Dose-finding clinical assay of triletide in gastric and duodenal ulceration.
Three groups of 15 patients with endoscopically confirmed active gastric or duodenal ulcer were treated over a period of 8 weeks with daily doses of 1, 1.5 or 2 g triletide, an anti-ulcer agent which acts by enhancing the mucosal defence capacity. Intensity of epigastric pain and of heartburn and weekly consumption of standard antacid tablets, as well as possible accessory symptoms, were recorded every other week, endoscopy was repeated at the end of treatment and routine haematology and haematochemistry performed before and after treatment. The proportion of patients found to be endoscopically healed was significantly correlated to the log of the dose used, giving an ED50, under the test conditions, of 1.2 g/day (86.7% healed at 2 g/day). The improvement in each assessed symptom was significantly correlated with time according to an exponential regression. The computed exponent indicated that each higher dose resulted in a significantly faster regression of symptoms than each lower dose (mean time to decrease symptoms by 50%; 4.3 weeks at 2 g/day; 7.4 weeks at 1.5 g/day; and 20.8 weeks at 1 g/day). Moreover, two-ways analysis of variance indicated a significant dose-time interaction (p less than 0.01); thus, the improvement provided at any given time was more than proportional to the used dose. Tolerance was good at all three dose levels and no variations in haematology and haematochemistry could be detected. It is concluded that triletide, at a dose of between 1.5 and 2 g/day according to the patient's condition, appears to be an effective and well-tolerated means of promoting healing and controlling symptoms in peptic ulcer patients.


Passion matters but not equally everywhere: Predicting achievement from interest, enjoyment, and efficacy in 59 societies.
How to identify the students and employees most likely to achieve is a challenge in every field. American academic and lay theories alike highlight the importance of passion for strong achievement. Based on a Western independent model of motivation, passionate individuals-those who have a strong interest, demonstrate deep enjoyment, and express confidence in what they are doing-are considered future achievers. Those with less passion are thought to have less potential and are often passed over for admission or employment. As academic institutions and corporations in the increasingly multicultural world seek to acquire talent from across the globe, can they assume that passion is an equally strong predictor of achievement across cultural contexts? We address this question with three representative samples totaling 1.2 million students in 59 societies and provide empirical evidence of a systematic, cross-cultural variation in the importance of passion in predicting achievement. In individualistic societies where independent models of motivation are prevalent, relative to collectivistic societies where interdependent models of motivation are more common, passion predicts a larger gain (0.32 vs. 0.21 SD) and explains more variance in achievement (37% vs. 16%). In contrast, in collectivistic societies, parental support predicts achievement over and above passion. These findings suggest that in addition to passion, achievement may be fueled by striving to realize connectedness and meet family expectations. Findings highlight the risk of overweighting passion in admission and employment decisions and the need to understand and develop measures for the multiple sources and forms of motivation that support achievement.


SbMYB15 transcription factor mitigates cadmium and nickel stress in transgenic tobacco by limiting uptake and modulating antioxidative defence system.
Plants require different inorganic minerals in an appropriate amount for growth; however, imbalance can limit growth and productivity. Heavy metal accumulation causes toxicity and generates signalling crosstalk with reactive oxygen species (ROS), phytohormones, genes and transcription factors (TFs). The MYB (myeloblastoma) TFs participate in plant processes such as metabolism, development, cell fate, hormone pathways and responses to stresses. This is the first report towards characterisation of R2R3-type MYB TF, SbMYB15, from succulent halophyte Salicornia brachiata Roxb. for heavy metal tolerance. The SbMYB15 showed >5-fold increased transcript expression in the presence of CdCl2 and NiCl2•6H2O. The constitutive overexpression of SbMYB15 conferred cadmium and nickel tolerance in transgenic tobacco, with improved growth and chlorophyll content. Further, the transgenics showed reduced generation of reactive oxygen species (H2O2 and O2•-) as compared with the wild-type (WT) with both Cd2+ and Ni2+ stress. Transgenics also showed low uptake of heavy metal ions, increased scavenging activity of the antioxidative enzymes (CAT and SOD) and higher transcript expression of antioxidative genes (CAT1 and MnSOD). Thus, the present study signifies that SbMYB15 can be deployed for developing heavy metal tolerance in crop plants via genetic engineering.


Lack of an association between alleles of interleukin-1 alpha and interleukin-1 receptor antagonist genes and Graves' disease in a North American Caucasian population.
Although an association between the human leukocyte antigen (HLA) allele DR3 and Graves' disease (GD) is well documented, the potential role of non-HLA-linked alleles in susceptibility to GD is an area of active investigation. In an attempt to study the potential role of two non-HLA susceptibility alleles in GD and Graves' ophthalmopathy, we examined 286 North American Caucasian individuals (145 normal controls and 141 individuals with GD) for the presence of the A2 allele of the interleukin-1 (IL-1) receptor antagonist gene. In addition, we examined a subset of this population (83 normal controls and 89 individuals with GD) for a specific polymorphism within exon 5 of the IL-1 alpha gene. We found the A2 allelic frequencies (0.25 and 0.23, respectively) and carriage rates (43% and 41%, respectively) in the two groups to be nearly identical. However, findings in the subgroup of patients with the extrathyroidal manifestations of GD (Graves' ophthalmopathy, pretibial dermopathy, and acropachy) suggested a trend toward a higher prevalence of the A2 allele in patients with more severe disease. The allelic frequency (0.28) and carriage rate (47%) of the IL-1 alpha exon 5 polymorphism in individuals with GD were nearly identical to those of the control population (0.28% and 45%, respectively). In summary, we were unable to demonstrate an association between these alleles and GD in our study population. We conclude that neither the A2 allele of the IL-1 receptor antagonist gene nor the IL-1 alpha exon 5 polymorphism confers increased susceptibility to GD.


The smooth muscle cell. III. Elastin synthesis in arterial smooth muscle cell culture.
Primate arterial smooth muscle cells and skin fibroblasts were examined for their ability to synthesize elastin in culture. In the presence of the lathyrogen beta-aminopropionitrile, the smooth muscle cells incorporate [3H]lysine into a lysyl oxidase substrate that was present in the medium and associated with the cell layer. A component having a mol wt of 72,000 and an electrophoretic mobility similar to that of authentic tropoelastin was isolated from the labeled smooth muscle cells by coacervation and fractionation with organic solvents. In the absence of beta-aminopropionitrile, long-term cultures of smooth muscle cells incorporated [14C]lysine into desmosine and isodesmosine, the cross-link amino acids unique to elastin. In contrast, no desmosine formation occurred in the fibroblast cultures. These characteristics demonstrate that arterial smooth muscle cells are capable of synthesizing both soluble and cross-lined elastin in culture.


Performic Acid oxidation of proteins.
INTRODUCTIONDisulfide bond cleavage is a prerequisite to many peptide-mapping strategies. It facilitates protein unfolding and thus optimizes proteolytic digestion. It also simplifies the interpretation of peptide maps by removing possible peptide fragment(s) in the mixture that are held together by disulfide bonds. This protocol describes the performic acid oxidation method for cleaving disulfide bonds. It is convenient for determining the combined cysteine and cystine content and the total methionine content of a protein.


Prostatic intraepithelial neoplasia.
High-grade prostatic intraepithelial neoplasia (PIN) is now accepted as the most likely pre-invasive stage of adenocarcinoma, a decade after its first formal description. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma. The only method of detection is biopsy; PIN does not significantly elevate serum prostate-specific antigen concentration or its derivatives and cannot be detected by ultrasound. Most studies suggest that most patients with PIN will develop carcinoma within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype that are similar to cancer rather than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.


Differential repetitive DNA methylation in multiple myeloma molecular subgroups.
Multiple myeloma (MM) is characterized by a wide spectrum of genetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear element 1 (LINE-1), Alu and satellite alpha (SAT-alpha) sequences has been associated with chromosomal instability in cancer. Methylation status of repetitive elements in MM has never been investigated. In the present study, we used a quantitative bisulfite-polymerase chain reaction pyrosequencing method to evaluate the methylation patterns of LINE-1, Alu and SAT-alpha in 23 human myeloma cell lines (HMCLs) and purified bone marrow plasma cells from 53 newly diagnosed MM patients representative of different molecular subtypes, 7 plasma cell leukemias (PCLs) and 11 healthy controls. MMs showed a decrease of Alu [median: 21.1 %5-methylated cytosine (%5mC)], LINE-1 (70.0%5mC) and SAT-alpha (77.9%5mC) methylation levels compared with controls (25.2, 79.5and 89.5%5mC, respectively). Methylation levels were lower in PCLs and HMCLs compared with MMs (16.7 and 14.8%5mC for Alu, 45.5 and 42.4%5mC for LINE-1 and 33.3 and 43.3%5mC for SAT-alpha, respectively). Notably, LINE-1 and SAT-alpha methylation was significantly lower in the non-hyperdiploid versus hyperdiploid MMs (P = 0.01 and 0.02, respectively), whereas Alu and SAT-alpha methylation was significantly lower in MMs with t(4;14) (P = 0.02 and 0.004, respectively). Finally, we correlated methylation patterns with DNA methyltransferases (DNMTs) messenger RNA levels showing in particular a progressive and significant increase of DNMT1 expression from controls to MMs, PCLs and HMCLs (P < 0.001). Our results indicate that global hypomethylation of repetitive elements is significantly associated with tumor progression in MM and may contribute toward a more extensive stratification of the disease.


Living with genome instability: plant responses to telomere dysfunction.
Loss of telomere function in metazoans results in catastrophic damage to the genome, cell cycle arrest, and apoptosis. Here we show that the mustard weed Arabidopsis thaliana can survive up to 10 generations without telomerase. The last five generations of telomerase-deficient plants endured increasing levels of cytogenetic damage, which was correlated with developmental anomalies in both vegetative and reproductive organs. Mutants ultimately arrested at a terminal vegetative state harboring shoot meristems that were grossly enlarged, disorganized, and in some cases, dedifferentiated into a callusoid mass. Unexpectedly, late-generation mutants had an extended life-span and remained metabolically active. The differences in plant and animal responses to dysfunctional telomeres may reflect the more plastic nature of plant development and genome organization.


