Nonclinical Safety Evaluation of VX15/2503, a Humanized IgG4 Anti-SEMA4D Antibody.
The humanized IgG4 monoclonal antibody VX15/2503 bound with 1 to 5 nmol/L affinity to purified recombinant semaphorin 4D (SEMA4D; CD100) produced using murine, rat, cynomolgus macaque, and human sequences. The affinity for native SEMA4D expressed on macaque T lymphocytes was approximately 0.6 nmol/L. Tissues from rats and cynomolgus macaques demonstrated specific staining only with resident lymphocytes. Single-dose and one-month toxicology/PK studies used VX15/2503 dose levels of 0 to 100 mg/kg. No toxicity was observed with either species in these studies, thus the no observed adverse effect level (NOAEL) was 100 mg/kg. Cmax, exposure, and half-life values were similar for both rats and macaques. The NOAEL in a primate maximum feasible dose study was 200 mg/kg. Saturation of T-cell-associated SEMA4D occurred following administration of single doses of 0.1 mg/kg and above; five weekly injections of VX15/2503 at a dose level of 100 mg/kg produced saturation lasting for more than 120 and 130 days, respectively, for rats and primates. Macaques administered five weekly doses of VX15/2503 showed dose-dependent reductions of 2- to 3-fold in T-cell SEMA4D (cSEMA4D) expression levels compared with controls. Reduced cSEMA4D expression levels continued until serum antibody concentrations were 2 to 5 μg/mL, and thereafter normal cSEMA4D levels were restored. On the basis of these data, a phase I clinical study of the safety and tolerability of VX15/2503 was conducted, enrolling adult patients with advanced solid tumor diseases; a single-dose, dose escalation, phase I safety study was also initiated with subjects with multiple sclerosis.


Removal of lower urinary tract stones by percutaneous cystolithotomy: 68 cases (2012-2017).
To describe the use and outcome of percutaneous cystolithotomy (PCCL) for removal of urethral and bladder stones in dogs and cats. Retrospective case series. Sixty-eight client-owned dogs and cats. Records were reviewed and analyzed for dogs and cats that underwent PCCL between January 2012 and December 2017. Signalment, clinical presentation, laboratory and imaging data, procedure time, use of lithotripsy, biopsy, perioperative and immediate postoperative complications, hospitalization times, stone composition, and urine culture results were recorded. Owners were contacted by phone or email 3 weeks after the procedure. Follow-up communications with the owner and referring veterinarian were also recorded. Seventy percutaneous cystolithotomies were performed in 59 dogs and nine cats. The median duration of the procedure was 95 minutes (45-420), and lithotripsy was required in 3% (2/70) of PCCL. Complications during the procedure were reported in one case. In eighty-three percent of procedures (58/70), animals were discharged within 24 hours postoperative. Twenty-four percent (16/68) of animals had minor complications (lower urinary tract signs), and one dog had a major complication (surgical wound dehiscence) during the 3 weeks after the operation. Long-term follow-up revealed stone recurrence in 21% of cases followed more than a year after the procedure (7/33). Percutaneous cystolithotomy allowed removal of bladder and urethral stones with rapid postoperative recovery and few major perioperative or short-term postoperative complications. Percutaneous cystolithotomy provides an attractive minimally invasive surgical alternative for removal of lower urinary tract stones in small animals.


Improving colorimetric assays through protein enzyme-assisted gold nanoparticle amplification.
The discovery of the DNA-mediated assembly of gold nanoparticles was a great moment in the history of science; this understanding and chemical control enabled the rational design of functional nanomaterials as novel probes in biodetection. In contrast with conventional probes such as organic dyes, gold nanoparticles exhibit high photostability and unique size-dependent optical properties. Because of their high extinction coefficients and strong distance dependent optical properties, these nanoparticles have emerged over the past decade as a promising platform for rapid, highly sensitive colorimetric assays that allow for the visual detection of low concentrations of metal ions, small molecules, and biomacromolecules. These discoveries have deepened our knowledge of biological phenomena and facilitated the development of many new diagnostic and therapeutic tools. Despite these many advances and continued research efforts, current nanoparticle-based colorimetric detection systems still suffer from several drawbacks, such as limited sensitivity and selectivity. This Account describes the recent development of colorimetric assays based on protein enzyme-assisted gold nanoparticle amplification. The benefits of such detection systems include significantly improved detection sensitivity and selectivity. First, we discuss the general design of enzyme-modified nanoparticle systems in colorimetric assays. We show that a quantitative understanding of the unique properties of different enzymes is paramount for effective biological assays. We then examine the assays for nucleic acid detection based on different types of enzymes, including endonucleases, ligases, and polymerases. For each of these assays, we identify the underlying principles that contribute to the enhanced detection capability of nanoparticle systems and illustrate them with selected examples. Furthermore, we demonstrate that the combination of gold nanoparticles and specific enzymes can probe enzyme dynamics and function with high specificity, offering substantial advantages in both sensitivity and specificity over conventional detection methods. The screening of nuclease, methyltransferase, protease, and kinase activities can be colorimetrically performed in a straightforward manner. Finally, we discuss examples of colorimetric assays for metal ions and small molecules that constitute important advances toward visual monitoring of enzyme catalytic functions and gene expression. Although these enzyme-assisted assay methods hold great promise for myriad applications in biomedicine and bioimaging, the application of the described techniques in vivo faces formidable challenges. In addition, researchers do not fully understand the interactions of gold nanoparticles with enzyme molecules. This understanding will require the development of new techniques to probe enzyme substrate dynamics at the particle interface with higher spatial resolution and chemical specificity.


Biological Activity of Some Aromatic Plants and Their Metabolites, with an Emphasis on Health-Promoting Properties.
The biological activities of four aromatic plants, namely frankincense, myrrh, ginger, and turmeric, were reviewed in the current study. The volatile fraction (essential oil) as well as the nonvolatile fraction of these four plants showed different promising biological activities that are displayed in detail. These activities can include protection from and/or alleviation of some ailment, which is supported with different proposed mechanisms of action. This review aimed to finally help researchers to get a handle on the importance of considering these selected aromatic plants, which have not been thoroughly reviewed before, as a potential adjuvant to classical synthetic drugs to enhance their efficiency. Moreover, the results elicited in this review encourage the consumption of these medicinal plants as an integrated part of the diet to boost the body's overall health based on scientific evidence.


South Africa youths' higher-risk sexual behaviour: an eco-developmental analysis.
Despite their high levels of knowledge about HIV and AIDS, young people ages 15-24 years in South Africa remain disproportionately affected by the epidemic. Young people's continued susceptibility to HIV infection has been consistently linked to intractable higher-risk sexual behaviours. This paper uses multivariate techniques and secondary data from two nationally representative surveys to illuminate individual and socio-structural factors that play a significant role in youths' continued engagement in higher-risk behaviour, despite their high awareness about HIV and AIDS. The findings show that notwithstanding progress in terms of increased condom use and reduced incidence of other sexually transmitted infections, the average age of sexual debut remains low, multiple sexual partnerships are prevalent, and inconsistent condom use is widespread among young people. Factors significantly associated with these risk behaviours occur at the individual and structural levels and include issues of race, gender, poverty and susceptibility to peer pressure. The paper concludes by recommending that future HIV-prevention interventions in South Africa should aim at building resilience among youths by promoting affirmative, supportive interventions that emphasize the potentials of young people.


Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum.
Corynebacterium glutamicum is used for the large-scale production of L-glutamate, but the efflux of this amino acid is poorly understood. This study shows that addition of ethambutol (EMB) to growing cultures of C. glutamicum causes L-glutamate efflux at rates of up to 15 nmol min(-1) (mg dry wt)(-1), whereas in the absence of EMB, no efflux occurs. EMB is used for the treatment of Mycobacterium tuberculosis, and at a molecular level it targets a series of arabinosyltransferases (EmbCAB). The single arabinosyltransferase-encoding emb gene of C. glutamicum was placed under the control of a Tet repressor (TetR). Experiments with this strain, as well as with an emb-overexpressing strain, coupled with biochemical analyses showed that: (i) emb expression was correlated with L-glutamate efflux, (ii) emb overexpression increased EMB resistance, (iii) EMB caused less arabinan deposition in cell wall arabinogalactan, and (iv) EMB caused a reduced content of cell-wall-bound mycolic acids. Thus EMB addition resulted in a marked disordering of the cell envelope, which was also discernible by examining cellular morphology. In order to further characterize the cellular response to EMB addition, genome-wide expression profiling was performed using DNA microarrays. This identified 76 differentially expressed genes, with 18 of them upregulated more than eightfold. Among these were the cell-wall-related genes ftsE and mepA (encoding a secreted metalloprotease); however, genes of central metabolism were largely absent. Given that an altered lipid composition of the plasma membrane of C. glutamicum can result in L-glutamate efflux, we speculate that major structural alterations of the cell envelope are transmitted to the membrane, which in turn activates an export system, perhaps via increased membrane tension.


Effect of the Interactions between Oppositely Charged Cellulose Nanocrystals (CNCs) and Chitin Nanocrystals (ChNCs) on the Enhanced Stability of Soybean Oil-in-Water Emulsions.
Chitin nanocrystals (ChNCs) and cellulose nanocrystals (CNCs) have been recently used to stabilize emulsions; however, they generally require significant amounts of salt, limiting their applicability in food products. In this study, we developed nanoconjugates by mixing positively charged ChNCs and negatively charged CNCs at various ChNC:CNC mass ratios (2:1, 1:1, and 1:2), and utilized them in stabilizing soybean oil-water Pickering emulsions with minimal use of NaCl salt (20 mM) and nanoparticle (NP) concentrations below 1 wt%. The nanoconjugates stabilized the emulsions better than individual CNC or ChNC in terms of a reduced drop growth and less creaming. Oppositely charged CNC and ChNC neutralized each other when their mass ratio was 1:1, leading to significant flocculation in the absence of salt at pH 6. Raman spectroscopy provided evidence for electrostatic interactions between the ChNCs and CNCs, and generated maps suggesting an assembly of ChNC bundles of micron-scale lengths intercalated by similar-size areas predominantly composed of CNC. The previous measurements, in combination with contact angles on nanoparticle films, suggested that the conjugates preferentially exposed the hydrophobic crystalline planes of CNCs and ChNCs at a 1:1 mass ratio, which was also the best ratio at stabilizing soybean oil-water Pickering emulsions.


