Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins.
Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system and is removed from the synaptic cleft by sodium-dependent glutamate transporters. To date, five distinct glutamate transporters have been cloned from animal and human tissue: GLAST (EAAT1), GLT-1 (EAAT2), EAAC1 (EAAT3), EAAT4, and EAAT5 (refs 1-5). GLAST and GLT-1 are localized primarily in astrocytes, whereas EAAC1 (refs 8, 9), EAAT4 (refs 9-11) and EAAT5 (ref 5) are neuronal. Studies of EAAT4 and EAAC1 indicate an extrasynaptic localization on perisynaptic membranes that are near release sites. This localization facilitates rapid glutamate binding, and may have a role in shaping the amplitude of postsynaptic responses in densely packed cerebellar terminals. We have used a yeast two-hybrid screen to identify interacting proteins that may be involved in regulating EAAT4--the glutamate transporter expressed predominately in the cerebellum--or in targeting and/or anchoring or clustering the transporter to the target site. Here we report the identification and characterization of two proteins, GTRAP41 and GTRAP48 (for glutamate transporter EAAT4 associated protein) that specifically interact with the intracellular carboxy-terminal domain of EAAT4 and modulate its glutamate transport activity.


Association between Mycobacterium avium subspecies paratuberculosis infection and milk production in two California dairies.
The association between Mycobacterium avium ssp. paratuberculosis (MAP) and milk production was estimated on 2 California dairies using longitudinal data from 5,926 cows. Both study herds had moderate MAP seroprevalence, housed cows in freestalls, and had Johne's disease control programs. Cow MAP status was determined using both serum ELISA and fecal culture results from cows tested at dry-off and from whole-herd tests. Potential confounders were evaluated based on a causal diagram. Mixed models with 2 functions (splines) for days in milk (DIM) representing milk production pre- and postpeak used in similar studies were further modified to use each cow's observed DIM at peak and lactation length. Cows that were seropositive produced 2.5kg less 4% fat-corrected milk (FCM) per day than their seronegative herdmates. In addition, cows that were fecal-culture positive by liquid culture and confirmed by PCR produced 2.2kg less 4% FCM per day than their fecal-culture negative herdmates. The decrease in milk production in MAP test-positive compared with test-negative cows started in the second lactation. A switch in MAP status in either ELISA or fecal culture results from positive to negative had no significant association with milk production. Modified DIM functions that used the observed DIM at peak had better model fit than another function that assumed a fixed peak at 60 DIM. Cows that tested positive for MAP on serum ELISA or fecal culture produced less milk than cows that tested negative, and the association between MAP and milk production was not confounded by mastitis, elevated somatic cell counts, or uterine or metabolic cow conditions.


Oxidation-reduction potential as a control variable for the anaerobic stage during anaerobic-aerobic p-nitrophenol degradation.
Combined anaerobic-aerobic processes are a viable alternative for the treatment of xenobiotic compounds that are difficult to treat by traditional processes. The variable nature of the sequencing batch reactors, SBR, systems allows manipulation of the selective pressure on the microorganisms. Then, the activity of the community can be dynamically adjusted to meet changing effluents conditions. To improve the response of the SBR to changing influent conditions, several efforts have been made to automate and control the duration of the sequential phases of the SBR. The objective of this work is to present and discuss the feasibility of the use of the oxidation-reduction potential, ORP, as a control variable for the determination of the anaerobic phase length in an anaerobic-aerobic SBR used to degrade p-nitrophenol, PNP. The control of the anaerobic phase of the anaerobic-aerobic reactor was achieved with software developed at the Institute of Engineering-UNAM. During the anaerobic stage, the PNP is reduced to p-aminophenol, PAP. As a consequence of the compound transformation, there is a change in the oxidation-reduction potential of the culture medium. This change was used to indicate the minimal concentration of PNP and, as a consequence, the maximal PAP concentration. The feasibility of the algorithm for using the variations in the ORP to determine on-line the length of the anaerobic stage in an anaerobic-aerobic process was demonstrated in our laboratory.


Continuing education for medical professionals: a reflective model.
The Royal Colleges and their Faculties have moved continuing professional development up the agenda of doctors in the UK. The low educational value and failure to change professional practice of much continuing medical education has led to criticism of its emphasis on formal, didactic teaching and academic knowledge. The ubiquitous scientific or technical bias in medical education makes questionable assumptions about the nature of professional knowledge, how professionals learn, and the linkage of theory and practice in professional work. Given its narrow conception of professional knowledge, it is hardly surprising that the effectiveness of continuing medical education has proven difficult to evaluate. These points of criticism suggest that a more systematic and coherent approach to continuing education is required. The adoption of the concept of continuing professional development, which draws on learning by reflective practice, marks an important step in this direction. Continuing professional development emphasises self-directed learning, professional self-awareness, learning developed in context, multidisciplinary and multilevel collaboration, the learning needs of individuals and their organisations, and an inquiry-based concept of professionalism. It also involves a widening of accountability to patients, the community, managers and policymakers, and a form of evaluation which is internal, participatory and collaborative rather than external and scientific in character.


Antibody-mediated resistance against duck enteritis virus infection.
Vaccination of ducks with an apathogenic strain of duck enteritis virus resulted in protection against challenge with the virulent Lake Andes strain of duck enteritis virus by intramuscular inoculation or contact exposure. Antisera produced in the vaccinated ducks were able to transfer resistance against the challenge strain to recipient ducks. Antisera against duck enteritis virus were cytotoxic for duck enteritis virus-infected duck embryo fibroblasts in the presence of guinea pig complement. These in vivo and in vitro data suggest that the humoral immune mechanism plays a role in protecting ducks from duck enteritis virus infection.


The development of working memory: exploring the complementarity of two models.
The aim of the paper was to further explore the complementarity of the working memory models postulated by Pascual-Leone and Baddeley. Five-, six-, eight-, and nine-year-old children were assessed on two working memory tasks that have frequently been used within the respective streams of research: the Mr. Peanut task and the Corsi blocks task. Results indicated a developmental increase in spatial short-term memory for both tasks. Concurrent spatial suppression reduced performance on the two tasks in all four age groups. By contrast, articulatory suppression interfered with recall only on the Mr. Peanut task, and in only the older children. The two models were shown to make their own specific contribution to the interpretation of the data, attesting to their complementarity. Pascual-Leone's theory offered a clear explanation of the results concerning the central aspects of working memory, that is, the stepwise age-related increase in performance, whereas Baddeley's model provided a convincing account of the findings regarding the peripheral phonological and visuo-spatial components, that is, the effects of articulatory and spatial suppression.


FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer.
Lung cancer is one of the leading causes of cancer mortality worldwide. The therapeutic effect of chemotherapy is limited due to the resistance of cancer cells, which remains a challenge in cancer therapeutics. In this work, we found that flap endonuclease 1 (FEN1) is overexpressed in lung cancer cells. FEN1 is a major component of the base excision repair pathway for DNA repair systems and plays important roles in maintaining genomic stability through DNA replication and repair. We showed that FEN1 is critical for the rapid proliferation of lung cancer cells. Suppression of FEN1 resulted in decreased DNA replication and accumulation of DNA damage, which subsequently induced apoptosis. Manipulating the amount of FEN1 altered the response of lung cancer cells to chemotherapeutic drugs. A small-molecule inhibitor (C20) was used to target FEN1 and this enhanced the therapeutic effect of cisplatin. The FEN1 inhibitor significantly suppressed cell proliferation and induced DNA damage in lung cancer cells. In mouse models, the FEN1 inhibitor sensitized lung cancer cells to a DNA damage-inducing agent and efficiently suppressed cancer progression in combination with cisplatin treatment. Our study suggests that targeting FEN1 may be a novel and efficient strategy for a tumor-targeting therapy for lung cancer.


Effects of glucagon and other peptides on fixation of CO2 by rat liver mitochondria.
Glucagon and glucagon fragments from the carboxyl terminal end of the protein act at 0.01 to 0.1 mM concentrations on isolated rat liver mitochondria to sustain the rate of fixation of CO2 in the presence of pyruvate. The rate of decarboxylation of pyruvate is also increased by these substances. Similar effects are found with bacitracin, vanocomycin and cephalothin but not with any other of the proteins, peptides and antibiotics tested. The action of glucagon requires the presence of added magnesum ion. The addition of glucagon results in a better maintenance of adenosine triphosphate (ATP), and it leads to a greater degree of swelling of the mitochondria during the incubation. The effect of glucagon is partially mimicked by atractyloside, but it appears that glucagon is not exerting its effect by an atractyloside-like action. Added ATP obliterates the effect of added glucagon by sustaining fixation of CO2 However in incubations made in the presence of lower than usual levels of inorganic phosphate (2 mM vs. 8 mM) an effect of glucagon can be seen in the presence of ATP.


Thioredoxin specifically cross-desensitizes monocytes to MCP-1.
Thioredoxin (Trx) is a protein disulfide oxidoreductase which can be secreted and acts as a cytokine. As we recently reported that Trx is chemotactic, we investigated whether it desensitizes monocytes or PMN to other chemokines. Preincubation for 15 min with Trx inhibited the chemotactic response of monocytes to MCP-1, but not to fMLP. This effect was independent of whether Trx was present during the chemotaxis assay or only during the preincubation. Preincubation (5 min) with Trx also inhibited the increase in intracellular Ca(2+) induced by MCP-1 in monocytes, but not that induced by fMLP. Preincubation with Trx did not affect the chemotactic response induced in PMN by IL-8. The inhibition of chemotactic and Ca(2+) responses to MCP-1 in monocytes was not due to a down-regulation of the MCP-1 receptor, as shown by receptor binding studies. The Ca(2+) response to MCP-1 was also inhibited by Trx in a CCR2-transfected cell line. It is suggested that Trx inhibits monocyte responses to chemokines by acting downstream of the chemokine receptors. Since there are high concentrations of circulating Trx in infection and inflammatory diseases, this might act as an inhibitor of monocyte migration in vivo.


