No long-term effect two years after intrauterine exposure to dexamethasone on dentate gyrus volume, neuronal proliferation and differentiation in common marmoset monkeys

Abstract Glucocorticoids are prenatally administered to promote the maturation of the lungs. They, however, can affect neuronal proliferation and differentiation. In newborn marmoset monkeys, intrauterine hyperexposure to dexamethasone (DEX) resulted in a significantly decreased proliferation rate in the hippocampal dentate gyrus without affecting neuronal differentiation. In this study, marmoset monkeys received 5 mg/kg body weight DEX either during early (days 42-48) or late (days 90-96) pregnancy. The volume of the dentate granule cell layer as well as the proliferation and neuronal differentiation in the dentate gyrus of their 2-year-old offspring were investigated. The density of proliferating cells (Ki-67), apoptotic cells (in situ tailing) and cells differentiating to neurons (double cortin, TUC-4 and calretinin) were determined immunohistochemically. Analysis of the dentate granule cell layer volume showed no significant differences between early or late DEX-exposed marmosets and untreated control animals. Similarly, proliferation and neuronal differentiation in DEX-treated animals was not significantly different in comparison with controls. In summary, the decreased proliferation rate observed in newborn marmosets after intrauterine exposure to DEX was no longer detectable in their 2-year-old siblings suggesting no long-lasting effect of prenatal hyperexposure to DEX on neuronal proliferation and differentiation in the dentate gyrus of marmoset monkeys.     

A Pilot Trial of the Alpha-1 Adrenergic Antagonist, Prazosin, for Alcohol Dependence

Background:  Current medications for alcohol dependence (AD) show only modest efficacy. None target brain noradrenergic pathways. Theory and preclinical evidence suggest that noradrenergic circuits may be involved in alcohol reinforcement and relapse. We therefore tested the α-1 adrenergic receptor antagonist, prazosin, as a pharmacotherapy for AD.
Methods:  We randomized 24 participants with AD but without posttraumatic stress disorder to receive either prazosin or placebo in a 6-week, double-blind pilot study. Medication was titrated to a target dose of 4 mg QAM, 4 mg QPM, and 8 mg QHS by the end of week 2. Participants received 5 medical management treatment sessions. Participants were reminded 3 times each day via a text pager to take medications and to call a telephone monitoring system once daily to provide self-reports of alcohol consumption and craving, the primary outcome measures. Results were analyzed using mixed linear regression adjusted for drinking days per week at baseline and week number.
Results:  Twenty of the 24 (83%) subjects completed. Among the completers, the prazosin group reported fewer drinking days per week than the placebo group during the final 3 weeks of the study. Since only 1 woman was randomized to placebo and only three women completed the trial, the following results focus on the 17 male completers. The prazosin group reported fewer drinking days per week and fewer drinks per week during the final 3 weeks of the study; average total number of drinking days for the placebo group 5.7 (SEM 1.9) versus 0.9 (SEM 0.5) for the prazosin group, and average total number of drinks 20.8 (SEM 6.5) for the placebo group versus 2.6 (SEM 1.3) for the prazosin group. Rates of adverse events were equivalent across conditions.
Conclusions:  Prazosin holds promise as a pharmacologic treatment for AD and deserves further evaluation in a larger controlled trial.     

Is increased body mass index associated with the incidence of testicular germ cell cancer?

Purpose  Epidemiological and ecological evidences suggest a positive association of overweight and obesity with the risk of testicular germ cell cancer (GCC). Previous controlled trials reported conflicting results. The present study aimed to analyse the putative association of overweight with GCC risk in a large patient sample and to summarize previous data. Methods  A total of 8,498 GCC patients were enrolled in a nationwide multicentric case control study. Self-reported body dimensions were recorded for calculation of the body mass index (BMI; kg/m²). For comparison, 2,070 age-matched male probands of the latest German National Health Survey (NHS) were employed. Patients and controls were categorized according to age as follows: 18–29, 30–39, and 40–49 years, respectively, and according to BMI, as follows: <18.5; 18.5 to <25; 25 to <30; >30 kg/m², respectively. Frequencies of BMI-categories in the three age groups were tabulated and compared statistically. The literature was searched for previous controlled trials regarding BMI and GCC risk. Results  The median BMI of all GCC patients is 24.69 kg/m². Overall comparison of frequencies of BMI categories of cases and controls did not reveal any significant difference. However, in young men (18–29 years) BMI categories 25 to <30 kg/m² and >30 kg/m² were significantly more frequent in GCC patients than in controls (p < 0.00001). Nineteen previous studies were identified in the literature, one of which being clearly in accordance with the present hypothesis, one being antithetical while the remaining studies were inconclusive in various aspects. Conclusion  The results of this population-based study lend support to two hypotheses regarding the pathogenesis of GCC: First, as high-calorie nutrition is the most important reason for increased BMI, it appears conceivable that nutritional factors are involved in the pathogenesis of GCC. Second, as nonseminoma is the most prevalent histological subtype among younger patients, the association of increased BMI with incidence of GCC in this particular subgroup may point to divergent pathogenetic pathways of nonseminoma and seminoma, respectively.     

