Phosphoinositide 3-kinase is involved in the induction of the human sperm acrosome reaction downstream of tyrosine phosphorylation

In somatic cells phosphoinositide 3-kinase (PI 3-kinase) is activated upon interaction with both receptor tyrosine kinases (RTK) and G- proteins resulting in the production of moieties involved in the inositol phospholipid signalling pathway. As G proteins, RTK and the inositol phospholipids have all been implicated in the human sperm acrosome reaction, experiments were carried out to determine whether PI 3-kinase was also involved in this phenomenon. Wortmannin is a selective inhibitor of PI 3-kinase and was shown to significantly inhibit the acrosome reaction induced by both mannose-bovine serum albumin (mannose-BSA) (10, 50 and 100 nM) and a polyclonal antibody raised against an extracellular region of the sperm zona receptor kinase (ZRK, at 100 nM only). Wortmannin did not inhibit the A23187- or progesterone-induced acrosome reaction. These results suggest that PI 3- kinase is involved in the human sperm acrosome reaction. The levels of tyrosine phosphorylation of sperm proteins as detected by Western blotting using antiphosphotyrosine antibodies was not affected by wortmannin in agonist (A23187 and mannose-BSA)-stimulated spermatozoa. This indicated that PI 3-kinase operates downstream of tyrosine phosphorylation in the signal transduction cascade which leads to the human sperm acrosome reaction.      

Magnetic resonance angiography

Pulse sequences that permit selective detection of moving spins in a magnetic resonance image have been developed. Experiments were performed by the authors to produce projected angiographic data without the use of contrast agents, with the intensity of each image pixel determined by the macroscopic velocity of the detected spins. With this method, suppression of nonmoving spins is essentially complete, yielding a high dynamic range in signal intensity for detected vessels. Selective detection of moving spins is not dependent on pulsatile flow. Consequently, not only arterial structures, but also venous structures can easily be visualized. High-resolution angiographic images can be obtained by combining the flow experiment with surface coil techniques.     

Long-term visual results in eyes cured for retinoblastoma by radiation

Twenty-four eyes from 18 patients cured for retinoblastoma by radiation on an average 12 years previously, were re-examined with respect to visual performance. The macular functions, i.e. visual acuity, colour vision and contrast sensitivity demonstrated performances predictable from tumour localization and radiation dose to the macula. The rod functions, i.e. visual field and dark adaptation were found to be relatively resistant to the radiation treatment. A special problem encountered in two-eyed patients was the unavoidable amblyopia due to unequal handicaps in the two eyes at the vulnerable age.     

Females have lower skin surface pH than men

Background/aims: It is of great interest to describe the many functions and properties of the skin in order to better understand reactions that result in different skin abnormalities, as a prerequisite in the development of skin products and topical medicines. Skin surface pH is considered a critical parameter of skin wellbeing and is typically studied on the forearm skin. Despite many previous investigations, this is an extensive field that still needs a great deal of research. The aim of our study was to investigate gender related differences, differences between right and left arms, anatomical variation and daytime variation in skin surface pH.
Methods: Skin surface pH was measured on the flexor surface of the forearm on eleven healthy volunteers (6 men and 5 women). A Mettler Toledo pH meter (pH meter 1140) was used. The subjects were measured once every hour from 8 a.m. to 3 p.m. in five areas from the elbow to the wrist. In each of the five areas, three measurements were performed next to each other, and the mean of these was used in subsequent calculations.
Results: A statistically significant difference in skin pH between men (mean pH=5.80) and women (mean pH=5.54) was found, with women being more acidic than men ( P <0.01). No difference between right and left arm was found. In men, the area closest to the wrist had significantly lower pH values compared with the proximal sites. This was not the case in women. Skin surface pH decreased during normal working hours in both genders.
Conclusion: Spontaneous skin surface pH was found to be significantly lower in women, as compared to men – albeit, the difference was small and of unknown relevance. Nevertheless, comparative studies on skin surface pH should be balanced with respect to gender. There appeared to be no right/left difference and no systematic change during the working day. Also, measurements should not be conducted close to the wrist.     

