Somatic hypermutation of immunoglobulin genes is independent of the Bloom''s syndrome DNA helicase

The aim of these studies was to examine the effects of imidazoles on testosterone secretion and testicular interstitial fluid (TIF) formation through measurement of serum LH, serum testosterone, TIF testosterone, and TIF volumes. Imidazole, 1-methylimidazole, 4-methylimidazole (4-MI), and ketoconazole, an oral imidazole antifungal agent, caused dose-dependent decreases in testosterone secretion and TIF formation. Imidazole, 2-methylimidazole, and 4-MI decreased LH secretion. 4-MI decreased testosterone secretion 1-6 h after injection, increased testosterone at 8-16 h, decreased LH secretion at 4 h, decreased TIF volumes at 1-8 h, and slightly increased TIF volumes at 24 h. 4-MI blocked the stimulatory effects of hCG on testosterone secretion and prevented an expected increase in LH secretion after the 4-MI-induced decrease in testosterone secretion. 4-MI also reversed the effects of three other stimulants of testosterone secretion that presumably act through three different testicular regulatory systems: N-methyl-D,L-aspartate, an excitatory amino acid; NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor; and naltrexone, an opioid antagonist. These results support the hypothesis that imidazoles inhibit testicular function and male reproductive function through inhibition of testosterone secretion, TIF formation, and LH secretion regulatory systems.     

Localization of atrial natriuretic peptide receptors in the rat tongue and hard palate

The effect of a naturally occurring plant phenolic constituent (the acylphloroglucinol derivative, jensenone, derived from Eucalyptus jensenii) on the food intake of two folivorous marsupials, the common ringtail (Pseudocheirus peregrinus) and the common brushtail possum (Trichosurus vulpecula) was studied. When fed diets containing varying concentrations of jensenone, both species regulated their intake of jensenone so as not to exceed a ceiling intake. This ceiling was about twice as high for common ringtails as for common brushtails from northern Australia. Southern populations of common ringtails showed greatly reduced capacities to tolerate jensenone. When common brushtails were injected (0.5 mg.kg-0.75 body mass) with ondansetron (a selective antagonist of serotonin 5HT3 receptors), they ate significantly more jensenone than animals injected with physiological saline. The same pattern was observed when common ringtails were fed diets containing both jensenone and ondansetron (0.0035 mg.g-1 wet mass of diet). Ondansetron injection had no effect on food intake when the food did not contain jensenone while the addition of higher doses of ondansetron to diets of common ringtails very slightly reduced food intakes of a non-jensenone diet. When common brushtails were given 50 mg of jensenone by gastric lavage, their average subsequent intake of dietary jensenone matched the difference between the daily threshold and the dose given, although the response of individuals was highly variable. Lavage with water alone had no effect on subsequent jensenone intake compared with the pre-dose period. We interpret these results as evidence that the antifeedant effects of jensenone and related compounds are partly mediated by serotonin action on 5HT3 receptors most likely via "nausea" to condition a food aversion.     

Catecholamine response during 12 days of high-altitude exposure (4, 300 m) in women

Atrial natriuretic peptide (ANP) has been considered a potential candidate participating in the inhibitory control of pituitary-adrenal secretory activity. Here, we investigated the influence of ANP, infused at two different doses and over infusion intervals of two different durations, on the release of ACTH and cortisol after stimulation with CRH and with combined administration of CRH and vasopressin (VP). In young healthy men, three experiments were conducted. In Exp I, ACTH/cortisol secretory responses to CRH (50 microg) were examined during and after a 45-min period of ANP infusion at a rate of 4.4 microg/min (starting 15 min before CRH injection). In Exp II, ACTH/cortisol secretory responses to CRH (50 microg) were examined during and after a 90-min infusion period of ANP administered at rates of 4.4 and 8.8 microg/min. In Exp III, ANP was infused at a rate of 4.4 microg/min over 90 min, but instead of CRH, a combined administration of CRH (50 microg) and VP (0.5 IU infused within 5 min) was employed to stimulate ACTH/cortisol release. ANP diminished pituitary-adrenal secretory responses within the first hour after stimulation with exogenous secretagogues. Thereafter, the effect of ANP turned in the opposite direction, with distinctly enhanced concentrations of ACTH and cortisol during the third hour after stimulation. The inhibitory effect of ANP during the first hour of the pituitary-adrenal response was more pronounced on concentrations of cortisol than ACTH and was also more pronounced after combined administration of CRH/VP than after stimulation with CRH alone. Increasing the dose of ANP enhanced the late stimulatory effect on ACTH/cortisol release, thereby terminating the early period of inhibited ACTH/cortisol release more abruptly. The late stimulatory effect was enhanced with prolonged infusion of ANP. In addition, it was associated with reduced hematocrit, increased urine volumes collected, increased heart rate, and enhanced plasma VP concentrations. Together, these changes suggest that the late stimulatory effect of ANP on ACTH/cortisol release reflects an effect secondary to its hypovolemic actions. This stimulatory effect originating from peripheral systemic actions of ANP after exogenous administration appears to override a more direct inhibitory action of the peptide on pituitary-adrenal secretory activity. Therefore, we would expect that with localized release into portal hypophyseal blood the inhibitory component of the action of ANP on pituitary-adrenal secretory activity prevails.     