Prognostic relevance of FDG PET in patients with neurofibromatosis type-1 and malignant peripheral nerve sheath tumours

Purpose In patients with neurofibromatosis type-1 (NF1) and malignant peripheral nerve sheath tumours (MPNSTs), survival rates are low and time to death is often less than 2 years. However, there are patients with a more favourable prognosis who develop metastases rather late or not at all. Since histopathology and tumour grading are not well correlated with prognosis, we aimed to evaluate the potential of ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET) for prediction of patient outcome in MPNST. Methods FDG PET was performed in 16 patients with NF1 and MPNSTs. Standardised uptake values (SUVs) were calculated for each tumour and correlated to tumour grade and patient outcome in terms of survival or death. Results Three patients with tumour grade II had an SUV <3. None of these patients developed metastases or died during a follow-up of 41–62 months. Thirteen patients with tumour grades II and III had an SUV >3. Only one of these patients is still alive after 20 months; the remaining 12 died within 4–33 months. SUV predicted long-term survival with an accuracy of 94%, compared with 69% for tumour grade. In Kaplan-Meier survival analysis, patients with an SUV >3 had a significantly shorter mean survival time, 13 months, than patients with an SUV <3, in whom the mean survival time was 52 months. Tumour grading did not reveal differences in survival time (15 vs 12 months). Conclusion Tumour SUV obtained by FDG PET was a significant parameter for prediction of survival in NF1 patients with MPNSTs while histopathological tumour grading did not predict outcome.     

Randomized trial of onsite versus referral primary medical care for veterans in addictions treatment

BACKGROUND: Patients presenting for treatment of substance use disorders (SUDs) often exhibit medical comorbidities that affect functional health status and healthcare costs. Providing primary care within addictions clinics (onsite care) may improve medical and SUD treatment outcomes in this population. OBJECTIVE: The objective of this study was to compare outcomes among Veterans' Administration (VA) patients who receive medical care within the SUD clinic and those referred to a general medicine clinic at the same facility. METHODS: Veterans entering SUD treatment with a chronic medical condition and no current primary care were randomized to receive primary medical care: 1) onsite in the VA SUD clinic (n = 358), or 2) in the VA general internal medicine clinic (n = 362). Subjects were assessed at baseline and at 3, 6, and 12 months postrandomization. Intention-to-treat analyses used random-effects regression. MEASURES: Measures included SF-36 Physical and Mental Component Summaries (PCS, MCS), VA service utilization, SUD treatment retention, Addiction Severity Index (ASI) scores, 30-day abstinence, and total VA healthcare costs. RESULTS: Over the study year, patients assigned to onsite care were more likely to attend primary care (adjusted odds ratio [OR] = 2.20; 95% confidence interval [CI] = 1.53-3.15) and to remain engaged in SUD treatment at 3 months (adjusted OR = 1.36; 1.00-1.84). Overall, outcomes on the MCS (but not the PCS) and the ASI improved significantly over time but did not differ by treatment condition. Total VA healthcare costs did not differ reliably across conditions. CONCLUSIONS: Compared with referral care, providing primary care within a VA addiction clinic increased primary care access and initial SUD treatment retention but showed no effect on overall health status or costs.     

The role of protein kinase A in the ethanol-induced increase in spontaneous GABA release onto cerebellar Purkinje neurons

Ethanol increases miniature inhibitory postsynaptic current frequency and decreases the paired-pulse ratio, which suggests that ethanol increases both spontaneous and evoked GABA release, respectively. We have shown previously that ethanol increases GABA release at the rat interneuron-Purkinje cell synapse and that this ethanol effect involves calcium release from internal stores; however, further exploration of the mechanism responsible for ethanol-enhanced GABA release was needed. We found that a cannabinoid receptor 1 (CB1) agonist, WIN-55212, and a GABA(B) receptor agonist, baclofen, decreased baseline spontaneous GABA release and prevented ethanol from increasing spontaneous GABA release. The CB1 receptor and GABA(B) receptor are Galpha i-linked G protein-coupled receptors with common downstream messengers that include adenylate cyclase and protein kinase A (PKA). Adenylate cyclase and PKA antagonists blocked ethanol from increasing spontaneous GABA release, whereas a PKA antagonist limited to the postsynaptic neuron did not block ethanol from increasing spontaneous GABA release. These results suggest that presynaptic PKA plays an essential role in ethanol-enhanced spontaneous GABA release. Similar to ethanol, we found that the mechanism of the cannabinoid-mediated decrease in spontaneous GABA release involves internal calcium stores and PKA. A PKA antagonist decreased baseline spontaneous GABA release. This effect was reduced after incubating the slice with a calcium chelator, BAPTA-AM, but was unaffected when BAPTA was limited to the postsynaptic neuron. This suggests that the PKA antagonist is acting through a presynaptic, calcium-dependent mechanism to decrease spontaneous GABA release. Overall, these results suggest that PKA activation is necessary for ethanol to increase spontaneous GABA release.     