Differentiation of the Follicular Neoplasm on the Gray-Scale US by Image Selection Subsampling along with the Marginal Outline Using Convolutional Neural Network.
We conducted differentiations between thyroid follicular adenoma and carcinoma for 8-bit bitmap ultrasonography (US) images utilizing a deep-learning approach. For the data sets, we gathered small-boxed selected images adjacent to the marginal outline of nodules and applied a convolutional neural network (CNN) to have differentiation, based on a statistical aggregation, that is, a decision by majority. From the implementation of the method, introducing a newly devised, scalable, parameterized normalization treatment, we observed meaningful aspects in various experiments, collecting evidence regarding the existence of features retained on the margin of thyroid nodules, such as 89.51% of the overall differentiation accuracy for the test data, with 93.19% of accuracy for benign adenoma and 71.05% for carcinoma, from 230 benign adenoma and 77 carcinoma US images, where we used only 39 benign adenomas and 39 carcinomas to train the CNN model, and, with these extremely small training data sets and their model, we tested 191 benign adenomas and 38 carcinomas. We present numerical results including area under receiver operating characteristic (AUROC).


[The usefulness of the evaluation of volumetric and posturographic parameters in the differential diagnosis of hydrocephalus].
A variety of diagnostic methods in normal pressure hydrocephalus and brain atrophy, it testifies to the difficulties in contrast to both teams. Develop a safe diagnostic tool having comparable statistical accuracy of the infusion test results would be of great clinical significance. The chances of implementing such a procedure in clinical practice, it may be a combination of these syndromes in the functional assessment (Posturography) the assessment of morphological CNS (volumetric). To evaluate and summary of the results of two non-invasive diagnostic methods morphological (posturography) and functional (volumetric) with results that were obtained from tests infusion. The evaluation of volumetric and posturographic research was conducted in 39 patients including 27 patients with brain atrophy (BA) and in 12 patients with hydrocephalus (NPH). Volumetric measurements were made using proprietary software VisNow. Posturographic measurements performed using manual posturograph Pro-Med. Both the volume of CSF obtained by volumetric assessment, as well as the values of the analyzed parameters posturographic, highly correlate with the results of resistance resorption (R). The BA radius values sway with eyes open and closed R_OZ R_OO were consistent with test results infusion of 100% in the NPH radius values showed 75% compliance with the test results infusion. Volumetric parameters: the volume of CSF contained in the subarachnoid space and basal cisterns (SV) and the volume of CSF system intracranial ventricular (VV) were found in both patients NPH and BA 100% compatible resorption resistance (R). Simultaneous use of two non-standard methods of non-invasive (posturographic and volumetric) in the diagnostic process is a proposal to recognize normal pressure hydrocephalus and brain atrophy non-invasive methods, while maintaining very high statistical significance.


Apolipoprotein E4 and sex affect neurobehavioral performance in primary school children.
Apolipoprotein E4 (apoE4) and female sex are risk factors for developing Alzheimer's disease. It is unclear whether apoE4 contributes to behavioral function at younger ages. Standard neuropsychological assessments [intelligence quotient (IQ), attention, and executive function] and a test developed in this laboratory (Memory Island test of spatial learning and memory) were used to determine whether E4 and sex affect neuropsychological performance in healthy primary school children (age 7-10). A medical history was also obtained from the mother to determine whether negative birth outcomes were associated with apoE4. Mothers of apoE4+ children were more likely to report that their newborn was placed in an intensive care unit. A sex difference in birth weight was noted among apoE4- (males > females), but not apoE4+, offspring. Conversely, among apoE4+, but not apoE4- children, there was a sex difference in the Wechsler Abbreviated Scale of Intelligence (WASI) vocabulary score favoring boys. ApoE4- girls had better visual recall than apoE4+ girls or apoE4- boys on the Family Pictures test. Finally, apoE4+, unlike apoE4-, children did not show spatial memory retention during the Memory Island probe trial. Thus, apoE4 may affect neurobehavioral performance, particularly spatial memory, and antenatal health decades before any clinical expression of neurodegenerative processes.


Spontaneous pneumothorax in medical practice in a general hospital.
Eighty patients with spontaneous pneumothoraces treated in the University Department of Medicine, Singapore General Hospital from January 1981 to March 1983 were reviewed. There were 75 males and 5 females. Their ages ranged from 15 to 92 years. Dyspnea was the chief representing symptom in 59 patients (74%) followed by chest pain in 47 patients (59%). One patient was admitted with loss of consciousness. Pneumothorax with no discernable associated disease was present in 36 patients (45%) whereas 34 (43%) had chronic obstructive airways disease. Of the remaining 10 patients, active pulmonary tuberculosis was present in 5, bronchogenic carcinoma in 2, bronchial asthma in 2 and bronchopneumonia in 1 percent. Pneumothorax occurred equally on both sides. Single episode of pneumothorax was present in 64 patients (80%). Recurrent pneumothoraces were only present in 16 patients (20%). 57 patients (71%) required chest tube insertion while 14 patients (18%) in addition required either medical or surgical pleurodesis. Death occurred in 6 patients (7.5%) mainly in those with chronic obstructive airways disease. In this study the majority of pneumothoraces occurred in patients with either no underlying pulmonary disease or those with chronic obstructive bronchitis and emphysema. A bimodal age presentation was noted, with the younger patients having no underlying respiratory disorders.


Monte Carlo calculations of lung dose in ORNL phantom for boron neutron capture therapy.
Monte Carlo simulations were performed to evaluate dose for possible treatment of cancers by boron neutron capture therapy (BNCT). The computational model of male Oak Ridge National Laboratory (ORNL) phantom was used to simulate tumours in the lung. Calculations have been performed by means of the MCNP5/X code. In this simulation, two opposite neutron beams were considered, in order to obtain uniform neutron flux distribution inside the lung. The obtained results indicate that the lung cancer could be treated by BNCT under the assumptions of calculations.


Genetic inhibition of autophagy promotes p53 loss-of-heterozygosity and tumorigenesis.
Autophagy is an evolutionarily conserved lysosomal degradation pathway that plays an essential role in enabling eukaryotic organisms to adapt to nutrient deprivation and other forms of environmental stress. In metazoan organisms, autophagy is essential for differentiation and normal development; however, whether the autophagy pathway promotes or inhibits tumorigenesis is controversial, and the possible mechanisms linking defective autophagy to cancer remain unclear. To determine if autophagy is important for tumor suppression, we inhibited autophagy in transgenic zebrafish via stable, tissue-specific expression of a dominant-negative autophagy protein Atg5K130R. In heterozygous tp53 mutants, expression of dominant-negative atg5K130R increased tumor incidence and decreased tumor latency compared to non-transgenic heterozygous tp53 mutant controls. In a tp53-deficient background, Tg(mitfa:atg5K130R) mutantsdeveloped malignant peripheral nerve sheath tumors (MPNSTs), neuroendocrine tumors and small-cell tumors. Expression of a Sox10-dependent GFP transgene in the tumors demonstrated their origin from neural crest cells, lending support to a model in which mitfa-expressing cells can arise from sox10+ Schwann cell precursors. Tumors from the transgenic animals exhibited increased DNA damage and loss-of-heterozygosity of tp53. Taken together, our data indicate that genetic inhibition of autophagy promotes tumorigenesis in tp53 mutant zebrafish, and suggest a possible role for autophagy in the regulation of genome stability during oncogenesis.


Annular lupus vulgaris: an unusual case undiagnosed for five years.
Tuberculosis is still a serious problem in both developing and developed countries. It is often confused with various cutaneous disorders both clinically and histopathologically.A 46-year-old woman attended our clinic with progressive, asymptomatic, annular skin lesions on her right upper extremity for 5 years. She had received many different therapies for these lesions at other institutions previously but these medications were not effective and the lesions deteriorated. On dermatological examination, well-demarcated, irregular bordered, violaceous colored, elevated and crusted annular lesions on her right hand dorsum and forearm were observed. She was diagnosed as having lupus vulgaris clinically and histopathologically. Antituberculosis therapy was administered and regression of the lesions started in the second week of medication.We report a case of long-standing, undiagnosed and uncommon, annular form of lupus vulgaris. We want to stress that clinical and histopathological findings are still important for the diagnosis of cutaneous tuberculosis.


Simultaneous quantification of Echinacea species, Flos Lonicerae, Radix Scutellaria and Fructus Forsythiae combinations by rapid resolution liquid chromatography.
Echinacea angustifolia and E. purpurea are commonly used in North America for their anti-bacterial effects. Flos Lonicerae, Radix Scutellaria and Fructus Forsythiae are traditional Chinese medicinal herbs commonly used for the treatment of complaints such as pneumonia, acute upper respiratory tract infection, and acute bronchitis. A reproducible, simple, and reliable rapid resolution liquid chromatographic (RRLC) method has been developed to analyze extracts of products formulated containing E. angustifolia, E. purpurea, Flos Lonicerae, Radix Scutellariae and Fructus Forsythiae simultaneously in one run in less than 6 minutes. The method uses a C18-HST column, a mobile phase consisting of 0.1% aqueous phosphoric acid solution and acetonitrile, and UV detection at 327 nm and 229 nm. A stability test was performed that revealed that chlorogenic acid is more stable in acidic pH, and hence it is best to keep the extract of E. augustifolia, E. purpurea, Flos Lonicerae, Radix Scutellariae and Fructus Forsythiae in mild acidic conditions at approximately pH 5.


Oronasal fistula reconstruction using tongue flap with simultaneous iliac bone graft: a case report.
The ultimate goal of cleft palate repair is to achieve an intact palate with the separation of the oral and nasal cavities. However, some patients develop an oronasal fistula in the secondary palate after palatoplasty. Postoperatively, a secondary palatal oronasal fistula may develop, leading to functional problems. In this study, we describe a patient with recurrent oronasal fistula and alveolar cleft with multiple failed previous reconstructions at another clinic. The oronasal fistula and alveolar cleft were repaired using a tongue flap and an iliac bone graft, respectively. The patient demonstrated excellent clinical progress with no recurrence of the oronasal fistula at the 1-year follow-up.


Confirmation of multiple seizure susceptibility QTLs on chromosome 15 in C57BL/6J and DBA/2J inbred mice.
To confirm seizure susceptibility (SZS) quantitative trait loci (QTLs) on chromosome (chr) 15 identified previously using C57BL/6J (B6) and DBA/2J (D2) mice and to refine their genomic map position, we studied a set of three congenic strains in which overlapping segments of chr 15 from D2 were transferred onto the B6 background. We measured thresholds for generalized electroshock seizure (GEST) and maximal electroshock seizure (MEST) in congenic strains and B6-like littermates and also tested their responses to kainic acid (KA) and pentylenetetrazol (PTZ). Results document that MEST is significantly lower in strains 15M and 15D, which harbor medial and distal (telomeric) segments of chr 15 (respectively) from D2, compared with strain 15P, which harbors the proximal (acromeric) segment of chr 15 from D2, and with control littermates. Congenic strains 15P and 15M exhibited greater KA SZS compared with strain 15D and B6-like controls. All congenic strains were similar to controls with regard to PTZ SZS. Taken together, results suggest there are multiple SZS QTLs on chr 15 and that two QTLs harbor gene variants that affect MEST and KA SZS independently. The MEST QTL is refined to a 19 Mb region flanked by rs13482630 and D15Mit159. This interval contains 350 genes, 183 of which reside in areas where the polymorphism rate between B6 and D2 is high. The KA QTL interval spans a 65 Mb region flanked by markers D15Mit13 and rs31271969. It harbors 83 genes in highly polymorphic areas, 310 genes in all. Complete dissection of these loci will lead to identification of genetic variants that influence SZS in mice and provide a better understanding of seizure biology.


