Enhanced biological activity of antisense oligonucleotides complexed with glycosylated poly-L-lysine.
We sought to exploit glycosylated poly-L-lysine (pLK) to increase the uptake and biological antisense activity of a phosphorothioate oligonucleotide (pt-odn) [pt-odn complementary to the 3' noncoding region of intercellular adhesion molecule-1 (ICAM-1) (odn(ICAM-1))] complementary to the 3'-noncoding region of ICAM-1 in A549 cells. Dose-dependent inhibition of ICAM-1 expression was obtained (IC50 = 500 nM) through treatment of cells with odn(ICAM-1) complexed with pLK carrying fucose residues in the presence of 100 microM chloroquine. Alteration in the charge ratio between fucosylated pLK and pt-odn had a significant effect on the efficacy of inhibition (optimal conditions, charge ratio = 1.1). This effect was also dependent on the number of fucose moieties per pLK. Free pt-odn or pt-odn complexed with nonglycosylated pLK gave no inhibition at concentrations of < or = 2 microM. Two control pt-odn (one was targeted against an unrelated gene not present in these cells, gag(HIV), and the other had a randomized sequence) gave no inhibition of ICAM-1 expression in the presence or absence of pLK carrying fucose residues at concentrations of < or = 2 microM. When complexed with pLK carrying 100 fucose residues, the amount of cell-associated pt-odn was increased by 15-fold compared with the free pt-odn. Nongycosylated pLK also increased the amount of cell-associated pt-odn by >10 fold but did not alter the biological activity. These results demonstrate clearly the potential of glycosylated pLK as a pt-odn transporter.


Fungal microbiomes are determined by host phylogeny and exhibit widespread associations with the bacterial microbiome.
Interactions between hosts and their resident microbial communities are a fundamental component of fitness for both agents. Though recent research has highlighted the importance of interactions between animals and their bacterial communities, comparative evidence for fungi is lacking, especially in natural populations. Using data from 49 species, we present novel evidence of strong covariation between fungal and bacterial communities across the host phylogeny, indicative of recruitment by hosts for specific suites of microbes. Using co-occurrence networks, we demonstrate marked variation across host taxonomy in patterns of covariation between bacterial and fungal abundances. Host phylogeny drives differences in the overall richness of bacterial and fungal communities, but the effect of diet on richness was only evident in the mammalian gut microbiome. Sample type, tissue storage and DNA extraction method also affected bacterial and fungal community composition, and future studies would benefit from standardized approaches to sample processing. Collectively these data indicate fungal microbiomes may play a key role in host fitness and suggest an urgent need to study multiple agents of the animal microbiome to accurately determine the strength and ecological significance of host-microbe interactions.


Unrecognized Celiac Disease in Children Presenting for Rheumatology Evaluation.
Current clinical guidelines do not consider patients with rheumatic conditions to be at high risk for celiac disease (CD) despite numerous reported associations between the two in adults and children. The objective of this study was to evaluate the prevalence of CD among patients presenting for pediatric rheumatology evaluation. A total of 2125 patients presenting for initial evaluation by the Division of Pediatric Rheumatology at the Hospital for Special Surgery between June 2006 and December 2013 were screened for CD as a part of the standard initial serologic evaluation. The charts of these patients were evaluated retrospectively at the end of this period. 36 patients (30 girls, 6 boys, mean age 9.4 ± 4.3 years, range 2-16 years) received a diagnosis of CD after serologic testing and evaluation by pediatric gastroenterology. Eight additional patients with known diagnoses of CD presented during this time period. The total prevalence of CD over this 6.5-year period was 2.0%. The most common presenting complaints among patients diagnosed with CD were myalgias, arthralgias, and rash. Less frequently, patients reported gastrointestinal complaints including abdominal pain, nausea, and diarrhea. All patients reported improvement or complete resolution of their musculoskeletal symptoms after initiation of a gluten-free diet. This study identified 36 new cases of CD among children presenting for rheumatology evaluation, for an overall prevalence rate of 2.0%. The majority of patients who ultimately received a diagnosis of CD presented with extraintestinal manifestations. These results underscore the importance of screening children presenting for rheumatology evaluation for CD.


Intranasal Piperine-Loaded Chitosan Nanoparticles as Brain-Targeted Therapy in Alzheimer's Disease: Optimization, Biological Efficacy, and Potential Toxicity.
Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50nm), PDI (0.24), and ZP (+56.30mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3544-3556, 2015.


Cognitive correlates of HVOT performance differ between individuals with mild cognitive impairment and normal controls.
To clinically characterize performance on the Hooper Visual Organization Test (HVOT) among participants with mild cognitive impairment (MCI) and to identify naming and executive functioning correlates associated with HVOT performance among MCI participants and normal controls (NC). The HVOT is a common neuropsychological instrument that measures visuospatial skills and agnosia. It has, however, been criticized for its multifactorial nature, as several studies have reported executive or language correlates of HVOT performance. To our knowledge, simultaneous comparison of executive functioning and language demands of the HVOT has never been performed among an older cohort. The HVOT, two tests of executive functioning [Trail Making Test, Part B (TMT-B), Controlled Oral Word Association (COWA)] and two tests of naming [abbreviated Boston Naming Test (BNT), Animal Naming] were administered to 222 NC, 166 MCI, and 68 Alzheimer's disease (AD) individuals. HVOT scores were significantly different between all three groups in the expected direction (AD<MCI<NC). Linear regression among NC participants revealed that COWA, age, and BNT were significantly associated with HVOT scores, accounting for 12%, 6%, and 4% of HVOT variance, respectively. Among MCI participants, the BNT accounted for 43% of HVOT variance. Neither TMT-B nor Animal Naming was a significant predictor for either group. Among NC participants, rapid word generation (i.e., COWA), a measure of executive functioning, is the most salient predictor of HVOT performance. In contrast, lexical retrieval (i.e., BNT) is the most salient language or executive functioning predictor of HVOT performance among MCI participants. These findings extend previous claims that the HVOT is multifactorial by suggesting that reduced HVOT performance in MCI patients may be related to mild lexical retrieval impairments.


Alternative splicing and bioinformatic analysis of human U12-type introns.
U12-type introns exist, albeit rarely, in a variety of multicellular organisms. Splicing of U12 intron-containing precursor mRNAs takes place in the U12-type spliceosome that is distinct from the major U2-type spliceosome. Due to incompatibility of these two spliceosomes, alternative splicing involving a U12-type intron may give rise to a relatively complicated impact on gene expression. We studied alternative U12-type intron splicing in an attempt to gain more mechanistic insights. First, we characterized mutually exclusive exon selection of the human JNK2 gene, which involves an unusual intron possessing the U12-type 5' splice site and the U2-type 3' splice site. We demonstrated that the long and evolutionary conserved polypyrimidine tract of this hybrid intron provides important signals for inclusion of its downstream alternative exon. In addition, we examined the effects of single nucleotide polymorphisms in the human WDFY1 U12-type intron on pre-mRNA splicing. These results provide mechanistic implications on splice-site selection of U12-type intron splicing. We finally discuss the potential effects of splicing of a U12-type intron with genetic defects or within a set of genes encoding RNA processing factors on global gene expression.


Use of complementary and alternative medicine by patients seen at the dermatology department of a tertiary care center.
The use of complementary and alternative medicine (CAM) among patients with dermatologic conditions has not been well studied. The aim of this study was to evaluate the frequency and pattern of CAM use in patients referred to the dermatology department of a tertiary care center. Patients referred to the dermatology department of an academic tertiary referral center between February 2, 2010, and February 10, 2010, were invited to participate in an 86-question survey regarding CAM use during the previous year. A total of 300 patients completed the survey, of whom 154 (51%) were women. Eighty-two percent (n = 247) of the respondents had used some type of CAM during the previous year. The most frequently used treatment and technique was massage therapy (33%), and the most commonly used vitamin was vitamin C (31%). Herbs or other dietary supplements were used by 58% (n = 173) of patients. Seventy-eight percent (n = 235) of patients stated that physicians should consider incorporating CAM approaches into their treatment recommendations, and 89% of patients (n = 267) stated that our dermatology department should study CAM approaches in research studies. CAM utilization is high among patients at a large academic dermatology department. Patients indicated a strong preference for having CAM approaches incorporated into their treatment recommendations and believed in the value of clinical studies to further refine the role of CAM.


Effects of base curvature on squeeze pressures in contact lenses.
Calculations are made of the effects of base curvature on squeeze pressures in hard contact lenses during blinking. An axisymmetrical model with parabolic profile is used of a cylindrical body (the lens) moving along its axis toward a rigid surface (the eye), from which it is separated by a tear film. The results are compared with those obtained from a two-dimensional model having the same parabolic profile. It is found that the maximum pressures in the axisymmetric case are precisely one-half of those in the corresponding two-dimensional one, irrespective of the base curvature. Thus, estimated pressures using the latter model are likely to be too large. A simple formula is also obtained which shows the effect of base curvature on the force. The calculated pressures (and hence forces) will be further reduced if lens deformation occurs as is the case in soft contact lenses.


Cholera toxin-like toxin released by Salmonella species in the presence of mitomycin C.
Several serotypes of Salmonella were shown to release increased amounts of a cholera toxin-like toxin during culture in vitro with mitomycin C (MTC). Filter-sterilized culture supernatants containing the toxin caused elongation of Chinese hamster ovary cells, which could be blocked by heating the supernatants at 100 degrees C for 15 min or by adding mixed gangliosides or monospecific cholera antitoxin. When MTC was not added to the Salmonella cultures, little or no toxin was detected in crude, unconcentrated culture supernatants. Optimal production of toxin was observed in the presence of 0.5 micrograms of MTC per ml in shake flask cultures of Casamino Acids-yeast extract medium, Syncase, or peptone saline at 37 degrees C. Meat infusion media (heart infusion and brain heart infusion) plus MTC resulted in poor toxin yield. Culture filtrates frequently could be diluted 1:8 and still result in elongation of Chinese hamster ovary cells.


