Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part II - contemporary contextual research.
In recent years there has been a renewed interest concerning the ways in which the gastrointestinal tract - its functional integrity and microbial residents - might influence human mood (e.g. depression) and behavioral disorders. Once a hotbed of scientific interest in the early 20th century, this area lay dormant for decades, in part due to its association with the controversial term 'autointoxication'. Here we review contemporary findings related to intestinal permeability, small intestinal bacterial overgrowth, lipopolysaccharide endotoxin (LPS) exposure, D-lactic acid, propionic acid, and discuss their relevance to microbiota and mental health. In addition, we include the context of modern dietary habits as they relate to depression, anxiety and their potential interaction with intestinal microbiota.


Managing agricultural emissions to the atmosphere: state of the science, fate and mitigation, and identifying research gaps.
The impact of agriculture on regional air quality creates significant challenges to sustainability of food supplies and to the quality of national resources. Agricultural emissions to the atmosphere can lead to many nuisances, such as smog, haze, or offensive odors. They can also create more serious effects on human or environmental health, such as those posed by pesticides and other toxic industrial pollutants. It is recognized that deterioration of the atmosphere is undesirable, but the short- and long-term impacts of specific agricultural activities on air quality are not well known or understood. These concerns led to the organization of the 2009 American Chemical Society Symposium titled . An outcome of this symposium is this special collection of 14 research papers focusing on various issues associated with production agriculture and its effect on air quality. Topics included emissions from animal feeding operations, odors, volatile organic compounds, pesticides, mitigation, modeling, and risk assessment. These papers provide new research insights, identify gaps in current knowledge, and recommend important future research directions. As the scientific community gains a better understanding of the relationships between anthropogenic activities and their effects on environmental systems, technological advances should enable a reduction in adverse consequences on the environment.


Investigation of vancomycin resistant Enterococcus faecium outbreak in neonatal intensive care unit.
Enterococci are one of the major agents of community-acquired and nosocomial infections. In this study we aimed to analyze the clonal relation of the vancomycin-resistant Enterococci outbreak seen at the Neonate Intensive Care Unit (NICU) of Uludag University Hospital. Vancomycin resistance gene was investigated in the Enterococcus faecium strains and pulsed field gel electrophoresis (PFGE) was used to investigate the genetic relation between outbreak strains. Enterococci grown in all patient samples were identified as Enterococcus faecium by BD Phoenix 100 (Becton Dickinson, USA). We found vanA resistance gene in all of the swab samples by Xpert VanA/B test on Cepheid (Cepheid, USA). PFGE band patterns revealed two different strains, of which the majority of them (22/24) had the same clonal origin. The common clonal origin was also isolated from rectal probes. Perianal swab culture positivity was evaluated as colonization but culture growth in two blood cultures, two urine cultures and one wound culture was evaluated as infection and treated with linezolid. All of the patients survived the outbreak. Besides the infection control precautions determining the genetic relation between outbreak strains which can be done in the microbiology laboratory is necessary to control an outbreak. PFGE is a reliable method in the microbiologic analysis of outbreaks. Molecular microbiologic analysis of outbreak strains will contribute to prove the epidemiologic and evolution of outbreaks.


Millionaires and mental health: Proposition 63 in California.
In November 2004 California passed Proposition 63, a landmark piece of mental health and fiscal legislation. This initiative places a 1 percent tax on adjusted gross income over dollar 1 million, affecting about 30,000 taxpayers and raising dollar 1.8 billion (a 31 percent increase) in new revenues over the first three years to support county-operated mental health systems. Our analysis suggests that Proposition 63 passed with strong support from Democrats, urban dwellers, and social workers and in counties with high rates of homelessness. Proposition 63 faces challenges in implementation and provides unprecedented opportunities for transformation and change.


Incorporation of labelled glycine into reduced glutathione of intact human erythrocytes by enzyme-catalysed exchange. A nuclear-magnetic-resonance study.
1H, 2H and 15N n.m.r. spectroscopy was used to monitor the incorporation of free glycine into the glycine residue of reduced glutathione (GSH) in suspensions of intact human erythrocytes. The following results were obtained. (i) By using 1H spin-echo n.m.r. the exchange reaction between [2H5]glycine and the protonated glycine residue of GSH was studied at various [2H5]glycine concentrations, thus enabling the calculation of an apparent Michaelis constant (Km) and maximal velocity (Vmax.) for the process. (ii) The reaction is catalysed by glutathione synthetase and proceeds most rapidly in the absence of glucose, which is the main physiological energy source of the erythrocyte. (iii) 15N n.m.r. spectroscopy, with a one-pulse sequence, and 2H n.m.r. spectroscopy, with an inversion recovery method, enabled demonstration of the incorporation of labelled glycine into an intra-erythrocyte peptide, consistent with incorporation into GSH. (iv) The exchange reaction, although inhibited by glucose, appeared not to be dependent on low ATP or 2,3-bisphosphoglycerate concentrations.


Interleukin 2 deficiency is a common feature of autoimmune mice.
IL 2 production was studied in autoimmune mice to assess the role of this lymphokine in the pathogenesis of murine lupus. Spleen and lymph node cells from autoimmune-susceptible mice show an age-dependent loss in the ability to produce functional IL 2. This defect correlates with disease expression and is most severe in MLR/Mp-Ipr/Ipr mice. MLR/Mp-Ipr/Ipr thymocytes gradually lose responsiveness to IL 2 with age. These results suggest that the immunoregulatory abnormalities of autoimmune mice may be due in part to IL 2 deficiency.


[Sonography in cystoid cervical space occupying lesions].
A retrospective analysis of fluid-filled cervical space-occupying lesions is performed. The high echogenicity of some cervical cysts is due to the difference of the acoustic impedance of water and agglomerated cholesterol crystals. A sonomorphological differential diagnosis of cystoid cervical tumors and fluid accumulations is performed. Uncommon criteria of cysts and new techniques for the differentiation of cystoid cervical lesions are discussed. The clinical role of sonography in the diagnosis of cervical cysts and cystoid lesions is evaluated on the basis of 180 histologically proved cases.


Diagnostic accuracy of in-house real-time PCR assay for Mycobacterium tuberculosis: a systematic review and meta-analysis.
In recent years, studies on the diagnostic accuracy of in-house real-time PCR (hRT-PCR) assay for the detection of Mycobacterium tuberculosis (Mtb) have been reported with unignorable discrepancies. To assess the overall accuracy of the hRT-PCR assay for Mtb diagnosis in different samples for individuals with active pulmonary and extra-pulmonary Mtb infection, a systematic review and meta-analysis were performed. The PUBMED, EMBASE, Web of Science, and Cochrane databases were searched up to June 2017 for eligible studies that estimated diagnostic sensitivity and specificity with the hRT-PCR assay in respiratory and non-respiratory samples in pulmonary and extra-pulmonary Mtb infection patients, with Mtb culture as the reference standard. Bivariate random effect models were used to provide pooled estimation of diagnostic accuracy. Further, subgroup and meta-regression analyses were performed to explore sources of heterogeneity. The risk of bias was assessed by the QUADAS-2 tool. Of the 3589 candidate studies, 18 eligible studies met our inclusion criteria. Compared to Mtb culture data, the pooled sensitivity and specificity were 0.96 and 0.92, respectively. The diagnostic odds ratio (DOR) was 192.96 (95% CI 68.46, 543.90), and the area under the summary ROC curve (AUC) was 0.9791. There was significant heterogeneity in sensitivity and specificity among the enrolled studies (p < 0.001). The studies with high-quality assessment and application of respiratory specimen were associated with better accuracy. In low-income/high-burden settings, our results suggested that the hRT-PCR assay could be a useful test for the diagnosis of TB with high sensitivity and specificity.


Protective effects of melittin on tumor necrosis factor-α induced hepatic damage through suppression of apoptotic pathway and nuclear factor-kappa B activation.
Melittin, a major polypeptide in honeybee venom, have been used to treat inflammatory disease. Various studies have demonstrated the anti-bacterial, anti-viral, anti-inflammatory and anticancer effects of bee venom and melittin. However, the precise mechanism of melittin in liver disease is not yet known. Apoptosis contributes to liver inflammation and fibrosis. Knowledge of the apoptotic mechanisms is important to develop new and effective therapies for treatment of cirrhosis. In the present study, we investigated the anti-apoptotic effect of melittin on tumor necrosis factor (TNF)-α/actinomycin (Act) D-induced apoptosis in hepatocytes. Our results show significant protection from DNA damage by melittin treatment compared with corresponding TNF-α/Act D-treated hepatocytes without melittin. Melittin inhibited TNF-α/Act D-induced activation of the caspase, bcl-2 family of proteins and poly ADP-ribose polymerase (PARP)-1. Our results also indicate that melittin decreased nuclear factor-kappa B (NF-κB) by degradation of phosphorylation of IκB kinase (p-IKK) and NF-κB DNA binding activity in TNF-α/Act D-treated hepatocytes. These results suggest that melittin possesses a potent suppressive effect on apoptotic responses in TNF-α/Act D-treated hepatocytes via the NF-κB pathway.


Faster Compared With Standard Insulin Aspart During Day-and-Night Fully Closed-Loop Insulin Therapy in Type 1 Diabetes: A Double-Blind Randomized Crossover Trial.
We evaluated the safety and efficacy of day-and-night fully closed-loop insulin therapy using faster (Faster-CL) compared with standard insulin aspart (Standard-CL) in young adults with type 1 diabetes. In a double-blind, randomized, crossover trial, 20 participants with type 1 diabetes on insulin pump therapy (11 females, aged 21.3 ± 2.3 years, HbA1c 7.5 ± 0.5% [58.5 ± 5.5 mmol/mol]) underwent two 27-h inpatient periods with unannounced afternoon moderate-vigorous exercise and unannounced/uncovered meals. We compared Faster-CL and Standard-CL in random order. During both interventions, the fuzzy-logic control algorithm DreaMed GlucoSitter was used. Glucose sensor data were analyzed by intention-to-treat principle with the difference (between Faster-CL and Standard-CL) in proportion of time in range 70-180 mg/dL (TIR) over 27 h as the primary end point. The proportion of TIR was similar for both arms: 53.3% (83% overnight) in Faster-CL and 57.9% (88% overnight) in Standard-CL (P = 0.170). The proportion of time in hypoglycemia <70 mg/dL was 0.0% for both groups. Baseline-adjusted interstitial prandial glucose increments 1 h after meals were greater in Faster-CL compared with Standard-CL (P = 0.017). The gaps between measured plasma insulin and estimated insulin-on-board levels at the beginning, at the end, and 2 h after the exercise were smaller in the Standard-CL group (P = 0.029, P = 0.003, and P = 0.004, respectively). No severe adverse events occurred. Fully closed-loop insulin delivery using either faster or standard insulin aspart was safe and efficient in achieving near-normal glucose concentrations outside postprandial periods. The closed-loop algorithm was better adjusted to the standard insulin aspart.