Methionine enkephalin and isosteric analogues. Part II.: Receptor conformation of methionine enkephalin.
Biological activities are reported for two different types of analogues of methionine enkephalin. Cyclic analogues, bridged between the amino- and carboxy- terminals of the parent peptide, are inactive. In contrast, significant levels of activity are displayed by linear isosterically modified analogues in which the Tyr1-Gly2 peptide bond is replaced by either -CH2NH- or -CH2CH2-. Similar replacements of the Gly2-Gly3 peptide bond yield compounds with much reduced potency. These modifications serve as useful probes of the receptor conformation. Based on these findings, a model is proposed for interaction between enkephalin and its receptor.


Superoxide Anion-Mediated Afterglow Mechanism-Based Water-Soluble Zwitterion Dye Achieving Renal-Failure Mice Detection.
Afterglow materials-based biological imaging has promising application prospects, due to negligible background. However, currently available afterglow materials mainly include inorganic materials as well as some organic nanoparticles, which are difficult to translate to the clinic, resulting from non-negligible metabolic toxicity and even leakage risk of inorganic heavy metals. Although building small organic molecules could solve such obstacles, organic small molecules with afterglow ability are extremely scarce, especially with a sufficient renal metabolic capacity. To address these issues, herein, we designed water-soluble zwitterion Cy5-NF with renal metabolic capacity and afterglow luminescence, which relied on an intramolecular cascade reaction between superoxide anion (O2•-, instead of 1O2) and Cy5-NF to release afterglow luminescence. Of note, compared with different reference contrast agents, zwitterion Cy5-NF not only had excellent afterglow properties but also had a rapid renal metabolism rate (half-life period, t1/2, around 10 min) and good biocompatibility. Unlike prior afterglow nanosystems possessing a large size, for the first time, zwitterion Cy5-NF has achieved the construction of water-soluble renal metabolic afterglow contrast agents, which showed higher sensitivity and signal-to-background ratio in afterglow imaging than fluorescence imaging for the kidney. Moreover, zwitterion Cy5-NF had a longer kidney retention time in renal-failure mice (t1/2 more than 15 min). More importantly, zwitterion Cy5-NF can be metabolized very quickly even in severe renal-failure mice (t1/2 around 25-30 min), which greatly improved biosecurity. Therefore, we are optimistic that the O2•--mediated afterglow mechanism-based water-soluble zwitterion Cy5-NF is very promising for clinical application, especially rapid detection of kidney failure.


Economic impact of combining metformin with dipeptidyl peptidase-4 inhibitors in diabetic patients with renal impairment in spanish patients.
To evaluate resource use and health costs due to the combination of metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with diabetes and renal impairment in routine clinical practice. An observational, retrospective study was performed. Patients aged ≥30 years treated with metformin who initiated a second oral antidiabetic treatment in 2009 to 2010 were included. Two groups of patients were analysed: metformin+DPP-4 inhibitors and other oral antidiabetics. The main measures were: compliance, persistence, metabolic control (glycosylated hemoglobin< 7%) and complications (hypoglycemia, cardiovascular events) and total costs. Patients were followed up for 2 years. We included 395 patients, mean age 70.2 years, 56.5% male: 135 patients received metformin+DPP-4 inhibitors and 260 patients received metformin+other oral antidiabetics. Patients receiving DPP-4 inhibitors showed better compliance (66.0% vs. 60.1%), persistence (57.6% vs. 50.0%), and metabolic control (63.9% vs. 57.3%), respectively, compared with those receiving other oral antidiabetics (P<0.05), and also had a lower rate of hypoglycemia (20.0% vs. 47.7%) and lower total costs (€ 2,486 vs. € 3,002), P=0.001. Despite the limitations of the study, patients with renal impairment treated with DPP-4 inhibitors had better metabolic control, lower rates (association) of hypoglycaemia, and lower health costs for the Spanish national health system.


Respiratory health services reported by U.S. mining facilities in the National Occupational Health Survey of Mining (1984-1989).
This report describes the involvement of mine management personnel at U.S. mines in providing environmental and medical services related to respiratory health. The data were obtained by means of a questionnaire that was administered to mine management personnel at 491 mines and mills during May 1984 to August 1989. The data indicate that 62% of U.S. miners worked at facilities that provided at least a portion of workers with chest X-rays, and 41% worked at facilities that provided at least a portion of workers with pulmonary function tests. Eighty-five percent of miners worked at facilities in which the company required a medical examination of all new employees; the majority were required by company policy to have a medical examination before returning to work after an illness. However, only 2% of miners were required by company policy to have an exit medical examination when their employment ended. This report underscores the need for respiratory health to remain a primary concern of all persons who provide occupational health services to miners.


The reproducibility and prognostic value of serial measurements of heart rate response to regadenoson during myocardial perfusion imaging.
The heart rate response (HRR, percentage change from baseline) to regadenoson during myocardial perfusion imaging (MPI) can provide incremental prognostic value in patients with known or suspected coronary artery disease. Our purpose was to evaluate the variability and prognostic value of HRR on serial measurements. We studied 648 consecutive patients (61 ± 11 years, 48 % with diabetes) who underwent two regadenoson MPI studies (16 ± 9 months between studies). HRR <30 % was defined as abnormal. All-cause mortality was determined by chart review and verified using the US Social Security Death Master File. HRR was well correlated between the two studies (intraclass correlation coefficient 0.72, 95 % CI 0.67 - 0.76) with no systematic bias (mean difference 0.88 %, p = 0.2) or proportional bias (p = 0.5) by Bland-Altman analysis in all patients and in those with normal MPI on both studies. Of the 308 patients (48 %) with normal baseline HRR (HRR-1), 33 % had developed a blunted HRR on the second MPI study (HRR-2). Older age, male gender, end-stage renal disease, and abnormal baseline left ventricular ejection fraction were independent predictors of a new-onset abnormal HRR. During a mean follow-up of 2.4 ± 1.2 years, 55 patients (8.5 %) died. Patients with a blunted HRR-1 had increased mortality risk irrespective of their HRR-2 (p = 0.9, log-rank test). Among patients with normal HRR-1, a blunted HRR-2 was an independent predictor of all-cause mortality beyond clinical and traditional MPI data (hazard ratio 2.83, 95 % CI 1.14 - 7.03). Finally, patients with a normal HRR-1 and HRR-2 had the lowest event rate, while those with any abnormal HRR had an increased risk of death (hazard ratio 2.5, 95 % CI 1.2 - 5.4). There was good correlation in the HRR to regadenoson on serial measurements without systematic or proportional biases. Patients with consistently normal HRR had the best prognosis.


Myocardial postconditioning: anaesthetic considerations.
"Recently, it has been shown that the heart can be protected against the ischemia-reperfusion injury if brief coronary occlusions are performed just at the beginning of the reperfusion. This procedure has been called postconditioning (PostC). It can also be elicited by pharmacological interventions, which are named pharmacological PostC. In general, PostC reduces the reperfusion- induced injury, blunts oxidant-mediated damages and attenuates the local inflammatory response to reperfusion, decreases infarct size, diminishes apoptosis, neutrophil activation, and endothelial dysfunction. The mechanisms that participate in PostC are still not completely understood. In this regard, adenosine, glycine, bradykinin, ciclosporin A are involved in PostC triggering. Similar to ischemic preconditioning, PostC triggers several signaling pathways and molecular components, including nitric oxide (NO), protein kinase C, adenosine triphosphate-sensitive potassium channels, the Reperfusion Injury Salvage Kinases (RISK) pathway, which comprises phosphatidylinositol-3-OH kinase (PI3K) and extracellular signal-regulated kinase (ERK 1/2), and, finally, the Survivor Activating Factor Enhancement (SAFE) pathway. In this review, we describe the mechanisms of reperfusion-induced injury as well as the proposed protective pathways activated by PostC, which seem to converge in inhibition of mitochondrial permeability transition pores opening. On the other hand, experimental evidence indicates that volatile anesthetics and opioids are capable of exerting cardioprotective effects under certain conditions, constituting a very useful pharmacological PostC. Thus, the first minutes of reperfusion represent a window of opportunity for triggering the aforementioned mediators, which acting in concert lead to protection of the myocardium against reperfusion injury. Pharmacological, especially anesthetic, PostC may have a promising future in the clinical scenarios in the operating room."


UK National Clinical Guidelines in Paediatric Dentistry: diagnosis, prevention and management of dental erosion.
This revised Clinical Guideline in Paediatric Dentistry replaces the previously published ninth guideline (Shaw L, O'Sullivan E. Int J Paediatr Dent 2000; 10: 356-365). The process of guideline production began in 1994, resulting in first publication in 1997. Each guideline has been circulated widely for consultation to all UK consultants in paediatric dentistry, council members of the British Society of Paediatric Dentistry (BSPD), and to people of related specialities recognized to have expertise in the subject. The final version of this guideline is produced from a combination of this input and thorough review of the published literature. In the case of the present guideline, an internationally recognized expert in the field was invited to be a co-author (AM). The intention is to encourage improvement in clinical practice and to stimulate research and clinical audit in areas where scientific evidence is inadequate. Evidence underlying recommendations is scored according to the SIGN classification and guidelines should be read in this context. Further details regarding the process of paediatric dentistry guideline production in the UK is described in the Int J Paediatr Dent 1997; 7: 267-268.


