[The x-ray semeiotics of spinal involvement in psoriasis].
X-ray examinations of the bone and joint system in psoriasis patients with pain syndromes in the limb joints have revealed spinal involvement in many cases. The authors have distinguished and described x-ray semeiotics of the inflammatory (spondylitis, spondyloarthritis, sacroiliitis), degenerative dystrophic (intervertebral osteochondrosis, spondylarthrosis deformans, spondylosis), and mixed or combined (inflammatory + degenerative dystrophic) involvements of the spine in psoriasis.


Psychological responses to U.S. statewide restrictions and COVID-19 exposures: A longitudinal study.
The COVID-19 pandemic has generated debate as to whether community-level behavioral restrictions are worth the emotional costs of such restrictions. Using a longitudinal design, we juxtaposed the relative impacts of state-level restrictions and case counts with person-level direct and media-based exposures on distress, loneliness, and traumatic stress symptoms (TSS) during the COVID-19 pandemic in the United States. From March 18, 2020 to April 18, 2020 and September 9, 2020 to October 16, 2020, a representative probability sample of U.S. adults (N = 5,594) completed surveys of their psychological responses and personal direct and media-based exposures to the COVID-19 pandemic. Survey data were merged with publicly available data on the stringency of state-level mitigation policies (e.g., school/business closures) during this period and longitudinal case/death counts for each state. Three multilevel models (outcomes: distress, loneliness, TSS) were constructed. Measurements of dependent variables (Level 1) were nested within respondents (Level 2) who were nested within states (Level 3). State-level mitigation, cases, or deaths were not associated with any dependent variables (all p's > .05). However, person-level exposures, including having contracted COVID-19 oneself (distress b = .22, p < .001; loneliness b = .13, p = .03; TSS b = .18, p = .001), knowing others who were sick (distress b = .04, p < .001; loneliness b = .02, p < .001; TSS b = .05, p < .001) or died (distress b = .10, p = .001; loneliness b = .10, p = .003; TSS b = .16, p < .001), and exposure to pandemic-related media (distress b = .12, p < .001; loneliness b = .09, p < .001; TSS b = .16, p < .001), were positively associated with outcomes. Personal exposures to COVID-19 are more strongly associated with psychological outcomes than statewide mitigations levied to stop disease spread. Results may inform public health response planning for future disease outbreaks. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Irreversible inhibition of calmodulin-sensitive cyclic nucleotide phosphodiesterase.
Photolysis of solutions containing 4-azido-7-phenylpyrazolo-[1,5a]-1,3,5-triazine (APPT) and calmodulin-sensitive cyclic nucleotide phosphodiesterase resulted in reduction of both cyclic GMP and cyclic AMP hydrolytic activity. The inactivation was dependent upon both time of exposure to ultraviolet irradiation and the initial concentration of APPT. The photo-induced inactivation could be attenuated by the presence of cyclic GMP, 1-methyl-3-isobutylxanthine, and papaverine. alpha-Chymotrypsin treatment caused the enzyme to be fully active in the absence of calmodulin but this treatment did not alter the ability of APPT to inactivate the enzyme. Thus, inhibition of calmodulin-binding did not contribute to the photo-induced inactivation. These data indicate that APPT acts as a photoaffinity agent to covalently modify the APPT-binding site of calmodulin-sensitive phosphodiesterase.


Initial diagnoses of patients ultimately diagnosed with prion disease.
Prion diseases are rapidly progressive neurodegenerative diseases that frequently mimic other forms of dementia making them difficult to diagnose. To explore factors associated with the initial diagnoses of cases later determined to be caused by prion disease in an attempt to recognize key clinical variables that impact the timely diagnosis of prion disease. A retrospective chart review performed at Johns Hopkins Medicine and the Department of Veterans Affairs Health Care System (1995-2008) was conducted. Ninety-two subjects with definite or probable prion disease were included in the analyses. Demographic, clinical, diagnostic test results, neuropathologic, molecular, and genetic data were collected using a standardized instrument and compared between initial diagnosis groups. Cases were separated into five broad categories pertaining to their initial diagnoses: prion disease, non-prion-related dementia, psychiatric disorder, stroke, and other. The majority of cases did not receive an initial diagnosis of prion disease (n = 76, 83%). The plurality of subjects received an initial diagnosis of a non-prion disease related dementia (n = 33, 36%). Mean survival times varied between initial diagnosis groups (p = 0.042). Times to cerebrospinal fluid 14-3-3 analysis and electroencephalogram also differed between initial diagnosis groups. Most patients with prion disease are initially diagnosed with a non-prion disease related dementia. Several clinical features were associated with initial diagnoses including survival time, onset of specific symptoms, and times to 14-3-3 analyses and electroencephalogram. Expanding our knowledge of the various clinical presentations of prion disease, especially dementia, may aid in the earlier diagnoses of these rapidly progressive diseases.


Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development.
Unlike most cancers, adrenocortical carcinomas (ACCs) are more frequent in women than in men, but the underlying mechanisms of this sexual dimorphism remain elusive. Here, we show that inactivation of Znrf3 in the mouse adrenal cortex, recapitulating the most frequent alteration in ACC patients, is associated with sexually dimorphic tumor progression. Although female knockouts develop metastatic carcinomas at 18 months, adrenal hyperplasia regresses in male knockouts. This male-specific phenotype is associated with androgen-dependent induction of senescence, recruitment, and differentiation of highly phagocytic macrophages that clear out senescent cells. In contrast, in females, macrophage recruitment is delayed and dampened, which allows for aggressive tumor progression. Consistently, analysis of TCGA-ACC data shows that phagocytic macrophages are more prominent in men and are associated with better prognosis. Together, these data show that phagocytic macrophages are key players in the sexual dimorphism of ACC that could be previously unidentified allies in the fight against this devastating cancer.


Genotyping of Clostridium perfringens Isolates from Domestic Livestock in Saudi Arabia.
The present study was undertaken to confirm the genetic identity of Clostridium perfringens isolates from domestic livestock in Saudi Arabia and to characterize the genes encoding to alpha, beta, epsilon, and iota (α-, β-, ε-, and ι-) toxins. C. perfringens were confirmed in 104 out of 136 isolates on multiplex polymerase chain reaction using specific primers amplifying genes related to toxins produced by C. perfringens. Genes encoding α-toxins were detected in 104 samples. Of the isolates, 80.8% were diagnosed as type A, 15.4% as type D, 2.9% as type C, and 0.96% as type B. None of the isolates has genes encoding iota (ι-) toxin. All isolates investigated yielded enterotoxin (cpe) products and none yielded β2 (cpb2-toxin) or NetB products. PLC gene sequences encoding α-toxin showed >96.7% similarity. Isolates which had α-toxins as well as enterotoxin (cpe) are regarded as type F. Phylogenetic analysis using maximum likelihood analysis yielded two clades, and the majority of the isolates were in one group while only two isolates clustered on the second clade. Within the Kingdom of Saudi Arabia strains, 54 variable positions and 23 polymorphic amino acids were noticed. Isolates with ε- and β-toxins were variable and were found to be close to those published for C. perfringens. ETX gene sequences encoding ε-toxins were found to be related to CPE sequences.


Coxsackievirus B3 infection alters plasma membrane of neonatal skin fibroblasts.
Replication of coxsackievirus B3 occurred for days in cultures of murine neonatal skin fibroblasts in the absence of cytopathology and resulted in alteration of the plasma membrane. Dual immunofluorescence studies showed that the lectin Ulex europaeus agglutinin I bound only to cells producing viral capsid antigens. Cultures of coxsackievirus B3-inoculated murine neonatal skin fibroblasts showed maximum binding of this lectin at 72 h postinoculation. These data show that in a nonlytic infection a picornavirus can alter the surface of an infected cell.


QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease.
Previously, we identified QIL1 as a subunit of mitochondrial contact site (MICOS) complex and demonstrated a role for QIL1 in MICOS assembly, mitochondrial respiration, and cristae formation critical for mitochondrial architecture (Guarani et al., 2015). Here, we identify QIL1 null alleles in two siblings displaying multiple clinical symptoms of early-onset fatal mitochondrial encephalopathy with liver disease, including defects in respiratory chain function in patient muscle. QIL1 absence in patients' fibroblasts was associated with MICOS disassembly, abnormal cristae, mild cytochrome c oxidase defect, and sensitivity to glucose withdrawal. QIL1 expression rescued cristae defects, and promoted re-accumulation of MICOS subunits to facilitate MICOS assembly. MICOS assembly and cristae morphology were not efficiently rescued by over-expression of other MICOS subunits in patient fibroblasts. Taken together, these data provide the first evidence of altered MICOS assembly linked with a human mitochondrial disease and confirm a central role for QIL1 in stable MICOS complex formation.


Medical Countermeasures for Children in Radiation and Nuclear Disasters: Current Capabilities and Key Gaps.
Despite children's unique vulnerability, clinical guidance and resources are lacking around the use of radiation medical countermeasures (MCMs) available commercially and in the Strategic National Stockpile to support immediate dispensing to pediatric populations. To better understand the current capabilities and shortfalls, a literature review and gap analysis were performed. A comprehensive review of the medical literature, Food and Drug Administration (FDA)-approved labeling, FDA summary reviews, medical references, and educational resources related to pediatric radiation MCMs was performed from May 2016 to February 2017. Fifteen gaps related to the use of radiation MCMs in children were identified. The need to address these gaps was prioritized based upon the potential to decrease morbidity and mortality, improve clinical management, strengthen caregiver education, and increase the relevant evidence base. Key gaps exist in information to support the safe and successful use of MCMs in children during radiation emergencies; failure to address these gaps could have negative consequences for families and communities. There is a clear need for pediatric-specific guidance to ensure clinicians can appropriately identify, triage, and treat children who have been exposed to radiation, and for resources to ensure accurate communication about the safety and utility of radiation MCMs for children. (Disaster Med Public Health Preparedness. 2019;13:639-646).