Achalasia-like findings in a case with delayed diagnosis of H-type tracheoesophageal fistula.
H-type tracheoesophageal fistula (TEF) may lead to chronic respiratory disease if the diagnosis is delayed. Long-standing fistula causes esophageal distention which is named as pneumoesophagus or megaesophagus and possibly affects the motility of the esophageal body which may also be encountered as a part of tracheoesophageal anomalies. Both dysmotility and megaesophagus may mimic achalasia radiologically and the patient may be advised an unnecessary esophagocardiomyotomy. The authors report a 15-year-old adolescent with H-type TEF who has been diagnosed during investigations for chronic respiratory disease due to presumptive diagnosis of achalasia. The authors emphasize that a complete anatomical and functional evaluation of the upper gastrointestinal tract should be done before recommending operation for achalasia in patients with chronic respiratory disease. H-type TEF should be investigated to avoid unnecessary cardiomyotomy.


The Carroll rating scale for depression. II. Factor analyses of the feature profiles.
Factor analyses were conducted for the Hamilton depression rating scale (HRS) and the self administered Carroll counterpart (CRS). The factor loadings for the respective first factors were similar; those for the respective second factors showed strict sign consistency but only moderate consistency of magnitude; the loadings for the respective third factors showed no particular consistency. The first three CRS and first three HRS factor scores were computed for each individual and correlations were computed from these factor scores. The first and second factors were highly correlated but the third factors were negatively correlated indicating that they were not measuring the same thing. The first factors of the CRS and HRS correlated highly with their respective raw total scores and were indices of the severity of illness. The self-administered CRS (with matching weights) is a credible alternative to the HRS for routine clinical assessment of the severity of depression.


[Should children be treated with ephedrine mixture?].
Lower respiratory tract infections are common in small children, and are often associated with obstruction of the respiratory tract and coughing. In Norway, symptomatic treatment with ephedrine is common in children. The clinical effect of such treatment is not sufficiently documented and serious adverse drug reactions have been reported in small children administered sympathomimetic medication. This article presents current knowledge of clinical effects and adverse drug reactions of ephedrine in infants and children, and discusses the practical implications of these findings.


Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda.
Retrospective cohort studies of tuberculosis suggest that active tuberculosis accelerates the progression of HIV infection. The validity of these findings has been questioned because of their retrospective design, diverse study populations, variable compliance with anti-tuberculous therapy and use of anti-retroviral medication. To assess the impact of tuberculosis on survival in HIV infection we performed a prospective study among HIV-infected Ugandan adults with and without tuberculosis. In a prospective cohort study, 230 patients with HIV-associated tuberculosis and 442 HIV-infected subjects without tuberculosis were followed for a mean duration of 19 months for survival. To assess changes in viral load over 1 year, 20 pairs of tuberculosis cases and controls were selected and matched according to baseline CD4 lymphocyte count, age, sex and tuberculin skin test status. During the follow-up period, 63 out of of 230 tuberculosis cases (28%) died compared with 85 out of 442 controls (19%), with a crude risk ratio of 1.4 [95% confidence interval (CI), 1.07-1.87]. Most deaths occurred in patients with CD4 lymphocyte counts < 200 x 10(6) cells/l at baseline (n = 99) and occurred with similar frequency in the tuberculosis cases (46%) and the controls (44%). When the CD4 lymphocyte count was > 200 x 10(6)/l, however, the relative risk of death in HIV-associated tuberculosis was 2.1 (95% CI, 1.27-3.62) compared with subjects without tuberculosis. For subjects with a CD4 lymphocyte count > 200 x 10(6)/l, the 1-year survival proportion was slightly lower in the cases than in the controls (0.91 versus 0.96), but by 2 years the survival proportion was significantly lower in the cases than in the controls (0.84 versus 0.91; P < 0.02; log-rank test). For subjects with a CD4 lymphocyte count of 200 x 10(6) cells/l or fewer, the survival proportion at 1 year for the controls was lower than cases (0.59 versus 0.64), but this difference was not statistically significant (P = 0.53; logrank test). After adjusting for age, sex, tuberculin skin test status, CD4 lymphocyte count, and history of HIV-related infections, the overall relative hazard for death associated with tuberculosis was 1.81 (95% CI, 1.24-2.65). In a nested Cox regression model, the relative hazard for death was 3.0 (95% CI, 1.62-5.63) for subjects with CD4 lymphocyte counts > 200 x 10(6)/l and 1.5 (95% CI, 0.99-2.40) for subjects with a CD4 lymphocyte count of 200 x 10(6)/l or fewer. The findings from this prospective study indicate that active tuberculosis exerts its greatest effect on survival in the early stages of HIV infection, when there is a reserve capacity of the host immune response. These observations provide a theoretical basis for the treatment of latent tuberculous infection in HIV-infected persons.


Hydration Status in Adolescent Alpine Skiers During a Training Camp.
Maintaining euhydration is important for optimal health, performance and recovery, but can be challenging for alpine skiers when training in a relatively cold but dry environment. This study aimed to evaluate hydration status, fluid loss and fluid intake in adolescent alpine skiers during a training camp. Twelve athletes aged 14.3 ± 0.9 years volunteered to participate in the study. Athletes resided at an altitude of 1600 m and trained between 1614 and 2164 m. During eight consecutive days, urine specific gravity was measured before each morning training session using a refractometer. Changes in body weight representing fluid loss and ad libitum fluid intake during each morning training session were assessed using a precision scale. Mean pre-training urine specific gravity remained stable throughout the training camp. Individual values ranged between 1.010 and 1.028 g/cm3with 50 to 83% of athletes in a hypohydrated state (urine specific gravity ≥ 1.020 g/cm3). Mean training induced fluid loss remained stable throughout the training camp (range -420 to -587 g) with individual losses up to 1197 g (-3.5%). Fluid intake was significantly lower than fluid loss during each training session. To conclude, urine specific gravity values before training indicated insufficient daily fluid intake in more than half of the athletes. Furthermore, fluid intake during training in adolescent alpine skiers was suboptimal even when drinks were provided ad libitum. Coaches and athletes should be encouraged to carefully monitor hydration status and to ensure that alpine skiers drink sufficiently during and in between training sessions.


Scale-up in twin-screw wet granulation: impact of formulation properties.
The focus of this study was to investigate the sensitivity of different drug formulations to differences in process parameters based on previously developed scale-up strategies. Three different formulations were used for scale-up experiments from a QbCon® 1 with a screw diameter of 16 mm and a throughput of 2 kg/h to a QbCon® 25 line with a screw diameter of 25 mm and a throughput of 25 kg/h. Two of those formulations were similar in their composition of excipients but had a different API added to the blend to investigate the effect of solubility of the API during twin-screw wet granulation, while the third formulation was based on a controlled release formulation with different excipients and a high fraction of HPMC. The L/S-ratio had to be set specifically for each formulation as depending on the binder and the overall composition the blends varied significantly in their response to water addition and their overall granulation behavior. Before milling there were large differences in granule size distributions based on scale (Earth Mover's Distance 140-1100 µm, higher values indicating low similarity) for all formulations. However, no major differences in granule properties (e.g. Earth Mover's Distance for GSDs: 23-88 µm) or tablet tensile strength (> 1.8 MPa at a compaction pressure of 200 MPa for all formulations with a coefficient of variation < 0.1, indicating high robustness for all formulations) were observed after milling, which allowed for a successful scale-up independent of the selected formulations.


Effect of imazaquin applications on the growth, leaf chlorophyll and yield of soybean in the Guinea savanna of Nigeria.
Field trials were conducted during the wet seasons of 1989, 1991, 1994 and 1995 to evaluate the effects of pre-emergence and post-emergence applications of four rates of imazaquin (0.00; 0.15; 0.30 and 0.45kg a.i/ha) on the growth, leaf chlorophyll types and grain yield of soybean c.v. SAMSOY 2. Imazaquin applications had no significant effect on the growth of soybean roots on most of the sampling dates, but pre-and post-emergence applications of imazaquin at 0.30 and 0.45kg a.i/ha reduced soybean root nodules at 5 and 7 weeks after planting (WAP). Soybean shoot growth was generally reduced at 5WAP by the pre-emergence and at 7WAP by the higher rates (0.30 & 0.45kg a.i/ha) of post-emergence application of imazaquin. Pre-and post-emergence applications of imazaquin showed a strong tendency to reduce the concentration of chlorophyll a and total chlorophyll at 3 and 5WAP respectively. The concentrations of chlorophyll types in soybean leaves at 9WAP was generally comparable among most treatments especially in 1991. Whole plant fresh weight of soybean at 7WAP was reduced by all rates of post-emergence application of imazaquin. However, there was no significant difference in the whole plant dry weight of soybean at 3 to 7 WAP in 1989 and at 3, 5 and 9WAP in 1991. In each trial, pre-and post-emergence applications of soybean significantly increased the grain yield of soybean compared with the control treatment. This study showed that, inhibition of soybean shoot growth and leaf chlorophyll concentration was transient and that soybean plants require about 6 weeks for complete recovery from imazaquin phytotoxicity.


Central oscillators responsible for sympathetic nerve discharge.
The current state of knowledge concerning central mechanisms responsible for the generation of background discharges in sympathetic nerves is examined. It is apparent from recent investigations that the classic concept of a randomly discharging and diffusely organized central network onto which rhythms (cardiac- and respiratory-related) are imposed by extrinsic inputs has not passed the test of time. Rather, brain stem as well as spinal networks that govern the discharges of sympathetic nerves are inherently capable of rhythm generation. Sympathetic nerve rhythms inherent to the central nervous system imply the existence of neuronal circuits that are capable of oscillatory activity. Central oscillators provide a mechanism for synchronization of the activity of populations of sympathetic neurons in the absence of periodic input from sources extrinsic to the central nervous system. Indeed, the thesis is developed that, rather than creating rhythms in sympathetic nerve discharge, the function of periodic input from extrinsic sources such as the baroreceptors is to entrain rhythms of central origin. Finally, the problems associated with the identification of neuronal types that comprise central oscillators which govern the discharges of sympathetic nerves are discussed.


