2 %) reported limiting sex without condoms to peak fertility. None reported sperm washing or manual insemination. Safer conception behaviors including HIV-serostatus disclosure, condom use, and ART at the time of conception were not associated with desired pregnancy. In light of low pregnancy planning and HIV-serostatus disclosure, interventions to improve understandings of serodiscordance and motivate mutual HIV-serostatus disclosure and pregnancy planning are necessary first steps before couples or individuals can implement specific safer conception strategies.


A cytotoxic type III secretion effector of Vibrio parahaemolyticus targets vacuolar H+-ATPase subunit c and ruptures host cell lysosomes.
Vibrio parahaemolyticus is one of the human pathogenic vibrios. During the infection of mammalian cells, this pathogen exhibits cytotoxicity that is dependent on its type III secretion system (T3SS1). VepA, an effector protein secreted via the T3SS1, plays a major role in the T3SS1-dependent cytotoxicity of V. parahaemolyticus. However, the mechanism by which VepA is involved in T3SS1-dependent cytotoxicity is unknown. Here, we found that protein transfection of VepA into HeLa cells resulted in cell death, indicating that VepA alone is cytotoxic. The ectopic expression of VepA in yeast Saccharomyces cerevisiae interferes with yeast growth, indicating that VepA is also toxic in yeast. A yeast genome-wide screen identified the yeast gene VMA3 as essential for the growth inhibition of yeast by VepA. Although VMA3 encodes subunit c of the vacuolar H(+)-ATPase (V-ATPase), the toxicity of VepA was independent of the function of V-ATPases. In HeLa cells, knockdown of V-ATPase subunit c decreased VepA-mediated cytotoxicity. We also demonstrated that VepA interacted with V-ATPase subunit c, whereas a carboxyl-terminally truncated mutant of VepA (VepAΔC), which does not show toxicity, did not. During infection, lysosomal contents leaked into the cytosol, revealing that lysosomal membrane permeabilization occurred prior to cell lysis. In a cell-free system, VepA was sufficient to induce the release of cathepsin D from isolated lysosomes. Therefore, our data suggest that the bacterial effector VepA targets subunit c of V-ATPase and induces the rupture of host cell lysosomes and subsequent cell death.


Whey peptides improve wound healing following caesarean section in rats.
We sought to determine whether postcaesarean treatment with whey peptides (WP) affects the healing of skin and uterine incision in rats during puerperium. Forty-eight rats were randomly divided into two groups. After a caesarean section, twenty-four rats were intragastrically administered WP, while others were administered a control vehicle. On days 7, 14 and 21 after delivery, the serum total protein/albumin concentration, skin tensile strength, uterine bursting pressure, skin/uterine hydroxyproline (Hyp) concentration and histological characteristics of the scar were measured in eight rats in each group. In the WP group, the albumin concentration, skin tensile strength, uterine bursting pressure and Hyp concentration in the skin increased significantly on days 21, 7, 14 and 21, respectively. Low neutrophil count and smaller scar width in the skin incision were found in the WP group on day 7. Postcaesarean treatment with WP promoted significant wound healing in the skin incision, and had a significant wound healing potential in the uterus.


[Adjunctive acne therapies--2010].
Modern acne therapy is based on the application of anticomedogenic, antimicrobial, or antiinflammatory substances, and antiandrogens. Additionally, traditional or newly developed therapeutic approaches may be considered, including pharmacologic (dapsone, zinc) and physical measures (phototherapy, photodynamic therapy, laser, comedone extraction, abrasives). This article reviews such adjunctive therapies with regard to efficacy and their roles in the therapy of acne.


Biological and Clinical Implications of Clonal Heterogeneity and Clonal Evolution in Multiple Myeloma.
Clonal heterogeneity and clonal evolution have emerged as critical concepts in the field of oncology over the past four decades, largely thanks to the implementation of novel technologies such as comparative genomic hybridization, whole genome/exome sequencing and epigenetic analysis. Along with the identification of cancer stem cells in the majority of neoplasia, the recognition of intertumor and intratumor variability has provided a novel perspective to understand the mechanisms behind tumor evolution and its implication in terms of treatment failure and cancer relapse or recurrence. First hypothesized over two decades ago, clonal heterogeneity and clonal evolution have been confirmed in multiple myeloma (MM), an incurable cancer of plasma cells, almost universally preceded by a pre-malignant conditioned named monoclonal gammopathy of undetermined significance (MGUS). The genetic events and molecular mechanisms underlying such evolution have been difficult to dissect. Moreover, while a role for the bone marrow microenvironment in supporting MM cell survival, proliferation and drug-resistance has been well established, whether it is directly involved in driving evolution from MGUS to MM is at present unclear. We present in this review a historical excursus on the concepts of clonal heterogeneity and clonal evolution in MM with a special emphasis on their role in the progression from MGUS to MM; the contribution of the microenvironment; and the clinical implications in terms of resistance to treatment and disease relapse/recurrence.


Effect of 2 mg Versus 4 mg of Intravenous Zoledronic Acid on Bone Mineral Density at the Lumbar Spine in Indian Postmenopausal Women with Osteoporosis: A Double-blind Parallel-arm Randomized Controlled Trial.
The primary purpose was to compare the effect of 2 mg and 4 mg of intravenous zoledronic acid (ZA) on change in the lumbar spine (LS) bone mineral density (BMD) at the end of 1 year in postmenopausal women with osteoporosis. The secondary objectives were changes in BMD at the total hip and femoral neck, change in bone turnover markers (BTMs), and the incidence of new fractures. This was a double-blind, parallel-arm, randomized control trial with an allocation ratio of 1:1 done in 70 postmenopausal women with osteoporosis. The mean (±standard deviation) percentage increase in LS BMD at the end of 1 year was 4.86% ± 3.05% and 5.35% ± 3.73% in the 2 mg and 4 mg group, respectively. The dose of 2 mg ZA proved to be inferior to 4 mg with a noninferiority margin of 0.5%. There was no difference in BMD change at hip and BTMs between the two groups at the end of 1 year. Only one patient in 4 mg group developed two new vertebral fractures during a 12-month follow-up. Acute-phase reactions were the most common (43%) side-effects noted without any difference between the two groups (P = 0.63). This study failed to show the noninferiority of 2 mg ZA compared to 4 mg ZA for change in LS BMD at the end of 1 year.


Treadmill training after spinal cord injury: it's not just about the walking.
Body weight-supported treadmill training (BWSTT) is being used throughout the world as a method for improving functional ambulation after spinal cord injury (SCI). This therapy, however, is very labor-intensive, and recent evidence suggests that it may not be superior to other more conventional forms of rehabilitation for improving locomotor ability. Recognizing that the value of BWSTT may extend well beyond its potential to improve functional ambulation is important, and the physiological and psychological benefits associated with this whole-body upright exercise may justify its use in both the acute and chronic SCI populations.