A critical life stage of the Atlantic salmon Salmo salar: behaviour and survival during the smolt and initial post-smolt migration.
The anadromous life cycle of Atlantic salmon Salmo salar involves long migrations to novel environments and challenging physiological transformations when moving between salt-free and salt-rich waters. In this article, (1) environmental factors affecting the migration behaviour and survival of smolts and post-smolts during the river, estuarine and early marine phases, (2) how behavioural patterns are linked to survival and (3) how anthropogenic factors affect migration and survival are synthesized and reviewed based on published literature. The timing of the smolt migration is important in determining marine survival. The timing varies among rivers, most likely as a consequence of local adaptations, to ensure sea entry during optimal periods. Smolts and post-smolts swim actively and fast during migration, but in areas with strong currents, their own movements may be overridden by current-induced transport. Progression rates during the early marine migration vary between 0.4 and 3.0 body lengths s(-1) relative to the ground. Reported mortality is 0.3-7.0% (median 2.3) km(-1) during downriver migration, 0.6-36% (median 6.0) km(-1) in estuaries and 0.3-3.4% (median 1.4) km(-1) in coastal areas. Estuaries and river mouths are the sites of the highest mortalities, with predation being a common cause. The mortality rates varied more among studies in estuaries than in rivers and marine areas, which probably reflects the huge variation among estuaries in their characteristics. Behaviour and survival during migration may also be affected by pollution, fish farming, sea lice Lepeophtheirus salmonis, hydropower development and other anthropogenic activities that may be directly lethal, delay migration or have indirect effects by inhibiting migration. Total mortality reported during early marine migration (up to 5-230 km from the river mouths) in the studies available to date varies between 8 and 71%. Hence, the early marine migration is a life stage with high mortalities, due to both natural and human influences. Factors affecting mortality during the smolt and post-smolt stages contribute to determine the abundance of spawner returns. With many S. salar populations in decline, increased mortality at these stages may considerably contribute to limit S. salar production, and the consequences of human-induced mortality at this stage may be severe. Development of management actions to increase survival and fitness at the smolt and post-smolt stages is crucial to re-establish or conserve wild populations.


National Income, Inequality and Global Patterns of Cigarette Use.
Declining tobacco use in high-income nations and rising tobacco use in low- and middle-income nations raises questions about the sources of worldwide patterns of smoking. Theories posit a curvilinear influence of national income based on the balance of affordability and health-cost effects. In addition, however, economic inequality, gender inequality and government policies may moderate the rise and fall in smoking prevalence with national income. This study tests these arguments using aggregate data for 145 nations and measures of smoking prevalence circa 2000. The results show nonlinear effects of national income for males that take the form of an inverted U, but show linear effects for females. They also show non-additive effects of economic inequality for males that moderate both the rise and decline of smoking with national income and non-additive effects of gender equality for females that moderate the positive effect of national income.


Active methylotrophs in the sediments of Lonar Lake, a saline and alkaline ecosystem formed by meteor impact.
Lonar Lake is a unique saline and alkaline ecosystem formed by meteor impact in the Deccan basalts in India around 52,000 years ago. To investigate the role of methylotrophy in the cycling of carbon in this unusual environment, stable-isotope probing (SIP) was carried out using the one-carbon compounds methane, methanol and methylamine. Denaturing gradient gel electrophoresis fingerprinting analyses performed with heavy (13)C-labelled DNA retrieved from sediment microcosms confirmed the enrichment and labelling of active methylotrophic communities. Clone libraries were constructed using PCR primers targeting 16S rRNA genes and functional genes. Methylomicrobium, Methylophaga and Bacillus spp. were identified as the predominant active methylotrophs in methane, methanol and methylamine SIP microcosms, respectively. Absence of mauA gene amplification in the methylamine SIP heavy fraction also indicated that methylamine metabolism in Lonar Lake sediments may not be mediated by the methylamine dehydrogenase enzyme pathway. Many gene sequences retrieved in this study were not affiliated with extant methanotrophs or methylotrophs. These sequences may represent hitherto uncharacterized novel methylotrophs or heterotrophic organisms that may have been cross-feeding on methylotrophic metabolites or biomass. This study represents an essential first step towards understanding the relevance of methylotrophy in the soda lake sediments of an unusual impact crater structure.


Surface-immobilised micelles via cucurbit[8]uril-rotaxanes for solvent-induced burst release.
The fabrication, characterisation and controlled burst release of naphthol-functionalised micellar (NFM) nanostructures, which were grafted onto gold surfaces through cucurbit[8]uril (CB[8]) mediated host-guest interactions are described. NFMs undergo a facile change in morphology from micelles to diblock copolymers in direct response to exposure to organic solvents, including tetrahydrofuran (THF), toluene and chloroform. This induced transition in conformation lends itself to potential applications including nanocarriers for triggered burst-release of guest molecules. Nile Red was investigated as a NFM encapsulated model hydrophobic cargo inside the surface-attached micelles, which could be fully released upon exposure to THF as measured by both atomic force microscopy and UV/vis spectroscopy.


Rubredoxin-related maturation factor guarantees metal cofactor integrity during aerobic biosynthesis of membrane-bound [NiFe] hydrogenase.
The membrane-bound [NiFe] hydrogenase (MBH) supports growth of Ralstonia eutropha H16 with H2 as the sole energy source. The enzyme undergoes a complex biosynthesis process that proceeds during cell growth even at ambient O2 levels and involves 14 specific maturation proteins. One of these is a rubredoxin-like protein, which is essential for biosynthesis of active MBH at high oxygen concentrations but dispensable under microaerobic growth conditions. To obtain insights into the function of HoxR, we investigated the MBH protein purified from the cytoplasmic membrane of hoxR mutant cells. Compared with wild-type MBH, the mutant enzyme displayed severely decreased hydrogenase activity. Electron paramagnetic resonance and infrared spectroscopic analyses revealed features resembling those of O2-sensitive [NiFe] hydrogenases and/or oxidatively damaged protein. The catalytic center resided partially in an inactive Niu-A-like state, and the electron transfer chain consisting of three different Fe-S clusters showed marked alterations compared with wild-type enzyme. Purification of HoxR protein from its original host, R. eutropha, revealed only low protein amounts. Therefore, recombinant HoxR protein was isolated from Escherichia coli. Unlike common rubredoxins, the HoxR protein was colorless, rather unstable, and essentially metal-free. Conversion of the atypical iron-binding motif into a canonical one through genetic engineering led to a stable reddish rubredoxin. Remarkably, the modified HoxR protein did not support MBH-dependent growth at high O2. Analysis of MBH-associated protein complexes points toward a specific interaction of HoxR with the Fe-S cluster-bearing small subunit. This supports the previously made notion that HoxR avoids oxidative damage of the metal centers of the MBH, in particular the unprecedented Cys6[4Fe-3S] cluster.


Adult mesenchymal stem cells: is there a role for purine receptors in their osteogenic differentiation?
The role played by mesenchymal stem cells (MSCs) in contributing to adult tissue homeostasis and damage repair thanks to their differentiation capabilities has raised a great interest, mainly in bone regenerative medicine. The growth/function of these undifferentiated cells of mesodermal origin, located in specialized structures (niches) of differentiated organs is influenced by substances present in this microenvironment. Among them, ancestral and ubiquitous molecules such as adenine-based purines, i.e., ATP and adenosine, may be included. Notably, extracellular purine concentrations greatly increase during tissue injury; thus, MSCs are exposed to effects mediated by these agents interacting with their own receptors when they act/migrate in vivo or are transplanted into a damaged tissue. Here, we reported that ATP modulates MSC osteogenic differentiation via different P2Y and P2X receptors, but data are often inconclusive/contradictory so that the ATP receptor importance for MSC physiology/differentiation into osteoblasts is yet undetermined. An exception is represented by P2X7 receptors, whose expression was shown at various differentiation stages of bone cells resulting essential for differentiation/survival of both osteoclasts and osteoblasts. As well, adenosine, usually derived from extracellular ATP metabolism, can promote osteogenesis, likely via A2B receptors, even though findings from human MSCs should be implemented and confirmed in preclinical models. Therefore, although many data have revealed possible effects caused by extracellular purines in bone healing/remodeling, further studies, hopefully performed in in vivo models, are necessary to identify defined roles for these compounds in favoring/increasing the pro-osteogenic properties of MSCs and thereby their usefulness in bone regenerative medicine.


Association between green tea consumption and lung cancer risk.
Green tea is a popular beverage and its health benefits are well known. However, inconsistent results have been reported in observational studies concerning the association between green tea consumption and the lung cancer risk. In this commentary, several methodological issues underlying the measurement of tea exposure are highlighted. The recommendations should be useful for designing and planning prospective cohort studies to ascertain the protective effect of green tea against lung cancer.


Effects of bisphosphonate on oxidative stress levels in patients with different types of cancer.
We investigated the effects of bisphosphonate (BP) on oxidative stress levels in blood of patients with cancer. In total, 19 patients with cancer and 21 healthy subjects were included in the study. BP was intravenously administrated to the participants for 6 weeks. The patients had higher lipid peroxidation (LP) levels in the plasma and erythrocyte samples but lower glutathione peroxidase (GSH-Px) and plasma vitamin E values. In patients treated with BP, calcium and LP levels decreased, but GSH-Px and vitamin E values improved. In conclusion, we observed that treatment with BP alleviated oxidative stress induced by cancer.


Modeling electrochromic poly-dioxythiophene-containing materials through TDDFT.
A DFT/TDDFT model was developed to predict the chemical properties for three colored to nearly transmissive electrochromic polymers synthesized by the John Reynolds's group. Using a functional-basis set pairing of mPW1PBE/cc-PVDZ along with the conductor polarizable calculation model (CPCM), simulated neutral spectra showed a strong correlation to the experimental UV-Vis data where the largest absolute peak maximum difference was 14 nm. Frontier molecular orbitals, electronic transitions, and ground-state geometries of these systems were evaluated to provide further information about the oxidative process the polymers undergo. Here we report the first colorimetric model using this level of theory.


