Awareness of Epistaxis and Its First Aid Management Among Teachers Working in Schools of Al-Baha Region, Saudi Arabia.
Background Epistaxis (nosebleed) is a frequent emergency presentation in the emergency department (ED). Generally, any harm to the nasal mucosa lining can lead the nose to bleed. The etiologies of epistaxis are widely classified as environmental, local, systemic, and medication-related causes. The initial management for epistaxis is first aid. First aid by applying pressure on the nostrils is essential to stop the bleeding and minimize discomfort. This study intends to evaluate teachers' awareness regarding epistaxis first aid management inside schools in Al-Baha region, Saudi Arabia. Methodology A cross-sectional study was conducted among a target of 439 teachers regarding epistaxis first aid management inside schools in Al-Baha region, Saudi Arabia. Data were collected using a structured questionnaire and analyzed using descriptive statistics and a chi-square test. Results Of the teachers, 50.7% had received training regarding epistaxis, while 49.3% had never been trained. Also, 73.3% considered that applying nasal compression may help stop bleeding, while the rest were completely unaware. On further investigation, tilting the head forward would be done by 56.27% of the teachers, while 40.73% said that the head should be tilted back. Of the teachers, 53.3% would go to the emergency if bleeding continued for more than 10 minutes. No association between age, gender, and working area, and training received regarding the management of epistaxis was found (p>0.05), but teachers from a scientific background, as compared to those from a literature background, were able to answer better regarding the management of epistaxis (p<0.05). Conclusion The study highlights knowledge gaps regarding epistaxis first aid management inside schools in Al-Baha region, Saudi Arabia. The research highlights the need for focused training programs and awareness efforts to enhance teachers' knowledge and first aid practices. Addressing misknowledge and mispractices, enhancing the practices and attitudes of healthcare providers toward appropriate feeding practices, and promoting a supportive and safe environment could all contribute to the improvement of quality of life and health among the population of Saudi Arabia.


An end to end workflow for differential gene expression using Affymetrix microarrays.
In this article, we walk through an end-to-end Affymetrix microarray differential expression workflow using Bioconductor packages. This workflow is directly applicable to current "Gene" type arrays, e.g. the HuGene or MoGene arrays but can easily adapted to similar platforms. The data re-analyzed is a typical clinical microarray data set that compares inflammed and non-inflammed colon tissue in two disease subtypes. We will start from the raw data CEL files, show how to import them into a Bioconductor ExpressionSet, perform quality control and normalization and finally differential gene expression (DE) analysis, followed by some enrichment analysis. As experimental designs can be complex, a self contained introduction to linear models is also part of the workflow.


Granular cell tumor of the testicular tunica albuginea: a case report.
Granular cell tumor (GCT) is exceedingly rare in the genitourinary tract. We report a case of GCT arising in the tunica albuginea of the testis. A 42-year-old male presented with a painless left testicular mass. Scrotal ultrasound studies showed an intratesticular mass that was suspicious for a testicular malignancy; a left orchiectomy was subsequently performed. Grossly, there was a well-circumscribed tumor mass in the periphery of the testis abutting the tunica albuginea. Microscopically, the tumor was poorly delimited and located in the tunica albuginea with minimal infiltration to the underlying testicular parenchyma. The lesion consisted of clusters and sheets of large polygonal cells dissected by fibrous septa. The tumor cells had indistinct cellular borders, abundant granular eosinophilic cytoplasm, and small nuclei with indistinct nucleoli. No cytologic atypia or increased mitotic activity was seen. Immunohistochemically, the tumor cells were positive for S-100, inhibin-α, and CD68 and negative for calretinin, Melan-A, and WT-1. Ki-67 showed a low proliferation index (<1%). The morphology, in conjunction with immunohistochemical profile, led to a diagnosis of GCT of the tunica albuginea. Although GCT can occur in almost any location of the body, it has not been described to involve the human testis.


Remote loading of aloe emodin in gemini-based cationic liposomes.
Anthraquinone compound aloe-emodin (AE) has shown antineoplastic, antibacterial, antiviral, and anti-inflammatory properties and scavenging activity on free radicals. Because of these therapeutic features, AE has been attracting increasing interest and could be applied in the curing of many diseases. However, until now the physicochemical features of this compound have not been fully investigated; furthermore, its wide application might be hindered by its scarce solubility in aqueous media (∼19 μM). The inclusion of AE in nanocarriers, such as cationic liposomes, could allow its delivery effectively and selectively to target sites, reducing side effects in the remaining tissues. In this work, the weak acid nature of AE, because of its two phenolic functions, was exploited to load it remotely in the internal aqueous phase of liposomes in response to a difference in pH between the inside and outside of the liposomes, pHin > pHout. The inclusion of AE in gemini-based cationic liposomes by the acetate gradient method was obtained at high AE/lipid ratios (up to 1:30).


Spatial Smoothing Effect on Group-Level Functional Connectivity during Resting and Task-Based fMRI.
Spatial smoothing is a preprocessing step applied to neuroimaging data to enhance data quality by reducing noise and artifacts. However, selecting an appropriate smoothing kernel size can be challenging as it can lead to undesired alterations in final images and functional connectivity networks. However, there is no sufficient information about the effects of the Gaussian kernel size on group-level results for different cases yet. This study investigates the influence of kernel size on functional connectivity networks and network parameters in whole-brain rs-fMRI and tb-fMRI analyses of healthy adults. The analysis includes {0, 2, 4, 6, 8, 10} mm kernels, commonly used in practical analyses, covering all major brain networks. Graph theoretical measures such as betweenness centrality, global/local efficiency, clustering coefficient, and average path length are examined for each kernel. Additionally, principal component analysis (PCA) and independent component analysis (ICA) parameters, namely kurtosis and skewness, are evaluated for the functional images. The findings demonstrate that kernel size directly affects node connections, resulting in modifications to functional network structures and PCA/ICA parameters. However, network metrics exhibit greater resilience to these changes.


Initial characterization of a protochordate histocompatibility locus.
The colonial protochordate, Botryllus schlosseri, undergoes a natural transplantation reaction which is controlled by a single, highly polymorphic locus called the Fu/HC. We are using map-based cloning to identify Fu/HC gene(s), and have currently delineated their location to an approximately 1-cM region of the B. schlosseri genome. The Fu/HC physical map currently consists of 85 sequence-tagged sites mapped on a minimum tiling path of 800 kb which consists of five contigs, with four gaps remaining to be crossed, and is estimated to be 75% completed. Approximately half this region has been sequenced throughout the locus, allowing the first analysis of a metazoan histocompatibility locus outside of vertebrates. This has resulted in the identification of 18 predicted genes, a number of which have been found to be expressed. Several of these genes are well conserved among the chordates; however, none of the predicted or expressed genes are linked within the genome of any organism in the databases. In addition, the Fu/HC is one of the most polymorphic loci ever described, and physical mapping has revealed that the locus is quite dynamic, and includes features such as hotspots of recombination.


[Histopathological study of gastric polyps. A report of 65 cases].
In a retrospective study of the specimens of gastric polypectomy, carried out between January 1992 and December 2002, we analysed the demographic and histological aspects of 65 polyps. This study revealed hyperplastic polyps in 66%, adenomatous lesions in 9.2%, Peutz-Jeghers polyps in 7.7%, inflammatory fibroid polyps in 6.15%, two cases of focal foveolar hyperplasia (3%), two cases of Brunner's gland heterotopia (3%), 1 pancreatic heterotopia (1.5%), 1 fundic gland polyp (1.5%) and 1 carcinoid tumor (1.5%). All adenomas and two Peutz-Jeghers polyps include intraepithelial neoplasia. Moreover, we identified a case of Brunner's gland heterotopia, which contain a focus of plane tubular adenoma with high-grade intraepithelial neoplasia. Other lesions were found within the polyps or into the surrounding gastric mucosa, such as intestinal metaplasia and Helicobacter Pylori gastritis. This work allowed us to recommend complete removal of gastric polyps and the realization of biopsies of the nonpolypoid gastric mucosa in the search of intraepithelial neoplasia or other lesions with malignant potential.


Platelet-Rich Plasma Treatment With Physical Therapy in Chronic Partial Supraspinatus Tears.
Despite the insufficient evidence, due to potential contribution to the improvement, platelet-rich plasma (PRP) is emerging as a promising method. The aim of this study was to assess the effectiveness of PRP injection in partial supraspinatus tears by comparing with physical therapy (PT). Seventy patients with chronic partial supraspinatus tears in magnetic resonance imaging were randomized into two groups; PRP (n = 35) and PT (n = 35). Before the treatment, at the end of the treatment and at the 12th month after the end of the treatment, range of motion (ROM), visual analog scale (VAS) for pain, Disabilities of Arm, Shoulder and Hand questionnaire (DASH), Neer's, Hawkins' and drop arm tests and Beck Depression Inventory were investigated. Statistical analysis was made for 62 subjects (PRP group, n = 30; PT group, n = 32). There were no differences between the groups according to demographic data. At the 12th month after the end of the treatment, significant improvement in ROM was detected in both groups, pain was reduced significantly in both groups and improvement of the DASH score was observed in both groups. At all the evaluation steps, increases in ROM degrees were significantly higher in the PT group than the PRP group. For VAS in activity and in rest, after the treatment, improvement was higher in the PT group than the PRP group. However, improvement of the DASH score of the PRP group was significantly better than the PT group. When we compared with PT, PRP seemed to be a well-tolerated application which showed promising results in patients with chronic partial supraspinatus tears.


A Case Report of Takotsubo Cardiomyopathy With Dengue.
A 74-year-old woman with well-controlled hypertension and dyslipidemia with acute fever was diagnosed with dengue infection. She had non-anginal central chest pain which was associated with ST elevation and T inversions in V1 to V6 with prolonged QT interval. Her high-sensitivity troponin was elevated. There was echocardiographic evidence of severe left ventricular dysfunction (ejection fraction 35%; Simpson method) with apical ballooning suggestive of takotsubo cardiomyopathy. No left ventricular basal hyperkinesia was noted. The patient was managed as per the national dengue guidelines of Sri Lanka. Her cardiac condition was managed conservatively. She did not experience dengue complications such as dengue shock syndrome or dengue hemorrhagic fever or pulmonary edema secondary to severe LV dysfunction. The clinical symptoms and echocardiographic findings of takotsubo cardiomyopathy resolved parallel to dengue fever.