MgcRacGAP, a new human GTPase-activating protein for Rac and Cdc42 similar to Drosophila rotundRacGAP gene product, is expressed in male germ cells.
In a search for new partners of the activated form of Rac GTPase, we have isolated through a two-hybrid cloning procedure a human cDNA encoding a new GTPase-activating protein (GAP) for Rho family GTPases. A specific mRNA of 3.2 kilobases was detected in low abundance in many cell types and found highly expressed in testis. A protein of the predicted size 58 kDa, which we call MgcRacGAP, was detected in human testis as well as in germ cell tumor extracts by immunoblotting with antibodies specific to recombinant protein. In vitro, the GAP domain of MgcRacGAP strongly stimulates Rac1 and Cdc42 GTPase activity but is almost inactive on RhoA. N-terminal to its GAP domain, MgcRacGAP contains a cysteine-rich zinc finger-like motif characteristic of the Chimaerin family of RhoGAPs. The closest homolog of MgcRacGAP is RotundRacGAP, a product of the Drosophila rotund locus. In situ hybridization experiments in human testis demonstrate a specific expression of mgcRacGAP mRNA in spermatocytes similar to that of rotundRacGAP in Drosophila testis. Therefore, protein sequence similarity and analogous developmental and tissue specificities of gene expression support the hypothesis that RotundRacGAP and MgcRacGAP have equivalent functions in insect and mammalian germ cells. Since rotundRacGAP deletion leads to male sterility in the fruit fly, the mgcRacGAP gene may prove likewise to play a key role in mammalian male fertility.


Antiangiogenic and antitumor effects of Trypanosoma cruzi Calreticulin.
In Latin America, 18 million people are infected with Trypanosoma cruzi, the agent of Chagas' disease, with the greatest economic burden. Vertebrate calreticulins (CRT) are multifunctional, intra- and extracellular proteins. In the endoplasmic reticulum (ER) they bind calcium and act as chaperones. Since human CRT (HuCRT) is antiangiogenic and suppresses tumor growth, the presence of these functions in the parasite orthologue may have consequences in the host/parasite interaction. Previously, we have cloned and expressed T. cruzi calreticulin (TcCRT) and shown that TcCRT, translocated from the ER to the area of trypomastigote flagellum emergence, promotes infectivity, inactivates the complement system and inhibits angiogenesis in the chorioallantoid chicken egg membrane. Most likely, derived from these properties, TcCRT displays in vivo inhibitory effects against an experimental mammary tumor. TcCRT (or its N-terminal vasostatin-like domain, N-TcCRT) a) Abrogates capillary growth in the ex vivo rat aortic ring assay, b) Inhibits capillary morphogenesis in a human umbilical vein endothelial cell (HUVEC) assay, c) Inhibits migration and proliferation of HUVECs and the human endothelial cell line Eahy926. In these assays TcCRT was more effective, in molar terms, than HuCRT: d) In confocal microscopy, live HUVECs and EAhy926 cells, are recognized by FITC-TcCRT, followed by its internalization and accumulation around the host cell nuclei, a phenomenon that is abrogated by Fucoidin, a specific scavenger receptor ligand and, e) Inhibits in vivo the growth of the murine mammary TA3 MTXR tumor cell line. We describe herein antiangiogenic and antitumor properties of a parasite chaperone molecule, specifically TcCRT. Perhaps, by virtue of its capacity to inhibit angiogenesis (and the complement system), TcCRT is anti-inflammatory, thus impairing the antiparasite immune response. The TcCRT antiangiogenic effect could also explain, at least partially, the in vivo antitumor effects reported herein and the reports proposing antitumor properties for T. cruzi infection.


Persistence in fluctuating environments for interacting structured populations.
Individuals within any species exhibit differences in size, developmental state, or spatial location. These differences coupled with environmental fluctuations in demographic rates can have subtle effects on population persistence and species coexistence. To understand these effects, we provide a general theory for coexistence of structured, interacting species living in a stochastic environment. The theory is applicable to nonlinear, multi species matrix models with stochastically varying parameters. The theory relies on long-term growth rates of species corresponding to the dominant Lyapunov exponents of random matrix products. Our coexistence criterion requires that a convex combination of these long-term growth rates is positive with probability one whenever one or more species are at low density. When this condition holds, the community is stochastically persistent: the fraction of time that a species density goes below δ approaches zero as δ approaches zero. Applications to predator-prey interactions in an autocorrelated environment, a stochastic LPA model, and spatial lottery models are provided. These applications demonstrate that positive autocorrelations in temporal fluctuations can disrupt predator-prey coexistence, fluctuations in log-fecundity can facilitate persistence in structured populations, and long-lived, relatively sedentary competing populations are likely to coexist in spatially and temporally heterogeneous environments.


Relationship between tissue sensitization and IgE antibody production in rats infected with the nematode, Nippostrongylus brasiliensis.
In Nippostrongylus brasiliensis rats, tracheal sensitivity to worm allergens developed prior to intestinal sensitivity and correlated with the early local synthesis of reaginic antibody in the mediastinal (bronchial) lymph nodes. Skin and intestinal sensitivity to worm allergens more nearly correlated with serum reaginic antibody and its synthesis by mesenteric lymph nodes and other tissues. Prostaglandins appeared to modulate intestinal responsiveness to worm allergens. Thus, local reagin synthesis and other microenvironmental factors influence local tissue sensitization and responsiveness to allergens.


Gray matter volumetric abnormalities associated with the onset of psychosis.
Patients with psychosis display structural brain abnormalities in multiple brain regions. The disorder is characterized by a putative prodromal period called ultra-high-risk (UHR) status, which precedes the onset of full-blown psychotic symptoms. Recent studies on psychosis have focused on this period. Neuroimaging studies of UHR individuals for psychosis have revealed that the structural brain changes observed during the established phases of the disorder are already evident prior to the onset of the illness. Moreover, certain brain regions show extremely dynamic changes during the transition to psychosis. These neurobiological features may be used as prognostic and predictive biomarkers for psychosis. With advances in neuroimaging techniques, neuroimaging studies focusing on gray matter abnormalities provide new insights into the pathophysiology of psychosis, as well as new treatment strategies. Some of these novel approaches involve antioxidants administration, because it is suggested that this treatment may delay the progression of UHR to a full-blown psychosis and prevent progressive structural changes. The present review includes an update on the most recent developments in early intervention strategies for psychosis and potential therapeutic treatments for schizophrenia. First, we provide the basic knowledge of the brain regions associated with structural abnormalities in individuals at UHR. Next, we discuss the feasibility on the use of magnetic resonance imaging (MRI)-biomarkers in clinical practice. Then, we describe potential etiopathological mechanisms underlying structural brain abnormalities in prodromal psychosis. Finally, we discuss the potentials and limitations related to neuroimaging studies in individuals at UHR.


