Untargeted Phytochemical Profiling, Antioxidant, and Antimicrobial Activities of a Tunisian Capsicum annuum Cultivar.
Peppers are among the spices possessing a wide plethora of biological properties due to their excellent supply of health-related metabolites. Capsicum annuum L. (Solanaceae) is cultivated throughout Tunisia, and there is a shortage of information on the identification of the secondary metabolites in the seeds of this species as well as on their biological activities. In the present work, we intended to undertake a chemical characterization of the bioactive compounds from the hydro-methanolic seed extract of C. annuum as well as an evaluation of its broad spectrum of antimicrobial and antioxidant activities. The chemical profile was evaluated by RP-HPLC-DAD-QTOF-MS/MS, whereas the total phenol and flavonoid content, antioxidant, and antimicrobial activities were determined in in vitro assays. In this work, 45 compounds belonging to various phytochemical classes, such as organic acids (2), phenolic compounds (4 phenolic acids and 5 flavonoids), capsaicinoids (3), capsianosides (5), fatty acids (13), amino acids (1), sphingolipids (10), and steroids (2) were identified in the hydro-methanolic seed extract of C. annuum. The phenolic and flavonoid content (193.7 mg GAE/g DW and 25.1 mg QE/g DW, respectively) of the C. annuum extract correlated with the high antiradical activity (IC50 = 45.0 µg/mL), reducing power (EC50 = 61.3 µg/mL) and chelating power (IC50 = 79.0 µg/mL) activities. The hydro-methanolic seed extract showed an important antimicrobial activity against seven bacterial and four fungal strains. In fact, the inhibition zones (IZs) for bacteria ranged from 9.00 ± 1.00 mm to 12.00 ± 0.00 mm; for fungi, the IZs ranged from 12.66 ± 0.57 mm to 13.66 ± 0.57 mm. The minimal inhibition concentration and minimal bactericidal concentration values showed that the extract was more effective against fungi than bacteria.


Posterior pituitary tumours: patient outcomes and determinants of disease recurrence or persistence.
Posterior pituitary tumours (PPTs) are rare neoplasms with the four recognised subtypes unified by thyroid transcription factor -1 (TTF-1) expression, according to the 2017 WHO classification. Though traditionally defined as low-grade neoplasms, a substantial proportion of them show recurrence/persistence following surgery. We selected patients with PPTs in our cohort of 1760 patients operated for pituitary tumours over the past 10 years (2010-2019). The clinical, radiological, hormonal, histopathological profiles and long-term outcomes of the three cases identified (two pituicytomas and one spindle cell oncocytoma, SCO) were analysed. Following a literature review, data of all published cases with documented TTF-1 positive pituicytomas and SCOs were analysed to determine the predictors of recurrence/persistence in these tumours. Patients presented with compressive features or hypogonadism. Two had sellar-suprasellar masses. One had a purely suprasellar mass with a pre-operative radiological suspicion of pituicytoma. Two were operated by transsphenoidal surgery and one transcranially guided by neuronavigation. Histopathology confirmed spindle cells in a storiform arrangement and low Ki67 index. Immunohistochemistry showed positive TTF-1, S-100 expression and variable positivity for EMA, vimentin and GFAP. Re-evaluation showed recurrence/persistence in two patients. A literature review of recurrent/persistent pituicytoma (n = 17) and SCO (n = 9) cases revealed clinical clues (headache for pituicytomas, male gender for SCO), baseline tumour size (≥20.5 mm with sensitivity exceeding 80%) and longer follow-up duration as determinants of recurrence/persistence. PPTs are rare sellar masses with quintessential TTF-1 positivity. Recurrent/persistent disease following surgery is determined by greater tumour size at baseline and duration of follow-up. This warrants intensive and long-term surveillance in these patients.


Career satisfaction and the role of mentorship: a survey of pediatric hospitalists.
Attending physicians' career satisfaction is associated with higher patient satisfaction, better patient care, and even medical student career choice. Previous studies indicate that adequate mentorship improves job satisfaction, but finding mentors may be challenging for some hospitalists. Little is known about pediatric hospitalist career satisfaction or the role of mentorship. The goal of this study was to assess career satisfaction among pediatric hospitalists, determine which interventions may improve satisfaction, and investigate the role of mentorship in satisfaction. This study included the use of an anonymous electronic cross-sectional survey sent to the American Academy of Pediatrics' Section on Hospital Medicine Listserv between November 2009 and January 2010. A total of 222 pediatric hospitalists responded; 92% agreed with the statement, "Overall, I am pleased with my work." Of the 23 satisfaction statements, "I have adequate mentorship in my career" was rated lowest (< or = .001); only 44% agreed. Adequate mentorship was significantly correlated with overall career satisfaction, having sufficient opportunity for promotion, feeling valued by one's administration, and wishing to remain at one's current hospital. Adequate mentorship was negatively correlated with planning to change specialty or leave clinical medicine. Mentorship satisfaction did not differ by age, years as a hospitalist, gender, or practice setting. Of the 15 potential interventions, creating a formal mentorship program ranked in the top 5. Only increasing base salary received a significantly higher score. Although surveyed hospitalists have substantial overall career satisfaction, lack of mentorship is a significant problem that spans the demographic spectrum. Establishing a mentorship program may be an effective way for hospitalist groups to improve satisfaction.


The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control.
Nuclear export of mRNA is tightly linked to transcription, nuclear mRNA processing, and subsequent maturation in the cytoplasm. Tip-associated protein (TAP) is the major nuclear mRNA export receptor, and it acts coordinately with various factors involved in mRNA expression. We screened for protein factors that associate with TAP and identified several candidates, including RNA helicase DDX3. We demonstrate that DDX3 directly interacts with TAP and that its association with TAP as well as mRNA ribonucleoprotein complexes may occur in the nucleus. Depletion of TAP resulted in nuclear accumulation of DDX3, suggesting that DDX3 is, at least in part, exported along with messenger ribonucleoproteins to the cytoplasm via the TAP-mediated pathway. Moreover, the observation that DDX3 localizes transiently in cytoplasmic stress granules under cell stress conditions suggests a role for DDX3 in translational control. Indeed, DDX3 associates with translation initiation complexes. However, DDX3 is probably not critical for general mRNA translation but may instead promote efficient translation of mRNAs containing a long or structured 5' untranslated region. Given that the DDX3 RNA helicase activity is essential for its involvement in translation, we suggest that DDX3 facilitates translation by resolving secondary structures of the 5'-untranslated region in mRNAs during ribosome scanning.


Progressive resistance training to prevent arm lymphedema in the first year after breast cancer surgery: Results of a randomized controlled trial.
Existing research suggests that progressive resistance training (PRT) after breast cancer (BC) surgery is safe, but the preventive effect on arm lymphedema has yet to be determined. Women aged 18 to 75 years who were undergoing BC surgery with axillary lymph node dissection were eligible for the study. Recruited on the day of surgery, participants were allocated to intervention or usual care by computer randomization. The intervention consisted of PRT 3 times per week: in the first 20 weeks as a supervised group exercise and in the last 30 weeks as a self-administered exercise. The primary outcome was arm lymphedema, which was defined as a >3% increase in the interlimb volume difference by water displacement. Measurements were made at the baseline and at a 12-month follow-up by physiotherapists blinded to group allocation. Analyses of effects included t tests and regression models; missing data were addressed by multiple imputation. Among the 158 randomized women, no mean group difference was found in arm volume (0.3%; 95% confidence interval, -1.7% to 2.3%) or lymphedema incidence (adjusted odds ratio, 1.2; 95% confidence interval, 0.5-2.8). None of the participants exited the program because of adverse events. This study provides no evidence that PRT can prevent arm lymphedema in the first year after BC, but the results corroborate the importance and safety of resistance training for patients, including women at high risk for lymphedema.


A novel polymeric drug delivery system for localized and sustained release of tacrolimus (FK506).
Despite substantial improvement in microsurgical techniques for nerve repair, recovery after peripheral nerve injury is usually incomplete. FK506, an FDA approved immunosuppressant, improves functional recovery and reinnervation following peripheral nerve injury in animal models. However, systemically delivered FK506 causes undesirable global immunosuppression. We have, therefore, engineered a biodegradable local delivery system for FK506 using fibrin gel as a drug reservoir that could be placed at a site of nerve injury. FK506 was incorporated into fibrin gel in solubilized, particulated, and poly(lactic-co-glycolic) acid (PLGA) microspheres-encapsulated forms. A tunable release of FK506 in the fibrin gel from days to weeks was observed with the rate of release being most rapid for the solubilized form and then the particulate form. The most prolonged period of release was seen with the PLGA microsphere-encapsulated form. As analyzed by in vitro dorsal root ganglion (DRG) neurite extension assay, PLGA microsphere encapsulation of FK506 did not alter the drug's properties and the released FK506 maintained its bioactivity over the entire period of release. This study suggests that local delivery of FK506 with fibrin hydrogel could be used to enhance peripheral nerve regeneration.


3,400 new expressed sequence tags identify diversity of transcripts in human brain.
We present the results of the partial sequencing of over 3,400 expressed sequence tags (ESTs) from human brain cDNA clones, which increases the number of distinct genes expressed in the brain, that are represented by ESTs, to about 6,000. By choosing clones in an unbiased manner, it is possible to construct a profile of the transcriptional activity of the brain at different stages. Proteins that comprise the cytoskeleton are the most abundant; however, a large variety of regulatory proteins are also seen. About half of the ESTs predicted to contain a protein-coding region have no matches in the public peptide databases and may represent new gene families.


Telehealth awareness in a US urban peritoneal dialysis clinic: From 2018 to 2019.
The 2018 Bipartisan Budget Act in the United States extended telehealth access to Medicare beneficiaries who receive home dialysis in which two of three monthly visits in a quarter may be performed by telehealth after three initial face-to-face monthly visits. The originating site (where the patient is located) can be a dialysis unit or the patient's home and without geographic restriction. Patient awareness and interest in this new telehealth benefit in urban patients has not been well characterized. Patients receiving peritoneal dialysis (PD) treatment located in an urban facility completed a survey to ascertain knowledge of telehealth and readiness and willingness to participate in telehealth for their monthly visit. A total of 30 patients participated: 37% who completed the survey had heard of telehealth and 40% were able to define telehealth in words and correctly identify an example of telehealth. None of the patients were aware of the 2018 US Bipartisan Budget Act which extended telehealth assess to Medicare beneficiaries. Almost everyone had a mobile phone (83%), owned a computer (50%), and had access to Internet services (90%). The majority of patients (73%) were willing to use telehealth services for their monthly visit with the physician. PD patients living in an urban setting appear to be ready and interested in using telehealth to perform their monthly visit with the physician.