Racial/ethnic disparities in medication use among veterans with hypertension and dementia: a national cohort study.
Hypertension and comorbid dementia are common illnesses affecting older adults disproportionally. Medication adherence is vital in achieving therapeutic outcomes. Use of antihypertensive and dementia medications may vary by race/ethnicity and has not been well explored. To evaluate the utilization of antihypertensive and dementia drugs and adherence in a national cohort of veterans aged 65 years or older with a diagnosis of both hypertension and dementia across different racial/ethnic groups. This was a retrospective cohort study that used 2 national databases of the Veterans Health Administration to estimate medication utilization and adherence rates among whites, African Americans, and Hispanics from 2000 to 2005. A medication possession ratio of 0.8 or greater defined adherence. The association between race/ethnicity and adherence was analyzed using multivariate logistic regression analysis. A total of 56,561 patients (70.5% white, 15.6% African American, 6.6% Hispanic) aged 65 years or older had diagnoses of dementia and hypertension. African Americans were less likely than whites to receive angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, acetylcholinesterase inhibitors, and memantine (p < 0.05). Hispanics were more likely than whites to be prescribed an ACE inhibitor and less likely to be prescribed an ARB, beta-blocker, nondihydropyridine calcium-channel blocker (CCB), loop diuretic, alpha-agonist, or potassium-sparing diuretic (PSD) (p < 0.05). Medication adherence was significantly lower in African Americans than whites in all classes except for ARBs, loop diuretics, and PSDs (p < 0.05). Being Hispanic was associated with significantly lower adherence rates than whites for dihydropyridine CCBs and acetylcholinesterase inhibitors (p < 0.05). Racial/ethnic differences exist in antihypertensive and dementia medication use in a cohort of older adults with hypertension and dementia. Adherence rates for a number of antihypertensive and dementia drugs are lower for minorities compared with whites. Healthcare providers should make special efforts to improve medication adherence among minorities.


Interlaboratory comparison of in vitro bioassays for screening of endocrine active chemicals in recycled water.
In vitro bioassays have shown promise as water quality monitoring tools. In this study, four commercially available in vitro bioassays (GeneBLAzer(®) androgen receptor (AR), estrogen receptor-alpha (ER), glucocorticoid receptor (GR) and progesterone receptor (PR) assays) were adapted to screen for endocrine active chemicals in samples from two recycled water plants. The standardized protocols were used in an interlaboratory comparison exercise to evaluate the reproducibility of in vitro bioassay results. Key performance criteria were successfully achieved, including low background response, standardized calibration parameters and high intra-laboratory precision. Only two datasets were excluded due to poor calibration performance. Good interlaboratory reproducibility was observed for GR bioassay, with 16-26% variability among the laboratories. ER and PR bioactivity was measured near the bioassay limit of detection and showed more variability (21-54%), although interlaboratory agreement remained comparable to that of conventional analytical methods. AR bioassay showed no activity for any of the samples analyzed. Our results indicate that ER, GR and PR, were capable of screening for different water quality, i.e., the highest bioactivity was observed in the plant influent, which also contained the highest concentrations of endocrine active chemicals measured by LC-MS/MS. After advanced treatment (e.g., reverse osmosis), bioactivity and target chemical concentrations were both below limits of detection. Comparison of bioassay and chemical equivalent concentrations revealed that targeted chemicals accounted for ≤5% of bioassay activity, suggesting that detection limits by LC-MS/MS for some chemicals were insufficient and/or other bioactive compounds were present in these samples. Our study demonstrated that in vitro bioassays responses were reproducible, and can provide information to complement conventional analytical methods for a more comprehensive water quality assessment.


Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II with reduced pK(a): antibacterial agents with an improved safety profile.
Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. N-Linked amino piperidines, such as 7a, generally show potent antibacterial activity, including against quinolone-resistant isolates, but suffer from hERG inhibition (IC(50) = 44 μM for 7a) and QT prolongation in vivo. We now disclose the finding that new analogues of 7a with reduced pK(a) due to substitution with an electron-withdrawing substituent in the piperidine moiety, such as R,S-7c, retained the Gram-positive activity of 7a but showed significantly less hERG inhibition (IC(50) = 233 μM for R,S-7c). This compound exhibited moderate clearance in dog, promising efficacy against a MRSA strain in a mouse infection model, and an improved in vivo QT profile as measured in a guinea pig in vivo model. As a result of its promising activity, R,S-7c was advanced into phase I clinical studies.


The management of multiple sclerosis in children: a European view.
About 3-5% of all patients with multiple sclerosis experience the onset of their disease under the age of 16. A significant proportion of paediatric multiple sclerosis patients develop significant cognitive disturbances and persistent physical disability. The high relapse rate and the morbidity in the paediatric multiple sclerosis population has triggered the use of disease-modifying therapies that have been shown to reduce relapse rate, disease progression and cognitive decline in adult patients with multiple sclerosis. Hard evidence for the right treatment and its appropriate timing is scarce in paediatric multiple sclerosis. Nevertheless, expertise in this field has grown thanks to recent open-label trials and experience generated in specialized centres. In spring 2009, a first meeting was held in Rotterdam with clinicians from 11 European countries (one from Canada) that are all active in the management of paediatric multiple sclerosis. One of the aims was to generate a common view on the management of paediatric multiple sclerosis patients. The result of this meeting is presented here to help standardize treatment and to support clinicians with less experience in this field.


Interaction energies and NMR indirect nuclear spin-spin coupling constants in linear HCN and HNC complexes.
The cooperativity effects on both the electronic energy and NMR indirect nuclear spin-spin coupling constants J of the linear complexes (HCN)n and (HNC)n (n = 1-6) are discussed. The geometries of the complexes were optimized at the MP2 level by using the cc-pVTZ basis sets. The spin-spin coupling constants were calculated at the level of the second-order polarization propagator approximation with use of the local dense basis set scheme based on the cc-pVTZ-J basis sets. We find strong correlations in the patterns of different properties such as interaction energy, hydrogen bond distances, and spin-spin coupling constants for both series of compounds. The intramolecular spin-spin couplings are with two exceptions dominated by the Fermi contact (FC) mechanism, while the FC term is the only nonvanishing contribution for the intermolecular couplings. The latter do not follow the Dirac vector model and are important only between nearest neighbors.


Research comparisons. Some limitations of international comparisons of research and development expenditures are considered.
In concluding, I will make some personal value judgments explicit. No value judgments need enter into a comparison of inputs, nor need they intrude into comparisons of technological progress and economic growth, except in the choice of these themes for investigation, but value judgments are inevitably involved in the consideration of policy measures which may flow from such comparisons. Insofar as it represents a conscious political decision, the scale of R & D activity and support for science in any particular country reflects a variety of policy goals, only some of which are economic. Moreover, the balance of "home" R & D and "imported" science and technology must also partly reflect political and cultural, as well as more narrowly conceived economic and technological, goals. My personal preference is for a more research-oriented society, both in Britian and in Europe, but for very different policy goals than those pursued in the U.S. and the U.S.S.R. I regard the proposals being canvassed in Britain for drastically cutting back the rate of growth of fundamental and applied research as short-sighted both culturally and economically, and I believe that the real possibilities of acquiring and using American know-how will depend increasingly on strengthening Europe's own R & D capacity. But wherever the balance may lie, all countries benefit to a very considerable extent from scientific and technological exchanges. Autarchy is inefficient, both for the world economy and for world science and technology.


The mechanism of alpha-adrenergic activation of the dog coronary artery.
Norepinephrine (NE) activates isolated coronary conduit arteries by stimulating Ca2+ uptake into the smooth muscle cells. Blockade of Ca2+ influx by removal of Ca2+ from the bathing medium or addition of 10 mM LaCl3 prevents the NE-induced contraction in the dog coronary artery but still allows NE to induce a rapid transient contraction in the rabbit aorta. Under these conditions, NE stimulates 45Ca2+ efflux from rabbit aorta but fails to do so in the coronary artery. The difference in behaviour between the two arteries is attributed by the presence of an intracellular NE-sensitive Ca2+ fraction in the rabbit aorta and its absence from the dog coronary artery. This difference also explains the much greater sensitivity of the NE-induced contractions in the dog coronary to the relaxant effects of the Ca2+ antagonists, D600 and SKF525A, than that seen in the rabbit aorta. High K+-induced contractions of both the coronary artery and the aorta are equally sensitive to the Ca2+ antagonists.


A novel intronic mutation in the DDP1 gene in a family with X-linked dystonia-deafness syndrome.
X-linked dystonia-deafness syndrome (Mohr-Tranebjaerg syndrome) is a rare neurodegenerative disease characterized by hearing loss and dystonia. So far, 7 mutations in the coding region of the DDP1 gene have been described. They consist of frameshift, nonsense, missense mutations or deletions. To investigate the presence of mutations in the DDP1 gene in a family with dystonia-deafness syndrome. Seven members belonging to 2 generations of a family with 2 affected subjects underwent genetic analysis. Mutational screening in the DDP1 gene was made through DNA direct sequencing. We found an intronic mutation in the DDP1 gene. It consists of an A-to-C substitution in the position -23 in reference to the first nucleotide of exon 2 (IVS1-23A>C). The mutation was present in 2 affected men and their respective unaffected mothers, whereas it was absent in the healthy men from this family and in 90 healthy controls. Intronic mutations in the DDP1 gene can also cause X-linked dystonia-deafness syndrome. In our case, the effect of the mutation could be due to a splicing alteration.


[Regression of left ventricular hypertrophy and improvement of its diastolic function in patients with arterial hypertension under influence of antihypertensive therapy].
Antihypertensive therapy with sequential addition of drugs (noliprel, noliprel-forte, metoprolol, amlodipine) for achievement of target blood pressure (BP) below 140/90 mm Hg was used in the treatment of 99 patients with arterial hypertension (AH) with (n=51) or without left ventricular (LV) hypertrophy (LVH). At initial Doppler study of transmitral blood flow all patient with LVH had type 1 (n=48) or type 2 (n=3) diastolic LV dysfunction. Among patients without LVH 13 had minor type 1 diastolic LV dysfunction. After 12 - 14 months of antihypertensive therapy in all 44 patients with moderate LVH (myocardial mass index below 140 g/m2) BP corresponded to target level. This was associated with 6% decrease of myocardial mass index (MMI) and its normalization in 2/3 of patients, restoration of diastolic function in 3/4 of patients and its improvement in other patients, decrease of functional class, in rease of 6 min walking distance, and improvement of quality of life according to questionnaire for patients with CHF. In 7 patients with pronounced LVH (MMI 140 g/m2) target BP was not achieved, LVMMI, diastolic function, and functional class did not change, however tolerance to physical effort and quality of life improved. Thus in all patients with AH without LVH target BP level was achieved. In minor initial diastolic dysfunction diastolic function restored to normality, functional class, tolerance to physical work and quality of life improved.