Incidence of hospital-acquired hyponatremia by the dose and type of diuretics among patients with acute heart failure and its association with long-term outcomes.
Diuretics are the cornerstone therapy for acute heart failure (AHF) but can lead to various electrolyte disturbances and inversely affect the patients' outcome. We aimed to evaluate whether (1) the dose of loop diuretics could predict hospital-acquired hyponatremia (HAH) during AHF treatment, (2) addition of thiazide diuretics could affect development of HAH, and (3) assess their impact on long-term outcomes. We analyzed the subjects enrolled in the multicenter AHF registry (WET-HF). Risk of HAH, defined as hyponatremia at discharge with normonatremia upon admission, was evaluated based on oral non-potassium-sparing diuretics via multivariate logistic regression analysis. Additionally, we performed one-to-one matched analysis based on propensity scores for thiazide diuretics use and compared long-term mortality. Of total 1163 patients (mean age 72.6±13.6 years, male 62.6%), 92 (7.9%) had HAH. Compared with low-dose loop diuretics users (<40mg; without thiazide diuretics), risks for developing HAH were significantly higher in patients with thiazide diuretics, regardless of the dose of loop diuretics (OR 2.67, 95% CI 1.13-6.34 and OR 2.31, 95% CI 1.50-5.13 for low- and high-dose loop diuretics, respectively). The association was less apparent in patients without thiazide diuretics (OR 1.29, 95% CI 0.73-2.27 for high-dose loop diuretics alone). Among 206 matched patients, all-cause and cardiac mortality rate was 27% and 14% in non thiazide diuretics users and 50% and 30% in thiazide diuretics users, respectively (HR 2.46, 95% CI 1.29-4.69, p=0.006 and HR 2.50, 95% CI 1.10-5.67, p=0.028, respectively) during a mean 19.3 months of follow-up. Thiazide diuretics use, rather than loop diuretics dose, was independently associated with HAH; and mortality was higher in thiazide diuretics users even after statistical matching.


Differential newborn DNA methylation among individuals with complex congenital heart defects and childhood lymphoma.
There is emerging evidence that children with complex congenital heart defects (CHDs) are at increased risk for childhood lymphoma, but the mechanisms underlying this association are unclear. Thus, we sought to evaluate the role of DNA methylation patterns on "CHD-lymphoma" associations. From >3 million live births (1988-2004) in California registry linkages, we obtained newborn dried bloodspots from eight children with CHD-lymphoma through the California BioBank. We performed case-control epigenome-wide association analyses (EWAS) using two comparison groups with reciprocal discovery and validation to identify differential methylation associated with CHD-lymphoma. After correction for multiple testing at the discovery and validation stages, individuals with CHD-lymphoma had differential newborn methylation at six sites relative to two comparison groups. Our top finding was significant in both EWAS and indicates PPFIA1 cg25574765 was hypomethylated among individuals with CHD-lymphoma (mean beta = 0.04) relative to both unaffected individuals (mean beta = 0.93, p = 1.5 × 10-12 ) and individuals with complex CHD (mean beta = 0.95, p = 3.8 × 10-8 ). PPFIA1 encodes a ubiquitously expressed liprin protein in one of the most commonly amplified regions in many cancers (11q13). Further, cg25574765 is a proposed marker of pre-eclampsia, a maternal CHD risk factor that has not been fully evaluated for lymphoma risk in offspring, and the tumor microenvironment that may drive immune cell malignancies. We identified associations between molecular changes present in the genome at birth and risk of childhood lymphoma among those with CHD. Our findings also highlight novel perinatal exposures that may underlie methylation changes in CHD predisposing to lymphoma.


Mental health outcomes among vulnerable residents after Hurricane Sandy: implications for disaster research and planning.
To evaluate mental health outcomes among New Jersey shore residents with health impairments and disabilities after Hurricane Sandy. Six months following Hurricane Sandy, a cross-sectional survey of 200 adults residing in beach communities directly exposed to the storm located in Monmouth County, NJ, was conducted. Post-traumatic stress disorder (PTSD), depression, mental health service use, and medication use. The average age of residents surveyed was 59 years (SD = 13.7) and 52.5 percent (95% CI = 45.5-59.4) reported recent hospitalizations, physical limitations, fair to poor health status, multiple chronic health conditions, or physical disabilities. A total of 14.5 percent (95% CI = 10.2-20.1) of residents screened positive for PTSD and 6.0 percent (95% CI = 3.1-10.2) met criteria for depression 6 months after Sandy. In addition, 20.5 percent (95% CI = 15.4-26.7) sought some type of professional counseling after Sandy and 30.5 percent (95% CI = 24.5-37.3) experienced PTSD symptoms, depression, sought professional mental health support, or used psychotropic medications. In multivariate analyses, the best predictors of mental health and service use were having sleep problems, suicidal thoughts, moderate or severe pain, and having high exposure hurricane-related events. Analyses also suggested that noncollege graduates were more likely to receive mental health services (OR = 3.10, p = 0.009), while women were less likely to have depression (OR = 0.12, p = 0.038). Having physical impairments and health conditions were not directly related to adverse mental health outcomes following Sandy, but having sleep problems, pain, or suicidal thoughts were. Further research is needed to assess the health status of community residents with serious health impairments over time following disasters.


Abdominal aortic aneurysm in a patient with low back pain.
Resident's case problem. The purpose of this report was to describe (1) the clinical reasoning that led a clinician to identify an abdominal aortic aneurysm (AAA) in a patient with low back pain requiring immediate medical referral, and (2) an evidence-based approach to clinical evaluation of patients with suspected AAA. The patient was unable to identify a specific mechanism of injury for his low back pain, lacked aggravating/easing factors for his symptoms, and complained of night pain and an inability to ease his symptoms with position changes. While the patient's symptoms remained unchanged during physical examination of the lumbar spine and hip, abdominal palpation revealed a strong, nontender pulsation over the midline of the upper and lower abdominal quadrants. Due to concern for an AAA, the patient was immediately referred to his physician. Subsequent computed tomography imaging revealed a prominent AAA, which measured up to 5.5 cm in greatest dimension and extended from below the renal arteries to the bifurcation of the iliac arteries. The patient initially deferred surgical intervention but eventually consented 6 months later, after repeat computed tomography imaging revealed that the AAA had progressed to 6.7 cm in greatest dimension. It is essential for physical therapists to be familiar with a diagnostic pathway to help identify AAA in patients presenting with apparent musculoskeletal complaints. Knowledge of the risk factors for AAA, understanding how to screen for nonmusculoskeletal symptoms, and a basic competence in abdominal palpation and how to interpret findings will help with the clinician's clinical decision making. Differential diagnosis, level 4. J Orthop Sports Phys Ther 2014;44(7):500-507. Epub 25 April 2014. doi:10.2519/jospt.2014.4935.