Patient Factors Associated With Appendectomy Within 30 Days of Initiating Antibiotic Treatment for Appendicitis.
Use of antibiotics for the treatment of appendicitis is safe and has been found to be noninferior to appendectomy based on self-reported health status at 30 days. Identifying patient characteristics associated with a greater likelihood of appendectomy within 30 days in those who initiate antibiotics could support more individualized decision-making. To assess patient factors associated with undergoing appendectomy within 30 days of initiating antibiotics for appendicitis. In this cohort study using data from the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) randomized clinical trial, characteristics among patients who initiated antibiotics were compared between those who did and did not undergo appendectomy within 30 days. The study was conducted at 25 US medical centers; participants were enrolled between May 3, 2016, and February 5, 2020. A total of 1552 participants with acute appendicitis were randomized to antibiotics (776 participants) or appendectomy (776 participants). Data were analyzed from September 2020 to July 2021. Appendectomy vs antibiotics. Conditional logistic regression models were fit to estimate associations between specific patient factors and the odds of undergoing appendectomy within 30 days after initiating antibiotics. A sensitivity analysis was performed excluding participants who underwent appendectomy within 30 days for nonclinical reasons. Of 776 participants initiating antibiotics (mean [SD] age, 38.3 [13.4] years; 286 [37%] women and 490 [63%] men), 735 participants had 30-day outcomes, including 154 participants (21%) who underwent appendectomy within 30 days. After adjustment for other factors, female sex (odds ratio [OR], 1.53; 95% CI, 1.01-2.31), radiographic finding of wider appendiceal diameter (OR per 1-mm increase, 1.09; 95% CI, 1.00-1.18), and presence of appendicolith (OR, 1.99; 95% CI, 1.28-3.10) were associated with increased odds of undergoing appendectomy within 30 days. Characteristics that are often associated with increased risk of complications (eg, advanced age, comorbid conditions) and those clinicians often use to describe appendicitis severity (eg, fever: OR, 1.28; 95% CI, 0.82-1.98) were not associated with odds of 30-day appendectomy. The sensitivity analysis limited to appendectomies performed for clinical reasons provided similar results regarding appendicolith (adjusted OR, 2.41; 95% CI, 1.49-3.91). This cohort study found that presence of an appendicolith was associated with a nearly 2-fold increased risk of undergoing appendectomy within 30 days of initiating antibiotics. Clinical characteristics often used to describe severity of appendicitis were not associated with odds of 30-day appendectomy. This information may help guide more individualized decision-making for people with appendicitis.


Bariatric Surgery in the Elderly Is Associated with Similar Surgical Risks and Significant Long-Term Health Benefits.
Older age (> 60) has been considered a relative contraindication for bariatric surgery due to increased complication risk. This study examined the risks and benefits of bariatric surgery for patients older than 60 years in Canadian population. This was a retrospective cohort study of the Ontario Bariatric Registry: a database recording peri-operative and post-operative outcomes of publicly funded bariatric surgeries across the province. Patients who completed 1 year follow-up, who underwent laparoscopic gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) between January 2010 and May 2013, were divided into older (> 60) and younger (> 60) cohorts, and outcomes were compared. Between January 2010 and May 2013, 3166 registry patients underwent LRYGB or LSG and completed 1-year follow-up. Of these, 204 (6.5%) were older than 60 years, with 175 (85.8%) undergoing LRYGB and 29 (14.2%) LSG. Demographics were similar, except for a higher number of males in the older group (59 (28.9%) versus 452 (15.3%) (p < 0.001)). No significant difference in complication rate was noted (15% for younger cohort versus 13.8% (p = 0.889)). The average percentage of excess weight loss was significantly higher in the younger population (60.72% versus 56.25% (p < 0.05)) overall, however not significantly in the LSG group. Reduction in medication use post-surgery for management of co-morbidities was significantly higher in the older patients (- 0.91 versus - 2.03 (p < 0.001)). The older cohort who underwent LRYGB or LSG was at no greater risk for intra-operative and post-operative complications and showed greater reduction in medication use post-surgery when compared to the younger cohort.


Renal transplantation in children ages 1 to 5 years.
Renal transplantation was carried out in 21 children ages 1 to 5 years. Eighteen received grafts from a living, related donor (LRD). Four children died, one following rejection, and three because of infection. Five children lost their initial grafts and two have received new transplants. Cumulative patient survival two and four years following LRD transplantation was 94% and 76%, respectively. This was similar to results found in children ages 6 to 14 years. Accelerated growth rates were seen in the first posttransplant year in those small children who were severely growth-retarded at the same time of transplantation and who achieved normal graft function. However, only one of these children ultimately reached the tenth percentile for height for chronological age. We conclude that renal transplantation is warranted in the very young child with renal failure.


Commensal isolates of methicillin-resistant Staphylococcus epidermidis are also well equipped to produce biofilm on polystyrene surfaces.
To study biofilm production and to detect icaAD, atlE and aap genes in 137 isolates of methicillin-resistant Staphylococcus epidermidis (MRSE) obtained from healthy individuals from the community (35 isolates), from hospitalized patients at the Antônio Pedro University Hospital (25 isolates) and from individuals from a home-care system (HCS; 77 isolates). Biofilm production was determined in vitro using polystyrene inert surfaces. icaAD, atlE and aap genes were detected using PCR. Hybridization experiments were also carried out to confirm some PCR results. Antimicrobial susceptibility testing was carried out using the NCCLS methods. Although many of the commensal MRSE isolates produced biofilms, the percentage of biofilm producers was significantly higher (P = 0.0107) among hospital isolates (76%) than among isolates from the community (60%) and from the HCS (57%). An association was observed between multiresistance and biofilm production for isolates obtained from healthy individuals from the community and from household contacts from the HCS (P < 0.0001). The concomitant presence of the ica operon and atlE and aap genes was associated with the strong biofilm-producer phenotype (P < 0.0001). Because many of the commensal MRSE isolates obtained from nares produced biofilms and carried icaAD, aap and atlE genes, biofilms or such genetic elements should not be used as markers for clinical significance. The biofilm environment seems to increase genetic exchanges and hence may contribute to multiresistance phenotypes.


Effects of a high n-3 fatty acid diet on membrane lipid composition of heart and skeletal muscle in normal swine and in swine with the genetic mutation for malignant hyperthermia.
Knowledge concerning the genetic defects underlying malignant hyperthermia (MH) has expanded rapidly in recent years. In contrast, our understanding of the accompanying physiological changes is less clear. In this regard, the aim of this study was to determine whether normal swine and swine susceptible to MH (both heterozygous and homozygous animals) differ in their abilities to incorporate n-3 (omega 3) fatty acids into their skeletal and heart muscles. Swine of each genotype were fed either a diet rich in n-3 fatty acids (i.e., 5% fish oil) or an equal caloric diet low in n-3 fatty acids (i.e., 5% coconut oil). All dietary supplementations were given over a 13-week period. Subsequently, for each muscle type the following was determined: 1) the relative fatty acid profiles of eight different phospholipid classes and of neutral lipids, and 2) the total phospholipid and the total lipid content. The incorporation of n-3 fatty acids (i.e., eicosapentaenoic acid and docosahexaenoic acid) occurred within the various phospholipids and neutral lipids without influencing their total lipid content. The increased content of n-3 fatty acids in neutral lipids of skeletal muscle was related to a decreased content of medium-chain saturated fatty acids, whereas an increased incorporation of n-3 fatty acids into the membrane phospholipids was often related to a decreased content of linoleic acid and/or arachidonic acid. In general, the pattern of n-3 fatty acid incorporation was considerably different between the normal animals and the MH homozygous and heterozygous animals. The significant interaction between diet-induced n-3 fatty acid profiles and the stress-susceptible MH genotype may indicate an altered mechanism for fatty acid turnover and a repair mechanism to maintain cellular functions and structure.


Relationship between illness perceptions, treatment adherence, and clinical outcomes in patients on maintenance hemodialysis.
Previous data indicate that negative perception of disease and non-adherence to recommended treatment may lead to unfavorable clinical outcomes in patients on maintenance hemodialysis (HD). However, a paucity of research addresses clinical outcomes in the end stage renal disease (ESRD) population as a function of patients' illness perceptions and their degree of adherence to recommended treatment. The study was conducted to examine illness perceptions and treatment adherence rates in patients on maintenance HD, and to determine if illness perceptions and adherence behaviors influence clinical outcomes. One hundred fifty-one patients completed the Revised Illness Perception Questionnaire and the ESRD-Adherence Questionnaire. Illness perceptions did not independently predict any clinical outcomes in patients on maintenance HD; however, specific adherence behaviors affected clinical outcomes. Therefore, strategies to enhance adherence should be rigorously pursued in this population to improve clinical outcomes.


Monitoring the endangered population of the antelope Kobus leche smithemani (Artiodactyla: Bovidae), in the Bangweulu Ecosystem, Zambia.
Black lechwe (Kobus leche smithemani) is a semi-aquatic medium sized antelope currently enlisted on the IUCN red list of endangered species and is only endemic to the Bangweulu basin of Zambia. Its population has significantly decreased due to floods that took place during the period 1930-1940 from over 250 000-15000 leading the Zambian government to gazette all habitats of Black lechwe into state protected areas, and to establish urgent management strategies needed to save the remaining population from extinction. Using retrospective data, our findings show that the population has increased from 15000 animals in 1954 to 55 632 in 2009. The current population is estimated at 34.77% (55 632/160 000) of the carrying capacity of the Bangweulu basin. Although the Black lechwe is one of the 42 species offered for consumptive utilization by the Zambia Wildlife Authority (ZAWA), only 0.12% and 0.08% of the current stock was offered for safari and resident hunting annually for the period 2005-2009, respectively. Annual quota utilization were estimated at 67% (n=37) and 81% (n=37) for safari and resident hunting, respectively. Hence, overall income obtained from utilization of Black lechwe is very low accounting for only 2.1% of the total revenue earned from wildlife utilization. Although the current population trend is showing a unit increase of 639 animals per year, it is still far below levels ideal for the lucrative utilization. In this study, we demonstrate that adverse ecological changes on wildlife species, can lead to their vulnerability and danger of extinction, and that their recovery to full carrying capacity may demand a considerable amount of time.