A complexity-based approach to batterer intervention programmes.
This paper was aimed at providing opinion by adopting a complexity-based approach to coordinating nursing science and psychology concerning psycho-educational intervention for batterers regarding their partner or ex-partner. Improving both disciplines' interrelationship should facilitate implementing relevant action, thereby engendering motivation for change in participants and modifying sexist attitudes and beliefs. The document has analyzed the importance of coordinating scientific disciplines' action and defined guidelines for an approach involving intervention as well as highlighting implications for practice and research.


Effect of diabetes on median and dorsal raphe nuclei efferent fibers to CA3 hippocampal area in rat.
Diabetes Mellitus (DM) is one of the most important metabolic disease causes in many side effects. The decrease of mental abilities and even some form of dementia followed prolonged diabetes has been reported. There are evidences that show hippocampus might be the site of neural involvement in patients with dementia followed diabetes. As hippocampus received main serotonergic efferents from brain stem raphe nuclei include dorsal raphe nucleus (DRN) and median raphe nucleus (MRN), it is possible that these efferent affected by diabetes. We used adult male Wistar rat in this study. Diabetes was induced by i.p. injection of streptozotocin (STZ). After 2, 4 and 6 months, HRP tracing were done for the efferent from DRN & MRN to CA3 of hippocampus. HRP Positive neuron of DRN & MRN and also the distribution of these cells were study by light microscopy. Statistical analysis was done by SPSS software. Microscopic study clearly showed significant decrease in HRP positive cells population in DRN & MRN after prolonged diabetes. Based on our finding ,the changes in the neural connection between serotonergic nuclei and hippocampus followed diabetes might be one of the reasons for dementia in these patients.


Brachial plexus compression due to subclavian artery pseudoaneurysm from internal jugular vein catheterization.
Internal jugular vein (IJV) catheterization has become the preferred approach for temporary vascular access for hemodialysis. However, complications such as internal carotid artery puncture, vessel erosion, thrombosis, and infection may occur. We report a case of brachial plexus palsy due to compression by right subclavian artery pseudoaneurysm as a result of IJV catheterization in a patient who was under maintenance hemodialysis.


How much insulin-like growth factor I (IGF-I) circulates? Impact of standardization on IGF-I assay accuracy.
There is a significant systematic difference between the normal range obtained from ethylenediamine tetraacetate plasma samples using the Genentech total insulin-like growth factor I (IGF-I) RIA and normal ranges for other total IGF-I RIAs. To determine whether the quality of the assay standard was the cause of this systematic difference, we analyzed commercially available preparations of recombinant human IGF-I (rhIGF-I) typical of those used as IGF-I immunoassay standards along with our own well characterized rhIGF-I assay standard. For the commercial standards, high performance liquid chromatography-derived purities were low, and some vendor-assigned protein concentrations were inconsistent with values from quantitative amino acid analysis. The Genentech rhIGF-I assay standard was highly pure and quantitatively correct. However, the poor quality of some commercial rhIGF-I preparations was not the primary reason for the systematic discrepancy between the Genentech total IGF-I RIA normal range and most other normal ranges. Most assays for total IGF-I are calibrated against the WHO International Reference Reagent (IRR) for IGF-I Immunoassays (87/518). The Genentech total IGF-I RIA is not calibrated against WHO IRR 87/518. The protein content assigned to WHO IRR 87/518 was a consensus value from a multicenter collaborative study. Physicochemical analyses showed that WHO IRR 87/518 is Met(-1)-IGF-I of low purity (44%), and that the assigned protein content is higher than the value determined by quantitative amino acid analysis. Thus, assays that are calibrated against WHO IRR 87/518 will report total IGF-I concentrations in excess of actual values. We believe that calibration against WHO IRR 87/518 is the cause of the systematic discrepancy between the Genentech IGF-I assay normal range and most other normal ranges, and that much of the plasma IGF-I concentration data in the literature are of questionable accuracy.


[Ethical problems in forensic-psychiatric assessment].
Forensic psychiatry as a subspecialty variously differs from general psychiatry. Therefore psychiatrists working in forensic psychiatry are confronted with ethical problems of other kind. In the following several ethical problems connecting with forensic psychiatric examination are pointed out. Finally the question is discussed, whether there is a need of special ethical guidelines for forensic psychiatry.


Inpatient and outpatient health care utilization of children and adolescents with type 1 diabetes before and after introduction of DRGs.
To analyze the frequency and length of hospital stays as well as the frequency of diabetes-associated outpatient visits of children and adolescents with type 1 diabetes before and after the introduction of DRGs (diagnosis-related groups) in German hospitals. For this prospective cohort study, data from 2000 (before introduction of DRGs) to 2008 (after introduction) was extracted from the German diabetes documentation software DPV. Incidence rates of hospitalizations, length of hospital stays as well as the incidence rates of outpatient visits of 21,502 children and adolescents were estimated. The associations between the target parameters and DRG introduction, age, sex, diabetes duration, calendar year and migration background were estimated using generalized linear mixed models. Incidence of hospitalization was 0.45 (95% CI 0.44-0.45) per person-year (PY), mean number of hospital days 2.77/PY (95% CI: 2.76-2.79). Children had 5.3 (95% CI: 5.3-5.3) outpatient visits per PY on average. The number of hospital stays, inpatient days, and outpatient visits decreased significantly between 2000 and 2008. Time of introduction of DRGs was related to a significant rise in the number of hospital stays and outpatient visits (p<0.05). There was no significant relation to the number of hospital days. Compared with children younger than eleven years of age, 11- to 14-year-old children had significantly more, adolescents older than 14 years significantly less hospital stays (RR 1.2, 95% CI: 1.14-1.23 and 0.92, 95%, CI: 0.87-0.97, respectively). Migration background was significantly associated with worse results for all analyzed target variables (RR 1.21 for hospital stays, 1.26 for hospital days, 1.07 number of outpatient visits). The introduction of DRGs in the care of patients with pediatric diabetes mellitus resulted in a leveling of the reduction of the number of outpatient visits and hospital stays. Especially adolescents at the age of puberty and patients from families with migration background seem to require particular attention in health care.


Exploring Inequality Through Service Learning in Higher Education: A Bibliometric Review Study.
Service learning (S-L) is an innovative methodology, which is extensively known worldwide. The implementation of this methodology involves classroom learning and real practice. It is based on a cooperative methodology, integrating community service and learning in a connected way. Its main strength lies in its great potential as a transformative social movement to reduce inequality. The main aim of this study was to understand and describe the field of S-L and inequality in higher education through a bibliometric analysis. A descriptive, retrospective, and cross-sectional methodology is used to describe the information obtained from the 20 references on the topic registered in the Scopus and Web of Science (WoS) databases using a mixed methodology. The quantitative and qualitative results show that most of the publications are concentrated in 2016, with the United States being the country with the largest amount of scientific production on this subject. It is also worth noting that most of the authors reported this approach as a powerful tool to develop consciousness, commitment, and responsibility toward inequality and social problems.


[Diagnosis and surgical policy in benign lesions of liver].
The results of the treatment of 430 patients with benign tumors of the liver (BTL), including hemangiomas (41), nonparasitic solitary cysts (49), polycystosis (65) and parasitic hepatic lesions (alveococcosis-91, echinococcosis-184). To determine the character of a volume structure the accuracy of ultrasound and duplex sonography was tested (87.1-91.7%), as well as the accuracy of computer tomography (91.4-96.8%), angiography (90.6-96.3%), serological and radioimmunoassays. The use of these methods has increased the accuracy of diagnosis 2.2 times (in hemangiomas), nonparasitic cysts-to 1.2 times. The proposed methods of differential diagnosis and choosing of a proper treatment policy in patients with BTL made it possible to formulate indications and contraindications for the surgery, work out an optimal treating policy, depending on a character, location of BTL. The improvement of the surgical technique has decreased the rate of morbidity and mortality (2.5 and 1.5 times respectively).


Chronic neurotrophin delivery promotes ectopic neurite growth from the spiral ganglion of deafened cochleae without compromising the spatial selectivity of cochlear implants.
Cochlear implants restore hearing cues in the severe-profoundly deaf by electrically stimulating spiral ganglion neurons (SGNs). However, SGNs degenerate following loss of cochlear hair cells, due at least in part to a reduction in the endogenous neurotrophin (NT) supply, normally provided by hair cells and supporting cells of the organ of Corti. Delivering exogenous NTs to the cochlea can rescue SGNs from degeneration and can also promote the ectopic growth of SGN neurites. This resprouting may disrupt the cochleotopic organization upon which cochlear implants rely to impart pitch cues. Using retrograde labeling and confocal imaging of SGNs, we determined the extent of neurite growth following 28 days of exogenous NT treatment in deafened guinea pigs with and without chronic electrical stimulation (ES). On completion of this treatment, we measured the spread of neural activation to intracochlear ES by recording neural responses across the cochleotopically organized inferior colliculus using multichannel recording techniques. Although NT treatment significantly increased both the length and the lateral extent of growth of neurites along the cochlea compared with deafened controls, these anatomical changes did not affect the spread of neural activation when examined immediately after 28 days of NT treatment. NT treatment did, however, result in lower excitation thresholds compared with deafened controls. These data support the application of NTs for improved clinical outcomes for cochlear implant patients.


Time trends for HIV-1 antiretroviral resistance among antiretroviral-experienced and naive pregnant women in New York City during 1991 to early 2001.
Time trends in the prevalence of drug resistance to antiretroviral therapy (ART) in pregnant women have not been studied. Treatment and prophylactic efficacy could be compromised by drug-resistant HIV strains. We conducted a repeated cross-sectional study of antiretroviral resistance mutations to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) and of major mutations to protease inhibitors (PIs) in virus isolates from 300 HIV-infected pregnant women in New York City from 1991 to early 2001. The overall prevalence of mutations for NRTIs from 1991 to early 2001 was higher for ART-experienced (25.6% [95% confidence interval (CI): 19.1% to 32.1%]) than ART-naive (8.6% [95% CI: 3.7% to 13.4%]) mothers (P < 0.002). For NNRTIs, the overall prevalence of mutations was somewhat higher among ART-experienced (5.8% [95% CI: 2.3% to 9.3%]) versus ART-naive (1.6% [95% CI: 0% to 3.7%]) women (P = 0.06), and increased over time for ART-naive women (0%-7.4%; P = 0.03) and ART-experienced women (0%-19.4%; P = 0.0002). The prevalence of PI-associated mutations was also higher overall among ART-experienced mothers (5.8% [95% CI: 2.3% to 9.3%] vs. 1.6% [95% CI: 0% to 3.7%]; P = 0.06), with increases over time seen for ART-naive women (0%-7.4%; P = 0.03) and ART-experienced women (0%-16.1%; P = 0.0008). The increasing prevalence of drug resistance in pregnant women, including those who are drug-naive, underscores the necessity for resistance testing to guide treatment to achieve suppression of the mother's virus.