The TCDD receptor in rat intestinal mucosa and its possible dietary ligands.
Induction of aryl hydrocarbon hydroxylase (AHH) by polycyclic aromatic hydrocarbons and other inducers such as 2,3,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to occur following binding of the inducer to a soluble receptor protein similar to steroid hormone receptors. This receptor is usually called the TCDD receptor, since TCDD has the highest affinity of all known ligands for the receptor. In the present paper a receptor for TCDD in cytosol from rat intestinal mucosa has been studied, using isoelectric focusing in polyacrylamide gel. This receptor's biochemical properties were found to be similar to those of the TCDD-receptor in rat liver cytosol. The dissociation constant (Kd) of the 3H-TCDD-receptor complex in rat intestinal mucosa was 0.7-3.1 nM, and it was present at a concentration of 70-80 fmol/mg protein. Starvation did not significantly increase the receptor level. The affinities of some potential dietary ligands for the TCDD receptor in rat intestinal mucosa were also studied. Indole-3-carbinol had 1/2,600 of the affinity of TCDD for the receptor protein. Butylated hydroxyanisole (BHA), transstilbene oxide and quercetinpentamethylether competed even more weakly with 3H-TCDD for binding to the receptor. The biological significance of the occurrence of low-affinity ligands of dietary origin for the TCDD receptor is uncertain at the present time.


Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti-proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2.
AAA (abdominal aortic aneurysm) is an important cause of sudden death in older adults, but there is no current effective drug therapy for this disease. The UCNs (urocortins1-3) and their receptors: CRFR (corticotrophin-releasing factor receptor)-1 and -2 have been implicated in various CVDs (cardiovascular diseases). We assessed the relative expression of UCN1-3 in AAA by qRT-PCR (quantitative reverse transcription-PCR) and ELISA, and examined in vitro how UCN2 affects human aortic VSMC (vascular smooth muscle cell) Akt phosphorylation, pro-inflammatory cytokine IL (interleukin)-6 secretion, proliferation, cell cycle and apoptosis. UCN2 and CRFR2 expression were significantly up-regulated in biopsies from the AAA body. AAA body biopsies released high amounts of UCN2 in vitro. Median plasma UCN2 concentrations were 2.20 ng/ml (interquartile range 1.14-4.55 ng/ml, n=67) in AAA patients and 1.11 ng/ml (interquartile range 0.76-2.55 ng/ml, n=67) in patients with non-aneurysmal PAD (peripheral artery disease) (P=0.001). Patients with UCN2 in the highest quartile had a 4.12-fold (95% confidence interval, 1.37-12.40) greater prevalence of AAA independent of other risk factors, P=0.012. In vitro, UCN2 significantly inhibited VSMC Akt phosphorylation and proliferation in a dose-dependent manner. UCN2 induced VSMC G1 cell-cycle arrest and increased IL-6 secretion over 24 h. The CRFR2 antagonist astressin-2B significantly abrogated the effects of UCN2 on VSMCs. In conclusion, UCN2 is significantly associated with AAA and inhibits VSMC proliferation by inducing a G1 cell cycle arrest suggesting a plausible regulatory role in AAA pathogenesis.


A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity.
Excessive mitochondrial fission is associated with the pathology of a number of neurodegenerative diseases. Therefore, inhibitors of aberrant mitochondrial fission could provide important research tools in addition to potential leads for drug development. Using a rational approach, we designed a novel and selective peptide inhibitor, P110, of excessive mitochondrial fission. P110 inhibits Drp1 enzyme activity and blocks Drp1/Fis1 interaction in vitro and in cultured neurons, whereas it has no effect on the interaction between Drp1 and other mitochondrial adaptors, as demonstrated by co-immunoprecipitation. Furthermore, using a model of Parkinson's disease (PD) in culture, we demonstrated that P110 is neuroprotective by inhibiting mitochondrial fragmentation and reactive oxygen species (ROS) production and subsequently improving mitochondrial membrane potential and mitochondrial integrity. P110 increased neuronal cell viability by reducing apoptosis and autophagic cell death, and reduced neurite loss of primary dopaminergic neurons in this PD cell culture model. We also found that P110 treatment appears to have minimal effects on mitochondrial fission and cell viability under basal conditions. Finally, P110 required the presence of Drp1 to inhibit mitochondrial fission under oxidative stress conditions. Taken together, our findings suggest that P110, as a selective peptide inhibitor of Drp1, might be useful for the treatment of diseases in which excessive mitochondrial fission and mitochondrial dysfunction occur.


Use of low dose computed tomography with 3D reconstructions for the prenatal evaluation of suspected skeletal dysplasia.
Sonographic evaluation of congenital skeletal dysplasias is often challenging. Ultrasound may be limited in demonstrating the skeleton and may overlook specific signs of skeletal abnormality. Computed tomography (CT) with 3D reconstruction was proposed as an aid in the diagnosis of skeletal dysplasias. To describe our experience with 3D-CT imaging for the evaluation of suspected skeletal dysplasias. The study group comprised 20 pregnant women carrying 22 fetuses, referred for further evaluation by CT following sonographic suspicion of fetal skeletal dysplasia at 17-39 weeks of gestation. Examinations were performed using various CT protocols. Radiation exposure was decreased during the study period, with eventual lowering of the dose to 1-3 mSv. Meticulous review of the skeleton and long bone measurements were performed on 3D reconstructions. For cases of pregnancy termination, the postmortem diagnosis was compared retrospectively with the CT findings. Very low dose CT protocols provided excellent diagnostic images. Of 22 fetuses suspected of having skeletal dysplasia on ultrasound, 8 were found by CT to be dysplastic and in 7 the pregnancy was terminated. Postmortem findings, when available, concurred with the CT diagnosis. The remaining 14 fetuses within this cohort were found to be normal according to CT and were carried to term. 3D-CT may be a valuable complimentary imaging tool to ultrasound for the diagnosis of skeletal dysplasias. With low dose protocols, this examination is relatively safe, and in the appropriate clinical context may assist in making difficult decisions prenatally.