Discovery of trypanocidal coumarins with dual inhibition of both the glycerol kinase and alternative oxidase of Trypanosoma brucei brucei.
African trypanosomiasis, sleeping sickness in humans or nagana in animals, is a potentially fatal neglected tropical disease and a threat to 65 million human lives and 100 million small and large livestock animals in sub-Saharan Africa. Available treatments for this devastating disease are few and have limited efficacy, prompting the search for new drug candidates. Simultaneous inhibition of the trypanosomal glycerol kinase (TGK) and trypanosomal alternative oxidase (TAO) is considered a validated strategy toward the development of new drugs. Our goal is to develop a TGK-specific inhibitor for coadministration with ascofuranone (AF), the most potent TAO inhibitor. Here, we report on the identification of novel compounds with inhibitory potency against TGK. Importantly, one of these compounds (compound 17) and its derivatives (17a and 17b) killed trypanosomes even in the absence of AF. Inhibition kinetics revealed that derivative 17b is a mixed-type and competitive inhibitor for TGK and TAO, respectively. Structural data revealed the molecular basis of this dual inhibitory action, which, in our opinion, will aid in the successful development of a promising drug to treat trypanosomiasis. Although the EC50 of compound 17b against trypanosome cells was 1.77 µM, it had no effect on cultured human cells, even at 50 µM.-Balogun, E. O., Inaoka, D. K., Shiba, T., Tsuge, C., May, B., Sato, T., Kido, Y., Nara, T., Aoki, T., Honma, T., Tanaka, A., Inoue, M., Matsuoka, S., Michels, P. A. M., Watanabe, Y.-I., Moore, A. L., Harada, S., Kita, K. Discovery of trypanocidal coumarins with dual inhibition of both the glycerol kinase and alternative oxidase of Trypanosoma brucei brucei.


Psychocutaneous disease: Clinical perspectives.
Psychocutaneous disease, defined in this review as primary psychiatric disease with skin manifestations, is commonly encountered in dermatology. Dermatologists can play an important role in the management of psychocutaneous disease because patients visit dermatology for treatment of their skin problems but often refuse psychiatric intervention. This review describes common psychocutaneous syndromes, including delusional, factitious, obsessive-compulsive and related, and eating disorders, as well as psychogenic pruritus, cutaneous sensory (pain) syndromes, posttraumatic stress disorder, and sleep-wake disorders. The updated classification of these disorders in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition is included. Strategies for management are reviewed.


Factors affecting heart rate as measured at home among treated hypertensive patients: the Japan home versus office blood pressure measurement evaluation (J-HOME) study.
We previously reported that a resting heart rate measured at home (home HR) of >or=70 beats per minute was a powerful predictor of the risk of cardiovascular disease mortality, and identified factors affecting home HR in the general Japanese population. The present study examines factors affecting home HR in hypertensive patients treated with antihypertensive medications. Home HR was measured using a home blood pressure (BP) device. Information about the characteristics of the patients was collected using questionnaires administered by a physician. Among 3,400 patients, 3,086 measured home HR both in the morning and evening. The mean values of home HR in the morning and evening were 67.2+/-9.1 and 69.6+/-9.2 beats per minute, respectively. Multivariate linear regression analysis showed that lower age, diabetes mellitus, habitual smoking, higher diastolic BP, and the lack of beta-blocker or angiotensin-converting enzyme inhibitor use were determinants of elevated morning or evening home HR. These results suggest that adequate control of risk factors for cardiovascular disease such as smoking and diabetes mellitus or use of heart rate-lowering agents might help to decrease home HR in treated hypertensive patients.


Animal models for metabolic, neuromuscular and ophthalmological rare diseases.
Animal models are important tools in the discovery and development of treatments for rare diseases, particularly given the small populations of patients in which to evaluate therapeutic candidates. Here, we provide a compilation of mammalian animal models for metabolic, neuromuscular and ophthalmological orphan-designated conditions based on information gathered by the European Medicines Agency's Committee for Orphan Medicinal Products (COMP) since its establishment in 2000, as well as from a review of the literature. We discuss the predictive value of the models and their advantages and limitations with the aim of highlighting those that are appropriate for the preclinical evaluation of novel therapies, thereby facilitating further drug development for rare diseases.


Tachycardia and fibrillation detection by automatic implantable cardioverter-defibrillators: sequential testing in time domain.
The automatic implantable cardioverter-defibrillator (AICD), a device that delivers a high-energy shock (10-30 J) directly to the heart when life-threatening arrhythmias are detected, must accurately detect ventricular fibrillation (VF) and ventricular tachycardia (VT) rhythms. The signal-processing problem is how to accurately distinguish normal sinus rhythm or supraventricular tachycardia from malignant VT and VF signals. An approach based on discriminating probability distributions of interbeat intervals in electrogram signals recorded from atrial and ventricular leads is described. A sequential hypothesis-testing algorithm that allows desired false positive and false negative rates and the time it takes to detect the arrhythmias to be preset is presented. A tradeoff between reliability and duration of test is noted; a decision can be reached in a shorter time if higher error rates are accepted as permissible. In an analysis of 85 cases of VF and 85 cases of VT, 53% of VF cases and 66% of VT cases were classified after 1 s, 97.6% of VF cases and 100% of VT cases were classified after 5 s, and within 7 s, all the remaining VF cases were classified.


The standardisation of fluorine-18.
The Australian Nuclear Science and Technology Organisation (ANSTO) maintains and disseminates the Australian standards of activity measurement. The standards include all nuclear medicine gamma-emitters and pure positron emitters. Calibration factors for the ANSTO 4 pi ionisation chamber for pure positron emitters have been traditionally determined from primary standardisations of cobalt-60 and sodium-22. Activity estimates of pure beta emitters have been previously determined by using 4 pi beta-gamma coincidence (efficiency tracer) counting. This method was adapted to test activity estimates of short-lived pure positron emitters made using the 4 pi ionisation chamber. Detailed are methods whereby the activity of fluorine-18 can be measured. The first method is an efficiency tracing method developed in this work. The method directly tests 4 pi ionisation chamber fluorine-18 activity estimates. The gamma-gamma method was carried out to confirm this.


Celiac Disease Symptoms in Athletes: Prevalence Indicators of Perceived Quality of Life.
Celiac disease (CD) is a common gastrointestinal pathology; however, prevalence and comorbidities are unknown in collegiate athletics. (1) Athletes will have similar odds of CD as general population estimates (approximately 1 in 141) based on self-report and signs and symptoms, (2) athletes scoring higher on the Celiac Symptom Index (CSI) will have lower self-reported quality of life (QoL), (3) athletes scoring higher on the CSI will have higher depression scores, and (4) athletes scoring higher on the CSI will have higher perceived stress scores. Epidemiological cross-sectional study. Level 4. The CSI, WHO Quality of Life-BREF, Beck Depression Inventory, and Perceived Stress Scale were used to assess patients' signs and symptoms of CD and psychosocial measures/QoL in male and female National Collegiate Athletic Association (all divisions) athletes (N = 141). Participants also self-reported a formal diagnosis of CD. Chi-square analyses determined CD prevalence. Odds ratios determined risk for either being diagnosed with CD or reporting more symptoms than the general population. Correlational analyses determined whether symptoms correlated with QoL and psychosocial measures. Athletes were 3.85 times (95% CI, 0.42-34.89) more likely to report a CD diagnosis and were 18.36 times (95% CI, 2.40-140.48) more likely to report a high degree of CD symptoms than the general population. Athletes with more symptoms had worse physical, psychological, social, and environmental QoL indicators and higher depression and perceived stress scores. Athletes may be a higher risk population for experiencing CD and report greater signs/symptoms compared with general population estimates. Additionally, athletes with higher CD symptom scores also reported poorer QoL. Allied health care professionals should be aware of the diversity of CD symptoms and be prepared to refer athletes when gastrointestinal symptoms persist to ensure proper care and unhampered performance.


Heterogeneous cytogenetic abnormalities in small cell lung cancer cell lines.
Ten cell lines were established from different biopsies from nine patients with small cell lung cancer (SCLC). These were established from metastases in the marrow (7), breast (1), pleural fluid (1), and spinal cord (1) and had been in culture for periods varying from 1 to 11 months. All cell lines exhibited typical cytological features of SCLC, and produced neuron specific enolase. All lines examined (5) contained dense core granules and were tumorigenic when injected intracranially into nude mice. None of the six cell lines tested had an amplified oncogene (c-myc or n-myc) previously reported to be amplified in SCLC. Detailed chromosome analyses were undertaken and showed that a structural abnormality of chromosome 3(p11p23) was a frequent (6 of 10) but not invariable finding. Our study and one other indicate that there is not a unique chromosome abnormality present in all cases of SCLC, although loss of chromosome 13 and structural abnormalities of chromosome 3 were frequently found. A feature of these SCLC cell lines established from metastatic deposits was the complexity of the karyotypes due to numerical and structural chromosomal abnormalities.


Regulation of recombinant human brain tandem P domain K+ channels by hypoxia: a role for O2 in the control of neuronal excitability?
The tandem P domain potassium channels, TREK1 and TASK1, are expressed throughout the brain but expression patterns do not significantly overlap. Since normal pO2 in central nervous tissue is as low as 20 mmHg and can decrease even further in ischemic disease, it is important that the behaviour of human brain ion channels is studied under conditions of acute and chronic hypoxia. This is especially true for brain-expressed tandem P-domain channels principally because they are important contributors to neuronal resting membrane potential and excitability. Here, we discuss some recent data derived from two recombinant tandem P-domain potassium channels, hTREK1 and hTASK1. Hypoxia represents a potent inhibitory influence on both channel types and occludes the activation by arachidonic acid, intracellular acidosis and membrane deformation of TREK1. This casts doubt on the idea that TREK1 activation during brain ischemia might facilitate neuroprotection via hyperpolarising neurons in which it is expressed. Interestingly, hypoxia is unable to regulate alkalotic inhibition of TREK1 suggesting that this channel may be more intimately involved in control of excitability during physiological or pathological alkalosis.


In situ mechanotransduction via vinculin regulates stem cell differentiation.
Human mesenchymal stem cell (hMSC) proliferation, migration, and differentiation have all been linked to extracellular matrix stiffness, yet the signaling pathway(s) that are necessary for mechanotransduction remain unproven. Vinculin has been implicated as a mechanosensor in vitro, but here we demonstrate its ability to also regulate stem cell behavior, including hMSC differentiation. RNA interference-mediated vinculin knockdown significantly decreased stiffness-induced MyoD, a muscle transcription factor, but not Runx2, an osteoblast transcription factor, and impaired stiffness-mediated migration. A kinase binding accessibility screen predicted a cryptic MAPK1 signaling site in vinculin which could regulate these behaviors. Indeed, reintroduction of vinculin domains into knocked down cells indicated that MAPK1 binding site-containing vinculin constructs were necessary for hMSC expression of MyoD. Vinculin knockdown does not appear to interfere with focal adhesion assembly, significantly alter adhesive properties, or diminish cell traction force generation, indicating that its knockdown only adversely affected MAPK1 signaling. These data provide some of the first evidence that a force-sensitive adhesion protein can regulate stem cell fate.