A radical rupture in the paradigm of modern medicine: conflicts of interest, fiduciary obligations, and the scientific ideal.
Conflicts of interest serve as a cipher for a radical rupture in the Flexnerian paradigm of medicine, and they can only be addressed if we recognize that health care is now practiced by institutions, not just individual physicians. By showing how "appropriate utilization of services" or "that which is medically indicated" is a function of socioeconomic factors related to institutional responsibilities, I point toward an administrative and organizational ethic as a needed component for addressing conflicts of interest. The argument is developed by reviewing three important books. First, I consider Mark Rodwin's attempt to configure the economic structures of medicine so that classical fiduciary and scientific ideals can be fostered. Second, I consider E. Haavi Morreim's attempt to modify the classical ideals in order to account for new economic realities. Finally, by considering essays in a recent volume on conflicts of interest edited by Spece, Shimm, and Buchanan, I argue for a constructive dialectic between the approaches of Rodwin and Morreim. In order to properly address conflicts of interest, there must be a radical reassessment of medicine that accounts for the interrelation between scientific, ethical, and economic concerns. Until institutions come into view and professional ethics is developed to account for their role, legitimate interests and obligations of diverse parties cannot be harmonized.


Microfluidic radiosynthesis of [18F]FEMPT, a high affinity PET radiotracer for imaging serotonin receptors.
Continuous-flow microfluidics has shown increased applications in radiochemistry over the last decade, particularly for both pre-clinical and clinical production of fluorine-18 labeled radiotracers. The main advantages of microfluidics are the reduction in reaction times and consumption of reagents that often result in increased radiochemical yields and rapid optimization of reaction parameters for 18F-labeling. In this paper, we report on the two-step microfluidic radiosynthesis of the high affinity partial agonist of the serotonin 1A receptor, [18F]FEMPT (pKi = 9. 79; Ki = 0.16 nM) by microfluidic radiochemistry. [18F]FEMPT was obtained in ≈7% isolated radiochemical yield and in >98% radiochemical and chemical purity. The molar activity of the final product was determined to be >148 GBq/µmol (>4 Ci/µmol).


Shame, guilt, self-hatred and remorse in the psychotherapy of Vietnam combat veterans who committed atrocities.
The soldiers who perpetrated atrocities during the Vietnam War are a group much less studied than the victims of violence during peacetime. These soldiers were catalyzed by war to express a darker side of their humanity, a side that our society often chosses to ignore. At some level their experiences relate to us all. In the future more young men and, probably young women, will be sent to war. Once they have been transformed by military training and the hellish conditions of war, society tends to forget them--to leave them wandering in a no man's land of their own tortured thoughts and feelings. We need to understand more about how such transformations of the self beset our returning soldiers. And, once this has happened, we need to know how to help them reintegrate into society and reconnect with others in a meaningful way. A psychotherpy that embraces the patient's need to express remorse is necessary in order to help these patients work through their guilt and self-hatred. These are the main objectives of treatment.


Assessing the Risk of Hypoglycemia Secondary to Propranolol Therapy for the Treatment of Supraventricular Tachycardia in Infants.
Supraventricular tachycardia (SVT) is the most common arrhythmia among infants. Prevention of SVT is frequently managed through propranolol therapy. Hypoglycemia is a known adverse effect of propranolol therapy, but little research has been done on the incidence and risk of hypoglycemia in treatment of SVT in infants with propranolol. This study attempts to offer insight into the risk of hypoglycemia associated with propranolol therapy when treating infantile SVT to help inform future glucose screening guidelines. We conducted a retrospective chart review of infants treated with propranolol in our hospital system. Inclusion criteria were infants < 1 year of age who received propranolol for the treatment of SVT. A total of 63 patients were identified. Data was collected on sex, age, race, diagnosis, gestational age, nutrition source (Total Parenteral Nutrition (TPN) vs oral), weight (kg), weight for length (kg/cm), propranolol dose (mg/kg/day), comorbidities, and whether or not a hypoglycemic event was identified (< 60 mg/dL). Hypoglycemic events were identified in 9/63 (14.3%) patients. Of the patients with hypoglycemic events, 9/9 (88.9%) had comorbid conditions. Patients with hypoglycemic events had significantly lower weight and propranolol dose than those without hypoglycemic events. Weight for length also tended to increase risk for hypoglycemic events. The high incidence of comorbid conditions in the patients who had hypoglycemic events suggests that hypoglycemic monitoring may only be necessary in patients with conditions predisposing to hypoglycemia.


Expression of insulin-like growth factor-I and insulin-like growth factor-binding protein-1 in the rat uterus during decidualization.
Decidualization of the uterus involves proliferation and differentiation of uterine cells. The effects of decidualization on uterine expression of insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) have been examined in the hypophysectomized-ovariectomized (hypox-ovx) rat and the pituitary-intact (ovx) rat. Decidualization was induced by uterine stimulation of animals treated with a combination of 17 beta-estradiol and progesterone. The patterns of change in uterine IGF-I mRNA and IGFBP-1 mRNA abundance were similar to hypox-ovx rats, hypox-ovx rats replaced with GH and T4, and ovx rats. The changes in IGF-I mRNA abundance were temporally related to 17 beta-estradiol injections. IGFBP-1 mRNA was undetectable early in the decidualization process and reached maximal levels on day 6. Mechanical separation of the deciduoma tissue from the underlying myometrium revealed that the deciduoma tissue was depleted in IGF-I mRNA, while the majority of the IGFBP-1 was located in the deciduoma tissue. The in situ hybridization technique was used to localize IGF-I and IGFBP-1 mRNA in the decidualized uterus. The majority of the IGF-I expression was localized to the outer stroma and smooth muscle cell layer, whereas IGFBP-1 mRNA was detected in uterine epithelial cells and stromal glands. These experiments demonstrated that uterine IGF-I and IGFBP-1 expression during the process of decidualization are pituitary independent. Furthermore, our observations support the hypothesis that the expression of IGFBP-1, a protein capable of inhibiting the mitogenic activity of IGF-I, in deciduoma tissue may inhibit paracrine IGF-1 actin and allow for the differentiation of stromal tissue.


A Systematic Review of Medicinal Plants of Kenya used in the Management of Bacterial Infections.
Kenya's vision 2030 partly aims at ensuring adequate health care for all, and the integration of traditional healthcare practices into the national healthcare system would present a more rapid alternative towards the realization of universal health coverage in Kenya. Currently, research on Kenyan medicinal plants with potential antibacterial activity remains vastly fragmented across numerous literature studies and databases; thus, it is imperative to collate and appraise these data for the ease of future research and possible clinical application. Objective. This review aims at exploring and compiling research evidence on medicinal plants used in the management of bacterial infections in Kenya, with a focus on their efficacy and safety. Methodology. A comprehensive web-based systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was executed to highlight the Kenyan medicinal plants used for the management of bacterial infections in Kenya. This review includes studies published until January 2021 from the PubMed, Science Direct, AJOL, and Google Scholar databases. Results. A total of 105 Kenyan medicinal plants belonging to 43 families have their in vitro activity against various human pathogenic bacteria evaluated. Plants from the Lamiaceae, Rutaceae, and Fabaceae families were the most commonly studied. Aloe secundiflora, Toddalia asiatica, Senna didymobotrya, Warbugia ugandensis, Tithonia diversifolia, Fuerstia africana, Olea africana, and Harrisonia abyssinica were the plants frequently evaluated within Kenya. The plants with the strongest antimicrobial activities were Toddalia asiatica, Hagenia abyssinica, Ocimum gratissimum, Harrisonia abyssinica, Senna didymobotrya, Olea Africana, Camellia sinensis, and Tarmarindus indica. Conclusion. Based on a published work, it is evident that traditional medicine is seemingly an acceptable and efficient system among Kenyan communities in the management of bacterial infections. Kenya's rich biodiversity with diverse secondary metabolites presents a promising source of new therapeutic alternatives with possibly different mechanisms of action against bacteria.


Evidence and Counterevidence in Motion Perception.
Sensory neurons gather evidence in favor of the specific stimuli to which they are tuned, but they could improve their sensitivity by also taking counterevidence into account. The Bours-Lankheet model for motion detection uses counterevidence that relies on a specific combination of the ON and OFF channels in the early visual system. Specifically, the model detects pairs of flashes that occur separated in space and time. If the flashes have the same contrast polarity, they are interpreted as evidence in favor of the corresponding motion. But if they have opposite contrasts, they are interpreted as evidence against it. This mechanism provides an explanation for reverse-phi (the perceived reversal of an apparent motion stimulus due to periodic contrast-inversions) that is a conceptual departure from the standard explanations of the effect. Here, we investigate this counterevidence mechanism by measuring directional tuning curves of neurons in the primary visual and middle temporal cortex areas of awake, behaving macaques using constant-contrast and inverting-contrast moving dot stimuli. Our electrophysiological data support the Bours-Lankheet model and suggest that the counterevidence computation occurs at an early stage of neural processing not captured by the standard models.