Human miR-3145 inhibits influenza A viruses replication by targeting and silencing viral PB1 gene.
MicroRNAs (miRNAs) play an important role in the regulation of gene expression and are involved in many cellular processes including inhibition of viral replication in infected cells. In this study, three subtypes of influenza A viruses (pH1N1, H5N1 and H3N2) were analyzed to identify candidate human miRNAs targeting and silencing viral genes expression. Candidate human miRNAs were predicted by miRBase and RNAhybrid based on minimum free energy (MFE) and hybridization patterns between human miRNAs and viral target genes. In silico analysis presented 76 miRNAs targeting influenza A viruses, including 70 miRNAs that targeted specific subtypes (21 for pH1N1, 27 for H5N1 and 22 for H3N2) and 6 miRNAs (miR-216b, miR-3145, miR-3682, miR-4513, miR-4753 and miR-5693) that targeted multiple subtypes of influenza A viruses. Interestingly, miR-3145 is the only candidate miRNA targeting all three subtypes of influenza A viruses. The miR-3145 targets to PB1 encoding polymerase basic protein 1, which is the main component of the viral polymerase complex. The silencing effect of miR-3145 was validated by 3'-UTR reporter assay and inhibition of influenza viral replication in A549 cells. In 3'-UTR reporter assay, results revealed that miR-3145 triggered significant reduction of the luciferase activity. Moreover, expression of viral PB1 genes was also inhibited considerably (P value < 0.05) in viral infected cells expressing mimic miR-3145. In conclusion, this study demonstrated that human miR-3145 triggered silencing of viral PB1 genes and lead to inhibition of multiple subtypes of influenza viral replication. Therefore, hsa-miR-3145 might be useful for alternative treatment of influenza A viruses in the future.


Aloe vera Extract Suppresses Proliferation of Neuroblastoma Cells In Vitro.
Neuroblastoma is a pediatric solid tumor refractory to eradication by chemotherapy. To determine whether Aloe vera (AV), a pontial anticancer reagent, could be useful in neuroblastoma therapy, we investigated the anti-proliferative effects of an AV protein extract. Human neuroblastoma cell lines (IMR-32, TGW, CHP-126 and NBL-S) were cultured with AV protein extract and proliferation status was assessed by cell counting, Ki-67 staining and gene expression. Among tested lines, the number of viable, AV-treated IMR-32 cells significantly decreased 1.98-fold by day 2 and 1.33-fold by day 5 of culture relative to untreated controls (p<0.05). Treatment also decreased the number of Ki-67(+) IMR-32 cells by 13% by day 5 (p<0.05) and, unlike untreated controls, CCND2 mRNA expression levels became undetectable by day 1. AV-protein extract suppresses human IMR-32 neuroblastoma cell proliferation, possibly by suppressing CCND2 transcript levels in vitro.


[Specific features with of intramedullary osteosynthesis with blocking in fractures of the shin bones at different levels].
The results of closed intramedullary osteosynthesis with blocking were analyzed in 180 patients with open (in 22) and closed (in 158 patients) fractures of shin bones fulfilled within the period from 3 days to 3.5 months after trauma. In 16 patients the intramedullary canal was drilled out. The exact reposition of the shin-bone in closed intramedullary osteosynthesis was obtained in 142 patients: the terms of consolidation in this case were (6.4+/-1.3) months. The examination of all the patients in the period from 6 months to 2 years after operation has shown consolidation of the shin-bone fracture in 176 (97.7%) of them.


A SARS-CoV-2 targeted siRNA-nanoparticle therapy for COVID-19.
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans. Despite several emerging vaccines, there remains no verifiable therapeutic targeted specifically to the virus. Here we present a highly effective small interfering RNA (siRNA) therapeutic against SARS-CoV-2 infection using a novel lipid nanoparticle (LNP) delivery system. Multiple siRNAs targeting highly conserved regions of the SARS-CoV-2 virus were screened, and three candidate siRNAs emerged that effectively inhibit the virus by greater than 90% either alone or in combination with one another. We simultaneously developed and screened two novel LNP formulations for the delivery of these candidate siRNA therapeutics to the lungs, an organ that incurs immense damage during SARS-CoV-2 infection. Encapsulation of siRNAs in these LNPs followed by in vivo injection demonstrated robust repression of virus in the lungs and a pronounced survival advantage to the treated mice. Our LNP-siRNA approaches are scalable and can be administered upon the first sign of SARS-CoV-2 infection in humans. We suggest that an siRNA-LNP therapeutic approach could prove highly useful in treating COVID-19 disease as an adjunctive therapy to current vaccine strategies.


Nano-scale three dimensional surface relief features using single exposure counterpropagating multiple evanescent waves interference phenomenon.
In this paper, fabrication of nano-scale 3-D features by total internal reflection generated single exposure counter propagating multiple evanescent waves interference lithography (TIR-MEWIL) in a positive tone resist is investigated numerically. Using a four incident plane waves configuration from an 364nm wavelength illumination source, the simulated results indicate that the proposed technique shows potential in realizing periodic surface relief features with diameter as small as 0.08lambda and height-to-diameter aspect ratio as high as 10. It is also demonstrated that the sensitivity of multiple evanescent waves' interference depends on the polarization and phase of the incident plane waves, and can be tailored to obtain different geometry features. A modified cellular automata algorithm has been employed to simulate three-dimensional photoresist profiles that would result from exposure to the studied evanescent waves interference configurations.


What will Donald Trump's presidency mean for health? A scorecard.
US Presidents make their mark on health, for better or worse. Donald Trump campaigned on a populist platform to "make America great again". While the actual policies his administration will pursue-and the priority he will place on each of them-remain in many ways uncertain, both his statements and his nominations for key government posts suggest that his presidency could have profound implications for health. His proposal to repeal and replace the Affordable Care Act with a "better reform", his stance on reproductive rights, and his approaches to other areas, such as science policy and climate change, coupled with his stated intention to put "America first" are creating anxiety and uncertainty about America's domestic health policies and its global leadership role in areas such as security and development. We propose criteria on which the global health community can judge the success or failure of a Trump presidency, based on a selection of the 17 Sustainable Development Goals that apply to health.


Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial.
Oral administration of cartilage-derived type II collagen (CII) has been shown to ameliorate arthritis in animal models of joint inflammation, and preliminary studies have suggested that this novel therapy is clinically beneficial and safe in patients with rheumatoid arthritis (RA). The present study was undertaken to test the safety and efficacy of 4 different dosages of orally administered CII in patients with RA. Two hundred seventy-four patients with active RA were enrolled at 6 different sites and randomized to receive placebo or 1 of 4 dosages (20, 100, 500, or 2,500 microg/day) of oral CII for 24 weeks. Efficacy parameters were assessed monthly. Cumulative response rates (percentage of patients meeting the criteria for response at any time during the study) were analyzed utilizing 3 sets of composite criteria: the Paulus criteria, the American College of Rheumatology criteria for improvement in RA, and a requirement for > or = 30% reduction in both swollen and tender joint counts. Eighty-three percent of patients completed 24 weeks of treatment. Numeric trends in favor of the 20 microg/day treatment group were seen with all 3 cumulative composite measures. However, a statistically significant increase (P = 0.035) in response rate for the 20 microg/day group versus placebo was detected using only the Paulus criteria. The presence of serum antibodies to CII at baseline was significantly associated with an increased likelihood of responding to treatment. No treatment-related adverse events were detected. The efficacy seen with the lowest dosage is consistent with the findings of animal studies and with known mechanisms of oral tolerance in which lower doses of orally administered autoantigens preferentially induce disease-suppressing regulatory cells. Positive effects were observed with CII at the lowest dosage tested, and the presence of serum antibodies to CII at baseline may predict response to therapy. No side effects were associated with this novel therapeutic agent. Further controlled studies are required to assess the efficacy of this treatment approach.


Postcopulatory sexual selection is associated with accelerated evolution of sperm morphology.
Rapid diversification of sexual traits is frequently attributed to sexual selection, though explicit tests of this hypothesis remain limited. Spermatozoa exhibit remarkable variability in size and shape, and studies report a correlation between sperm morphology (sperm length and shape) and sperm competition risk or female reproductive tract morphology. However, whether postcopulatory processes (e.g., sperm competition and cryptic female choice) influence the speed of evolutionary diversification in sperm form is unknown. Using passerine birds, we quantified evolutionary rates of sperm length divergence among lineages (i.e., species pairs) and determined whether these rates varied with the level of sperm competition (estimated as relative testes mass). We found that relative testes mass was significantly and positively associated with more rapid phenotypic divergence in sperm midpiece and flagellum lengths, as well as total sperm length. In contrast, there was no association between relative testes mass and rates of evolutionary divergence in sperm head size, and models suggested that head length is evolutionarily constrained. Our results are the first to show an association between the strength of sperm competition and the speed of sperm evolution, and suggest that postcopulatory sexual selection promotes rapid evolutionary diversification of sperm morphology.


[Hemodynamic characteristics during 2-chamber electrostimulation of the heart].
Cardiac output was investigated in coronary patients with temporary (15) and permanent (16) programmed two-chamber electrostimulation of the heart, using different induced atrioventricular interval values. The study was based on integral rheoplethysmography, peripheral volumetric sphygmography, sectoral echocardiography and two-dimensional doppler echocardiography with color code. The adjustment of atrioventricular interval in two-chamber cardiac electrostimulation can modulate cardiac output by means of changing the duration and rate of left-ventricular filling flow, produced by the atrial systole.


Prevalence of dental anomalies in Saudi orthodontic patients.
This study aimed to investigate the prevalence of dental anomalies and study the association of these anomalies with different types of malocclusion in a random sample of Saudi orthodontic patients. Six hundred and two randomly selected pretreatment records including orthopantomographs (OPG), and study models were evaluated. The molar relationship was determined using pretreatment study models, and OPG were examined to investigate the prevalence of dental anomalies among the sample. The most common types of the investigated anomalies were: impaction followed by hypodontia, microdontia, macrodontia, ectopic eruption and supernumerary. No statistical significant correlations were observed between sex and dental anomalies. Dental anomalies were more commonly found in class I followed by asymmetric molar relation, then class II and finally class III molar relation. No malocclusion group had a statistically significant relation with any individual dental anomaly. The prevalence of dental anomalies among Saudi orthodontic patients was higher than the general population. Although, orthodontic patients have been reported to have high rates of dental anomalies, orthodontists often fail to consider this. If not detected, dental anomalies can complicate dental and orthodontic treatment; therefore, their presence should be carefully investigated during orthodontic diagnosis and considered during treatment planning.