Cd1d-restricted cellular lysis by peripheral blood lymphocytes: relevance to the inflammatory bowel diseases.
The CD1d molecule has been implicated to play a role in inflammatory bowel diseases (IBD), possibly through its presentation of an intestinal antigen trigger. To understand the role of the CD1d class I-like protein in IBD, we investigated the molecule's expression in diseased intestinal tissue and determined its potential to undergo specific recognition by intraepithelial and peripheral blood lymphocytes (PBLs) derived from IBD patients. We have observed an increase in precipitable CD1d in inflamed tissues, which suggests CD1d up-regulation in IBD; this was not accompanied by the occurrence of CD1d-specific cytotoxicity by lymphocytes isolated from the same tissue sites. In contrast, we have observed CD1d-specific cytotoxicity by PBLs from both patients and normal controls mediated by a possibly unique type of lymphocytic cell. These observations support a model in which intestinal inflammation may be initiated by circulating PBLs following the tissue-specific upregulation of CD1d. These activated PBLs may then be the source of the extraintestinal manifestations observed with IBD. We therefore propose that the cells responsible for this activity may play a role in regulating immune responses through the specific recognition of CD1d-specific antigen(s).


Interpreting epidemiological evidence in the presence of multiple endpoints: an alternative analytic approach using the 9-year follow-up of the Seychelles child development study.
The potential for ill-informed causal inference is a major concern in published longitudinal studies evaluating impaired neurological function in children prenatally exposed to background levels of methyl mercury (MeHg). These studies evaluate a large number of developmental tests. We propose an alternative analysis strategy that reduces the number of comparisons tested in these studies. Using data from the 9-year follow-up of 643 children in the Seychelles child development study, we grouped 18 individual endpoints into one overall ordinal outcome variable as well as by developmental domains. Subsequently, ordinal logistic regression analyses were performed. We did not find an association between prenatal MeHg exposure and developmental outcomes at 9 years of age. Our proposed framework is more likely to result in a balanced interpretation of a posteriori associations. In addition, this new strategy should facilitate the use of complex epidemiological data in quantitative risk assessment.


Delayed versus classic orthostatic hypotension: clinical and prognostic implications.
Purpose: Orthostatic hypotension (OH) is a common disorder, especially among hospitalised patients. Classic OH is defined as occurring 3 or less minutes of orthostatic stress, and delayed OH as occurring after 3 min of stress. We aimed to compare clinical characteristics and prognosis between inpatients with classic vs. delayed OH.Methods: We performed a retrospective analysis of data from 358 inpatients, aged ≥60 years, who were evaluated for the occurrence of OH at the initial phase of ambulation in four previous prospective studies in our department. Demographic, clinical and prognostic data were compared between patients with (n = 191) vs. without (n = 167) OH, classic (n = 138) vs. delayed (n = 53) OH and seated (n = 115) vs. standing (n = 76) OH.Results: Demographic characteristics, duration of bed rest, the main reasons for admission and the use of offending medications were comparable between the delayed and classic OH groups. Mean maximal postural diastolic (p < .001) and systolic (p = .063) blood pressure falls were higher among patients with classic v. delayed OH. No statistically significant difference between the patients with classic and delayed OH were observed in the occurrence of OH-related symptoms (62.3 vs. 69.8%, p = .42). During a median follow-up of 5.5 years, no statistically significant differences in survival were observed between patients with vs. without OH (p = .14), classic vs. delayed OH (p = .68) and seated vs. standing OH (p = .067). On multivariate analysis, these variables remained not significantly associated with decreased survival.Conclusions: Among inpatients, delayed OH is associated with a lesser magnitude of orthostatic blood pressure fall than classic OH. However, rates of symptomatic OH and long-term mortality were comparable between the groups. Thus, among hospitalised patients, delayed OH should be considered as posing the same severity as classic OH.


[Concept analysis and critical thinking: a complementary relationship in nursing].
The purpose of this paper is to demonstrate the relationship between the concept analysis process and critical thinking skills in nursing. Utilizing a discursive essay approach, it is argued that the concept analysis technique enhances critical thinking. The steps of the concept analysis are analyzed as to the inherent cognitive operations that represent critical reasoning processes. Reflecting on an experience with undergraduate nursing students, the technique of concept analysis is evaluated as a didactic activity that enhances critical thinking. It is concluded that both processes complement each other in the rethinking of nursing and in confronting challenging practice situations.


Visuoperceptual learning in alcoholic Korsakoff syndrome.
Relative to the characteristically profound deficits of explicit memory, components of implicit memory remain largely intact in patients with alcohol-induced Korsakoff syndrome (KS). Perceptual priming occurs in KS and transfer of learning has been consistently observed on mirror reading, a perceptual reversal task. Although priming also occurs with fragmented pictures, a perceptual closure task, it is unclear whether transfer of learning can occur. This study examined visuoperceptual learning in 4 men with alcoholic KS, 9 recently detoxified alcoholic men (ALC), 21 healthy age-matched normal control men (NC), and 6 young normal control men (YNC). Subjects were tested with the Gollin Incomplete Pictures Test at initial and 1-hour and 1-day retest sessions. Both alcoholic groups (KS, ALC) were impaired in visuoperceptual ability. All subject groups showed visuoperceptual learning. The KS group showed additional learning after continued exposure to the stimuli, despite their nonmnemonic visuospatial deficits and profound explicit memory impairment for the test stimuli. Transfer of learning to similar but new stimuli was not evident in either the KS or young healthy control subjects; learning occurred only for the specific items presented. The persistence of learning beyond the life of the percept, which was independent of declarative features (such as item recall), suggests that perceptual learning and memory reflects an intact cognitive memory process in KS. This process is likely mediated by posterior cortical networks relatively unaffected in KS and that are independent of the hippocampal-diencephalic declarative memory system.


[Blood glucose, C-peptide and glucagon levels in patients with a labile course of diabetes mellitus during use of the device "Biostator"].
Altogether 100 patients with insulin-dependent diabetes mellitus of a labile course were treated using the Biostator unit (artificial pancreas). The control group (20 persons) was treated with divided doses of insulin within a day. A study was made of glycemia, the range of its deviations, daily glucosuria, diuresis, the basal level of C-peptide and glucagon in the study and control groups prior to and after treatment. Statistically significant improvement of the values in the study group was observed, that, in the authors' opinion, can be attributed to the improvement of insulin-glucagon ratio at the expense fo an increase in the basal secretion of C-peptide as a result of the use of the artificial pancreas.


Tongue strength and endurance among typically developing children and children with idiopathic speech sound disorders in the United Arab Emirates.
Tongue strength and endurance in adults have been extensively studied, but data on these parameters in young children remain largely unavailable. This study aimed to collect normative objective tongue strength and endurance data from a pediatric population in the United Arab Emirates (UAE) and to examine the effects of age and sex on these parameters. This normative study included a total of 65 typically developing (TD; n = 36) children and children with idiopathic speech sound disorders (ISSDs; n = 29). The participants were assigned to four age groups (range: 3-8 years) and stratified by sex. Data on their tongue strength and endurance were collected using the Iowa Oral Performance Instrument. Tongue strength scores and endurance time increased with age in both the TD and ISSD groups. Sex had no statistically significant effects on tongue strength or endurance in either group. Furthermore, tongue strength and endurance time scores were higher in the TD group than in the ISSD group. The data obtained in this study would add important normative data to the database of standardized measurements for maximal strength and endurance scores in the pediatric population of the UAE. Future research is encouraged to collect additional data that can help healthcare professionals objectively evaluate children with feeding, swallowing, and speech sound production difficulties.


A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer.
The primary objective of this study was to compare the effects of pomegranate juice on PSA doubling times (PSADT) in subjects with rising PSA levels after primary therapy for prostate cancer. Double-blind, placebo-controlled multi-institutional study, evaluated the effects of pomegranate liquid extract on serum PSA levels. The primary end point of this study was change in serum PSADT. Additional secondary and exploratory objectives were to evaluate the safety of pomegranate juice and to determine the interaction of manganese superoxide dismutase (MnSOD) AA genotype and pomegranate treatment on PSADT. One-hundred eighty-three eligible subjects were randomly assigned to the active and placebo groups with a ratio of 2:1 (extract N=102; placebo N=64; juice N=17). The majority of adverse events were of moderate or mild grade. Median PSADT increased from 11.1 months at baseline to 15.6 months in the placebo group (P<0.001) compared with an increase from 12.9 months at baseline to 14.5 months in the extract group (P=0.13) and an increase from 12.7 at baseline to 20.3 in the juice group (P=0.004). However, none of these changes were statistically significant between the three groups (P>0.05). Placebo AA patients experienced a 1.8 month change in median PSADT from 10.9 months at baseline to 12.7 months (P=0.22), while extract patients experienced a 12 month change in median PSADT from 13.6 at baseline to 25.6 months (P=0.03). Compared with placebo, pomegranate extract did not significantly prolong PSADT in prostate cancer patients with rising PSA after primary therapy. A significant prolongation in PSADT was observed in both the treatment and placebo arms. Men with the MnSOD AA genotype may represent a group that is more sensitive to the antiproliferative effects of pomegranate on PSADT; however, this finding requires prospective hypothesis testing and validation.


Effect on gastric function and symptoms of drinking wine, black tea, or schnapps with a Swiss cheese fondue: randomised controlled crossover trial.
To compare the effects of drinking white wine or black tea with Swiss cheese fondue followed by a shot of cherry schnapps on gastric emptying, appetite, and abdominal symptoms. Randomised controlled crossover study. 20 healthy adults (14 men) aged 23-58. Cheese fondue (3260 kJ, 32% fat) labelled with 150 mg sodium (13)Carbon-octanoate was consumed with 300 ml of white wine (13%, 40 g alcohol) or black tea in randomised order, followed by 20 ml schnapps (40%, 8 g alcohol) or water in randomised order. Cumulative percentage dose of (13)C substrate recovered over four hours (higher values indicate faster gastric emptying) and appetite and dyspeptic symptoms (visual analogue scales). Gastric emptying was significantly faster when fondue was consumed with tea or water than with wine or schnapps (cumulative percentage dose of (13)C recovered 18.1%, 95% confidence interval 15.2% to 20.9% v 7.4%, 4.6% to 10.3%; P<0.001). An inverse dose-response relation between alcohol intake and gastric emptying was evident. Appetite was similar with consumption of wine or tea (difference 0.11, -0.12 to 0.34; P=0.35), but reduced if both wine and schnapps were consumed (difference -0.40, -0.01 to -0.79; P<0.046). No difference in dyspeptic symptoms was present. Gastric emptying after a Swiss cheese fondue is noticeably slower and appetite suppressed if consumed with higher doses of alcohol. This effect was not associated with dyspeptic symptoms. ClinicalTrials.gov NCT00943696.