Using the Reproductive Life Plan in contraceptive counselling.
Having children or not is one of the most important decisions that a person will make in his or her lifetime. The Reproductive Life Plan (RLP) is a protocol that aims to encourage both women and men to reflect on their reproductive intentions and to find strategies for successful family planning, for example to have the wanted number of children and to avoid unwanted pregnancies as well as ill-health that may threaten reproduction. The RLP was developed in an American context for promotion of reproductive health in a life cycle perspective. Few studies have systematically evaluated the effectiveness of using an RLP protocol in clinical practice. This article describes the application of using the RLP protocol in contraceptive counselling in Sweden.


Clinical and radiological outcomes of conservative treatment for unilateral sagittal split fractures of C1 lateral mass.
The aim of this study was to assess the effect of transverse atlantal ligament (TAL) integrity on clinical and radiological outcomes in patients with unilateral sagittal split fracture (USSF) of the C1 lateral mass (LM). Twenty-six consecutive patients (16 men and 10 women; mean age: 52 years (range: 32-69)) with C1 LM USSF were included in this study. Sixteen were TAL injury group (nine of type I injuries and seven of type II injuries according to Dickman's classification) and ten were TAL intact group. All cases were conservatively treated with a rigid brace for TAL intact or by halo-vest stabilization for TAL injury for three months. The mean follow-up was 16 months (range, 12-47 months). The results were compared with radiological assessment of fracture healing, LM displacement and Neck visual analog scale. At the last follow-up, for TAL intact group, total LM displacement (LMD), unilateral LMD of fracture side, atlanto-dental interval, basion-dental interval, clivus canal angle, and atlanto-occipital joint axis angle were maintained compared to initial presentation. However, for TAL injury group, all radiological parameters were worsened. The worsening of radiological parameters was more severe in type I injury than type II injury except for total LMD and unilateral LMD. Neck visual analog scale significantly decreased and patient's satisfaction was higher in TAL intact group compared to TAL injury group. Conservative treatment for USSF of C1 LM with TAL injury failed to achieve healing of the fracture, which resulted in lateral displacement of C1 LM. This caused coronal and sagittal malalignment of occipitocervical junction, resulting in unsatisfactory clinical outcomes. Our results suggest that early surgical stabilization should be considered in USSF of C1 LM with TAL injury, especially type I injury. However, conservative treatment may be sufficient for a USSF of the C1 LM with TAL intact. Level III, Therapeutic Study.


Psychometric Properties of the Oral Health Impact Profile and New Methodological Approach.
Evaluate the validity, reliability, and factorial invariance of the complete Portuguese version of the Oral Health Impact Profile (OHIP) and its short version (OHIP-14). A total of 1,162 adults enrolled in the Faculty of Dentistry of Araraquara/UNESP participated in the study; 73.1% were women; and the mean age was 40.7 ± 16.3 yr. We conducted a confirmatory factor analysis, where χ(2)/df, comparative fit index, goodness of fit index, and root mean square error of approximation were used as indices of goodness of fit. The convergent validity was judged from the average variance extracted and the composite reliability, and the internal consistency was estimated by Cronbach standardized alpha. The stability of the models was evaluated by multigroup analysis in independent samples (test and validation) and between users and nonusers of dental prosthesis. We found best-fitting models for the OHIP-14 and among dental prosthesis users. The convergent validity was below adequate values for the factors "functional limitation" and "physical pain" for the complete version and for the factors "functional limitation" and "psychological discomfort" for the OHIP-14. Values of composite reliability and internal consistency were below adequate in the OHIP-14 for the factors "functional limitation" and "psychological discomfort." We detected strong invariance between test and validation samples of the full version and weak invariance for OHIP-14. The models for users and nonusers of dental prosthesis were not invariant for both versions. The reduced version of the OHIP was parsimonious, reliable, and valid to capture the construct "impact of oral health on quality of life," which was more pronounced in prosthesis users.


Chelation in metal intoxication. XX: Effect of pre-treatment with chelators on the distribution of mercury.
The effect of pre-treatment with sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), sodium diethyldithiocarbamate (DDC) and calcium trisodium diethylenetriaminepentaacetate (DTPA) on the fate of injected mercuric chloride in rats was investigated. DMPS was the most effective chelator in reducing the uptake of Hg (203) in tissues and was the only chelator to enhance the urinary excretion of Hg (203). The results suggest affinity of Hg towards sulfur moiety and that the protective effects of pre-treatment are also shared by non-steroidal thiol chelators.


Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer.
Accumulating evidence suggests that both levels and activity of the estrogen receptor (ER) and the progesterone receptor (PR) are dramatically influenced by growth-factor receptor (GFR) signaling pathways, and that this crosstalk is a major determinant of both breast cancer progression and response to therapy. The phosphatidylinositol 3-kinase (PI3K) pathway, a key mediator of GFR signaling, is one of the most altered pathways in breast cancer. We thus examined whether deregulated PI3K signaling in luminal ER+ breast tumors is associated with ER level and activity and intrinsic molecular subtype. We defined two independent molecular signatures of the PI3K pathway: a proteomic (reverse-phase proteomic array) PI3K signature, based on protein measurement for PI3K signaling intermediates, and a PI3K transcriptional (mRNA) signature based on the set of genes either induced or repressed by PI3K inhibitors. By using these signatures, we scored each ER+ breast tumor represented in multiple independent expression-profiling datasets (four mRNA, n = 915; one protein, n = 429) for activation of the PI3K pathway. Effects of PI3K inhibitor BEZ-235 on ER expression and activity levels and cell growth were tested by quantitative real-time PCR and cell proliferation assays. Within ER+ tumors, ER levels were negatively correlated with the PI3K activation scores, both at the proteomic and transcriptional levels, in all datasets examined. PI3K signature scores were also higher in ER+ tumors and cell lines of the more aggressive luminal B molecular subtype versus those of the less aggressive luminal A subtype. Notably, BEZ-235 treatment in four different ER+ cell lines increased expression of ER and ER target genes including PR, and treatment with IGF-I (which signals via PI3K) decreased expression of ER and target genes, thus further establishing an inverse functional relation between ER and PI3K. BEZ-235 had an additional effect on tamoxifen in inhibiting the growth of a number of ER+ cell lines. Our data suggest that luminal B tumors have hyperactive GFR/PI3K signaling associated with lower ER levels, which has been correlated with resistance to endocrine therapy. Targeting PI3K in these tumors might reverse loss of ER expression and signaling and restore hormonal sensitivity.


Low Pressure Low Frequency Jet Ventilation: Techniques, Safety and Complications.
Manual jet ventilation is a specialized oxygenation and ventilation technique that is not available in all facilities due to lack of technical familiarity and fear of complications. The objective is to review our center's 15 year experience with low pressure low frequency jet ventilation (LPLFJV). Retrospective review of procedures utilizing LPLFJV from 2005 to 2019 were performed collecting patient demographic, surgery type and complications. Fisher exact test, Chi square, and t-test were used to determine statistical significance. Four hundred fifty-seven patients underwent a total of 891 microlaryngeal surgeries-279 cases for voice disorders, 179 for lesions, and 433 for airway stenosis. The peak jet pressure for all cases did not exceed 20 psi and average peak pressure for the last 100 procedures in this case series was 14.9 ± 4.6 psi. The average lowest oxygen saturation for all cases was 95% ± 0.6%. Brief intubation was required in 154 cases (17%). Surgical duration was significantly longer for cases requiring intubation P < .001. The need for intubation was not associated with smoking or cardiopulmonary disease, but was strongly associated with body mass index (BMI). Intubation rates were 7% for normal weight (BMI < 25, N = 216), 13% for overweight (BMI 25-30, N = 282), 24% for obese (BMI 30-40, N = 342), and 37% for morbidly obese (BMI > 40, N = 52) patients. Three patients developed respiratory distress in the recovery unit and 2 patients required intubation. LPLFJV assisted by intermittent endotracheal intubation is an exceedingly safe and effective intraoperative oxygenation and ventilationmodality for a broad variety of laryngeal procedure.


Scurvy in a 10-year-old boy.
Scurvy, or hypovitaminosis C, is an uncommon condition that exists today primarily within certain unique populations-particularly the elderly subjects, patients with neurodevelopmental disabilities or psychiatric illnesses, or others with unusual dietary habits. Vitamin C is an essential nutrient in the human body, and is important in synthesizing collagen factor whose faulty production is responsible for most of the clinical manifestations of scurvy. These clinical manifestations can include dystrophic or corkscrew hairs, gingival hyperplasia, and weakened blood vessel walls, causing bleeding in the skin, joints, and other organs. Although rare in the Unites States, the presence of scurvy should not be forgotten because of its presence among susceptible populations. Moreover, with its diagnosis, treatment and cure is one of the simplest in modern medicine. We report a case of scurvy in a 10-year-old autistic child.