Effect of pollination on floral longevity and costs of delaying fertilization in the out-crossing Polygala vayredae Costa (Polygalaceae).
The effect of pollination on flower life span has been widely studied, but so far little attention has been paid to the reproductive consequences of delayed pollination in plants with long floral life spans. In the present study, Polygala vayredae was used to answer the following questions. (1) How does male and female success affect the floral longevity of individual flowers? (2) How does delaying fertilization affect the female fitness of this species? Floral longevity was studied after experimental pollinations involving male and/or female accomplishment, bagging and open pollination. The reproductive costs of a delay in the moment of fertilization were evaluated through fruit set, seed-ovule ratio and seed weight, after pollination of flowers that had been bagged for 2-18 d. Senescence of the flowers of P. vayredae was activated by pollen reception on the stigmatic papillae, while pollen removal had no effect on floral longevity. Nonetheless, a minimum longevity of 8 d was detected, even after successful pollination and pollen dissemination. This period may be involved with the enhancement of male accrual rates, as the female accomplishment is generally achieved after the first visit. Floral life span of open-pollinated flowers was variable and negatively correlated with pollinator visitation rates. Delayed pollination had a major impact on the reproductive success of the plant, with fruit set, seed-ovule ratio and seed weight being significantly diminished with the increase of flower age at the moment of fertilization. A strong relationship between pollination and floral longevity was observed. Flowers revealed the ability to extend or reduce their longevity, within some limits, in response to the abundance of efficient pollinators (i.e. reproductive fulfilment rates). Furthermore, with scarce or unpredictable pollinators, a long floral life span could maintain the opportunity for fertilization but would also have reproductive costs on production of offspring. Reduced female fitness late in the flower's life could shift the cost-benefit balance towards a shorter life span, partially counteracting the selection for longer floral life span potentially mediated by scarce pollination services.


Topical antifungal agents: an update.
So many topical antifungal agents have been introduced that it has become very difficult to select the proper agent for a given infection. Nonspecific agents have been available for many years, and they are still effective in many situations. These agents include Whitfield's ointment, Castellani paint, gentian violet, potassium permanganate, undecylenic acid and selenium sulfide. Specific antifungal agents include, among others, the polyenes (nystatin, amphotericin B), the imidazoles (metronidazole, clotrimazole) and the allylamines (terbinafine, naftifine). Although the choice of an antifungal agent should be based on an accurate diagnosis, many clinicians believe that topical miconazole is a relatively effective agent for the treatment of most mycotic infections. Terbinafine and other newer drugs have primary fungicidal effects. Compared with older antifungal agents, these newer drugs can be used in lower concentrations and shorter therapeutic courses. Studies are needed to evaluate the clinical efficacies and cost advantages of both newer and traditional agents.


Traveling wave and soliton solutions of coupled nonlinear Schrödinger equations with harmonic potential and variable coefficients.
Exact traveling wave and soliton solutions, including the bright-bright and dark-dark soliton pairs, are found for the system of two coupled nonlinear Schrödinger equations with harmonic potential and variable coefficients, by employing the homogeneous balance principle and the F-expansion technique. A kind of shape-changing soliton collision is identified in the system. The collision is essentially elastic between the two solitons with opposite velocities. Our results demonstrate that the dynamics of solitons can be controlled by selecting the diffraction, nonlinearity, and gain coefficients.


Expression of aquaporin 3 and 5 as a potential marker for distinguishing dry mouth from Sjögren's syndrome.
A study was performed to investigate whether expression of aquaporin (AQP) 3 and 5 has potential as a marker for distinguishing dry mouth from Sjögren's syndrome. Twenty-five patients underwent labial minor salivary gland biopsy (dry mouth, n = 9; Sjögren's syndrome, n = 16; control, n = 8). All patients were interviewed about their medical history and subjective oral symptoms, and intraoral examinations were conducted. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to examine the expression and localization of AQP3 and 5. Significant differences in oral dryness, dry eye, medical history, and Saxon test results were revealed among the groups. However, there were no significant inter-group differences in expression of mRNA for AQP3 and 5. Immunohistochemical staining for AQP3 was localized mainly in the basolateral and part of the ductal cell membrane, and was barely evident in the apical membrane of acinar cells. AQP5 was localized to the basolateral and apical membrane and cytoplasm, but not the ductal cell membrane. Staining intensity for AQP3 in the apical membrane was significantly stronger in Sjögren's syndrome, and that for AQP5 was significantly weaker in dry mouth. Taken together, the present data suggest that expression of AQP3 and 5 may be a marker for distinguishing between patients with dry mouth and those with Sjögren's syndrome.


Structure and promoter analysis of Math3 gene, a mouse homolog of Drosophila proneural gene atonal. Neural-specific expression by dual promoter elements.
ath3, a vertebrate basic helix-loop-helix gene homologous to Drosophila proneural gene atonal, can directly convert non-neural cells into neurons with the anterior features. In the mouse, ath3 expression initially occurs widely in the developing nervous system and then gradually becomes restricted to the neural retina. Here, we characterized the genomic organization and promoter activity of mouse ath3 (Math3). Math3 gene consists of two exons separated by an 8-kilobase intron, and the whole protein-coding region is located in the second exon. Transcription starts at two sites, which are 75 nucleotides apart from each other, and there is no typical TATA box in the upstream region of either start site. Transient transfection analysis showed that the 5'-region of Math3 can direct efficient expression in neuroblastoma cells but not in glioma or fibroblast cells. Deletion studies revealed that the proximal 193-base pair region, which contains the downstream transcription initiation site but not the upstream site, is essential for the Math3 promoter activity and can direct efficient expression in neuroblastoma cells. In contrast, retrovirus-mediated promoter analysis demonstrated that a region further upstream is additionally necessary for retinal expression. These results indicate that Math3 promoter contains two essential regulatory regions, the proximal 193-base pair region, which confers efficient neural-specific expression, and a region further upstream, required for retinal expression.


Fluid mechanics of eating, swallowing and digestion - overview and perspectives.
From a very simplistic viewpoint, the human digestive system can be regarded as a long tube (with dramatic variations in diameter, cross-section, wall properties, pumping mechanisms, regulating valves and in-line sensors). We single out a few fluid mechanical phenomena along the trajectory of a food bolus from the mouth to the small intestine and discuss how they influence sensorial perception, safe transport, and nutrient absorption from a bolus. The focus is on lubrication flows between the tongue and palate, the oropharyngeal stage of swallowing and effects of flow on absorption in the small intestine. Specific challenges and opportunities in this research area are highlighted.


Robust passive and active efflux of cellular cholesterol to a designer functional mimic of high density lipoprotein.
The ability of HDL to support macrophage cholesterol efflux is an integral part of its atheroprotective action. Augmenting this ability, especially when HDL cholesterol efflux capacity from macrophages is poor, represents a promising therapeutic strategy. One approach to enhancing macrophage cholesterol efflux is infusing blood with HDL mimics. Previously, we reported the synthesis of a functional mimic of HDL (fmHDL) that consists of a gold nanoparticle template, a phospholipid bilayer, and apo A-I. In this work, we characterize the ability of fmHDL to support the well-established pathways of cellular cholesterol efflux from model cell lines and primary macrophages. fmHDL received cell cholesterol by unmediated (aqueous) and ABCG1- and scavenger receptor class B type I (SR-BI)-mediated diffusion. Furthermore, the fmHDL holoparticle accepted cholesterol and phospholipid by the ABCA1 pathway. These results demonstrate that fmHDL supports all the cholesterol efflux pathways available to native HDL and thus, represents a promising infusible therapeutic for enhancing macrophage cholesterol efflux. fmHDL accepts cholesterol from cells by all known pathways of cholesterol efflux: unmediated, ABCG1- and SR-BI-mediated diffusion, and through ABCA1.


Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes.
We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations. We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design. Fasting (7.3 +/- 0.5 vs. 7.9 +/- 0.5 mmol/l) and peak postprandial (14.1 +/- 0.6 vs. 15.9 +/- 0.9 mmol/l) glucose concentrations were lower (P < 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 +/- 1.6 vs. 23.7 +/- 1.3 mg/ml per 5 h, P < 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 +/- 270 vs. 1,277 +/- 312 pmol/l per 5 h, P = 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments. Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.


Generalized Redistribute-to-the-Right Algorithm: Application to the Analysis of Censored Cost Data.
Medical cost estimation is a challenging task when censoring of data is present. Although researchers have proposed methods for estimating mean costs, these are often derived from theory and are not always easy to understand. We provide an alternative method, based on a replace-from-the-right algorithm, for estimating mean costs more efficiently. We show that our estimator is equivalent to an existing one that is based on the inverse probability weighting principle and semiparametric efficiency theory. We also propose an alternative method for estimating the survival function of costs, based on the redistribute-to-the-right algorithm, that was originally used for explaining the Kaplan-Meier estimator. We show that this second proposed estimator is equivalent to a simple weighted survival estimator of costs. Finally, we develop a more efficient survival estimator of costs, using the same redistribute-to-the-right principle. This estimator is naturally monotone, more efficient than some existing survival estimators, and has a quite small bias in many realistic settings. We conduct numerical studies to examine the finite sample property of the survival estimators for costs, and show that our new estimator has small mean squared errors when the sample size is not too large. We apply both existing and new estimators to a data example from a randomized cardiovascular clinical trial.


A model for (re)building consumer trust in the food system.
The article presents a best practice model that can be utilized by food system actors to assist with (re)building trust in the food system, before, during and after a food incident defined as 'any situation within the food supply chain where there is a risk or potential risk of illness or confirmed illness or injury associated with the consumption of a food or foods' (Commonwealth of Australia. National Food Incident Response Protocol. Commonwealth of Australia, Canberra, 2012). Interviews were undertaken with 105 actors working within the media, food industry and food regulatory settings across Australia, New Zealand (NZ) and the United Kingdom (UK). Interview data produced strategy statements, which indicated participant views on how to (re)build consumer trust in the food system. These included: (i) be transparent, (ii) have protocols and procedures in place, (iii) be credible, (iv) be proactive, (v) put consumers first, (vi) collaborate with stakeholders, (vii) be consistent, (viii) educate stakeholders and consumers, (ix) build your reputation and (x) keep your promises. A survey was designed to enable participants to indicate their agreement/disagreement with the ideas, rate their importance and provide further comment. The five strategies considered key to (re)building consumer trust were used to develop a model demonstrating best practice strategies for (re)building consumer trust in the food system before, during and after a food incident. In a world where the food system is increasingly complex, strategies for (re)building and fostering consumer trust are important. This study offers a model to do so which is derived from the views and experiences of actors working across the food industry, food regulation and the media.