Structure-based thermodynamic analysis of HIV-1 protease inhibitors.
A structural parametrization of the binding and folding energetics previously developed in this laboratory accounts quantitatively for the binding of 13 HIV-1 protease inhibitors for which high-resolution structures are available (A77003, A78791, A76928, A74704, A76889, VX478, SB203386, SB203238, SB206343, U100313, U89360, A98881, CGP53820). The binding free energies for the inhibitors are predicted with a standard deviation of +/- 1.1 kcal/mol or +/- 10%. Furthermore, the formalism correctly predicts the observed change in inhibition constant for the complex of A77003 and the resistant protease mutant V82A, for which the high-resolution structure is also available. The analysis presented here provides a structural mapping of the different contributions to the binding energetics. Comparison of the binding map with the residue stability map indicates that the binding pocket in the protease molecule has a dual character: half of the binding site is defined by the most stable region of the protein, while the other half is unstructured prior to inhibitor or substrate binding. This characteristic of the binding site accentuates cooperative effects that permit mutations in distal residues to have a significant effect on binding affinity. These results permit an initial assessment of the effects of mutations on the activity of protease inhibitors.


The Effect of Patellar Height by Using Insall Salvati Index on Pain, Function, Muscle Strength and Postural Stability in Patients with Primary Knee Osteoarthritis.
The Insall-Salvati Index (ISI) is the ratio of the patellar tendon length to the length of the patella. This ratio is the most commonly used method for evaluating patellar placement and patellofemoral imbalance. The position of the patella is important for the knee joint function and also for biomechanics. The abnormal position of the patella may lead to patellofemoral malalignment and instability. Herein, we aimed to analyze the relationship between the ISI and pain, physical function, muscle strength, fall risk, and postural stability in patients with primary knee osteoarthritis (OA). Sixty-two symptomatic knees of 45 patients (aged between 40 -75 years) who were suffering from the primary knee OA according to the American College of Rheumatology criteria were included retrospectively in the study. Patients with stages II and III osteoarthritis according to the Kellgren-Lawrence (K/L) radiological grading system were included. The ISI was measured on the lateral knee radiograph in a 30° flexed posture. Visual Analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) and Lequesne indexes were recorded for evaluating pain and function. Tetrax Interactive Balance System was used to assess fall risk and postural stability. Isokinetic muscle strength measurements of quadriceps and hamstrings were recorded at the constant angular velocities of 60 and 180°/sec. The mean age of the study population was 58.52 ±8.01 years. The frequency of the patellar situation types was as follows; patella alta; 15 (24.2%), patella baja; n=2(3.2%), and normal patellar height; n=45(72.6%). The mean ISI was 1.19 ±0.17 on the right side and 1.18±0.16 on the left side. There was no significant correlation between the ISI and VAS, WOMAC and Lequesne indexes, postural stability scores, and isokinetic measurements (r<0.3, p>0.05). In primary knee OA, the ISI may not have an effect on pain, physical function, fall risk, postural stability, and isokinetic muscle strength. KA18/170.


Searching for the noninvasive biomarker holy grail: are urine proteomics the answer?
Recently, biobehavioral nursing scientists have focused their attention on the search for biomarkers or biological signatures to identify patients at risk for various health problems and poor disease outcomes. In response to the national impetus for biomarker discovery, the measurement of biological fluids and tissues has become increasingly sophisticated. Urine proteomics, in particular, may hold great promise for biobehavioral focused nursing scientists for examination of symptom-and syndrome-related research questions. Urine proteins are easily accessible secreted proteins that provide direct and indirect windows into bodily functions. Advances in proteomics and biomarker discovery provide new opportunities to conduct research studies with banked and fresh urine to benefit diagnosis, prognosis, and evaluation of outcomes in various disease populations. This article provides a review of proteomics and a rationale for utilizing urine proteomics in biobehavioral research. It addresses as well some of the challenges involved in data collection and sample preparation.


Investigation of the Prognostic Significance of Neuroendocrine Differentiation in Gleason Score 7 to 10 Prostate Adenocarcinoma in Patients With Distant Metastasis After Definitive Radiotherapy.
We investigated the prognostic implications of neuroendocrine differentiation (NED) in prostate adenocarcinoma detected by chromogranin A (CgA) in patients who developed distant metastasis (DM) after radiotherapy. Patients with Gleason score 7 to 10 conventional acinar prostate adenocarcinoma treated with definitive radiotherapy and with core biopsy CgA staining completed were reviewed. Patients who developed DM, defined as disease beyond the primary tumor or pelvic lymph nodes, underwent detailed chart review. Statistical analysis included Kaplan-Meier estimates and descriptive statistics to compare based on quantification of CgA staining. Thirty-five patients had confirmed DM. Twenty-five patients had less than 1% of cells staining positive for CgA, and 10 patients had more than 1%. Median overall survival (OS) time was 3.26 and 1.04 years, respectively (P = .52). Median cause-specific survival (CSS) was 6.15 and 1.04 years, respectively (P = .21). Fifty-six percent of patients with CgA less than 1% died of prostate cancer compared with 90% of those with CgA more than 1% (P = .059). There were no significant differences in sites of metastatic disease or administration of systemic therapies. No significant differences in OS and CSS were observed based on NED detected by CgA. Reduced median survival time and increased cancer-related death in cases with focal NED generates the hypothesis of inferior outcomes among patients with documented DM.


Inhibition of adjuvant arthritis in rats by electroporation with interleukin-1 receptor antagonist.
To assess the protective effects of the cytokine inhibitor interleukin-1 receptor antagonist (IL-1ra) on gene induction, an electroporation technique to treat adjuvant-induced arthritis (AIA) in rats was established, and its advantage was estimated in the present study. Electroporation with human IL-1ra was performed in Lewis rats before and after induction of AIA. Local inflammation was evaluated by monitoring hind paw swelling, whereas histological evaluations were performed using paraffin embedded sections of hind paw specimens stained with hematoxylin and eosin. In addition, serum IL-1? levels were analyzed using an enzyme-linked immunosorbent assay. Induction of IL-1ra by our electroporation method inhibited systematic body weight loss and enhancement of local inflammation after intradermal injection of heat-killed Mycobacterium tuberculosis. Notably, IL-1ra electroporation reduced paw swelling, inflammation, and bone erosion scores in embedded sections and serum IL-1? levels induced in AIA rats. The IL-1ra gene induction using the present electroporation technique inhibited local and systematic inflammation in AIA rats. These results indicate that this method may represent a novel pharmacotherapy strategy for arthritis.


Clinical and genetic analysis of an inherited case of thyroid adenoma/cancer.
We studied a family in which thyroid neoplasms appeared to occur through genetic inheritance. Six blood relations, including the two probands, had thyroid carcinoma, and six others had benign thyroid tumors. When both parents had a thyroid neoplasm, their children frequently had thyroid neoplasms; this was confirmed through two generations of this family. To clarify the mechanism of inheritance, we performed chromosomal analysis, Southern blot analysis of three variable number of tandem repeats markers and HLA typing on two probands, and examined their RET proto-oncogenes, and p53 and RB tumor suppressor genes. We could not find any positive data on genetic analysis, although our data were limited. In conclusion, we studied a family in which thyroid neoplasms have occurred partly through genetic inheritance, although environmental factors may have influenced the occurrence of thyroid diseases. A search for a predisposing gene, using the microsatellite technique, is required to clarify the gentic factors involved.


Attitudes of Pulmonary and Critical Care Training Program Directors toward Quality Improvement Education.
Quality improvement (QI) is a required component of fellowship training in pulmonary, critical care, and sleep medicine. However, little is known about how training programs approach QI education. We sought to understand the perceptions of pulmonary, critical care, and sleep medicine training program directors toward QI education. We developed and fielded an internet survey of pulmonary, critical care, and sleep medicine training program directors during 2013. Survey domains included program characteristics, the extent of trainee and faculty involvement in QI, attitudes toward QI education, and barriers to successful QI education in their programs. A total of 75 program directors completed the survey (response rate = 45.2%). Respondents represented both adult (n = 43, 57.3%) and pediatric (n = 32, 42.7%) programs. Although the majority of directors (n = 60, 80.0%) reported substantial fellow involvement in QI, only 19 (26.0%) reported having a formal QI education curriculum. QI education was primarily based around faculty mentoring (n = 46, 61.3%) and lectures (n = 38, 50.7%). Most directors agreed it is an important part of fellowship training (n = 63, 84.0%). However, fewer reported fellows were well integrated into ongoing QI activities (n = 45, 60.0%) or graduating fellows were capable of carrying out independent QI (n = 28, 50.7%). Key barriers to effective QI education included lack of qualified faculty, lack of interest among fellows, and lack of time. Training program directors in pulmonary, critical care, and sleep medicine value QI education but face substantial challenges to integrating it into fellowship training.


Molybdenum, xanthine oxidase and riboflavin levels in tamoxifen treated postmenopausal women with breast cancer.
40 cases postmenopausal women with breast cancer constituted the study group and 20 sex and age matched formed the control group. The study group of untreated patients showed nonsignificant decrease in molybdenum but significant decrease in blood xanthine oxidase and riboflavin levels. Tamoxifen treated patients showed nonsignificant increase in molybdenum, after 3 months, significant increase after 6 months and significant increase in xanthine oxidase and riboflavin levels. Thus tamoxifen when given in breast cancer helps in amelioration of the diseased condition.


