How to diagnose and manage Cushing's disease during pregnancy, when hypercortisolism is mild?

Diagnosis of mild Cushing's disease (CD) can be difficult in pregnant women, because its clinical and biochemical features can be erroneously interpreted as consequence of the gestation. Corticotropin releasing hormone (CRH) and desmopressin (DDAVP) tests are currently used to confirm CD, but data concerning adrenocorticotropic hormone (ACTH) response during pregnancy are lacking. A woman with mild cushingoid features was evaluated during the first trimester of gestation. Serum cortisol was normal at morning, but increased at midnight and incompletely suppressed by 1-mg dexamethasone overnight administration. Also 24-h urinary free cortisol levels were mildly elevated. She delivered vaginally a healthy newborn at the 39th week of an uneventful pregnancy. After delivery, an ACTH-secreting microadenoma was surgically removed. During the first trimester of gestation and after delivery, human CRH (h-CRH) and DDAVP-stimulated ACTH peaks were higher than those measured in 22 healthy premenopausal women. While the ACTH/h-CRH peak was intermediate between those measured in the healthy women and in 9 CD female patients, ACTH/DDAVP peak was in the range of CD patients and dramatically higher than those of healthy women. However, ACTH increase after h-CRH was significantly higher after delivery than during gestation (p?相似文献   

Optimization of electroporation parameters for the intramuscular delivery of plasmids in pigs

Increased transgene expression after plasmid transfer to the skeletal muscle is obtained with electroporation in many species, but optimum conditions are not well defined. Using a plasmid with a muscle-specific secreted embryonic alkaline phosphatase (SEAP) gene, we have optimized the electroporation conditions in a large mammal (pig). Parameters tested included electric field intensity, number of pulses, lag time between plasmid injection and electroporation, and plasmid delivery volume. Electric pulses, between 0.4 and 0.6 Amp constant current, applied 80 sec after the injection of 0.5 mg SEAP-expressing plasmid in a total volume of 2 mL produced the highest levels of expression. Further testing demonstrated that electroporation of a nondelineated injection site reduces the levels of SEAP expression. These results demonstrate that electroporation parameters such as amperage, lag time, and the number of pulses are able to regulate the levels of reporter gene expression in pigs.     

Proteins associated with diseases show enhanced sequence correlation between charged residues

MOTIVATION: Function of proteins or a network of interacting proteins often involves communication between residues that are well separated in sequence. The classic example is the participation of distant residues in allosteric regulation. Bioinformatic and structural analysis methods have been introduced to infer residues that are correlated. Recently, increasing attention has been paid to obtain the sequence properties that determine the tendency of disease-related proteins (Abeta peptides, prion proteins, transthyretin, etc.) to aggregate and form fibrils. Motivated in part by the need to identify sequence characteristics that indicate a tendency to aggregate, we introduce a general method that probes covariations in charged residues along the sequence in a given protein family. The method, which involves computing the sequence correlation entropy (SCE) using the quenched probability P(sk)(i,j) of finding a residue pair at a given sequence separation, sk, allows us to classify protein families in terms of their SCE. Our general approach may be a useful way in obtaining evolutionary covariations of amino acid residues on a genome wide level. RESULTS: We use a combination of SCE and clustering based on the principle component analysis to classify the protein families. From an analysis of 839 families, covering approximately 500,000 sequences, we find that proteins with relatively low values of SCE are predominantly associated with various diseases. In several families, residues that give rise to peaks in P(sk)(i,j) are clustered in the three-dimensional structure. For the class of proteins with low SCE values, there are significant numbers of mixed charged-hydrophobic (CH) and charged-polar (CP) runs. Our findings suggest that the low values of SCE and the presence of (CH) and/or (CP) may be indicative of disease association or tendency to aggregate. Our results led to the hypothesis that functions of proteins with similar SCE values may be linked. The hypothesis is validated with a few anecdotal examples. The present results also lead to the prediction that the overall charge correlations in proteins affect the kinetics of amyloid formation--a feature that is common to all proteins implicated in neurodegenerative diseases.     

Novel approach to microbiological air monitoring in show caves

Air microbial pollution in touristic areas poses a risk for both the integrity of an ecosystem and human health. Microbiological monitoring together with environmental parameters monitoring allows for the assessment of the impacts and formulation of sound management decisions to protect humans and ecosystems. Four show caves from the Carpathian Mountains were selected for our study. The caves were sampled monthly to obtain an overview of the changes that occur over a yearly cycle. For the microbial monitoring, we used RIDA^®COUNT test plates, while the environmental parameters were monitored with a variety of devices. Second and third generations of microbes extracted from the plates were grown on specific media for the purpose of 16S rRNA and 18S rRNA extraction and taxa identification. The bacterial communities identified in the air samples in the four investigated show caves were dominated by Staphylococcus, while regarding the fungi communities, Penicillium was more likely to occur in the touristic part of the caves and Cladosporium in the non-visited passages. Together with data on number of visitors, number of bats and radon levels we were able understand the impact of tourists on the cave environment and to generate microbiological risk maps for human health. This type of comprehensive study can be used not only to protect the integrity of a touristic area from the impacts caused by the introduction of allochthonous organic matter, but also for the protection of the tourists and guides from potential pathogenic taxa.     