Pigs fed cholesterol neonatally have increased cerebrum cholesterol as young adults.
Sixty-eight female neonatal pigs selected for seven (Experiment 1) or eight (Experiment 2) generations for high (HG) or low (LG) plasma cholesterol were used to test the hypothesis that neonatal dietary cholesterol fed during the first 4 or 8 wk of postnatal life increases the cholesterol content of the cerebrum in young adulthood following free access to a high-fat (15%), high-cholesterol (0.5%) diet from 8 to 20 or 24 wk of age. Pigs were removed from their dams at 1 d of age and given free access to a sow-milk replacer diet containing 9.5% coconut fat and 0 or 0.5 % cholesterol. All pigs (except four HG and four LG pigs in Experiment 2, which were deprived of cholesterol throughout the study) were fed the high-fat, high-cholesterol diet from 8 wk to termination at 20 or 24 wk of age. Cerebrum weight and cholesterol concentration were higher in pigs fed cholesterol neonatally than in those deprived of cholesterol neonatally in both experiments, but weight and cholesterol concentration were unaffected by genetic line. Cholesterol concentrations in longissimus and semitendinosus muscles and in subcutaneous fat were unaffected by diet or genetic line. We conclude that dietary cholesterol deprivation during the first 4 to 8 wk of life in piglets is associated with lower cholesterol concentration and total content in the young adult cerebrum than in pigs supplemented with cholesterol in early life. These data support previous observations and suggest the possibility of a metabolic need for neonatal dietary cholesterol in normal brain development.


The Lung Microbiome of Three Young Brazilian Patients With Cystic Fibrosis Colonized by Fungi.
Microbial communities infiltrate the respiratory tract of cystic fibrosis patients, where chronic colonization and infection lead to clinical decline. This report aims to provide an overview of the diversity of bacterial and fungal species from the airway secretion of three young CF patients with severe pulmonary disease. The bacterial and fungal microbiomes were investigated by culture isolation, metataxonomics, and metagenomics shotgun. Virulence factors and antibiotic resistance genes were also explored. A. fumigatus was isolated from cultures and identified in high incidence from patient sputum samples. Candida albicans, Penicillium sp., Hanseniaspora sp., Torulaspora delbrueckii, and Talaromyces amestolkiae were isolated sporadically. Metataxonomics and metagenomics detected fungal reads (Saccharomyces cerevisiae, A. fumigatus, and Schizophyllum sp.) in one sputum sample. The main pathogenic bacteria identified were Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, and Achromobacter xylosoxidans. The canonical core CF microbiome is composed of species from the genera Streptococcus, Neisseria, Rothia, Prevotella, and Haemophilus. Thus, the airways of the three young CF patients presented dominant bacterial genera and interindividual variability in microbial community composition and diversity. Additionally, a wide diversity of virulence factors and antibiotic resistance genes were identified in the CF lung microbiomes, which may be linked to the clinical condition of the CF patients. Understanding the microbial community is crucial to improve therapy because it may have the opposite effect, restructuring the pathogenic microbiota. Future studies focusing on the influence of fungi on bacterial diversity and microbial interactions in CF microbiomes will be welcome to fulfill this huge gap of fungal influence on CF physiopathology.


Neighboring base sequence effect on DNA damage.
Guanine is the most strongly oxidized base in DNA; generation of a guanine radical cation as an intermediate in an oxidation reaction leads to migration through a resulting cationic hole in the DNA π-stack until it is trapped by irreversible reaction with water or other free radicals. In the case of normal sequences, the primary position of Guanine oxidations by one-electron oxidants such as carbonate radical anions, BPT(7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene), and riboflavin are 5'-G in GG doublets and the central G in a GGG triplet. According to results, the properties of guanine oxidation on abasic site containing sequences are independent from the position of AP(apurinic/apyrimidinic) site in the presence of carbonate radical anions under a short irradiation time, although this radical is exposed to solvent by the existence of an abasic site. The lack of abasic site effect on guanine oxidative damage by the carbonate radical may be due to a sequence-independent property of the initial electron transfer rate in the hole injection step, or may relate to an electron transfer mechanism with large reorganization energy dependency. Consequently, the carbonate radical anions may easily migrate to another single G in the charge re-distribution step. Meanwhile, there is a strong dependency on the presence of an AP(apurinic/apyrimidinic) site in the cleavage patterns of guanine oxidations by physically large oxidizing agents, such as BPT(7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene) and riboflavin. These radicals show strong AP(apurinic/apyrimidinic) site dependency and clear G-site selectivity.Communicated by Ramaswamy H. Sarma.


Toxoplasmosis knowledge and preventive behavior among pregnant women in the city of Imperatriz, Maranhão, Brazil.
The aim of this study was to assess toxoplasmosis knowledge and preventive behavior, and relate these to socioeconomic, pre-natal and environmental issues among pregnant women served by the Family Health Strategy in the municipality of Imperatriz, Maranhão, Brazil. This is a cross-sectional study performed by applying a structured and pre-tested questionnaire to a sample of 239 pregnant women. Only 23.4% of the pregnant women had good knowledge of the disease, primarily in the area of prevention, and 58.9% adopted suitable preventive behaviors. The results obtained show a significant association of various toxoplasmosis risk factors, such as drinking untreated water (OR = 2.1245; IC95% = 1.20-3.73; p = 0.0128), contact with cats (OR = 7.6875; IC95% = 4.22-13.97; p < 0,0001), cleaning cat feces (OR = 6.8738; IC95% = 3.02-15.60; p < 0.0001), eating raw meat (OR = 5.7405; IC95% = 3.21-10.24 and handling sand/cat litter OR = 10.7376; IC95% = 4.64-24.85; p < 0.0001). This shows a need for continued education on toxoplasmosis for the pregnant women seen by the Imperatriz FHS, and for more comprehensive preventive measures, with public health and education policies that take into consideration economic, social, environmental and cultural issues.


Relating structure to evolution in class II viral membrane fusion proteins.
Enveloped viruses must fuse their lipid membrane to a cellular membrane to deliver the viral genome into the cytoplasm for replication. Viral envelope proteins catalyze this critical membrane fusion event. They fall into at least three distinct structural classes. Class II fusion proteins have a conserved three-domain architecture and are found in many important viral pathogens. Until 2013, class II proteins had only been found in flaviviruses and alphaviruses. However, in 2013 a class II fusion protein was discovered in the unrelated phlebovirus genus, and two unexpectedly divergent envelope proteins were identified in families that also contain prototypical class II proteins. The structural relationships of newly identified class II proteins, reviewed herein, shift the paradigm for how these proteins evolved.


Arbuscular mycorrhizal fungi in a wetland constructed for benzene-, methyl tert-butyl ether- and ammonia-contaminated groundwater bioremediation.
Arbuscular mycorrhizal fungi (AMF), which are present in most natural environments, have demonstrated capacity to promote biodegradation of organic pollutants in the greenhouse. However, it is not certain whether AMF can spontaneously establish in phytoremediation systems constructed to decontaminate groundwater, because of the unusual conditions during the construction and operation of such systems. To assess this possibility, root samples from a wetland constructed for the phytoremediation of groundwater contaminated with benzene, methyl tert-butyl ether and ammonia were analysed. Substantial AMF colonization was observed in plant roots sampled close to the inlet of a basin filled with fine gravel and planted with Phragmites australis. In addition, analysis of a fragment of the nuclear large ribosomal subunit, amplified by nested PCR, revealed the presence of AMF molecular operational taxonomic units closely related to Funneliformis mosseae and Rhizophagus irregularis in the samples. These findings demonstrate the capacity of generalist AMF strains to establish spontaneously, rapidly and extensively in groundwater bioremediation technical installations.


Standardization of lipid and lipoprotein determinations for pediatric screening procedures.
Standardization of lipid and lipoprotein measurements is of concern to laboratories that serve pediatric as well as adult populations, since preventive measures taken during pediatric years can help control atherosclerotic cardiovascular problems that can arise during adult years. Multiple analytical and physiologic problems that exist inherently in the lipids and lipoproteins and in application of measurements to the pediatric population must be controlled to gain standardization and produce highly precise and accurate results. Reference values from well-described, observed pediatric populations have been published for use in interpreting analytical results. In collaboration with NHLBI, the CDC has offered lipid and lipoprotein standardization services for the United States since 1957 and, on an international scale, has cooperated with WHO since 1962. Standardization activities have been primarily concerned with total and HDL cholesterol and triglyceride determinations for cardiovascular epidemiologic and clinical trial investigations.


Cardiac silhouette findings and mediastinal lines and stripes: radiograph and CT scan correlation.
Despite the increased use of CT imaging, chest radiography remains a very important diagnostic modality in the evaluation of lung parenchymal and mediastinal diseases, providing a vast amount of useful information. This information is generally derived from the relationships among the normal anatomic structures of the mediastinum, pleura, and lungs, which represent the basis of the "cardiac silhouette" and "mediastinal lines-and-stripes" concepts that potentially play an important role in the establishment of a diagnosis or a spectrum of diagnoses before proceeding to CT imaging. The capability of recognizing an abnormal chest radiograph on the basis of the displacement, deformation, or obscuration of one of these structures when compared with those in normal findings is often mandatory prior to requesting a potentially useful CT scan examination. Therefore, radiologists, trainees, and physicians must be familiar with the anatomic basis of those findings to be able to recognize the normal and abnormal appearance of structures when developing an appropriate differential diagnosis. In this review, we briefly describe the cardiac silhouette concepts and the mediastinal lines-and-stripes configurations as they relate to the radiographic and CT scan appearance of structures for a spectrum of pathologic diseases and list the possible underlying causes of the displacement, deformation, or obscuration of the structures.