Implementing and evaluating care and support planning: a qualitative study of health professionals' experiences in public polyclinics in Singapore.
Two polyclinics in Singapore modified systems and trained health professionals to provide person-centred Care and Support Planning (CSP) for people with diabetes within a clinical trial. We aimed to investigate health professionals' perspectives on CSP to inform future developments. Qualitative research including 23 semi-structured interviews with 13 health professionals and 3 co-ordinators. Interpretive analysis, including considerations of how different understandings, enactments, experiences and evaluative judgements of CSP clustered across health professionals, and potential causal links between them. Both polyclinic teams introduced CSP and sustained it through COVID-19 disruptions. The first examples health professionals gave of CSP 'going well' all involved patients who came prepared, motivated and able to modify behaviours to improve their biomedical markers, but health professionals also said that they only occasionally saw such patients in practice. Health professionals' accounts of how they conducted CSP conversations varied: some interpretations and reported enactments were less clearly aligned with the developers' person-centred aspirations than others. Health professionals brought different communication skill repertoires to their encounters and responded variably to challenges to CSP that arose from: the linguistic and educational diversity of patients in this polyclinic context; the cultural shift that CSP involved; workload pressures; organisational factors that limited relational and informational continuity of care; and policies promoting biomedical measures as key indicators of healthcare quality. While all participants saw potential in CSP, they differed in the extent to which they recognised relational and experiential benefits of CSP (beyond biomedical benefits), and their recommendations for continuing its use beyond the clinical trial were contingent on several considerations. Our analysis shows how narrower and broader interpretive emphases and initial skill repertoires can interact with situational challenges and respectively constrain or extend health professionals' ability to refine their skills with experiential learning, reduce or enhance the potential benefits of CSP, and erode or strengthen motivation to use CSP. Health professionals' interpretations of CSP, along with their communication skills, interact in complex ways with other features of healthcare systems and diverse patient-circumstance scenarios. They warrant careful attention in efforts to implement and evaluate person-centred support for people with long-term conditions.


Metal cation cross-linked nanocellulose hydrogels as tissue engineering substrates.
The use of cellulose materials for biomedical applications is attractive due to their low cost, biocompatibility, and biodegradability. Specific processing of cellulose to yield nanofibrils further improves mechanical properties and suitability as a tissue engineering substrate due to the similarity to the fibrous structure, porosity, and size-scale of the native extracellular matrix. In order to generate the substrate, nanocellulose hydrogels were fabricated from carboxylated cellulose nanofibrils via hydrogelation using metal salts. Hydrogels cross-linked with Ca(2+) and Fe(3+) were investigated as tissue culture substrates for C3H10T1/2 fibroblast cells. Control substrates as well as those with physically adsorbed and covalently attached fibronectin protein were evaluated with X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR), and enzyme linked immunosorbent assay (ELISA). Significantly more cells were attached to surfaces modified with protein, with the highest number of cells adhered to the calcium cross-linked hydrogels with covalently attached protein.


Babesia gibsoni infection in a dog from indiana.
A 10-year-old spayed female mixed-breed dog was presented to the Purdue University Veterinary Teaching Hospital (PUVTH) with complaints of persistent anemia with occasional exacerbations, anorexia, and lethargy. The dog had been presented to the referring veterinarian 2 months prior with multiple bite wounds received during a fight with 3 Pit Bull Terriers. The dog was discharged after the wounds were cleaned and surgically closed. Upon admission to the PUVTH, blood was collected for a complete blood count and biochemical analysis. Microscopic examination of peripheral blood smears revealed intraerythrocytic protozoal parasites consistent with Babesia gibsoni. Molecular analysis confirmed that the organism was B. gibsoni and that its 18S ribosomal RNA sequence was identical to that of other B. gibsoni isolates from Oklahoma, North Carolina, and Okinawa, Japan. Hematologic changes included moderately severe, regenerative, macrocytic, normochromic anemia, with poikilocytosis, polychromasia, anisocytosis, and a marked increase in nucleated RBCs. Biochemical changes included increased serum alanine aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase activities. The dog was treated with imidocarb, but despite initial clinical improvement, the dog died 2 weeks after the first dose. A necropsy was not performed. The infection in this dog is the first reported case of B. gibsoni infection in Indiana. Because of the widespread geographical distribution of the organism, veterinarians and veterinary clinical pathologists throughout the United States should carefully examine Romanowsky-stained blood smears from patients with acute hemolytic anemia for small intraerythrocytic babesial parasites.


Cognitive and developmental outcome of conservatively treated children with congenital hyperinsulinism.
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants. Its management can be extremely complicated, and may involve medical therapy and surgery. The mainstay of the treatment is to maintain normoglycemia, since hypoglycemia during infancy can have severe neurological consequences. To assess the cognitive and developmental levels and the adaptive skills achieved by children with CHI who were treated medically over the past decade. Fourteen children with CHI, under the age of 10 years, who received medical treatment only, underwent a physical and neurological examination and standardized assessments that included the Bayley Scale of Infant and Toddler Development, 3rd Edition, or Kaufman Assessment Battery for Children, the Vineland Adaptive Behavior Scales and the Achenbach Child Behavior Checklist (CBCL) parent questionnaire form. Twelve children (86%) achieved normal range scores in the cognitive and development assessments (Bayley Scale of Infant and Toddler Development or Kaufman Assessment Battery for Children). Only two showed cognitive achievements below the normal range. The Vineland questionnaire, which was based on parental report, showed below normal adaptive skills in eight patients (57%). In contrast to previous studies showing a high prevalence of neurodevelopmental difficulties in children with congenital hyperinsulinism, our study showed normal cognitive achievements in most children. This may be attributed to the earlier recognition and better management of the disease in the past decade.


Extracellular matrix sensing via modulation of orientational order of integrins and F-actin in focal adhesions.
Specificity of cellular responses to distinct cues from the ECM requires precise and sensitive decoding of physical information. However, how known mechanisms of mechanosensing like force-dependent catch bonds and conformational changes in FA proteins can confer that this sensitivity is not known. Using polarization microscopy and computational modeling, we identify dynamic changes in an orientational order of FA proteins as a molecular organizational mechanism that can fine-tune cell sensitivity to the ECM. We find that αV integrins and F-actin show precise changes in the orientational order in an ECM-mediated integrin activation-dependent manner. These changes are sensitive to ECM density and are regulated independent of myosin-II activity though contractility can enhance this sensitivity. A molecular-clutch model demonstrates that the orientational order of integrin-ECM binding coupled to directional catch bonds can capture cellular responses to changes in ECM density. This mechanism also captures decoupling of ECM density sensing from stiffness sensing thus elucidating specificity. Taken together, our results suggest relative geometric organization of FA molecules as an important molecular architectural feature and regulator of mechanotransduction.


The socioeconomic distribution of non-communicable diseases in Europe: findings from the European Social Survey (2014) special module on the social determinants of health.
A range of non-communicable diseases (NCDs) has been found to follow a social pattern whereby socioeconomic status predicts either a higher or lower risk of disease. Comprehensive evidence on the socioeconomic distribution of NCDs across Europe, however, has been limited. Using cross-sectional 2014 European Social Survey data from 20 countries, this paper examines socioeconomic inequalities in 14 self-reported NCDs separately for women and men: heart/circulatory problems, high blood pressure, back pain, arm/hand pain, foot/leg pain, allergies, breathing problems, stomach/digestion problems, skin conditions, diabetes, severe headaches, cancer, obesity and depression. Using education to measure socioeconomic status, age-controlled adjusted risk ratios were calculated and separately compared a lower and medium education group with a high education group. At the pooled European level, a social gradient in health was observed for 10 NCDs: depression, diabetes, obesity, heart/circulation problems, hand/arm pain, high blood pressure, breathing problems, severe headaches, foot/leg pain and cancer. An inverse social gradient was observed for allergies. Social gradients were observed among both genders, but a greater number of inequalities were observed among women. Country-specific analyses show that inequalities in NCDs are present everywhere across Europe and that inequalities exist to different extents for each of the conditions. This study provides the most up-to-date overview of socioeconomic inequalities for a large number of NCDs across 20 European countries for both women and men. Future investigations should further consider the diseases, and their associated determinants, for which socioeconomic differences are the greatest.


Investigation of the reliability, accuracy, and efficiency of gated IMRT delivery with a commercial linear accelerator.
This work reports an investigation on the reliability, accuracy, and efficiency of gated intensity modulated radiation therapy (IMRT) delivery with a commercial linear accelerator. The dosimetry measurements of segmented multileaf collimated IMRT (SMLC-IMRT) were performed by using radiographic films and a two-dimensional diode array. Testing involved a series of IMRT fields from actual patients combined with some manually generated fields. To examine the delivery time, dosimetry plans of standard beamlet IMRT, direct-aperture-optimized (DAO) IMRT, compensator IMRT, and three-dimensional conformal radiotherapy with wedges were delivered with and without gating. The results demonstrated that the gated SMLC-IMRT can be reliably and accurately delivered on this type of accelerators, as long as extremely high interruption frequencies and very low number of monitor units per segment are avoided. Beam flatness exceeded 5% and monitor linearity deviated more than 3% for the gated operation with 2.5 s breathing cycle and 20% duty cycle with segment sizes less than 10 MU. Gating does not change multi leaf collimator (MLC) positioning accuracy. The DAO IMRT is preferred for gated delivery because of its short delivery time.


Adaption and validation of simplified Chinese version of the Low Back Pain Knowledge questionnaire (sC-LKQ).
Low back pain (LBP) knowledge questionnaire (LKQ) was developed by a Brazilian research group in 2009. It has been cross-culturally adapted to many languages with good reliability and validity. This work aimed to translate and validate the LKQ into a simplified Chinese version and to evaluate the self-efficacy in LBP among Chinese participants from China and Hungary. A total of 431 people participated in this research, which lasted from September 2021 to June 2022 and was conducted on the Credamo online platform. The simplified Chinese LKQ (sC-LKQ) was generated through translation and cross-cultural adaptation guidelines. The participants were selected to fill out demographic questions, the sC-LKQ, and the Roland-Morris Disability Questionnaire (RMDQ). The reliability and validity of the data were evaluated using SPSS 28.0. The sC-LKQ showed good internal consistency (Cronbach's alpha was 0.79), and the intraclass correlation value was 0.85. There were five components in the questionnaire with good construct validity. The scores of RMDQ had negatively correlated with sC-LKQ. In the Chinese population, the sC-LKQ demonstrated excellent psychometric qualities and could be used to evaluate self-efficacy in clinical practice and research.