[Study on combination components and effectiveness of Chinese traditional herbal formulas].
Chinese herbal prescriptions enhance the clinical curative effect through the use of multi-composition formulas, and the combined use of several components from herbal extracts is an enhanced mode of formulae organization and compatibility. The research with the combination components is under the guidance of the traditional Chinese medical theory which apply medical therapy following syndrome differentiation. The purpose is to enhance drug safety, clinical suitability, and to use drugs with clearer ingredients and mechanisms of action, with more stable and controllable product quality for commercial production. So the study of combination components must establish the methodology of combining standard components, confirming the main components through trial design, removing the poisonous components, and ascertaining dosage and ratios of all the components used. The mode of combination component has three forms: the one from the combined use of prepared medicinal herbs, the one from directly combined use of components, and the one from the standard ingredient composition of single herb. These three forms strictly follow the mechanisms of multi-component and multi-target medical intervention. The significance of using combined effective components is to ensure the accuracy and safety of clinical dosage, enhance the clinical effectiveness, reduce the use of medicinal herbs, decrease the side-effects, and to promote modern Chinese medicines that have clear ingredients and mechanisms. Our study on the chemistry and pharmacology of Chinese herbs provided scientific foundation to the combination effective components. Nowadays the modern medicine is faced with the complicated disease spectra, meanwhile, the single-ingredient chemical drug is not able to achieve satisfactory curative effect. So there is a need to develop new medicine with effective combination components to meet new opportunities and challenges. Therefore, it has becomes a new mode of developing combined components from effective traditional formulas and from single standard ingredient under traditional Chinese medicine theory, unlike the conventional way of clinic--experience based drug development. This new mode will promote the academic research and the industry development of traditional Chinese medicine.


Is exclusive breastfeeding and its duration related to cardio respiratory fitness in childhood?
This study investigated the effect of breastfeeding on cardio respiratory fitness (CRF) in students of Kermanshah, Iran. In this retrospective cohort study, 246 students with the mean ± SD age of 7.28 ± 0.50 years, mean breastfeeding ± SD duration of 8.20 ± 10.26 months, and body mass index (BMI) of 16.96 ± 3.03 kg/m(2) participated. Students had no CVD, liver or kidney diseases. Children were categorized in three groups of over 6 months breast-fed (>6 months group), less than 6 months breast-fed (≤6 months group), and formula group. The physician measured CRF calculating VO2 max; and reported the results as fitness or no fitness. The probable confounders were gender, BMI, fat-free mass, fat mass, mother's BMI, dietary Poly Unsaturated Fatty Acid (PUFA) and folate, beginning time of supplementary nutrition, physical activity, and birth weight. Breastfeeding more than 6 months was positively associated with CRF (p value < 0.001) before and after adjustment for confounders. The risk ratio (RR) of no CRF was 3.22 times more than >6 months group. VO2 max (ml/kg/min) was significantly the highest in >6 months group (p value = 0.001). Breastfeeding more than 6 months has positive effects on CRF, and the early nutrition may be a predictor for adolescence physical health.


Brain pericytes ABCA1 expression mediates cholesterol efflux but not cellular amyloid-β peptide accumulation.
In brain, excess cholesterol is metabolized into 24S-hydroxycholesterol (24S-OH-chol) and eliminated into the circulation across the blood-brain barrier. 24S-OH-chol is a natural agonist of the nuclear liver X receptors (LXRs) involved in peripheral cholesterol homeostasis. The effects of this oxysterol on the pericytes embedded in the basal lamina of this barrier (close to the brain compartment) have not been previously studied. We used primary cultures of brain pericytes to demonstrate that the latter express LXR nuclear receptors and their target gene ATP-binding cassette, sub-family A, member 1 (ABCA1), known to be one of the major transporters involved in peripheral lipid homeostasis. Treatment with 24S-OH-chol caused an increase in ABCA1 expression that correlated with a reverse cholesterol transfer to apolipoprotein E, apolipoprotein A-I, and high density lipoprotein particles. Inhibition of ABCA1 decreased this efflux. As pericytes are able to internalize the amyloid-β peptides which accumulate in brain of Alzheimer's disease patients, we then investigated the effects of 24S-OH-chol on this process. We found that the cellular accumulation process was not modified by 24S-OH-chol treatment. Overall, our results highlight the importance of the LXR/ABCA1 system in brain pericytes and suggest a new role for these cells in brain cholesterol homeostasis.


A severe vicious cycle in uncontrolled subarachnoid hemorrhage: the effects on cerebral blood flow and hemodynamic responses upon intracranial hypertension.
In subarachnoid hemorrhage (SAH), Cushing postulated that the increase in systemic arterial pressure (SAP) in response to elevation of intracranial pressure (ICP) was beneficial to cerebral perfusion. However, in uncontrolled SAH, the increased SAP may cause more bleeding into the subarachnoid space and further increase the ICP. We created an animal model to simulate SAH by connecting a femoral arterial catheter to the subarachnoid space. The global cerebral blood flow (CBF) was measured with a venous outflow method. The purposes were to observe the CBF change under the simulated SAH, and to evaluate the effects of an adrenergic blocker and a vasodilator. In addition, spectral analysis of the aortic pressure and flow was employed for the analysis of hemodynamic changes at various ICP levels. When the femoral arterial blood was allowed to flow into the subarachnoid space, the ICP was elevated. The Cushing response to increased ICP caused an increase in SAP. A vicious cycle was generated between ICP and SAP. The CBF under the vicious cycle was greatly depressed. The dog developed pulmonary edema (PE) within 5 mins. An alpha-adrenergic blocker (phentolamine) and a vasodilator (nitroprusside) were beneficial to the reduction of SAP and ICP, improvement of CBF, and prevention of PE. Hemodynamic analysis revealed that graded increases in ICP caused increases in SAP, total peripheral resistance, arterial impedance, and pulse reflection with decreases in stroke volume, cardiac output and arterial compliance. The hemodynamic changes may contribute to acute left ventricular failure that leads to pressure and volume loading in the lung circulation, and finally acute PE.


Evaluation of quality of life: impact of allergic rhinitis on asthma.
Health-related quality of Life (HRQOL) has been considered an important variable to be managed in airway diseases. Allergy and asthma can reduce HRQOL as a result of profound physical and psychosocial complications. Most patients with asthma also suffer from rhinitis, which also impairs quality of life. However, the impact of allergic rhinitis on asthmatic patients has not been investigated. Our objective was to evaluate HRQOL in patients with asthma alone, allergic rhinitis alone, or both diseases. We compared HRQOL in 316 patients with both diseases or either asthma or rhinitis using the Short Form-36 questionnaire. Data were also collected on patients' sociodemographic characteristics, atopic state, body mass index (BMI), and education. A total of 232 patients with allergic rhinitis, 40 with asthma, and 44 with both diseases were enrolled. The mean (SD) age was 32 (13) years and 65% were females. HRQL was significantly lower in patients with asthma, with or without rhinitis, than in those with allergic rhinitis alone. Female sex, older age, increased BMI and less educational status were found to be the major determinants of impaired quality of life in patients with allergic rhinitis or asthma. The impact of rhinitis on asthma seems to play a minor role in HRQOL.


[Levels of insecticide resistance and its mechanisms in a strain of Aedes aegypti of Santiago de Cuba].
As a result of the most recent dengue outbreak in Santiago de Cuba province, a strain of this vector was studied to determine the levels of sensitivity and/or resistance to organophosphate and pyrethoid insecticides. The results of bioassays showed low levels of resistance to fention, malathion and deltametrine, moderate levels of resistance to temephos, metyl-pirimifos and cipermetrine and high levels of resistance to chlorpirifios. According to the results obtained from the use of S.S.S. phosphotrithiate trybutil synergist, it was shown that esterases play an important role in resistance to temephos and chlorpirifos. Piperonyl butoxide synergist disclosed that multifunction oxidases were not involved in the resistance to any of the evaluated insecticides. Biochemical techniques were applied to detect esterase-, glutathione-S-transferase- and acetylcholineaterase-mediated resistance mechanisms of Aedes aegypti. In accordance with the high frequency values observed in each of the mechanisms, it was proved that esterases and glutathione-S-transferase were involved in the insecticide resistance but acetylcholinesterases were not. However, acetylcholinesterase gen was found in Aedes aegypti for the first time though at low frequency. The polyacrylamide-gel electrophoresis made it possible to observe a well-stained band with a relative mobility value of 0.779; this band was called A4 it was not observed in the reference strain and may be associated to organophosphate resistance which remains to be proved in future research.


The human papillomavirus E6/E7 genes induce discordant changes in the expression of cell growth regulatory proteins.
The E6/E7 oncoproteins of human papillomavirus (HPV) types 16 and 18 are responsible for the efficient immortalization of human genital keratinocytes and we have recently reported that such immortalized cells display alterations in the expression of cyclin A, cyclin B, and cdc-2. To determine whether these alterations were the consequence of E6/E7 protein expression or whether they resulted from the process of cellular immortalization, we multiply-infected primary genital keratinocytes with a retrovirus expressing the HPV-18 E6/E7 genes and examined the cells for acute, pre-immortalization changes in several critical cell growth regulatory proteins including cyclin A, cyclin B, cdc-2, p53 and c-myc. In addition, we simultaneously evaluated the expression of the E6/E7, bcl-2 and involucrin genes to determine whether there were accompanying alterations in the expression of viral genes or in cellular genes related to cell apoptosis and the state of keratinocyte differentiation. The cell cycle regulating proteins (cyclin A, cyclin B, cdc-2 and p53) change significantly within days after retroviral infection. Cyclin B and cdc-2 increase over 4-fold by three passages and remain relatively constant thereafter through passage 21, whereas the levels of p53 protein decrease 25% by passage three. Increases in the expression of cyclin A, cyclin B and cdc-2, and decreases in p53 are therefore among the earliest observable changes in cell regulatory proteins following E6/E7 gene expression and may be important contributors to the development of cell immortalization. The expressions of viral E6/E7 genes, c-myc, bcl-2 and involucrin exhibit progressive changes with increased passage numbers until passage 21, presumably reflecting the selective outgrowth of immortalized cells.