Hepatitis B virus reactivation by immunosuppressive therapy in patients with autoimmune diseases: risk analysis in Hepatitis B surface antigen-negative cases.
To evaluate the risk of reactivation of resolved hepatitis B virus (HBV) by immunosuppressive therapy in patients with autoimmune diseases. Thirty-five patients with autoimmune diseases were included in our study; all were hepatitis B surface antigen (HBsAg)-negative and antibody against hepatitis B core antigen-positive. They were followed for 8-124 weeks and clinical outcomes were analyzed, including serum levels of HBV-DNA and aminotransferase every 4 weeks during their immunosuppressive therapy for underlying autoimmune diseases. If HBV-DNA was detected during the immunosuppressive therapy, HBsAg, antibody against HBsAg (anti-HBs), hepatitis B e antigen (HBeAg), and antibody against HBeAg were also monitored every 4 weeks. HBV-DNA was detected in 6 out of 35 patients. Anti-HBs titer was significantly lower in the patients in whom HBV-DNA was detected compared with the others at baseline: 2.83 (range 0.24-168.50) mIU/ml vs 99.94 (range 0.00-5342.98) mIU/ml, respectively (p = 0.036). Outcomes of the 6 patients with HBV reactivation were as follows: HBV-DNA turned negative in 2 patients without nucleic acid analog (NAA) and 1 with NAA; 2 died due to bacterial sepsis; and 1 died due to autoimmune hemolytic anemia. Significant elevation of aminotransferase was found in only 1 patient, but HBsAg converted to positive in 2 patients and HBeAg converted to positive in 1 patient. Reactivation of resolved HBV can occur during standard immunosuppressive therapy for autoimmune diseases. The low titer of baseline anti-HBs may carry its risk.


Multiple conformational states of repair patches in chromatin during DNA excision repair.
In mammalian cells, newly synthesized DNA repair patches are highly sensitive to digestion by staphylococcal nuclease (SN), but with time, they acquire approximately the same nuclease resistance as the DNA in bulk chromatin. We refer to the process which restores native SN sensitivity to repaired DNA as chromatin rearrangement. We find that during repair of ultraviolet damage in human fibroblasts, repair patch synthesis and ligation occur at approximately the same rate, with ligation delayed by about 4 min, but that chromatin rearrangement is only 75% as rapid. Thus, repair-incorporated nucleotides can exist in at least three distinct states: unligated/unrearranged, ligated/unrearranged, and ligated/rearranged. Inhibition of repair patch synthesis by aphidicolin or hydroxyurea results in inhibition of both patch ligation and chromatin rearrangement, confirming that repair patch completion and/or ligation are prerequisites for rearrangement. We also analyze the kinetics of SN digestion of repair-incorporated nucleotides at various extents of rearrangement and find the data to be consistent with the existence of two or more forms of unrearranged repair patch which have different sensitivities to digestion by SN. These data indicate that the chromatin rearrangement which restores native SN sensitivity to repaired DNA is a multistep process. The multiple forms of unrearranged chromatin with different SN sensitivities may include the unligated/unrearranged and ligated/unrearranged states. If so, the differences in SN sensitivity must arise from differences in chromatin structure, because SN does not differentiate between ligated and unligated repair patches in naked DNA.


Facial asymmetry and condylar hyperplasia: considerations for diagnosis in 27 consecutives patients.
Facial asymmetry associated with condylar hyperplasia (CH) has been become the object of study in recent years. The aim of this study is to demonstrate the importance of analyzing the presence of CH in cases of facial asymmetry. Twenty-seven consecutive patients were studied without distinction of age or gender; all the patients consulted for treatment of facial and/or mandibular asymmetry and voluntarily agreed to participate in the study. All the patients underwent facial cone beam tomography and bilateral TMJ as well as a detailed history where they indicated the progression of the disease; in cases of active evolution determined by clinical analysis and imaging, a SPECT analysis was performed to define the isotope uptake. 29.6% of the subjects with scintigram exhibited active CH with a more than 10% difference in uptake between the two condyles; 18.5% presented differences in uptake between 5% and 10%. Active CH was related to the age and gender of the subjects, being more prevalent in women than in men. The aggression level of the uptake was also related to the subject's age. 55% of the subjects presented with some type of orthodontic treatment with no diagnosis of TMJ pathology in the initial consultation. It can be concluded that CH is associated with facial asymmetries and must be studied integrally before assessing treatment options.


Therapeutic actions of the Chinese herbal formulae with cold and heat properties and their effects on ultrastructures of synoviocytes in rats of the collagen-induced arthritis.
The therapeutic actions of Qing Luo Yin with heat property and Wen Luo Yin with cold property on pain, swelling of the ankle, arthritis index and ultrastructures of synoviocytes were compared in rats of type II collagen-induced arthritis (CIA), with tripterygium glycosidorum (TG) used as control. The results indicated that both QLY and WLY could reduce pain, swelling of the ankle and the arthritis index of CIA, and QLY had better effects in reducing the swelling of the ankle and controlling the secondary pathological lesions as compared with WLY. Investigation on the ultrastructures of synoviocytes indicated that both QLY and WLY could reduce the number of Golgi apparatus, rough surface endoplasmic reticulum, dense bodies, matrix filaments and vacuoles so as to suppress the excessive secretion of synoviocytes in rats of CIA.


Rapid detection method for hepatitis A virus from lettuce by a combination of filtration and integrated cell culture-real-time reverse transcription PCR.
We have developed a rapid and simple method for filtration using a positively charged membrane to concentrate hepatitis A virus (HAV) from lettuce and an integrated cell culture-real-time reverse transcription PCR (ICC-real-time RT-PCR) to detect infectious HAV. The most suitable buffer for HAV concentration by filtration was 100 mM Tris-HCl, 50 mM glycine (pH 9.5). Filtration using the NanoCeram matrix was compared with polyethylene glycol precipitation for viral concentration from lettuce inoculated with 6 log RNA copies of HAV. The recovery rate of filtration was statistically higher than that of polyethylene glycol precipitation (47.3 versus 24.9%, respectively). The sensitivity of ICC-real-time RT-PCR for detection of infectious HAV was determined by inoculation of FRhK-4 cells with HAV (4 log to 0 log RNA copies). ICC-real-time RT-PCR detected infectious HAV on average 5 days earlier than cytopathic effects at all inoculation levels. HAV recovered from lettuce (approximately 3 log RNA copies) was also analyzed with ICC-real-time RT-PCR. Infectious HAV was detected within 2 days postinfection by ICC-real-time RT-PCR, whereas cytopathic effects were not observed until 7 days postinfection. Coupled with a virus concentration and purification system using a positively charged membrane, ICC-real-time RT-PCR has the potential to become a novel and rapid method for the detection of infectious HAV in vegetables.


Early life nutrient restriction impairs blood-brain metabolic profile and neurobehavior predisposing to Alzheimer's disease with aging.
Prenatal nutrient restriction (NR) culminating in intra-uterine growth restriction (IUGR) with postnatal catch up growth leads to diabesity. In contrast, postnatal NR with growth restriction (PNGR) superimposed on IUGR (IPGR) protects young and aging adults from this phenotype. We hypothesized that PNGR/IPGR will compromise the blood-brain metabolic profile impairing neurobehavior and predisposing to Alzheimer's disease (AD). NR (50%) in late gestation followed by cross-fostering of rat pups to either ad lib fed (CON) or NR (50%) lactating mothers generated CON, IUGR, PNGR and IPGR male (M) and female (F) offspring that were examined through the life span. In PNGR/IPGR plasma/CSF glucose and lactate decreased while ketones increased in (M) and (F) (PN21, PN50). In addition increased brain glucose transporters, Glut1 & Glut3, greater brain derived neurotrophic factor (BDNF), reduced Glut4, with unchanged serotonin transporter concentrations were noted in (F) (PN50-60). While (F) displayed more hyperactivity, both (F) and (M) exhibited anxiety although socially and cognitively unimpaired (PN25-28&50). Aging (15-17 m) (F) not (M), expressed low plasma insulin, reduced brain IRS-2, pAkt, and pGSK-3β(Ser9), unchanged pPDK1, pTau or lipoprotein receptor related protein 1 (LRP1), higher glial fibrillary acidic protein (GFAP) and spinophilin but a 10-fold increased amyloid-β42. We conclude that therapeutically superimposing PNGR on IUGR (IPGR) should be carefully weighed in light of unintended consequences related to perturbed neurobehavior and potential predilection for AD.


Studies on a temperature-sensitive mutant of fowl plague virus having a mutation in gene 7 coding for the M protein.
A fowl plague virus (FPV) temperature-sensitive mutant, ts 303/1 having a ts mutation in gene 7 coding for the matrix (M) protein has been obtained. The mutant induced synthesis of virus-specific RNA and polypeptides as well as ribonuclear protein (RNP) formation in cells under non-permissive conditions; however, haemagglutinin cleavage was reduced, functionally active haemagglutinin and neuraminidase were absent and virions were not formed. In mutant-infected cells at 36 degrees C haemagglutinin cleavage was also reduced and virions formed had an altered NP:M ratio as well as a decreased haemagglutinin content. A population of virions formed under these conditions was heterogeneous both in morphology and in buoyant density. The data obtained suggest that a mutation in the M proteins of orthomyxoviruses can affect processing of the haemagglutinin and impair final stages of virion morphogenesis.


Protein C inhibitor regulates hepatocyte growth factor activator-mediated liver regeneration in mice.
We recently reported that human protein C inhibitor (PCI), a major inhibitor of activated protein C (APC), inhibits hepatocyte growth factor activator (HGFA) by forming HGFA-PCI complexes in vitro. In this study, we evaluated whether PCI regulates HGFA-mediated liver regeneration in a human PCI gene transgenic (hPCI-Tg) mouse model. After partial hepatectomy in hPCI-Tg and wild-type (WT) mice, the degree of liver regeneration, protein and mRNA expression of HGFA, proHGF activation, plasma levels of PCI and HGFA-PCI complex, and other markers were evaluated in the remnant liver. We also evaluated the effect of anti-human PCI antibody on liver regeneration, which significantly decreased in hPCI-Tg mice compared to WT mice. HGFA mRNA levels in naive and remnant livers after hepatectomy were the same in both WT and hPCI-Tg mice; however, plasma HGFA levels and HGF activation in the liver were lower in hPCI-Tg than in WT mice. There was no difference in plasma levels of transaminases and inflammatory cytokines. However, sinusoidal congestion and bleeding were detected and the serum hyaluronic acid level was elevated in hPCI-Tg mice, indicating that human PCI aggravates sinusoidal injury by inhibiting the cytoprotective effect of APC. APC decreased thrombin-induced IL-6 production in isolated hepatic nonparenchymal cells (NPCs) in vitro. This impaired liver regeneration was reversed by anti-human PCI antibody treatment in vivo. PCI regulates liver regeneration after hepatectomy by forming an HGFA-PCI complex and aggravates hepatic NPC injury by inhibiting the cytoprotective effect of APC. Anti-PCI antibody treatment may be a novel therapy for improving liver regeneration.