[Diagnosis of the temporomandibular joint dysfunction by graphic reconstruction of mandibular movements].
A total of 974 patients with suspected abnormalities of the temporomandibular joint (TMJ) were examined; diseases were detected in 371 patients. The test group consisted of 40 patients, control group of 18 patients. Analysis of the results of graphic recording of mandibular movements and clinical x-ray data in patients of the main and control groups helped develop the strategy for the diagnosis of TMJ dysfunction, based on the functional methods of examination (oral functionography and non-oral axiography).


In vitro platforms for evaluating liver toxicity.
The liver is a heterogeneous organ with many vital functions, including metabolism of pharmaceutical drugs and is highly susceptible to injury from these substances. The etiology of drug-induced liver disease is still debated although generally regarded as a continuum between an activated immune response and hepatocyte metabolic dysfunction, most often resulting from an intermediate reactive metabolite. This debate stems from the fact that current animal and in vitro models provide limited physiologically relevant information, and their shortcomings have resulted in "silent" hepatotoxic drugs being introduced into clinical trials, garnering huge financial losses for drug companies through withdrawals and late stage clinical failures. As we advance our understanding into the molecular processes leading to liver injury, it is increasingly clear that (a) the pathologic lesion is not only due to liver parenchyma but is also due to the interactions between the hepatocytes and the resident liver immune cells, stellate cells, and endothelial cells; and (b) animal models do not reflect the human cell interactions. Therefore, a predictive human, in vitro model must address the interactions between the major human liver cell types and measure key determinants of injury such as the dosage and metabolism of the drug, the stress response, cholestatic effect, and the immune and fibrotic response. In this mini-review, we first discuss the current state of macro-scale in vitro liver culture systems with examples that have been commercialized. We then introduce the paradigm of microfluidic culture systems that aim to mimic the liver with physiologically relevant dimensions, cellular structure, perfusion, and mass transport by taking advantage of micro and nanofabrication technologies. We review the most prominent liver-on-a-chip platforms in terms of their physiological relevance and drug response. We conclude with a commentary on other critical advances such as the deployment of fluorescence-based biosensors to identify relevant toxicity pathways, as well as computational models to create a predictive tool.


Population-based breast cancer screening: policy advice for a New Zealand screening programme. Breast Cancer Screening Policy Advisory Group.
The Ministry of Health appointed the Breast Cancer Screening Policy Advisory Group in 1995 to provide policy advice on the establishment of a population-based screening programme in New Zealand. The group recommended that an organised mammographic screening programme be part of a strategic approach to breast cancer detection and management with the aim of reducing mortality from breast cancer. Service specifications should be based on those of the pilot programmes in Otago-Southland and Waikato, but modified according to the lessons learned, with special attention to such areas as recruitment and information systems. Women between the ages of 50-69 should be invited for screening every two years, and screening should be free of charge. Because of the uncertain value of general population screening by mammography in women under the age of 50, the programme should not be extended to younger women, including those at high risk, at the present time. Further reviews of the issue should be commissioned when new evidence becomes available. Pilot programmes in New Zealand have demonstrated that screening can be performed with acceptable standards in comparison with overseas trials but considerable planning and commitment will be required for the expected benefits to be experienced nationally. Implementation of a successful national programme will involve attention to key areas such as programme management, recruitment and quality standards to deliver a high quality service to a substantial proportion of the eligible population.


Short-term biomarkers of tumor promotion in mouse skin treated with petroleum middle distillates.
Topical application of certain petroleum middle distillates (PMD) to mice produces skin tumors after long latency, and initiation/promotion protocols indicate that this effect is associated with their tumor promoting activity. Since induction of sustained, potentiated epidermal hyperplasia is predictive of promoting activity, five compositionally distinct PMD [hydrodesulfurized kerosene (API 81-07); hydrodesulfurized PMD (API 81-10); odorless light petroleum hydrocarbons; severely hydrotreated light vacuum distillate (LVD); and lightly refined paraffinic oil (LRPO)] were assessed for their effects on epidermal hyperplasia. PMD were administered (2 x/week for 2 weeks) to skin of CD-1 mice. Four quantitative biomarkers of epidermal hyperplasia were evaluated: epidermal thickness, number of nucleated epidermal cells per unit length of basement membrane, labeling (BrdUrd) index of epidermal cells, and induction of epidermal ornithine decarboxylase (ODC) activity. As positive controls, 12-O-tetradecanoylphorbol-13-acetate (TPA) and n-dodecane were utilized. PMD-induced skin irritation was evaluated visually and/or histopathologically. All five PMD produced dose-dependent, skin irritation and epidermal hyperplasia. On a weight basis the magnitude of the maximal PMD-induced effects was similar to that produced by n-dodecane, but > 1000-fold less than that produced by TPA. Epidermal hyperplasia and subacute skin irritancy produced by the five PMD were similar. Of the four short-term markers of tumor promotion assessed, labeling index and epidermal ODC activity were predictive of the relative promoting activities of those PMD for which tumorigenicity bioassay data are available, i.e., API 81-07 > API 81-10 > LRPO. An apparent discrepancy to the predictability of epidermal ODC activity occurred with LRPO:toluene [1:1 (v/v)]. This mixture is nontumorigenic, yet significantly induced epidermal ODC activity. This mixture, however, produced severe epidermal toxicity that precluded any meaningful analysis of short-term biomarkers in relationship to biological activity.


Enterprising tendency and interpersonal communication of nursing students.
To identify general enterprising tendency and competence in interpersonal communication of nursing students and correlate them with personal and academic variables. A cross-sectional study at a university in São Paulo, SP, Brazil. Three instruments were used for data collection: 1 - A questionnaire with personal and academic variables; 2 - The General measure of Enterprising Tendency test (GET); and 3 - The Interpersonal Communication Competence Scale (Escala de Competência em Comunicação Interpessoal - ECCI). The sample consisted of 150 participants. The highest averages were on the GET 'Need for Achievement' dimension (M = 7.88; SD = 2.12 and median = 8.00) and the ECCI 'Availability' dimension (M = 12.50; SD = 1.99 and median = 13.00). Students in the less advanced periods of the course obtained higher averages on the GET 'Drive and Determination' dimension (p = 0.032), while those who performed paid work a higher average on the ECCI 'Interaction Management' dimension (p = 0.030). Higher Education Institutions should look for strategies to teach the content of these competencies in a more dynamic and engaging way throughout education which encompass the student's capacity and the needs of the labor market.


Physical Therapist Clinical Reasoning and Action for Individuals With Undiagnosed Lower Extremity Tumors: A Report of 3 Cases.
Study Design Resident's case problem. Background Although rare in the general population, bone and soft tissue tumors may be more frequently encountered in patients seeking physical therapy because of the propensity of their initial symptoms to mimic those of commonly treated musculoskeletal disorders. Screening for tumors requires the physical therapist to be attentive to unexpected findings. The purpose of this paper was to describe the clinical-reasoning and screening processes of physical therapists who facilitated the timely recognition of bone and soft tissue tumors in 3 patients referred through medical channels. Diagnosis The referral diagnoses were lumbar spinal stenosis, calcaneal bursitis, and postexcisional quadriceps weakness. When comprehensively examined, each of the patients had either atypical examination findings or failed to respond to physical therapy treatment. After the physical therapists alerted the appropriate medical providers of the examination findings, diagnoses of high-grade osteosarcoma of the pelvis, chondroma of the knee, and liposarcoma of the thigh followed. Discussion Tumors of the lower extremity can initially mimic common musculoskeletal pathology. Physical therapists must remain alert for red flags, atypical signs and symptoms, and poor responses to treatment, even when patients are referred through medical channels. Particular attention is necessary in the case of unusual symptoms in the lower extremity, where over half of primary malignant tumors occur. Level of Evidence Differential diagnosis, level 5. J Orthop Sports Phys Ther 2017;47(5):359-366. Epub 29 Mar 2017. doi:10.2519/jospt.2017.7037.


Knee implant imaging at 3 Tesla using high-bandwidth radiofrequency pulses.
To investigate the impact of high-bandwidth radiofrequency (RF) pulses used in turbo spin echo (TSE) sequences or combined with slice encoding for metal artifact correction (SEMAC) on artifact reduction at 3 Tesla in the knee in the presence of metal. Local transmit/receive coils feature increased maximum B1 amplitude, reduced SAR exposition and thus enable the application of high-bandwidth RF pulses. Susceptibility-induced through-plane distortion scales inversely with the RF bandwidth and the view angle, hence blurring, increases for higher RF bandwidths, when SEMAC is used. These effects were assessed for a phantom containing a total knee arthroplasty. TSE and SEMAC sequences with conventional and high RF bandwidths and different contrasts were tested on eight patients with different types of implants. To realize scan times of 7 to 9 min, SEMAC was always applied with eight slice-encoding steps and distortion was rated by two radiologists. A local transmit/receive knee coil enables the use of an RF bandwidth of 4 kHz compared with 850 Hz in conventional sequences. Phantom scans confirm the relation of RF bandwidth and through-plane distortion, which can be reduced up to 79%, and demonstrate the increased blurring for high-bandwidth RF pulses. In average, artifacts in this RF mode are rated hardly visible for patients with joint arthroplasties, when eight SEMAC slice-encoding steps are applied, and for patients with titanium fixtures, when TSE is used. The application of high-bandwidth RF pulses by local transmit coils substantially reduces through-plane distortion artifacts at 3 Tesla.