Program of rehabilitative exercise and education to avert vascular events after non-disabling stroke or transient ischemic attack (PREVENT Trial): a multi-centred, randomised controlled trial.
Despite lack of outward signs, most individuals after non-disabling stroke (NDS) and transient ischemic attack (TIA) have significant cardiovascular and cerebrovascular disease and are at high risk of a major stroke, hospitalization for other vascular events, or death. Most have multiple modifiable risk factors (e.g., hypertension, physical inactivity, hyperlipidaemia, diabetes, tobacco consumption, psychological stress). In addition, accelerated rates of depression, cognitive decline, and poor quality of sleep have been reported following TIA, which correlate with poor functional outcomes and reduced quality of life. Thus, NSD and TIA are important warning signs that should not be overlooked. The challenge is not unlike that facing other 'silent' conditions - to identify a model of care that is effective in changing people's current behaviors in order to avert further morbidity. A single blind, randomized controlled trial will be conducted at two sites to compare the effectiveness of a program of rehabilitative exercise and education versus usual care in modifying vascular risk factors in adults after NDS/TIA. 250 adults within 90 days of being diagnosed with NDS/TIA will be randomly allocated to a 12-week program of exercise and education (PREVENT) or to an outpatient clinic assessment and discussion of secondary prevention recommendations with return clinic visits as indicated (USUAL CARE). Primary outcome measures will include blood pressure, waist circumference, 12-hour fasting lipid profile, and 12-hour fasting glucose/hemoglobin A1c. Secondary measures will include exercise capacity, walking endurance, physical activity, cognitive function, depression, goal attainment and health-related quality of life. Outcome assessment will be conducted at baseline, post-intervention, and 6- and 12-month follow-ups. Direct health care costs incurred over one year by PREVENT versus USUAL CARE participants will also be compared. Ethical approval for the trial has been obtained from the relevant Human Research Ethics Boards. Whether timely delivery of an adapted cardiac rehabilitation model is effective in attaining and maintaining vascular risk reduction targets in adults after NDS/TIA is not yet known. We anticipate that the findings of this trial will make a meaningful contribution to the knowledge base regarding secondary stroke prevention.


[Accreditation: the outcome is worth the time and money].
When the Canadian Council on Health Services Accreditation adopted the Client-centered Accreditation Program (CCAP), we had to assess our methods and results and encourage the staff at all levels and the users to be involved. A complete change, considerable benefits: improved staff knowledge of the organisation, support and understanding within the teams, improved training through team meetings, more room for the patients and their families. Is accreditation costly? One cannot put a price on the degree of satisfaction experienced by the staff within a team who listens to their opinions and strives to make the daily routine as rewarding as possible.


Interstitial tissue concentrations of cefpodoxime.
Microdialysis is a technique that allows the measurement of concentrations of free antibiotic in tissue. The free antibiotic concentration is responsible for the antibacterial effect at the target site. We used microdialysis in animal and human studies to investigate the tissue penetration of cefpodoxime. In the animal study, total plasma and free muscle and lung concentrations of cefpodoxime were measured after male Wistar rats had received either 10 mg/kg or 20 mg/kg i.v. cefpodoxime over 5 h or a continuous i.v. infusion of 260 microg/h cefpodoxime after a loading dose of 6 mg/kg. Free muscle concentrations of cefpodoxime were similar to free lung concentrations and therefore provided a surrogate measure of cefpodoxime concentrations at the pulmonary target site. In an open, randomized, two-way crossover, single-dose study in six healthy male volunteers, total plasma and free muscle concentrations were measured after a single oral dose of cefpodoxime 400 mg or cefixime 400 mg. The total plasma concentrations of each antibiotic were similar and higher than free muscle concentrations. The tissue penetration of cefpodoxime was, however, greater than that of cefixime, as shown by two-fold higher peak free muscle concentrations after dosing with cefpodoxime than with cefixime (2.1 mg/L versus 0.9 mg/L). In addition, the area under the curve for tissue (AUC(t)) of cefpodoxime (400 mg) was more than double that of cefixime (400 mg), based on free antibiotic concentrations (15.4 mg x h/L versus 7.3 mg x h/L). These findings indicate that, taking into account pharmacokinetic/pharmacodynamic considerations, cefpodoxime is likely to be more efficacious than cefixime, due to its greater tissue penetration.


Influence of hydrographic features on larval fish distribution during the south-westerly monsoon in the waters of Taiwan, western North Pacific Ocean.
The spatial distribution patterns of fish larvae and the relationships with hydrographic conditions in the waters surrounding Taiwan were studied in August 2004 when the south-westerly monsoon prevailed. A total of 6566 fish larvae were identified, belonging to 80 families, 129 genera and 230 species. Cluster analysis revealed two station groups, one associated with the South China Sea Surface Current (SCSSC) and the other with the Kuroshio Current (KC). The SCSSC group was characterized by mostly coastal and neritic species, and the KC group was predominated by oceanic species. Larger fish larvae were generally more abundant in the neritic waters west of Taiwan where the SCSSC prevails than in the waters east of Taiwan where the KC prevails. The combination of chlorophyll a, zooplankton and nitrite best explained the relationship of larval fish distribution and environmental variables, implying that the distribution of fish larvae in summer was closely linked to the food source. The changing of monsoons potentially affects the succession of water masses and the transport and assemblage of fish larvae in this study area.


The interface between undergraduate and graduate medical education.
The principal current problem related to the interface between undergraduate and graduate medical education is the lack of preparation of graduating medical students to assume many of the patient-care responsibilities required in certain graduate programs. There are two sides to the interface, and both require attention if the problem is to be resolved. The educational quality of the generally permissive fourth year of medical school should be examined in terms of the need for medical schools to prepare students for graduate educational programs. An effective broad first year of graduate medical education requires the development of institutional policy by all clinical departmental directors jointly and the delegation of operational responsibility to a small group of professionals.


Expression of a human coxsackie/adenovirus receptor transgene permits adenovirus infection of primary lymphocytes.
Replication-defective adenoviruses are effective vehicles for gene transfer, both for the repair of defective genes and for studies of gene function in primary cells. Many cell types, including lymphocytes, are refractory to adenovirus infection because they lack the Coxsackie/adenovirus receptor (CAR) needed for virus attachment. To extend the advantages of adenovirus-mediated gene transfer to primary lymphoid populations and other cell types lacking endogenous CAR, we produced a mouse that expresses human (h) CAR as a transgene under control of a murine MHC class I promoter. hCAR protein is expressed on T and B lymphocytes from a variety of organs (spleen, lymph node, bone marrow, thymus, and peritoneum). These lymphocytes are susceptible to adenovirus infection, as demonstrated by reporter green fluorescent protein gene expression, with the fraction of expressing cells as high as 70%. Some lymphocyte subpopulations required stimulation subsequent to adenovirus infection for reporter expression. This activation requirement is a restriction imposed by the promoter used in the adenovirus construct. In subpopulations requiring activation, the elongation factor 1 promoter was far superior to a hCMV promoter for directing green fluorescent protein production. We also find that hCAR mRNA is produced in nonlymphoid tissues from all founder lines, including tissues that do not express endogenous murine CAR, suggesting the opportunity for effecting gene delivery to and testing gene function in a wide variety of primary cell types previously resistant to gene transfer.


Re-engineering the process of surgical informed consent.
We have created a clinical performance support system that transforms surgical informed consent into an interactive process capable of evolving in response to institution-specified, provider-specified and patient-specified needs. The system functions in several capacities, including: (1) a source of standardized and comprehensive content and format the transmission of procedure-related risk and complications; (2) as expert critique, providing cues in an effort to reduce the effects of biased risk appraisal; (3) captures and archives clinician behavior relating to use, modification and disclosure of standardized knowledge sources; (4) provides just-in-time access to procedural descriptions information relating to risks and complications; (5) captures, archives and makes available to the clinician patient use of procedure-related knowledge resources. By design, the system will be used to assess the relationship between clinician perception and heuristics surrounding risk appraisal and disclosure and patient perceptions based on response to the disclosure process. The system prototype is currently being deployed in a breast surgery unit at the Beth Israel Deaconess Medical Center.


Mecillinam alone and in combination with ampicillin or moxalactam in experimental Escherichia coli meningitis.
The activity of mecillinam, ampicillin and moxalactam alone and in combination was determined in a lapin meningitis model and a mouse meningitis model against two Escherichia coli strains isolated from infants with meningitis. Both strains were highly susceptible in vitro to the antibiotics, and responded well in systemic mouse protection tests (PD50 less than 4 mg/kg). Continuous infusion of mecillinam in the lapin model over nine hours was effective in sterilizing the CSF of three of four animals infected with one strain. This prompt bacteriologic response to mecillinam alone precluded the possibility of constant infusion administration for synergy studies. Therefore, single dose administration was used to demonstrate the synergistic potential of mecillinam with ampicillin in the lapin meningitis model against the E. coli Kl # 2 strain. The combination of moxalactam and mecillinam was synergistic against the E. coli Kl # 2 strain in the mouse meningitis model. The synergistic potential of these combinations could not be reliably predicted by in vitro tests, time kill curves or systemic mouse protection tests.


Weighed dietary intakes in patients with chronic liver disease.
Poor dietary intake is assumed to be a major causal factor in the malnutrition observed in patients with chronic liver disease. However, the dietary habits of this patient population are poorly documented. The aim of this study was to assess weighed dietary intakes in hospitalized patients with chronic liver disease. Twenty patients with liver disease (10 men, 10 women; mean +/- SD age, 46.2 +/- 10.9 yr, mean weight, 63.3 +/- 8.0 kg, mean body mass index, 22.1 +/- 2.8 kg/m2; 10 alcoholic, 10 nonalcoholic) and 20 general medical patients, matched for age and sex, underwent a 3-d weighed assessment of dietary intake. No significant differences were observed in food intake or dietary composition between the patients with liver disease and the hospital controls. Patients with alcoholic liver disease showed significant differences in dietary energy, protein, and carbohydrate intakes compared with the patients with nonalcoholic liver disease when data were expressed in absolute terms but not when expressed relative to body weight; dietary composition was similar in both groups. Overall, patients with chronic liver disease, especially those with alcohol-related injury, consume a diet comparable with that ingested by other hospital patients both in amount and composition.


Expression of matrix metalloproteinases in patients with bipolar disorder.
High cardiovascular mortality rates have been reported in patients with bipolar disorder (BD). Studies indicate that matrix metalloproteinases (MMPs) are implicated in cardiovascular diseases. We evaluated the expression pattern of MMP-2 and MMP-9 in blood from patients with BD during acute mania and after euthymia, in comparison with healthy controls. Twenty patients and 20 controls were recruited and matched for sex and age. MMP messenger RNA (mRNA) levels were measured using real-time quantitative polymerase chain reaction (PCR). Body mass index (BMI) was calculated for all subjects. There were no significant differences in MMP-2 and MMP-9 mRNA expression between patients and controls. mRNA levels were not significantly different during mania and euthymia. However, MMP-2 mRNA levels were negatively associated with BMI in BD patients and positively associated with BMI in controls. There was no difference in the pattern of MMP-9 expression between patients and controls. Our results suggest a different pattern of association between MMP-2 and BMI in BD patients as compared with controls. Despite some study limitations, we believe that the role of MMPs in BD should be further investigated to elucidate its relationship with cardiovascular risk.