The comparative analysis of the three dilatation techniques in percutaneous nephrolithotomy: Which one is safer?
Introduction of the "access sheet" is one of the most important steps steps of the percutaneous nephrolithotomy (PNL) intervention. In creating the access tract, various dilatators (balloon, metal) are used and different need-based dilatation tools were developed. In this study, we aimed to compare the mechanical Amplatz dilatation (AD), balloon dilatation (BD) and one-shot dilatation (OSD) methods in a retrospective manner. A total of 182 patients (127 males and 55 females), who underwent PNL surgery in Urology Department of Fatih Sultan Mehmet Research and Training Hospital between January 2016 and September 2018, were included in this study. The average age was 47.34 ± 12.68 years (age range 15-80) and average BMI was 27.15 ± 5.01 kg/m2 (range between 17.12 and 40.75 kg/m2). There was a prominent difference in terms of operation duration (p = 0.032). Meaningful difference was found among the groups in terms of dilation fluoroscopy time (p = 0.001), with a notable shorter time in OSD group than the others (p < 0.05). Beside this, there was no difference between the AD and BD groups in terms of fluoroscopy times (p > 0.05). Also, there was no difference among the groups by Clavien complication rate (p > 0.05). There was a prominent difference among the groups in terms of hemoglobin decrement (p = 0.012; p < 0.05). The hemoglobin decrease in OSD group was significantly lower than in AD and BD groups (p < 0.05; p < 0.01). On the contrary, there was no meaningful difference between AD and BD groups with this regard (p > 0.05). As a result, we have concluded that the use of OSD modality in PNL interventions could be superior to other methods with respect to its feasibility, cost-effectiveness, shorter radiation exposure / fluoroscopy time and it could be a preferable way of treatment especially in developing countries.


Gtpbp2 is required for BMP signaling and mesoderm patterning in Xenopus embryos.
Smad proteins convey canonical intracellular signals for activated receptors in the TGFβ superfamily, but the activity of Smads and their impact on target genes are further regulated by a wide variety of cofactors and partner proteins. We have identified a new Smad1 partner, a GTPase named Gtpbp2 that is a distant relative of the translation factor eEf1a. Gtpbp2 affects canonical signaling in the BMP branch of the TGFβ superfamily, as morpholino knockdown of Gtpbp2 decreases, and overexpression of Gtpbp2 enhances, animal cap responses to BMP4. During Xenopus development, gtpbp2 transcripts are maternally expressed and localized to the egg animal pole, and partitioned into the nascent ectodermal and mesodermal cells during cleavage and early gastrulation stages. Subsequently, gtpbp2 is expressed in the neural folds, and in early tadpoles undergoing organogenesis gtpbp2 is expressed prominently in the brain, eyes, somites, ventral blood island and branchial arches. Consistent with its expression, morpholino knockdown of Gtpbp2 causes defects in ventral-posterior germ layer patterning, gastrulation and tadpole morphology. Overexpressed Gtpbp2 can induce ventral-posterior marker genes and localize to cell nuclei in Xenopus animal caps, highlighting its role in regulating BMP signaling in the early embryo. Here, we introduce this large GTPase as a novel factor in BMP signaling and ventral-posterior patterning.


Multiple forms of glucagon and somatostatin isolated from the intestine of the southern-hemisphere lamprey Geotria australis.
Current views on Agnathan phylogeny favor the hypothesis that the genera of holarctic lampreys belong to a single family (Petromyzontidae) and form an interrelated progression in which Petromyzon is near to Ichthomyzon at the base of the phylogenetic tree and Lampetra is the most derived. A stock similar to that of contemporary Ichthomyzon is considered to have given rise to the southern hemisphere lamprey Geotria australis, the sole member of the Geotriidae. In the present study, two molecular forms of glucagon were isolated from an extract of G. australis intestine that differed in structure by six amino acid residues. One form shows two amino acid substitutions (Leu14 --> Met and Ala29 --> Ser) compared with the single molecular form of glucagon isolated from the sea lamprey Petromyzon marinus and the second form shows three substitutions (Asp15 --> Glu, Ser16 --> Ala, Ile24 --> Thr) compared with the single glucagon isolated from the river lamprey Lampetra fluviatilis. As Petromyzon and Lampetra glucagons differ by six amino acid residues, the data suggest that a duplication of the glucagon gene occurred prior to or early in lamprey evolution. Although both genes are strongly expressed in G. australis, the expression of one gene predominates in P. marinus while that of the other gene predominates in L. fluviatilis. Previous work has shown that, in the islet organ of G. australis, preprosomatostatin is processed almost exclusively to somatostatin-33. However, the present study demonstrates that somatostatin-14 is the major molecular form in G. australis intestine with somatostatin-33 present only as a minor component. This result demonstrates a tissue-dependent pathway of posttranslational processing of preprosomatostatin in the Geotria enteropancreatic system.


Interaction among heme oxygenase, nuclear factor-kappaB, and transcription activating factors in cardiac hypertrophy in hypertension.
Deoxycorticosterone acetate-induced hypertension is a volume overload and human primary aldosteronism model characterized by severe cardiac lesions attributed to elevated inflammation, oxidative stress, fibrosis, and hypertrophy. An important cytoprotective pathway that counteracts tissue insults is the heme oxygenase (HO) system. Although the HO-1 gene promoter contains consensus binding sites for proinflammatory/oxidative transcription factors like nuclear factor-kappaB, activating protein (AP)-1, and AP-2, the effects of HO inducers on these transcription factors in cardiac lesions of deoxycorticosterone acetate hypertension are not fully understood. Hemin therapy normalized systolic blood pressure and markedly reduced the left:right ventricular ratio, left ventricular wall thickness, and left ventricle:body weight ratio, whereas the HO blocker, chromium mesoporphyrin, exacerbated cardiac fibrosis/hypertrophy in deoxycorticosterone acetate-hypertensive rats. The cardioprotection by hemin was accompanied by increased HO-1, HO activity, cGMP, superoxide dismutase, catalase, the total antioxidant capacity alongside the reduction of 8-isoprostane, AP-1, AP-2, nuclear factor-kappaB, and c-Jun-NH(2)-terminal kinase, whereas chromium mesoporphyrin abolished the hemin effects. Furthermore, hemin therapy attenuated transforming growth factor-beta(1) and extracellular matrix proteins like fibronectin and collagen, with a corresponding reduction of histopathologic lesions, including longitudinal/cross-sectional muscle fiber thickness, scarring, muscular hypertrophy, coronary arteriolar thickening, and collagen deposition. The suppression of AP-1, AP-2, nuclear factor-kappaB, and c-Jun-NH(2)-terminal kinase proinflammatory/oxidative mediators in the left ventricle of hemin-treated animals is a novel observation that may account for cardioprotection in deoxycorticosterone acetate hypertension. By concomitantly upregulating HO activity and cGMP and potentiating the total antioxidant status, hemin therapy reduced hypertension, suppressed oxidative stress, and attenuated extracellular matrix and remodeling proteins, with a reduction of histopathologic lesions that characterize cardiac fibrosis, hypertrophy, and end-stage organ damage.


Neural substrates of cognitive skill learning in Parkinson's disease.
While cognitive skill learning is normally acquired implicitly through frontostriatal circuitry in healthy individuals, neuroimaging studies suggest that patients with Parkinson's disease (PD) do so by activating alternate, intact brain areas associated with explicit memory processing. To further test this hypothesis, 10 patients with PD and 12 healthy controls were tested on a modified, learning version of the Tower of London task while undergoing positron emission tomography at four different time points over the course of learning. Despite having less accurate problem solving abilities than controls, PD patients were able to acquire the skill learning task. However, as compared to controls, they maintained higher levels of cerebral blood flow activity in the dorsolateral prefrontal cortex and hippocampus and showed an increase in activity in the frontopolar cortex and posterior cingulate over the course of learning. These findings reflect a shift to the explicit memory system in PD patients, enabling them to learn this cognitive skill, which is normally acquired by control subjects using implicit learning strategies and frontostriatal circuitry.


Predicting driving after drinking over time among college students: the emerging role of injunctive normative perceptions.
Despite prevention efforts, driving after drinking (DAD) is a prevalent high-risk behavior among college students and is a leading cause of death and injury. Examination of factors predicting future DAD behavior is necessary to develop efficacious targeted interventions to reduce this behavior among college students. The current study evaluated demographic, social cognitive, and behavioral predictors of DAD using longitudinal data. Participants were 655 nonabstaining college students (67.2% female; 60.3% White; Mage = 19.3 years) who completed online surveys at two time points 12 months apart. Results revealed that participants consistently overestimated their peers' approval (injunctive norms) of DAD. In a three-step hierarchical logistic regression model, injunctive norms, age, and past DAD behavior uniquely contributed to the prediction of this behavior 12 months later. Neither sex nor membership in a sorority or fraternity emerged as significant predictors. The findings provide important new insights into the longitudinal predictors of DAD among college students and highlight the need for DAD interventions, particularly among older students.


The Relationship Between Cervical Degeneration and Global Spinal Alignment in Patients With Adult Spinal Deformity.
To examine the relationship between cervical degeneration and spinal alignment by comparing patients with adult spinal deformity versus the control cohort. The effect of degeneration on cervical alignment has been controversial. Cervical and full-length spine radiographs of 57 patients with adult spinal deformity and 78 patients in the control group were reviewed. Adult spinal deformity was classified into 3 types based on the primary characteristics of the deformity: "Degenerative flatback" group, "Positive sagittal imbalance" group, and "Hyperthoracic kyphosis" group. Cervical degeneration was assessed using the cervical degeneration index scoring system. The "Degenerative flatback" group had significantly higher total cervical degeneration index score (25±7) than the control group (16±8), the "Positive sagittal imbalance" group (18±8), and the "Hyperthoracic kyphosis" group (12±7) (P<0.01). The "Degenerative flatback" group had significantly less cervical lordosis than the other groups. This reduced amount of cervical lordosis was thought to be induced by a compensatory decrease in thoracic kyphosis. In this group, increased cervical degeneration was significantly associated with a decrease in cervical lordosis. Significantly greater compensatory increase in cervical lordosis was noted in the "Positive sagittal imbalance" group (20±15 degrees) and the "Hyperthoracic kyphosis" group (26±9 degrees) compared with the control group (11±12 degrees) (P<0.02). Flat cervical spine coexisted with cervical degeneration when compensatory hypothoracic kyphosis was induced by degenerative flatback. In other situations, cervical lordosis could increase as a compensatory reaction against sagittal imbalance or hyperthoracic kyphosis.