Ni-Rh-based bimetallic conductive MOF as a high-performance electrocatalyst for the oxygen evolution reaction.
Metal-organic frameworks (MOFs) have recently been considered the promising catalysts due to their merits of abundant metal sites, versatile coordination groups, and tunable porous structure. However, low electronic conductivity of most MOFs obstructs their direct application in electrocatalysis. In this work, we fabricate an Ni-Rh bimetallic conductive MOF ([Ni2.85Rh0.15(HHTP)2]n/CC) grown in situ on carbon cloth. Abundant nanopores in the conductive MOFs expose additional catalytic active sites, and the advantageous 2D π-conjugated structure helps accelerate charge transfer. Owing to the introduction of Rh, [Ni2.85Rh0.15(HHTP)2]n/CC exhibited substantially improved oxygen evolution reaction (OER) activity and exhibited only an overpotential of 320 mV to achieve the current density of 20 mA cm-2. The remarkable OER performance confirmed by the electrochemical tests could be ascribed to the synergistic effect caused by the doped Rh together with Ni in [Ni2.85Rh0.15(HHTP)2]n/CC, thereby exhibiting outstanding electrocatalytic performance.


Pan-European meteorological and snow indicators of climate change impact on ski tourism.
Ski tourism plays a major socio-economic role in the snowy and mountainous areas of Europe such as the Alps, the Pyrenees, Nordic Europe, Eastern Europe, Anatolia, etc. Past and future climate change has an impact on the operating conditions of ski resorts, due to their reliance on natural snowfall and favorable conditions for snowmaking. However, there is currently a lack of assessment of past and future operating conditions of ski resorts at the pan-European scale in the context of climate change. The presented work aims at filling this gap, as part of the "European Tourism" Sectoral Information System (SIS) of the Copernicus Climate Change Services (C3S). The Mountain Tourism Meteorological and Snow Indicators (MTMSI) were co-designed with representatives of the ski tourism industry, including consulting companies. They were derived from statistically adjusted EURO-CORDEX climate projections (multiple GCM/RCM pairs for RCP2.6, RCP4.5 and RCP8.5) using the UERRA 5.5 km resolution surface reanalysis as a reference, used as input to the snow cover model Crocus, with and without accounting for snow management (grooming, snowmaking). Results are generated for 100 m elevation bands for NUTS-3 geographical areas spanning all areas relevant to ski tourism in Europe. This article introduces the underpinning elements for the generation of this product, and illustrates results at the pan-European scale as well as for smaller scale case studies. A dedicated visualization app allows for easy navigation into the multiple dimensions of this dataset, thereby fulfilling the needs of a broad range of users.


Incidence and outcome of small for gestational age foetuses: an experience from a secondary care hospital.
The objective of the study was to determine the frequency and outcome of Small for Gestational Age (SGA) foetuses, and its association with the mode of delivery, foetal birthweight, maternal age and gestational age. It was a hospital-based descriptive study, conducted at Aga Khan Hospital for Women, Karachi, from January 2009 to December 2010. Mode of deliveries, foetal birthweight, maternal age and gestational age of SGA foetuses were recorded and analszed. Of a total of 6024 deliveries during the study period, 722 (11.98%) had SGA foetuses. Maternal age in such cased ranged between 20-40 years in 588 (81.44%), while 406 (56.23%) of these deliveries were in between 34-37 weeks of gestation. Besides, 396 (54.84%) cases were delivered vaginally. The incidence of SGA increased from 2009 to 2010 (13.13% vs 10.76%). The frequency of SGA foetuses tends to be significantly higher in Pakistan compared to the Western world. Prenatal care and better management can potentially avoid the occurrence of SGA deliveries, perinatal morbidity and mortality.


Magnetically Induced Alignment of Natural Products for Stereochemical Structure Determination via NMR.
Anisotropic NMR has gained increasing popularity to determine the structure and specifically the configuration of small, flexible, non-crystallizable molecules. However, it suffers from the necessity to dissolve the analyte in special media such as liquid crystals or polymer gels. Generally, small degrees of alignment are also caused by an anisotropic magnetic susceptibility of the molecule, for example, induced by aromatic moieties. For this mechanism, the alignment can be predicted via density functional theory. Here we show that both residual dipolar couplings and residual chemical shift anisotropies can be acquired from natural products without special sample preparation using magnetically induced alignment. On the two examples of the novel natural product gymnochrome G and the alkaloid strychnine, these data, together with the predicted alignment, yield the correct configuration with high certainty.


Sphingolipids as Emerging Mediators in Retina Degeneration.
The sphingolipids ceramide (Cer), sphingosine-1-phosphate (S1P), sphingosine (Sph), and ceramide-1-phosphate (C1P) are key signaling molecules that regulate major cellular functions. Their roles in the retina have gained increasing attention during the last decade since they emerge as mediators of proliferation, survival, migration, neovascularization, inflammation and death in retina cells. As exacerbation of these processes is central to retina degenerative diseases, they appear as crucial players in their progression. This review analyzes the functions of these sphingolipids in retina cell types and their possible pathological roles. Cer appears as a key arbitrator in diverse retinal pathologies; it promotes inflammation in endothelial and retina pigment epithelium (RPE) cells and its increase is a common feature in photoreceptor death in vitro and in animal models of retina degeneration; noteworthy, inhibiting Cer synthesis preserves photoreceptor viability and functionality. In turn, S1P acts as a double edge sword in the retina. It is essential for retina development, promoting the survival of photoreceptors and ganglion cells and regulating proliferation and differentiation of photoreceptor progenitors. However, S1P has also deleterious effects, stimulating migration of Müller glial cells, angiogenesis and fibrosis, contributing to the inflammatory scenario of proliferative retinopathies and age related macular degeneration (AMD). C1P, as S1P, promotes photoreceptor survival and differentiation. Collectively, the expanding role for these sphingolipids in the regulation of critical processes in retina cell types and in their dysregulation in retina degenerations makes them attractive targets for treating these diseases.


Indicators associated with suicidal ideation and suicide attempts among 16-35-year-old Danes: a national representative population study.
In this study indicators associated with suicidal ideation and suicide attempts in a nationwide representative sample (N=3184) of Danes aged 16-35 years were examined. The study was cross-sectional and had three aims: (1) to draw a profile of persons with and without suicidal tendency established on a combined quartered variable on current suicidal thoughts and/or ever attempted suicide; (2) to explore whether the different suicidal tendencies constitute a severity continuum; and (3) to identify factors of significance for suicidal tendency. Factors included were demographic characteristics, living conditions, social network, external health risks, lifestyle, health-related quality of life, symptoms, morbidity, and illness behavior. A continuum hypothesis was not supported, as the multiple logistic regression analysis showed no clear gradient in the different forms of suicidal tendency. Cohabitation status (single, p < 0.0001), exposure to violent threats (p < 0.0001), exposure to sexual abuse (p < 0.0001), being a daily smoker (p < 0.0001), doing nothing to stay healthy (p < 0.0004), poor mental health (p < 0.0001), mental symptoms within the past 2 weeks (p = 0.0003), contact with psychologist (p < 0.0001), and absence from work due to illness (p = 0.005) were indicators significantly related to suicidal tendency.


Sensitivity to cholinergic drug treatments of aged rats with variable degrees of spatial memory impairment.
As a first step, the present experiment aimed at characterizing learning and memory capabilities, as well as some motor and sensorimotor faculties, in aged (24-26.5 months) Long-Evans female rats. As a second step, a psychopharmacological approach was undertaken in order to examine the sensitivity of aged rats to muscarinic blockade and to cholinomimetic treatments. Young adult (3-5.5 months) and aged rats were tested for beam-walking performance, locomotor activity in the home cage and an open field, and spatial learning/memory performance in a water maze and a radial maze. Spontaneous alternation rates were assessed in a T-maze. Statistical analysis discriminated between aged rats showing moderate impairment (AMI) and those showing severe impairment (ASI) in the water maze test. Beside their different degrees of impairment in the water maze, AMI and ASI rats were similarly (no significant difference) impaired in beam-walking capabilities, home cage activity and radial maze performance. In the spontaneous alternation task aged rats were not impaired and, in the open-field test, AMI rats were hypoactive, but not as much as ASI rats. Neither of the cognitive deficits was correlated with a locomotor or a sensorimotor variable, or with the body weight. When tested in the radial maze, a low dose of scopolamine (0.1 mg/kg i.p.) produced memory impairments which were significant in AMI and ASI rats, but not in young rats. Combined injections of scopolamine and physostigmine (0.05 and 0.1 mg/kg) or tacrine (THA, 3 mg/kg) showed physostigmine (0.1 mg/kg) to compensate for the scopolamine-induced impairments only in AMI rats. whereas THA was efficient in both AMI and ASI rats. The results indicate: (i) that rats with different degrees of spatial memory impairment in the water maze are similarly hypersensitive to muscarinic blockade when tested in a radial maze test; and (ii) that under the influence of a dose of scopolamine which is subamnesic in young rats, aged rats respond to anticholinesterase treatments according to the level of performance achieved in the water maze: moderately impaired rats are sensitive to both physostigmine and THA, whereas more severely impaired rats are sensitive only to THA.


Tricyclic antidepressant amitriptyline inhibits autophagic flux and prevents tube formation in vascular endothelial cells.
Amitriptyline is a tricyclic antidepressant and an inhibitor of lysosomal acid sphingomyelinase (ASM). Amitriptyline is well known for its cardiovascular side effects and toxicity in psychiatric patients. However, the mechanisms underlying the cardiovascular side effects of amitriptyline remain largely undefined. This study aimed to determine the effects of amitriptyline on angiogenic capability of vascular endothelial cells in physiological settings and identify its mechanism of action. The ex vivo aortic ring angiogenesis and in vitro-cultured endothelial cell tube formation assay were used to assess the effects of amitriptyline on endothelial angiogenic capability. It was demonstrated that amitriptyline impaired the angiogenesis of aortic rings, which was similar to that found in aortic rings with haploinsufficiency of the ASM gene. In cultured mouse microvascular endothelial cells (MVECs), amitriptyline impaired the proliferation and tube formation under basal condition, which were accompanied by attenuated angiogenic signalling pathways such as endothelial nitric oxide synthase, Akt and Erk1/2 pathways. Mechanistically, amitriptyline inhibited autophagic flux without affecting autophagosome biogenesis at basal condition. ASM gene silencing or autophagy inhibition mimics the inhibitory effects of amitriptyline on endothelial cell proliferation and tube formation. Collectively, our data suggest that amitriptyline inhibits endothelial cell proliferation and angiogenesis via blockade of ASM-autophagic flux axis. It is implicated that the cardiovascular side effects of amitriptyline may be associated with its inhibitory action on physiological angiogenesis.