Antimony to Cure Visceral Leishmaniasis Unresponsive to Liposomal Amphotericin B

We report on 4 patients (1 immunocompetent, 3 immunosuppressed) in whom visceral leishmaniasis had become unresponsive to (or had relapsed after) treatment with appropriate doses of liposomal amphotericin B. Under close follow-up, full courses of pentavalent antimony were administered without life-threatening adverse events and resulted in rapid and sustained clinical and parasitological cure.     

Sex-and age-based differences in the delivery and outcomes of critical care

Background

Previous studies have suggested that a patient''s sex may influence the provision and outcomes of critical care. Our objective was to determine whether sex and age are associated with differences in admission practices, processes of care and clinical outcomes for critically ill patients.

Methods

We used a retrospective cohort of 466 792 patients, including 24 778 critically ill patients, admitted consecutively to adult hospitals in Ontario between Jan. 1, 2001, and Dec. 31, 2002. We measured associations between sex and age and admission to the intensive care unit (ICU); use of mechanical ventilation, dialysis or pulmonary artery catheterization; length of stay in the ICU and hospital; and death in the ICU, hospital and 1 year after admission.

Results

Of the 466 792 patients admitted to hospital, more were women than men (57.0% v. 43.0% for all admissions, p < 0.001; 50.1% v. 49.9% for nonobstetric admissions, p < 0.001). However, fewer women than men were admitted to ICUs (39.9% v. 60.1%, p < 0.001); this difference was most pronounced among older patients (age ≥ 50 years). After adjustment for admission diagnoses and comorbidities, older women were less likely than older men to receive care in an ICU setting (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.66–0.71). After adjustment for illness severity, older women were also less likely than older men to receive mechanical ventilation (OR 0.91, 95% CI 0.81– 0.97) or pulmonary artery catheterization (OR 0.80, 95% CI 0.73– 0.88). Despite older men and women having similar severity of illness on ICU admission, women received ICU care for a slightly shorter duration yet had a longer length of stay in hospital (mean 18.3 v. 16.9 days; p = 0.006). After adjustment for differences in comorbidities, source of admission, ICU admission diagnosis and illness severity, older women had a slightly greater risk of death in the ICU (hazard ratio 1.20, 95% CI 1.10–1.31) and in hospital (hazard ratio 1.08, 95% CI 1.00–1.16) than did older men.

Interpretation

Among patients 50 years or older, women appear less likely than men to be admitted to an ICU and to receive selected life-supporting treatments and more likely than men to die after critical illness. Differences in presentation of critical illness, decision-making or unmeasured confounding factors may contribute to these findings.It is generally believed that access to an intensive care unit (ICU), the care received and subsequent clinical outcomes are determined primarily by need and severity of illness. However, in other areas of health care, sociodemographic characteristics have been found to influence treatment decisions and care delivery.^1–6 For example, women are believed to have a lower incidence of coronary artery disease than men;² however, they are also less likely to undergo intensive evaluation and treatment for this condition and may have a higher rate of early mortality after acute myocardial infarction.^7,8 Previous studies from various jurisdictions have suggested that there may be sex-based differences in critical illness and ICU admission patterns,^3,4,6,9 although there have been no consistent findings of sex-based differences in the provision of care or clinical outcomes.^{1,3,4,6,10–12}The Canadian health care system is based on the principle of equal access for all citizens. This presents a unique opportunity to explore sex-related differences in ICU care. We hypothesized that age and sex might be associated with differences in admission practices, processes of care and clinical outcomes for critically ill patients, and we explored these relations over a 2-year period in a diverse sample of hospitals in Ontario.     