Tyrosine Kinase Inhibitors for the Elderly.
Until few years ago non-specific cytotoxic agents were considered the tip of the arrow as first line treatment for lung cancer. However; age > 75 was considered a major drawback for this kind of therapy. Few exceptions were made by doctors based on the performance status of the patient. The side effects of these agents are still severe for several patients. In the recent years further investigation of the cancer genome has led to targeted therapies. There have been numerous publications regarding novel agents such as; erlotinib, gefitinib and afatinib. In specific populations these agents have demonstrated higher efficiency and this observation is explained by the overexpression of the EGFR pathway in these populations. We suggest that TKIs should administered in the elderly, and with the word elderly we propose the age of 75. The treating medical doctor has to evaluate the performance status of a patient and decide the best treatment in several cases indifferent of the age. TKIs in most studies presented safety and efficiency and of course dose modification should be made when necessary. Comorbidities should be considered in any case especially in this group of patients and the treating physician should act accordingly.


The clinical consequences of advanced imaging techniques in Barrett's esophagus.
Evaluation of patients with Barrett's esophagus (BE) using dye-based chromoendoscopy, optical chromoendoscopy, autofluorescence imaging, or confocal laser endomicroscopy does not significantly increase the number of patients with a diagnosis of early neoplasia compared with high-definition white light endoscopy (HD-WLE) with random biopsy analysis. These newer imaging techniques are not more effective in standard surveillance of patients with BE because the prevalence of early neoplasia is low and HD-WLE with random biopsy analysis detects most cases of neoplasia. The evaluation and treatment of patients with BE and early-stage neoplasia should be centralized in tertiary referral centers, where procedures are performed under optimal conditions, by expert endoscopists. Lesions that require resection are almost always detected by HD-WLE, although advanced imaging techniques can detect additional flat lesions. However, these are of limited clinical significance because they are effectively eradicated by ablation therapy. No endoscopic imaging technique can reliably assess submucosal or lymphangio-invasion. Endoscopic resection of early-stage neoplasia in patients with BE is important for staging and management. Optical chromoendoscopy can also be used to evaluate lesions before endoscopic resection and in follow-up after successful ablation therapy.


Possible glyphosate tolerance mechanism in pitted morningglory (Ipomoea lacunosa L.).
Natural tolerance of Ipomoea lacunosa to glyphosate has made it problematic in the southeastern U.S. since the adoption of glyphosate-resistant crops. Experiments were conducted to determine (i) the variability in tolerance to glyphosate among accessions, (ii) if there is any correlation between metabolism of glyphosate to aminomethylphosponic acid (AMPA) or sarcosine and the level of tolerance, and (iii) the involvement of differential translocation in tolerance to glyphosate. Fourteen I. lacunosa accessions had GR50 values ranging from 58 to 151 grams of acid equivalent per hectare (ae/ha) glyphosate, a 2.6-fold variability in tolerance to glyphosate. There was no evidence of the most tolerant (MT) accession metabolizing glyphosate to AMPA more rapidly than the least tolerant (LT) accession. Metabolism to sarcosine was not found. (14)C-glyphosate absorption was similar in the two accessions. LT accession translocated more (14)C-glyphosate than MT accession at 24 and 48 h after treatment. Differential translocation partly explains glyphosate tolerance in MT accession.


Mesoscopic behavior from microscopic Markov dynamics and its application to calcium release channels.
A major challenge in biology is to understand how molecular processes determine phenotypic features. We address this fundamental problem in a class of model systems by developing a general mathematical framework that allows the calculation of mesoscopic properties from the knowledge of microscopic Markovian transition probabilities. We show how exact analytic formulae for the first and second moments of resident time distributions in mesostates can be derived from microscopic resident times and transition probabilities even for systems with a large number of microstates. We apply our formalism to models of the inositol trisphosphate receptor, which plays a key role in generating calcium signals triggering a wide variety of cellular responses. We demonstrate how experimentally accessible quantities, such as opening and closing times and the coefficient of variation of inter-spike intervals, and other, more elaborated, quantities can be analytically calculated from the underlying microscopic Markovian dynamics. A virtue of our approach is that we do not need to follow the detailed time evolution of the whole system, as we derive the relevant properties of its steady state without having to take into account the often extremely complicated transient features. We emphasize that our formulae fully agree with results obtained by stochastic simulations and approaches based on a full determination of the microscopic system's time evolution. We also illustrate how experiments can be devised to discriminate between alternative molecular models of the inositol trisphosphate receptor. The developed approach is applicable to any system described by a Markov process and, owing to the analytic nature of the resulting formulae, provides an easy way to characterize also rare events that are of particular importance to understand the intermittency properties of complex dynamic systems.


The effect of danazol in the treatment of chronic cystic mastitis.
Danazol in a dose of 400 mg daily was administrated to 40 patients with chronic cystic mastitis and resulted in a marded improvement in both objective and subjective symptoms in 87.5% of the patients studied. Three patients showed partial relief of symptoms and 1 patient showed no improvement after 1 month of treatment at which time she withdrew from the study. One patient had a worsening of her condition and was withdrawn from the study after 3.5 months of therapy. Nineteen of the 40 patients in the study had a secondary diagnosis of pelvic endometriosis confirmed histologically, and all these patients showed a marked improvement of symptoms during the Danazol treatment. Patients developed amenorrhea after 3 to 4 months of Danazol therapy, and symptoms such as dysmenorrhea, premenstrual pelvic pain, and tension abated at the same time. A mild, but well-tolerated weight gain was the major side effect of Danazol administration. No significant changes in the levels of plasma E1, E2, FSH, LH, or progesterone could be demonstrated in specimens drawn from 11 patients before and during the course of Danazol administration.


Robust quantum dot exciton generation via adiabatic passage with frequency-swept optical pulses.
The energy states in semiconductor quantum dots are discrete as in atoms, and quantum states can be coherently controlled with resonant laser pulses. Long coherence times allow the observation of Rabi flopping of a single dipole transition in a solid state device, for which occupancy of the upper state depends sensitively on the dipole moment and the excitation laser power. We report on the robust population inversion in a single quantum dot using an optical technique that exploits rapid adiabatic passage from the ground to an excited state through excitation with laser pulses whose frequency is swept through the resonance. This observation in photoluminescence experiments is made possible by introducing a novel optical detection scheme for the resonant electron hole pair (exciton) generation.


[Roentgenological and pathomorphological changes in the canine heart during 6-months hypokinesia].
The effect of 6-month hypokinesia on the cardiac function and pathomorphological changes in 8 dogs was investigated. The heart size during systolic and diastolic contractions, stroke volume and contractile function were measured once a month, using an X-ray unit and a kymograph. After the hypokinetic exposure 6 dogs were sacrificed and their hearts were examined morphologically and histochemically. The recovery processes were investigated on 2 other dogs that were allowed to survive for 30 days after exposure. The 6-month hypokinesia led to a significant decrease in the heart size, stroke volume, cardiac index, and the contractile function. Post-mortem morphological examinations revealed atrophic changes in the myocardium. Electron-microscopy investigations demonstrated focal destructive changes in myofibers and in mitochondria: some of them were denser while others had a more transparent matrix and degraded crystae. Histochemical data (increased acid and alkaline phosphatase) also suggested atrophic and destructive changes in the myocardium. The above changes did not return to normal within 30 days of the recovery period.


[Influence of biphosphonates on the integration process of endosseous implants evaluated using single photon emission computerized tomography (SPECT)].
Biphosphonates are a large class of drugs which inhibits the resorbing activity of osteoclasts. The aim of this study was to evaluate the influence of topical application of the biphosphonate alendronate on the integration process of endosseus implants placed in a partially edentulous patient. After incision and elevation of a mucoperiosteal flap and carrying out the osteotomy, 2 SLA implants 10 mm long and 3.5 mm wide were inserted in the area of # 4.5 and 4.6. Before placement of # 4.5, a paste made of grinded tablets of alendronate and Rifocin was applied in the osteotomy. Fifteen days after stage I, an evaluation of the osteoblastic peri-implant activity was carried out using single photon emission computerized tomography. Healing was within normal limits. Four months after stage I, the 2 implants were uncovered and considered clinically and radiographically integrated. The osteoblastic activity was judged similar bet-ween the 2 implants in terms of quality of biological response. Osseous scintigraphy and the achievement of implant osseointegration demonstrate the lack of toxicity of the topical application of the biphosphonate alendronate during the initial osseous healing. However, new experimental studies and clinical trials are necessary to confirm the results obtained.


What do dental college clinicians know about oral cancer and its risk factors? An assessment among final year students, interns and faculty members in saudi arabia.
The ability of health care professionals to perform oral cancer examination depends partly on their knowledge of the disease and its risk factors. This study aimed to assess and compare the knowledge of final year students, interns and faculty members regarding oral cancer and its risk factors. A 35-item questionnaire about knowledge of oral cancer and its risk factors was distributed among participants from Jazan University's Dental School. A minimum score of 18 was the cut-off point for an acceptable total score of oral cancer knowledge [OCTS]. Descriptive statistics described the relations between demographics variables and knowledge levels of participants. The differences between OCTS, diagnostic-clinical examination knowledge [DCK] and supportive knowledge [SK] and sex and occupation were analyzed using independent t-test and ANOVAs respectively. A total of 72 students, 68 interns and 88 faculty members completed the questionnaires (N = 228); with an average age of 23.8 ± 0.9 years, 25.1 ± 1.5 years and 40.6 ± 9.1 years with 55.1% males. OCTS was 20.2 ± 3.6 out of 35. No significant difference between OCTS and participants' sex was found (t (203) = 1.342, p = .181, 95% CI for difference -.302 ــ 1.589). No significant differences in OCTS between students, interns and faculty members (F (2, 225) = 2.116, p = .123). A significant difference in SK between final year students, interns, and faculty members was founded (F (2, 194) = 5.62, p = .004). Knowledge of oral cancer and its risk factors among Jazan Dental School's final year students, interns and faculty members is acceptable. However, due to the high rate of oral cancer in Jazan, emphasizing knowledge of oral cancer and its risk factors in the curriculum of Jazan Dental School is required. Key words:Oral cancer, risk factors, knowledge, dental education, curriculum, dental students, dentists.