Ontology-based diagnostic decision support in radiology.
The Radiology Gamuts Ontology (RGO) is a knowledge model of diseases, interventions, and imaging manifestations. RGO incorporates 16,822 terms with their synonyms and abbreviations and 55,393 relationships between terms. Subsumption defines the relationship between more general and more specific terms; causality relates disorders and their imaging manifestations. We explored the application of the RGO to build an interactive decision support system for radiological diagnosis. The Gamuts DDx system was created to apply the RGO's knowledge: it identifies a list of potential diagnoses in response to one or more user-specified imaging observations. The system also identifies a set of observations that allow one to narrow the diagnosis, and dynamically narrows or expands the list of diagnoses as imaging findings are selected or deselected. The functionality has been implemented as a web-based user interface and as a web service. The current work demonstrates the feasibility of exploiting the RGO's causal knowledge to provide interactive decision support for diagnosis of imaging findings. Ongoing efforts include the further development of the system's knowledge base and evaluation of the system in clinical use.


Challenges and suggestions for defining replication "success" when effects may be heterogeneous: Comment on Hedges and Schauer (2019).
Psychological scientists are now trying to replicate published research from scratch to confirm the findings. In an increasingly widespread replication study design, each of several collaborating sites (such as universities) independently tries to replicate an original study, and the results are synthesized across sites. Hedges and Schauer (2019) proposed statistical analyses for these replication projects; their analyses focus on assessing the extent to which results differ across the replication sites, by testing for heterogeneity among a set of replication studies, while excluding the original study. We agree with their premises regarding the limitations of existing analysis methods and regarding the importance of accounting for heterogeneity among the replications. This objective may be interesting in its own right. However, we argue that by focusing only on whether the replication studies have similar effect sizes to one another, these analyses are not particularly appropriate for assessing whether the replications in fact support the scientific effect under investigation or for assessing the power of multisite replication projects. We reanalyze Hedges and Schauer's (2019) example dataset using alternative metrics of replication success that directly address these objectives. We reach a more optimistic conclusion regarding replication success than they did, illustrating that the alternative metrics can lead to quite different conclusions from those of Hedges and Schauer (2019). (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Adult neurogenesis in the intact and epileptic dentate gyrus.
Neurogenesis persists throughout life in the adult mammalian dentate gyrus. Adult-born dentate granule cells integrate into existing hippocampal circuitry and may provide network plasticity necessary for certain forms of hippocampus-dependent learning and memory. Neural stem cells and neurogenesis in the adult dentate gyrus are regulated by a variety of environmental, physiological, and molecular factors. These include aging, stress, exercise, neurovascular components of the stem cell niche, growth factors, neurotransmitters, and hormones. Seizure activity also influences dentate granule cell neurogenesis. Production of adult-born neurons increases in rodent models of temporal lobe epilepsy, and both newborn and pre-existing granule neurons contribute to aberrant axonal reorganization in the epileptic hippocampus. Prolonged seizures also disrupt the migration of dentate granule cell progenitors and lead to hilar-ectopic granule cells. The ectopic granule neurons appear to integrate abnormally and contribute to network hyperexcitability. Similar findings of granule cell layer dispersion and ectopic granule neurons in human TLE suggest that aberrant neurogenesis contributes to epileptogenesis or learning and memory disturbances in this epilepsy syndrome.


Weak polyelectrolyte-based multilayers via layer-by-layer assembly: Approaches, properties, and applications.
Layer-by-layer (LbL) assembly is a nanoscale technique with great versatility, simplicity and molecular-level processing of various nanoscopic materials. Weak polyelectrolytes have been used as major building blocks for LbL assembly providing a fundamental and versatile tool to study the underlying mechanisms and practical applications of LbL assembly due to its pH-responsive charge density and molecular conformation. Because of high-density uncompensated charges and high-chain mobility, weak polyelectrolyte exponential multilayer growth is considered one of the fastest developing areas for organized molecular films. In this article, we systematically review the current status and developments of weak polyelectrolyte-based multilayers including all-weak-polyelectrolyte multilayers, weak polyelectrolytes/other components (e.g. strong polyelectrolytes, neutral polymers, and nanoparticles) multilayers, and exponentially grown weak polyelectrolyte multilayers. Several key aspects of weak polyelectrolytes are highlighted including the pH-controllable properties, the responsiveness to environmental pH, and synergetic functions obtained from weak polyelectrolyte/other component multilayers. Throughout this review, useful applications of weak polyelectrolyte-based multilayers in drug delivery, tunable biointerfaces, nanoreactors for synthesis of nanostructures, solid state electrolytes, membrane separation, and sensors are highlighted, and promising future directions in the area of weak polyelectrolyte-based multilayer assembly such as fabrication of multi-responsive materials, adoption of unique building blocks, investigation of internal molecular-level structure and mechanism of exponentially grown multilayers, and exploration of novel biomedical and energy applications are proposed.


On the roles of function and selection in evolving systems.
Physical laws-such as the laws of motion, gravity, electromagnetism, and thermodynamics-codify the general behavior of varied macroscopic natural systems across space and time. We propose that an additional, hitherto-unarticulated law is required to characterize familiar macroscopic phenomena of our complex, evolving universe. An important feature of the classical laws of physics is the conceptual equivalence of specific characteristics shared by an extensive, seemingly diverse body of natural phenomena. Identifying potential equivalencies among disparate phenomena-for example, falling apples and orbiting moons or hot objects and compressed springs-has been instrumental in advancing the scientific understanding of our world through the articulation of laws of nature. A pervasive wonder of the natural world is the evolution of varied systems, including stars, minerals, atmospheres, and life. These evolving systems appear to be conceptually equivalent in that they display three notable attributes: 1) They form from numerous components that have the potential to adopt combinatorially vast numbers of different configurations; 2) processes exist that generate numerous different configurations; and 3) configurations are preferentially selected based on function. We identify universal concepts of selection-static persistence, dynamic persistence, and novelty generation-that underpin function and drive systems to evolve through the exchange of information between the environment and the system. Accordingly, we propose a "law of increasing functional information": The functional information of a system will increase (i.e., the system will evolve) if many different configurations of the system undergo selection for one or more functions.


Disseminated Burkitt's Lymphoma with a Pancreatic Mass in a HIV Positive Woman Diagnosed by Axillary Lymph Node Biopsy.
Burkitt's Lymphoma (BL) is a highly aggressive B cell lymphoma of non-Hodgkin's type usually presenting in extranodal sites for endemic and sporadic types of the disease. Like other non-Hodgkin's Lymphomas (NHL), HIV positive associated BL is associated with peripheral lymphadenopathy. We present a case of 22-year-old newly diagnosed HIV positive female patient who presented with generalized peripheral lymphadenopathy and obstructive jaundice. Initial work up was suggestive of acute pancreatitis with further evaluation revealing a pancreatic head mass. BL was confirmed both by axillary lymph node biopsy and immunohistochemistry, highlighting the importance of high index of suspicion and prompt histopathological diagnosis to enable treatment of this fatal disease that is potentially curable.


Narcolepsy in children: a practical guide to its diagnosis, treatment and follow-up.
Narcolepsy is a neurological syndrome characterised by daytime somnolence and cataplexy which often begins in childhood. Failing to recognise the condition may lead to mislabelling a child as lazy or depressed. The diagnostic criteria for narcolepsy vary with age. In children 8 years and older a Multiple Sleep Latency Test with an average latency of less than 8 minutes, and 2 or more sleep onset REM episodes supports the diagnosis. Human leucocyte antigen (HLA) marker DQbeta1 -0602 has been associated with narcolepsy. The current evidence supports the hypothesis that transmission of narcolepsy is multifactorial. with at least two genes, one of which is non-HLA related. The goal of all therapeutic approaches in narcolepsy is to control the narcoleptic symptoms and allow the patient to continue to fully participate in personal and academic activities. This usually requires a combination of behavioural therapy along with medication. Medications for patients with excessive sleepiness are usually stimulants, including amphetamines. However, a novel wake promoting agent, modafinil, is now available. Cataplexy can be controlled by medications with noradrenergic reuptake-blocking properties, such as clomipramine and fluoxetine, through their active metabolites. Increased awareness of narcolepsy is important to allow earlier diagnosis. Research on the effects different medications have, specifically on children with narcolepsy, has been very limited.


Anxiolytic-like effects observed in rats exposed to the elevated zero-maze following treatment with 5-HT2/5-HT3/5-HT4 ligands.
The present study examined the effects of administering selective 5-HT antagonists and agonists to rats tested in the elevated zero-maze (EZM) model of anxiety. The EZM paradigm has advantages over the elevated plus-maze (EPM) paradigm with respect to measuring anxiety, yet has been utilized less frequently. Three experiments were conducted each with a diazepam control (0.25, 0.5 and 0.75 mg/kg). In the first experiment, we administered the 5-HT2C antagonist RS 102221 (0.5, 1.0, and 2.0 mg/kg) and 5-HT2C agonist MK-212 (0.25, 0.5 and 0.75 mg/kg); in the second experiment, we administered the 5-HT3 antagonist Y-25130 (0.1, 1.0 and 3.0 mg/kg) and 5-HT3 agonist SR 57227A (0.1, 1.0 and 3.0 mg/kg), and in the third experiment, we administered the 5-HT4 antagonist RS 39604 (0.01, 0.1, 1.0 mg/kg) and 5-HT4 agonist RS 67333 (0.01, 0.1 and 0.5 mg/kg). The administration of 5-HT2/3/4 subtype antagonists all generated behavioral profiles indicative of anxiolytic-like effects in the EZM, which was apparent from examination of both traditional and ethological measures. While little effect was observed from 5-HT2 and 5-HT3 agonists, the 5-HT4 agonist RS 67333 was found to produce a paradoxical anxiolytic-like effect similar to that produced by the 5-HT4 antagonist RS 39604. We conclude by discussing the implications of these findings.