A systematic approach towards the development of a set of quality indicators for public reporting in community-based maternity care.
to demonstrate the process and outcome of a systematic approach towards the development of a set of quality indicators for public reporting on quality of community-based maternity care. a four-stepped approach was adopted. Firstly, we defined key elements of community-based maternity care, by performing a systematic search on care guidelines/ standards. Secondly, the literature was searched for existing indicators for maternity care, which were subsequently categorised according to the key elements and systematically selected on suitability of public presentation. The emerging set of indicators suitable for public reporting was presented to five health-care professionals using a Delphi technique (step 3). Based on the comments of the professionals, the set was adjusted and subsequently presented to the health-care consumers (a sample of pregnant women) in step four to test its validity, after which the final set was composed. health-care professionals in the field of maternity care and pregnant women. key elements of community-based maternity care were extracted from eight guidelines and care standards. We then extracted 10 documents with 223 indicators in total, from which 19 indicators covering the key elements were included in the first set and presented to experts. Based on their comments three indicators were deleted and four indicators were added to the set or slightly rephrased. These were subsequently judged by 13 pregnant women. Seventy-five per cent of the indicators were judged positively by them; no indicator was judged negatively. The set of indicators was thus left unchanged after this final step. KEY CONCLUSIONS AND IMPLICATIONS FOR CLINICAL PRACTICE: the systematic approach adopted in this study resulted in an indicator set that was considered valid by both maternity care professionals and pregnant women, and is likely to satisfy the essential requirements on clinimetric properties. The next step will be to pilot test the indicator set on feasibility in daily clinical practice and to refine the set when necessary. In the future, maternity care professionals may use the set to present the quality of care they provide and to define issues of improvement. Pregnant women may use the information to make a founded choice between maternity care professionals, which ultimately should result in improved safety and quality of maternity care as well as patient satisfaction. Although we focused on the Dutch, community-based maternity care system, the approach used may be extrapolated to other care processes and health-care systems. Extrapolation of the results itself (i.e. the indicator set) may need to be limited to systems with an emphasis on community-based maternity care.


Electronic health records and support for primary care teamwork.
Consensus that enhanced teamwork is necessary for efficient and effective primary care delivery is growing. We sought to identify how electronic health records (EHRs) facilitate and pose challenges to primary care teams as well as how practices are overcoming these challenges. Practices in this qualitative study were selected from those recognized as patient-centered medical homes via the National Committee for Quality Assurance 2011 tool, which included a section on practice teamwork. We interviewed 63 respondents, ranging from physicians to front-desk staff, from 27 primary care practices ranging in size, type, geography, and population size. EHRs were found to facilitate communication and task delegation in primary care teams through instant messaging, task management software, and the ability to create evidence-based templates for symptom-specific data collection from patients by medical assistants and nurses (which can offload work from physicians). Areas where respondents felt that electronic medical record EHR functionalities were weakest and posed challenges to teamwork included the lack of integrated care manager software and care plans in EHRs, poor practice registry functionality and interoperability, and inadequate ease of tracking patient data in the EHR over time. Practices developed solutions for some of the challenges they faced when attempting to use EHRs to support teamwork but wanted more permanent vendor and policy solutions for other challenges. EHR vendors in the United States need to work alongside practicing primary care teams to create more clinically useful EHRs that support dynamic care plans, integrated care management software, more functional and interoperable practice registries, and greater ease of data tracking over time.


Assessment of a bovine co-culture, scaffold-free method for growing meniscus-shaped constructs.
Using a self-assembly (SA), scaffoldless method, five high-density co-cultures with varied ratios of meniscal fibrochondrocytes (MFCs) and articular chondrocytes (ACs) were seeded into novel meniscus-specific, ring-shaped agarose wells. The following ratios of MFCs to ACs were used: 0% MFC, 25% MFC, 50% MFC, 75% MFC, and 100% MFC. Over 4 weeks, all ratios of cells self-assembled into three-dimensional constructs with varying mechanobiological and morphological properties. All groups stained for collagen II (Col II), and all groups except the 0% MFC group stained for collagen I (Col I). It was found that the tensile modulus was proportional to the percentage of MFCs employed. The 100% MFC group yielded the greatest mechanical stiffness with 432.2 +/- 47 kPa tensile modulus and an ultimate tensile strength of 23.7 +/- 2.4 kPa. On gross inspection, the 50% MFC constructs were the most similar to our idealized meniscus shape, our primary criterion. A second experiment was performed to examine the anisotropy of constructs as well as to directly compare the scaffoldless, SA method with a poly-glycolic acid (PGA) scaffold-based construct. When compared to PGA constructs, the SA groups were 2-4 times stiffer and stronger in tension. Further, at 8 weeks, SA groups exhibited circumferential fiber bundles similar to native tissue. When pulled in the circumferential direction, the SA group had significantly higher tensile modulus (226 +/- 76 kPa) than when pulled in the radial direction (67 +/- 32 kPa). The PGA constructs had neither a directional collagen fiber orientation nor differences in mechanical properties in the radial or circumferential direction. It is suggested that the geometric constraint imposed by the ring-shaped, nonadhesive mold guides collagen fibril directionality and, thus, alters mechanical properties. Co-culturing ACs and MFCs in this manner appears to be a promising new method for tissue engineering fibrocartilaginous tissues exhibiting a spectrum of mechanical and biomechanical properties.


Stability of serum total and free prostate specific antigen under varying storage intervals and temperatures.
Measurement of total serum prostate specific antigen (PSA) is widely used as an aid to early detection of prostate cancer. Measurement of the ratio of free-to-total PSA (percentage of free PSA) may help increase specificity of PSA testing. We prospectively studied the effects of varying the storage temperature and interval on total and free PSA levels. We measured the baseline total and free serum PSA levels in 36 volunteers (mean age 66 years) and then retested aliquots of these serum samples after varying storage intervals (24 hours, 2 weeks and 9 months) at 3 different temperatures (4C, -20C and -70C). Volunteers represented a spectrum of prostatic conditions (PSA levels 2.0 to 4.0 ng./ml., PSA levels greater than 4.0 ng./ml. without cancer and PSA levels greater than 2.0 ng./ml. with prostate cancer). We used repeated measures analysis of variance to test for changes in total and free PSA levels as a function of time and temperature. We also evaluated the impact of storage at different temperatures and times on the percentage of free PSA. Across groups total and free serum PSA decreased from the baseline level differentially as a function of longer storage interval and higher temperature (p <0.05). No significant difference was found for change in total PSA at 24 hours, 2 weeks or 9 months for storage temperatures of -20C compared with -70C. A significant change from baseline level was found for free PSA when stored in -20C compared with -70C for 2 weeks but the magnitude of the change was modest. For storage intervals up to 9 months total PSA is more stable than free PSA under temperature conditions ranging from 4C to -70C. This differential stability has important implications for the clinical evaluation of percentage of free PSA to distinguish between benign and malignant diseases of the prostate.