Proteinuria and leg ulcers in homozygous sickle cell disease.
In a survey of 407 patients with homozygous sickle cell disease in Jamaica, 50 had proteinuria of '+' or more on dipstick testing and 231 had had leg ulcers. Both proteinuria and ulcers began to occur mainly in the second decade of life and their prevalence increased with age thereafter. When allowance was made for this there was no significant association between the two, and it is therefore likely that they result from independent effects of the haemoglobinopathy on the kidneys and skin. Though asymptomatic and relatively common, proteinuria in sickle cell disease is not a benign finding since it is associated with renal failure in patients over 40 years old.


Postmortem findings in suicide victims. Implications for in vivo imaging studies.
Alterations in serotonergic and noradrenergic receptor binding in membrane homogenates from the brain of suicide victims suggest a biological substrate for the vulnerability to commit suicide. We and others have employed high-resolution quantitative autoradiography of full coronal sections of the prefrontal cortex to map the locus of maximal change in receptor binding. We found alterations in binding to the serotonin transporter, the 5-HT1A, and the 5-HT2A receptors primarily in the ventral and ventrolateral prefrontal cortex of suicide victims. Importantly, these changes are often modest in magnitude and anatomically restricted to one or two Brodmann areas. Furthermore, we have found that care in case selection is essential, because sex, age, drugs, and comorbid diagnoses contribute to receptor binding. The implications for in vivo imaging are considerable, directing the focus of such studies toward the ventrolateral prefrontal cortex. However, because ligands are limited, as is the resolution of current methods, including PET, automated analyses that produce statistical images, rather than manual selection of individual slices, will likely lack the ability to detect the discrete receptor changes found postmortem. Alternatively, the advantages of examining large numbers of subjects, imaging the entire brain, obtaining detailed clinical information in the living patient, and magnifying the changes with neuropharmacological challenges present a promising outlook for making major advances into the identification of brain abnormalities associated with suicide risk.


[Experimental and clinicolaboratory evaluation of complex therapy efficacy in arboviral infections].
Search for drugs efficient in prophylaxis and treatment of dangerous infections (especially arboviral ones) is rather actual, since no specific therapy is available. Many-year investigations of interferon inductors showed that they had immunomodulating, antiviral and antiinflammatory effects and were low toxic. The present study demonstrated that the protective effect was the following: Venezuelan equine encephalitis (VEE)--cycloferon > amixin = ridostin, Rift Valley fever (RVF)--cycloferon > amixin > ridostin, predator pox (PP)--cycloferon > amixin = ridostin, that was obvious that cycloferon was the most active agent in the treatment of VEE, RVF and PP, thus making it possible to acknowledge its priority in prophylaxis and therapy of dangerous viral infections (DVI). Ribavirin in combination with cycloferon solution or cycloferon tablets provided shorter periods of the fever, minimized the intoxication syndrome, promoted earlier resolution of hemorrhagic eruption and lowered the frequency of complications, which was in favour of the disease prognosis.


Assessment of Autonomic Dysfunction in Acute Stroke Patients at a Tertiary Care Hospital.
In patients who present with acute cerebro-vascular disease, autonomic function testing is usually not given its due importance. This is because of the complex nature of the autonomic function tests and the relative technical difficulty faced in administering the tests to the patients. A simple and non-invasive method to assess the autonomic dysfunction is measurement of resting Heart Rate Variability (HRV). To study the pattern of autonomic dysfunction among patients admitted with acute stroke and to study the relationship between autonomic dysfunction and the morbidity and mortality associated with acute stroke. The study was carried out on 97 patients who were admitted with diagnosis of acute stroke. Patients with conduction abnormalities on ECG were excluded from the study. Resting ECG tracings were obtained for a period of 5 minutes. The frequency domain analysis of HRV was performed by a Fast Fourier transform of the RR intervals. The High Frequency (HF) was representative of the parasympathetic activity while low frequency is representative of baroreceptor mediated parasympathetic and sympathetic activity and Low Frequency (LF)/HF ratio was a measure of the sympathovagal balance. Statistical analysis was carried out with student's t-test and chi-square test and p-value ≥ 0.05 was taken to be statistically significant. The mean age of the patients was 60.84±14.12 years. A total of 41 patients were females and 77 patients had ischemic stroke. Out of the total 97, 60 patients had evidence suggestive of increased sympathetic activity with a mean LF/HF ratio of 2.03±0.88. These patients had significantly higher mean systolic BP, diastolic BP and National Institute of Health Stroke Scale (NIHSS) values when compared to patients with reduced LF/HF ratio (166.33±24.81 vs 148.54±19.42, p=0.0003, 100.33±18.73 vs 88.76±12.66, p=0.0013, 15.77±8.22 vs 11.49±6.63, p=0.0088 respectively). These patients also had a higher mortality rate. This study highlights the problem of autonomic dysfunction among patients with stroke. Patients with autonomic dysfunction had higher morbidity and mortality in the acute phase of stroke in this study and also had higher blood pressure readings. This is a small scale study whose findings need to be validated further by larger population studies.


Regulation of renin secretion and arterial pressure during prolonged baroreflex activation: influence of salt intake.
Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as antihypertensive therapy for patients with resistant hypertension. However, the influence of variations in salt intake on blood pressure lowering during baroreflex activation (BA) has not yet been determined. As the sensitivity of arterial pressure to salt intake is linked to the responsiveness of renin secretion, we determined steady-state levels of arterial pressure and neurohormonal responses in 6 dogs on low, normal, and high salt intakes (5, 40, 450 mmol/d, respectively) under control conditions and during a 7-day constant level of BA. Under control conditions, there was no difference in mean arterial pressure at low (92±1) and normal (92±2 mm Hg) sodium intakes, but pressure increased 9±2 mm Hg during high salt. Plasma renin activity (2.01±0.23, 0.93±0.20, 0.01±0.01 ng angiotensin I/mL/h) and plasma aldosterone (10.3±1.9, 3.5±0.5, 1.7±0.1 ng/dL) were inversely related to salt intake, whereas there were no changes in plasma norepinephrine. Although mean arterial pressure (19-22 mm Hg) and norepinephrine (20%-40%) were lower at all salt intakes during BA, neither the changes in pressure nor the absolute values for plasma renin activity or aldosterone in response to salt were different from control conditions. These findings demonstrate that suppression of sympathetic activity by BA lowers arterial pressure without increasing renin release and indicate that changes in sympathetic activity are not primary mediators of the effect of salt on renin secretion. Consequently, blood pressure lowering during BA is independent of salt intake.


Ambient ultrafine particles provide a strong adjuvant effect in the secondary immune response: implication for traffic-related asthma flares.
We have previously demonstrated that intranasal administration of ambient ultrafine particles (UFP) acts as an adjuvant for primary allergic sensitization to ovalbumin (OVA) in Balb/c mice. It is important to find out whether inhaled UFP exert the same effect on the secondary immune response as a way of explaining asthma flares in already-sensitized individuals due to traffic exposure near a freeway. The objective of this study is to determine whether inhalation exposure to ambient UFP near an urban freeway could enhance the secondary immune response to OVA in already-sensitized mice. Prior OVA-sensitized animals were exposed to concentrated ambient UFP at the time of secondary OVA challenge in our mobile animal laboratory in Los Angeles. OVA-specific antibody production, airway morphometry, allergic airway inflammation, cytokine gene expression, and oxidative stress marker were assessed. As few as five ambient UFP exposures were sufficient to promote the OVA recall immune response, including generating allergic airway inflammation in smaller and more distal airways compared with the adjuvant effect of intranasally instilled UFP on the primary immune response. The secondary immune response was characterized by the T helper 2 and IL-17 cytokine gene expression in the lung. In summary, our results demonstrated that inhalation of prooxidative ambient UFP could effectively boost the secondary immune response to an experimental allergen, indicating that vehicular traffic exposure could exacerbate allergic inflammation in already-sensitized subjects.


[Statistical analysis of pharmacological data: a proposal for the data analysis of repeated measurements].
This paper considers the method of data analysis for a pharmacological experiment with multiple dose groups, in which a response variable is observed repeatedly at several time periods. The in-appropriateness of conventionally used statistical methods such as the t-test, Dunnett's multiple comparison procedure and analysis of variance method is pointed out. We recommended that the dose-response relationship should be estimated as a response function of time incorporating the dose effect as parameters. We also propose to adopt a strategy that the researcher tests some hypotheses on the parameters in the response function appropriate to the objective of the experiment after estimating parameters of the response function based on the observed data. A numerical example applying the strategy to real data is presented.


HIV prevalence and risk behaviours among men having sex with men in Nigeria.
To evaluate HIV and syphilis prevalence among men who have sex with men (MSM) in Nigeria, and assess their HIV-related risk behaviours and exposure to HIV prevention interventions. Cross-sectional study using respondent-driven sampling conducted in Lagos, Kano and Cross River states, Nigeria, between July and September 2007. A total of 879 MSM participated, 293 from each state. Eight participants (1.1%, CI 0.1% to 2.2%) in Cross River, 27 (9.3%, CI 5.7% to 15.4%) in Kano and 74 (17.4%, CI 12.3% to 23.2%) in Lagos tested positive for HIV. No syphilis was detected. The median age was 22 years. MSM reported an average of 4.2 male anal sex partners in the past 6 months. Between 24.4% (Lagos) and 36.0% (Kano) of MSM reported selling sex to other men. Up to 49.7% of MSM reported sex with a girlfriend and ≤ 6.5% purchased sex from female sex workers. Consistent condom use in commercial sex with other men over the past 6 months ranged from 28.0% (Cross River) to 34.3% (Kano), in contrast to between 23.9% (Kano) and 45.8% (Lagos) for non-commercial sex. Associations with HIV positivity included age in the three states, having been the receptive partner in anal sex in the past 6 months in Lagos and in Lagos and Kano feeling at risk of HIV. Large differentials in HIV prevalence between states together with high mobility, inconsistent condom use and behavioural links with female sex partners, have the potential for further HIV transmission within MSM networks, and between MSM and the general population.