Alcohol-aggravated episodic pain in humans with SCN11A mutation and ALDH2 polymorphism.
Mutations in Nav1.9 encoded by SCN11A have been associated with episodic pain, small-fiber neuropathy, and congenital insensitivity to pain. In this study, we collected and characterized one Chinese family with episodic pain. The SCN11A mutation (c.664C>A/p.Arg222Ser) was identified and cosegregated with the episodic pain phenotype. In addition, we found that alcohol intake triggered intense pain attacks and detected the ALDH2 polymorphism (c.1510G>A/p.Glu504Lys) in 3 patients with episodic pain. The alcohol-aggravated pain symptom and this ALDH2 polymorphism were also reconfirmed in our previously reported episodic pain patient with the Nav1.9 mutation (p.Ala808Gly, patient III-2 in HBBJ family). To assess the pathogenicity of the Nav1.9 mutation and the new trigger, we introduced a mutation (p.Ala796Gly) into the mouse (orthologous mutation in human is p.Ala808Gly). The alteration hyperpolarized channel activation, increased the residual current through noninactivating channels, and induced hyperexcitability of dorsal root ganglion (DRG) neurons in Scn11a mice. The Scn11a mice showed increased sensitivity to mechanical, heat, and cold stimuli, and hypersensitivity to acetaldehyde and formalin, which could account for the alcohol intake-induced pain phenotype in patients. Moreover, acetaldehyde increased the mutant mNav1.9 channel current and excitability of Scn11a mouse DRG neurons. Parecoxib (an anti-inflammatory medication) relieved the heat hypersensitivity in Scn11a mice not receiving inflammatory stimuli and significantly decreased the hyperexcitability of DRG neurons in Scn11a mice. These results indicated that Scn11a mice recapitulated many clinical features of patients and suggested that Nav1.9 channel contributes significantly to the inflammatory pain state.


The Effect of Music Therapy on Anxiety and Various Physical Findings in Patients With COPD in a Pulmonology Service.
This interventional study was carried out to determine the effect of music therapy on anxiety and the various physical findings in patients with chronic obstructive pulmonary disease in the pulmonary diseases service. Ninety-six patients (28 females, 68 males) of 114 adult patients who were hospitalized between November 10, 2013, and March 10, 2014, were included in the study. Ninety-six patients were separated in 3 groups. The data for the study were collected from a questionnaire form of sociodemographic and clinical characteristics, a patient follow-up form, and the Beck Anxiety Scale. SPPS 11.5 was used for data analysis. The Kolmogorov-Smirnov Test was used to determine whether the data showed normal distribution. The nonparametric Kruskal-Wallis Test was used to determine the differences between mean anxiety scores on day 0, day 5, and day 15, and the differences in physiological findings on day 0, day 5, and day 15. There was a significant decrease in anxiety level average on day 5 (P ≤ .0001) and day 15 (P ≤ .0001) of the study in both the Western classical music and Turkish classical music groups compared with control group. There was also a significant decrease in systolic blood pressure and diastolic blood pressure averages in both music groups compared with control group (P ≤ .005). There was no significant difference in heart rates and respiration rate average between the Western classical music and Turkish classical music groups compared with the control group (P > .05).


Optimizing communication between medical professionals and people living with dementia.
A growing body of research evidence indicates that improving communication with people living with dementia (PLWD) has a positive effect on their quality of life. Policy initiatives internationally highlight the prevalence of poor communication practices in care environments in general and medical contexts in particular as priority areas for improvement. Currently available communication interventions exhibit shortcomings, and their application remains unusual. A spectrum of multidisciplinary professional and lay stakeholders, including PLWD, took part in an iterative consultation process in the UK. This aimed to develop a communications advice package which would meet their needs, and involved observation of practice in a variety of care contexts and semi-structured focus group and individual interviews. Lay participants reported dissatisfaction with current communicative practices, particularly during contact with medical professionals. Both lay and professional participants reported general dissatisfaction with currently available communication advice. An agreed version of a dementia toolkit for effective communication (DEMTEC) was produced. This consists of three "levels". The foundation Level 1 details beliefs about the psychosocial effects of dementia on communication, as well as empowering approaches to communication involving PLWD. Level 2 consists of practical considerations and advice in eight key areas. Level 3 uses case studies to show how the principles and advice in preceding levels are applicable to individuals in different care contexts and at different stages of dementia. The project has produced a free-to-users instrument that is empirically supported and adaptable to individual PLWD and to a range of health, care and sociocultural environments.


Alcohol Outlets, Neighborhood Retail Environments, and Pedestrian Injury Risk.
Alcohol outlet density has been associated with increased pedestrian injury risk. It is unclear whether this is because alcohol outlets are located in dense retail areas with heavy pedestrian traffic or whether alcohol outlets contribute a unique neighborhood risk. We aimed to compare the pedestrian injury rate around alcohol outlets to the rate around other, similar retail outlets that do not sell alcohol. A spatial analysis was conducted on census block groups in Baltimore City. Data included pedestrian injury emergency medical services (EMS) records from January 1, 2014 to April 15, 2015 (n = 848); locations of alcohol outlets licensed for off-premise (n = 726) and on-premise consumption (n = 531); and corner (n = 398) and convenience stores (n = 192) that do not sell alcohol. Negative binomial regression was used to determine the relationship between retail outlet count and pedestrian injuries, controlling for key confounding variables. Spatial autocorrelation was also assessed and variable selection adjusted accordingly. Each additional off-premise alcohol outlet was associated with a 12.3% increase in the rate of neighborhood pedestrian injury when controlling for convenience and corner stores and other confounders (incidence rate ratio [IRR] = 1.123, 95% confidence interval [CI] = 1.065, 1.184, p < 0.001). The attributable risk was 4.9% (95% CI = 0.3, 8.9) or 41 additional injuries. On-premise alcohol outlets were not significant predictors of neighborhood pedestrian injury rate in multivariable models (IRR = 0.972, 95% CI = 0.940, 1.004, p = 0.194). Off-premise alcohol outlets are associated with pedestrian injury rate, even when controlling for other types of retail outlets. Findings reinforce the importance of alcohol outlets in understanding neighborhood pedestrian injury risk and may provide evidence for informing policy on liquor store licensing, zoning, and enforcement.


Non-invasive prospective targeting of arterial P(CO2) in subjects at rest.
Accurate measurements of arterial P(CO(2)) (P(a,CO(2))) currently require blood sampling because the end-tidal P(CO(2)) (P(ET,CO(2))) of the expired gas often does not accurately reflect the mean alveolar P(CO(2)) and P(a,CO(2)). Differences between P(ET,CO(2)) and P(a,CO(2)) result from regional inhomogeneities in perfusion and gas exchange. We hypothesized that breathing via a sequential gas delivery circuit would reduce these inhomogeneities sufficiently to allow accurate prediction of P(a,CO(2)) from P(ET,CO(2)). We tested this hypothesis in five healthy middle-aged men by comparing their P(ET,CO(2)) values with P(a,CO(2)) values at various combinations of P(ET,CO(2)) (between 35 and 50 mmHg), P(O(2)) (between 70 and 300 mmHg), and breathing frequencies (f; between 6 and 24 breaths min(-1)). Once each individual was in a steady state, P(a,CO(2)) was collected in duplicate by consecutive blood samples to assess its repeatability. The difference between P(ET,CO(2)) and average P(a,CO(2)) was 0.5 +/- 1.7 mmHg (P = 0.53; 95% CI -2.8, 3.8 mmHg) whereas the mean difference between the two measurements of P(a,CO(2)) was -0.1 +/- 1.6 mmHg (95% CI -3.7, 2.6 mmHg). Repeated measures ANOVAs revealed no significant differences between P(ET,CO(2)) and P(a,CO(2)) over the ranges of P(O(2)), f and target P(ET,CO(2)). We conclude that when breathing via a sequential gas delivery circuit, P(ET,CO(2)) provides as accurate a measurement of P(a,CO(2)) as the actual analysis of arterial blood.


Effect of Lingual Frenotomy on Tongue and Lip Rest Position: A Nonrandomized Clinical Trial.
Introduction The tongue plays an important role in the development of craniofacial structures. At rest, the light and constant pressure of the tongue against the hard palate, counterbalanced by the pressure provided by proper lip sealing, serves as a guide for maxillary growth. Ankyloglossia makes tongue coupling against the hard palate difficult, impacting maxillary development, which may lead to breathing disorders. Objective To verify the effect of lingual frenotomy on the resting position of the tongue and lips in infants with ankyloglossia. Methods The sample consisted of 334 infants aged between 1 and 60 days old diagnosed with ankyloglossia. The groups were divided in: a) experimental group (EG), which consisted of infants whose mothers agreed with lingual frenotomy; b) control group (CG), which consisted of infants whose mothers either refused lingual frenotomy or were waiting for surgery. Both the position of the lips and of the tongue at rest were assessed while the infants were sleeping during the quiet sleep phase. For mothers who refused their infants to undergo the surgical procedure, a follow-up of the infants was proposed to verify possible interference of the frenulum with the resting position of the tongue and lips. Infants whose mothers agreed with surgery were referred for lingual frenotomy. Results Regarding the position of the tongue and lips at rest at the initial and final assessments, the statistical analysis demonstrated significant differences between both groups. Conclusion Lingual frenotomy enabled infants diagnosed with ankyloglossia to maintain both tongue coupling against the hard palate and closed lips at rest.


Estimating colony sizes of emerging bats using acoustic recordings.
The decline of bats demands more widespread monitoring of populations for conservation and management. Current censusing methods are either prone to bias or require costly equipment. Here, we report a new method using passive acoustics to determine bat count census from overall acoustic amplitude of the emerging bat stream. We recorded the video and audio of an emerging colony of Mexican free-tailed bats from two cave locations across multiple nights. Instantaneous bat counts were calculated from the video frames, and the bat stream's acoustic amplitude corresponding to each video frame was determined using three different methods for calculating acoustic intensity. We found a significant link between all three acoustic parameters and bat count, with the highest R (2) of 0.742 linking RMS pressure and bat count. Additionally, the relationship between acoustics and population size at one cave location could accurately predict the population size at another cave location. The data were gathered with low-cost, easy-to-operate equipment, and the data analysis can be easily accomplished using automated scripts or with open-source acoustic software. These results are a potential first step towards creating an acoustic model to estimate bat population at large cave colonies worldwide.