Evaluation of the aquatic toxicity of two veterinary sulfonamides using five test organisms.
The aquatic toxicity of sulfaquinoxaline (SQO) and sulfaguanidine (SGD) was evaluated on the following test organisms: Daphnia magna (reproduction test), Pseudokirchneriella subcapitata, Scenedesmus dimorphus, Synecococcus leopoliensis (algal growth inhibition test) and Lemna gibba (duckweed growth inhibition test). Furthermore, the additivity of the two compounds was measured on D. magna (acute immobilisation test) and P. subcapitata (algal growth inhibition test) using the isobologram method. Results show that SQO and SGD are more toxic to green algae and daphnids, respectively, than other veterinary sulfonamides (SAs) and that their mixtures have a less then additive interaction. Taking into account the highest concentrations detected so far in surface waters for SQO (0.112 μg L(-1)) and for SGD (0.145 μg L(-1)) and the lowest NOECs obtained with the five test organisms, divided by an assessment factor of 10, the following PNECs and risk quotients (RQs) were calculated. SQO: PNEC 2 μg L(-1); RQ 0.056. SGD: PNEC 39.5 μg L(-1); RQ 0.004. Consequently, at the concentrations actually detected in the aquatic environment, the two SAs alone should not harm the freshwater organisms. However, it seems advisable, for veterinary mass treatments, the use of other SAs that have a lesser impact on the aquatic environment. Furthermore, considering the high probability of having complex mixtures of different SAs residues in water, each individual contamination should be evaluated by applying to the SAs mixtures the conservative criteria of additivity.


Autism, oxytocin and interoception.
Autism is a pervasive developmental disorder characterized by profound social and verbal communication deficits, stereotypical motor behaviors, restricted interests, and cognitive abnormalities. Autism affects approximately 1% of children in developing countries. Given this prevalence, identifying risk factors and therapeutic interventions are pressing objectives—objectives that rest on neurobiologically grounded and psychologically informed theories about the underlying pathophysiology. In this article, we review the evidence that autism could result from a dysfunctional oxytocin system early in life. As a mediator of successful procreation, not only in the reproductive system, but also in the brain, oxytocin plays a crucial role in sculpting socio-sexual behavior. Formulated within a (Bayesian) predictive coding framework, we propose that oxytocin encodes the saliency or precision of interoceptive signals and enables the neuronal plasticity necessary for acquiring a generative model of the emotional and social 'self.' An aberrant oxytocin system in infancy could therefore help explain the marked deficits in language and social communication—as well as the sensory, autonomic, motor, behavioral, and cognitive abnormalities—seen in autism.


[Education and health regarding citizenship: a nurses' group practice].
This study was run in a community committee of Nossa Senhora da Aparecida, a surrounding city of Joao Pessoa, Paraiba. It aimed at characterizing nursing practice there and discussing its occurrence. The analysis was run based on eight inhabitants and four nurses speeches through semistructured interviews whose data were collected qualitatively. It focused on the discussion which evolved from questions regarding to education and health from the perspective of exercising citizenship. In the participants of the study representations, education seemed dynamic and implied awareness ... a question of life. Health is comprehended under 3 points of view: the one of welfare, the one of suffering and the one of biological balance. The perspective of citizenship exercise reveals itself sometimes as conformism, through silence or resignation and sometimes as resistance, through the ideal manifestation and courage for fighting for better life condition.


Expression and distribution of voltage-gated ion channels in ferret sinoatrial node.
Spontaneous diastolic depolarization in the sinoatrial (SA) node enables it to serve as pacemaker of the heart. The variable cell morphology within the SA node predicts that ion channel expression would be heterogeneous and different from that in the atrium. To evaluate ion channel heterogeneity within the SA node, we used fluorescent in situ hybridization to examine ion channel expression in the ferret SA node region and atrial appendage. SA nodal cells were distinguished from surrounding cardiac myocytes by expression of the slow (SA node) and cardiac (surrounding tissue) forms of troponin I. Nerve cells in the sections were identified by detection of GAP-43 and cytoskeletal middle neurofilament. Transcript expression was characterized for the 4 hyperpolarization-activated cation channels, 6 voltage-gated Na(+) channels, 3 voltage-gated Ca(2+) channels, 24 voltage-gated K(+) channel α-subunits, and 3 ancillary subunits. To ensure that transcript expression was representative of protein expression, immunofluorescence was used to verify localization patterns of voltage-dependent K(+) channels. Colocalizations were performed to observe any preferential patterns. Some overlapping and nonoverlapping binding patterns were observed. Measurement of different cation channel transcripts showed heterogeneous expression with many different patterns of expression, attesting to the complexity of electrical activity in the SA node. This study provides insight into the possible role ion channel heterogeneity plays in SA node pacemaker activity.


The herpes simplex virus JMP mutant enters receptor-negative J cells through a novel pathway independent of the known receptors nectin1, HveA, and nectin2.
The herpes simplex virus type 1(JMP) [HSV-1(JMP)] mutant was selected for its ability to grow and form plaques in receptor-negative J cells. It enters J cells through a novel gD-dependent pathway, independent of all known HSV receptors, nectin1, nectin2, and HveA. Evidence that the pathway is dependent on a nectin3 binding site on HSV-1(JMP) and requires three mutations in gD rests on the following. We derived monoclonal antibodies to nectin3 and show that J cells express nectin3. HSV-1(JMP) entry and cell-to-cell spread were inhibited by soluble nectin3-Fc, demonstrating that virions carry a binding site for nectin3. The site is either directly involved in HSV-1(JMP) entry, or nectin3 binding to its site affects the gD domains involved in entry (entry site). HSV-1(JMP) entry and cell-to-cell spread in J cells were also inhibited by soluble nectin1-Fc, showing that the nectin1 binding site on gD(JMP) overlaps with the entry site or that nectin1 binding to gD affects the entry site. gD(JMP) carries three mutations, S140N, R340H, and Q344R. The latter two lie in the C tail and are present in the parental HSV-1(MP). HSV-1 strain R5000 carrying the S140N substitution was not infectious in J cells, indicating that this substitution was not sufficient. We constructed two recombinants, one carrying the three substitutions and the other carrying the two C-tail substitutions. Only the first recombinant infected J cells with an efficiency similar to that of HSV-1(JMP), indicating that the three mutations are required for the novel entry pathway. The results highlight plasticity in gD which accounts for changes in receptor usage.


Inequalities in time from stopping paid work to death: findings from the ONS Longitudinal Study, 2001-2011.
UK state pension eligibility ages are linked to average life expectancy, which ignores wide socioeconomic disparities in both healthy and overall life expectancy. Investigate whether there are occupational social class differences in the amount of time older adults live after they stop work, and how much of these differences are due to health. Participants were 76 485 members of the Office for National Statistics Longitudinal Study (LS), who were 50-75 years at the 2001 census and had stopped work by the 2011 census. Over 10 years of follow-up, we used censored linear regression to estimate mean differences in years between stopping work and death by occupational social class. After adjustment for age, both social class and health were independent predictors of postwork duration (mean difference (95% CI): unskilled class vs professional: 2.7 years (2.4 to 3.1); not good vs good health: 2.4 years (1.9 to 2.9)), with LS members in the three manual classes experiencing ~1 additional year of postwork duration than professional workers (interaction p values all <0.001). Further adjustment for gender and educational qualifications was reduced but did not eliminate social class and postwork duration associations. We estimate the difference in postwork years between professional classes in good health and unskilled workers not in good health as 5.1 years for women (21.0 vs 26.1) and 5.5 years for men (19.5 vs 25.0). Lower social class groups are negatively affected by uniform state pension ages, because they are more likely to stop work at younger ages due to health reasons.


Synergism of Dam, MutH, and MutS in methylation-directed mismatch repair in Escherichia coli.
DNA mismatch repair (MMR) is a critical mutation surveillance system for recognizing and repairing erroneous insertion, deletion, and disincorporation of base. Major components of mismatch repair system consist of MutH, MutL, and MutS. Dam methylates adenine to distinguish newly synthesized daughter strands from the parent strands. Employing a tyrosine-auxotrophic E. coli FX-11 strain, the mutation frequency can be determined by the number of tyrosine revertants and the cell viability of FX-11 with deficiencies in dam and mismatch repair proteins. This study showed that mutS defect produced a higher mutation frequency than mutH did. Interestingly, double defects in dam and mutS synergistically produced a dramatically higher spontaneous mutation frequency than the summation of mutation frequencies of FX-11 strains with individual deficiency of dam or mutS, suggesting that Dam may work with MutHL to partially accomplish the task of recognizing the mismatch sites to retain partial mismatch repair capacity.


Unplanned Hospital Readmissions and Reoperations After Pediatric Spinal Fusion Surgery.
Retrospective review. To investigate the rates and reasons for unplanned readmissions and reoperation after pediatric spinal fusion surgery at our institution and to identify risk factors by analyzing patient and surgical characteristics. Unplanned readmission and reoperation were defined as unplanned events within 90 days of the index surgery. The rate of unplanned readmission and reoperation after pediatric spinal fusion surgery is not well established. Clinical records were reviewed for all children who underwent spinal fusion surgical procedures for spinal deformity correction performed by 1 surgeon from 2000 through 2013 at our institution. Inclusion criteria were age of 10 to 18 years at surgery, fusion spanning more than 5 vertebral levels, and 3 months of clinical or radiographical follow-up (1002 patients met these criteria). Univariate and multivariate logistic regression models were created. Statistical significance was set at a P value of less than 0.05 for all analyses. The overall 90-day unplanned readmission and reoperation rates were 8.0% and 3.8%, respectively. The most common causes of readmission were wound dehiscence (1.8%), deep wound infection (1.5%), pulmonary complications (1%), and superficial wound infection (0.9%). Univariate analysis showed that readmission was significantly associated with a higher number of levels fused, greater estimated blood loss, longer length of stay, and certain diagnoses; reoperation was significantly associated with a higher number of levels fused and certain diagnoses. On multivariate analysis, only patient diagnosis was found to be significantly associated with readmission and reoperation; patients with congenital scoliosis, genetic or syndromic scoliosis, cerebral palsy, and other neuromuscular disorders had significantly higher rates. Unplanned readmission rate after pediatric spinal fusion surgery was 8%, most commonly for wound dehiscence and deep and superficial infections. Increased intraoperative blood loss, higher number of levels fused, and certain diagnoses are risk factors for unplanned readmission. 4.