Predictors of sleeping under cost-free mosquito bed nets among children under-five years in Mbarara, Uganda: a household survey.
In 2010, Uganda Malaria Control Programme distributed cost-free mosquito bed nets to households with children under-five years and pregnant women in selected sub-counties. We assessed the factors associated with sleeping under costfree mosquito nets among children under-five years in Nyakayojo sub-county, Mbarara District, Uganda. 381 households with at least a child under-five years and benefited from cost-free bed nets in Nyakayojo were randomly selected. Caregivers of children were interviewed using a questionnaire. 74% children slept under bed nets a night before the study. Children from households with ≥2 nets [aOR=1.75; 95% CI: 1.09-2.81, p=0.02], female caregiver [aOR=2.11; 95% CI: 1.16-3.79, p=0.01] and children from households that did not face problems (skin irritation, torn nets, suffocation, night sweating, nasal congestion and candle fire) when sleeping under bed nets [aOR=1.81; 95% CI: 1.10-2.98, p=0.02] were more likely to use nets. Main reason for not sleeping under a net was damage to the net (47.1%). The proportion of children sleeping under nets was comparable to MDG target. Improvements in use of mosquito nets by children can be achieved through increasing number of nets in a household.


Myelomeningocele, temperament patterns, and parental perceptions.
Description of temperament profiles of children has largely been reported in typically developing populations. Children undergo individualized assessments of achievement (developmental/academic) and receive individualized interventions. In contrast, their individual behavioral styles are not evaluated as completely, if at all. For children with developmental disabilities, description of temperament characteristics can provide better understanding of the already complex child. This study describes temperament characteristics in a group of children with myelomeningocele and shunted hydrocephalus (MM/SH). A consecutive cohort study with historical control group measuring temperament characteristics was conducted at a tertiary-level, university affiliated, interdisciplinary spina bifida program. Analysis includes group comparisons. Primary caregivers of 46 children (age range: 5-12 years) with MM/SH completed age-appropriate Carey Temperament Scales questionnaires as a component of a larger developmental study. The Carey Temperament Scales comprise a series of behavioral rating instruments that assess 9 temperament characteristics: activity, adaptability, approach-withdrawal, mood, intensity, attention/persistence, distractibility, sensory threshold, and rhythmicity/predictability. The Carey questionnaires used in this study were (1) the Behavioral Style Questionnaire for children aged 5 to 7 years and (2) the Middle Childhood Temperament Questionnaire for those aged 8 to 12 years. Both questionnaires assess the same temperament characteristics; the contexts within which items were rated were designed to better reflect developmental levels. Children were excluded when there were comorbid diagnoses of attention-deficit/hyperactivity disorder or mental retardation. One-sample normal tests (Bonferroni corrected) revealed that children within the MM/SH group differed significantly from the standardized population in 5 dimensions: (1) adaptability (less adaptable), (2) approach/withdrawal (poor first approach/greater withdrawal), (3) distractibility (more distractible), (4) attention/persistence (less attentive/persistent), and (5) predictability/rhythm (less predictable). Caregiver perceptions of having a difficult-to-manage child were significantly correlated with negative mood, more intensity of response, and less adaptability. Temperament profiles previously described in typically developing populations (eg, "easy" or "difficult child") were not prominent profiles in this group of children with MM/SH. A constellation of temperament characteristics not commonly recognized may place these children at risk for being contributors to and recipients of misunderstandings of social cues and have implications for successful learning within academic, home/community, and medical settings.


Effect of Antiplatelet Drugs on D-Dimer Levels: A Systematic Review and Meta-analysis.
D-dimer is a product of fibrinolysis. In clinical practice, D-dimer levels are commonly used to rule out venous thromboembolism. Antiplatelet drugs may influence D-dimer levels, potentially affecting the accuracy of this diagnostic tool. To evaluate the effect of antiplatelet drugs on D-dimer levels, we performed a systematic review and meta-analysis of all published articles on this topic (PROSPERO registration number CRD42017058932). We electronically searched EMBASE, MEDLINE Epub, Cochrane, Web of Science, and Google Scholar (100 top relevance) (last search on October 5, 2017). We included randomized controlled trials, cohort studies, and cross-sectional studies conducted in humans, with a drug exposure time of at least 7 days. Two reviewers independently selected eligible articles and extracted the data. Five controlled trials, 7 cohort studies, and 5 cross-sectional studies were finally included. Meta-analysis involving all 1117 participants showed no change in dimer levels (standardized mean difference: -0.015, 95% confidence interval, 0.182-0.151, P = 0.855). In conclusion, antiplatelet drugs do not seem to influence D-dimer levels.


Suggested use of vaccines in diabetes.
Diabetes has emerged as a disease of major public health importance in India affecting the rich and the poor alike. Conventionally, comprehensive diabetes management is aimed at preventing micro and macro vascular complications. However, morbidity and mortality due to infections are also significant. In developing countries like India, the concept of adult immunization is far from reality. Recently the H1N1 pandemic has triggered the necessity for considering immunization in all age groups for the prevention of vaccine-preventable fatal infectious diseases. Considering the economics of immunization in a developing country, providing free vaccines to all adults may not be a practical solution, although the free universal immunization program for children is in existence for several decades. There is no consensus on the use of vaccines in diabetes subjects in India. However, there are some clinics offering routine pneumococcal, influenza and other vaccinations. Patients with diabetes have a deranged immune system making them more prone for infections. Hospitalization and death due to pneumococcal disease and influenza are higher in diabetes patients. They, like other healthy individuals, have a normal humoral response to vaccination with clinically significant benefits. The American Diabetes Association, Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention, World Health Organization, United Kingdom Guidelines and a number of other scientific organizations have well defined guidelines for vaccination in diabetes. In this article we make some suggestions for clinicians in India, regarding use of vaccines in subjects with diabetes.


[Healthcare regulation and healthcare management as tools to assure comprehensiveness and equity in health].
Healthcare production that assures comprehensiveness and equity has posed a challenge for Brazil's Unified National Health System. The aim of this study was to contribute to the debate on the issue, analyzing an experience with municipal healthcare management using regulation to improve quality of care. We conducted a case study in which data were obtained through direct observation, interviews, written narratives, and document analysis. The research subjects were health services managers and health workers. The results feature the concept of a living network, produced actively by building relations between the health workers in the different services. The study highlights the measures to support the care produced by the teams, based on healthcare regulation and work processes management. The results were expressive in upgrading the care, reducing the waiting lines for the specialties, and increasing the health workers' satisfaction. The key feature in the process was the evident need to enrich (through acts) the technical knowledge with light technologies and active movements by management in the production of care.


The majority of the Saccharomyces cerevisiae septin complexes do not exchange guanine nucleotides.
We show here that affinity-purified Saccharomyces cerevisiae septin complexes contain stoichiometric amounts of guanine nucleotides, specifically GTP and GDP. Using a (15)N-dilution assay read-out by liquid chromatography-tandem mass spectrometry, we determined that the majority of the bound guanine nucleotides do not turn over in vivo during one cell cycle period. In vitro, the isolated S. cerevisiae septin complexes have similar GTP binding and hydrolytic properties to the Drosophila septin complexes (Field, C. M., al-Awar, O., Rosenblatt, J., Wong, M. L., Alberts, B., and Mitchison, T. J. (1996) J. Cell Biol. 133, 605-616). In particular, the GTP turnover of septins is very slow when compared with the GTP turnover for Ras-like GTPases. We conclude that bound GTP and GDP play a structural, rather then regulatory, role for the majority of septins in proliferating cells as GTP does for alpha-tubulin.


Experimental approaches to assess melanocytes mosaicism in segmental vitiligo.
Vitiligo is an autoimmune disease of the skin that results in localized or disseminated white macules. One common feature of several existing classification protocols is the distribution of the disease into two main subtypes, non-segmental vitiligo (NSV) and segmental vitiligo (SV). SV is characterized by depigmentation spreading within one or more skin segments while NSV is widespread. Several clinical-epidemiological observations suggest that SV has distinct autoimmune pathophysiology compared to NSV. Furthermore, the clinical distribution pattern of SV lesions closely resembles other melanocyte mosaicism diseases. These observations led us to hypothesize that SV is caused by a localized autoimmune reaction targeting epidermal mosaicism melanocytes. Here, we proposed examples of experimental approaches to assess mosaicism in SV patients.


The neural site of attention matches the spatial scale of perception.
What is the neural locus of visual attention? Here we show that the locus is not fixed but instead changes rapidly to match the spatial scale of task-relevant information in the current scene. To accomplish this, we obtained electrical, magnetic, and hemodynamic measures of attention from human subjects while they detected large-scale or small-scale targets within multiscale stimulus patterns. Subjects did not know the scale of the target before stimulus onset, and yet the neural locus of attention-related activity between 250 and 300 ms varied according to the scale of the target. Specifically, maximal attention-related activity spread from a high-level, relatively anterior visual area (the lateral occipital complex) for large-scale targets to include a lower-level, more posterior area (visual area V4) for small-scale targets. This rapid change indicates that the neural locus of attention in visual cortex is not static but is instead determined rapidly and dynamically by means of an interaction between top-down task information and local information about the current visual input.


Clinical and experimental evidence of Bcl-2 involvement in the response to photodynamic therapy.
The role of apoptosis related proteins in the response of human malignancies to photodynamic therapy (PDT) is under investigation. The aim of the study was to examine the role of p53 and of bcl-2 protein expression in the response to PDT. Paraffin-embedded material from 37 patients with early esophageal cancer treated with PDT (argon dye laser after intravenous injection of hematoporphyrine derivative) was studied immunohistochemically for p53 protein nuclear accumulation and bcl-2 cytoplasmic expression. Patients with residual disease after two rounds of PDT received definitive radiotherapy. In a subsequent in vitro study, W138 human lung fibroblasts and W138-SV-40 virus transformed were assessed for their sensitivity to PDT. The constitutive bcl-2 overexpression of the transformed cells vs. normal cells (assessed with RT-PCR) was 16-fold. Positive bcl-2 and p53 expression was noted in 10 out of 36 (27%) and 14 out of 36 (39%) patients, respectively. Seven out of 11 tumors (63%) with bcl-2 expression responded completely to PDT vs. 6 out of 26 (23%) of cases with no bcl-2 expression (p = 0.02). No association of p53, T-stage and of histology grade with response to PDT or PDT/RT was noted. The sensitivity to PDT of transformed human fibroblasts compared to normal ones was 4 times more at a fluence of 4.3 J/cm2 (4% vs. 1% cell kill) as well as at a fluence of 5.4 J/cm2 (8% vs. 2% cell kill). Bcl-2 protein expression is associated with favorable response to PDT and can be used as a predictor of cancer response to PDT. This finding can be explained by experimental studies showing that PDT induces selective degradation of the bcl-2 protein, leading to apoptosis by decreasing the bcl-2/bax ratio. Studies on PDT combination with agents targeting bcl-2 (i.e. taxanes) are on going to eventually assess a super-additive effect.