Further analysis of the Crouzon mouse: effects of the FGFR2(C342Y) mutation are cranial bone-dependent.
Crouzon syndrome is a debilitating congenital disorder involving abnormal craniofacial skeletal development caused by mutations in fibroblast growth factor receptor-2 (FGFR2). Phenotypic expression in humans exhibits an autosomal dominant pattern that commonly involves premature fusion of the coronal suture (craniosynostosis) and severe midface hypoplasia. To further investigate the biologic mechanisms by which the Crouzon syndrome-associated FGFR2(C342Y) mutation leads to abnormal craniofacial skeletal development, we created congenic BALB/c FGFR2(C342Y/+) mice. Here, we show that BALB/c FGFR2(C342Y/+) mice have a consistent craniofacial phenotype including partial fusion of the coronal and lambdoid sutures, intersphenoidal synchondrosis, and multiple facial bones, with minimal fusion of other craniofacial sutures. This phenotype is similar to the classic and less severe form of Crouzon syndrome that involves significant midface hypoplasia with limited craniosynostosis. Linear and morphometric analyses demonstrate that FGFR2(C342Y/+) mice on the BALB/c genetic background differ significantly in form and shape from their wild-type littermates and that in this genetic background the FGFR2(C342Y) mutation preferentially affects some craniofacial bones and sutures over others. Analysis of cranial bone cells indicates that the FGFR2(C342Y) mutation promotes aberrant osteoblast differentiation and increased apoptosis that is more severe in frontal than parietal bone cells. Additionally, FGFR2(C342Y/+) frontal, but not parietal, bones exhibit significantly diminished bone volume and density compared to wild-type mice. These results confirm that FGFR2-associated craniosynostosis occurs in association with diminished cranial bone tissue and may provide a potential biologic explanation for the clinical finding of phenotype consistency that exists between many Crouzon syndrome patients.


CRM1 mediates nuclear export of nonstructural protein 2 from parvovirus minute virus of mice.
The nonstructural protein 2 (NS2) from parvovirus minute virus of mice (MVMp) is a 25-kDa polypeptide which localizes preferentially to the cytoplasm and associates with cellular proteins in cytoplasm. These lines of evidence suggest that NS2 is positively exported from the nucleus to cytoplasm and functions in cytoplasm. We report here that nuclear export of NS2 is inhibited by leptomycin B (LMB), a drug that specifically blocks nuclear export signal (NES)-chromosomal region maintenance 1 (CRM1) interactions. CRM1 binds specifically to the 81- to 106-amino-acid (aa) region of NS2, and the region of NS2 actually functions as a NES. Interestingly, this region appears to be distinct from a typical NES sequence, which consists of leucine-rich sequences. These results indicate that NS2 protein is continuously exported from the nucleus by a CRM1-dependent mechanism and suggest that CRM1 also exports to distinct type of NESs.


Correlation between androstenedione and 17-hydroxyprogesterone levels in the saliva and plasma of patients with congenital adrenal hyperplasia.
Congenital adrenal hyperplasia (CAH) or adrenogenital syndrome is the most common cause of female ambiguous genitalia. Management of such patients involves medical treatment using glucocorticoids such as hydrocortisone, prednisone or dexamethasone. Monitoring is done by measurement of 17-hydroxyprogesterone (17-OHP) or androstenedione in serum, plasma or saliva. The aim of this study was to develop a system of monitoring steroid treatment in CAH patients using only saliva. We studied the saliva of 24 CAH patients who received glucocorticoid replacement therapy. The patients were asked to collect saliva upon awakening, and in the afternoon and evening. The levels of 17-OHP and androstenedione in the saliva as well as in serum were then measured by immunoassay. There was a significant positive correlation between 17-OHP in serum and in saliva (R equals 0.929, p-value less than 0.01). A significant positive correlation between androstenedione level in saliva and serum was also found (R equals 0.611, p-value less than 0.01). This study also revealed a significant positive correlation between androstenedione and 17-OHP in serum (R equals 0.647, p-value less than 0.01) and saliva (R equals 0.799, p-value less than 0.01). All patients showed increased level of 17-OHP and androstenedione in the sample collected upon awakening. Determination of salivary androstenedione and 17-OHP in CAH patients could be a useful alternative to the measurement of these hormones in serum.


The effect of malaria on stunting: an instrumental variables approach.
Previous studies have found mixed evidence for an effect of malaria on stunting, but have suffered from concerns about confounding and/or power. Currently, an effect of malaria on stunting is not included in the Lives Saved Tool (LiST) model. We used instrumental variables regression with the sickle cell trait and random assignment to bednets as instruments in the analysis of data on children aged 0-2 y from a bednet trial in western Kenya. We estimated that one additional clinical malaria episode per year increases the odds of a child being stunted by 6% (OR estimate: 1.06, 95% CI 1.01 to 1.11). Our finding that malaria affects stunting suggests that an effect of malaria on stunting in young children should be considered in the LiST model.


Principle of the moving-mirror-pair interferometer and the tilt tolerance of the double moving mirror.
A novel type of interferometer, the moving-mirror-pair interferometer, is presented, and its principle and properties are studied. The new interferometer is built with three flat mirrors, which include two flat moving mirrors fixed as a single moving part by a rigid structure and one flat fixed mirror. The optical path difference (OPD) is obtained by the straight reciprocating motion of the double moving mirror, and the OPD value is four times the physical shift value of the double moving mirror. The tilt tolerance of the double moving mirror of the novel interferometer is systematically analyzed by means of modulation depth and phase error. Where the square aperture is concerned, the formulas of the tilt tolerance were derived. Due to the novel interferometer's large OPD value and low cost, it is very applicable to the high-spectral-resolution Fourier-transform spectrometers for any wavenumber region from the far infrared to the ultraviolet.


Selective Allosteric Modulation of N-Terminally Cleaved, but Not Full Length CCL3 in CCR1.
Chemokines undergo post-translational modification such as N-terminal truncations. Here, we describe how N-terminal truncation of full length CCL3(1-70) affects its activity at CCR1. Truncated CCL3(5-70) has 10-fold higher potency and enhanced efficacy in β-arrestin recruitment, but less than 2-fold increased potencies in G protein signaling determined by calcium release, cAMP and IP3 formation. Small positive ago-allosteric ligands modulate the two CCL3 variants differently as the metal ion chelator bipyridine in complex with zinc (ZnBip) enhances the binding of truncated, but not full length CCL3, while a size-increase of the chelator to a chloro-substituted terpyridine (ZnClTerp), eliminates its allosteric, but not agonistic action. By employing a series of receptor mutants and in silico modeling we describe residues of importance for chemokine and small molecule binding. Notably, the chemokine receptor-conserved Glu2877.39 interacts with the N-terminal amine of truncated CCL3(5-70) and with Zn2+ of ZnBip, thereby bridging their binding sites and enabling the positive allosteric effect. Our study emphasizes that small allosteric molecules may act differently toward chemokine variants and thus selectively modulate interactions of specific chemokine subsets with their cognate receptors.


A Multi-Sensor Stochastic Energy-Based Vibro-Localization Technique with Byzantine Sensor Elimination.
This paper presents an occupant localization technique that determines the location of individuals in indoor environments by analyzing the structural vibrations of the floor caused by their footsteps. Structural vibration waves are difficult to measure as they are influenced by various factors, including the complex nature of wave propagation in heterogeneous and dispersive media (such as the floor) as well as the inherent noise characteristics of sensors observing the vibration wavefronts. The proposed vibration-based occupant localization technique minimizes the errors that occur during the signal acquisition time. In this process, the likelihood function of each sensor-representing where the occupant likely resides in the environment-is fused to obtain a consensual localization result in a collective manner. In this work, it becomes evident that the above sources of uncertainties can render certain sensors deceptive, commonly referred to as "Byzantines." Because the ratio of Byzantines among the set sensors defines the success of the collective localization results, this paper introduces a Byzantine sensor elimination (BSE) algorithm to prevent the unreliable information of Byzantine sensors from affecting the location estimations. This algorithm identifies and eliminates sensors that generate erroneous estimates, preventing the influence of these sensors on the overall consensus. To validate and benchmark the proposed technique, a set of previously conducted controlled experiments was employed. The empirical results demonstrate the proposed technique's significant improvement (3~0%) over the baseline approach in terms of both accuracy and precision.


Combined Loss of Ghrelin Receptor and Cannabinoid CB1 Receptor in Mice Decreases Survival but does not Additively Reduce Body Weight or Eating.
Ghrelin administration increases food intake, body weight (BW), adiposity, and blood glucose. In contrast, although mouse models lacking ghrelin or its receptor (Growth Hormone Secretagogue Receptor (GHSR)) exhibit life-threatening hypoglycemia in starvation-like states, they do not exhibit appreciable reductions in food intake, BW, adiposity, blood glucose, or survival when food availability is unrestricted. This suggests the existence of a parallel neuromodulatory system that can compensate for disruptions in the ghrelin system in certain settings. Here, we hypothesized that the cannabinoid CB1 receptor (CB1R) may encode this putative redundancy, and as such, that genetic deletion of both GHSR and CB1R would exaggerate the metabolic deficits associated with deletion of GHSR alone. To test this hypothesis, we assessed food intake, BW, blood glucose, survival, and plasma acyl-ghrelin in ad libitum-fed male wild-type mice and those that genetically lack GHSR (GHSR-nulls), CB1R (CB1R-nulls), or both GHSR and CB1R (double-nulls). BW, fat mass, and lean mass were similar in GHSR-nulls and wild-types, lower in CB1R-nulls, but not further reduced in double-nulls. Food intake, plasma acyl-ghrelin, and blood glucose were similar among genotypes. Deletion of either GHSR or CB1R alone did not have a statistically-significant effect on survival, but double-nulls demonstrated a statistical trend towards decreased survival (p = 0.07). We conclude that CB1R is not responsible for the normal BW, adiposity, food intake, and blood glucose observed in GHSR-null mice in the setting of unrestricted food availability. Nor is CB1R required for plasma acyl-ghrelin secretion in that setting. However, GHSR may be protective against exaggerated mortality associated with CB1R deletion.


Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site.
Proper hedgehog (Hh) signaling is crucial for embryogenesis and tissue regeneration. Dysregulation of this pathway is associated with several types of cancer. The monoclonal antibody 5E1 is a Hh pathway inhibitor that has been extensively used to elucidate vertebrate Hh biology due to its ability to block binding of the three mammalian Hh homologs to the receptor, Patched1 (Ptc1). Here, we engineered a murine:human chimeric 5E1 (ch5E1) with similar Hh-binding properties to the original murine antibody. Using biochemical, biophysical, and x-ray crystallographic studies, we show that, like the regulatory receptors Cdon and Hedgehog-interacting protein (Hhip), ch5E1 binding to Sonic hedgehog (Shh) is enhanced by calcium ions. In the presence of calcium and zinc ions, the ch5E1 binding affinity increases 10-20-fold to tighter than 1 nm primarily because of a decrease in the dissociation rate. The co-crystal structure of Shh bound to the Fab fragment of ch5E1 reveals that 5E1 binds at the pseudo-active site groove of Shh with an epitope that largely overlaps with the binding site of its natural receptor antagonist Hhip. Unlike Hhip, the side chains of 5E1 do not directly coordinate the Zn(2+) cation in the pseudo-active site, despite the modest zinc-dependent increase in 5E1 affinity for Shh. Furthermore, to our knowledge, the ch5E1 Fab-Shh complex represents the first structure of an inhibitor antibody bound to a metalloprotease fold.


Good Bugs vs Bad Bugs: Evaluation of Inhibitory Effect of Selected Probiotics against Enterococcus faecalis.
The main goal of endodontics is the prevention of apical periodontitis. This is due to the presence of persistent pathogenic microorganisms, such as Enterococcus faecalis, and its ability to directly cause acute and chronic inflammation in the periapical tissues. Lactobacillus has been shown to promote health in the intestines as well as to inhibit the growth of certain problematic oral bacteria. This study explores shifting the established paradigm of endodontic treatment, which has focused on eliminating all bacteria from the canal system and on elimination of the problematic bacteria through introducing probiotics. A preliminary work was performed to evaluate the possible effectiveness of probiotics in preventing the growth of E. faecalis. Two probiotic cultures Lactobacillus plantarum ATCC 8041 and Lactobacillus rhamnosus ATCC 7408 were selected to check their antimicrobial activity against E. faecalis ATCC 29212 by two methods: agar cup/well diffusion method and deferred antagonism test. Agar cup method: A total of 0.5 mL of requisite test pathogen culture was inoculated into 20 mL of molten sterile Mueller and Hinton agar and cooled to 45 ± 2°C. Circular wells of diameter 10 mm were punched in each of the poured plates. Appropriately diluted test samples were added to the above-punched wells. The plates were incubated upright position at 37°C for 24 hours in aerobic conditions. Postincubation, zone of inhibition was measured. The cell-free supernatant of Lactobacillus species was also evaluated for antimicrobial activity. Deferred antagonism test: The test probiotic strain was standardized to 0.1 optical density (OD) at 600 nm and inoculated in a 1 cm wide diametric streak across the surface of trypticase soy agar + yeast extract + calcium carbonate (TSYCa) agar using a sterile cotton swab. Then, the plate agar containing the test strain was incubated at 37°C for 24 hours under aero-philic condition and then standardized to 0.1 OD at 600 nm for overnight (18 hours, 37°C). A purified culture of indicator strain (pathogen) was streaked at right angles to the line of original producer growth. Postincubation plates were observed for the inhibition zone width of the indicator strain. Under the conditions of this study, Lactobacilli had an inhibitory effect on the growth of E. faecalis by agar cup method but not by deferred antagonism test. This pilot study demonstrated that probiotics show a potential in root canal therapy. If probioitcs are effective against end-odontic pathogens, they can be potentially used as intracanal medicaments. This will be a novel concept of introducing bac-teriotherapy in endodontics and replacing pathogenic bacteria by healthy bacteria, normal flora.


Estrogen blocks homocysteine-induced endothelial dysfunction in porcine coronary arteries(1,2).
The objective of this study was to examine the effect of estrogen combined with homocysteine on vasomotor function and endothelial integrity in intact porcine coronary arteries. Pig coronary artery rings were incubated with estrogen, homocysteine, or estrogen and homocysteine for 24 h. Myographic analysis was performed with thromboxane A2 analog U46619 for contraction and bradykinin or sodium nitroprusside for relaxation. Endothelial nitric oxide synthase (eNOS) levels were determined by immunohistochemistry. Levels of superoxide anion were assessed by lucigenin-enhanced chemiluminescence analysis. Endothelium-dependent vasorelaxation (bradykinin) for the homocysteine alone group was 62% compared with control (P < 0.05), and endothelium-dependent vasorelaxation for the estrogen alone group was 85% compared with control (P > 0.05). Endothelium-dependent vasorelaxation for the estrogen-homocysteine combined group was 79% compared with 89% for control (P > 0.05). There were no differences in endothelium-independent vasorelaxation (sodium nitroprusside) or in smooth muscle contractility (U46619) between all three groups and control. In addition, the eNOS immunoreactivity was declined in the homocysteine group and had no major change in the estrogen or estrogen plus homocysteine-treated group as compared with controls. The superoxide free radical measurement showed a marked increase in the homocysteine group, no major change from controls in the estrogen group, and a much-lessened effect in the combination of estrogen and homocysteine. These data demonstrate that combining estrogen with homocysteine significantly blocks the effect of homocysteine on impairing endothelium-dependent vasorelaxation as well as on decreasing eNOS expression and increasing oxidative stress in porcine coronary arteries. This study suggests that estrogen may play a role in preventing homocysteine-mediated endothelial dysfunction and may be of benefit in the hyperhomocysteinemic patient.


Polycystic ovary syndrome in adolescent girls.
Polycystic ovary syndrome (PCOS) has traditionally been thought of as a triad of oligomenorrhea, hirsutism, and obesity. PCOS is now recognized as a heterogeneous disorder that results in overproduction of androgens primarily from the ovary leading to anovulation and hirsutism and is associated with insulin resistance. Symptoms in the adolescent include oligomenorrhea, hirsutism, acne, and weight gain. These symptoms are often attributed to normal pubertal events, which can lead to a delay in diagnosis. Insulin resistance, impaired glucose tolerance and diabetes have been shown to occur in adolescents with PCOS. Treatment should be instituted early to decrease symptoms and long-term sequellae of PCOS. Weight loss, oral contraceptives and antiandrogens are very effective in treating the symptoms of this disorder. Insulin-sensitizing medications show promise, but should be used with caution until larger randomized trials have shown short- and long-term benefit and efficacy over traditional therapies in the adolescent population.


Duplex high-throughput flow cytometry screen identifies two novel formylpeptide receptor family probes.
Of recent, clinical interest have been two related human G-protein coupled receptors: formylpeptide receptor (FPR), linked to antibacterial inflammation and malignant glioma cell metastasis; and FPR like-1 (FPRL1), linked to chronic inflammation in systemic amyloidosis, Alzheimer's disease, and prion diseases. In association with the National Institutes of Health (NIH) Molecular Library Screening Network, we implemented a flow-cytometry-based high-throughput screening (HTS) approach for identifying selective small molecule FPR and FPRL1 ligands. The screening assay measured the ability of test compounds to competitively displace a high-affinity, fluorescein- labeled peptide ligand from FPR, FPRL1, or both. U937 cells expressing FPR and rat basophil leukemia (RBL) cells expressing FPRL1 were tested together in a "duplex" format. The U937 cells were color coded with red-fluorescent dye allowing their distinction during analysis. Compounds, cells, and fluorescent ligand were sequentially combined (no wash) in 15 microl assay volumes in 384-well plates. Throughput averaged approximately 11 min per plate to analyze approximately 4,000 cells ( approximately 2,000/receptor) in a 2 microl aspirate from each well. In primary single concentration HTS of 24,304 NIH Small Molecule Repository compounds, 253 resulted in inhibition >30% (181 for FPR, 72 for FPRL1) of which 40 had selective binding inhibition constants (K(i)) < or = 4 microM (34 for FPR and 6 for FPRL1). An additional 1,446 candidate compounds were selected by structure-activity-relationship analysis of the hits and screened to identify novel ligands for FPR (3570-0208, K(i) = 95 +/- 10 nM) and FPRL1 (BB-V-115, K(i) = 270 +/- 51 nM). Each was a selective antagonist in calcium response assays and the most potent small molecule antagonist reported for its respective receptor to date. The duplex assay format reduced assay time, minimized reagent requirements, and provided selectivity information at every screening stage, thus proving to be an efficient means to screen for selective receptor ligand probes.


[Hexane-2,5-dione bis-(thio-semi-carba-zon-ato)]nickel(II).
In the title compound, [Ni(C8H14N6S2)], the Ni(II) ion is coordinated by N2S2 donor atoms of the tetradentate thio-semicarbazone ligand, and has a slightly distorted square-planar geometry. In the crystal, inversion-related mol-ecules are linked via pairs of N-H⋯N and N-H⋯S hydrogen bonds, forming R 2 (2)(8) ring motifs. Mol-ecules are further linked by slightly weaker N-H⋯N, N-H⋯S and C-H⋯S hydrogen bonds, forming two-dimensional networks which lie parallel to the bc plane.


Arylallenes and the halogeno-B(C6F5)2 reagents: facile formation of 2-borylindenes.
Phenylallene reacts rapidly with ClB(C6F5)2 to give the respective 2-borylindene. Several substituted allenylarenes form the respective 2-B(C6F5)2 boryl-substituted indenes upon treatment with ClB(C6F5)2 or BrB(C6F5)2 as well. Bis- and tris-allenylarenes form the corresponding products featuring multiple five-membered ring annulations, including a symmetrical tris-borylated dihydro-1H-trindene derivative. The B(C6F5)2 borylindenes show fluorescence properties.


Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist.
CTL-associated antigen 4 (CTLA-4) engagement negatively regulates T cell activation and function and promotes immune tolerance. However, it has been difficult to explore the biology of selective engagement of CTLA-4 in vivo because CTLA-4 shares its ligands, B7-1 and B7-2, with CD28. To address this issue, we developed a Tg mouse expressing a single-chain, membrane-bound anti-CTLA-4 Ab (scFv) on B cells. B and T cells developed normally and exhibited normal phenotype in the steady state and after activation in these mice. However, B cells from scFv Tg+ mice (scalphaCTLA4+) prevented T cell proliferation and cytokine production in mixed lymphocyte reactions. Additionally, mice treated with scalphaCTLA4+ B cells had decreased T cell-dependent B cell Ab production and class switching in vivo after antigen challenge. Furthermore, expression of this CTLA-4 agonist protected NOD mice from spontaneous autoimmune diabetes. Finally, this disease prevention occurred in Treg-deficient NOD.B7-1/B7-2 double-knockout mice, suggesting that the effect of the CTLA-4 agonist directly attenuates autoreactive T cell activation, not Treg activation. Together, results from this study demonstrate that selective ligation of CTLA-4 attenuates in vivo T cell responses, prevents development of autoimmunity, and represents a novel immunotherapeutic approach for the induction and maintenance of peripheral tolerance.


Preliminary observations suggesting that treatment with modafinil improves fatigue in patients with orthostatic intolerance.
Many patients who suffer from orthostatic intolerance (OI) may also have severe fatigue and extreme exercise intolerance. In some of these patients, fatigue may be so severe that they are unable to maintain employment. In some, even the activities of the daily living may be compromised. We report on the use of modafinil in a subgroup of patients who failed therapy with commonly used medication for fatigue in patients with OI. The study was approved by the institutional review board. A retrospective nonrandomized analysis was preformed on 60 patients evaluated at our autonomic center for OI from 2003 to 2010. The diagnosis of OI was based on patient history, physical examination, and reponse to head up tilt table testing. All these patients had fatigue as their predominant symptom. Multiple trials of stimulants including methylphenidate, amphetamine, or dextroamphetamine failed to provide symptomatic relief of fatigue in these patients. Each patient received modafinil (100-200 mg daily). The mean follow-up period was 9 ± 3 months. A treatment was considered successful if it provided symptomatic relief from fatigue for the patient. Sixty patients, age 29 ± 15, 52 women were included in the analysis. Migraine (57%) and joint hypermobility syndrome (33%) were common comorbidities. Out of 60 patients, 40 patients reported initial improvement with initiation of modafinil therapy. Twenty patients reported no change in their symptoms of fatigue. Of the 40 patients who showed initial improvement in their symptoms 4 had eventual recurrence of fatigue after 3 months of modafinil therapy. Thirty-six patients continued to demonstrate symptom relief from fatigue for more than 6 months. In a selective group of patients of OI, modafinil may improve fatigue.


Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis.
Atherosclerosis is a chronic, inflammatory disorder characterized by the deposition of excess lipids in the arterial intima. The formation of macrophage-derived foam cells in a plaque is a hallmark of the development of atherosclerosis. Lipid homeostasis, especially cholesterol homeostasis, plays a crucial role during the formation of foam cells. Recently, lipid droplet-associated proteins, including PAT and CIDE family proteins, have been shown to control the development of atherosclerosis by regulating the formation, growth, stabilization and functions of lipid droplets in macrophage-derived foam cells. This review focuses on the potential mechanisms of formation of macrophage-derived foam cells in atherosclerosis with particular emphasis on the role of lipid homeostasis and lipid droplet-associated proteins. Understanding the process of foam cell formation will aid in the future discovery of novel therapeutic interventions for atherosclerosis.


Eosinophilic esophagitis: allergic contribution, testing, and management.
Both basic science and clinical data indicate a strong role for allergy as a cause of eosinophilic esophagitis. As a result, one of the desired goals of therapy is identification and elimination of food antigens that trigger the allergic inflammatory pathway. Traditional methods for identification of causative food antigens include induction of symptoms with exposure to the antigen, demonstration of serum IgE antibodies against antigens and induction of immediate (IgE) or delayed (Th2) reactions against dermal instillation of antigens. Although some data support the use of these tests in patients with eosinophilic esophagitis, they are limited in this disease. This limitation results from an inability to provoke recognizable symptoms and a lack of concordance between allergies identified in the skin and the blood with the antigens that trigger esophageal disease. As a result, allergy therapy in eosinophilic esophagitis consists of global elimination of food antigens with an elemental diet or exclusion of the most common antigens. As compliance is difficult with these strategies, the mainstay of allergy therapy in eosinophilic esophagitis has become the use of medications that blunt the allergic pathway such as steroids with a future aimed toward more specific inhibitors of this pathway in eosinophilic esophagitis specifically.


Ether- and ester-bound iso-diabolic acid and other lipids in members of acidobacteria subdivision 4.
Recently, iso-diabolic acid (13,16-dimethyl octacosanedioic acid) has been identified as a major membrane-spanning lipid of subdivisions 1 and 3 of the Acidobacteria, a highly diverse phylum within the Bacteria. This finding pointed to the Acidobacteria as a potential source for the bacterial glycerol dialkyl glycerol tetraethers that occur ubiquitously in peat, soil, lakes, and hot springs. Here, we examined the lipid composition of seven phylogenetically divergent strains of subdivision 4 of the Acidobacteria, a bacterial group that is commonly encountered in soil. Acid hydrolysis of total cell material released iso-diabolic acid derivatives in substantial quantities (11 to 48% of all fatty acids). In contrast to subdivisions 1 and 3 of the Acidobacteria, 6 out of the 7 species of subdivision 4 (excepting "Candidatus Chloracidobacterium thermophilum") contained iso-diabolic acid ether bound to a glycerol in larger fractional abundance than iso-diabolic acid itself. This is in agreement with the analysis of intact polar lipids (IPLs) by high-performance liquid chromatography-mass spectrometry (HPLC-MS), which showed the dominance of mixed ether-ester glycerides. iso-Diabolic acid-containing IPLs were not identified, because these IPLs are not released with a Bligh-Dyer extraction, as observed before when studying lipid compositions of subdivisions 1 and 3 of the Acidobacteria. The presence of ether bonds in the membrane lipids does not seem to be an adaptation to temperature, because the five mesophilic isolates contained a larger amount of ether lipids than the thermophile "Ca. Chloracidobacterium thermophilum." Furthermore, experiments with Pyrinomonas methylaliphatogenes did not reveal a major influence of growth temperature over the 50 to 69°C range.


AID Biology: A pathological and clinical perspective.
Activation-induced cytidine deaminase (AID), primarily expressed in activated mature B lymphocytes in germinal centers, is the key factor in adaptive immune response against foreign antigens. AID is responsible for producing high-affinity and high-specificity antibodies against an infectious agent, through the physiological DNA alteration processes of antibody genes by somatic hypermutation (SHM) and class-switch recombination (CSR) and functions by deaminating deoxycytidines (dC) to deoxyuridines (dU), thereby introducing point mutations and double-stranded chromosomal breaks (DSBs). The beneficial physiological role of AID in antibody diversification is outweighed by its detrimental role in the genesis of several chronic immune diseases, under non-physiological conditions. This review offers a comprehensive and better understanding of AID biology and its pathological aspects, as well as addresses the challenges involved in AID-related cancer therapeutics, based on various recent advances and evidence available in the literature till date. In this article, we discuss ways through which our interpretation of AID biology may reflect upon novel clinical insights, which could be successfully translated into designing clinical trials and improving patient prognosis and disease management.


Experimental infection of lambs with ovine adenovirus isolate RTS-151: clinical, microbiological, and serologic responses.
Twelve 1-week-old colostrum-deprived lambs that were inoculated with ovine adenovirus isolate RTS-151 developed a mild febrile response between postinoculation days (PID) 4 and 10. They were inactive and some had serous nasal discharges; their respiratory rates and efforts were increased. Virus was isolated from nasal secretions from PID 2 to PID 8. Virus also was isolated from tracheal fluid and lung tissue of most lambs at necropsy (between PID 2 and 12), but not from liver, kidney, small intestine, and feces, indicating that the infection was confined to the respiratory tract. Four control lambs remained healthy and neither virus nor serum antibody was detected.


Relationship between anthropometric and haematological parameters among third trimester pregnant women in Sokoto State, Northwest Nigeria.
The pregnancy state in a woman's life is a unique state in terms of the desirable physiological changes and the exciting reversal of the changes soon after the termination of the pregnancy. It is considered essential that to guarantee a good feto-maternal outcome the attainment of optimum anthropometric and haematological parameters are key. Our study assessed the anthropometric and haematological changes and also looked at the relationship that exists between these parameters among pregnant women.We carried out a cross-sectional descriptive study which considered 160 apparently healthy, singleton, third trimester pregnant women attending ANC at the State Specialist Hospital and 58 apparently healthy non-pregnant controls sourced from the Sokoto metropolis population. Each subject or control enrolled was contacted 3 times at 2 weekly intervals. And at each occasion they are assessed for changes in the anthropometric and haematological parameters. The response rate was 93.6% (3 pregnants and 11 controls were loss to follow up). The pregnant and control subgroups mean ages were 28.02 ± 6.81 years and 26.89 ± 5.84 years respectively (p = 0.265). Weekly weight gains of 0.48kg among the pregnant sub-group against 0.13kg obtained in the control group were recorded. BMI increase of about 0.19kg/m2 per week among the pregnant sub-group and only 0.05kg per week in the controls. 95% of the distribution of pregnant sub-group has haemoglobin and haematocrit of ≥8.9g/dL and ≥26% respectively. Among the pregnant sub-group, mean weekly haemoglobin and haematocrit drop of 0.24g/dL and 0.74% were respectively recorded. A steady rise in WBC was recorded but platelets counts dropped at an average of 5.04 x 103 /μL per week. A positive correlation between BMI and haemoglobin levels was observed (r > 0 and p < 0.05). No particular regularity in the relationship between BMI and WBC was noticed. We conclude that there was optimum weight gain and good haematological indices for those with good BMI during the third trimester of pregnancy. There was a positive correlation between BMI and plasma haemoglobin level but WBC showed no particular relationship with the anthropometric changes. We therefore, recommend that good education to improve the socio- economic wellbeing of the girl-child be encouraged to boost self sufficiency for better weight gains and to facilitate access to good healthcare so that the ideal anthropometric and haematological parameters can be achieved during pregnancy to guarantee good feto-maternal outcome.