Personalized dose selection in radiation therapy using statistical models for toxicity and efficacy with dose and biomarkers as covariates.
Selection of dose for cancer patients treated with radiation therapy (RT) must balance the increased efficacy with the increased toxicity associated with higher dose. Historically, a single dose has been selected for a population of patients (e.g., all stage III non-small cell lung cancer). However, the availability of new biologic markers for toxicity and efficacy allows the possibility of selecting a more personalized dose. We consider the use of statistical models for toxicity and efficacy as a function of RT dose and biomarkers to select an optimal dose for an individual patient, defined as the dose that maximizes the probability of efficacy minus the sum of weighted toxicity probabilities. This function can be shown to be equal to the expected value of the utility derived from a particular family of bivariate outcome utility matrices. We show that if dose is linearly related to the probability of toxicity and efficacy, then any marker that only acts additively with dose cannot improve efficacy, without also increasing toxicity. Using a dataset of lung cancer patients treated with RT, we illustrate this approach and compare it to non-marker-based dose selection. Because typical metrics used in evaluating new markers (e.g., area under the ROC curve) do not directly address the ability of a marker to improve efficacy at a fixed probability of toxicity, we utilize a simulation study to assess the effects of marker-based dose selection on toxicity and efficacy outcomes.


Program-Based Teaching and Learning To Increase Competency in Undergraduate Medical Students Using a Model of the Revised National Tuberculosis Control Program.
Teaching methods need continuous innovation to encourage undergraduate medical students to enhance their competency level and skills. Every undergraduate medical student should be able to discuss the Revised National Tuberculosis Control Program (RNTCP) and Direct Observed Treatment Short (DOTS) course recommended by the World Health Organization (WHO). The DOTS strategy was launched in 1992, with the objective of detecting at least 70% of new sputum-positive tuberculosis (TB) patients and curing at least 85% of such patients. The aim of this study was to improve the competency level of Undergraduate (UG) Bachelor of Medicine and Bachelor of Surgery (MBBS) students by teaching them the objectives of the RNTCP at a program implementation site in the medical college. The RNTCP could be considered and conducted as Program-Based Teaching and Learning (PBTL) for the UG medical students. The following skills were to be implemented in the RNTCP PBTL: Sputum Collection, Ziehl-Neelsen staining and Grading, Mantoux test, and TB Culture and Molecular test (Gene Xpert). Phase II undergraduate MBBS students (N = 104) participated in the PBTL. This study was conducted in the RNTCP laboratory of a tertiary-care teaching medical college hospital. This descriptive study included advanced skill-based teaching such as Directly Observed Practical Skill, Demonstration-Observation-Assistance-Performance, Video Demonstrations, Role Play, and Group interaction as teaching tools. Pre-/post-test, Objective Structured Practical Examination, and frequently asked questions were used as assessment tools. The pre- and post-test marks were compared, and other assessments were also analyzed using SPSS. At the end of the teaching program, the feedback forms were collected from students and analyzed. The mean score obtained for 104 MBBS students in the pre-test, post-test, and other assessment tools were 213.3 and 487.5, respectively (p < 0.001). We conclude that skill-based teaching and learning tools to teach public health program like RNTCP provide valuable essential skills for undergraduate medical students. This Program Based Teaching and Learning could be successfully extended to all medical colleges.


Hand-assisted laparoscopic colon and rectal cancer surgery: feasibility, short-term, and oncological outcomes.
Hand-assisted laparoscopic surgery (HALS) is an established alternative to laparoscopic-assisted surgery, but limited data exist regarding its applicability for colorectal cancer (CRC). We report short-term outcomes in a large series of CRC patients who underwent HALS between 2004 and 2009. A prospectively maintained database was used to identify all CRC patients. Patients with colon cancer (CC) and rectal cancer (RC) were considered separately. Three patients with synchronous CC and RC were excluded. Data are frequency (%) or median (interquartile range). Between 2004 and 2009, 323 CRC patients underwent a HALS procedure. Median age was 65 (53-73) years, 39% were women, and the median BMI was 27 (24-31) kg/m(2). Diagnoses included 194 colon cancers (CC, 56.7% stage I/II), 129 rectal cancers (RC, 62.7% stage I/II). Operative time was less for CC than RC (157 vs 204 min; P < .0001). Conversion to laparotomy occurred in similar proportions of CC and RC cases (14% vs 10%; P = .38); lymph nodes retrieval was also similar (18 vs 18; P = .45). Overall duration of stay was 5 (4-7) days. At 30 days, postoperative complications occurred in similar proportions of CC and RC patients (28% vs 30%; P = .72). There was 1 mortality (0.5%). For the subgroup with 3 year follow-up, (73 CC and 45 RC patients), the overall survival was 80% and 88% (CC and RC, respectively), and disease free survival 79% and 85%, respectively. Colon and rectal cancer can be resected safely using HALS techniques. Conversion rates are low, complication rates expected, durations of hospital stay shorter, and the number of lymph nodes retrieved is high.


Continuous deformation versus faulting through the continental lithosphere of new zealand
Seismic anisotropy and P-wave delays in New Zealand imply widespread deformation in the underlying mantle, not slip on a narrow fault zone, which is characteristic of plate boundaries in oceanic regions. Large magnitudes of shear-wave splitting and orientations of fast polarization parallel to the Alpine fault show that pervasive simple shear of the mantle lithosphere has accommodated the cumulative strike-slip plate motion. Variations in P-wave residuals across the Southern Alps rule out underthrusting of one slab of mantle lithosphere beneath another but permit continuous deformation of lithosphere shortened by about 100 kilometers since 6 to 7 million years ago.


Multimodal infiltration of local anaesthetic in total knee arthroplasty; is posterior capsular infiltration worth the risk? a prospective, double-blind, randomised controlled trial.
Multimodal infiltration of local anaesthetic provides effective control of pain in patients undergoing total knee arthroplasty (TKA). There is little information about the added benefits of posterior capsular infiltration (PCI) using different combinations of local anaesthetic agents. Our aim was to investigate the effectiveness of the control of pain using multimodal infiltration with and without infiltration of the posterior capsule of the knee. In a double-blind, randomised controlled trial of patients scheduled for unilateral primary TKA, 86 were assigned to be treated with multimodal infiltration with (Group I) or without (Group II) PCI. Routine associated analgesia included the use of bupivacaine, morphine, ketorolac and epinephrine. All patients had spinal anaesthesia and patient-controlled analgesia (PCA) post-operatively. A visual analogue scale (VAS) for pain and the use of morphine were recorded 24 hours post-operatively. Side effects of the infiltration, blood loss, and length of stay in hospital were recorded. There were no statistically significant differences between the groups in relation to: VAS pain scores in the first 24 hours post-operatively (p = 0.693), the use of morphine in the PCA (p = 0.647), blood loss (p = 0.625), and length of stay (p = 0.17). There were no neurovascular complications in either group. The multimodal infiltration of local anaesthetic with infiltration of the posterior capsule did not provide significant added analgesic benefits or reduce the use of morphine after TKA. Multimodal infiltration is a satisfactory technique for the management of pain in these patients without the attendant risks of PCI. Cite this article: Bone Joint J 2017; 99-B:483-8.


Dendritic cell membrane CD83 enhances immune responses by boosting intracellular calcium release in T lymphocytes.
CD83 is a marker of mDCs directly related to their lymphostimulatory ability. Some data suggest that it has a central role in the immune system regulation, but how this function is performed remains to be determined. This work aimed to analyze the influence of CD83, present in mDCs, in the modulation of calcium signaling in T lymphocytes. Mo were differentiated into iDCs and activated with TNF-α. iDCs were treated, 4 h before activation, with siRNACD83, to reduce CD83 expression. Purified allogeneic T lymphocytes were labeled with the calcium indicator Fluo-4-AM, and calcium mobilization in the presence of mDCs was analyzed. CD83 knockdown mDCs induced lower calcium signal amplitude in T lymphocytes (29.0±10.0) compared with siRNAscr-treated mDCs (45.5±5.3). In another set of experiments, surface mDC CD83 was blocked with a specific mAb, and again, decreased calcium signaling in T lymphocytes was detected by flow cytometry and microscopy (fluorescence and confocal). In the presence of antibody, the percentage of responding T cells was reduced from 58.14% to 34.29%. As expected, anti-CD83 antibodies also reduced the proliferation of T lymphocytes (as assessed by CFSE dilution). Finally, in the absence of extracellular calcium, CD83 antibodies abrogated T cell signaling induced by allogeneic mDCs, suggesting that the presence of CD83 in mDC membranes enhances T lymphocyte proliferation by boosting calcium release from intracellular stores in these cells.


Universal quenching probe system: flexible, specific, and cost-effective real-time polymerase chain reaction method.
We have developed a flexible, specific, and cost-effective real-time polymerase chain reaction (PCR) method. In this technique, a quenching probe (QProbe) and a nonfluorescent 3'-tailed probe are used. The QProbe is a singly labeled oligonucleotide bearing a fluorescent dye that is quenched via electron transfer between the dye and a guanine base at a particular position. The nonfluorescent 3'-tailed probe consists of two parts: one is the target-specific sequence on the 5' side, and the other is complementary to the QProbe on the 3' side. When the QProbe/nonfluorescent 3'-tailed probe complex hybridizes with the target in PCR, the fluorescence of the dye is quenched. Fluorescence quenching efficiency is proportional to the amount of the target. We called this method the universal QProbe system. This method substantially reduces the cost of real-time PCR setup because the same QProbe can be used for different target sequences. Moreover, this method allows accurate quantification even in the presence of nonspecific PCR products because the use of nonfluorescent 3'-tailed probe significantly increases specificity. Our results demonstrate that this method can accurately and reproducibly quantify specific nucleic acid sequences in crude samples, comparable with conventional TaqMan chemistry. Furthermore, this method is also applicable to single-nucleotide polymorphism (SNP) genotyping.