Surgical models for cardiac regeneration in neonatal mice.
Although amphibian and fish models of heart regeneration have existed for decades, a mammalian equivalent has long remained elusive. Our discovery of a brief postnatal window for heart regeneration in neonatal mice has led to the establishment of surgical models for cardiac regenerative studies in mammals for the first time. This protocol describes a 10-min surgical procedure to induce cardiac injury in 1-d-old neonatal mice. This allows for the analysis of cardiac regeneration after surgical amputation of the left ventricle (LV) (apical resection) and coronary artery occlusion (myocardial infarction (MI)). A comparative analysis of neonatal and adult responses to myocardial injury should enable identification of the key differences between regenerative and nonregenerative responses to cardiac injury. This protocol can also be adapted to the growing repertoire of genetic models available in the mouse, and it provides a valuable tool for unlocking the molecular mechanisms that guide mammalian heart regeneration during early postnatal life.


Understanding culturally safe aged care from the perspectives of older Aboriginal Australians in rural and remote communities.
Aboriginal and Torres Strait Islander peoples face challenges in accessing aged care and are less likely to use some services than their non-Indigenous counterparts. Culturally safe care is increasingly recognised as an enabler to improve access and quality of care. This study explored older Aboriginal peoples' perceptions and experience of culturally safe aged care. We conducted semi-structured interviews with sixty-three older Aboriginal people, purposively sampled from three rural and remote geographic locations in South Australia, between April and October 2018, with participants who were both receiving and not receiving aged care services. We asked participants how organisations do or could meet their aged care needs. We analysed interview data inductively into themes. These themes were incorporated into six principles of culturally safe aged care which were subsequently endorsed by participants and study stakeholders. Participants described culturally safe aged care services as those which facilitated or maintained connection to participants' culture, traditional lands and community. Five themes were identified: maintaining cultural identity, culturally informed service delivery, culturally competent workforce, culturally supportive environments and partnerships and collaboration within the aged care service system. Addressing cultural safety in aged care will require organisations to adapt their policies, service delivery, environments and work practices to meet the needs of older Aboriginal peoples. SO WHAT? Identifying culturally safe aged care from the perspectives of older Aboriginal and Torres Strait Islander peoples provides timely insight to how services may be better designed and implemented to promote quality of life.


Cell-to-cell heterogeneity in growth rate and gene expression in Methylobacterium extorquens AM1.
Cell-to-cell heterogeneity in gene expression and growth parameters was assessed in the facultative methylotroph Methylobacterium extorquens AM1. A transcriptional fusion between a well-characterized methylotrophy promoter (P(mxaF)) and gfp(uv) (encoding a variant of green fluorescent protein [GFPuv]) was used to assess single-cell gene expression. Using a flowthrough culture system and laser scanning microscopy, data on fluorescence and cell size were obtained over time through several growth cycles for cells grown on succinate or methanol. Cells were grown continuously with no discernible lag between divisions, and high cell-to-cell variability was observed for cell size at division (2.5-fold range), division time, and growth rate. When individual cells were followed over multiple division cycles, no direct correlation was observed between the growth rate before a division and the subsequent growth rate or between the cell size at division and the subsequent growth rate. The cell-to-cell variability for GFPuv fluorescence from the P(mxaF) promoter was less, with a range on the order of 1.5-fold. Fluorescence and growth rate were also followed during a carbon shift experiment, in which cells growing on succinate were shifted to methanol. Variability of the response was observed, and the growth rate at the time of the shift from succinate to methanol was a predictor of the response. Higher growth rates at the time of the substrate shift resulted in greater decreases in growth rates immediately after the shift, but full induction of P(mxaF)-gfp(uv) was achieved faster. These results demonstrate that in M. extorquens, physiological heterogeneity at the single-cell level plays an important role in determining the population response to the metabolic shift examined.


Quantitative pulsed Doppler measurement of common femoral artery blood flow variables during postocclusive reactive hyperemia.
Quantitative blood flow measurements were performed on 37 normal lower limbs with a 128-channel digital pulsed Doppler (MDPD) system. The evolution of mean flow (QM), peak systolic flow (QS), diastolic flow (QD), and prograde stroke volume (PSV) was observed at rest, during postocclusive reactive hyperemia (PORH), and at 1-, 2-, and 3-min intervals. The QM at rest was 2.9 +/- 1.1 ml/s; PORH induced a four- to fivefold increase in QM and PSV secondary to a slight increase in QS and the disappearance of the reverse protodiastolic component of resting flow. Reverse flow was restored after 1 min. Both QS and QD returned to resting values after 2 min, whereas QM remained significantly higher after 3 min. To provide a better description of the hyperemic response, we also studied the evolution of the pulsatility index as as applied the flow curve (PIQ). Similarly, the systolic amplitude index (SAI) is presented. Our study demonstrates that pulsed Doppler techniques can be used for noninvasive quantitative assessment of blood flow at rest and during PORH. The values obtained on normal subjects provide base-line data for further investigation of pathological conditions.


Epidermal nerve fiber density, oxidative stress, and mitochondrial haplogroups in HIV-infected Thais initiating therapy.
We explored associations between mitochondrial DNA (mtDNA) haplogroups, epidermal nerve fiber density (ENFD), and HIV-associated sensory neuropathy (HIV-SN) in a randomized trial of Thai patients initiating antiretroviral therapy (ART). The South East Asia Research Collaboration with Hawaii 003 study evaluated toxicity of nucleoside reverse transcriptase inhibitors (stavudine vs. zidovudine vs. tenofovir). We present secondary analyses of mtDNA haplogroups and ENFD changes. ENFD, peripheral blood mononuclear cell mitochondrial complex I and IV, and 8-oxo-deoxyguanine (8-oxo-dG) were quantified. Peripheral blood mononuclear cell mtDNA sequences were obtained for haplogroup determination. Multivariate regression of ENFD change was performed. Paired ENFD was available from 118 patients. Median age, CD4 cell count, and height at entry were 34 years, 172 cells/μl, and 162 cm, respectively. Major haplogroups included M (42%), F (21%), and B (16%). Baseline ENFD, CD4 cell count, randomized ART, and biomarkers did not differ by haplogroup. Haplogroup B patients were older (P=0.02) at baseline, and had an increase in median ENFD (+1.5 vs. -2.9 fibers/mm; P=0.03) and 8-oxo-dG break frequency (+0.05 vs. 0.00; P=0.05) compared to other haplogroups. In a multivariate model, haplogroup B was associated with increased ENFD (β=3.5, P=0.009) at week 24, whereas older age (P=0.02), higher baseline CD4 cell count, (P=0.03), higher complex I level (P=0.03), and higher ENFD (P<0.001) at baseline were all associated with decreased ENFD. Three of the six HIV-SN cases were haplogroup B (P=0.05). Thai persons belonging to mtDNA haplogroup B had increased ENFD and 8-oxo-dG on ART, and were more likely to develop HIV-SN. These results suggest that mtDNA variation influences early oxidative damage and ENFD changes.


Post-traumatic complications of arachnoid cysts and temporal lobe agenesis.
Six patients with arachnoidal cysts of the middle cranial fossa who presented with raised intracranial pressure are described. All of them had a history of trauma though in two of them it was a remote incident. They all showed radiological changes of an expanded middle cranial fossa and temporal lobe agenesis. The relationship of trauma to these congenital lesions is discussed.


Deficiencies of the complement system in man.
Deficiencies of components of the complement system in man are described. Clq was reconstituted in patients with severe combined immunodeficiency after bone marrow transplantation. Clr deficiency is associated with vascular disease and upper respiratory infections. Reconstitution of complement occurred in one patient with Clr deficiency after kidney transplantation. Our C2-deficient patient who developed systemic lupus erythematosus had elevated levels of C3. Following blood transfusion, ie by providing C2, dramatic activation of complement occurred in vivo.


Diet Quality and Protein-Bound Uraemic Toxins: Investigation of Novel Risk Factors and the Role of Microbiome in Chronic Kidney Disease.
This study aims to explore the associations between diet quality, uraemic toxins, and gastrointestinal microbiota in the chronic kidney disease (CKD) population. This is a baseline cross-sectional study of adults with CKD participating in a randomized controlled trial of prebiotic and probiotic supplementation. Dietary intake was measured using a seven-day diet history method, administered by a specialist dietitian. Diet quality was assessed using plant-based diet index (PDI) (overall PDI, healthy PDI, and unhealthy PDI), food group analysis, protein intake, fiber intake, and dietary protein-to-fiber ratio. Serum uraemic toxins (free and total; indoxyl sulfate and p-cresyl sulfate) were determined by ultraperformance liquid chromatography. Gastrointestinal microbiota richness, diversity, composition, and functional capacity were analyzed via metagenomic sequencing. Sixty-eight adults [median age: 70 (interquartile range: 58-75) years, 66% male] with an estimated glomerular filtration rate of 34 ± 11 mL/min/1.73 m2 were included, with 40 participants completing the optional fecal substudy. Dietary fiber intake was associated with lower levels of total indoxyl sulfate, whereas the healthy plant-based diet index was associated with lower levels of free p-cresyl sulfate. A higher protein-to-fiber ratio was associated with an increased relative abundance of unclassified members of order Oscillospirales. Intake of vegetables and whole grains was correlated with Subdoligranulum formicile, whereas an unclassified Prevotella species was correlated with potatoes and food items considered discretionary, including sweet drinks, sweet desserts, and animal fats. Diet quality may influence uraemic toxin generation and gut microbiota diversity, composition, and function in adults with CKD. Well-designed dietary intervention studies targeting the production of uraemic toxins and exploring the impact on gut microbiome are warranted in the CKD population.


Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa.
Cryptococcal meningitis (CM)-related mortality may be prevented by screening patients for sub-clinical cryptococcal antigenaemia (CRAG) at antiretroviral-therapy (ART) initiation and pre-emptively treating those testing positive. Prior to programmatic implementation in South Africa we performed a cost-effectiveness analysis of alternative preventive strategies for CM. Cost-effectiveness analysis. Using South African data we modelled the cost-effectiveness of four strategies for patients with CD4 cell-counts <100 cells/µl starting ART 1) no screening or prophylaxis (standard of care), 2) universal primary fluconazole prophylaxis, 3) CRAG screening with fluconazole treatment if antigen-positive, 4) CRAG screening with lumbar puncture if antigen-positive and either amphotericin-B for those with CNS disease or fluconazole for those without. Analysis was limited to the first year of ART. The least costly strategy was CRAG screening followed by high-dose fluconazole treatment of all CRAG-positive individuals. This strategy dominated the standard of care at CRAG prevalence ≥0.6%. Although CRAG screening followed by lumbar puncture in all antigen-positive individuals was the most effective strategy clinically, the incremental benefit of LPs and amphotericin therapy for those with CNS disease was small and additional costs were large (US$158 versus US$51 per person year; incremental cost effectiveness ratio(ICER) US$889,267 per life year gained). Both CRAG screening strategies are less costly and more clinically effective than current practice. Primary prophylaxis is more effective than current practice, but relatively cost-ineffective (ICER US$20,495). CRAG screening would be a cost-effective strategy to prevent CM-related mortality among patients initiating ART in South Africa. These findings provide further justification for programmatic implementation of CRAG screening.