[Vesicoureteral reflux in renal transplantation].
Frequency of vesicoureteral reflux (VUR) variants was studied with miction cystography in 40 patients with chronic renal insufficiency. In 8 (20%) patients VUR was in their kidneys. The kidney was transplanted in 30 patients. The rate of urological complications was compared in ureterocystostomy by our technique and other procedures. In patients operated by our technique VUR did not occur. In 3 of 10 patients operated by other methods VUR into the transplant was found. Own kidney on the side of the reflux was removed in 4 patients after kidney transplantation. Indication for removal of own kidneys after allotransplantation of the kidney is urinary infection, arterial hypertension, pain in the lumbar spine. The proposed technique of ureterocystostomy has advantages in prevention of VUR into the renal transplant.


Self-powered broadband photodetection enabled by facile CVD-grown MoS2/GaN heterostructures.
Achieving self-powered photodetection without biasing is a notable challenge for photodetectors. In this work, we demonstrate the successful fabrication of large-scale van der Waals epitaxial molybdenum disulfide (MoS2) on a p-GaN/sapphire substrate using a straightforward chemical vapor deposition (CVD) technique. Our research primarily centers on the characterization of these photodetectors produced through this method. The MoS2/GaN heterojunction photodetector showcases a broad and extensive photoresponse spanning from ultraviolet A (UVA) to near-infrared (NIR). When illuminated by a 532 nm laser, its self-powered photoresponse is characterized by a rise time (τr) of ∼18.5 ms and a decay time (τd) of ∼123.2 ms. The photodetector achieves a responsivity (R) of ∼0.13 A W-1 and a specific detectivity (D*) of ∼3.8 × 1010 Jones at zero bias. Additionally, while utilizing a 404 nm laser, the photodetector reaches a maximum R and D* of ∼1.7 × 104 A/W and ∼1.6 × 1013 Jones, respectively, at Vb = 5 V. The operational mechanism of the device can be explained by the diode characteristics involving a tunneling current in the presence of reverse bias. The exceptional performance of these photodetectors can be attributed to the pristine interface between the CVD-grown MoS2 and GaN, providing an impeccably clean tunneling surface. Additionally, our investigation has unveiled that MoS2/GaN heterostructure photodetectors, featuring MoS2 coverage percentages spanning from 20% to 50%, exhibit improved responsivity capabilities at an external bias voltage. As a result, this facile CVD growth technique for MoS2 photodetectors holds significant potential for large-scale production in the manufacturing industry.


Hemangiopericytomas of the skull base.
Intracranial hemangiopericytomas are frequently located along the dural sinuses along the skull base and represent rare, aggressive CNS neoplasms that are difficult to distinguish from meningiomas based on both imaging and gross characteristics. The authors of this study describe 3 patients with these lesions and review the pertinent literature. Two men and 1 woman, whose median age at the time of the initial presentation was 37 years (range 20-53 years), constitute this series. They underwent multimodal treatment consisting of resection, embolization, radiation therapy, and in 1 case chemotherapy. Two of the 3 patients treated were alive after a mean follow-up of 93 months (range 4-217 months). One patient died 217 months after the initial diagnosis. The longest tumor progression-free interval after the initial or secondary resection was 43 months (range 4-84 months). Hemangiopericytomas have been reclassified as mesenchymal non-meningothelial tumors. They have an inevitable tendency to recur locally and metastasize distally. The mainstay of therapy remains an aggressive attempt to achieve gross-total resection at the initial surgery. Postoperative adjuvant radiotherapy should be offered to all patients, regardless of the degree of resection achieved. Diligent long-term follow-up is paramount as local recurrences and distal metastases can develop sometimes years after the initial treatment.


Antiadrenergic effects of adenosine in pressure overload hypertrophy.
In the present study, we sought to evaluate whether the antiadrenergic action of adenosine in the heart is altered in pressure overload hypertrophy produced in rats by suprarenal aortic banding. Epicardial and coronary effluent adenosine and inosine concentrations and release were significantly elevated in compensated pressure overload hypertrophy but not in hearts with left ventricular failure. In pressure overload hearts, the contractile response to beta-adrenergic stimulation was less inhibited by incremental concentrations of either adenosine or the selective A(1) receptor agonist chloro-N:(6)-cyclopentyl adenosine than in controls. Furthermore, the extent of desensitization to the antiadrenergic actions of adenosine in pressure overload hypertrophy appeared to be proportional to the extent of chamber dilation and dysfunction. A 60-minute infusion of adenosine produced a sustained antiadrenergic effect that lasted up to 45 minutes after the infusion was terminated in both controls and hearts with compensated hypertrophy. This effect was not observed in the decompensated left ventricular failure group. Subsequent infusion with adenosine of the A(2A) receptor antagonist 8-(3-chlorostyryl)-caffeine to counteract the proadrenergic effect of A(2A) receptor stimulation did not alter the decreased sensitivity to the antiadrenergic actions of adenosine in hypertrophied hearts. Finally, isolated myocytes from hypertrophied hearts demonstrated a decreased ability to suppress isoproterenol-elicited increases in [Ca(2+)](i) transients in the presence of adenosine and the A(2A) receptor antagonist compared with myocytes from control hearts. Myocardial adenosine concentrations increase during the compensated phase of pressure overload hypertrophy but then decrease when there is evidence of decompensation. The antiadrenergic actions of adenosine transduced via the myocardial A(1) receptor are diminished in pressure overload hypertrophied hearts. These factors may render these hearts more vulnerable to the detrimental effects of chronically increased sympathetic activity.


Ionization behavior, stoichiometry of association, and accessibility of functional groups in the active layers of reverse osmosis and nanofiltration membranes.
We characterized the fully aromatic polyamide (PA) active layers of six commercial reverse osmosis (RO) and nanofiltration (NF) membranes and found that in contrast to their similar elemental composition, total concentration of functional groups, and degree of polymerization, the ionization behavior and spatial distribution of carboxylic (R-COOH) groups within the active layers can be significantly different. We also studied the steric effects experienced by barium ion (Ba2+) in the active layers by determining the fraction of carboxylate (R-COO-) groups accessible to Ba2+; such fraction, referred to as the accessibility ratio (AR), was found to vary within the range AR=0.40-0.81, and to be generally independent of external solution pH. Additionally, we studied an NF membrane with a sulfonated polyethersulfone (SPES) active layer, and found that the concentration of sulfonate (R-SO3-) groups in the active layer was 1.67 M, independent of external solution pH and approximately three times higher than the maximum concentration (approximately 0.45+/-0.25 M) of R-COO- groups in PA active layers. The R-SO3- groups were found to be highly accessible to Ba2+ (AR=0.95+/-0.01).


Vane blood-bathed technique reveals the significance of adrenergic reaction in myocardial infarction.
Using the blood-bathed technique of Vane we induced acute coronary occlusion in the dog and subsequently detected adrenaline release into the circulatory system, determined the rate of release and documented its significance for induction of cardiac arrhythmias. In the intact anesthetized dog, adrenaline excess of the magnitude released after coronary occlusion was sufficient to injure the healthy myocardium and to induce unfavorable metabolic systemic alterations. Subsequently, clinical research has documented that a serious clinical course of acute myocardial infarction is associated not only with enhanced excretion of catecholamines but also with augmentation of plasma renin activity and aldosterone levels. The positive therapeutic effect of aldosterone antagonists in acute myocardial infarction has been documented. The clinical value of our results, which were obtained in experimental and clinical studies, was later confirmed in multi-center trials.


The severity and role of somatic depressive symptoms in psychological networks in a longitudinal sample of peripartum women.
The inclusion of somatic symptoms in assessing peripartum depression (PPD), which encompasses depression during pregnancy and the postpartum period, has remained controversial, as there is substantial overlap between somatic depression symptoms and normal features of pregnancy/postpartum. This study examined whether trajectories differed by PPD symptom subscale and whether PPD symptom networks changed as a function of the peripartum phase. 418 women with a history of neuropsychiatric illness participated in a longitudinal observational study, completing symptom questionnaires assessing affective, cognitive, and somatic symptoms throughout pregnancy and the first year postpartum. Assessments were grouped into five peripartum phases: three trimesters of pregnancy and early/late postpartum. Two analyses were performed. First, a series of multilevel spline regression models examined depression subscale trajectories over peripartum phase. Second, symptom networks and related metrics were estimated for each peripartum phase and compared. Somatic symptoms were most severe and had the most variable peripartum trajectory. The role of somatic symptoms within the networks also changed as a function of peripartum phase. Our results suggest that somatic symptoms can be severe and may play a crucial role in the maintenance of PPD. Thus, somatic symptoms should not be disregarded when assessing for PPD in obstetrical, psychiatric, and pediatric clinics, and clinical research.


Distinct FGFs promote differentiation of excitatory and inhibitory synapses.
The differential formation of excitatory (glutamate-mediated) and inhibitory (GABA-mediated) synapses is a critical step for the proper functioning of the brain. An imbalance in these synapses may lead to various neurological disorders such as autism, schizophrenia, Tourette's syndrome and epilepsy. Synapses are formed through communication between the appropriate synaptic partners. However, the molecular mechanisms that mediate the formation of specific synaptic types are not known. Here we show that two members of the fibroblast growth factor (FGF) family, FGF22 and FGF7, promote the organization of excitatory and inhibitory presynaptic terminals, respectively, as target-derived presynaptic organizers. FGF22 and FGF7 are expressed by CA3 pyramidal neurons in the hippocampus. The differentiation of excitatory or inhibitory nerve terminals on dendrites of CA3 pyramidal neurons is specifically impaired in mutants lacking FGF22 or FGF7. These presynaptic defects are rescued by postsynaptic expression of the appropriate FGF. FGF22-deficient mice are resistant to epileptic seizures, and FGF7-deficient mice are prone to them, as expected from the alterations in excitatory/inhibitory balance. Differential effects of FGF22 and FGF7 involve both their distinct synaptic localizations and their use of different signalling pathways. These results demonstrate that specific FGFs act as target-derived presynaptic organizers and help to organize specific presynaptic terminals in the mammalian brain.