Inflammation and type one diabetes.
Type one diabetes (T1D) is a complex T cell-mediated autoimmune disease, the defining feature of which is the destruction of the insulin-secreting beta- (β)- cell. Both genetic and environmental factors combine to precipitate disease, and the outcome of the pathological process is dependent on multiple inter-related factors. In this review, the mechanisms behind the initiation and propagation of the autoimmune response are analysed, and the contribution of differing T-helper (T(h)) subsets--in particular T(h)1- and T(h)17-related cytokines--to the disease process are discussed. An argument is then synthesized that proposes that the β-cell's response to stress and inflammation is the critical determinant in predicting disease outcome and that, immunologically, a delicate balance exists between regulation and inflammation at the site of islet infiltration. Strategies for disease intervention, therefore, will not only require the induction of T-cell tolerance by tipping the balance towards regulation but will also need to contain approaches that result in the scavenging of inflammatory mediators, in order to facilitate repair. Ultimately, given that clinical diabetes presents late in the autoimmune process, strategies for β-cell regeneration must now be addressed. There is thus a requirement for an increased, collaborative effort between stem cell biologists and immunologists in order to tailor an optimal therapeutic strategy for the treatment of this debilitating disease.


Helper component proteinase of the genus Potyvirus is an interaction partner of translation initiation factors eIF(iso)4E and eIF4E and contains a 4E binding motif.
The multifunctional helper component proteinase (HCpro) of potyviruses (genus Potyvirus; Potyviridae) shows self-interaction and interacts with other potyviral and host plant proteins. Host proteins that are pivotal to potyvirus infection include the eukaryotic translation initiation factor eIF4E and the isoform eIF(iso)4E, which interact with viral genome-linked protein (VPg). Here we show that HCpro of Potato virus A (PVA) interacts with both eIF4E and eIF(iso)4E, with interactions with eIF(iso)4E being stronger, as judged by the data of a yeast two-hybrid system assay. A bimolecular fluorescence complementation assay on leaves of Nicotiana benthamiana showed that HCpro from three potyviruses (PVA, Potato virus Y, and Tobacco etch virus) interacted with the eIF(iso)4E and eIF4E of tobacco (Nicotiana tabacum); interactions with eIF(iso)4E and eIF4E of potato (Solanum tuberosum) were weaker. In PVA-infected cells, interactions between HCpro and tobacco eIF(iso)4E were confined to round structures that colocalized with 6K2-induced vesicles. Point mutations introduced to a 4E binding motif identified in the C-terminal region of HCpro debilitated interactions of HCpro with translation initiation factors and were detrimental to the virulence of PVA in plants. The 4E binding motif conserved in HCpro of potyviruses and HCpro-initiation factor interactions suggest new roles for HCpro and/or translation factors in the potyvirus infection cycle.


ACTION-EHR: Patient-Centric Blockchain-Based Electronic Health Record Data Management for Cancer Care.
With increased specialization of health care services and high levels of patient mobility, accessing health care services across multiple hospitals or clinics has become very common for diagnosis and treatment, particularly for patients with chronic diseases such as cancer. With informed knowledge of a patient's history, physicians can make prompt clinical decisions for smarter, safer, and more efficient care. However, due to the privacy and high sensitivity of electronic health records (EHR), most EHR data sharing still happens through fax or mail due to the lack of systematic infrastructure support for secure, trustable health data sharing, which can also cause major delays in patient care. Our goal was to develop a system that will facilitate secure, trustable management, sharing, and aggregation of EHR data. Our patient-centric system allows patients to manage their own health records across multiple hospitals. The system will ensure patient privacy protection and guarantee security with respect to the requirements for health care data management, including the access control policy specified by the patient. We propose a permissioned blockchain-based system for EHR data sharing and integration. Each hospital will provide a blockchain node integrated with its own EHR system to form the blockchain network. A web-based interface will be used for patients and doctors to initiate EHR sharing transactions. We take a hybrid data management approach, where only management metadata will be stored on the chain. Actual EHR data, on the other hand, will be encrypted and stored off-chain in Health Insurance Portability and Accountability Act-compliant cloud-based storage. The system uses public key infrastructure-based asymmetric encryption and digital signatures to secure shared EHR data. In collaboration with Stony Brook University Hospital, we developed ACTION-EHR, a system for patient-centric, blockchain-based EHR data sharing and management for patient care, in particular radiation treatment for cancer. The prototype was built on Hyperledger Fabric, an open-source, permissioned blockchain framework. Data sharing transactions were implemented using chaincode and exposed as representational state transfer application programming interfaces used for the web portal for patients and users. The HL7 Fast Healthcare Interoperability Resources standard was adopted to represent shared EHR data, making it easy to interface with hospital EHR systems and integrate a patient's EHR data. We tested the system in a distributed environment at Stony Brook University using deidentified patient data. We studied and developed the critical technology components to enable patient-centric, blockchain-based EHR sharing to support cancer care. The prototype demonstrated the feasibility of our approach as well as some of the major challenges. The next step will be a pilot study with health care providers in both the United States and Switzerland. Our work provides an exemplar testbed to build next-generation EHR sharing infrastructures.


Trends in ixodid tick abundance and distribution in Great Britain.
The popular, but rarely documented, view in Britain is that ticks have increased in distribution and abundance over recent years. To assess this, we gathered evidence for changes in tick distribution and abundance by distributing a survey questionnaire throughout Britain and by analysing trends in the prevalence of tick infestation on red grouse chicks Lagopus lagopus scoticus Latham (Galliformes: Tetranoidae), gathered over 19 years at three Scottish sites, and on deer (Cetartiodactyla: Cervidae) culled over 11 years on 26 Ministry of Defence (MoD) estates. Based on the survey, the current known distribution of Ixodes ricinus Linnaeus (Acari: Ixodidae) has expanded by 17% in comparison with the previously known distribution. The survey indicated that people perceive there to be more ticks today than in the past at 73% of locations throughout Britain. Reported increases in tick numbers coincided spatially with perceived increases in deer numbers. At locations where both tick and deer numbers were reported to have increased, these perceived changes occurred at similar times, raising the possibility of a causal link. At other locations, tick numbers were perceived to have increased despite reported declines in deer numbers. The perceptions revealed by the survey were corroborated by quantitative data from red grouse chicks and culled deer. Tick infestation prevalence increased over time on all grouse moors and 77% of MoD estates and decreased at six locations.


Semantic diversity: a measure of semantic ambiguity based on variability in the contextual usage of words.
Semantic ambiguity is typically measured by summing the number of senses or dictionary definitions that a word has. Such measures are somewhat subjective and may not adequately capture the full extent of variation in word meaning, particularly for polysemous words that can be used in many different ways, with subtle shifts in meaning. Here, we describe an alternative, computationally derived measure of ambiguity based on the proposal that the meanings of words vary continuously as a function of their contexts. On this view, words that appear in a wide range of contexts on diverse topics are more variable in meaning than those that appear in a restricted set of similar contexts. To quantify this variation, we performed latent semantic analysis on a large text corpus to estimate the semantic similarities of different linguistic contexts. From these estimates, we calculated the degree to which the different contexts associated with a given word vary in their meanings. We term this quantity a word's semantic diversity (SemD). We suggest that this approach provides an objective way of quantifying the subtle, context-dependent variations in word meaning that are often present in language. We demonstrate that SemD is correlated with other measures of ambiguity and contextual variability, as well as with frequency and imageability. We also show that SemD is a strong predictor of performance in semantic judgments in healthy individuals and in patients with semantic deficits, accounting for unique variance beyond that of other predictors. SemD values for over 30,000 English words are provided as supplementary materials.


A Randomized Trial of Continuous Noninvasive Blood Pressure Monitoring During Noncardiac Surgery.
Intraoperative hypotension is associated with postoperative mortality. Early detection of hypotension by continuous hemodynamic monitoring might prompt timely therapy, thereby reducing intraoperative hypotension. We tested the hypothesis that continuous noninvasive blood pressure monitoring reduces intraoperative hypotension. Patients ≥45 years old with American Society of Anesthesiologists physical status III or IV having moderate-to-high-risk noncardiac surgery with general anesthesia were included. All participating patients had continuous noninvasive hemodynamic monitoring using a finger cuff (ClearSight, Edwards Lifesciences, Irvine, CA) and a standard oscillometric cuff. In half the patients, randomly assigned, clinicians were blinded to the continuous values, whereas the others (unblinded) had access to continuous blood pressure readings. Continuous pressures in both groups were used for analysis. Time-weighted average for mean arterial pressure <65 mm Hg was compared using 2-sample Wilcoxon rank-sum tests and Hodges Lehmann estimation of location shift with corresponding asymptotic 95% CI. Among 320 randomized patients, 316 were included in the intention-to-treat analysis. With 158 patients in each group, those assigned to continuous blood pressure monitoring had significantly lower time-weighted average mean arterial pressure <65 mm Hg, 0.05 [0.00, 0.22] mm Hg, versus intermittent blood pressure monitoring, 0.11 [0.00, 0.54] mm Hg (P = .039, significance criteria P < .048). Continuous noninvasive hemodynamic monitoring nearly halved the amount of intraoperative hypotension. Hypotension reduction with continuous monitoring, while statistically significant, is currently of uncertain clinical importance.


Mechanisms, pathophysiological roles and methods for analyzing mitophagy - recent insights.
In 2012, we briefly summarized the mechanisms, pathophysiological roles and methods for analyzing mitophagy. As then, the mitophagy field has continued to grow rapidly, and many new molecular mechanisms regulating mitophagy and molecular tools for monitoring mitophagy have been discovered and developed. Therefore, the purpose of this review is to update information regarding these advances in mitophagy while focusing on basic molecular mechanisms of mitophagy in different organisms and its pathophysiological roles. We also discuss the advantage and limitations of current methods to monitor and quantify mitophagy in cultured cells and in vivo mouse tissues.


In vivo phosphorylation and membrane association of the fyn proto-oncogene product in IM-9 human lymphoblasts.
The protein product of the src-related proto-oncogene, fyn, was isolated from IM-9 cells with antibodies specific for the amino-terminal 22 residues of the fyn protein. Peptide mapping demonstrated that the fyn protein was distinct from the closely related c-src and c-fgr proteins. The fyn protein from IM-9 cells incorporated [3H]myristate in vivo and was found to be membrane associated. Phosphoamino acid analysis demonstrated that the fyn protein from IM-9 cells was phosphorylated in vivo predominantly on tyrosine and threonine with only a small amount of phosphoserine detected. the major chymotryptic phosphopeptide of the fyn protein was phosphorylated exclusively on tyrosine. This peptide was specifically precipitated by antibodies directed against a peptide modeled on the closely related carboxy termini of the c-src and fyn proteins. These results provide direct evidence for phosphorylation of tyrosine-531 in the carboxy-terminal chymotryptic peptide of the fyn protein. Phosphorylation of the corresponding site in the closely related c-src protein (tyrosine-527) represses src kinase activity and transforming ability. Loss of the phosphorylation site at tyrosine-531 may similarly contribute to the transforming abilities of carboxy-terminal deletion mutants of the fyn protein.