Effect of nanoparticle stabilization and physicochemical properties on exposure outcome: acute toxicity of silver nanoparticle preparations in zebrafish (Danio rerio).
Nanotechnology has vast potential for expanded development and novel application in numerous sectors of society. With growing use and applications, substantial production volumes and associated environmental release can be anticipated. Exposure effect of nanoparticles (NP) on biological systems may be intrinsic to their physicochemical properties introducing unknown associated risk. Herein, we expand the knowledge of health and environmental impact of silver nanoparticles (AgNPs), testing the acute toxicity of 14 AgNP preparations on developing zebrafish embryos (Danio rerio). Toxicological end points, including mortality, hatching rate, and heart rate were recorded. Concentration, stabilization agent and physicochemical properties were monitored as contributing outcome factors. Our findings indicate wide ranging LC50 24 h postfertilization values (0.487 ppm (0.315, 0.744 95% CI) to 47.89 ppm (18.45, 203.49 95% CI)), and indicate surface charge and ionic dissolution as key contributory factors in AgNP exposure outcome.


Development of highly stable and low toxic cationic liposomes for gene therapy.
Cationic liposomes with high stability and low cytotoxicity for gene therapy have been developed. Luciferase plasmid DNA (pLuc) was used as a model gene. The empty liposomes and niosomes were prepared by freeze dried empty liposomes (FDEL) method. The entrapment of pLuc in the liposomes was by reconstitution of the lyophilized dried vesicles with the plasmid solution. The morphology of the vesicles showing multilamellar structure was characterized by transmission electron microscope (TEM) and cryo-TEM. Cytotoxicity of the vesicular formulations was investigated on mouse melanoma cell lines (B16F10) by MTT assay. Cationic lposomes and niosomes containing the cationic lipid DDAB were less cytotoxic than other bilayer vesicular formulations. The pLuc entrapped in the cationic DPPC/Chol/DDAB liposomes (at 1:1:1 molar ratio) exhibited higher stability than other vesicular formulations and the pLuc in solution when stored at 4, 30 and 50 degrees C for 8 weeks. The entrapment efficiency determined by gel electrophoresis and gel documentation of the pLuc in this liposomal formulation was 100%. Luciferase gene expression of pLuc-loaded in cationic liposomes (lipoplexes) in HeLa cell lines was evaluated from luciferase activity determined by a luminometer at 24 and 48 h incubation. Percentages of cell proliferation of the lipoplexes on HeLa cell line at 24 and 48 h incubation were evaluated by the WST-1 assay. When the amount of DPPC or cholesterol was increased in the lipoplexes, the higher amount of DDAB was needed to protect pLuc from enzymatic degradation. However, DPPC and cholesterol exceeded 33 and 50% mol, respectively gave no gene expression. The DPPC/Chol/DDAB (at 1:1:1 molar ratio) lipoplex has demonstrated moderately lower luciferase gene expression and low cytoxicity. This lipoplex with the DDAB/pLuc weight ratio of 14:1 was the most desirable formulation for gene therapy because of its high stability, high luciferase gene expression and low cytotoxicity.


Matching Pursuit for Denoising Raman Spectra, Based on Genetic Algorithm and Hermite Atoms.
Due to its various advantages, Raman spectroscopy has become a powerful tool in different fields of science and engineering; however, in specific applications, this technique's limiting factor is closely related to the inherent noise of the Raman spectra. To eliminate the noise of a Raman spectrum, preserving its position, intensity, and width characteristic, we propose using a genetic matching pursuit-Hermite atoms (GMP-HAs) algorithm in this work. This algorithm helps recover Raman spectra immersed in Gaussian noise with the least number of atoms. The noise-free Raman signal is reconstructed with the GMP-HAs algorithm, transforming the typical best-matching atom search into an optimization problem. Specifically, we maximize the fitness function, defined as the correlation between current residual and Hermite atoms, with the genetic algorithm MI-LXPM encoded in a real domain and avoiding local maxima, by adding a stopping criterion based on an exponential adjustment according to the algorithm's behavior in the presence of noise. Simulated and biological Raman spectra are used to evaluate the proposed algorithm and compare its performance with typically known methods for denoising, such as the Savitzky- Golay filter (SG) and basis pursuit denoising. Using the signal-to-noise ratio (S/N)metric resulted in a 0.31 dB advantage in the S/N product for the proposed algorithm with respect to SG. Additionally, it is shown that the algorithm uses only 25.3% of the number of atoms needed by the matching pursuit algorithm. The results indicate that the GMP-HAs algorithm has better denoising capabilities, and at the same time, the Raman spectra are decomposed with fewer atoms compared to known sparse algorithms.


Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load.
Intracellular calcium (Ca) alternans in cardiac myocytes have been shown in many experimental studies, and the mechanisms remain incompletely understood. We recently developed a "3R theory" that links Ca sparks to whole cell Ca alternans through three critical properties: randomness of Ca sparks; recruitment of a Ca spark by neighboring Ca sparks; and refractoriness of Ca release units. In this study, we used computer simulation of a physiologically detailed mathematical model of a ventricular myocyte couplon network to study how sarcoplasmic reticulum (SR) Ca load and other physiological parameters, such as ryanodine receptor sensitivity, SR uptake rate, Na-Ca exchange strength, and Ca buffer levels affect Ca alternans in the context of 3R theory. We developed a method to calculate the parameters used in the 3R theory (i.e., the primary spark rate and the recruitment rate) from the physiologically detailed Ca cycling model and paced the model periodically to elicit Ca alternans. We show that alternans only occurs for an intermediate range of the SR Ca load, and the underlying mechanism can be explained via its effects on the 3Rs. Furthermore, we show that altering the physiological parameters not only directly changes the 3Rs but also alters the SR Ca load, having an indirect effect on the 3Rs as well. Therefore, our present study links the SR Ca load and other physiological parameters to whole cell Ca alternans through the framework of the 3R theory, providing a general mechanistic understanding of Ca alternans in ventricular myocytes.


Ranolazine inhibits NaV1.5-mediated breast cancer cell invasiveness and lung colonization.
Na(V)1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients' death. In breast cancer cells, Na(V)1.5 activity promotes the proteolytic degradation of the extracellular matrix and enhances cell invasiveness. In this study, we showed that the extinction of Na(V)1.5 expression in human breast cancer cells almost completely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated that ranolazine (50 μM) inhibited Na(V)1.5 currents in breast cancer cells and reduced Na(V)1.5-related cancer cell invasiveness in vitro. In vivo, the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by Na(V)1.5-expressing human breast cancer cells. Taken together, our results demonstrate the importance of Na(V)1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with Na(V) activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments.


Proteomic analysis of Mrr1p- and Tac1p-associated differential protein expression in azole-resistant clinical isolates of Candida albicans.
Azole resistance in Candida albicans is frequently caused by the overexpression of multi-drug efflux pump genes MDR1, CDR1, and CDR2 due to gain-of-function mutations in the zinc cluster transcription factors Mrr1p and Tac1p. In this study, we performed a comparative proteomic analysis to identify proteins whose expression level is influenced by these transcription factors. Both 2-DE and PMF were used to examine the expression profiles of six pairs of matched C. albicans isolates carrying gain-of-function mutations in either MRR1 or TAC1 resulting in the overexpression of either MDR1 or CDR1 and CDR2. Using this approach, 17 differentially expressed proteins were identified in the MDR1-overexpressing isolates, while 14 were identified in the isolates that overexpress CDR1 and CDR2. Furthermore, we found that the expression of many of these proteins was increased in a wild-type strain of C. albicans after the introduction of a gain-of-function allele of MRR1 or TAC1. Moreover, disruption of MRR1 and TAC1 in isolates carrying gain-of-function mutations resulted in decreased expression of these proteins, confirming their regulation by Mrr1p or Tac1p. Several proteins involved in heat shock and carbohydrate metabolism were differentially expressed in all clinical isolate sets, but these proteins were not dependent upon either Tac1p or Mrr1p.


The Risk of Peripheral Arterial Disease after Parathyroidectomy in Patients with End-Stage Renal Disease.
The changes of the risk of peripheral arterial disease (PAD) in patients with end-stage renal disease after parathyroidectomy are scant. We used a nationwide health insurance claims database to select all dialysis-dependent patients with end-stage renal disease aged 18 years and older for the study population in 2000 to 2006. Of the patients with end-stage renal disease, we selected 947 patients who had undergone parathyroidectomy as the parathyroidectomy group and frequency matched 3746 patients with end-stage renal disease by sex, age, years since the disease diagnosis, and the year of index date as the non-parathyroidectomy group. We used a multivariate Cox proportional hazards regression analysis with the use of a robust sandwich covariance matrix estimate, accounting for the intra-cluster dependence of hospitals or clinics, to measure the risk of peripheral arterial disease for the parathyroidectomy group compared with the non-parathyroidectomy group after adjusting for sex, age, premium-based income, urbanization, and comorbidity. The mean post-op follow-up periods were 5.08 and 4.52 years for the parathyroidectomy and non-parathyroidectomy groups, respectively; the incidence density rate of PAD in the PTX group was 12.26 per 1000 person-years, significantly lower than the data in the non-PTX group (24.09 per 1000 person-years, adjusted HR = 0.66, 95% CI = 0.46-0.94). Parathyroidectomy is associated with reduced risk of peripheral arterial disease in patients with end-stage renal disease complicated with severe secondary hyperparathyroidism.


An evaluation of fedratinib for adult patients with newly diagnosed and previously treated myelofibrosis.
Myelofibrosis (MF) is a life-shortening myeloproliferative neoplasm that has multiple features such as clonal proliferation, fibrosis and splenomegaly. Until recently, ruxolitinib, a Janus Kinase (JAK) 1/2 inhibitor was the only targeted therapy approved for transplant-ineligible patients with MF and who require treatment for symptoms and/or splenomegaly. However, the discontinuation rate with ruxolitinib at 3 to 5 years is high and mostly due to loss of response or toxicity, and these patients had no subsequent treatment. Fedratinib, a selective JAK2 inhibitor, was approved by the Food and Drug Administration (FDA) in August 2019 for the treatment of intermediate-2 or high-risk primary or secondary MF, regardless of prior JAK inhibitor treatment for the management of symptoms and splenomegaly. We discuss herein the development of fedratinib and its pharmacology and pharmacokinetics as well as the clinical development and the future directions. We used PubMed for the search of articles related to fedratinib and myelofibrosis. Fedratinib provided a second-line treatment for patients with MF who failed or discontinued ruxolitinib. New combinations of JAK inhibitors with other targeted therapies are a must in order to improve the management of MF.