Technical note: Extrapolation of hepatic glycogen concentration of the whole organ by performing a liver biopsy.
Glycogen, a complex polysaccharide, is the form of storage of glucose in mammals that can be released rapidly when needed. Recent studies have mainly reported hepatic glycogen concentration for early-lactating cows, when the energy demand is higher than the energy supply from dry matter intake, driving the cow to use the energy stored as hepatic glycogen. Generally, liver samples are obtained through percutaneous needle biopsies in the right lobe of the liver. Our objective was to analyze the variation of glycogen concentration in the livers of Holstein and Jersey cows among different liver locations representing all lobes, to evaluate whether samples obtained by liver biopsies are representative of the whole organ. Liver from 10 culled lactating cows (5 Holstein and 5 Jersey cows) from 30 to 113 mo of age at slaughter were obtained. Each liver was sampled no more than 3 h after death on the following sites: 3 sites in the right lobe (1 to 3), 2 in the diaphragmatic surface of the left lobe (4 and 5), 3 in the visceral surface of the left lobe (6 to 8), 1 in the quadrate lobe (9), and 1 in the caudate lobe (10). Samples were snap frozen in liquid N2 and were then analyzed for glucose concentration after conversion of glycogen to glucose using amyloglucosidase (EC 18.104.22.168). Glycogen results are reported as grams of glucose per 100 g of wet weight of liver (i.e., percent of wet weight of liver). Liver weights averaged 5.1 [standard deviation (SD) 1.2, minimum 3.3, maximum 6.2] kg for Holstein and 6.0 (SD 1.8, minimum 4.7, maximum 8.9) kg for Jersey cows. Holstein cows [1.31, standard error of the mean (SEM) 0.05% of wet weight] had greater liver glycogen concentration than did Jersey cows (0.75, SEM 0.05% of wet weight). No significant difference was noted among the 10 liver locations regarding glycogen concentration and averaged, for both breeds, 1.03% of wet weight (SEM 0.10). These results suggest that, in dairy cows, percutaneous needle liver biopsy in the right lobe is an accurate technique to fairly extrapolate glycogen concentration of the whole organ.


Factors of Prenatal Depression by Stress-vulnerability and Stress-coping Models.
This study aimed to identify related factors of prenatal depression by stress-vulnerability and stress-coping models for pregnant women. A cross-sectional survey design with a convenience sampling was used. A total of 107 pregnant women who visited a general hospital in a metropolitan city were recruited from August to October, 2013. A structured questionnaire included the Korean version of Beck Depression Inventory II, and the instruments measuring Self-Esteem, Marital Satisfaction, Pregnancy Stress, Stressful Life Events, and Coping. The data were analyzed using descriptive statistics, t-test, Parson's correlation analysis, and stepwise multiple regression. The mean score of prenatal depression was 11.95+/-6.2, then showing 19.6% with mild depression, 15.0% with moderate depression, and 0.9% with severe depression on BDI II scale. Prenatal depression had positive correlation with pregnancy stress (r=.55, p<.01), stressful life events (r=.26, p<.01) and negative correlation with self-esteem (r=-.38, p<.01), marital satisfaction (r=-.40, p<.01), and coping (r=-.21, p<.05). Factors of pregnancy stress, self-esteem, stressful life events, and planned pregnancy explained 38% of the total variance of prenatal depression. These findings show that health providers need to assess prenatal depression and to control the influencing factors.


Cardiovascular origins of preeclampsia.
To review the current data on maternal cardiovascular adaptation in normal pregnancy and preeclampsia. Defective placentation causes early-onset preeclampsia, a disease entity that is considered more or less distinct from late-onset preeclampsia. The latter has been attributed as 'maternal' preeclampsia. There are inconsistencies with the placental origins hypothesis, especially when considering the lack of a causative association with abnormal placental histology or impaired fetal growth. An alternative explanation is that placental dysfunction is secondary to maternal cardiovascular maladaptation in pregnancy. The concept that placental dysfunction is secondary to a maternal disorder is not new when one considers the clinical similarities between preeclampsia and gestational diabetes - both pregnancy-specific conditions that are cured by birth. It is accepted that gestational diabetes develops when the maternal pancreas is unable to manage the increasing glucose load of pregnancy. It is now apparent that pregnancy presents a substantial cardiovascular load on the maternal heart, and that cardiovascular dysfunction precedes the disorder, predominates in the clinical syndrome and persists for several decades postpartum. It is time to consider the evidence that failure of the maternal cardiovascular system to adapt to pregnancy may well be the primary mechanism leading to secondary placental dysfunction in preeclampsia. Many of the existing paradoxes of preeclampsia challenge the placental origin hypothesis and are explained if one considered preeclampsia to be a cardiovascular syndrome.


Abnormal eating attitudes in young insulin-dependent diabetics.
All insulin-dependent diabetics between the ages of 16 and 25 years attending the diabetic clinic at the Royal Infirmary, Edinburgh, (152 women and 139 men) were asked to complete the EAT, the EDI, and the GHQ, and to provide a control subject (sibling or close friend) of similar age who would do likewise. Marked differences were found between diabetic women (but not men) and their controls in eating attitudes, in many of the psychological characteristics associated with eating disorders, and in GHQ scores. Although some of the women had classic anorexia nervosa or bulimia, others with abnormal eating attitudes did not fulfil the formal criteria. Overall, diabetics were significantly heavier than controls but the differences in eating attitudes were not eliminated by correcting for overweight. Abnormal scores were associated with high HbA1 levels and independently with retinopathy. The weight gain and psychological effects of diabetes are identified as probably of aetiological importance in the abnormal eating attitudes of young diabetic women.


Modulatory effects of Pycnogenol in a rat model of insulin-dependent diabetes mellitus: biochemical, histological, and immunohistochemical evidences.
A number of experimental and clinical findings have consistently demonstrated the protective effects of Pycnogenol (PYC) in the management of diabetes. However, the protective mechanism by which PYC provides protection in a model type I diabetes has not been studied. This study examines the beneficial effect of PYC on hyperglycemia, inflammatory markers, and oxidative damage in diabetic rats. We also evaluated the possible mechanism of action of PYC which might be that it stimulates beta islet expression, which has been implicated in the process of insulin secretion and diabetes management. Diabetes was induced in rats by an intraperitoneal injection of streptozotocin (STZ; 60 mg/kg body weight) followed by free access to 5 % glucose for the next 24 h. Four days after STZ injection, rats were supplemented with PYC (10 mg/kg body weight) for 4 weeks. At the end of the experiment, blood was drawn, and rats were then sacrificed, and their livers and pancreases were dissected for biochemical and histological assays. The level of fasting blood glucose and glycosylated hemoglobin significantly increased but amylase, insulin, and hepatic glycogen level decreased in the STZ group. PYC significantly augmented these effects in STZ + PYC group. The STZ group showed elevated level of nitric oxide, tumor necrosis factor-α, and interleukin-1beta in serum which were decreased by PYC treatment. Moreover, PYC significantly ameliorated increased thiobarbituric reactive substances, protein carbonyl, and decreased levels of glutathione, glutathione-s-transferase, and catalase activity in the liver and pancreas of the STZ rats. Histopathological and immunohistochemical examination also revealed a remarkable protective effect of PYC. The study suggests that PYC is effective in reducing diabetic-related complications in a type I model of diabetes and might be beneficial for the treatment of diabetic patients.


Characterization of angiotensin I, II, and III from mouse as position-5 isoleucine [Ile5] angiotensins. An HPLC Study.
Angiotensin I was generated in vitro in mouse plasma by addition of mouse submaxillary renin. After deproteinization on Dowex 50W-X2 ion exchange resin, the samples were separated by reverse phase liquid chromatography and the fractions analysed by radio-immunoassay for angiotensin I. Angiotensin I from mouse was injected into the jugular vein of a nephrectomized rat in order to generate angiotensin II and III of mouse origin. Carotid arterial blood was collected immediately, centrifuged and the plasma deproteinized and separated on high pressure liquid chromatography (HPLC). The fractions were analysed for angiotensin I, II and III by radioimmunoassays. Retention times for mouse angiotensins in the liquid chromatography system were compared to synthetic [Val5] and [Ile5] angiotensin I, II and III. All three mouse angiotensins coincided with the corresponding synthetic [Ile5] angiotensins during elution, suggesting the same type of angiotensin in mouse and man. An additional study on rat angiotensins confirmed previous findings by other investigators, indicating that the angiotensins of this animal were also of the [Ile5] type.


Impact of ASUMA Intervention on HIV Risk Behaviors among Puerto Rican Adolescents.
The purpose of this manuscript is to assess and compare HIV risk behaviors among early adolescents after a three-year pilot study. A total of 135 public and private junior high schools students completed the intervention protocol. A self-administered questionnaire was given at baseline and at the end of the third year (fourth measure). Descriptive and inferential analyses were performed using SPSS 20.0. About 60% of the students were 14 years old at the fourth measure. The proportion of students that did not report at least one HIV risk behavior at baseline and those that reported any risk behavior at the fourth measure was lower in the intervention group (45.0%) than in the control group (54.5%). The proportion of students that reported at least one HIV risk behavior at baseline and those that did not report any HIV risk behavior at the fourth measure was higher in the intervention group than in the control group (33.3% vs. 8.3%). The proportion of students engaging in HIV risk behaviors was higher in the control group than in the intervention group at the fourth measure, suggesting that A Supportive Model for HIV Risk Reduction in Early Adolescence (ASUMA) intervention might be a promising initiative to reduce adolescents' engagement in HIV risk behaviors.


Aphrophoridae Role in Xylella fastidiosa subsp. pauca ST53 Invasion in Southern Italy.
The Philaenus spumarius L. (Hemiptera Aphrophoridae) is a xylem-sap feeder vector that acquires Xylella fastidiosa subsp. pauca ST53 during feeding on infected plants. The bacterium is the plant pathogen responsible for olive quick decline syndrome that has decimated olive trees in Southern Italy. Damage originates mainly from the insect vector attitude that multiplies the pathogen potentialities propagating Xf in time and space. The principal action to manage insect-borne pathogens and to contain the disease spread consists in vector and transmission control. The analysis of an innovative and sustainable integrated pest management quantitative strategy that targets the vector and the infection by combining chemical and physical control means demonstrates that it is possible to stop the Xylella invasion. This review updates the available topics addressing vectors' identification, bionomics, infection management, and induced disease by Xylella invasion to discuss major available tools to mitigate the damage consequent to the disease.