Rater bias in psychological research: when is it a problem and what can we do about it?
Rater bias is a substantial source of error in psychological research. Bias distorts observed effect sizes beyond the expected level of attenuation due to intrarater error, and the impact of bias is not accurately estimated using conventional methods of correction for attenuation. Using a model based on multivariate generalizability theory, this article illustrates how bias affects research results. The model identifies 4 types of bias that may affect findings in research using observer ratings, including the biases traditionally termed leniency and halo errors. The impact of bias depends on which of 4 classes of rating design is used, and formulas are derived for correcting observed effect sizes for attenuation (due to bias variance) and inflation (due to bias covariance) in each of these classes. The rater bias model suggests procedures for researchers seeking to minimize adverse impact of bias on study findings.


Providing specimen transport through an online marketplace in the Northern region of Ghana.
Integrated diagnostic networks, which are themselves dependent on robust specimen transport solutions, are fundamental to effective healthcare systems. This study aimed to pilot an online marketplace for the transport of specimens throughout a laboratory network in Ghana. Independent drivers were matched with health facilities that required specimen transport using a suite of mobile applications and web portals developed for this study. This marketplace was piloted with seven drivers, two laboratories, and five health facilities in Ghana's Northern region from March 2019 to October 2019. During the pilot, 182 deliveries were completed for 691 patients, including 4118 laboratory tests for antenatal care, disease surveillance, and clinical testing. Testing included 34 tests for communicable and non-communicable diseases. All but two specimens (laboratory cancellations) were successfully delivered and tested. The median time from request to encrypted emailing of results was 19.7 h, while that for a drop-off request was 0.9 h. In the midwife registry, the median time from patient visit to result recording was 1 day, compared to 4 days in the same months in 2018, and the number of mothers without documented testing decreased from 41 to 3. Similarly, the proportion of tuberculosis specimen deliveries from Buipe Polyclinic to Tamale Zonal Laboratory taking over 1 day fell from 62% at baseline to 3% during the pilot. An online marketplace successfully orchestrated the delivery of laboratory specimens under a variety of clinical circumstances, reducing overall turn-around time without diminution of the overall specimen delivery process. This study established the efficacy of an online marketplace to orchestrate timely and high-quality delivery of specimens within a laboratory network.


Inhibition spectra of the human pancreatic endopeptidases.
The present work describes the effect of seven naturally occurring proteinase inhibitors on the human pancreatic endopeptidases cationic trypsin, anionic trypsin, chymotrypsin I, chymotrypsin II, and protease E (an elastase-like protease). The inhibitors tested in order of their decreasing effectiveness were alpha-1-proteinase inhibitor (alpha-1-antitrypsin), lima bean trypsin inhibitor, soybean trypsin inhibitor, Bowman-Birk (soybean) inhibitor, Kunitz pancreatic trypsin inhibitor, porcine Kazal inhibitor, and chicken ovomucoid. The human trypsins demonstrated a higher degree of susceptibility to these inhibitors than did the chymotrypsins while human protease E showed remarkably little inhibition by any of these naturally occurring proteinase inhibitors except for alpha-1-proteinase inhibitor. The contribution of each of these proteolytic enzymes to the total proteolytic activity of crude extracts was also investigated using specific active-site directed reagents. These studies revealed that the trypsins constituted approximately 35% of the proteolytic activity while the chymotrypsins represent approximately 32% of the total proteolytic activity. Human protease E and possibly human pancreatic elastase are responsible for approximately 21% of this activity as measured on crude pancreatic extracts.


Effect of somatostatin on meal-stimulated pancreatic exocrine secretions in dogs.
The effect of exogenously administered somatostatin (SRIF) on meal-stimulated secretions of the exocrine pancreas was studied in dogs with chronic pancreatic fistulas. Dogs were fed 600 gm. of raw meat, and pacreatic output of water, bicarbonate, and protein was measured. Bicarbonate and protein secretions rose markedly postfeeding in all control animals. Four hundred micrograms or 100 mug. of SRIF infused for one hour together with a meal completely prevented the postfeeding rise in pancreatic secretions. SRIF (100 mug./hr.) infused one hour after a meal suppressed pancreatic secretions to basal levels within 30 minutes. Pancreatic secretions rose promptly after discontinuation of SRIF in all dogs. These data indicate (1) SRIF completely prevents pancreatic bicarbonate and enzyme responses when given together with a meal; (2) it completely suppresses already initiated pancreatic responses when given one hour after a meal; (3) 100 mug. of SRIF is as effective as 400 mug. in suppressing the postprandial rise in pancreatic secretions. We conclude that SRIF severely interferes with pancreatic secretions during normal alimentation and that this observation should be considered if SRIF is to be used as a therapeutic agent.


Histone acetylation, acetyltransferases, and ataxia--alteration of histone acetylation and chromatin dynamics is implicated in the pathogenesis of polyglutamine-expansion disorders.
Eukaryotic chromosomal DNA is packaged into nucleosomes to form a dynamic structure known as chromatin. The compaction of DNA within chromatin poses a unique hindrance with regards to the accessibility of the DNA to enzymes involved in replication, transcriptional regulation, and repair. The physical structure and physiological activity of chromatin are regulated through a diverse set of posttranslational modifications, histone exchange, and structural remodeling. Of the covalent chromatin modifications, the acetylation of lysine residues within histone proteins by acetyltransferase enzymes, such as GCN5, is one of the most prevalent and important steps in the regulation of chromatin function. Alteration of histone acetyltransferase activity can easily result in the dysregulation of gene transcription and ultimately the onset of a disease state. Many transcription factors contain polyglutamine regions within their primary sequence. Mutations resulting in the elongation of these polyglutamine tracts are associated with a disease family known as the polyglutamine expansion disorders. Spinocerebellar ataxia type 7 (SCA7) is one of the nine diseases that are grouped in this family and is caused by polyglutamine expansion of the ataxin-7 protein, which is a component of the GCN5-containing human SAGA histone acetyltransferase complex. Mutation of ataxin-7 in this manner has been shown to disrupt the structural integrity of the SAGA complex and result in aberrant chromatin acetylation patterns at the promoters of genes involved in the normal function of tissues that are affected by the disease. The specific aspects of molecular pathology are not currently understood; however, studies carried out in laboratory systems ranging from the budding yeast Saccharomyces cerevisiae to transgenic mouse models and cultured human cells are poised to allow for the elucidation of disease mechanisms and subsequent therapeutic approaches.


Depression and ways of coping with stress: a preliminary study.
Coping with stress is defined as all activities undertaken by a human in a stressful situation. The effect of stress on depression, its role in triggering the subsequent phases of the disease, and the factors that mediate the stress-depression relationship become more and more often subjects of research in psychiatry and psychology. Factors important for the formation of depressive symptoms and disease progression are significantly associated with coping strategies used in the face of stress. The main aim of the study was to evaluate the most popular strategies of coping with stress in people with depression in comparison to healthy subjects. Initial research was carried on 80 patients aged from 20 to 66 years with a diagnosis of depression. The control group consisted of 30 healthy subjects aged 22 to 57 years. Analysis of the most popular strategies of coping with stress was performed with the Multiphasic Inventory for Measuring Coping (COPE) by Carver, Scheier, and Weintraub. In contrast with healthy people, patients with depression in stressful situations more often use strategies based on avoidance and denial and have more difficulties in finding positive aspects of stressful events. Depression may be an important factor in the negative assessment of one's own ability to cope with difficult situations and can aggravate a tendency to perceive stressful events as overwhelming.


Genetic analysis of early onset cerebellar ataxia with retained tendon reflexes in four Tunisian families.
Spinocerebellar ataxias comprise a poorly understood group of inherited degenerative neurological diseases. Attempts to classify hereditary ataxias on the basis of the neurological features or specific clinical signs such as tendon reflex changes have proven to be unsatisfactory. Early onset cerebellar ataxia (EOCA) is generally inherited as an autosomal-recessive trait. Thus far, we do not have accurate answers to several questions about its classification. However, significant clinical heterogeneity observed in four Tunisian families with typical EOCA clinical features reinforces the hypothesis of genetic heterogeneity underlying this phenotype. We have demonstrated that three of the four families studied were not linked to Friedreich's ataxia (FA), vitamin E deficiency ataxia (AVED), and autosomal dominant cerebellar ataxia (ADCA) loci. The fourth family showed homozygosity for a large pathological expansion of GAA repeat in all patients, the parents being heterozygous for this mutation. We have also noted, in the case of the family studied, that there was instability in the transmission of the mutation, along with a phenomenon of anticipation comparable to that observed in dominant triplet repeat diseases. EOCA is thus clinically indistinguishable from FA, yet genetically independent of all known candidate genes. Genetic mapping is required for research into the causal gene and an understanding of the disease's physiopathologic mechanisms.


Redescription of Metabronema magnum (Nematoda: Cystidicolidae), a swimbladder parasite of the carangid fish Gnathanodon speciosus off New Caledonia.
The cystidicolid nematode Metabronema magnum (Taylor, 1925) is redescribed from specimens collected from the swimbladder of the fish (golden trevally) Gnathanodon speciosus (Forsskål) (Carangidae, Perciformes) off New Caledonia, South Pacific (a new geographical record). The light and scanning electron microscopical examination made it possible to study in detail the morphology of this so far little-known species. Its pseudolabia were found to possess distinct anterior protrusions (protuberances), sublabia are absent, only four cephalic papillae are present, deirids are bifurcated, and the male possesses six pairs of postanal papillae. By its morphology, M. magnum seems to be most similar to species of Salvelinema Trofimenko, 1962, also from the swimbladder of fishes, differing from them mainly in the presence of median wedge-shaped outgrowths in the mouth, lateral alae, the longer spicule on the right side, and a fewer number of pairs of preanal papillae in the male. Since the morphology of M. magnum considerably differs from that of other representatives of the Cystidicolidae, Metabronema in Rasheed's (1966) conception is considered a valid genus.