Factors associated with exclusive breastfeeding at discharge during the COVID-19 pandemic in 17 WHO European Region countries

Both the consumption of breastmilk in infancy and a person’s season of birth influences his or her health, educational, professional, and behavioral outcomes. Further, season of birth effects differ by sex. However, current research, for the most part, neglects to examine if season of birth and breastfeeding are related. This paper examines the impact of sex-based variations in season of birth on breastfeeding likelihood and duration in the U.S. Using data from children born to female respondents of the National Longitudinal Survey of Youth 1979 (born between 1970 and 2012), this study examines with Probit, Negative Binomial, and Ordinary Least Squares (OLS) regressions if a child’s season of birth and sex are correlated with breastfeeding incidence and duration. The breastfeeding incidence and duration data are self-reported by the mother. Season of birth has a small but statistically significant impact on the incidence and duration of breastfeeding, which varies depending on the sex of the infant. Mothers giving birth to sons in the spring are 13.5% less likely to breastfeed than those giving birth to sons in the winter (with a p - value of 0.0269). Mothers with daughters born in the summer or fall (autumn) breastfeed slightly longer than mothers with daughters born in the spring. On average, mothers of summer-born daughters breastfeed 4.1% longer (with a 95% confidence interval of 0.3 - 7.8) and those with fall-born daughters 3.8% longer (with a 95% confidence interval of 0 - 7.5). Mothers giving birth to daughters in the spring are also significantly less likely to reach the breastfeeding six-week duration target (compared to fall and winter births) and the one-year duration target (compared to fall births). These findings suggest that the costs and benefits of breastfeeding an infant vary with the season of birth and the sex of the child. This finding could explain some of the season of birth effects previously identified in the literature. Further, policymakers seeking to increase breastfeeding rates should consider the reduced breastfeeding rates and durations for children born in the spring.     

CXCL1 and CXCL2 Inhibit the Axon Outgrowth in a Time- and Cell-Type-Dependent Manner in Adult Rat Dorsal Root Ganglia Neurons

The ability to regrow their axons after an injury is a hallmark of neurons in peripheral nervous system which distinguish them from central nervous system neurons. This ability is influenced by their intrinsic capacity to regrow and by the extracellular environment which needs to be supportive of regrowth. CXCL1 [Chemokine (C-X-C motif) Ligand 1] and CXCL2 [Chemokine (C-X-C motif) Ligand 2] are two low-molecular-weight chemokines which can influence neuronal proliferation, differentiation and neurogenesis, but which are also upregulated by injury or inflammation. In this study we investigated the effects of long-term incubation (24, 48 and 72 h) with different concentrations of CXCL1 (0.4, 4 or 40 nM) or CXCL2 (0.36, 3.6 or 36 nM) on the axon outgrowth of adult rat dorsal root ganglia neurons in culture. The results showed that both chemokines significantly inhibited the axon outgrowth, with large and medium NF200 (NeuroFilament 200) (+) dorsal root ganglia neurons affected quicker, compared to small IB4 (Isolectin B4) (+) dorsal root ganglia neurons which were affected after longer exposure. Blocking CXCR2 (C-X-C motif chemokine receptor 2) which mediates the effects of CXCL1 and CXCL2 prevented these effects, suggesting that CXCR2 may represent a new therapeutic target for promoting the axon outgrowth after a peripheral nerve injury.

     

Production of Two Vaccinating Recombinant Rotavirus Proteins in the Milk of Transgenic Rabbits

Rotaviruses are the main cause of infantile viral gastroenteritis worldwide leading to approximately 500,000 deaths each year mostly in the developing world. For unknown reasons, live attenuated viruses used in classical vaccine strategies were shown to be responsible for intussusception (a bowel obstruction). New strategies allowing production of safe recombinant non-replicating rotavirus candidate vaccine are thus clearly needed. In this study we utilized transgenic rabbit milk as a source of rotavirus antigens. Individual transgenic rabbit lines were able to produce several hundreds of micrograms per ml of secreted recombinant VP2 and VP6 proteins in their milk. Viral proteins expressed in our model were immunogenic and were shown to induce a significant reduction in viral antigen shedding after challenge with virulent rotavirus in the adult mouse model. To our knowledge, this is the first report of transgenic mammal bioreactors allowing the rapid co-production of two recombinant viral proteins in milk to be used as a vaccine.     

Kinetics of hydrogen peroxide decomposition by catalase: hydroxylic solvent effects

The effect of water–alcohol (methanol, ethanol, propan-1-ol, propan-2-ol, ethane-1,2-diol and propane-1,2,3-triol) binary mixtures on the kinetics of hydrogen peroxide decomposition in the presence of bovine liver catalase is investigated. In all solvents, the activity of catalase is smaller than in water. The results are discussed on the basis of a simple kinetic model. The kinetic constants for product formation through enzyme–substrate complex decomposition and for inactivation of catalase are estimated. The organic solvents are characterized by several physical properties: dielectric constant (D), hydrophobicity (log P), concentration of hydroxyl groups ([OH]), polarizability (α), Kamlet-Taft parameter (β) and Kosower parameter (Z). The relationships between the initial rate, kinetic constants and medium properties are analyzed by linear and multiple linear regression.