A rare case of hepatoid adenocarcinoma of the lung.
Hepatoid adenocarcinoma of the lung is a special type of primary origin in the lung with obvious pathological features and short survival time. However, standard treatment guidelines have not yet been established. Herein, we report a case of hepatoid adenocarcinoma with the primary lesion located in the left upper lung. The tumour size was reduced after four cycles of combined therapy. Subsequent postoperative pathology confirmed complete remission.


Epidemiological survey of zoonotic helminths in feral cats in Gran Canaria island (Macaronesian archipelago-Spain).
The presence of zoonotic parasites in feral cats have been widely considered all over the world. In Gran Canaria (Macaronesian archipelago, Canary Islands, Spain) the number of feral cats has grown out of control in urban and rural areas. 48 of Felis catus captured in different Gran Canaria areas were studied. Animals were necropsied and several organs were systematically examined in order to collect and identify macroscopic parasites. In addition, coprological tests were done in 28 cats. There were no statistically significant differences in the prevalence rate among sex, age or capture area, showing an overall prevalence of helminths of 77.1%. The most common tapeworms were Dipylidium caninum (64.6%) and Taenia taeniaeformis (31.3%), followed by the nematodes Toxocara cati (20.8%), Ancylostoma tubaeforme (18.8%), Aelurostrongylusabstrusus (10.4%) and Truchuris vulpis (2.08%). We also find several eggs of Alaria alata in the small intestine of one cat (2.08%), being the first description of this trematode in cats in the Canary Islands. Aproximatelly, 40% of the studied cats harboured more than one parasite. High rates of zoonotic species found in these animals suggest the need of controling parasitic infections and preventive measures against them.


Gastrointestinal mast cells. New approaches for analyzing their function in vivo.
Mast cells have been implicated in a variety of physiologic or pathologic responses in the gastrointestinal tract; however, the precise contributions of the mast cell to these reactions have been difficult to define. This article discusses general aspects of mast cell biology, outlines new approaches for the analysis of mast cell function in vivo, and reviews recent evidence indicating that mast cells can produce a wide spectrum of multifunctional cytokines.


Salvianolic acid A reverses the paclitaxel resistance and inhibits the migration and invasion abilities of human breast cancer cells by inactivating transgelin 2.
Multidrug resistance and tumor migration and invasion are the major obstacles to effective breast cancer chemotherapy, but the underlying molecular mechanisms remain unclear. This study investigated the potential of transgelin 2 and salvianolic acid A to modulate the resistance and the migration and invasion abilities of paclitaxel-resistant human breast cancer cells (MCF-7/PTX). MCF-7/PTX cells were found to exhibit not only a high degree of resistance to paclitaxel, but also strong migration and invasion abilities. Small interfering RNA-mediated knockdown of TAGLN2 sensitized the MCF-7/PTX cells to paclitaxel, and inhibited their migration and invasion abilities. In addition, we also observed that combined salvianolic acid A and paclitaxel treatment could reverse paclitaxel resistance, markedly inhibit tumor migration and invasion, and suppress the expression of transgelin 2 in MCF-7/PTX cells. These findings indicate that salvianolic acid A can reverse the paclitaxel resistance and inhibit the migration and invasion abilities of human breast cancer cells by down-regulating the expression of transgelin 2, and hence could be useful in breast cancer treatments.


Low Serum Magnesium Levels Are Associated With Hemorrhagic Transformation After Thrombolysis in Acute Ischemic Stroke.
Background: In patients with acute ischemic stroke, hemorrhagic transformation is a major complication after intravenous thrombolysis. This study aimed to investigate the relationship between serum magnesium levels and hemorrhagic transformation (HT) after thrombolytic therapy. Methods: We retrospectively analyzed data from 242 patients who received thrombolytic therapy at the Second Affiliated Hospital of the Wenzhou Medical University in China. Baseline serum magnesium levels were measured before intravenous thrombolysis, and the occurrence of HT was evaluated using computed tomography images reviewed within 24-36 h after therapy. The relationship between serum magnesium levels and HT was examined using multivariate logistic regression, subgroup analysis, and restricted cubic spline models. Results: Of the 242 included patients, 43 (17.8%) developed HT. Patients with HT had significant lower serum magnesium levels than those without HT (0.81 ± 0.08 vs. 0.85 ± 0.08 mmol/L, p = 0.007). Multivariable logistic regression analysis indicated that patients with higher serum magnesium levels had lower risk of HT (OR per 0.1-mmol/L increase 0.43, 95% CI 0.27-0.73, p = 0.002). However, this association did not persist when baseline levels of serum magnesium were higher than the median value (0.85 mmol/L) in subgroup analysis (OR per 0.1-mmol/L increase 0.58, 95% CI 0.14-2.51, p = 0.47). This threshold effect was also observed in the restricted cubic spline model when serum magnesium levels were above 0.88 mmol/L. No association between symptomatic HT and serum magnesium levels was observed in our study (OR per 0.1-mmol/L increase 0.52, 95% CI 0.25-1.11, p = 0.092). Conclusions: Lower serum magnesium levels in patients with ischemic stroke are associated with an increased risk of HT after intravenous thrombolysis, but perhaps only when serum magnesium is below a certain minimal concentration.


Magnetic resonance functional nano-hydroxyapatite incorporated poly(caprolactone) composite scaffolds for in situ monitoring of bone tissue regeneration by MRI.
In this study, we have reported the incorporation of a multi-modal contrast agent based on hydroxyapatite nanocrystals, within a poly(caprolactone)(PCL) nanofibrous scaffold by electrospinning. The multifunctional hydroxyapatite nanoparticles (MF-nHAp) showed simultaneous contrast enhancement for three major molecular imaging techniques. In this article, the magnetic resonance (MR) contrast enhancement ability of the MF-nHAp was exploited for the purpose of potentially monitoring as well as for influencing tissue regeneration. These MF-nHAp containing PCL scaffolds were engineered in order to enhance the osteogenic potential as well as its MR functionality for their application in bone tissue engineering. The nano-composite scaffolds along with pristine PCL were evaluated physico-chemically and biologically in vitro, in the presence of human mesenchymal stem cells (hMSCs). The incorporation of 30-40 nm sized MF-nHAp within the nanofibers showed a substantial increase in scaffold strength, protein adsorption, proliferation, and osteogenic differentiation of hMSCs along with enhanced MR functionality. This preliminary study was performed to eventually exploit the MR contrast imaging capability of MF-nHAp in nanofibrous scaffolds for real-time imaging of the changes in the tissue engineered construct.


Impact of marital status in patients undergoing radical cystectomy for bladder cancer.
Married (vs. unmarried) individuals have improved health status and longer life expectancies in a variety of benign and malignant disease states, including prostate, breast, head/neck, and lung cancers. We sought to evaluate a cohort of patients undergoing cystectomy for bladder cancer to evaluate the impact of marital status on demographic, peri-operative, and pathological outcomes in order to better understand the factors which may contribute to the survival differences observed. Two-hundred and two patients underwent radical cystectomy and urinary diversion for bladder cancer. Patients were categorized based on marital status as either married or unmarried (widowed, divorced, never married). Correlations were made to demographic factors (age, race, gender, BMI, tobacco use, alcohol use), perioperative factors (pre-op renal function (creatinine), hematocrit, EBL, hospital stay, choice of diversion), and pathological outcomes (organ-confined status, LN positivity). Of the 202 patients, 74% were married. Married individuals (vs. unmarried) were more often male (84 vs. 62%) and had a higher BMI (28.1 vs. 25.9). Married persons had a significantly lower pre-op creatinine (1.1 vs. 1.4) and higher hematocrit (39 vs. 34). Hospital stay was shorter in married patients by a mean of 1.6 days. Regarding operative pathology, married patients had a higher rate of organ-confined disease (59 vs. 47%) (P = 0.05, 0.08 on multivariate) and trended towards a lower rate of LN positivity (15 vs. 21%; P = 0.10, 0.12 multivariate). In patients undergoing cystectomy for bladder cancer, married individuals appear to have improved pre-operative laboratory variables, shorter hospitalization, and improved pathological outcomes versus unmarried patients in our case series. These findings may support the evidence (observed in other tumor types and other disease states) that married persons present earlier than unmarried individuals, and this may help explain the improved survival outcomes that have been observed in married patients with bladder cancer.


New imaging reagents for lipid dense regions in live cells and the nucleus in fixed MCF-7 cells.
Two new uracil (U) and 5-flurouracil (5-FU) labeled ruthenium(ii)-polypyridyl based cellular imaging reagents are reported. Confocal laser scanning microscopic images with live and paraformaldehyde (PFA) fixed MCF-7 cells are examined using these two low-cytotoxic reagents. Experimental results show that these two complexes, appropriately functionalized with U (1) and 5-FU (2), have specific affinity for the lipid dense regions like the endoplasmic reticulum, cell membrane, and cytoplasmic vacuoles in live MCF-7 cells, and dye internalization in these regions happened following an endocytosis pathway. Interestingly, these two complexes are found to be localized in the nucleus of the PFA fixed cells. For fixed cells, presumably the lipid layer disruption helped in the explicit localization of the complexes 1 and 2 in the cell nucleus through specific interaction with cellular DNA. Poor and non-specific internalization of an analogous model complex 3, without having a U or 5-FU moiety, reveals the definite influence of U or 5-FU as well as the role of lipophilicity of the respective complex 1 and 2 in the cellular internalization process. Apart from these, a large Stokes shift (∼160 nm) and an appreciably long lived 3MLCT excited state (∼320 ns) in aq. buffer medium (pH 7.4) are other key features for complexes 1 and 2. Unlike the common nuclear DNA staining reagents like DAPI, these low-cytotoxic reagents are found to be highly stable towards photo-bleaching upon irradiation with 455 nm at the MLCT band for these complexes.