Insights into the Zinc-Dependent Deacetylase LpxC: Biochemical Properties and Inhibitor Design.
The bacterial enzyme UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC), catalyzing the first committed step of lipid A biosynthesis, represents a promising target in the development of novel antibiotics against Gram-negative bacteria. Structure, catalytic reaction mechanism and regulation of the Zn2+-dependent metalloamidase have been intensively investigated. The enzyme is required for growth and viability of Gram-negative bacteria, displays no sequence homology with any mammalian protein, but is highly conserved in Gram-negative bacteria, thus permitting the development of Gram-negative selective antibacterial agents with limited off-target effects. Several smallmolecule LpxC inhibitors have been developed, like the substrate analog TU-514 (12a), the aryloxazoline L-161,240 (13w), the sulfonamide BB-78485 (23a), the N-aroyl-L-threonine derivative CHIR-090 (24a), the sulfone-containing pyridone LpxC-3 (43e), and the uridine-based inhibitor 1-68A (47a), displaying diverse inhibitory and antibacterial activities. Most of these compounds share a Zn2+-binding hydroxamate moiety attached to a structural element addressing the hydrophobic tunnel or the UDP binding site. The butadiynyl derivative ACHN-975 (28) is the first LpxC inhibitor entering clinical trials.


The use of plethysmography and oscillometry to compare long-acting bronchodilators in patients with COPD.
Forced expiratory volume in 1 s (FEV(1)) is the standard measurement used to measure drug effects in chronic obstructive pulmonary disease (COPD) clinical trials. Having previously shown that specific airway conductance (sGaw) measured using body plethysmography and impulse oscillometry (IOS) are more sensitive than FEV(1) for assessing short-acting bronchodilator effects in patients with COPD, we conducted the first randomized, placebo-controlled study to compare long-acting bronchodilators in COPD patients using these techniques. sGaw and IOS sensitively differentiated between the effects of tiotropium and salmeterol when FEV(1) measurements were similar. sGaw and IOS measurements are better than FEV(1) for sensitively assessing bronchodilator pharmacology and differentiating between treatments in COPD clinical trials. Assessment of bronchodilator pharmacology in chronic obstructive pulmonary disease (COPD) may be improved by using more sensitive methods than spirometry, such as impulse oscillometry (IOS) and body plethysmography. We sought to compare salmeterol (S) and tiotropium (Tio) using these methods. In this double-blind, randomized, four-way crossover study, 32 COPD patients received single doses of Tio (18 microg), S (50 and 100 microg) or placebo. Specific airway conductance (sGaw), forced expiratory volume in 1 s (FEV(1)) and IOS were measured pre- and up to 26 h postdose. Comparisons between treatments were analysed by weighted means (WM) between 0 and 12 (WM 0-12 h) and 12-24 h (WM 12-24 h) postdose. Data are expressed as mean difference (or geometric ratio for nonparametric data) with 95% confidence intervals. Tio and S100 significantly improved FEV(1), sGaw and IOS parameters up to 26 h and S50 up to 16 h. WM analysis showed no difference between Tio and S100 in FEV(1) for 0-12 h or 12-24 h. Maximum mid-expiratory flow (-0.06; -0.11, -0.01) and R35 (0.02; 0.01, 0.03) demonstrated superiority of S100 compared with Tio for WM 0-12 h sGaw (1.12; 1.02, 1.23), R5 (-0.06; -0.09, -0.02), R15 (-0.03; -0.05, -0.01), and resonant frequency (RF) (-2.30; -3.83, -0.77) showed superiority of Tio compared with S100 for WM 12-24 h. At 26 h, sGaw, R5, R15, X5 and RF also showed superiority of Tio compared with S100. sGaw and IOS parameters sensitively differentiated between the effects of Tio and S when FEV(1) measurements were similar. Clinical trials in patients with COPD should use IOS and sGaw to assess comprehensively bronchodilator pharmacology.


Improving the recognition of eating gestures using intergesture sequential dependencies.
This paper considers the problem of recognizing eating gestures by tracking wrist motion. Eating gestures are activities commonly undertaken during the consumption of a meal, such as sipping a drink of liquid or using utensils to cut food. Each of these gestures causes a pattern of wrist motion that can be tracked to automatically identify the activity. Previous works have studied this problem at the level of a single gesture. In this paper, we demonstrate that individual gestures have sequential dependence. To study this, three types of classifiers were built: 1) a K-nearest neighbor classifier which uses no sequential context, 2) a hidden Markov model (HMM) which captures the sequential context of subgesture motions, and 3) HMMs that model intergesture sequential dependencies. We built first-order to sixth-order HMMs to evaluate the usefulness of increasing amounts of sequential dependence to aid recognition. On a dataset of 25 meals, we found that the baseline accuracies for the KNN and the subgesture HMM classifiers were 75.8% and 84.3%, respectively. Using HMMs that model intergesture sequential dependencies, we were able to increase accuracy to up to 96.5%. These results demonstrate that sequential dependencies exist between eating gestures and that they can be exploited to improve recognition accuracy.


Copolymers comprising 2,7-carbazole and bis-benzothiadiazole units for bulk-heterojunction solar cells.
On the basis of theoretical considerations of the intramolecular charge transfer (ICT) effect, we have designed a series of donor (D)-acceptor (A) conjugated polymers based on bis-benzothiadiazole (BBT). A PPP-type copolymer of electron-rich 2,7-carbazole (CZ) and electron-deficient BBT units poly[N-(2-decyltetradecyl)-2,7-carbazole-co-7,7'-{4,4'-bis-(2,1,3-benzothiadiazole)}] (PCZ-BBT), a PPV-type copolymer poly[N-(2-decyltetradecyl)-2,7-carbazolevinylene-co-7,7'-{4,4'-bis-(2,1,3-benzothiadiazolevinylene)}] (PCZV-BBTV), and a tercopolymer based on carbazole, thiophene, and BBT poly[N-(2-decyltetradecyl)-2,7-(di-2-thienyl)carbazole-co-7,7'-{4,4'-bis-(2,1,3-benzothiadiazole)}] (PDTCZ-BBT) have been synthesized to understand the influence of BBT acceptor structure and linkage on the photovoltaic characteristics of the resulting materials. Both the HOMO and LUMO of the resulting polymers are found to be deeper-lying than those of benzothiadiazole-based polymers. The measured electrochemical band gaps (eV) are in the following order: PDTCZ-BBT (1.65 eV) < PCZV-BBTV (1.69 eV) < PCZ-BBT (1.75 eV). All the polymers provide a photovoltaic response when blended with a fullerene derivative as an electron acceptor. The best cell reaches a power conversion efficiency of 2.07 % estimated under standard solar light conditions (AM1.5G, 100 mW cm(-2)). We demonstrate for the first time that BBT-based polymers are promising materials for use in bulk-heterojunction solar cells.