Progesterone in saliva: pitfalls and consequent implications for accuracy of the determination.
The concentration of steroid hormones in saliva is believed to reflect the concentration of free hormone in blood. Because the assay for progesterone in saliva has not been rigorously validated, we investigated some of the analytical variables involved. Saliva samples were divided into two portions. One was centrifuged and the supernate used for extraction; the other was homogenized by sonication and used as such for extraction. Progesterone concentrations in homogenized whole saliva were double or triple those in supernates. By equilibrium dialysis we established that 85% of progesterone was in the free form in supernates but only 60 to 70% in homogenized whole saliva, depending upon the phase of the cycle of the subjects. Salivary flow was stimulated by crystals of citric acid; unstimulated and stimulated saliva samples were obtained from the same person. Progesterone concentrations were significantly (p less than 0.02) higher in stimulated samples than in unstimulated ones, particularly in samples collected during the luteal phase.


Neurochemical correlates of major depression in primary dementia.
Biogenic amine neurotransmitters and metabolites as well as choline acetyltransferase activity were quantified in eight brain regions from 37 demented patients, with or without major depression, and 10 controls with no history of dementia or depression. The middle frontal and temporal cortex, prosubiculum and entorhinal cortex of the hippocampus, substantia nigra, thalamus, amygdala, and caudate were examined. Demented patients with major depression exhibited a 10-fold to 20-fold reduction in the level of norepinephrine in the cortex, along with relative preservation of choline acetyltransferase activity in subcortical regions, compared with demented patients who were not depressed. Serotonin levels were reduced in all eight brain regions, but the reduction did not reach statistical significance in any region examined. A para-doxical increase in dopamine levels was observed in the entorhinal cortex of depressed, demented patients, although no consistent pattern of change in the level of this neurotransmitter emerged across brain regions. Our results indicate that the development of major depression in primary dementia is associated with a profile of concurrent neurochemical changes that is largely consistent with existing neurochemical hypotheses of idiopathic affective disorders, and qualitatively distinct from that associated with primary dementia.


Plasma insulin-like growth factor I is inversely associated with colorectal adenoma recurrence: a novel hypothesis.
The insulin-like growth factor I (IGF-I) axis has been proposed to be a significant factor in the development of certain cancers, including colorectal. However, results from epidemiologic studies suggest modest effects on colorectal cancer risk. Using cross-sectional and prospective study designs within the same cohort of men who had at least one adenoma at baseline, we investigated whether plasma IGF-I, IGF-I binding protein 1, and IGF-I binding protein 3 were associated with colorectal adenoma characteristics at baseline and whether their levels were related to odds for adenoma recurrence. Plasma levels of each marker were measured at baseline in 299 male participants in the Wheat Bran Fiber Trial, who were followed prospectively for recurrence of their adenomatous lesions. In cross-sectional analyses, plasma IGF-I was significantly positively associated with the presence of adenomas with any villous features (P = 0.04). In contrast, IGF-I levels were inversely associated with odds of colorectal adenoma recurrence, with adjusted odds ratios (95% confidence interval) of 0.55 (0.29-1.01) and 0.49 (0.26-0.91) for the second and third tertiles of IGF-I, respectively, compared with the first tertile (P(trend) = 0.02). The inverse association was stronger for advanced adenoma recurrence (P(trend) = 0.02) than for nonadvanced recurrence (P(trend) = 0.10). These results suggest that, once an adenoma is removed, higher IGF-I levels reduce the odds of the formation of new lesions in the colorectum.


An experimental analysis of in vivo guidance cues used by axons of spinal interneurons in the chick embryo: evidence for chemotropism and related guidance mechanisms.
To clarify axonal guidance mechanisms involved in pathway formation by spinal interneurons, the pattern of axonal outgrowth was examined following three kinds of perturbations: (1) rotation of three segments of the neural tube around the dorsal-ventral axis by 90 degrees or 180 degrees (D-V rotation), (2) rotation of three segments of the neural tube around the rostral-caudal axis (R-C rotation), and (3) transplantation of brainstem into thoracic spinal segments (BS transplantation). Following D-V rotation, it was observed that circumferential axons near the junction between rotated graft (RG) and host cord changed their course so as to project toward the ectopic floor plate. This supports the notion that the floor plate exerts a chemotropic-like effect on the directional projection of circumferential axons. The longitudinal fibers in the ventral funiculus (VF) were able to grow through the transplant junction when the VF was well apposed to the VF of the RG. However, in most cases, the longitudinal fibers in the VF that were not apposed to the VF of the RG made a medial turn at the junction. After turning, some of them made a U-turn into the contralateral VF, whereas others grew circumferentially around the junction zone, then exited the spinal cord; still others directly entered the RG. The majority of fibers that entered the RG were located in the VF, though a small number of such fibers were also located in both the lateral and dorsal funiculus (LF and DF, respectively). The fibers that entered the LF shifted ventrally, whereas the fibers in the DF remained within the DF. These results suggest that there may be some matching mechanism between specific fibers and the funiculus through which the fibers normally project. Moreover, there may be a barrier between the LF and the DF that prevents the fibers in the DF from shifting ventrally. In R-C rotation experiments, the projection of axons of dorsolateral border cells (DLB-cells), which are known to give rise almost exclusively to commissural ascending axons, was examined. Following the injection of HRP into the rostral junctional region, retrogradely labeled DLB-cells were observed in the rotated segments only on the side contralateral to the injection. Labeled DLB-cells were also observed in the segments caudal to the rotated segments. These results suggest that putative rostrocaudal directional cues that guide the axons of DLB-cells may arise from outside of the segments in which the decision to turn is made.(ABSTRACT TRUNCATED AT 400 WORDS)


Spray-Dried Succinylated Soy Protein Microparticles for Oral Ibuprofen Delivery.
The potential value of succinylated soy protein (SPS) as a wall material for the encapsulation of ibuprofen (IBU), a model hydrophobic drug, by spray-drying was investigated. A succinylation rate of 93% was obtained for soy protein isolate, with a molar ratio of 1/1.5 (NH2/succinic anhydride). The solubility profile at 37°C showed that this chemical modification decreased the solubility of the protein below its isoelectric point, whereas solubility increased in alkaline conditions. Various SPS/IBU ratios (90/10, 80/20, and 60/40) were studied and compared with the same ratio of soy protein isolate (SPI/IBU). High encapsulation efficiency was achieved (91-95%). Microparticles were spherical and between 4 and 8 μm in diameter. The spray-drying of protein/IBU solutions appeared to be beneficial, as it resulted in an amorphous solid dispersion of IBU within the microparticles, coupled with an increase in the thermal stability of IBU. In vitro release was evaluated in acidic (pH 1.2 in the presence of pepsin) and neutral (pH 6.8) conditions similar to those in the gastrointestinal (GI) tract. IBU was released significantly more slowly at pH 1.2, for both proteins. However, this slowing was particularly marked for SPS, for which rapid (within 2 h) and complete release was observed at pH 6.8. These results validate the hypothesis that SPS is suitable for use as a coating material for hydrophobic active pharmaceutical ingredients (APIs) due to its pH sensitivity, which should delay IBU release in the gastrointestinal tract.


The role of radiation therapy and chemotherapy in the management of airway tumors other than small-cell carcinoma and non-small-cell carcinoma.
In rare pulmonary tumors, the choice of local and systemic therapy is frequently dictated by the histologic cell type and (generally) by extrapolation from the existing therapeutic literature for that cell type's more common presentation; however, this approach might change. We are in the midst of a new biological and technological era in how approach and treat cancer. In a phase I trial for non-small-cell lung cancer, Hayman et al safely treated with radiation doses as high as 102.9 Gy (to limited volumes) using three-dimensional, conformal radiation [100]. Such techniques facilitate radiation dose escalation for thoracic neoplasms while minimizing normal tissue toxicity, potentially enhancing the therapeutic ratio. Furthermore, the entire human genome has been sequenced recently, and scientists are now in the process of discovering the functions of previously unknown sequences and their protein products. DNA microarrays can be used to analyze small tissue samples for the presence of gene variations or mutations (genotyping), performing the equivalent of several thousand "Southern blot" experiments in only a few days. In the future, patients might receive individually tailored therapy based upon unique molecular-genetic alterations of the tumor.


Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.
Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.


Linking home care interventions and hospitalization outcomes for frail and non-frail elderly patients.
Structured clinical data generated using standardized terminologies such as the Omaha System are available for evaluating healthcare quality and patient outcomes. New intervention management grouping approaches are needed to deal with large, complex clinical intervention data sets. We evaluated 56 intervention groups derived using four data management approaches with a data set of 165,700 interventions from 14 home care agencies to determine which approaches and interventions predicted hospitalizations among frail (n = 386) and non-frail (n = 1,364) elders. Hospitalization predictors differed for frail and non-frail elders. Low frequencies in some intervention groups were positively associated with hospitalization outcomes, suggesting that there may be a mismatch between the level of care that is needed and the level of care that is provided.