[The hemodynamic effects of the in-vivo administration of insulin-like growth-factor I].
Recent studies have demonstrated that IGF-I has several biological activities that correlate with the GH axis, by acting as a cell protecting factor and a promoting compound in different tissues and organs. Our latest findings have demonstrated a potential application of IGF-I in the treatment of postischemic renal injury, which frequently appears after a kidney transplant. The beneficial effect of the renal postoperative recovery probably correlates with the regulation of the vascular tone, in which IGF-I plays a role with other cytokines. However, this rises the question whether IGF-I has any effect on the general hemodynamic status. This study was designed to underline the intraoperative hemodynamic effect of exogenous IGF-I in an experimental setting of renal transplantation in swine. Twelve female swine underwent a left renal autotransplantation. At the reperfusion the animals were separated in two groups. Group one served as control. Group two received 400 micrograms of IGF-I (added to the flushing solution). The animals were kept under complete hemodynamic monitoring over the operation. Among the different parameters studied (mean arterial pressure, mean pulmonary arterial pressure, pulmonary wedge pressure, central venous pressure, cardiac output, oxygen extraction ratio, systemic vascular resistance, oxygen delivery and oxygen consumption), any statistically significant difference between group one and two were observed. While the clinical administration of IGF-I requires further studies, the in vivo administration of this peptide is apparently well tolerated, and does not cause any hemodynamic instability to the operation.


Antibody response in patients with Gaucher disease after repeated infusion with macrophage-targeted glucocerebrosidase.
Recent clinical data have shown that enzyme replacement therapy with macrophage-targeted glucocerebrosidase (GCR) can be effective in treating type 1 Gaucher disease. Sera from 262 patients, repeatedly infused with GCR, were assessed for the presence of antibodies to this therapeutic protein. Patient serum samples obtained at 3-month intervals were assessed by enzyme-linked immunosorbent assay and those with values greater than two standard deviations above the mean value obtained with a pool of normal human sera were further characterized by radioimmunoprecipitation. At the time of these analyses, the duration of patient treatment varied from 3 months to approximately 3 years. Of the 262 patients analyzed, 34 (12.9%) showed IgG antibodies, as confirmed by radioimmunoprecipitation. All patients who seroconverted did so within 1 year of treatment. The predominant antibody developed was the IgG1 subclass. Fourteen patients in the study experienced periodic symptoms suggestive of immediate hypersensitivity. Nine of these 14 patients had antibody to GCR as determined by radioimmunoprecipitation, whereas 5 patients were antibody negative. There was no evidence of the development of IgE antibodies in these 14 patients. The presence of GCR antibodies did not appear to effect efficacy of therapy in any of the patients treated to date.


Neuraminidase inhibitors as a strategy for influenza treatment: pros, cons and future perspectives.
Introduction: Influenza represents a major public health threat worldwide. Implementation of good personal health and hygiene habits, together with vaccination, is the most effective tools to reduce influenza burden both in community and in healthcare setting. However, achieving adequate vaccination rates is challenging, and vaccination does not always guarantee complete protection. Neuraminidase inhibitors represent an important measure to reduce the risk of influenza-related complications among high-risk patients developing influenza infection. Areas covered: Neuraminidase inhibitors have been proven to be safe and effective in reducing influenza severity, duration of symptoms, hospitalizations, and influenza-related-mortality. Here the authors review the available data on neuraminidase inhibitors, including the mechanism of action, pharmacokinetics, efficacy, safety and current indications for their use in clinical practice. Expert opinion: Although vaccination is the most effective tool to reduce influenza-associated morbidity and mortality, neuraminidase inhibitors represent an important option for the treatment of patients with influenza infection, particularly in high-risk categories. Moreover, antivirals play an important role in influenza prevention and prophylaxis in selected settings.


Radiation therapy for histologically confirmed primary central nervous system germinoma.
To evaluate survival and patterns of recurrence in patients with primary central nervous system germinoma treated with radiation therapy. Data regarding 48 patients with histologically confirmed, primary central nervous system germinoma were reviewed. All had been operated on at the Mayo Clinic between the years 1935 and 1993. Thirty-two patients (67%) were treated since 1973. The study group included 39 males and 9 females, with a median age at diagnosis of 17 years (range, 6-42 years). Twelve patients (25%) were treated with craniospinal axis irradiation, 11 (23%) received whole-brain irradiation without spinal axis irradiation, and 24 (50%) underwent partial-brain irradiation. Treatment volumes were unknown in one patient. The median dose to the primary tumor was 44.00 Gy (range, 7.44-59.40 Gy). The median follow-up was 5.5 years (range, 4 months to 37 years). Actuarial 5-year and 10-year survival for the entire study group of patients was 80%. There was a trend toward improved survival in patients treated after 1973 (introduction of computed tomography) with 5-year and 10-year survival of 91% vs. 63% in prior years (p = 0.07). For the group of 31 patients treated since 1973 with known treatment volumes, the spinal axis failure rate at 5 years was 49% for patients treated with partial brain fields (11 patients) vs. 0% for those having undergone whole brain (10 patients) or craniospinal axis (10 patients) irradiation (p = 0.007). The rate of brain failure was also significantly higher in patients receiving less than whole-brain irradiation; at 5 years, 45% of the patients treated with partial-brain fields had intracranial recurrence of disease compared to 6 % of patients treated with craniospinal axis or whole-brain irradiation (p = 0.01). Among the 32 modern era patients, the rate of brain failure was higher in patients who received doses less than 40 Gy (median dose, 48.55 Gy; range, 30.60-59.40 Gy) to the primary tumor (5-year brain failure rate 52% vs. 11%, p = 0.002). The long-term survival of patients with histologically proven CNS germinoma treated with radiation is excellent. Whole-brain or craniospinal axis irradiation appears to result in fewer spine and brain failures than does partial-brain irradiation. Furthermore, the administration of doses greater than 40 Gy to the primary tumor is associated with better local control.


Cdc42 negatively regulates endocytosis during apical membrane maintenance in live animals.
Lumen establishment and maintenance are fundamental for tubular organs physiological functions. Most of the studies investigating the mechanisms regulating this process have been carried out in cell cultures or in smaller organisms, whereas little has been done in mammalian model systems in vivo. Here we used the salivary glands of live mice to examine the role of the small GTPase Cdc42 in the regulation of the homeostasis of the intercellular canaliculi, a specialized apical domain of the acinar cells, where protein and fluid secretion occur. Depletion of Cdc42 in adult mice induced a significant expansion of the apical canaliculi, whereas depletion at late embryonic stages resulted in a complete inhibition of their postnatal formation. In addition, intravital subcellular microscopy revealed that reduced levels of Cdc42 affected membrane trafficking from and toward the plasma membrane, highlighting a novel role for Cdc42 in membrane remodeling through the negative regulation of selected endocytic pathways.


The effects of infant deaths on the risk of subsequent birth: a comparative analysis of DHS data from Ghana and Kenya.
This paper examines the conditions under which there might be a strong or weak relationship between childhood mortality and fertility at the micro level. The premise is that as a society undergoes transition during which a conscious effort is made to space and limit birth, the effect associated with infant death on the risk of subsequent birth reduces. Using the 1998 DHS data from Ghana and Kenya, our multivariate hazard models show that women who have experienced infant deaths tend to have a higher risk of subsequent births than those without any infant deaths at all parities studied in both countries. In a comparative context, however, the magnitude of the effect associated with infant death was weaker in Kenya at all parities, corroborating the hypothesis that the effect indeed reduces in the course of transition. Besides infant deaths, other demographic, socioeconomic and sociocultural factors were also found to associate with the risk of births. The limitations and policy implications of the findings are discussed.


Multichannel transforms for signal/image processing.
This paper presents a novel approach to the Fourier analysis of multichannel time series. Orthogonal matrix functions are introduced and are used in the definition of multichannel Fourier series of continuous-time periodic multichannel functions. Orthogonal transforms are proposed for discrete-time multichannel signals as well. It is proven that the orthogonal matrix functions are related to unitary transforms (e.g., discrete Hartley transform (DHT), Walsh-Hadamard transform), which are used for single-channel signal transformations. The discrete-time one-dimensional multichannel transforms proposed in this paper are related to two-dimensional single-channel transforms, notably to the discrete Fourier transform (DFT) and to the DHT. Therefore, fast algorithms for their computation can be easily constructed. Simulations on the use of discrete multichannel transforms on color image compression have also been performed.


Local or Not Local: Investigating the Nature of Striatal Theta Oscillations in Behaving Rats.
In the cortex and hippocampus, neuronal oscillations of different frequencies can be observed in local field potentials (LFPs). LFPs oscillations in the theta band (6-10 Hz) have also been observed in the dorsolateral striatum (DLS) of rodents, mostly during locomotion, and have been proposed to mediate behaviorally-relevant interactions between striatum and cortex (or between striatum and hippocampus). However, it is unclear if these theta oscillations are generated in the striatum. To address this issue, we recorded LFPs and spiking activity in the DLS of rats performing a running sequence on a motorized treadmill. We observed an increase in rhythmical activity of the LFP in the theta-band during run compared to rest periods. However, several observations suggest that these oscillations are mainly generated outside of the striatum. First, theta oscillations disappeared when LFPs were rereferenced against a striatal recording electrode and the imaginary coherence between LFPs recorded at different locations within the striatum was null. Second, 8% of the recorded neurons had their spiking activity phase-locked to the theta rhythm. Third, Granger causality analyses between LFPs simultaneously recorded in the cortex and the striatum revealed that the interdependence between these two signals in the theta range was mostly accounted for by a common external source. The most parsimonious interpretation of these results is that theta oscillations observed in striatal LFPs are largely contaminated by volume-conducted signals. We propose that striatal LFPs are not optimal proxies of network dynamics in the striatum and should be interpreted with caution.


Chronic active hepatitis associated with diclofenac sodium therapy.
Diclofenac sodium (Voltarol, Geigy Pharmaceuticals) is a non-steroidal anti-inflammatory derivative of phenylacetic acid. Although generally well-tolerated, asymptomatic abnormalities of liver function have been recorded and, less commonly, severe hepatitis induced by diclofenac. The patient described developed chronic active hepatitis after six months therapy with diclofenac sodium which progressed despite the withdrawal of the drug, a finding not previously reported.


Self-stimulation in the ventromedial hypothalamus.
Male Sprague-Dawley rats pressed a bar for electrical stimulation of the ventromedial hypothalamus. The threshold for such behavior correlated positively with the threshold to stop feeding and the threshold to escape from prolonged stimulation at the same electrode site. The results again open the question of the role that the ventromedial area is playing in positively reinforcing and punishment systems.