Extremely efficient internal exciton dissociation through edge states in layered 2D perovskites.
Understanding and controlling charge and energy flow in state-of-the-art semiconductor quantum wells has enabled high-efficiency optoelectronic devices. Two-dimensional (2D) Ruddlesden-Popper perovskites are solution-processed quantum wells wherein the band gap can be tuned by varying the perovskite-layer thickness, which modulates the effective electron-hole confinement. We report that, counterintuitive to classical quantum-confined systems where photogenerated electrons and holes are strongly bound by Coulomb interactions or excitons, the photophysics of thin films made of Ruddlesden-Popper perovskites with a thickness exceeding two perovskite-crystal units (>1.3 nanometers) is dominated by lower-energy states associated with the local intrinsic electronic structure of the edges of the perovskite layers. These states provide a direct pathway for dissociating excitons into longer-lived free carriers that substantially improve the performance of optoelectronic devices.


Celecoxib and NS-398 enhance photodynamic therapy by increasing in vitro apoptosis and decreasing in vivo inflammatory and angiogenic factors.
Photodynamic therapy (PDT) elicits both apoptotic and necrotic responses within treated tumors and produces microvascular injury leading to inflammation and hypoxia. PDT also induces expression of angiogenic and survival molecules including vascular endothelial growth factor, cyclooxygenase-2 (COX-2), and matrix metalloproteinases. Adjunctive administration of inhibitors to these molecules improves PDT responsiveness. In the current study, we examined how the combination of PDT and COX-2 inhibitors improve treatment responsiveness. Photofrin-mediated PDT combined with either celecoxib or NS-398 increased cytotoxicity and apoptosis in mouse BA mammary carcinoma cells. Immunoblot analysis of protein extracts from PDT-treated cells also showed poly(ADP-ribose) polymerase cleavage and Bcl-2 degradation, which were further enhanced following combined therapy. Tumor-bearing mice treated with PDT and either celecoxib or NS-398 exhibited significant improvement in long-term tumor-free survival when compared with PDT or COX-2 inhibitor treatments alone. The combined procedures did not increase in vivo tumor-associated apoptosis. Administration of celecoxib or NS-398 attenuated tissue levels of prostaglandin E2 and vascular endothelial growth factor induced by PDT in treated tumors and also decreased the expression of proinflammatory mediators interleukin-1beta and tumor necrosis factor-alpha. Increased tumor levels of the antiinflammatory cytokine, interleukin 10, were also observed following combined treatment. This study documents for the first time that adjunctive use of celecoxib enhances PDT-mediated tumoricidal action in an in vivo tumor model. Our results also show that administration of COX-2 inhibitors enhance in vitro photosensitization by increasing apoptosis and improve in vivo PDT responsiveness by decreasing expression of angiogenic and inflammatory molecules.


White Matter Damage in the Cholinergic System Contributes to Cognitive Impairment in Subcortical Vascular Cognitive Impairment, No Dementia.
Cholinergic deficiency has been implicated in the pathogenesis of vascular cognitive impairment (VCI), but the extent of involvement and underlying mechanism remain unclear. In this study, targeting the early stage of VCI, we determined regional atrophy within the basal forebrain and deficiency in cholinergic pathways in 25 patients with vascular cognitive impairment no dementia (VCIND) compared to 24 healthy elderly subjects. By applying stereotaxic cytoarchitectonic maps of the nucleus basalis of Meynert (NbM), no significant atrophy was identified in VCIND. Using probabilistic tractography analysis, our study tracked the two major white matter tracks which map to cholinergic pathways. We identified significantly lower fractional anisotropy (FA) in VCIND. Mediation analysis demonstrated that FA in the tracked pathways could fully account for the executive dysfunction, and partly mediate the memory and global cognition impairment. Our study suggests that the fibers mapped to the cholinergic pathways, but not the NbM, are significantly impaired in VCIND. MRI-based in vivo tracking of cholinergic pathways together with NbM measurement may become a valuable in vivo marker for evaluating the cholinergic system in cognitive disorders.


A relationship-centred approach to managing pain in dementia.
The presence of pain in a person with dementia can often be missed. The diagnosis of dementia can overshadow the pain-inducing symptoms of other co-morbid conditions with distress behaviours being attributed to the behavioural and psychological symptoms of dementia. Such distress behaviours of a person with dementia often have a profound and alarming effect on family carers. This Admiral Nurse case study explores the assessment and management of pain in a person with dementia in partnership with the family carer.


Caged pancreatic islet for IDDM.
The goals of this research are to improve the functionality (insulin secretion rate and pattern) and to expand the life-span of immunoprotected pancreatic islets. The low functionality (less than 15% of the insulin release rate of native islets in pancreas) required a large number of islets within the implant, which causes complications in surgery and discomfort for patients. The limited life-span of the islets in a biohybrid artificial pancreas (BAP) may require frequent cell reseeding and cause further supply problems in islet transplantation. Improved islet functionality and prolonged life-span will minimize the volume of the BAP by reducing the number of islets needed for diabetic patients to achieve normoglycaemia and reduce problems associated with islet supply. It is hypothesized in this research that 1) by mimicking facilitated oxygen transport in avascular tissues, the immunoprotected islets release a higher amount of insulin, recover their intrinsic biphasic release pattern, and prolong their life-span, and 2) insulinotropic agents further promote insulin secretion from islets. Based on these hypotheses, a new BAP system will be designed which contains the water-soluble polymeric conjugates of oxygen carriers (or oxygen binding vehicles) and islet stimulants of sulfonylurea compounds and glucagon-like insulinotropic peptide-1 with entrapped islets in the BAP. The research examines their effects on islet viability, the amount of insulin secretion, the insulin release profile, and the life-span of immunoprotected pancreatic islets. Especially, the combined synergy effects of both hypotheses will be emphasized. The successful results in improving functionality and life-span of islets entrapped in an immunoprotected membrane can be applied in the delivery of microencapsulated therapeutic cells and to the miniaturization of a BAP. In addition, the approaches proposed in this research will provide a potential solution to the shortage problem of human cell or tissue sources.


Distinct patterns of folding and interactions with calnexin and calreticulin in human class I MHC proteins with altered N-glycosylation.
Calnexin is a lectin-like chaperone that binds to class I MHC molecules soon after their synthesis, retaining unassembled heavy chains and also assisting their folding. Following association with beta2-microglobulin (beta2m) in the endoplasmic reticulum, a large proportion of human class I molecules release from calnexin, whereas mouse class I molecules do not. We asked whether addition of a second N-glycan to the human class I molecule A*0201 at position 176, a site present in mouse, would affect its binding to calnexin. The 176dg mutant with N-glycans at positions 86 and 176, when transfected into CIR cells, demonstrated increased binding to calnexin, detectable both before and after association with beta2m, and reduced interaction with calreticulin and TAP relative to wild-type protein bearing a single N-glycan at position 86. Cell surface levels of the mutant were decreased only slightly relative to the wild type, suggesting that the protein is not misfolded or grossly altered structurally. A subpopulation of mutant molecules was retained in the endoplasmic reticulum, and surprisingly, these molecules reacted with w6/32, which recognizes an epitope present on transport-competent class I HLA complexes. Transfection into Daudi cells demonstrated that 176dg reacts with w6/32 in the absence of beta2m, suggesting that the Ab epitope can be induced by binding of calnexin. These data may explain previously noted differences between mouse and human class I MHC proteins and demonstrate that the location of N-oligosaccharides within proteins can influence their folding and interactions with chaperones such as calnexin and calreticulin.


Utility of human amniotic membrane allograft in re-epithelialization of the nasal tip.
Variations in skin thickness and contours pose significant challenges to reconstruction of the lower third of the nose. Human amniotic membrane allograft offers a potential alternative to tissue transfer in reconstruction of the lower third of the nose. We reviewed the procedure and photographs of a healthy 56-year-old male with a 22 × 18 mm lower third nasal defect involving full thickness skin and subcutaneous tissue. Following preparation for grafting, dehydrated human amniotic membrane was fashioned to the dimensions of the defect and applied. No further surgical intervention was provided for 3 months. Complete re-epithelialization of the nasal and adjacent defects was achieved with minimal scar formation. Human amniotic membrane allograft provides an efficacious and cosmetically acceptable alternative to local and regional tissue transfer.


An Integrated Framework for Gender Equity in Academic Medicine.
In 2008, the National Institutes of Health funded 14 R01 grants to study causal factors that promote and support women's biomedical careers. The Research Partnership on Women in Biomedical Careers, a multi-institutional collaboration of the investigators, is one product of this initiative.A comprehensive framework is needed to address change at many levels-department, institution, academic community, and beyond-and enable gender equity in the development of successful biomedical careers. The authors suggest four distinct but interrelated aspects of culture conducive to gender equity: equal access to resources and opportunities, minimizing unconscious gender bias, enhancing work-life balance, and leadership engagement. They review the collection of eight articles in this issue, which each address one or more of the four dimensions of culture. The articles suggest that improving mentor-mentee fit, coaching grant reviewers on unconscious bias, and providing equal compensation and adequate resources for career development will contribute positively to gender equity in academic medicine.Academic medicine must adopt an integrated perspective on culture for women and acknowledge the multiple facets essential to gender equity. To effect change, culture must be addressed both within and beyond academic health centers (AHCs). Leaders within AHCs must examine their institutions' processes, resources, and assessment for fairness and transparency; mobilize personnel and financial resources to implement evidence-based initiatives; and assign accountability for providing transparent progress assessments. Beyond AHCs, organizations must examine their operations and implement change to ensure parity of funding, research, and leadership opportunities as well as transparency of assessment and accreditation.