Pharmacokinetics of apomorphine in parkinsonian patients

Summary— Apomorphine, a dopamine agonist, has been used efficiently in parkinsonian patients to treat severe levodopa-induced on-off phenomenon. Motor improvement has been obtained both with continuous subcutaneous (SC) infusions, and multiple SC injections. So as to assist in the understanding of the clinical results, we studied the peripheral pharmacokinetics of apomorphine in 20 patients after intravenous (IV) or SC injections in the anterior abdominal wall and in the thigh at various doses, or SC infusion. Plasma apomorphine levels were measured by high-performance liquid chromatography with electrochemical detection. After an SC injection in the abdominal wall, the T_max was brief (16 ± 11 min) the drug was rapidly cleared from the plasma and had a short plasma half-life (69.7 ± 25.8 min). The AUC was similar following SC and IV injections, suggesting that apomorphine was completely absorbed from subcutaneous tissue. Inter-subject variability in drug absorption was large. We noticed a trend towards a more complete absorption following injection in the abdominal wall rather than in the thigh. In patients chronically treated by continuous SC infusion, the apparent plasma half-life was five times longer than that following SC or IV injections. These pharmacokinetic data may explain the rapid onset and brief duration of clinical effects, and the usefulness of individual titration for intermittent SC apomorphine injections, and the smoother motor response obtained with continuous SC infusions.     

Comorbidity of select anxiety and affective disorders with alcohol dependence in southwest California Indians

BACKGROUND: Native Americans, overall, have the highest prevalence of alcohol dependence of any US ethnic group. In several large national surveys, alcohol dependence has been significantly associated with higher rates of anxiety and affective disorders (comorbidity). However, the frequencies of these disorders and their comorbidity with alcohol dependence in Native American populations are relatively unknown. METHODS: Demographic information and DSM-III-R diagnoses were obtained by using the Semi-Structured Assessment for the Genetics of Alcoholism developed for the Collaborative Study on the Genetics of Alcoholism from 483 Southwest California Indian adults residing on contiguous reservations. The Semi-Structured Assessment for the Genetics of Alcoholism allowed differentiation of each anxiety and affective disorder into one of three types: independent of substance use, concurrent with alcohol use, and concurrent with drug use. RESULTS: Sixty-six percent of the men and 53% of the women sampled had a lifetime diagnosis of alcohol dependence. Fourteen percent of the sample had a lifetime independent anxiety disorder, and 14% of the sample had a lifetime independent affective disorder. Alcohol- and/or drug-concurrent major depression occurred in 8%, and other alcohol- and/or drug-concurrent anxiety and affective disorders each occurred in less than 1.1% of the sample. No significant comorbidity was found between alcohol dependence and independent agoraphobia, social phobia, or major depressive disorder. CONCLUSIONS: In this Southwest California Indian sample, rates of anxiety and affective disorders were substantially similar to those reported in the National Comorbidity Survey; however, comorbidity of independent disorders with alcohol dependence was not as pervasive as in the National Comorbidity Survey. Rates of concurrent anxiety and affective disorders were low. These data support the hypothesis that despite high rates of alcohol dependence, Southwest California Indians do not have higher rates of anxiety and affective disorders or comorbidity of these disorders with alcohol dependence than those reported in large surveys of non-American Indian populations.     

Recovery of contact hypersensitivity responses following murine bone marrow transplantation: comparison of gamma-irradiation and busulfan as preparative marrow-ablative agents