Proliferation of glycogen accumulating organisms induced by Fe(III) dosing in a domestic wastewater treatment plant.
To meet the effluent requirements given for the sensitive receiving body, the Southpest Wastewater Treatment Plant of Budapest, Hungary uses a combined activated sludge-biofilter system with chemical precipitation for P removal. Causes of the proliferation of glycogen accumulating organisms (GAOs) observed in the unaerated/oxic activated sludge unit of this system were investigated both in full-scale and in lab-scale experiments combined with a detailed analysis of the microbial communities. Concentration profile measurements throughout the 8-stage activated sludge unit indicated anaerobic conditions in the first two unaerated reactors and low orthophosphate level (< 1 mg l(-1)) in all of the stages that could not be attributed to the influent quality, but to Fe (III)-dosing to the returned activated sludge. Microbiological analysis revealed the presence of GAOs from the GB group in the Gammaproteobacteria and occasionally tetrad-forming organisms from Actinobacteria, and the absence of Rhodocyclus-related polyphosphate accumulating organisms (PAOs) in the activated sludge samples. Comparative lab-scale studies carried out in two identically arranged UCT-systems with staged anoxic reactors also confirmed that Fe (III)-dosing may result in phosphorus deficiency of the microbial niche, leading to the suppression of growth and EBPR activity of PAOs and to the proliferation of GAOs.


Oscillopsia: visual function during motion in the absence of vestibulo-ocular reflex.
To investigate (1) the effects of loss of vestibular function on spatiotemporal vision and (2) the mechanisms which enable labyrinthine defective (LD) patients to adapt to oscillopsia. Visual function and eye movements were assessed in seven normal subjects and four LD patients with oscillopsia due to absent vestibulo-ocular reflex. Temporal vision was assessed by measurement of threshold sensitivity for detection of a target which moved across a flickering, spatially uniform background field. Spatial vision was investigated by measurements of threshold sensitivity for the detection of a target moving across a spatially modulated background in the form of square wave gratings. Velocity discrimination was assessed with drifting gratings. All measurements were made under static conditions and during oscillatory movement of either the visual stimulus or the subject (1 Hz, peak velocity 50 degrees/s). Temporal responses--Normal subjects and LD patients exhibited similar responses while static and under body oscillation. Spatial responses--The two groups achieved similar results under static conditions but body oscillation reduced threshold sensitivities and shifted the spatial response function towards lower spatial frequencies in the LD patients only. Similar changes in the spatial responses were seen during oscillation of the visual stimulus but these occurred in both normal subjects and LD patients. Velocity discrimination--Two LD patients achieved normal velocity discrimination but the other two showed abnormal responses to visual stimulus movement; one displayed a loss of velocity discrimination during whole body oscillation, and the other mismatched the velocity of two moving grating stimuli. The changes in the spatial responses are attributed to the presence of retinal slip during visual stimulus motion in all subjects or body oscillation in the LD patients. It is concluded that any visual adaptation to oscillopsia achieved by the LD patients does not influence the measured spatial response functions, which arise at an early stage of visual processing. The abnormal velocity discrimination may relate to the progressive improvement in oscillopsia reported by LD patients.


Nailfold capillary density is importantly associated over time with muscle and skin disease activity in juvenile dermatomyositis.
To investigate the longitudinal association of nailfold capillary density (NCD; as a potential marker of activity) with various other clinical measures of disease activity and to evaluate baseline NCD as a predictor of disease outcome in children with JDM. Data from 809 clinic visits from 92 JDM patients were prospectively collected at each clinic visit over a time period of 5.5 years. The number of capillaries per millimetre at the distal nailfold was scored using a stereomicroscope. Disease activity was determined using the Childhood Myositis Assessment Scale (CMAS) and a modification of the validated disease activity score (DAS), which included three skin (SDAS) and three muscle (MDAS) criteria. An inception cohort subgroup (n=28) with a baseline visit at diagnosis was analysed separately. Both DAS subscores, MDAS (β = -0.04437, P < 0.0001) and SDAS (β = -0.1589, P < 0.0001), as well as the CMAS (β = 0.02165, P < 0.0001) were significantly associated with loss of end row nailfold capillary over time (multiple regression mixed-model analysis). All patients in the inception subcohort showed a reduced baseline NCD (diagnostic sensitivity = 100%) that improved as the disease improved, but this did not predict longer term outcome or course of disease. NCD is a marker of skin and muscle disease activity, and is an important measure of disease activity changes from visit to visit. Determination of capillary density may be useful when making treatment decisions. A decrease in NCD may be considered for inclusion in the diagnostic criteria due to its high sensitivity.


Heinz bodies induce clustering of band 3, glycophorin, and ankyrin in sickle cell erythrocytes.
In earlier model studies we demonstrated that artificially denatured hemoglobin binds to and clusters the protein, band 3, in the plane of the erythrocyte membrane. To determine whether denatured hemoglobin also clusters band 3 in vivo, we have compared the locations of denatured hemoglobin aggregates (Heinz bodies) with band 3 in sickle cells using phase contrast and immunofluorescence microscopy. We report that where Heinz bodies are found associated with the cytoplasmic surface of the membrane, clusters of band 3 are usually colocalized within the membrane. In contrast, normal erythrocyte membranes and regions of sickle cell membranes devoid of Heinz bodies display an uninterrupted staining of band 3. Similarly, ankyrin and glycophorin are periodically seen to aggregate at Heinz body sites, but the degree of colocalization is lower than for band 3. These data demonstrate that the binding of denatured hemoglobin to the membrane forces a redistribution of several major membrane components.


Reduction in migraine pain intensity in patients treated with erenumab: A post hoc analysis of two pivotal randomized studies.
Erenumab (erenumab-aooe in the US) effectively reduces monthly migraine days in episodic and chronic migraine. This traditional outcome does not capture the intensity of headache pain on days with migraine. This post hoc analysis of two pivotal randomized, placebo-controlled studies in patients with episodic migraine and chronic migraine examined the effect of erenumab 70 and 140 mg on migraine pain. Cumulative monthly migraine pain intensity is the sum of the peak pain intensity scores (0 = no migraine to 3 = migraine day with severe pain) on migraine days. Change from baseline in cumulative monthly migraine pain and average monthly pain intensity was assessed over months 4 to 6 for episodic migraine and month 3 for chronic migraine; change in average monthly pain intensity was assessed among monthly migraine days responders/non-responders. Efficacy analysis included 946 patients for the episodic migraine study and 656 patients for the chronic migraine study. Cumulative monthly migraine pain decreased significantly with erenumab versus placebo (p < 0.001, for episodic migraine and chronic migraine). In addition, monthly average migraine pain intensity decreased significantly with erenumab versus placebo for episodic migraine (p < 0.01); decreases were non-significant for chronic migraine. In comparison with placebo-treated patients, a greater proportion of erenumab-treated patients were pain intensity responders regardless of threshold used. Episodic migraine and chronic migraine patients with a ≥50% reduction in monthly migraine days (responders) had a greater reduction in monthly average pain intensity than non-responders. Erenumab reduced cumulative monthly migraine pain in episodic migraine and chronic migraine patients and significantly reduced monthly average migraine pain in episodic migraine, demonstrating treatment benefit beyond reduction in migraine frequency.Clinical Trial Registration: ClinicalTrials.gov, NCT02456740; ClinicalTrials.gov, NCT02066415.


Value of the ViziLite Plus System as a diagnostic aid in the early detection of oral cancer/premalignant epithelial lesions.
The aim of the study was to assess the value of the chemiluminescent light and 1% tolonium chloride as a diagnostic aid in the early detection of oral cancer/premalignant epithelial lesions. Thirty consecutive patients with 41 visually identified oral lesions suggestive of being premalignant underwent chemiluminescence and tolonium chloride examination followed by incisional biopsy with histopathologic evaluation. The biopsies of 34 lesions (82.92%) revealed no dysplasia, 3 lesions (7.32%) revealed mild dysplasia, 3 lesions (7.32%) demonstrated severe dysplasia, and 1 lesion (2.44%) was malignant (squamous cell carcinoma). The chemiluminescent examination improved the brightness (58.54% of the cases), sharpness (56.1% of the cases), texture (60.98% of the cases), and size of the lesion (53.66% of the cases). With references to serious pathologies, 7 cases (100.0%) were brighter, and size was more visualized in 6 cases (85.71%) when using chemiluminescence examination than under incandescent light. Twenty-five (73.53%) of nonserious pathology and 7 (100.0%) of serious pathology (6 dysplasias, 1 squamous cell carcinoma) were positively stained by toluidine blue. Three (8.82%) of nonserious pathology and 0 (0.0%) of serious pathology lesions were identified as true negatives when toluidine blue staining was used. The overall toluidine blue sensitivity and specificity were 81.8% and 37.5%, respectively. Chemiluminescent light demonstrates better visualization (brightness, size) of serious pathology lesions in comparison with conventional clinical oral examination under incandescent light. Toluidine blue demonstrates 100% sensitivity in staining serious pathology. The ViziLite Plus system may help the practitioner to visualize oral pathologies that are not readily detectable with conventional incandescent lighting.


Endosalpingiosis in pregnancy. Case report.
At caesarean section, an unusual cystic lesion was found on the anterior uterine surface and on both ovaries. Biopsy established a diagnosis of endosalpingiosis. The pathogenesis and possible significance of the lesion are discussed, this being the first time this condition has been described in pregnancy.