Antibody Detection and Dynamic Characteristics in Patients With Coronavirus Disease 2019.
The coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been rapidly spreading nationwide and abroad. A serologic test to identify antibody dynamics and response to SARS-CoV-2 was developed. The antibodies against SARS-CoV-2 were detected by an enzyme-linked immunosorbent assay based on the recombinant nucleocapsid protein of SARS-CoV-2 in patients with confirmed or suspected COVID-19 at 3-40 days after symptom onset. The gold standard for COVID-19 diagnosis was nucleic acid testing for SARS-CoV-2 by real-time reverse-transcription polymerase chain reaction (rRT-PCR). The serodiagnostic power of the specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against SARS-CoV-2 was investigated in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and consistency rate. The seroconversion of specific IgM and IgG antibodies were observed as early as the fourth day after symptom onset. In the patients with confirmed COVID-19, sensitivity, specificity, PPV, NPV, and consistency rate of IgM were 77.3% (51/66), 100%, 100%, 80.0%, and 88.1%, respectively, and those of IgG were 83.3% (55/66), 95.0%, 94.8%, 83.8%, and 88.9%. In patients with suspected COVID-19, sensitivity, specificity, PPV, NPV, and consistency rate of IgM were 87.5% (21/24), 100%, 100%, 95.2%, and 96.4%, respectively, and those of IgG were 70.8% (17/24), 96.6%, 85.0%, 89.1%, and 88.1%. Both antibodies performed well in serodiagnosis for COVID-19 and rely on great specificity. The antibodies against SARS-CoV-2 can be detected in the middle and later stages of the illness. Antibody detection may play an important role in the diagnosis of COVID-19 as a complementary approach to viral nucleic acid assays.


Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice.
Allogeneic hematopoietic cell transplantation (HCT) is the most effective therapy for hematopoietic malignancies through T-cell-mediated graft-vs-leukemia (GVL) effects but often leads to severe graft-vs-host disease (GVHD). Given that protein kinase Cθ (PKCθ), in cooperation with PKCα, is essential for T-cell signaling and function, we have evaluated PKCθ and PKCα as potential therapeutic targets in allogeneic HCT using genetic and pharmacologic approaches. We found that the ability of PKCα(-/-)/θ(-/-) donor T cells to induce GVHD was further reduced compared with PKCθ(-/-) T cells in relation with the relevance of both isoforms to allogeneic donor T-cell proliferation, cytokine production, and migration to GVHD target organs. Treatment with a specific inhibitor for both PKCθ and PKCα impaired donor T-cell proliferation, migration, and chemokine/cytokine production and significantly decreased GVHD in myeloablative preclinical murine models of allogeneic HCT. Moreover, pharmacologic inhibition of PKCθ and PKCα spared T-cell cytotoxic function and GVL effects. Our findings indicate that PKCα and θ contribute to T-cell activation with overlapping functions essential for GVHD induction while less critical to the GVL effect. Thus, targeting PKCα and PKCθ signaling with pharmacologic inhibitors presents a therapeutic option for GVHD prevention while largely preserving the GVL activity in patients receiving HCT.


ESTABLISHING A QUALITY IMPROVEMENT CULTURE WITHIN A LARGE INTEGRATED MEDICAL-DENTAL HEALTH SYSTEM WITH A POPULATION BASED FOCUS.
Quality improvement strategies have been an integral part of healthcare to attain improved care delivery and effective health outcomes. The dental quality initiative improvement (DQII) presented in this manuscript represents a case study of successful implementation of a quality improvement culture within a large integrated-medical-dental health system serving a largely rural population. The key elements of DQII included steering committee establishment, definition or dental quality measures and development/implementation of a dental quality analytics dashboard (DQAD) that provides relevant data on dental quality measures. Qualitative metrics were applied to look at the improvement in performance for the various measures relative to quality benchmarks. DQII facilitated improved oversight of care continuity and provider performance surrounding quality measures at granular and/or institutional level. Improvement associated with care delivery performance relative to benchmarks was observed. DQII further advanced the quality improvement culture prevalent in our learning healthcare environment with its focus on value-based care delivery. DQII initiative and establishment of DQAD provided ability to track performance in operational care delivery for dental providers in a clinical setting in real time.


Electron transfer dissociation of N-glycopeptides: loss of the entire N-glycosylated asparagine side chain.
The recently introduced electron transfer dissociation (ETD) technique opens new possibilities for the structural characterization of glycoproteins at the glycopeptide level. In this report, we investigate the ETD mass spectra of tryptic N-glycopeptides of the model glycoprotein horseradish peroxidase (HRP). Multiply protonated N-glycopeptides obtained by electrospray ionization were subjected to ETD. Fragment ions obtained by ETD were further analyzed by collision-induced dissociation (CID) (MS(3)) for their unambiguous structural assignment. The following fragmentation features were revealed: (1) c- and z-type peptide backbone cleavages were observed with retention of the intact glycan moiety revealing peptide sequence, glycan attachment site, and glycan mass; (2) to a lesser extent, glycosidic bond cleavages were registered with retention of the intact peptide sequence; and (3) a range of amino acid side chain losses did occur. Remarkably, the loss of the complete N-glycosylated asparagine side chain was observed. This loss of the glycan-modified side chain helps with the structural characterization of glycopeptides by allowing the facile deduction and verification of the glycan mass and the nature of the amino acid residue at the glycan attachment site. Importantly, informative ETD spectra were obtained in this study by reversed-phase nano-liquid chromatography (LC) coupled online to a radio-frequency (rf) quadrupole ion trap (QIT) mass spectrometer with alternating acquisition of CID and ETD mass spectra from an automatically selected set of precursors (data-dependent mode). Thus, our study brings nano-LC/QIT-MS(n) with CID and ETD to the fore as a powerful technique for glycoproteomics at the glycopeptide level.