Evidence for selective transformation of autoreactive immature plasma cells in mice deficient in Fasl.
Germline mutations in Fas and Fasl induce nonmalignant T cell hyperplasia and systemic autoimmunity and also greatly increase the risk of B cell neoplasms. B lymphomas occurring in Fasl mutant (gld) mice usually are immunoglobulin (Ig) isotype switched, secrete Ig, and are plasmacytoid in appearance but lack Myc translocations characteristic of other plasma cell (PC) neoplasms. Here, we explore the relationship between B cell autoreactivity and transformation and use gene expression profiling to further classify gld plasmacytoid lymphomas (PLs) and to identify genes of potential importance in transformation. We found that the majority of PLs derive from antigen-experienced autoreactive B cells producing antinuclear antibody or rheumatoid factor and exhibit the skewed Ig V gene repertoire and Ig gene rearrangement patterns associated with these specificities. Gene expression profiling revealed that both primary and transplanted PLs share a transcriptional profile that places them at an early stage in PC differentiation and distinguishes them from other B cell neoplasms. In addition, genes were identified whose altered expression might be relevant in lymphomagenesis. Our findings provide a strong case for targeted transformation of autoreactive B cells in gld mice and establish a valuable model for understanding the relationship between systemic autoimmunity and B cell neoplasia.


Optimal linear combinations of multiple diagnostic biomarkers based on Youden index.
In practice, usually multiple biomarkers are measured on the same subject for disease diagnosis. Combining these biomarkers into a single score could improve diagnostic accuracy. Many researchers have addressed the problem of finding the optimal linear combination based on maximizing the area under ROC curve (AUC). Actually, such combined score might have less than optimal property at the diagnostic threshold. In this paper, we propose the idea of using Youden index as an objective function for searching the optimal linear combination. The combined score directly achieves the maximum overall correct classification rate at the diagnostic threshold corresponding to Youden index; in other words, it is the optimal linear combination score for making the disease diagnosis. We present both empirical and numerical searching methods for the optimal linear combination. We carry out extensive simulation study to investigate the performance of the proposed methods. Additionally, we empirically compare the optimal overall classification rates between the proposed combination based on Youden index and the traditional one based on AUC and demonstrate a significant gain in diagnostic accuracy for the proposed combination. In the end, we apply the proposed methods to a real data set.


QT dynamics during treatment with sertindole.
Sertindole is a nonsedating atypical antipsychotic drug with low propensity to cause extrapyramidal side effects but it has been associated with a 20 ms QTc prolongation and increased risk of cardiac events. It is uncertain whether this drug-induced increase in cardiac risk might also be revealed by dynamic measures of the QT interval such as the ratio of QT variability to heart rate variability (variability ratio [VR]). The aim of this study was to investigate the effect of sertindole on QT dynamics. QTc and the VR were assessed in an observational study using 24-hour Holter monitoring at baseline and after 3 weeks of treatment with sertindole 16 mg. The VR was calculated by dividing the standard deviation of QT intervals with the standard deviation of heart rates. Outcome measures were compared using paired t-test. A total of 18 patients participated in the study, two were excluded from further analysis due to low amplitude of the T-wave. When patients were shifted to sertindole, the VR increased from 0.192 (SD 0.045) to 0.223 (SD 0.061), p = 0.02. The QTcF interval increased from 388 (SD 16) to 403 ms (SD 14), p = 0.002. There was no difference in heart rate 78 bpm (SD 8) versus 80 bpm (SD 10), p = 0.3 or heart rate variability (SDNN) 127 (SD 40) versus 115 ms (SD 45), p = 0.4. Sertindole was associated with 19 ms QTc prolongation and an increased ratio of QT variability to heart rate variability. Both measures may contribute to the increased cardiovascular mortality found with sertindole.


Prospective Studies of Minimally Invasive Glaucoma Surgeries: Systematic Review and Quality Assessment.
Glaucoma is a common blinding disease; while there is no cure, effective treatments include medications, laser, and incisional surgery. There is significant interest from patients and doctors to develop safer surgical options throughout the spectrum of disease, to minimize treatment burden in mild glaucoma patients and to minimize risk of complications in patients needing more aggressive treatment. Surgical procedures called Minimally or Micro-Invasive Glaucoma Surgery (MIGS) are growing in popularity. Eighty-seven prospective studies on MIGS were identified and assessed for quality. Most (74%) did not have a control group. Twelve of the highest quality were reviewed. MIGS procedures appeared to have fewer complications, and lowered intraocular pressure, and reduced medication use. Studies were limited by small sample size, narrow spectrum of glaucomatous disease, and/or conflicts of interest. There is a need for high quality, independently funded and performed, comparative studies on the MIGS to help make treatment decisions.


Angelica Dahurica ethanolic extract improves impaired wound healing by activating angiogenesis in diabetes.
Abnormal angiogenesis plays an important role in impaired wound healing and development of chronic wounds in diabetes mellitus. Angelica dahurica radix is a common traditional Chinese medicine with wide spectrum medicinal effects. In this study, we analyzed the potential roles of Angelica dahurica ethanolic extract (ADEE) in correcting impaired angiogenesis and delayed wound healing in diabetes by using streptozotocin-induced diabetic rats. ADEE treatment accelerated diabetic wound healing through inducing angiogenesis and granulation tissue formation. The angiogenic property of ADEE was subsequently verified ex vivo using aortic ring assays. Furthermore, we investigated the in vitro angiogenic activity of ADEE and its underlying mechanisms using human umbilical vein endothelial cells. ADEE treatment induced HUVECs proliferation, migration, and tube formation, which are typical phenomena of angiogenesis, in dose-dependent manners. These effects were associated with activation of angiogenic signal modulators, including extracellular signal-regulated kinase 1/2 (ERK1/2), Akt, endothelial nitric oxide synthase (eNOS) as well as increased NO production, and independent of affecting VEGF expression. ADEE-induced angiogenic events were inhibited by the MEK inhibitor PD98059, the PI3K inhibitor Wortmannin, and the eNOS inhibitor L-NAME. Our findings highlight an angiogenic role of ADEE and its ability to protect against impaired wound healing, which may be developed as a promising therapy for impaired angiogenesis and delayed wound healing in diabetes.


Effect of antibiotic pretreatment on glycoside/glycosidase-based colonic drug delivery.
The effect of antibiotic pretreatment on the intestinal distribution and hydrolysis of the prodrug prednisolone-beta-D-glucoside was studied in rats. A combination of neomycin, lincomycin, and metronidazole was administered twice daily by gastric intubation for three days to young adult male rats. On the fourth day, prednisolone-beta-D-glucoside was administered intragastrically. The distribution of prodrug and drug in the intestinal contents was significantly altered by the antibiotic treatment. In comparison with untreated rats, stomach to cecum transit time appeared to be reduced, and more prodrug was hydrolyzed in the small intestine. In addition, an appreciable amount of the dose was retained longer in the small intestine of treated animals. The total recovery of prodrug and drug was unaltered by the pretreatment. Possible explanations for the observed results are presented.


Synovial hypertrophy causing recurrent hemarthrosis after total knee replacement.
Recurrent hemarthrosis following total knee replacement is relatively uncommon and can result from causes that may not always be easy to diagnose. We report three patients with late-onset recurrent hemarthrosis following total knee replacement due to synovial hypertrophy and impingement, which were successfully treated by embolization.


Surface characterization of the thermal remodeling helical plant virus.
Previously, we have reported that spherical particles (SPs) are formed by the thermal remodeling of rigid helical virions of native tobacco mosaic virus (TMV) at 94°C. SPs have remarkable features: stability, unique adsorption properties and immunostimulation potential. Here we performed a comparative study of the amino acid composition of the SPs and virions surface to characterize their properties and take an important step to understanding the structure of SPs. The results of tritium planigraphy showed that thermal transformation of TMV leads to a significant increase in tritium label incorporation into the following sites of SPs protein: 41-71 а.a. and 93-122 a.a. At the same time, there was a decrease in tritium label incorporation into the N- and C- terminal region (1-15 a.a., 142-158 a.a). The use of complementary physico-chemical methods allowed us to carry out a detailed structural analysis of the surface and to determine the most likely surface areas of SPs. The obtained data make it possible to consider viral protein thermal rearrangements, and to open new opportunities for biologically active complex design using information about SPs surface amino acid composition and methods of non-specific adsorption and bioconjugation.


Different gating mechanisms in glutamate receptor and K+ channels.
The basic structural features of channel gating in glutamate receptors (GluRs) remain unknown. Here we used covalent modification of substituted cysteines and fast agonist application to study the contribution of the M3 segment in AMPA receptor GluR-A subunits to channel structure and gating. The pattern of accessibility of substituted cysteines to extracellularly applied methanethiosulfonate reagents and the rates of their modification by these reagents, measured in either the presence or absence of glutamate, indicate that M3 forms an alpha-helix that lines the pore of the channel and is involved in gating-related movements. The voltage dependence of modification rates places the tip of the M2 loop (the Q/R site) close to the middle of M3. All of these results are consistent with pore-forming domains in GluR and K+ channels having a similar structure but inverted membrane topology. Nevertheless, GluRs lack a glycine residue at a homologous structural position as the gating hinge glycine in K+ channels. Moreover, simultaneous substitution of the only two glycines in M3 of GluR-A with alanines produced channels with gating properties indistinguishable from wild type. Given the unique role of glycines in the flexibility ofalpha-helices, our results indicate that the M3 segment in GluR does not contain a glycine gating hinge and suggest that, in contrast to the homologous domain in K+ channels, M3 is rigid during gating. The different positioning and functional significance of glycines in a key structural domain may represent the basis for the distinct features of gating in GluR and K+ channels.