Influence of the indigenous gastrointestinal microbial flora on duodenal alkaline phosphatase activity in mice.
Alkaline phosphatase activity was assayed by two procedures in duodenal homogenates from specific pathogen-free (SPF) mice of various ages, adult germfree mice, adult ex-germ-free mice colonized with an indigenous microflora from the SPF mice, and adult ex-germ-free mice monocontaminated with a Lactobacillus sp. indigenous to the SPF mice. In the SPF neonates, the activity remained at low levels until at least 12 days of age, increased to high levels at 20 days of age, and then fell to adult levels between the early neonatal and later high levels. In the germ-free mice, the activity levels were significantly higher than the levels in SPF mice at any age. In contrast, in the ex-germ-free animals, colonized by an entire indigenous microflora, the values fell within the range for adult SPF animals. In the ex-germ-free mice colonized only by the Lactobacillus sp., the activity levels were intermediate between the values for germ-free and SPF mice. These findings show that the indigenous microbial flora influences considerably the intestinal alkaline phosphatase activity in the mouse.


The genomic organization of the Fanconi anemia group A (FAA) gene.
Fanconi anemia (FA) is a genetically heterogenous disease involving at least five genes on the basis of complementation analysis (FAA to FAE). The FAA gene has been recently isolated by two independent approaches, positional and functional cloning. In the present study we describe the genomic structure of the FAA gene. The gene contains 43 exons spanning approximately 80 kb as determined by the alignment of four cosmids and the fine localization of the first and the last exons in restriction fragments of these clones. Exons range from 34 to 188 bp. All but three of the splice sites were consistent with the ag-gt rule. We also describe three alternative splicing events in cDNA clones that result in the loss of exon 37, a 23-bp deletion at the 5' end of exon 41, and a GCAG insertion at the 3' portion also in exon 41. Sequence analysis of the 5' region upstream of the putative transcription start site showed no obvious TATA and CAAT boxes, but did show a GC-rich region, typical of housekeeping genes. Knowledge of the structure of the FAA gene will provide an invaluable resource for the discovery of mutations in the gene that accounts for about 60-66% of FA patients.


A case of Cushing's syndrome due to bilateral cortisol-secreting adenomas with unilateral DHEAS oversecretion.
A 39-year-old Japanese woman presented with typical clinical symptoms of Cushing's syndrome, including amenorrhea and hirsutism, for 2 years. The results of her initial endocrine evaluation were consistent with ACTH-independent Cushing's syndrome due to bilateral adrenal masses (diameters of 3.1 cm and 2.4 cm on the left and right, respectively). Serum dehydroepiandrosterone levels were 6,901 ng/mL (normal range 230-2,660 ng/mL). Bilateral laparoscopic adrenalectomies were performed (left adrenalectomy first and right adrenalectomy 3 months later). Following the left adrenalectomy, the results of the endocrine evaluations were still consistent with a diagnosis of ACTH-independent Cushing's syndrome. Serum dehydroepiandrosterone sulphate levels, however, were below the normal range (143 ng/mL). Unexpectedly, the patient's menstruation resumed 2.5 months after the left adrenalectomy. Pathological examination of the resected glands showed bilateral adrenocortical adenomas, one on the left with a diameter of 3 cm, and two on the right with diameters of 0.7 cm and 1.3 cm. Immunohistochemical analysis revealed side chain cleavage, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and 21-hydroxylase immunoreactivity in each adenoma. Dehydroepiandrosterone-sulfotransferase immunoreactivity was pronounced in the left adenoma, less pronounced in one of the right adenoma and weak in the other right adenoma. These results were consistent with clinical endocrine findings. Ours is the first case of a patient with bilateral cortisol-secreting adenomas with unilateral oversecretion of dehydroepiandrosterone sulphate. Resumption of menstruation after the correction of the dehydroepiandrosterone-sulphate excess, despite persistent cortisol excess, indicates the importance of adrenal androgens for the regulation of the menstrual cycle.


The differential processing of telomeres in response to increased telomeric transcription and RNA-DNA hybrid accumulation.
Telomeres are protective nucleoprotein structures at the ends of eukaryotic chromosomes. Despite the heterochromatic state of telomeres they are transcribed, generating non-coding telomeric repeat-containing RNA (TERRA). Strongly induced TERRA transcription has been shown to cause telomere shortening and accelerated senescence in the absence of both telomerase and homology-directed repair (HDR). Moreover, it has recently been demonstrated that TERRA forms RNA-DNA hybrids at chromosome ends. The accumulation of RNA-DNA hybrids at telomeres also leads to rapid senescence and telomere loss in the absence of telomerase and HDR. Conversely, in the presence of HDR, telomeric RNA-DNA hybrid accumulation and increased telomere transcription promote telomere recombination, and hence, delayed senescence. Here, we demonstrate that despite these similar phenotypic outcomes, telomeres that are highly transcribed are not processed in the same manner as those that accumulate RNA-DNA hybrids.


Human thyrotropin (TSH) variants designed by site-directed mutagenesis block TSH activity in vitro and in vivo.
TSH is a heterodimeric glycoprotein hormone synthesized in the pituitary and composed of a specific beta-subunit and a common alpha-subunit shared with FSH, LH, and human chorionic gonadotropin. The heterodimer was previously converted into a biologically active single chain protein by genetic fusion of the genes coding to both subunits in the presence of the carboxy-terminal sequence of human (h) chorionic gonadotropin-beta subunit as a linker [hTSHbeta-carboxyl-terminal peptide (CTP)-alpha]. N-linked carbohydrate-free single-chain TSH variants were constructed by site-directed mutagenesis and overlapping PCR: one devoid of both N-linked oligosaccharide chains on the alpha-subunit (hTSHbeta-CTP-alpha(deg)) and the other lacking also the oligosaccharides on the beta-subunit (hTSHbeta(deg)-CTP-alpha(deg)). These variants were expressed in Chinese hamster ovary cells and secreted into the culture media. We have previously reported that the variants block the activities of hTSH and thyroid-stimulating immunoglobulins in cultured human thyroid follicles. In the present study, binding affinity of hTSH variants to hTSH receptor and the localization of the antagonistic effect were examined. Moreover, the effect of these variants on TSH activity was tested in vivo. The results of the present study indicate that the hTSH variants bind to the hTSH receptor with high affinity. Experiments using forskolin also indicated that the N-linked carbohydrate-free TSH single-chain variants inhibit TSH activity at the receptor-binding site and not at a postreceptor level. Moreover, the variants significantly inhibited (about 50%) TSH activity with respect to thyroid hormone secretion in vivo in mice. These variants may offer a novel therapeutic strategy in treating hyperthyroidism.


Plasmodium food vacuole plasmepsins are activated by falcipains.
Intraerythrocytic malaria parasites use host hemoglobin as a major nutrient source. Aspartic proteases (plasmepsins) and cysteine proteases (falcipains) function in the early steps of the hemoglobin degradation pathway. There is extensive functional redundancy within and between these protease families. Plasmepsins are synthesized as integral membrane proenzymes that are activated by cleavage from the membrane. This cleavage is mediated by a maturase activity whose identity has been elusive. We have used a combination of cell biology, chemical biology, and enzymology approaches to analyze this processing event. These studies reveal that plasmepsin processing occurs primarily via the falcipains; however, if falcipain activity is blocked, autoprocessing can take place, serving as an alternate activation system. These results establish a further level of redundancy between the protease families involved in Plasmodium hemoglobin degradation.


TdTomato and EGFP identification in histological sections: insight and alternatives.
Tandem dimer Tomato (tdTomato) provides a useful alternative to enhanced green fluorescent protein (eGFP) for performing simultaneous detection of fluorescent protein in histological sections together with fluorescence immunohistochemistry (IHC). eGFP has many properties that make it useful for cell labeling; however, during simultaneous fluorescence IHC, the usefulness of eGFP may be limited. This limitation results from a fixation step required to identify eGFP in histological tissue sections that can mask antibody epitopes and adversely affect staining intensity. An alternative fluorescent protein, tdTomato, may assist concurrent detection of fluorescent protein within tissue sections and fluorescence IHC, because detection of tdTomato does not require tissue fixation. Tissue sections were obtained from various organs of mice ubiquitously expressing eGFP or tdTomato that were either unfixed or fixed with 4% paraformaldehyde. These tissues later were combined with fluorescence IHC. Both eGFP and tdTomato displayed robust signals in fixed frozen sections. Only tdTomato fluorescence, however, was detected in unfixed frozen sections. Simultaneous detection of fluorescence IHC and fluorescent protein in histological sections was observed only in unfixed frozen tdTomato tissue. For this reason, tdTomato is a useful substitute for eGFP for cell labeling when simultaneous fluorescence IHC is required.


Short-term treatment of asthma with budesonide versus placebo.
The effects of the topical steroid budesonide on bronchial hyperreactivity were evaluated in a patient group (A, n = 17) and a placebo-controlled patient group (B, n = 11). Group A was given budesonide 400 micrograms/12 h for 4 weeks and 200 micrograms/12 h for four more weeks. The drug proved efficient in controlling asthma clinically and improving the spirometric parameters: FVC (p < 0.05), FEF50 (p < 0.05) and FEV1 (p < 0.01). Bronchial hyperreactivity (PD20) decreased moderately in the treatment group (p < 0.1). On the contrary, basal spirometry and PD20 worsened in the control group. Some patients in group A showed peripheric eosinophilia (2/15) or in secretions (9/15), which persisted in one patient at end of treatment. Budesonide was effective in the clinical and spirometric control of asthma. We conclude that for a better assessment of the treatment of bronchial hyperreactivity with budesonide, the drug must be administered for a longer period of time. The differences between this study and previous ones is that the improvement in PD20 can be explained by the different characteristics of the patients selected for this study.


An empirical comparison of interpersonal and DSM-III approaches to classification of personality disorders.
In recent years, a number of authors have attempted to map correspondences between interpersonal models and traditional psychiatric classification. Many of the proposed relationships are plausible from a theoretical standpoint, but at present little empirical evidence has been gathered in support of these speculations. This paper describes the results of a project that suggests that the convergence of these two approaches to personality taxonomy is not as high as might be expected. In particular, it seems that DSM-III personality disorders are not as differentiated with respect to affiliative needs as has been hypothesized.