Sulphurous thermal water inhalations in the treatment of chronic rhinosinusitis.
The aim of this study was to evaluate the efficiency of sulphurous thermal water in the treatment of chronic rhinosinusitis (CRS). Eighty patients with CRS were included and randomly assigned into two groups. Patients underwent a 12-day course of warm vapour inhalations and nasal irrigations with sulphurous thermal water in group A, and a physiological solution in group B. Compared with group B, in group A the results were as follows: serum concentration of IgE was significantly lower (p<0.05) 12 days (76.27+26.3 mg/dl vs. 97.44±45.4) and 3 months after the beginning of the treatment (75.48+26.1 mg/dl vs. 98.37±41.4); IgA titers were not significantly higher 12 days (231.09±120.3 mg/dl vs. 220.44+114.4 mg/dl) and 3 months after the beginning of the treatment (235.44±118.5 mg/dl vs. 214.51±111.8 mg/dl); VAS scores were significantly (p<0.05) improved at 12 days (1.7+0.18 vs. 6.9±0.51) and 3 months after the start (1.8+0.22 vs. 7.1±0.59); NMIT was normal at 12 days (11.54±1.59 min vs. 17.38+1.83 min) and 3 months after the beginning of the treatment (11.46+2.07 min vs. 17.43±2.01 min); total nasal resistances were significantly (p<0.05) decreased at 12 days and 3 months. Our results indicate the efficiency and applicability of sulphurous thermal water in the treatment of CRS.


Treatment Effects in Retinal Angiomatous Proliferation Imaged with OCT Angiography.
This prospective case series is aimed at exploring optical coherence tomographic angiography (OCT-A) as a treatment monitoring tool in patients treated for retinal angiomatous proliferation (RAP). Twelve treatment-naïve RAP patients were included, with a median age of 79 years (range 65-90). Patients were imaged with an experimental 1,040-nm swept-source phase-resolved OCT-A instrument before and after treatment. Treatment consisted of either intravitreal bevacizumab or triamcinolone injections with or without photodynamic therapy (PDT). Abnormal blood flow after treatment was graded as increased, unchanged, decreased, or resolved. OCT-A images before and after treatment could be obtained in 9 patients. The median follow-up period was 10 weeks (range 5-19). After various treatments, the RAP lesion resolved in 7 patients, in 1 patient the OCT-A depicted decreased flow in the lesion, and 1 patient showed unchanged abnormal blood flow. Monotherapy with intravitreal bevacizumab injections resolved RAP in 1 out of 2 patients. Combined therapy of bevacizumab with PDT resolved RAP in 6 out of 7 patients. OCT-A visualized resolution of abnormal blood flow in 7 out of 9 RAP patients after various short-term treatment sequences. OCT-A may become an important noninvasive monitoring tool for optimizing treatment strategies in RAP patients.


Exploring the p53 connection of cervical cancer pathogenesis involving north-east Indian patients.
As per WHO, Cervical cancer (CaCx) is a global issue, being the fourth common cancer in women with incidence rate of 13.1 per 1 lakh women globally and accounting for 311000 deaths in the year 2018 itself globally. The molecular pathogenesis in Human papillomavirus (HPV) infected cases is inconclusive. The detection of molecular factors leading to progression of CaCx can be important in the diagnosis and management of the disease. p53 a known tumor suppressor gene having a regulative role in cell cycle has been highlighted as key factor in the prevention of cancer but its significance in CaCx cases has been variably documented. The present study therefore targeted to evaluate the significance of p53 profile in CaCx cases in ethnically distinct northeast Indian population. Blood and Tissue samples (N = 85) of cervical cancer patients were collected and screening for HPV was performed using PCR. Thereafter the differential mRNA expression(qPCR), Immunohistochemistry, Mutation (PCR direct sequencing method) of p53 was studied. Further p53 epigenetic profiling was done by Methylation specific PCR (MS-PCR) and western blotting by using p53 acetylation specific antibodies. Our findings revealed that the downregulation of p53 was associated with the progression of disease and the variation in downregulation based on p53 polymorphism was observed. Further hypermethylation and deacetylation of p53 was also found to be associated with the pathogenesis of CaCx. The downregulated expression and hypermethylation of p53 in lower grade of CaCx, together established its association with the progression of CaCx from lower to severe grade. Therefore, in CaCx patients of northeast Indian population, malfunctioning of p53 is found to have significant role in cervical cancer progression.


[Risk factors in suppurative meningitis in children (author's transl)].
Retrospective studies of the case histories of 237 children suffering from bacterial meningitis at the department of pediatrics, university of Graz, show the significant difference between cured, deceased and children with permanent sequels. The risk factors for the fatal outcome of meningitis were: age (less than 1 year), bacteria (pneumococcus), concomitant disease (pneumonia), low initial white cell count in the blood (less than or equal to 5000/cmm) as well as in cerebrospinal fluid (less than or equal to 4000/cmm), high cerebrospinal fluid protein (greater than or equal to 336 mg%) and a high bacterial inoculum (greater than or equal to 10(7) CFU/cmm). With all these risk factors at the time of diagnosis of purulent meningitis the chance for recovery is poor.


Sex differences in mortality after abdominal aortic aneurysm repair in the UK.
The UK abdominal aortic aneurysm (AAA) screening programmes currently invite only men for screening because the benefit in women is uncertain. Perioperative risk is critical in determining the effectiveness of screening, and contemporary estimates of these risks in women are lacking. The aim of this study was to compare mortality following AAA repair between women and men in the UK. Anonymized data from the UK National Vascular Registry (NVR) for patients undergoing AAA repair (January 2010 to December 2014) were analysed. Co-variables were extracted for analysis by sex. The primary outcome measure was in-hospital mortality. Secondary outcome measures included mortality by 5-year age groups and duration of hospital stay. Logistic regression was performed to adjust for age, calendar time, AAA diameter and smoking status. NVR-based outcomes were checked against Hospital Episode Statistics (HES) data. A total of 23 245 patients were included (13·0 per cent women). Proportionally, more women than men underwent open repair. For elective open AAA repair, the in-hospital mortality rate was 6·9 per cent in women and 4·0 per cent in men (odds ratio (OR) 1·48, 95 per cent c.i. 1·08 to 2·02; P = 0·014), whereas for elective endovascular AAA repair it was 1·8 per cent in women and 0·7 per cent in men (OR 2·86, 1·72 to 4·74; P < 0·001); the results in HES were similar. For ruptured AAA, there was no sex difference in mortality within the NVR; however, in HES, for ruptured open AAA repair, the in-hospital mortality rate was higher in women (33·6 versus 27·1 per cent; OR 1·36, 1·16 to 1·59; P < 0·001). Women have a higher in-hospital mortality rate than men after elective AAA repair even after adjustment. This higher mortality may have an impact on the benefit offered by any screening programme offered to women.