Evaluation of mortality rate and predictors of outcome in dogs receiving outpatient treatment for parvoviral enteritis.
OBJECTIVE To determine mortality rates and prognostic factors for dogs with parvoviral enteritis receiving outpatient treatment. DESIGN Retrospective case series and case-control study. ANIMALS 130 client-owned dogs with a diagnosis of parvoviral enteritis between August 1, 2012, and January 31, 2015, that were treated with outpatient care. PROCEDURES Medical records were reviewed and data extracted regarding dog age, body weight, breed, and vaccination history; treatments administered; and short-term (≥ 3 day) outcome (determined via telephone call with owner). Treatments were administered according to clinician preference. Mortality rates were calculated overall and for various signalment and treatment groupings and compared. RESULTS 97 (75%) dogs survived and 33 (25%) dogs failed to survive for ≥ 3 days after initial diagnosis of parvoviral enteritis. Compared with distributions in the general hospital population, Chihuahuas, German Shepherd Dogs, pit bull-type dogs, and males were overrepresented. No significant difference was identified between survivors and nonsurvivors regarding age, body weight, or sex. Dogs prescribed a caloric supplement fed every 2 to 4 hours had a mortality rate of 19% (16/85). Most of these dogs had also received fluids administered SC, an antiemetic, and antimicrobials. CONCLUSIONS AND CLINICAL RELEVANCE Clinicians should note the 25% mortality rate of the dogs with parvoviral enteritis that received outpatient care in this study setting when discussing treatment options with owners of affected dogs who are financially unable to pursue hospitalization.


Advances in leukocyte differential and peripheral blood stem cell enumeration.
Automated leukocyte differential counting has resulted in a marked improvement of the precision of leukocyte subclass enumeration. With advancement of this technology, algorithms have been developed to identify samples that require manual microscopic review. Complex flagging algorithms permit acceptable false-positive rates with effective use of microscopic review to identify significant morphologic abnormalities. Current literature indicates that the leukocyte differential is a poor case-finding index in both outpatient and inpatient populations. Development of highly automated technology has led to test over-utilization because of ease of performance despite recognized limitations in identifying clinically significant abnormalities. Enumeration of hematopoietic stem cells in harvested peripheral blood or bone marrow is critical for determining whether transplanted cells will produce adequate engraftment. Hematopoietic precursors express the CD34 antigen, are present as rare events in unmobilized blood, and are found in increased numbers after mobilization with chemotherapy with or without G-CSF. Flow cytometric detection of CD34+ cells is more rapid and precise than cell culture techniques and results are available in time to determine if further cell harvesting procedures will be necessary. CD34+ cell concentrations correlate with granulocyte-macrophage colony-forming unit counts as well as with time to engraftment. Although intralaboratory precision in measuring these infrequent events may be good, comparisons between different laboratories using aliquots of the same sample have yielded more variable results. Problems in determining precise and reproducible CD34+ cell concentrations may be due to nonspecific antibody binding, insufficient signal intensity of true positive events, differences in monoclonal antibodies and their fluorochrome conjugates, or failure of the total absolute leukocyte count to accurately reflect the population used for CD34 analysis.


Dilated Vein of the Filum Terminale on MRI: A Marker for Deep Lumbar and Sacral Dural and Epidural Arteriovenous Fistulas.
Conventional MR imaging can provide important clues regarding the location of a spinal vascular malformation. We hypothesized that a dilated vein of the filum terminale, identified as a curvilinear flow void on T2WI, could be an imaging marker for a lower lumbar (L3-L5) or sacral fistula. We retrospectively identified all spinal dural and spinal epidural arteriovenous fistulas from 2 large tertiary referral centers from 2005 to 2018. All patients had a lumbar spinal MR imaging and a conventional spinal angiography. Images were reviewed by 2 neuroradiologists who categorized the level of the arterial feeder to the fistula and the presence or absence of a dilated vein of the filum terminale on T2WI and T1 postcontrast images. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value of the presence of a dilated filum terminale vein for a deep lumbar or sacral fistula. One hundred sixty-two patients were included. An enlarged filum terminale vein was identified in 39 patients. Sensitivity, specificity, positive predictive value, and negative predictive value of the presence of a dilated filum terminale vein for a deep lumbar or sacral fistula were 86%, 98.3%, 94.9%, and 95.1%, respectively. The presence of a dilated vein of the filum terminale can accurately localize a spinal dural arteriovenous fistula/spinal epidural arteriovenous fistula to the lower lumbar or sacral spine in patients being evaluated for such lesions. This finding can be used to facilitate both noninvasive and conventional spinal angiography.


Treatment of mandibular osteomyelitis in two red-necked wallabies (Macropus rufogriseus) by means of intensive long-term parenteral drug administration and serial computed tomographic monitoring.
CASE DESCRIPTION 2 female red-necked wallabies (Macropus rufogriseus) were evaluated because of sudden-onset mandibular swelling, ptyalism, and hyporexia. CLINICAL FINDINGS Physical examination revealed a mandibular swelling with a fluctuant center in both wallabies. Hematologic analysis revealed leukocytosis with a mature neutrophilia and monocytosis in one wallaby (case 1) and a slight neutrophilia, hyperglobulinemia, and high serum alanine aminotransferase activity in the other (case 2). Cytologic examination of the swelling revealed a uniform population of gram-negative rods in case 1 and neutrophilic inflammation in case 2. Radiography revealed a soft tissue mandibular swelling with osteolucency around mandibular incisor roots in both wallabies. Computed tomography revealed changes consistent with chronic active mandibular osteomyelitis and reactive bone formation, but also sequestra formation not appreciable via radiography. TREATMENT AND OUTCOME Long-term antimicrobial treatment was initiated with clindamycin (17 to 21 mg/kg [7.7 to 9.5 mg/lb], IV, q 12 h for 40 to 55 days) and high-dose benzathine penicillin G (80,000 U/kg [36,364 U/lb], SC, q 12 h for 150 days). Serial CT was performed to evaluate response to treatment and resolution of disease. A CT scan 18 months after the initial evaluation revealed complete resolution of osteomyelitis and sequestra. CLINICAL RELEVANCE Advanced imaging and long-term treatment and management were integral to the successful outcome for these wallabies, given that the osseous changes visible on CT images were not visible on standard radiographs, guiding therapeutic decision-making. This report provides new therapeutic and diagnostic monitoring information to assist clinicians with similar cases.


Use of mRNA hybridization and radioimmunoassay to study mechanisms of drug-induced accumulation of enkephalins in rat brain structures.
The repeated administration of haloperidol or fenfluramine for several days led to an increase of enkephalin content in specific brain areas. In order to characterize the nature of the dynamic changes underlying this increase, we measured the content of proenkephalin mRNA (PE-mRNA), of high molecular weight (HMW) enkephalin precursors, and of low molecular weight enkephalin peptides (LMW) in various brain areas. To measure PE-mRNA, we hybridized the specific mRNA with a [32P]cDNA probe for human pheochromocytoma PE. HMW and LMW enkephalin content was measured by radioimmunoassay after separation of the immunoreactive peaks by Bio-Gel P-2 column chromatography and enzymatic digestion of the precursors. Haloperidol treatment increased enkephalins, the precursor, and PE-mRNA content in the striatum, suggesting that this drug might increase enkephalin steady state by increasing transcription, translation, or both processes. In contrast, fenfluramine increased hypothalamic and striatal enkephalin content by preferentially reducing neuropeptide utilization or decreasing its catabolism without changing its synthesis.


High sex ratios in rural China: declining well-being with age in never-married men.
In parts of rural China male-biased sex ratios at birth, combined with out-migration of women, have led to highly male-biased adult sex ratios, resulting in large numbers of men being unable to marry, in a culture where marriage and reproduction are an expectation. The aim of this study was to test the hypotheses that older unmarried men are more predisposed to depression, low self-esteem and aggression than both those who are married, and those who are younger and unmarried. Self-completion questionnaires were administered among men aged 20-40 in 48 villages in rural Guizhou province, southwestern China. Tools used included the Beck Depression Inventory, the Rosenberg's Self-esteem Scale and the Bryant-Smith Aggression Questionnaire. Regression models assessed psychological wellbeing while adjusting for socio-demographic variables. Completed questionnaires were obtained from 957 never-married men, 535 married men aged 30-40, 394 partnered men and 382 unpartnered men aged 20-29. After adjusting for socio-demographic variables, never-married men were more predisposed to depression (p < 0.05), aggression (p < 0.01), low self-esteem (p < 0.05) and suicidal tendencies (p < 0.001). All the psychological measures deteriorated with age in never-married men. In contrast, married men remained stable on these dimensions with age. Never-married men are a psychologically highly vulnerable group in a society where marriage is an expectation. Since the highest birth sex-ratio cohorts have not yet reached reproductive age, the social tragedy of these men will last for at least another generation.This article is part of the themed issue 'Adult sex ratios and reproductive decisions: a critical re-examination of sex differences in human and animal societies'.


Hydrogen-bonding interactions in T-2 toxin studied using solution and solid-state NMR.
The structure of T-2 toxin in the solid-state is limited to X-ray crystallographic studies, which lack sufficient resolution to provide direct evidence for hydrogen-bonding interactions. Furthermore, its solution-structure, despite extensive Nuclear Magnetic Resonance (NMR) studies, has provided little insight into its hydrogen-bonding behavior, thus far. Hydrogen-bonding interactions are often an important part of biological activity. In order to study these interactions, the structure of T-2 toxin was compared in both the solution- and solid-state using NMR Spectroscopy. It was determined that the solution- and solid-state structure differ dramatically, as indicated by differences in their carbon chemical shifts, these observations are further supported by solution proton spectral parameters and exchange behavior. The slow chemical exchange process and cross-relaxation dynamics with water observed between the hydroxyl hydrogen on C-3 and water supports the existence of a preferential hydrogen bonding interaction on the opposite side of the molecule from the epoxide ring, which is known to be essential for trichothecene toxicity. This result implies that these hydrogen-bonding interactions could play an important role in the biological function of T-2 toxin and posits towards a possible interaction for the trichothecene class of toxins and the ribosome. These findings clearly illustrate the importance of utilizing solid-state NMR for the study of biological compounds, and suggest that a more detailed study of this whole class of toxins, namely trichothecenes, should be pursued using this methodology.