Current drinking patterns in US veterans with a lifetime history of alcohol use disorder: Results from the National Health and Resilience in Veterans Study.
Background: Although more than 40% of US military veterans have lifetime histories of alcohol use disorder (AUD), little is known about the prevalence and correlates of current drinking patterns (i.e., abstinent, subthreshold, hazardous drinking) in this population. Objectives: To characterize the prevalence and key correlates of abstinence, subthreshold drinking, and hazardous drinking in a nationally representative sample of US veterans with lifetime AUD. Methods: Data from 1,282 veterans with lifetime AUD who participated in the National Health and Resilience in Veterans Study were analyzed using analyses of variance, chi-square analyses, and multinomial regression models. Results: Of the 1,282 veterans with lifetime AUD (of which 94.7% were males), 674 (48.2%) were past-year subthreshold drinkers, 317 (28.0%) were abstinent and 291 (23.8%) were hazardous drinkers. Abstinent veterans were older, less educated, less socially engaged, and had higher levels of religiosity than subthreshold and hazardous drinkers. They were also more likely to smoke, screen positive for PTSD, reported greater somatic symptoms than subthreshold drinkers, and had more physical difficulties and lifetime trauma than hazardous drinkers. Subthreshold drinkers were more likely than hazardous drinkers to be female and report physical health problems and less likely to smoke and be depressed. Conclusion: More than three-quarters of US veterans with lifetime AUD are currently abstinent or subthreshold drinkers. Factors associated with abstinence included older age, health problems, religiosity and social engagement. Results suggest a "J-shaped" relationship between current drinking patterns and health and psychosocial factors in veterans, with subthreshold drinkers generally having better health than abstinent and hazardous drinkers.


Effect of pH and Salt on Adsorption of Double-Stranded DNA on Graphene Oxide.
Graphene oxide (GO) has a large surface-to-volume ratio and hydrophobic hexagonal rings that can interact with biomolecules. Single-stranded DNA adsorbs strongly to the surface of GO via hydrophobic interactions. GO has been used in optical biosensors and biomedical platforms for the detection of DNA, proteins, and small molecules. This study was designed to measure the adsorption of double-stranded DNA (dsDNA) onto GO according to DNA length, salt concentration, and pH of the reaction. Results showed that dsDNA molecules were adsorbed progressively as the pH changed from 6.0 to 4.0. At high pH, dsDNA adsorption was enhanced by the presence of MgCl2 rather than NaCl. Desorption of DNA from GO, with triton X-100 led to the rapid release of DNA from GO in the presence of MgCl2.


Total ablative stereotactic body radiotherapy to primary and oligometastatic renal cell carcinoma in medically inoperable cases: An institutional analysis.
Stereotactic body radiotherapy (SBRT) has been found to be an effective and safe modality with excellent oncological outcome in medically inoperable primary renal cell carcinoma (RCC) and oligometastases. There is scarcity of data on the synchronous delivery of SBRT to primary and oligometastatic RCC in patients unfit for nephrectomy. Here, we report the findings of a retrospective study of prospectively collected data on "total ablative SBRT." Oligometastatic RCC patients with intact primary tumors were enrolled between May 2021 and June 2022. SBRT was synchronously delivered to the primary tumor and metastases. Demographics, treatment, oncologic outcomes, and toxicity were assessed. Kaplan-Meier estimates were generated for oncologic outcomes. The primary endpoint of this study was feasibility and tolerability. Eleven patients were enrolled between May 2021 and June 2022. One patient died at 2 months after SBRT due to viral pneumonitis (possibly COVID pneumonia). Nine patients (82%) had metastatic disease, while 2 (18%) were stage II. The average maximal diameter of primary was 68.7 mm (range, 23-128 mm). The SBRT doses for primary and metastasis ranged from 40 to 55 Gray (Gy) in 5 to 7 fractions and 22 to 40Gy in 2 to 5 fractions, respectively. The median follow-up period was 10.5 months (Range: 4-15 months). Response assessment was available for ten patients. Local control, marginal control, regional control and initial oligometastatic control (OMC) rates were 100%. OMC declined to 87.5% as one patient had recurrence in irradiated subcarinal lymphnode at 7 months. The metastatic control rate was 80% and loco-regional progression-free survival was 8 months (range, 4-15 months). Toxicities were minimal and manageable. At the last follow-up, 7 of 11 patients were alive with an overall survival of 63.5%. Six patients received systemic therapy after SBRT. Synchronous delivery of SBRT to primary and oligometastatic sites in patients unfit for nephrectomy was feasible and tolerable with good locoregional control. The total ablative SBRT strategy needs to be explored in similar cohorts.


Chip-scale nanofabrication of single spins and spin arrays in diamond.
We demonstrate a technique to nanofabricate nitrogen vacancy (NV) centers in diamond based on broad-beam nitrogen implantation through apertures in electron beam lithography resist. This method enables high-throughput nanofabrication of single NV centers on sub-100-nm length scales. Secondary ion mass spectroscopy measurements facilitate depth profiling of the implanted nitrogen to provide three-dimensional characterization of the NV center spatial distribution. Measurements of NV center coherence with on-chip coplanar waveguides suggest a pathway for incorporating this scalable nanofabrication technique in future quantum applications.


Poliovirus polypeptide precursors: expression in vitro and processing by exogenous 3C and 2A proteinases.
Plasmids have been constructed to generate substrates for the study of proteinases 2A and 3C of poliovirus. They contain the P1 (capsomer precursor) region of the poliovirus genome or P1 and part of P2 (a nonstructural precursor), which can be transcribed and translated in vitro. A transcript containing the entire 5' nontranslated region and the P1 region of the viral RNA gave poor translation in a reticulocyte translation system. Truncation of the 5' nontranslated region to its 3'-most segment gave acceptably good yields of radiolabeled P1. P1 was specifically processed to yield capsomer proteins by enzymes supplied in a postmitochondrial supernatant from poliovirus-infected cells. Thus, proteinase 3C can be supplied exogenously (in trans) and effect processing. This system may be used to provide P1 for the assay of proteinase 3C. Precursors that lacked either the 1A or 1D regions were poor substrates for proteinase 3C--observations that demonstrated a stringent structural requirement in processing by 3C. The translation product of a transcript encoding P1 and part of P2 was rapidly cleaved at the P1-P2 site in the absence of infected-cell extract. A transcript that contained a mutated 2A region gave a stable P1-P2 precursor that could be processed specifically by exogenous proteinase from infected-cell fractions. Processing of P1 appeared to require cleavage of the P1-P2 bond. These results support our previous data that 2A is the second polioviral proteinase and also provides a means of assaying proteinase 2A in vitro.


The immune response and the eye. I. The effects of monoclonal antibodies to T suppressor factors in anterior chamber-associated immune deviation (ACAID).
We report the effects of two monoclonal antibodies (mab) specific for murine T suppressor (Ts) factors (TsF) in anterior chamber (AC)-associated immune deviation (ACAID), as induced by AC inoculation of TNP-coupled syngeneic spleen cells (TNP-Spl). One mab (14-12) is specific for Ts effector factor and can block the induction of Ts cells in ACAID if given before or after AC injection of TNP-Spl. The other mab (14-30) is specific for Ts inducer factors and blocks suppression only after given after TNP-Spl. We also studied the surface phenotype of the Ts cells induced by AC injection of TNP-Spl. We show that at least two cells are required for the adoptive transfer of suppression in TNP-ACAID. One is Lyt-2+ and 14-12+, the other is I-J+. These Ts cells have the surface phenotype of Ts effector cells as seen in other systems. These results indicate that mab which bind TsF in other systems affect Ts cells in TNP-ACAID, and that the Ts cells induced in TNP-ACAID are only of the Ts effector type.


Importance of measurements at or after the J-point for evaluation of ST-segment deviation and resolution during treatment for acute myocardial infarction.
Determination of ST-segment deviation (STdev) and its resolution (STR) by reperfusion strategies have become important tools in the assessment of patients with acute myocardial infarction (AMI). STdev has been measured at different time-points, i.e. at 20-80 ms after the J-point. There are no data comparing STR at different time-points. STdev was measured using a new computer-assisted workflow. The intraclass correlation coefficients (ICC) for validity and agreement vs. classical manual measurements (n=1020) were both 0.996 (p<0.0001). The reliability indices were 0.991 (95% CI 0.990-0.992) for the manual vs. 0.995 (95% CI 0.995-0.996) for the computer-assisted method, indicating superiority of the latter. 12-lead STdev were determined on ECGs before (baseline) and 180 min after start of thrombolytic therapy, measured both at the J-point (STdev(J)) and 20 ms after the J-point (STdev(J20); n=2400). STdev(J20) was on average 0.01+/-0.03 mV higher than STdev(J) (p<0.0001) with a tendency towards larger differences for higher ST-elevations (p<0.001). Although the average STR calculated from STdev(J20) and STdev(J) was not statistically different in any infarct location group, in 26% of the patients the difference was >10%, and 11% of the patients were classified into another ST-resolution group. Analysing STdev only in the single lead with the highest ST-elevation at baseline (a simplified measurement which may eliminate the confounding effect of ST-depressions) showed an even higher classification discordance (14% of the patients). The time-point of STdev measurement is an important variable to be accounted for when evaluating ST resolution data. Uncontrolled extrapolation of classification schemes based on STdev(J20) to other time-points cannot be justified.


The Role of the Behavioral Approach System (BAS) in Bipolar Spectrum Disorders.
Bipolar spectrum disorders are characterized by highs and lows of mood, energy, motivation, cognition, and activity. The behavioral approach system (BAS) dysregulation theory provides an integrated model for understanding psychosocial and biological features of bipolar disorders. The theory emphasizes the role that sensitivity to rewards and goals plays in bipolar disorder. We review theory and evidence for the BAS-dysregulation model of bipolar disorders. We consider whether high BAS sensitivity is a correlate of, vulnerability factor for, and predictor of the course of bipolar spectrum disorders. We also discuss BAS-relevant life events as triggers of bipolar mood episodes. Finally, we address the implications of the BAS model for treatment and prevention of bipolar disorders and suggest directions for further research.