Bone marrow transplantation (BMT) is often followed by significant morbidity and mortality due to protracted immunodeficiency. We have hypothesized that the bone marrow-ablative regimen may delay the recovery of normal immune function following transplantation by impairing the interaction of host endothelial cells with circulating graft-derived lymphocytes. This report compares the relative effects of busulfan (an alkylating drug) and gamma-irradiation on the tissue- specific localization potential of lymphocytes and the eventual recovery of immune function within syngeneic murine transplant recipients. Localization of normal lymphocytes into peripheral lymph nodes of irradiated BMT recipients was markedly less (less than 50%) than in busulfan-treated or normal mice over the first 2 months post- BMT. This finding correlated with irradiation-induced endothelial cell edema and microvascular occlusions within lymphocyte-receptive areas of the nodal microvasculature. The effect of both preparative regimens on the recovery of contact hypersensitivity (CHS) was also analyzed. This response recovered more quickly (between 1 and 2 months) in busulfan- pretreated animals. Further experiments demonstrated that the decrease in CHS responsiveness appeared, in part, related to a depression in the capacity of lymphocytes to localize into skin sites of antigen deposition within irradiated mice. The impairment of tissue-specific lymphocyte localization may represent a novel mechanism by which whole body irradiation can contribute to delayed immunologic reconstitution following bone marrow transplantation.     

Organization of TNIK in dendritic spines

Tumor necrosis factor receptor‐associated factor 2 (TRAF2)‐ and noncatalytic region of tyrosine kinase (NCK)‐interacting kinase (TNIK) has been identified as an interactor in the psychiatric risk factor, Disrupted in Schizophrenia 1 (DISC1). As a step toward deciphering its function in the brain, we performed high‐resolution light and electron microscopic immunocytochemistry. We demonstrate here that TNIK is expressed in neurons throughout the adult mouse brain. In striatum and cerebral cortex, TNIK concentrates in dendritic spines, especially in the vicinity of the lateral edge of the synapse. Thus, TNIK is highly enriched at a microdomain critical for glutamatergic signaling. J. Comp. Neurol. 523:1913–1924, 2015 © 2015 Wiley Periodicals, Inc.     

Replacing sedentary time with sleep,light, or moderate-to-vigorous physical activity: effects on self-regulation and executive functioning

Recent attention has highlighted the importance of reducing sedentary time for maintaining health and quality of life. However, it is unclear how changing sedentary behavior may influence executive functions and self-regulatory strategy use, which are vital for the long-term maintenance of a health behavior regimen. The purpose of this cross-sectional study is to examine the estimated self-regulatory and executive functioning effects of substituting 30 min of sedentary behavior with 30 min of light activity, moderate-to-vigorous physical activity (MVPA), or sleep in a sample of older adults. This study reports baseline data collected from low-active healthy older adults (N = 247, mean age 65.4 ± 4.6 years) recruited to participate in a 6 month randomized controlled exercise trial examining the effects of various modes of exercise on brain health and function. Each participant completed assessments of physical activity self-regulatory strategy use (i.e., self-monitoring, goal-setting, social support, reinforcement, time management, and relapse prevention) and executive functioning. Physical activity and sedentary behaviors were measured using accelerometers during waking hours for seven consecutive days at each time point. Isotemporal substitution analyses were conducted to examine the effect on self-regulation and executive functioning should an individual substitute sedentary time with light activity, MVPA, or sleep. The substitution of sedentary time with both sleep and MVPA influenced both self-regulatory strategy use and executive functioning. Sleep was associated with greater self-monitoring (B = .23, p = .02), goal-setting (B = .32, p < .01), and social support (B = .18, p = .01) behaviors. Substitution of sedentary time with MVPA was associated with higher accuracy on 2-item (B = .03, p = .01) and 3-item (B = .02, p = .04) spatial working memory tasks, and with faster reaction times on single (B = ?23.12, p = .03) and mixed-repeated task-switching blocks (B = ?27.06, p = .04). Substitution of sedentary time with sleep was associated with marginally faster reaction time on mixed-repeated task-switching blocks (B = ?12.20, p = .07) and faster reaction time on mixed-switch blocks (B = 17.21, p = .05), as well as reduced global reaction time switch cost (B = ?16.86, p = .01). Substitution for light intensity physical activity did not produce significant effects. By replacing sedentary time with sleep and MVPA, individuals may bolster several important domains of self-regulatory behavior and executive functioning. This has important implications for the design of long-lasting health behavior interventions. Trial Registration clinicaltrials.gov identifier NCT00438347.