Ictal Epileptic Headache: When Terminology Is Not a Moot Question.
The relationship between headache and epilepsy is complex and despite the nature of this association is not yet clear. In the last few years, it has been progressively introduced the concept of the "ictal epileptic headache" that was included in the recently revised International Classification of Headaches Disorders 3rd edition (ICHD-3-revised). The diagnostic criteria for ictal epileptic headache (IEH) suggested in 2012 were quite restrictive thus leading to the underestimation of this phenomenon. However, these criteria have not yet been included into the ICHD-3 revision published in 2018, thus creating confusion among both, physicians and experts in this field. Here, we highlight the importance to strictly apply the original IEH criteria explaining the reasons through the analysis of the clinical, historical, epidemiological and pathophysiological characteristics of the IEH itself. In addition, we discuss the issues related to the neurophysiopathological link between headache and epilepsy as well as to the classification of these epileptic events as "autonomic seizure."


First report of the oriental mosquito Aedes albopictus on the West African island of Bioko, Equatorial Guinea.
The invasive oriental mosquito Aedes (Stegomyia) albopictus (Skuse) (Diptera: Culicidae) was detected on Bioko Island for the first time in November 2001. It was found to be well established breeding in artificial containers at Planta, near Malabo, the capital of Equatorial Guinea. Associated species of mosquito larvae were Aedes aegypti (L.), Ae. africanus (Theobald), Culex near decens Theobald, Cx. duttoni Theobald, Cx. quinquefasciatus Say, Cx. tigripes De Grandpré & De Charmoy, Eretmapodites quinquevittatus Theobald and Mansonia africana (Theobald). This is the third tropical African country to be invaded by Ae. albopictus, which has recently spread to many parts of the Americas and Europe--with vector competence for dengue, yellow fever and other arboviruses. In the Afrotropical environment, it will be interesting to monitor the ecological balance and/or displacement between introduced Ae. albopictus and indigenous Ae. aegpyti (domestic, peri-domestic and sylvatic populations).


The classification and management of acute orbital pseudotumors.
The clinical presentation, investigative findings, classification, and management of 17 acute pseudotumors based on patterns of orbital involvement is presented. Acute pseudotumors developed over days to weeks and were dominated by pain, neuropraxia, and inflammatory clinical features. Five patterns of acute inflammatory pseudotumor were seen. Anterior and diffuse acute pseudotumors were characterized by manifestations of inflammation of the globe and orbit including pain, lid swelling, ptosis, diplopia, uveitis, papillitis, optic neuropathy, and exudative retinal detachment. Anterior or diffuse orbital infiltration was noted on computerized tomography (CT) and ultrasound. Lacrimal involvement was characterized by local pain, tenderness, lid swelling and inflammation, with CT and ultrasound confirming an anterior inflammatory mass. Posterior or apical involvement led to an early optic neuropathy, and myositic lesions were characterized by features of muscle infiltration. Management with steroids was effective and could be followed by serial CT studies.


p21 gene polymorphisms in systemic lupus erythematosus.
Cyclin-dependent kinase inhibitor 1A (p21) is a negative regulator in the cell cycle. Development of sex-linked lupus-like syndrome in p21-/- mice and reduced p21 gene expression in patients with systemic lupus erythematosus (SLE) compared with those in healthy controls suggested that p21 is a susceptibility gene of SLE. We investigated the same by a case-control association study. Six single nucleotide polymorphisms, p21US G/A, p21DS C/A, p21-1022 G/A, p21C31 C/A, p21In2 G/C and p21UTR T/C, were genotyped in 516 SLE patients and 693 healthy controls. Association of genotypes and alleles with disease, disease phenotypes, haplotypes construction, linkage disequilibrium analysis and p21 mRNA expression were performed. We found a significant association of p21US A allele (OR = 0.23, 95% CI: 0.14-0.38, P < 0.001) and p21-1022 A allele (OR = 1.95, 95% CI: 1.37-2.78, P < 0.001) with SLE. We identified significant differences in the frequencies of haplotypes ht1-ACACCC, which contains p21US A allele, and ht2-GCACCC, which contains p21-1022 A allele, between SLE patients and controls (P < 0.0001). Besides, the p21US GA was associated with SLE patients suffering from arthritis (P = 0.003). We also observed differential p21 mRNA expressions among different genotypes of p21US and p21-1022 which were statistically significant. Our results suggested that the p21US A allele and p21-1022 A allele were both associated with the development of SLE, and the p21US A allele was associated with arthritis in SLE patients.


The current status of Helicobacter pylori vaccines: a review.
Helicobacter pylori, a Gram-negative flagellate bacterium that infects the stomach of more than half of the global population, is regarded as the leading cause of chronic gastritis, peptic ulcer disease, and even gastric adenocarcinoma in some individuals. Although the bacterium induces strong humoral and cellular immune responses, it can persist in the host for decades. It has several virulence factors, some of them having vaccine potential as judged by immunoproteomic analysis. A few vaccination studies involving a small number of infected or uninfected humans with various H. pylori formulations such as the recombinant urease, killed whole cells, and live Salmonella vectors presenting the subunit antigens have not provided satisfactory results. One trial that used the recombinant H. pylori urease coadministered with native Escherichia coli enterotoxin (LT) demonstrated a reduction of H. pylori load in infected participants. Although extensive studies in the mouse model have demonstrated the feasibility of both therapeutic and prophylactic immunizations, the mechanism of vaccine-induced protection is poorly understood as several factors such as immunoglobulin and various cytokines do not contribute to protection. Transcriptome analyses in mice have indicated the role of nonclassical immune factors in vaccine-induced protection. The role of regulatory T cells in the persistence of H. pylori infection has also been suggested. A recently developed experimental H. pylori infection model in humans may be used for testing several new adjuvants and vaccine delivery systems that have been currently obtained. The use of vaccines with appropriate immunogens, routes of immunization, and adjuvants along with a better understanding of the mechanism of immune protection may provide more favorable results.


Fuzzy state/disturbance observer design for T-S fuzzy systems with application to sensor fault estimation.
A novel fuzzy-observer-design approach is presented for Takagi-Sugeno fuzzy models with unknown output disturbances. In order to decouple the unknown output disturbance, an augmented fuzzy descriptor model is constructed by supposing the disturbance to be an auxiliary state vector. A fuzzy state-space observer is next designed for the augmented fuzzy descriptor system, and the simultaneous estimates of the original state and disturbance are thus obtained. The proposed observer technique is further applied to estimate sensor faults. Finally, a numerical example is given to illustrate the design procedure, and the simulation results show the desired tracking performance. The preknowledge of the disturbance and fault is not necessary for our design. Moreover, the considered disturbance and sensor fault can be in any form.


Array-based comparative genomic hybridization (aCGH) analysis is a useful tool for distinguishing primary pulmonary from metastatic neuroendocrine carcinoma to the lung.
Distinguishing primary from metastatic disease is vital for patient prognosis and care. This becomes a difficult task for both clinicians and pathologists when the clinical data, morphology, and immunohistochemistry (IHC) are not congruent. Array-based comparative genomic hybridization (aCGH) is a fairly recent technique that enables the analysis of whole tumor genome for discreet genetic abnormalities. As it is applicable to paraffin-embedded tissue, it could be suited for surgical pathology settings. We report a case of a 71-year-old woman diagnosed with uterine carcinosarcoma associated with high-grade neuroendocrine carcinoma (NEC). Six months later, the patient presented with pulmonary nodules. A wedge resection of one the nodules was performed and the histology and IHC were consistent with NEC. However, the diagnostic dilemma was whether the pulmonary lesions were primary of the lung or metastatic from the NEC component of the endometrium. Clinical, morphologic, and IHC analysis were not helpful to answer the above question. However, by revealing different genetic profiles of each of the 2 tumors, aCGH was suggestive of the existence of 2 independent primary tumors one endometrial and second pulmonary. In conclusion, aCGH is a powerful tool that is capable of revealing tumor gene fingerprinting and it can be used in routine surgical pathology especially in those cases where the other conventional techniques are not helpful.


Cyclic-diGMP signal transduction systems in Vibrio cholerae: modulation of rugosity and biofilm formation.
Cyclic di-guanylic acid (c-diGMP) is a second messenger that modulates the cell surface properties of several microorganisms. Concentrations of c-diGMP in the cell are controlled by the opposing activities of diguanylate cyclases and phosphodiesterases, which are carried out by proteins harbouring GGDEF and EAL domains respectively. In this study, we report that the cellular levels of c-diGMP are higher in the Vibrio cholerae rugose variant compared with the smooth variant. Modulation of cellular c-diGMP levels by overexpressing proteins with GGDEF or EAL domains increased or decreased colony rugosity respectively. Several genes encoding proteins with either GGDEF or EAL domains are differentially expressed between the two V. cholerae variants. The generation and characterization of null mutants of these genes (cdgA-E, rocS and mbaA) revealed that rugose colony formation, exopolysaccharide production, motility and biofilm formation are controlled by their action. Furthermore, epistasis analysis suggested that cdgC, rocS and mbaA act in convergent pathways to regulate the phenotypic properties of the rugose and smooth variants, and are part of the VpsR, VpsT and HapR signal transduction pathway.


Got daddy issues? Fathers impact on perinatal outcomes.
Mothers' genetics as well as their environment, behaviors, and social determinants of health are all important factors influencing short and long term childhood outcomes. There is an emerging body of literature investigating the extent to which fathers also contribute to their offspring's future health. We review fathers' impact on short term birth outcomes, longer term health, and neurodevelopment to emphasize the inter-relatedness of individual paternal traits. Factors that are linked to offspring outcomes include paternal demographics, race, stress, marriage and support, mental health, and the baseline health and behaviors of fathers. Several methodologic issues exist in current research such as maternal report of paternal information. Mechanisms proposed regarding paternal effect on progeny health range from genetic to reduction of stress of mothers through support. These are varied, possibly inter-related, and difficult to isolate as a single etiology. Future initiatives need to support fathers to allow them to support their families.