Morphological analysis and morphometry of the foramen magnum: an anatomical investigation.
The objectives were to study the morphology of the foramen magnum in dry skulls and to evaluate its antero-posterior diameter, transverse diameter and the foramen magnum index. The foramen magna of 53 dry human cadaver skulls that were obtained from the neuroanatomy laboratory were examined. Different shapes of the foramen magnum were macroscopically noted and classified. The antero-posterior and transverse diameters were measured and the average foraminal index was calculated. The foramen magnum shapes were determined as a round shape in 22.6% of cases, egg shape in 18.9%, tetragonal in 18.9%, oval in 15.1%, irregular in 15.1%, hexagonal in 5.6% and pentagonal in 3.8% of the cases. In 20.7% of skulls, the occipital condyle was observed to protrude into the foramen. The mean antero-posterior and transverse diameter of the foramen magnum was determined as 31 ± 2.4 mm and 25.2 ± 2.4 mm respectively. The average foramen magnum index was 1.2 ± 0.1. The present study has determined the various shapes of foramen magnum and its morphometry. The data obtained may be of useful to the neurosurgeon in analyzing the morphological anatomy of craniovertebral junction. The findings are also enlightening for the anthropologists, morphologists and clinical anatomists.


Role of gap junctions in endothelium-derived hyperpolarizing factor-mediated vasodilatation in rat renal artery.
To investigate the effects of gap junction inhibitors on endothelium-derived but nitric oxide (NO)- and prostacyclin (PGI2)-independent vasodilatations induced by carbachol in the rat isolated renal artery. Isolated renal arteries were mounted on a wire myograph apparatus were tissues treated with the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester hydrochloride (NAME; 100 micromol/L) and indomethacin (10 micromol/L) and precontracted with phenylephrine (0.1 micromol/L). NAME and indomethacin treated carbachol (0.01-10 micromol/L)- or sodium nitroprusside (SNP; 1-300 nmol/L)-induced mediated relaxations were observed in the presence of gap junction inhibitors. Carbachol produced a concentration-dependent relaxation in tissues treated with NAME (100 micromol/L) and indomethacin (10 micromol/L). This relaxation was not affected by hemoglobin (3 micromol/L), but was inhibited by charybdotoxin (200 nmol/L) and ouabain (30 micromol/L). The putative gap junction inhibitors, GAP 27 peptides with sequence homology to connexins 40 and 43 respectively reduced carbachol- but not SNP-induced relaxations mediated by endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxations. The inhibition by the connexin 43 inhibitor was greater than that of the connexin 40 inhibitor. The results indicate the presence of gap junctions sensitive to 43GAP 27 and 40GAP 27 in the rat renal artery and each of these different types of gap junctions plays a role in the NO- and PGI2-independent relaxations induced by carbachol in this blood vessel. However, connexin 43 appears to play a more predominant role in mediating gap junction communications in the rat renal artery.


Radiosensitivity of Prostate Cancer Cell Lines for Irradiation from Beta Particle-emitting Radionuclide ¹⁷⁷Lu Compared to Alpha Particles and Gamma Rays.
The purpose of the present study was to investigate the radiosensitivity of the prostate cancer cell lines LNCaP, DU145, and PC3 when irradiated with beta particles emitted from (177)Lu, and to compare the effect with irradiation using alpha particles or gamma rays. Cells were irradiated with beta particles emitted from (177)Lu, alpha particles from (241)Am, or gamma rays from (137)Cs. A non-specific polyclonal antibody was labeled with (177)Lu and used to irradiate cells in suspension with beta particles. A previously described in-house developed alpha-particle irradiator based on a (241)Am source was used to irradiate cells with alpha particles. External gamma-ray irradiation was achieved using a standard (137)Cs irradiator. Cells were irradiated to absorbed doses equal to 0, 0.5, 1, 2, 4, 6, 8, or 10 Gy. The absorbed doses were calculated as mean absorbed doses. For evaluation of cell survival, the tetrazolium-based WST-1 assay was used. After irradiation, WST-1 was added to the cell solutions, incubated, and then measured for level of absorbance at 450 nm, indicating the live and viable cells. LNCaP, DU145, and PC3 cell lines all had similar patterns of survival for the different radiation types. No significant difference in surviving fractions were observed between cells treated with beta-particle and gamma-ray irradiation, represented for example by the surviving fraction values (mean±SD) at 2, 6, and 10 Gy (SF2, SF6, and SF10) for DU145 after beta-particle irradiation: 0.700±0.090, 0.186±0.050 and 0.056±0.010, respectively. A strong radiosensitivity to alpha particles was observed, with SF2 values of 0.048±0.008, 0.018±0.006 and 0.015±0.005 for LNCaP, DU145, and PC3, respectively. The surviving fractions after irradiation using beta particles or gamma rays did not differ significantly at the absorbed dose levels and dose rates used. Irradiation using alpha particles led to a high level of cell killing. The results show that the beta-particle emitter (177)Lu as well as alpha-particles are both good candidates for radionuclide-therapy applications in the treatment of prostate cancer.


Expression and mapping of protein phosphatase 2A alpha in the developing rat heart.
Protein phosphatase 2A (PP2A) is a second messenger involved in cell cycle regulation, cell transformation, and cell fate determination. We previously identified a gene encoding the alpha catalytic subunit of PP2A in the embryonic rat heart, but its role in cardiac morphogenesis was unknown. In this study, we examined the developmental expression of PP2A alpha mRNA and protein in the heart using Northern and Western analysis, in situ hybridization, and immumohistochemical staining. We found two major PP2A alpha transcripts in the rat heart (1.8 and 2.4 kb), at all stages examined. By Western blotting, PP2A alpha protein levels were twice as high in the embryonic rat heart compared with the adult. In situ hybridization on embryonic d 12 showed that PP2A alpha mRNA was expressed in the heart, brain, tail, and limb buds. Cardiac PP2A alpha expression was regionally restricted to the atrium, ventricle, and truncus arteriosus. PP2A alpha expression did not extend into the more distal aortic sac or aortic arches. Cross-sectional hybridization revealed PP2A alpha mRNA in the epicardium, pericardium, and endothelium. Later in development, mRNA expression was also detected at high levels in mesenchymal cells populating the endocardial cushions and in myocardium. At term, PP2A alpha was highly expressed in endothelial cells, but not in the underlying myocardium. PP2A alpha protein had a similar distribution at all embryonic stages examined. These results show that there is transcriptional, translational, and cell-specific regulation of PP2A alpha during heart development. We speculate on the role of PP2A alpha-mediated dephosphorylation in cardiac morphogenesis and suggest a number of possible molecular targets.


HPA axis activity in patients with panic disorder: review and synthesis of four studies.
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may play a role in panic disorder. HPA studies in patients with panic disorder, however, have produced inconsistent results. Seeking to understand the inconsistencies, we reexamined endocrine data from four studies of patients with panic disorder, in light of animal data highlighting the salience of novelty, control, and social support to HPA axis activity. Patients with panic disorder were studied (1) at rest over a full circadian cycle, (2) before and after activation by a panicogenic respiratory stimulant (doxapram) that does not directly stimulate the HPA axis, and (3) before and after a cholecystokinin B (CCK-B) agonist that is panicogenic and does directly stimulate the HPA axis. Patients with panic disorder had elevated overnight cortisol levels, which correlated with sleep disruption. ACTH and cortisol levels were higher in a challenge paradigm (doxapram) than in a resting state study, and paradigm-related ACTH secretion was exaggerated in patients with panic disorder. Panic itself could be elicited without HPA axis activation. Patients with panic disorder showed an exaggerated ACTH response to pentagastrin stimulation, but this response was normalized by prior exposure to the experimental context or psychological preparation to reduce novelty and enhance sense of control. Novelty is one of a number of contextual cues known from animal work to activate the HPA axis. The HPA axis abnormalities seen in patients with panic disorder in the four experiments reviewed here might all be due to exaggerated HPA axis reactivity to novelty cues. Most of the published panic/HPA literature is consistent with the hypothesis that HPA axis dysregulation in panic is due to hypersensitivity to contextual cues. This hypothesis requires experimental testing.


Famotidine relieves symptoms of gastroesophageal reflux disease and heals erosions and ulcerations. Results of a multicenter, placebo-controlled, dose-ranging study. USA Merck Gastroesophageal Reflux Disease Study Group.
We conducted a double-blind, placebo-controlled, multicenter trial comparing the efficacy of famotidine 40 mg administered at bedtime (HS), 20 mg given twice daily (BID), and placebo to relieve heartburn and to heal endoscopically documented esophageal erosions or ulcerations. A total of 338 patients were randomized: 135 to receive famotidine 40 mg HS, 137 to receive famotidine 20 mg BID, and 66 to receive placebo. In the group given famotidine 20 mg BID, there was a significantly greater proportion of patients with complete relief of daytime heartburn, and both famotidine groups demonstrated statistically significant advantages over placebo in global scores or by successful outcome. Antacid consumption was significantly reduced in the group given famotidine 20 mg BID as compared with placebo. Both famotidine regimens resulted in a significantly greater proportion of patients with complete endoscopic healing than placebo, with the BID dosing being numerically superior to the 40-mg HS dose.


Design, synthesis and structure relationships of new N,N',N",N"'-tetrakis (omega-amino alkyl) tetraazamacrocycles.
A number of N,N',N",N"'-tetrakis (omega-aminoalkyl) tetraazamacrocycles and related compounds were synthesized and evaluated for their inhibitory effects on human immunodeficiency virus type 1 (HIV-1) and duck hepatitis B virus (DHBV) replication. The activity of these compounds was found to be highly dependent upon structural features: (i) the length of the alkyl linker connecting the nitrogen atoms of the macrocyclic ring to the exocyclic nitrogen atoms of the terminal amino groups (five methylenes favoured antiviral activity); (ii) substitution of the terminal amino groups of the linker reduced antiviral activity; and (iii) the size of the tetraazamacrocyclic ring (14 or 15 atoms) did not markedly affect the antiviral activity. Some analogues were potent inhibitors of HIV-1 replication, with anti-HIV activity similar to that of biscyclam (JM 2763). In contrast, other analogues were found to be highly toxic in duck hepatocyte primary culture, the 2.2.15 cell line and to a lesser extent in MT-4 cells. Structural parameters, macrocyclic ring size and metal-chelating ability have been used to develop a structure-activity relationship model in order to aid the design of antiviral molecules derived from N,N',N",N"'-tetrakis (omega-aminoalkyl) tetraazamacrocycles.