Inhibition of HIV-1 replication by P-TEFb inhibitors DRB, seliciclib and flavopiridol correlates with release of free P-TEFb from the large, inactive form of the complex.
The positive transcription elongation factor, P-TEFb, comprised of cyclin dependent kinase 9 (Cdk9) and cyclin T1, T2 or K regulates the productive elongation phase of RNA polymerase II (Pol II) dependent transcription of cellular and integrated viral genes. P-TEFb containing cyclin T1 is recruited to the HIV long terminal repeat (LTR) by binding to HIV Tat which in turn binds to the nascent HIV transcript. Within the cell, P-TEFb exists as a kinase-active, free form and a larger, kinase-inactive form that is believed to serve as a reservoir for the smaller form. We developed a method to rapidly quantitate the relative amounts of the two forms based on differential nuclear extraction. Using this technique, we found that titration of the P-TEFb inhibitors flavopiridol, DRB and seliciclib onto HeLa cells that support HIV replication led to a dose dependent loss of the large form of P-TEFb. Importantly, the reduction in the large form correlated with a reduction in HIV-1 replication such that when 50% of the large form was gone, HIV-1 replication was reduced by 50%. Some of the compounds were able to effectively block HIV replication without having a significant impact on cell viability. The most effective P-TEFb inhibitor flavopiridol was evaluated against HIV-1 in the physiologically relevant cell types, peripheral blood lymphocytes (PBLs) and monocyte derived macrophages (MDMs). Flavopiridol was found to have a smaller therapeutic index (LD50/IC50) in long term HIV-1 infectivity studies in primary cells due to greater cytotoxicity and reduced efficacy at blocking HIV-1 replication. Initial short term studies with P-TEFb inhibitors demonstrated a dose dependent loss of the large form of P-TEFb within the cell and a concomitant reduction in HIV-1 infectivity without significant cytotoxicity. These findings suggested that inhibitors of P-TEFb may serve as effective anti-HIV-1 therapies. However, longer term HIV-1 replication studies indicated that these inhibitors were more cytotoxic and less efficacious against HIV-1 in the primary cell cultures.


Development and Validation of the Chinese Version of Short-Form of Interpersonal Sensitivity Measure (IPSM).
This study was conducted to develop a short form of the Interpersonal Sensitivity Measure (IPSM), translated into Chinese. A total of 1237 Chinese undergraduates, divided into four groups, participated during various phases of scale development. Exploratory factor analysis supported a five-factor structure of the IPSM-C among Chinese undergraduates, which is in accordance with the original model established by Boyce and Parker that contained 36 items. We next developed a 15-item short form of the IPSM (IPSM-CS) whose structural validity was comparable to the full form. All IPSM-CS sub-scales, as well as the total scale, showed good internal consistency, test-retest reliability and criterion-related validity. The present results indicate that the IPSM-CS may be a useful and reliable alternative to the original IPSM for individuals fluent in Chinese.


Neuromuscular adaptations in human muscle following low intensity resistance training with vascular occlusion.
Low-intensity (approximately 50% of a single repetition maximum-1 RM) resistance training combined with vascular occlusion results in increases in muscle strength and cross-sectional area [Takarada et al. (2002) Eur J Appl Physiol 86:308-331]. The mechanisms responsible for this hypertrophy and strength gain remain elusive and no study has assessed the contribution of neuromuscular adaptations to these strength gains. We examined the effect of low-intensity training (8 weeks of unilateral elbow flexion at 50% 1 RM) both with (OCC) and without vascular occlusion (CON) on neuromuscular changes in the elbow flexors of eight previously untrained men [19.5 (0.4) years]. Following training, maximal voluntary dynamic strength increased (P<0.05) in OCC (22%) and CON (23%); however, isometric maximal voluntary contraction (MVC) strength increased in OCC only (8.3%, P<0.05). Motor unit activation, assessed by interpolated twitch, was high (approximately 98%) in OCC and CON both pre- and post-training. Evoked resting twitch torque decreased 21% in OCC (P<0.05) but was not altered in CON. Training resulted in a reduction in the twitch:MVC ratio in OCC only (29%, P<0.01). Post-activation potentiation (PAP) significantly increased by 51% in OCC (P<0.05) and was not changed in CON. We conclude that low-intensity resistance training in combination with vascular occlusion produces an adequate stimulus for increasing muscle strength and causes changes in indices of neuromuscular function, such as depressed resting twitch torque and enhanced PAP.


Immunology of urinary tract infections.
The urinary tract is constantly exposed to different microorganisms that colonize the gastrointestinal tract and the urinary tract is normally well prepared to resist infections by these microorganisms. This resistance to infection is mainly accomplished by the versatility of the immune system in the urinary tract, with both innate and adaptive immune responses. With the increasing knowledge of how the immune system works in the urinary tract and also the recognition of the virulence attributes of uropathogens, several potentially effective and tailored strategies to contain or prevent urinary tract infections have emerged.


What Are DPT Program Practices and Attitudes Related to Population Health, Prevention, Health Promotion, and Wellness? Results of a National Survey.
Noncommunicable diseases have increased in prevalence and are now responsible for the majority of the burden of disease. Aligning entry-level (professional) physical therapist education with these changing societal needs may position physical therapists to best address them. However, no comprehensive understanding of the practices and attitudes related to population health, prevention, health promotion, and wellness (PHPW) content among accredited US professional doctor of physical therapy (DPT) programs has been established. This study aims to identify practices and attitudes related to PHPW content among accredited US DPT programs. A mixed-methods cross-sectional design using an electronic survey was utilized. Program directors of each accredited DPT program were identified using an official Commission on Accreditation in Physical Therapy Education list and invited to ascertain the perceived importance of PHPW, describe the delivery of PHPW content, and identify factors that influence inclusion of PHPW content in US DPT programs. Individuals from 49% of 208 invited programs responded. Nearly all programs reported teaching prevention (96.1%), health promotion (95.1%), and wellness content (98.0%), while fewer reported teaching population health (78.4%). However, only 15% of PHPW topics were covered in depth. Facilitators and barriers to the delivery of PHPW content were reciprocal and included faculty with PHPW expertise, logistical flexibility and support, and the perceived importance of PHPW content. The majority of US DPT programs are teaching PHPW content. Lack of trained faculty and lack of professional competencies hinder further integration of PHPW content into curricula. The findings of this study highlight avenues for additional research to determine professional PHPW competencies and additional educational needs for faculty members.


[Autochthonous microbiota, probiotics and prebiotics].
The autochthonous microbiota is the community of microorganisms that colonizes the skin and mucosal surfaces. The symbiosis is, generally, mutualistic but it can become parasitic due to immune response alterations. The skin microbiota includes bacteria (95%), lipophilic fungi and mites. In the digestive apparatus, each cavity presents its own microbiota, which reaches its target organ during the perinatal period, originating complex and stable communities (homeostasis). The vaginal microbiota varies with the endocrine activity, significantly increasing during the fertile and pregnancy periods, when lactobacilli are the most abundant organisms. Four are the main benefits of the autochthonous microbiota: i) delivery of essential nutrients, such as vitamins and some amino acids; ii) utilization of undigestible diet components, the colonic microbiota degrades complex glycans and fulfils almost 20% of the calories present in a normal diet; iii) development of the immune system: the continuous contact with the immune system maintains it alert and in good shape to repel pathogens efficaciously and iv) microbial antagonism, hinders colonization of our mucosal surfaces by alochthonous, potentially pathogenic, organisms. This works through three mechanisms: colonization interference, production of antimicrobials and co-aggregation with the potential pathogens. The microbiota can, sporadically, produce damages: opportunistic endogenous infections and generation of carcinogenic compounds. Probiotics are "live microorganisms that when administered in adequate amounts, confer a health benefit to the consumer". Prebiotics are undigestible glycans that enhance the growth or activity of the intestinal microbiota, thus generating a health benefit. Synbiotics are mixes of probiotics and prebiotics that exert a synergistic health effect.


Childhood disorders of neurodegeneration with brain iron accumulation (NBIA).
Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of progressive complex motor disorders characterized by the presence of high brain iron, particularly within the basal ganglia. A number of autosomal recessive NBIA syndromes can present in childhood, most commonly pantothenate kinase-associated neurodegeneration (PKAN; due to mutations in the PANK2 gene) and phospholipase A2 group 6-associated neurodegeneration (PLAN; associated with genetic defects in PLA2G6). Mutations in the genes that cause these two neuroaxonal dystrophies are thought to disrupt the normal cellular functions of phospholipid remodelling and fatty acid metabolism. A significant proportion of children with an NBIA phenotype have no genetic diagnosis and there are, no doubt, additional as yet undiscovered genes that account for a number of these cases. NBIA disorders can be diagnostically challenging as there is often phenotypic overlap between the different disease entities. This review aims to define the clinical, radiological, and genetic features of such disorders, providing the clinician with a stepwise approach to appropriate neurological and genetic investigation, as well as a clinical management strategy for these neurodegenerative syndromes.


New developments in depression, anxiety, compulsiveness, and hallucinations in Parkinson's disease.
Increasing research efforts are focused on nonmotor aspects of Parkinson's disease (PD). Depression, anxiety, compulsivity (dopamine dysregulation symptoms), and hallucinations/psychosis are among these disorders, and all complicate the management of PD with negative influences on quality of life. There is a strong overlap between depression and apathy and likewise, depression and anxiety can coexist and require careful pharmacologic management. Dopamine dysregulation syndrome is linked to medication use and most clearly associated with dopamine agonists. In contrast, although hallucinations and psychosis do not occur unless patients with PD are treated with dopaminergic drugs, medication doses do not directly relate to this problem. Functional neuroimaging provides an excellent resource for investigating these behaviors as well as their anatomical and neurochemical bases. New treatments are being developed, but there have been very few large-scale randomized clinical trials to test the relative roles of new or available agents for abating these problematic behaviors.


Health checks in general practice: evidence first, not last.
Despite being ubiquitous in primary care, there is no accepted consensus on the definition and main components of health checks. They range from periodic health evaluations with a general physician, through the screening and diagnostic tests derived from these visits, to broader screening programs. Health checks may promote a fluid patient-provider relationship, improve the delivery of some preventive measures, and reduce the patient's anxiety. However, they can also expose patients to overdiagnosis and unnecessary interventions. Research on the benefits, harms, and cost-effectiveness of health checks is limited. As a consequence, health checks and screening programs are implemented in several countries and supported by national scientific societies based chiefly on their potential benefits on surrogate outcomes. There is also substantial variability regarding the target population (eg, initial age), tests, or intervals. We call for a rigorous assessment of the net effect of all health checks, taking into consideration common biases (eg, sticky-diagnosis and slippery-linkage biases), patient-important outcomes, potential adverse events, cost-effectiveness, as well as equity and feasibility of the proposed programs.