Research in practice: the second barrier of the human skin

A major function of human skin is to form an effective barrier between the environment and the inside of the organism. Especially important for this function is the activity of the physical barrier of the skin, which is mainly located in the stratum corneum. To improve this barrier function of the skin, skin protection agents are used. Recent studies have revealed that application of skin protection agents before exposition to xenobiotics does not generally reduce the percutaneous uptake of these compounds. These findings indicate that besides new study designs and improved test systems, there seems to be a need for new therapeutic approaches for more effective skin protection. In this light, new findings regarding a second barrier function of the human skin, the biochemical/toxicological barrier, could be of interest. A crucial part of this barrier function are members of the cytochrome P450 (CYP) family and efflux‐transport proteins of the multidrug resistance‐related protein family (MRPs), which are mainly expressed by basal layer keratinocytes. Recent studies have revealed that besides the physiological and protective function of these transport proteins and CYP enzymes in skin cells, the same proteins also play a role in the transport of contact allergens and activation of prohaptens to haptens causing contact dermatitis. Inhibition of this metabolism mediated activation of prohaptens and stimulation of the active elimination of contact allergens from skin cells could represent novel mechanisms improving the established tools for skin protection.     

Occurrence of an artifact in brain 18F-FDG PET with calculated attenuation correction

In infants, brain (18)F-FDG PET often requires sedation. To keep the sedation mild, the PET acquisition time should be kept short. Therefore, calculated attenuation correction is often preferred to measured attenuation correction. In addition, the infant should be positioned as comfortably as possible. Here, we report a case in which the infant's fist was near her head, resulting in severe artifacts when calculated attenuation correction was applied. Brain (18)F-FDG PET was performed for localization of a focus in an 11-mo-old girl with West's syndrome. After injection of 120 MBq of (18)F-FDG, a 20-min emission scan was obtained. Then, a 7-min hot transmission scan was acquired with 3 rotating (68)Ge/(68)Ga rod sources. Attenuation was corrected both by calculated attenuation correction and by measured attenuation correction using the transmission scan. Images reconstructed with calculated attenuation correction showed apparently increased (18)F-FDG uptake in the skin of the neck. The fist was not visible on the images because it was outside the reconstructed field of view. The lesion of increased (18)F-FDG uptake was not immediately recognizable as an artifact. It might have been misinterpreted as an active process, such as inflammation, in the skin. However, the lesion showed up neither on images reconstructed with measured attenuation correction nor on images without attenuation correction. Detailed analysis of each step in the calculated attenuation correction revealed that the fist caused the boundary detection algorithm to detect not the boundary of the head but a strongly extended boundary enclosing the fist and large "air areas" between the fist and the head. The result was a significant overestimation and overcorrection of attenuation, particularly in the region of skin near the fist.     

Novel specific human and mouse stromelysin‐1 (MMP‐3) and stromelysin‐2 (MMP‐10) antibodies for biochemical and immunohistochemical analyses

Matrix metalloproteinases (MMP) are a family of more than 25 zinc‐dependent enzymes that are centrally involved in cellular migration, tissue remodeling, cancer invasion and metastasis. Besides degrading extracellular matrix proteins, MMPs are crucial for growth factor and cytokine release and activation. At the same time, they can inactivate inflammatory mediators and enzymes themselves through protein degradation. Subclasses of MMPs include collagenases, gelatinases, stromelysins, membrane‐bound MMPs, and others. With regard to the stromelysin subfamily, three members exist, e.g., stromelysin‐1 (MMP‐3), stromelysin‐2 (MMP‐10), and stromelysin‐3 (MMP‐11). MMP‐3, and MMP‐10 share extensive similarities at the amino acid level that made it difficult to develop specific antibodies distinguishing between MMP‐3 and MMP‐10. Scrutinizing published data on and performing different analyses with detection of both stromelysins with commercially available or lab‐made antibodies showed ambiguous results with regard to specificity of antibodies used to date. We developed new specific antibodies against the most divergent parts of the active forms of both proteins. We assessed the specificity of our novel specific anti‐human and anti‐mouse MMP‐3 and MMP‐10 antibodies in cell lysates and different human and murine skin tissues. Tests analyzing specificity of the novel antibodies included Western immunoblotting, immunofluorescence, and immunohistochemistry on paraffin sections. Analyses demonstrated specific detection of respective protein for human or mouse samples except for the anti‐human MMP‐3 antibody. The aim of this summary was to call attention the MMP research community to distinguish clearly between both enzymes. Our new specific anti‐mouse MMP‐3 and both MMP‐10 antibodies allow us to address this detection problem and to enable comparative studies between both stromelysins with regard to their respective location and function in the tissue.