Pyrexia: aetiology in the ICU.
Elevation in core body temperature is one of the most frequently detected abnormal signs in patients admitted to adult ICUs, and is associated with increased mortality in select populations of critically ill patients. The definition of an elevated body temperature varies considerably by population and thermometer, and is commonly defined by a temperature of 38.0 °C or greater. Terms such as hyperthermia, pyrexia, and fever are often used interchangeably. However, strictly speaking hyperthermia refers to the elevation in body temperature that occurs without an increase in the hypothalamic set point, such as in response to specific environmental (e.g., heat stroke), pharmacologic (e.g., neuroleptic malignant syndrome), or endocrine (e.g., thyrotoxicosis) stimuli. On the other hand, pyrexia and fever refer to the classical increase in body temperature that occurs in response to a vast list of infectious and noninfectious aetiologies in association with an increase in the hypothalamic set point. In this review, we examine the contemporary literature investigating the incidence and aetiology of pyrexia and hyperthermia among medical and surgical patients admitted to adult ICUs with or without an acute neurological condition. A temperature greater than 41.0 °C, although occasionally observed among patients with infectious or noninfectious pyrexia, is more commonly observed in patients with hyperthermia. Most episodes of pyrexia are due to infections, but incidence estimates of infectious and noninfectious aetiologies are limited by studies with small sample size and inconsistent reporting of noninfectious aetiologies. Pyrexia commonly triggers a full septic work-up, but on its own is a poor predictor of culture-positivity. In order to improve culturing practices, and better guide the diagnostic approach to critically ill patients with pyrexia, additional research is required to provide more robust estimates of the incidence of infectious and noninfectious aetiologies, and their relationship to other clinical features (e.g., leukocytosis). In the meantime, using existing literature, we propose an approach to identifying the aetiology of pyrexia in critically ill adults.


Are oat products effective cholesterol-lowering agents?
Oat products have become popular as a treatment for hypercholesterolemia. This article was designed to address the following question: Do existing data support the conclusion that oat products are effective cholesterol-lowering agents? A comprehensive search found 11 eligible reports. Each report was analyzed for baseline data, research methodology, and study results. A quality score was assigned to each report. Nine of the 11 eligible reports scored 4 points or less (maximum possible score was 10). Specific design concerns included lack of comparison control groups, failure to randomize and blind subjects to treatment assignment, failure to control for important confounding variables, such as impact of dietary changes known to affect serum cholesterol levels, and inadequate time allotment for cholesterol level stabilization. In most reports, a wide response to oat products was noted. Ninety-five percent confidence levels for cholesterol change ranged from -47.0 percent to +23.8 percent. Despite widespread approval, available reports do not provide evidence to support or reject the purported beneficial effect of oat products in the treatment of hypercholesterolemia.


Progress Toward Universal Health Coverage: A Comparative Analysis in 5 South Asian Countries.
Achieving universal health coverage is one of the key targets in the newly adopted Sustainable Development Goals of the United Nations. To investigate progress toward universal health coverage in 5 South Asian countries and assess inequalities in health services and financial risk protection indicators. In a population-based study, nationally representative household (335 373 households) survey data from Afghanistan (2014 and 2015), Bangladesh (2010 and 2014), India (2012 and 2014), Nepal (2014 and 2015), and Pakistan (2014) were used to calculate relative indices of health coverage, financial risk protection, and inequality in coverage among wealth quintiles. The study was conducted from June 2012 to February 2016. Three dimensions of universal health coverage were assessed: access to basic services, financial risk protection, and equity. Composite and indicator-specific coverage rates, stratified by wealth quintiles, were then estimated. Slope and relative index of inequality were used to assess inequalities in service and financial indicators. Access to basic care varied substantially across all South Asian countries, with mean rates of overall prevention coverage and treatment coverage of 53.0% (95% CI, 42.2%-63.6%) and 51.2% (95% CI, 45.2%-57.1%) in Afghanistan, 76.5% (95% CI, 61.0%-89.0%) and 44.8% (95% CI, 37.1%-52.5%) in Bangladesh, 74.2% (95% CI, 57.0%-88.1%) and 83.5% (95% CI, 54.4%-99.1%) in India, 76.8% (95% CI, 66.5%-85.7%) and 57.8% (95% CI, 50.1%-65.4%) in Nepal, and 69.8% (95% CI, 58.3%-80.2%) and 50.4% (95% CI, 37.1%-63.6%) in Pakistan. Financial risk protection was generally low, with 15.3% (95% CI, 14.7%-16.0%) of respondents in Afghanistan, 15.8% (95% CI, 14.9%-16.8%) in Bangladesh, 17.9% (95% CI, 17.7%-18.2%) in India, 11.8% (95% CI, 11.8%-11.9%) in Nepal, and 4.4% (95% CI, 4.0%-4.9%) in Pakistan reporting incurred catastrophic payments due to health care costs. Access to at least 4 antenatal care visits, institutional delivery, and presence of skilled attendant during delivery were at least 3 times higher among the wealthiest mothers in Afghanistan, Bangladesh, Nepal, and Pakistan compared with the rates among poor mothers. Access to institutional delivery was 60 to 65 percentage points higher among wealthy than poor mothers in Afghanistan, Bangladesh, Nepal, and Pakistan compared with 21 percentage points higher in India. Coverage was least equitable among the countries for adequate sanitation, institutional delivery, and the presence of skilled birth attendants. Health coverage and financial risk protection was low, and inequality in access to health care remains a serious issue for these South Asian countries. Greater progress is needed to improve treatment and preventive services and financial security.


Patterns of fatigue related to advanced disease and radiotherapy in patients with cancer-a comparative cross-sectional study of fatigue intensity and characteristics.
This cross-sectional comparative study was designed to explore and describe the prevalence and patterns of cancer-related fatigue in patients with advanced cancer as well as patients undergoing curative radiotherapy. Another aim was to explore the association of anxiety and depression with fatigue. Patients with an advanced stage of disease (n = 228) and patients receiving radiotherapy (n = 81) completed the Borg Category Ratio Scale, the Multidimensional Fatigue Inventory and the Hospital Anxiety and Depression Scale. Patients with advanced disease had an increased probability of experiencing all aspects of fatigue except for mental fatigue as compared to patients undergoing radiation, e.g., odds ratio 11.5 (CI 5.8-22.7) for physical fatigue. Higher scores for depression than for anxiety were reported when patients had high levels of fatigue, with 23% of the patients classified as anxious and 39% depressed. The present study was carried out in order to address a gap in research by comparing the multidimensional aspects of fatigue in different groups of cancer patients. It is the intensity of fatigue that seems to be related to the underlying exposure to radiation or to the level of disease burden rather than the different fatigue profiles, such as the relation between physical and mental aspects.


Regional alterations in amyloid precursor protein and nerve growth factor across age in a mouse model of Down's syndrome.
Individuals with Down's syndrome (DS) develop the pathological hallmarks of Alzheimer's (AD) disease at an early age, subsequently followed by memory decline and dementia. We have utilized an animal model for DS, mice with segmental trisomy of chromosome 16 (Ts65Dn), to study biological events linked to memory loss. Previous studies demonstrated a cognitive decline and loss of cholinergic markers after 6-8 months of age. In the current study, we found increased levels of amyloid precursor protein (APP) in the striatum by 6-8 months of age, and in the hippocampus and parietal cortex by 13-16 months of age in Ts65Dn but not in normosomic mice. Additionally, Ts65Dn mice exhibited alterations in nerve growth factor (NGF) levels in the basal forebrain and hippocampus. Ts65Dn mice demonstrated a significant decline in NGF levels in the basal forebrain with age, as well as a reduction in hippocampal NGF by 13-16 months of age. These findings demonstrate that elevated APP and decreased NGF levels in limbic areas correlate with the progressive memory decline and cholinergic degeneration seen in middle-aged trisomic mice.


Hair and dietary supplements testing to identify contamination with roxadustat in an adverse analytical finding.
Roxadustat is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, which increases endogenous erythropoiesis. WADA has included roxadustat and other HIF stabilizers on its list of prohibited substances. We describe here the case of an elite athlete (female, 31 years old, 168 cm and 53 kg) with an adverse analytical finding (AAF) with concentration of roxadustat in her urine at 0.289 ng/mL in the A sample and 0.529 ng/mL in the B sample (83% higher than A). A stability study was carried out, showing total stability of roxadustat at this concentration in urine exposed to light for 50 h, so photoisomerization degradation cannot explain the difference in concentration. Her urine had been completely negative in a control test carried out three days previously, while roxadustat had been shown to be present in urine for at least 20 days after administration of pharmacologically effective doses to an athlete. Hair concentration was 0.39 and 0.35 pg/mg in the segments corresponding to the presumed period of intake, with few adjacent segments also positive (0.29-0.33 pg/mg), likely explained by cosmetic treatments. Concentrations found in a patient treated with a pharmacologically active dose (between 100 and 120 mg 3 days a week) were more than 100 times higher (between 41 and 57 pg/mg). Numerous supplements and pharmaceuticals taken by the athlete were analyzed. Only collagen powder showed the presence of roxadustat, at a very low but highly variable concentration (100 pg/g-1000 pg/g). A female volunteer (58 years old, 169 cm and 65 kg), taking this powder at the same doses as the athlete (10 g of powder 5 times for 6 days) presented 7 roxadustat-positive urine samples (although lower than those observed in the athlete) out of 34 sampled over 7 days, the difference in powder sampling location, age, weight, height, pharmacokinetic parameters variability and level of sporting activity between the athlete and the volunteer probably explaining the difference in concentrations observed. All these results could be consistent with an AAF due to contamination by dietary supplements, which are becoming increasingly common due to the current exposome of athletes in our society.