A new simple and rapid method to monitor the renal function based on pharmacokinetic consideration of endogeneous creatinine=.
Based on the linear single-compartment pharmacokinetic consideration of endogeneous creatinine a new equation is derived to estimate the true creatinine renal clearance and hence the renal function of a patient; By using this equation one can estimate clinically the creatinine renal clearance of a patient simply by measuring the creatinine serum levels at two different times without the necessity of urine collection. Almost a perfect prediction of the status of renal function in two anephric patients was demonstrated using this proposed methodmwith a sensitive assay technique for endogeneous creatinine, the proposed equation would enable on to monitor the creatinine clearance on an hourly basis= The method is especially valuable to monitor the rapidly changing (improving or deteriorating) renal function in all types of patients and also in certain groups of patients whose urine is difficult to ba accurately collected;


COVID-19 information exposure in digital media and implications for employees in the health care sector: findings from an online survey.
To estimate coronavirus disease 2019-related information consumption and related implications for health care professionals (medical and nonmedical personnel) during the pandemic. A cross-sectional on-line survey was distributed to employees of a major health care institution located in São Paulo, Brazil between April 3 and April 10, 2020. Data were analyzed using descriptive statistics. The sample comprised 2,646 respondents. Most participants (44.4%) reported excessive or almost excessive access to information about the novel coronavirus and 67.6% reported having increased their average time spent on social media. When asked how frequently they consider it was easy to determine the reliability of information, "sometimes" corresponded to 43.2% of the answers in contrast to 14.6% responding "always". Answers related to potential signs of information overload associated with the pandemic indicated that 31% of respondents felt stressed by the amount of information they had to keep up with almost every day or always. Overall, 80.0% of respondents reported having experienced at least one of the following symptoms: headache, eye twitching, restlessness or sleeping difficulty. The frequency of symptoms was higher among participants with a more negative information processing style regarding when dealing with large volumes of information relative to those with a positive information processing style. Likewise, symptoms were more frequently reported by participants who had increased their social media access relative to those reporting reduced access during the pandemic. Our survey provides a description of how health professionals consume COVID-19 related information during the pandemic, and suggests that excessive information exposure and high processing demands may impose psychological distress and affect mental health.


Chronic cortical and electromyographic recordings from a fully implantable device: preclinical experience in a nonhuman primate.
Analysis of intra- and perioperatively recorded cortical and basal ganglia local field potentials in human movement disorders has provided great insight into the pathophysiology of diseases such as Parkinson's, dystonia, and essential tremor. However, in order to better understand the network abnormalities and effects of chronic therapeutic stimulation in these disorders, long-term recording from a fully implantable data collection system is needed. A fully implantable investigational data collection system, the Activa® PC + S neurostimulator (Medtronic, Inc., Minneapolis, MN), has been developed for human use. Here, we tested its utility for extended intracranial recording in the motor system of a nonhuman primate. The system was attached to two quadripolar paddle arrays: one covering sensorimotor cortex, and one covering a proximal forelimb muscle, to study simultaneous cortical field potentials and electromyography during spontaneous transitions from rest to movement. Over 24 months of recording, movement-related changes in physiologically relevant frequency bands were readily detected, including beta and gamma signals at approximately 2.5 μV/[Formula: see text] and 0.7 μV/[Formula: see text], respectively. The system architecture allowed for flexible recording configurations and algorithm triggered data recording. In the course of physiological analyses, sensing artifacts were observed (∼1 μVrms stationary tones at fixed frequency), which were mitigated either with post-processing or algorithm design and did not impact the scientific conclusions. Histological examination revealed no underlying tissue damage; however, a fibrous capsule had developed around the paddles, demonstrating a potential mechanism for the observed signal amplitude reduction. This study establishes the usefulness of this system in measuring chronic brain and muscle signals. Use of this system may potentially be valuable in human trials of chronic brain recording in movement disorders, a next step in the design of closed-loop neurostimulation paradigms.


[What has happened to patient satisfaction with the care in general hospitals in the years from 1993-1995?].
Patient satisfaction with the hospitalization process is an important element in the measurement of quality of care. Information from a survey of patients' experiences could therefore help hospitals improve their service, and provide decision-makers with relevant information. We present the findings of a study of some 4,500 patients, aged 18+, released from hospitals in the fall of 1993 and of 1995 from the wards of 9 acute care hospitals, psychiatric and geriatric wards excluded. Self-administered questionnaires were sent and returned by mail, with an overall response rate of 82%. Despite the many changes in Israel's health system in general and its hospital system in particular, and the social and demographic changes between those 2 periods, patient satisfaction remained constant. Of those discharged from medical or surgical wards, 70% were satisfied to a "great" or "ver great" extent with their hospital experience. There was improvement in most areas of hospitalization in the course of the 2 years. The greatest improvement was with regard to admission, nursing staff, hotel services, in patient satisfaction food and supplies. On the other hand there was deterioration in visiting conditions and hours. Satisfaction with physicians, nurses and hotel services had the strongest links with general satisfaction.


A de novo synthesis citrate transporter, Vigna umbellata multidrug and toxic compound extrusion, implicates in Al-activated citrate efflux in rice bean (Vigna umbellata) root apex.
Al-activated organic acid anion efflux from roots is an important Al resistance mechanism in plants. We have conducted homologous cloning and isolated Vigna umbellata multidrug and toxic compound extrusion (VuMATE), a gene encoding a de novo citrate transporter from rice bean. Al treatment up-regulated VuMATE expression in the root apex, but neither in the mature root region nor in the leaf. The degree of up-regulation of VuMATE was both partially Al concentration and time dependent, consistent with the delay in the onset of the Al-induced citrate efflux in rice bean roots. While La(3+) moderately induced VuMATE expression, Cd(2+) and Cu(2+) did not induce the expression. Electrophysiological analysis of Xenopus oocytes expressing VuMATE indicated this transporter can mediate significant anion efflux across the plasma membrane. [(14) C]citrate efflux experiments in oocytes demonstrated that VuMATE is a H(+) -dependent citrate transporter. In addition, expression of VuMATE in transgenic tomato resulted in increased Al resistance, which correlated with an enhanced citrate efflux. Taken together, these findings suggest that VuMATE is a functional homolog of the known citrate transporters in sorghum, barley, maize and Arabidopsis. The similarities and differences of all the known citrate transporters associated with Al stress in the MATE family are also discussed.


The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3.
The common cytokine receptor gamma chain (gamma c), an essential component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is critical for the development and function of lymphocytes. Recently, a novel lymphokine (IL-21) and its receptor (IL-21R alpha) were described which profoundly affect the growth and activation state of B, T, and NK cells in concert with other lymphokines or stimuli [Parrish-Novak, J., et al. (2000) Nature 408, 57-63]. In this report, we show that gamma c is also a required signaling component of the IL-21 receptor (IL-21R) using the gamma c-deficient X-linked severe combined immunodeficiency (XSCID) lymphoblastoid cell line JT, and JT cells reconstituted with gamma c (JT/gamma c). Moreover, we demonstrate a functional requirement for both gamma c and the gamma c-associated Janus family tyrosine kinase 3 (JAK3) in IL-21-induced proliferation of pro-B-lymphoid cells engineered to express human IL-21R alpha (BaF3/IL-21R alpha). Retroviral-mediated transduction of wild-type gamma c into XSCID JT cells restored function to the IL-21R, as shown by IL-21-induced tyrosine phosphorylation of JAK1 and JAK3, and downstream activation of STAT5, in JT/gamma c cells as well as BaF3/IL-21R alpha and primary splenic B cells. In contrast, IL-21 failed to activate the JAK-STAT pathway in nonreconstituted JT cells. Monoclonal antibodies specific for the gamma c chain effectively inhibited IL-21-induced growth of BaF3/IL-21R alpha cells, supporting a functional role for this molecule in the IL-21R complex. In addition, the specific JAK3 tyrosine kinase inhibitor WHI-P131 significantly reduced IL-21-induced proliferation of BaF3/IL-21R alpha cells. Taken together, these results definitively demonstrate that IL-21-mediated signaling requires the gamma c chain, and indicate that JAK3 is an essential transducer of gamma c-dependent survival and/or mitogenic signals induced by this cytokine.


Solid-state fermentation of soybean and corn processing coproducts for potential feed improvement.
Two agro-industrial coproducts, soybean cotyledon fiber and distiller's dried grains with solubles (DDGS), were used as substrates to evaluate the effect of coculturing three different fungi, Aspergillus oryzae, Trichoderma reesei, and Phanerochaete chrysosporium, on enzyme production by solid-state fermentation (SSF). When soybean fiber was used as the substrate, a maximum xylanase activity of 757.4 IU/g and a cellulase activity of 3.2 IU/g were achieved with the inoculation and incubation of T. reesei and P. chrysosporium for 36 h, followed by A. oryzae for an additional 108 h. This inoculation scheme also resulted in the highest xylanase activity of 399.2 IU/g compared to other fungi combinations in the SSF of DDGS. A large-scale SSF by this fungus combination produced fermented products that had xylanase and cellulase activities of 35.9-57.0 and 0.4-1.2 IU/g, respectively. These products also had 3.5-15.1% lower fiber and 1.3-4.2% higher protein contents, suggesting a potential feed quality improvement.


TRPV1 Channel: A Noxious Signal Transducer That Affects Mitochondrial Function.
The Transient Receptor Vanilloid 1 (TRPV1) or capsaicin receptor is a nonselective cation channel, which is abundantly expressed in nociceptors. This channel is an important transducer of several noxious stimuli, having a pivotal role in pain development. Several TRPV1 studies have focused on understanding its structure and function, as well as on the identification of compounds that regulate its activity. The intracellular roles of these channels have also been explored, highlighting TRPV1's actions in the homeostasis of Ca2+ in organelles such as the mitochondria. These studies have evidenced how the activation of TRPV1 affects mitochondrial functions and how this organelle can regulate TRPV1-mediated nociception. The close relationship between this channel and mitochondria has been determined in neuronal and non-neuronal cells, demonstrating that TRPV1 activation strongly impacts on cell physiology. This review focuses on describing experimental evidence showing that TRPV1 influences mitochondrial function.