Life's Essential 8: Optimizing Health in Older Adults.
The population worldwide is getting older as a result of advances in public health, medicine, and technology. Older individuals are living longer with a higher prevalence of subclinical and clinical cardiovascular disease (CVD). In 2010, the American Heart Association introduced a list of key prevention targets, known as "Life's Simple 7" to increase CVD-free survival, longevity, and quality of life. In 2022, sleep health was added to expand the recommendations to "Life's Essential 8" (eat better, be more active, stop smoking, get adequate sleep, manage weight, manage cholesterol, manage blood pressure, and manage diabetes). These prevention targets are intended to apply regardless of chronologic age. During this same time, the understanding of aging biology and goals of care for older adults further enhanced the relevance of prevention across the range of functions. From a biological perspective, aging is a complex cellular process characterized by genomic instability, telomere attrition, loss of proteostasis, inflammation, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These aging hallmarks are triggered by and enhanced by traditional CVD risk factors leading to geriatric syndromes (eg, frailty, sarcopenia, functional limitation, and cognitive impairment) which complicate efforts toward prevention. Therefore, we review Life's Essential 8 through the lens of aging biology, geroscience, and geriatric precepts to guide clinicians taking care of older adults.


A magnetic shift register with out-of-plane magnetized layers.
Using out-of-plane magnetized layers, a lateral shift register made from discrete elements is demonstrated. By carefully designing the in-plane shape of the elements which make up the shift register, both the position of nucleation of new domains and the coercivity of the element can be controlled. The dipole field from a neighboring element, placed tens of nanometers away, creates a bias field on the nucleation site, which can be used to create a NOT gate. By chaining these NOT gates together, a shift register can be created where data bits consisting of neighboring layers with aligned magnetization are propagated synchronously under a symmetric applied magnetic field. The operation of a 16 element shift register is shown, including field coupled data injection.


Which health-related quality-of-life outcome when planning randomized trials: disease-specific or generic, or both? A common factor model.
The primary outcomes in trials are usually disease-specific measures (DSMs) designed to be responsive to changes in the condition caused by treatment. For purposes of cost-effectiveness analysis, treatment effects on the DSM are often "mapped" into treatment effects on a generic health-related quality-of-life (QOL) scale, such as EuroQol five-dimensional questionnaire. Trialists have the option of including generic QOL measures as trial outcomes. We consider the relative efficiency (estimate divided by its standard error) of treatment effects derived from the DSM, the generic QOL, the generic QOL indirectly estimated from the mapped DSM, and a pooled estimate combining the direct and indirect information on the generic QOL. By using a "common factor" theory of the relationship between the DSM and the generic QOL, we define the circumstances under which indirectly estimated generic QOL is more efficient than the direct one and when a pooled QOL estimate is more efficient than the DSM estimate. As long as the DSM is more responsive, there is always a threshold sample size above which the indirect estimate has better precision than the direct estimate. This threshold, however, increases as the (1) relative responsiveness ratio of the DSM to the generic QOL increases, (2) precision of the estimated mapping coefficient increases, and (3) true effect becomes smaller. The pooled estimate on the generic QOL may be more efficient than the DSM itself unless the reliability of the DSM is particularly high. Trials powered on DSMs are likely to have sufficient power to detect treatment effect on the generic QOL if a pooled estimate is used. We conclude that generic QOL instruments should be routinely included in randomized controlled trials. Information on mapping coefficients and on relative responsiveness should be collected more systematically to facilitate both evidence synthesis and trial design.


[Botulism and pregnancy].
Botulism during pregnancy is uncommon and raises concern due uncertainty about fetal impairment. This type of situation has not been reported to date. Treatment is basically symptomatic and based on nursing care. The prognosis is tightly correlated with the maternal status. Dietary hygiene is the basis of prevention. We describe a case of botulism occurring during the second quarter of pregnancy.


Reducing Pain and Anxiety during Second Trimester Genetic Amniocentesis Using Aromatic Therapy: A Randomized Trial.
To evaluate the benefit of aromatic therapy using menthol for decrease pain perception during amniocentesis. A prospective randomized study was conducted to compare pain level between groups ofpregnant women who underwent amniocentesis with and without aromatic therapy using menthol. Visual analogue scale (VAS) was usedfor pain assessment. The participants were askedfor their anticipated pain and anxiety level and level ofpain before and immediately after the procedure. Three hundred seventeen pregnant women were recruited into the present study, 158 in the menthol group and 159 in the non-menthol group. Mean VAS score of the post-procedure pain and anxiety did not differ significantly between the two groups. Mean VAS score of the anticipated pain influenced the mean VAS score of the pre-procedure anxiety and post-procedure pain and anxiety irrespective of the group. Mean VAS score of the pre-procedure anxiety and post-procedure pain and anxiety increased about 0.3 cm for each 1 cm of increasing mean VAS score of anticipated pain. Aromatic therapy using menthol was not significantly effective in reducing pain and anxiety during second trimester genetic amniocentesis.


Non-canonical Amino Acid Substrates of E. coli Aminoacyl-tRNA Synthetases.
In this comprehensive review, I focus on the twenty E. coli aminoacyl-tRNA synthetases and their ability to charge non-canonical amino acids (ncAAs) onto tRNAs. The promiscuity of these enzymes has been harnessed for diverse applications including understanding and engineering of protein function, creation of organisms with an expanded genetic code, and the synthesis of diverse peptide libraries for drug discovery. The review catalogues the structures of all known ncAA substrates for each of the 20 E. coli aminoacyl-tRNA synthetases, including ncAA substrates for engineered versions of these enzymes. Drawing from the structures in the list, I highlight trends and novel opportunities for further exploitation of these ncAAs in the engineering of protein function, synthetic biology, and in drug discovery.


Homocysteine and Glaucoma.
Elevated levels of homocysteine (Hcy), a non-proteinogenic amino acid, may lead to a host of manifestations across the biological systems, particularly the nervous system. Defects in Hcy metabolism have been associated with many neurodegenerative diseases including glaucoma, i.e., the leading cause of blindness. However, the pathophysiology of elevated Hcy and its eligibility as a risk factor for glaucoma remain unclear. We aimed to provide a comprehensive review of the relationship between elevated Hcy levels and glaucoma. Through a systemic search of the PubMed and Google Scholar databases, we found that elevated Hcy might play an important role in the pathogenesis of glaucoma. Further research will be necessary to help clarify the specific contribution of elevated Hcy in the pathogenesis of glaucoma. A discovery and conceptual understanding of Hcy-associated glaucoma could be the keys to providing better therapeutic treatment, if not prophylactic treatment, for this disease.


Cholesterol, a Major Component of Caveolae, Down-regulates Matrix Metalloproteinase-1 Expression through ERK/JNK Pathway in Cultured Human Dermal Fibroblasts.
Cholesterol is a major component of specialized membrane microdomains known as lipid rafts or caveolae, which modulate the fluidity of biological membranes. Membrane cholesterol therefore plays an important role in cell signaling and vesicular transport. In this study, we investigated the effects of cholesterol on matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. MMP-1 mRNA and protein expression were determined by RT-PCR and Western blotting, respectively. AP-1 DNA binding activity was detected by electrophoretic mobility shift assays. The amount of cholesterol was analyzed by cholesterol assay kit. We observed that MMP-1 mRNA and protein expression was dose-dependently decreased by cholesterol treatment. In contrast, cholesterol depletion by a cholesterol depletion agent, methyl-beta-cyclodextrin (MβCD) in human dermal fibroblasts, increased MMP-1 mRNA and protein expression in a dose-dependent manner. Also, we investigated the regulatory mechanism of MβCD-induced MMP-1 expression: cholesterol depletion by MβCD, activated ERK1/2 and JNK, but not p38 MAPK cascade, and it also significantly increased c-Jun phosphorylation, c-Fos expression and activator protein-1 binding activity. Furthermore, the inhibition of ERK or JNK with specific chemical inhibitors prevented MβCD-induced MMP-1 expression, which indicates that ERK and JNK play an important role in cholesterol depletion-mediated MMP-1 induction. In addition, MβCD-induced phosphorylation of ERK and JNK and MMP-1 expression were suppressed by cholesterol repletion. Our results suggest that cholesterol regulates MMP-1 expression through the control of ERK and JNK activity in human dermal fibroblasts.


Improvement of water quality through biological denitrification.
The present study was undertaken to observe the effect of biological denitrification process on water quality parameters. The results obtained in the present investigations show that the value of pH and alkalinity was increased due to generation of alkalinity during biological denitrification process. The obtained value of the DO in the treated water was found lower than the supplied water, which indicates, DO was consumed by the bacterium. The COD of the treated water was nil, which shows that the organics have been consumed by the bacterium during the denitrification process. The biological reduction of nitrate-nitrogen (from 50.79 mg/L to 0.57 mg/L) was found to be lower than the tolerance limit prescribed by WHO without changing the water quality.


A Novel Technique for Correcting Extensor Lag in Vascularized Toe PIP Joint Transfers.
The use of the vascularized second-toe proximal interphalangeal joint (PIPJ) for vascularized joint transfers (VJTs) allows for restoration of powerful pinch/grasp and range of movement of a PIPJ in the hand. However, because of the lack of central slip formation in the majority of toes, the reconstructed PIPJ often results in extension lag. Extension lag associated with poor central slip formation in the lesser toes can be corrected using central slip reconstruction methods such as the Stack method. However, such methods are often cumbersome and involve extensive dissection and soft tissue manipulation. We present a novel, reproducible, simple yet effective technique in recreating the insertion point of the extensor tendon in the reconstructed finger, hence correcting the issue of extensor lag in vascularized toe joint transfers. The crux of this technique empowers the surgeon with the ability to correct inherent extensor lag of toes in VTJs. This will hence nullify "toe PIPJ angles" as a preselection criteria in determining patients suitable for VJT, thus enabling more patients to benefit from VJTs.


Role of histamine in the aetiology of byssinosis. II. Lung histamine concentrations in guinea pigs chronically exposed to cotton and flax dusts.
Data presented in this study support the finding that cotton and flax dusts contain agents which potentiate the formation or accumulation of histamine or both in the lungs of guinea pigs exposed to dust, and that such agents are present at much higher levels in cotton dust than in flax dust. The potentiating effect may be through the recruitment of mast cells into the lung. Both cotton and flax dusts contain methylating enzyme inhibitory agents, whereas cotton dust also contains agents that inhibit histaminase activity; flax dust contains agents potentiating histamine activity. These agents working together result in the accumulation or depletion of histamine observed in the different groups of animals exposed to either cotton or flax dust in this study.