Corneal endothelial photography. Three-year revision. American Academy of Ophthalmology.
When properly done, corneal endothelial photography has been shown to be a relatively safe, reliable, and effective means to ascertain corneal endothelial cell density (cells/ mm2) and to provide information about endothelial cell morphometry. Currently, this procedure is not essential prior to routine cataract surgery, but may be indicated in situations in which the cornea is suspected of having endothelial abnormality and in which the accuracy of the estimated cell count from slit-lamp biomicroscopy is thought to be less than satisfactory. These situations include but are not limited to (1) eyes before secondary lens implantation; (2) eyes in which the status of the corneal endothelium is of concern because of a history of trauma, acute glaucoma, inflammation, or corneal transplantation; (3) eyes that contain intraocular lenses that are partially dislocated or are suspected of causing chronic inflammation or endothelial injury; and (4) eyes in which the fellow eye has a history of unexplained corneal edema.


The American Nurses Association Code of Ethics: a reflection on the ethics of respect and human dignity with nurse as expert.
The American Nurses Association Code of Ethics for Nurses calls for the nurse to practice with compassion and respect for every individual. What are the ethics and challenges of practicing professional nursing with expertise and educating a new generation of nurses while incorporating the interpretive statements into practice? This column differentiates the traditional biomedical views on human dignity and respect while exploring the embedded ethics of respect and self-determination and what it truly means to be an expert of nursing from the theoretical perspective of the human becoming school of thought.


Highly Subwavelength, Superdirective Cylindrical Nanoantenna.
A superdirective cylindrical nanoantenna is demonstrated with a multilayered cylindrical metamaterial-inspired structure. Targeting specific scattering coefficients for the dipole and higher-order modes, the ideal limit of needle radiation is demonstrated. A five-layer system is optimized to demonstrate its approach to the theoretical directivity bound. While the resulting structure is scalable to any frequency regime, its highly subwavelength overall size (λ_{0}/10) takes advantage of combinations of positive and negative permittivity materials in the optical regime.


Histological and Histomorphometric Evaluation of New Bone Formation after Maxillary Sinus Augmentation with Two Different Osteoconductive Materials: A Randomized, Parallel, Double-Blind Clinical Trial.
This study aimed to investigate the histological features of deproteinized equine bone mineral (DEBM) and anorganic bovine bone (ABB) after human sinus augmentation with the lateral approach. Twenty-three sinus augmentations were performed in 16 patients (male: 10/female: 6) using DEBM or ABB in a randomized fashion. Healing took place over the next 6 months. Bone core biopsies (N = 23) were obtained for each subject prior to placing the dental implants. The biopsies were processed for both histological descriptions and histomorphometric analysis. Statistical analyses were applied as appropriate, defining statistical significance as p < 0.05. Core bone biopsies revealed no differences in terms of newly formed bone between groups, or differences in terms of tissue inflammation. Both DEBM and ABB appear to be suitable biomaterials for bone augmentation in sinus lift surgery in the short term. However, dedicated studies are required to confirm these results and their stability in the long term.


Polymerase chain reaction in intraocular inflammation.
Polymerase chain reaction (PCR) is a technique involving enzymatic amplification of nucleic acid sequences in repeated cycles of denaturation, oligonucleotide annealing and DNA polymerase extension. It is a powerful molecular biologic tool that allows the rapid production of analytic quantities of DNA from small amounts of starting material. PCR can be performed on nearly any ocular specimen or biopsy. For diagnosis of uveitis, the obtained sample is usually an anterior chamber paracentesis or vitreous tap. PCR potentially is more sensitive than culture for detection of many organisms. By utilizing a secondary detection system in concert with the initial PCR reaction, perfect specificity can be assured. The initial application of PCR diagnostics to ophthalmic disease was in the detection of viral uveitis. PCR has also been implicated in studies of noninfectious uveitis. The most common application is HLA typing. A universal bacterial PCR can be very helpful for the diagnosis of bacterial endophthalmitis at an early stage of the disease.


Measurement of the release of inflammatory mediators from rat alveolar macrophages and alveolar type II cells following lipopolysaccharide or silica exposure: a comparative study.
Evidence suggests that hyperproduction of reactive oxidants and inflammatory mediators plays a critical role in adverse pulmonary responses to silica or lipopolysaccharide (LPS). The objective of this study was to evaluate the role of alveolar macrophages (AM) and alveolar epithelial type II cells (TII) in the induction of pulmonary inflammation and injury in response to these pulmonary toxicants. To support this objective, the release of several inflammatory mediators from primary rat AMs and TII cells was compared under similar culture and exposure conditions. The responsiveness of RLE-6TN, a rat type II cell line, was also compared to primary rat TII cells under the same culture conditions, following exposure to LPS or silica. The following findings were made. (1) Although AMs were generally found to release more inflammatory mediators than TII cells following LPS or silica exposure, primary TII cells clearly produced significant levels of mediators that could be capable of contributing considerably to lung inflammation and injury. (2) Since the responses of the RLE-6TN cell line to LPS or silica exposure were generally considerably less intense and required higher concentrations of stimulant than those measured in primary rat TII cells, RLE-6TN cells may not be an ideal substitute for primary TII cells in studying pulmonary inflammation. (3) LPS was more potent than silica in inducing inflammatory cytokine release from the three cell types. However, compared to LPS, silica exhibited equal or greater potency as an inducer of cellular oxidant generation, especially from primary TII cells.


Prevalence of perceived stigma and associated factors among primary caregivers of children and adolescents with mental illness, Addis Ababa, Ethiopia: Cross-sectional study.
Mental illness exposes persons to stigma and this stigma also affects family caregivers of persons with mental illness. The objective of the study was to assess the prevalence of perceived stigma and associated factors among primary caregivers of children and adolescents with mental illness, Addis Ababa, Ethiopia. A cross-sectional study design and systematic random sampling technique were used to recruit 408 participants at St. Paul's Hospital Millennium Medical College and Yekatit-12 Hospital Medical College, Addis Ababa, Ethiopia. We collected the data by face-to-face interview. Devaluation of Consumer Families Scale was used to measure perceived stigma. Patient Health Questionnaire-9 and Oslo-3 social support scale were the instruments used to assess the factors. Coded variables were entered into Epidata V.3.1 and exported to SPSS V.21 for analysis. Binary logistic regression was used for analysis. A total of 408 participants were interviewed, with a response rate of 96.5%. The magnitude of perceived stigma was 38.5% with 95% CI (33.6-43.1). Majority (68.6%) of the respondents were female. In the multivariate logistic regression, being mother (AOR = 2.8, 95% CI: 1.59, 4.91), absence of other caregiver (AOR = 2.0, 95% CI: 1.15, 3.49), poor social support (AOR = 3.9, 95% CI: 1.59, 6.13), and symptoms of depression (AOR = 2.9, 95% CI: 1.88, 3.65) were factors significantly associated with perceived stigma. The prevalence of perceived stigma among primary caregivers of children and adolescents with mental illness was high. Being mother, absence of other caregiver, poor social support, and symptoms of depression were factors significantly associated with perceived stigma.


Hepatic carbohydrate metabolism in the spontaneously diabetic Bio-Breeding Worcester rat.
The effects of diabetes on hepatic carbohydrate metabolism were investigated in spontaneously diabetic Bio-Breeding Worcester (BB/W) rats. The juvenile-onset-type syndrome displayed by these animals is characterized by beta-cell destruction with subsequent ketosis-prone insulinopenia. Livers from diabetic animals demonstrated increased adenosine 3',5'-cyclic monophosphate levels but subnormal total protein and glycogen content. Isolated perfused livers of diabetic BB/W rats demonstrated an increased rate of glucose production from [14C]lactate and an impaired rate of glycogen synthesis. These data were consonant with hepatic enzyme studies demonstrating markedly increased activities of component gluconeogenic (glucose-6-phosphatase, fructose-1,6-diphosphatase, phosphoenolpyruvate carboxykinase) and glycogenolytic (glycogen phosphorylase) enzymes with decreased activities of glycolytic (hexokinase, pyruvate kinase) and glycogenic (glycogen synthase) enzymes. These findings agree with previous studies using alloxan- and streptozotocin-induced diabetic animals and suggest that accelerated hepatic gluconeogenesis and impaired glucose utilization are pathognomonic of all insulin-deficient diabetic syndromes.


Influence of short-course antenatal antiretroviral therapy on viral load and mother-to-child transmission in subsequent pregnancies among HIV-infected women.
HIV-infected women not requiring treatment for their own health usually receive short-course antiretroviral therapy (ART) during pregnancy. Little is known about the effect of this on response to HAART in subsequent pregnancies. We analysed data from the UK and Ireland's National Study of HIV in Pregnancy and Childhood for 2000-2010. Analyses were restricted to live births among women not on ART at conception but receiving antenatal HAART. We compared risk of detectable viral load at delivery and mother-to-child transmission in two pregnancy groups: 'ART-naive' and 'HAART-experienced' (≥7 days of HAART during previous pregnancy). Multivariable analyses were conducted using logistic regression. There were 5,372 pregnancies in the ART-naive group and 605 in the HAART-experienced group. Overall, there was weak evidence of an increased risk of detectable viral load in the HAART-experienced group (adjusted odds ratio [aOR] 1.27; 95% CI 1.01, 1.60); however, the increased risk was apparent only among women who previously received non-nucleoside reverse transcriptase inhibitor-based HAART (aOR 1.81; 95% CI 1.25, 2.63), and not among those with previous protease-inhibitor-based HAART exposure (aOR 1.08; 95% CI 0.81, 1.45). There was no difference in mother-to-child transmission risk between the ART-naive and HAART-experienced groups (aOR 0.42; 95% CI 0.10, 1.78), although the number of transmissions was small. We found no increased risk of detectable viral load at delivery among women exposed to short-course, protease-inhibitor-based HAART during a previous pregnancy. However, women with prior exposure to non-nucleoside reverse transcriptase inhibitor-based HAART appeared to be at increased risk of not adequately suppressing the virus. These findings highlight the need for careful management of HIV-infected women presenting with repeat pregnancies.


Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction.
Although the Ras subfamily of GTPases consists of approximately 20 members, only a limited number of guanine nucleotide exchange factors (GEFs) that couple extracellular stimuli to Ras protein activation have been identified. Furthermore, no novel downstream effectors have been identified for the M-Ras/R-Ras3 GTPase. Here we report the identification and characterization of three Ras family GEFs that are most abundantly expressed in brain. Two of these GEFs, MR-GEF (M-Ras-regulated GEF, KIAA0277) and PDZ-GEF (KIAA0313) bound specifically to nucleotide-free Rap1 and Rap1/Rap2, respectively. Both proteins functioned as Rap1 GEFs in vivo. A third GEF, GRP3 (KIAA0846), activated both Ras and Rap1 and shared significant sequence homology with the calcium- and diacylglycerol-activated GEFs, GRP1 and GRP2. Similarly to previously identified Rap GEFs, C3G and Smg GDS, each of the newly identified exchange factors promoted the activation of Elk-1 in the LNCaP prostate tumor cell line where B-Raf can couple Rap1 to the extracellular receptor-activated kinase cascade. MR-GEF and PDZ-GEF both contain a region immediately N-terminal to their catalytic domains that share sequence homology with Ras-associating or RalGDS/AF6 homology (RA) domains. By searching for in vitro interaction with Ras-GTP proteins, PDZ-GEF specifically bound to Rap1A- and Rap2B-GTP, whereas MR-GEF bound to M-Ras-GTP. C-terminally truncated MR-GEF, lacking the GEF catalytic domain, retained its ability to bind M-Ras-GTP, suggesting that the RA domain is important for this interaction. Co-immunoprecipitation studies confirmed the interaction of M-Ras-GTP with MR-GEF in vivo. In addition, a constitutively active M-Ras(71L) mutant inhibited the ability of MR-GEF to promote Rap1A activation in a dose-dependent manner. These data suggest that M-Ras may inhibit Rap1 in order to elicit its biological effects.


[Diagnostic and therapeutic strategies for the management of severe mitral valve regurgitation].
Mitral regurgitation is the second most frequent valvular heart disease. Echocardiography is the principal examination to determine severity, mechanism and hemodynamic consequences of mitral regurgitation and consequently contributes to the assessment and accurate timing of the best treatment strategy. To clarify clinical decision making in severe mitral regurgitation, this review will discuss the diagnostic work-up and treatment options according to the most recent guidelines. Mitral valve surgery, preferably repair, is indicated in symptomatic patients with severe, organic mitral regurgitation. Chronic, functional mitral regurgitation is often medically treated (including cardiac resynchronization therapy if indicated), however surgery (preferably annuloplasty) can be recommended. Percutaneous MitraClip-implantation may be considered as an alternative option in symptomatic patients with severe mitral regurgitation who are considered inoperable. At present, there is no consensus on the optimal care in asymptomatic patients with severe, organic mitral regurgitation and preserved left ventricular function. A prospective trial is highly needed to elucidate this best treatment strategy.


The Impact of COVID-19 Lockdown on Diabetes Complication and Diabetes Management in People With Diabetes in Indonesia.
Aims: As the country with the seventh largest number of People with Diabetes (PWD) in the world, the Coronavirus disease 2019 (COVID-19) pandemic, and the Large Social Scale Restriction (LSSR) policy taken by the Indonesian government to reduce the number of COVID-19 transmissions is estimated to interfere diabetes management and will increase the incidence of diabetes complications. This study aims to determine the difficulties of diabetes management and its impact on diabetes morbidity during the COVID-19 pandemic in Indonesia. Methods: This study is a cross-sectional study using a national scale web survey. This research was conducted in Indonesia enrolling 1124 PWD aged 18 years or older. Diabetes complications are defined as self-assessed incidence of hypoglycemia, or Diabetic Foot Ulcer (DFU), or hospital admission experienced by PWD in Indonesia during the COVID-19 pandemic. The correlation between diabetes management difficulties and diabetes-related complications was measured using a modified cox regression test. Results: Diabetes management difficulties were experienced by 69.8% of PWD in Indonesia. The difficulties include attending diabetes consultation 30.1%, access to diabetes medication 12.4%, checking blood glucose levels 9.5%, controlling diet 23.8%, and performing regular exercise 36.5%. Diabetes-related complications occurred in 24.6% of subjects. Those who had diabetes management difficulties during the COVID-19 pandemic are prone to have diabetes complications by 1.4 times greater (PR: 1.41, 95% CI: 1.09-1.83) than those who did not. Conclusion: The COVID-19 pandemic and LSSR have impact on diabetes management and diabetes-related complications as assessed by PWD in Indonesia.


Phylogenetic utility of the major opsin in bees (Hymenoptera: Apoidea): a reassessment.
Major opsin (LW Rh) DNA sequence has been reported to provide useful data for resolving phylogenetic relationships among tribes of corbiculate bees based on analyses of 502 bp of coding sequence. However, the corbiculate tribes are believed to be of Cretaceous age, and strong support for insect clades of this age from small data sets of nucleotide sequence data has rarely been demonstrated. To more critically assess opsin's phylogenetic utility we generated an expanded LW Rh data set by sequencing the same gene fragment from 52 additional bee species from 24 tribes and all six extant bee families. Analyses of this data set failed to provide substantial support for monophyly of corbiculate bees, for relationships among corbiculate tribes, or for most other well-established higher-level relationships among long-tongued bees. However, monophyly of nearly all genera and tribes is strongly supported, indicating that LW Rh provides useful phylogenetic signal at lower taxonomic levels. When our expanded LW Rh data set is combined with a morphological and behavioral data set for corbiculate bees, the results unambiguously support the traditional phylogeny of the corbiculate bee tribes: (Euglossini + (Bombini + (Meliponini + Apini))). This implies a single origin of advanced eusocial behavior among bees rather than dual origins, as proposed by several recent studies.


Interspecific variation in conspecific negative density dependence can make species less likely to coexist.
Conspecific negative density dependence (CNDD) is thought to promote plant species diversity. Theoretical studies showing the importance of CNDD often assumed that all species are equally susceptible to CNDD; however, recent empirical studies have shown species can differ greatly in their susceptibility to CNDD. Using a theoretical model, we show that interspecific variation in CNDD can dramatically alter its impact on diversity. First, if the most common species are the least regulated by CNDD, then the stabilising benefit of CNDD is reduced. Second, when seed dispersal is limited, seedlings that are susceptible to CNDD are at a competitive disadvantage. When parameterised with estimates of CNDD from a tropical tree community in Panama, our model suggests that the competitive inequalities caused by interspecific variation in CNDD may undermine many species' ability to persist. Thus, our model suggests that variable CNDD may make communities less stable, rather than more stable.


Can gabapentin help reduce postoperative pain in arthroscopic rotator cuff repair? A prospective, randomized, double-blind study.
The aim of the study was to determine the effect of low-dose gabapentin on postoperative pain management in patients undergoing arthroscopic rotator cuff repair. This randomized, double-blinded, placebo-controlled study included 46 patients. The patients were divided into 2 groups according to the drug administered 2 hours before surgery, either 300 mg of gabapentin or placebo. The primary outcome measure was the visual analog scale (VAS) score at 2, 6, 12, and 24 hours postoperatively. The secondary outcome measures were fentanyl consumption and side effects during the first 2 hours in the postanesthesia care unit and then at 6 and 24 hours postoperatively. The patients were evaluated for side effects including nausea, vomiting, respiratory depression, dizziness, drowsiness, voiding difficulty, and pruritus. The VAS scores at 2, 6, and 12 hours postoperatively were significantly lower in the gabapentin group than in the placebo group (P = .023, P = .019, and P = .022, respectively). The consumption of fentanyl, over a period of 24 hours, was not different in the comparisons between the groups (P = .686). The incidence of side effects was similar in the 2 groups. A single dose of 300 mg of gabapentin reduced the VAS score during the first 24 hours postoperatively in patients undergoing shoulder arthroscopic rotator cuff repair, without significant side effects when compared with placebo. However, the fentanyl consumption did not differ between the gabapentin and placebo groups. Level I, randomized controlled trial.


Simultaneous Concentration of Bovine Viruses and Agricultural Zoonotic Bacteria from Water Using Sodocalcic Glass Wool Filters.
Infiltration and runoff from manured agricultural fields can result in livestock pathogens reaching groundwater and surface waters. Here, we measured the effectiveness of glass wool filters to simultaneously concentrate enteric viruses and bacteria of bovine origin from water. The recovery efficiencies were determined for bovine viral diarrhea virus types 1 and 2, bovine rotavirus group A, bovine coronavirus, poliovirus Sabin III, toxigenic Escherichia coli ,and Campylobacter jejuni seeded into water with three different turbidity levels (0.5, 215, and 447 NTU). Twenty liters of dechlorinated tap water (pH 7) were seeded with the test organisms, and then passed through a glass wool filter using a peristaltic pump (flow rate = 1 liter min(-1)). Retained organisms were eluted from the filters by passing beef extract-glycine buffer (pH 9.5) in the direction opposite of sample flow. Recovered organisms were enumerated by qPCR except for C. jejuni, which was quantified by culture. Mean recovery efficiencies ranged from 55 to 33% for the bacteria and 58 to 16% for the viruses. Using bootstrapping techniques combined with Analysis of Variance, recovery efficiencies were found to differ among the pathogen types tested at the two lowest turbidity levels; however, for a given pathogen type turbidity did not affect recovery except for C. jejuni. Glass wool filtration is a cost-effective method for concentrating several waterborne pathogens of bovine origin simultaneously, although recovery may be low for some specific taxa such as bovine viral diarrhea virus 1.


[Significance of preoperative CT diagnosis of Echinococcus cysts of the brain].
The preoperative diagnosis of hydatid disease of the brain is decisive for the outcome, i.e. the cyst must be removed unruptured. Eleven patients had typical CT findings of hydatid disease which was confirmed by operation. The CT findings are usually highly characteristic: The CT demonstrates a cystic spherical lesion, with sharply defined cyst walls. The CT values of the cyst contents are similar to that of CSF. There is usually no perifocal oedema.


Environmental demands associated with community mobility in older adults with and without mobility disabilities.
In this study, the influence of 8 dimensions of the physical environment on mobility in older adults with and without mobility disability was measured. This was done in order to identify environmental factors that contribute to mobility disability. Subjects were 36 older adults ((> or = 70 years of age) who were recruited from 2 geographic sites (Seattle, Wash, and Waterloo, Ontario, Canada) and were grouped according to level of mobility function (physically able [ability to walk 1/2 mile (0.8 km) or climb stairs without assistance], physically disabled). Subjects were observed and videotaped during 3 trips into the community (trip to grocery store, physician visit, recreational trip). Frequency of encounters with environmental features within each of the 8 dimensions was recorded. Differences in baseline characteristics and environmental encounters were analyzed using an analysis of variance or the Fisher exact test, as appropriate. Mobility disability among older adults was not associated with a uniform decrease in encounters with environmental challenges across all dimensions. Environmental dimensions that differed between subjects who were physically able and those with physical disability included temporal factors, physical load, terrain, and postural transition. Dimensions that were not different included distance, density, ambient conditions (eg, light levels and weather conditions), and attentional demands. Understanding the relationship of the environment to mobility is crucial to both prevention and rehabilitation of mobility disability in older adults. Among older adults, certain dimensions of the environment may disable community mobility more than others.