Pathologic complete response in renal cell carcinoma brain metastases treated with stereotactic radiosurgery.
Renal cell carcinoma (RCC) is often regarded as a radiation-resistant tumor. However, radiation therapy (RT) in the form of stereotactic radiosurgery (SRS) or whole-brain irradiation has been used to treat brain metastases from RCC. To date, there have been no clinical pathologic correlative findings before and after RT. Herein, we present a case of a patient with brain metastases from RCC treated with SRS. The diagnosis of clear-cell RCC was made in 2001 after right radical nephrectomy. He was also found to have lung metastases at diagnosis. He presented with neurologic symptoms in 2004, and magnetic resonance imaging showed 3 brain lesions with a significant amount of edema consistent with brain metastases. The largest lesion caused a midline shift and was surgically resected. Pathology revealed metastatic RCC. The other 2 smaller brain lesions were treated at 20 Gy respectively with shaped-beam SRS using the BrainLab Novalis system. No whole-brain irradiation was delivered. However, the patient had difficulty weaning off his steroids, and a magnetic resonance imaging performed 6 months after SRS was read as "progression of the lesions." He then underwent resection of both the irradiated brain lesions. Pathologic examination revealed necrotic tissues without any viable tumor identified. The patient has since been doing very well, now 18 months after SRS and 5 years from the initial diagnosis. This is the first reported case that demonstrates that precise high-dose radiation in the form of SRS can cause significant tumor cell death (pathologic complete response) in radiation-resistant brain metastases from RCC. This finding also provides a rationale to deliver stereotactic body RT for primary and metastatic RCC extracranially. A prospective clinical trial using stereotactic body RT for primary and metastatic RCC is under way.


Chrysin modulates ethanol metabolism in Wistar rats: a promising role against organ toxicities.
Hepato- and nephro-protective efficacy of chrysin was investigated against sequential increase of ethanol intake on the alteration of alcohol metabolizing enzymes-alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP 2E1), xanthine oxidase (XO) and oxidant/anti-oxidant status. Thirty female Wistar rats segregated into five groups, each with six animals, were put to different doses. Group I as control followed by Group II, III and IV were treated with ethanol (5,8,10 and 12 g/kg body weight per week respectively) for 4 weeks. While Group III and IV were administered with chrysin at 20 mg (D1) and 40 mg/kg body weight (D2), respectively, prior to ethanol administration. Group V was given only chrysin (D2). Various oxidative stress and ethanol metabolizing enzymes were estimated in hepatic and renal tissues. Ethanol administration significantly induced CYP 2E1, ADH and XO in liver and kidneys, respectively, along with an enhancement in levels of malondialdehyde and serum alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine and lactate dehydrogenase when compared with the control group and this enhancement is significantly normalized with chrysin administration. Oxidative stress markers: reduced glutathione, glutathione peroxidase, catalase and glutathione reductase were significantly (P < 0.001) depleted in the ethanol-treated group, while chrysin administration significantly restored all of these. Only chrysin administration did not show any adverse effect. Results demonstrate that chrysin administration prevents the liver and kidney of Wistar rats against oxidative damage during chronic ethanol consumption by inhibiting the activities of ADH, CYP 2E1, XO and catalase.


Alma-Ata 30 years on: revolutionary, relevant, and time to revitalise.
In this paper, we revisit the revolutionary principles-equity, social justice, and health for all; community participation; health promotion; appropriate use of resources; and intersectoral action-raised by the 1978 Alma-Ata Declaration, a historic event for health and primary health care. Old health challenges remain and new priorities have emerged (eg, HIV/AIDS, chronic diseases, and mental health), ensuring that the tenets of Alma-Ata remain relevant. We examine 30 years of changes in global policy to identify the lessons learned that are of relevance today, particularly for accelerated scale-up of primary health-care services necessary to achieve the Millennium Development Goals, the modern iteration of the "health for all" goals. Health has moved from under-investment, to single disease focus, and now to increased funding and multiple new initiatives. For primary health care, the debate of the past two decades focused on selective (or vertical) versus comprehensive (horizontal) delivery, but is now shifting towards combining the strengths of both approaches in health systems. Debates of community versus facility-based health care are starting to shift towards building integrated health systems. Achievement of high and equitable coverage of integrated primary health-care services requires consistent political and financial commitment, incremental implementation based on local epidemiology, use of data to direct priorities and assess progress, especially at district level, and effective linkages with communities and non-health sectors. Community participation and intersectoral engagement seem to be the weakest strands in primary health care. Burgeoning task lists for primary health-care workers require long-term human resource planning and better training and supportive supervision. Essential drugs policies have made an important contribution to primary health care, but other appropriate technology lags behind. Revitalisng Alma-Ata and learning from three decades of experience is crucial to reach the ambitious goal of health for all in all countries, both rich and poor.


Modeling of oxygen transport and cell killing in type-II photodynamic therapy.
Photodynamic therapy (PDT) provides an effective option for treatment of tumors and other diseases in superficial tissues and attracts attention for in vitro study with cells. In this study, we present a significantly improved model of in vitro cell killing through Type-II PDT for simulation of the molecular interactions and cell killing in time domain in the presence of oxygen transport within a spherical cell. The self-consistency of the approach is examined by determination of conditions for obtaining positive definitive solutions of molecular concentrations. Decay constants of photosensitizers and unoxidized receptors are extracted as the key indices of molecular kinetics with different oxygen diffusion constants and permeability at the cell membrane. By coupling the molecular kinetics to cell killing, we develop a modeling method of PDT cytotoxicity caused by singlet oxygen and obtain the cell survival ratio as a function of light fluence or initial photosensitizer concentration with different photon density or irradiance of incident light and other parameters of oxygen transport. The results show that the present model of Type-II PDT yields a powerful tool to quantitate various events underlying PDT at the molecular and cellular levels and to interpret experimental results of in vitro cell studies.


Natural hazards, disasters and violence against women and girls: a global mixed-methods systematic review.
Disasters triggered by climate and other natural hazards are increasing in frequency, severity and duration worldwide. Disasters disproportionately impact women and girls, with some evidence suggesting that violence against women and girls (VAWG) increases in disaster settings. Suggested risk factors for postdisaster VAWG include increased life stressors, failure of law enforcement, exposure to high-risk environments, exacerbation of existing gender inequalities and unequal social norms. We aim to systematically appraise the global literature on the association between disasters from natural hazards and VAWG. We conducted a systematic review using the following databases: Embase, Global Health, Medline, PubMed and Social Policy and Practice and searched grey literature. We included quantitative, qualitative or mixed-methods studies published in English language that examined the association between disasters from natural hazards and VAWG. We summarised the findings using a narrative synthesis approach. Of 555 non-duplicate records, we included a total of 37 quantitative, qualitative and mixed-methods studies. Among the quantitative studies, eight studies found a positive association between disaster exposure and increased VAWG, and four additional studies found positive associations with some violence types but not others. Qualitative findings offered insights into three hypothesised pathways: disaster exposure associated with (1) an increase of stressors that trigger VAWG; (2) an increase of enabling environments for VAWG and (3) an exacerbation of underlying drivers of VAWG. As the first known global systematic review on the relationship between disasters from natural hazards and VAWG, this review contributes to the evidence base. We were limited by the quality of quantitative studies, specifically study designs, the measurement of variables and geographic scope. The severe health consequences of VAWG and increasing frequency of extreme events means that rigorously designed and better quality studies are needed to inform evidence-based policies and safeguard women and girls during and after disasters.


[Open clinical trial with oral acyclovir for the prophylaxis of disease by Cytomegalovirus in low risk liver transplant recipients].
Checking the first 70 low risk liver transplantation performed in our hospital, who did not receive prophylaxis for Cytomegalovirus, we found that the incidence of Cytomegalovirus-infection and Cytomegalovirus-disease were 47% and 16% respectively. For this reason we started a prospective, open clinical study, to address the safety of acyclovir prophylaxis in low-risk liver transplant patients. Seventy patients did not receive acyclovir. Fifty patients received oral acyclovir during 3 months (800-3,200 mg/day). The occurrence of Cytomegalovirus infection was not modified (40%) but Cytomegalovirus disease decreased dramatically (4%, p < 0.01) during the first year after transplantation. Acyclovir was well tolerated. The incidence of leukopenia and renal failure were similar in both groups. Acyclovir did not improved the global survival of patients. Thus, oral acyclovir does not reduce Cytomegalovirus infection although it is efficient and safe in the prevention of Cytomegalovirus disease in low-risk liver transplantation, and prevents Herpes-simplex and Varicela-zoster symptomatic disease in this group of patients.


Delta 9-tetrahydrocannabinol alters cerebral metabolism in a biphasic, dose-dependent manner in rat brain.
delta 9-tetrahydrocannabinol (THC)-induced alterations in limbic and neocortical function are associated with deficiencies in short-term memory and recall. The 2-deoxy-D-glucose (2DG) autoradiographic method was used to examine the effect of acute THC administration (0, 0.2, 0.5, 2.0, 10.0 mg/kg) on regional brain metabolism in limbic and cortical brain regions of male rats. THC altered 2DG uptake in a biphasic, dose-dependent manner in most limbic and cortical structures, however most diencephalic and brainstem structures examined were unaffected. The 0.2 mg/kg THC dose significantly increased 2DG uptake relative to vehicle treatment in all cortical and selected limbic regions, whereas the 2.0 and 10.0 mg/kg THC doses decreased 2DG uptake in most of these regions. Certain limbic regions, particularly the hippocampus, are more sensitive to THC suggesting a selective regional action of the drug at lower doses. The incidence of enhanced metabolic activity in limbic and cortical regions is consistent with the occurrence of high density cannabinoid receptors in these regions.


Attachment to an endogenous laminin-like protein initiates sprouting by leech neurons.
Leech neurons in culture sprout rapidly when attached to extracts from connective tissue surrounding the nervous system. Laminin-like molecules that promote sprouting have now been isolated from this extracellular matrix. Two mAbs have been prepared that react on immunoblots with a approximately equal to 220- and a approximately equal to 340-kD polypeptide, respectively. These antibodies have been used to purify molecules with cross-shaped structures in the electron microscope. The molecules, of approximately equal to 10(3) kD on nonreducing SDS gels, have subunits of approximately equal to 340, 220, and 160-180 kD. Attachment to the laminin-like molecules was sufficient to initiate sprouting by single isolated leech neurons in defined medium. This demonstrates directly a function for a laminin-related invertebrate protein. The mAbs directed against the approximately equal to 220-kD chains of the laminin-like leech molecule labeled basement membrane extracellular matrix in leech ganglia and nerves. A polyclonal antiserum against the approximately equal to 220-kD polypeptide inhibited neurite outgrowth. Vertebrate laminin did not mediate the sprouting of leech neurons; similarly, the leech molecule was an inert substrate for vertebrate neurons. Although some traits of structure, function, and distribution are conserved between vertebrate laminin and the invertebrate molecule, our results suggest that the functional domains differ.