Effects of pulsed ultrasound on the frog heart: III. The radiation force mechanism

Earlier studies have shown that a single, millisecond duration pulse of ultrasound delivered to the frog heart in vivo during systole can produce a reduction in the developed aortic pressure, while a pulse delivered during diastole can produce a premature ventricular contraction. The threshold for these effects is 5-10 MPa with a 5-ms pulse. Since cardiac tissues respond to mechanical stimulation, the objective of this study was to investigate acoustic radiation force as a possible mechanism for the observed effects of ultrasound on the frog heart. In two experiments, the radiation force exerted on the heart was varied by varying the ultrasonic frequency and the acoustic beam width. Results of these studies indicated that the rate of occurrence of the reduced aortic pressure effect was directly correlated with the magnitude of the radiation force exerted on the heart. A third experiment tested the radiation force mechanism directly by placing an acoustic reflector on the frog heart. The acoustic reflector maximized the radiation force delivered to the heart, but eliminated direct interaction of the ultrasound with the heart and experimentally eliminated heating and cavitation as mechanisms of action. The reduced aortic pressure effect was observed with the reflector on the heart, indicating that radiation force is capable of producing this effect. No premature ventricular contractions were observed with the acoustic reflector over the heart, suggesting that another property of the exposure may be responsible for this bioeffect.     

Developing a computer workshop to facilitate computer skills and minimize anxiety for early childhood educators.

Early childhood educators (n=133) were assigned to 1 of 3 instructional conditions (direct, guided discovery, or no-exposure control) to assess the impact of computer workshops on their level of computer anxiety, computer knowledge, and comfort with computer technology. Groups were matched for computer experience and anxiety, early childhood education (ECE) experience, and ECE center. The direct and guided discovery groups attended a 3-hr hands-on workshop covering hardware, software, and Internet material. Immediately after the workshops, computer anxiety was lower and comfort with computer technology increased. Six months later, the control group had reduced computer anxiety, but the other groups maintained greater knowledge and comfort. Direct instruction reduced computer anxiety slightly but did not promote the acquisition of information of the guided condition. Overall, workshops provided gains that could translate into more effective and efficient computer use in the classroom. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A cross-cultural study of correlates of crime.

In a sample of 48 nonliterate societies, frequency of theft and personal crime were separately correlated wtih a number of variables which were suspected to be casual factors in the development of crime. Lack or limitation of opportunity for the young boy to form an identification with his father was associated with both types of crime. A high degree of socialization anxiety in childhood and a high degree of status differentiation in adulthood were significantly associated with theft only; a general adult attitude of suspicion and distrust was more decidedly associated with personal crime. (17 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lactate clearance and survival following injury

Previous reports cite optimization of O2 delivery (DO2) to 660 mL/min/m2, O2 consumption (VO2) to 170 mL/min/m2, and cardiac index (CI) of 4.5 L/min as predicting survival. We prospectively evaluated 76 consecutive patients with multiple trauma admitted directly to the ICU from the operating room or emergency department. Patients had serum lactate levels and oxygen transport measured on ICU admission and at 8, 16, 24, 36, and 48 hours. Patients were analyzed with respect to survival (S) versus nonsurvival (NS), lactate clearance to normal (< or = 2 mmol/L) by 24 and 48 hours, hemodynamic optimization as defined above, as well as Injury Severity Score (ISS), ICU stay (LOS), and admission blood pressure. All patients achieved non-flow-dependent VO2. There was no difference in CI, DO2, VO2, or ISS when S was compared with NS. All 27 patients whose lactate level normalized in 24 hours survived. If lactate levels cleared to normal between 24 and 48 hours, the survival rate was 75%. Only 3 of the 22 patients who did not clear their lactate level to normal by 48 hours survived. Ten of the 25 nonsurvivors (40%) achieved the above arbitrary optimization criteria. Fifteen of the survivors never achieved any of these criteria. Optimization alone does not predict survival. However, the time needed to normalize serum lactate levels is an important prognostic factor for survival in severely injured patients.     

Adeno-associated virus 2-mediated high efficiency gene transfer into immature and mature subsets of hematopoietic progenitor cells in human umbilical cord blood

Recombinant adeno-associated virus 2 (AAV) virions were constructed containing a gene for resistance to neomycin (neoR), under the control of either the herpesvirus thymidine kinase (TK) gene promoter (vTK-Neo), or the human parvovirus B19 p6 promoter (vB19-Neo), as well as those containing an upstream erythroid cell-specific enhancer (HS-2) from the locus control region of the human beta-globin gene cluster (vHS2-TK-Neo; vHS2-B19-Neo). These recombinant virions were used to infect either low density or highly enriched populations of CD34+ cells isolated from human umbilical cord blood. In clonogenic assays initiated with cells infected with the different recombinant AAV-Neo virions, equivalent high frequency transduction of the neoR gene into slow-cycling multipotential, erythroid, and granulocyte/macrophage (GM) progenitor cells, including those with high proliferative potential, was obtained without prestimulation with growth factors, indicating that these immature and mature hematopoietic progenitor cells were susceptible to infection by the recombinant AAV virions. Successful transduction did not require and was not enhanced by prestimulation of these cell populations with cytokines. The functional activity of the transduced neo gene was evident by the development of resistance to the drug G418, a neomycin analogue. Individual high and low proliferative colony-forming unit (CFU)-GM, burst-forming unit-erythroid, and CFU-granulocyte erythroid macrophage megakaryocyte colonies from mock-infected, or the recombinant virus-infected cultures were subjected to polymerase chain reaction analysis using a neo-specific synthetic oligonucleotide primer pair. A 276-bp DNA fragment that hybridized with a neo-specific DNA probe on Southern blots was only detected in those colonies cloned from the recombinant virus-infected cells, indicating stable integration of the transduced neo gene. These studies suggest that parvovirus-based vectors may prove to be a useful alternative to the more commonly used retroviral vectors for high efficiency gene transfer into slow or noncycling primitive hematopoietic progenitor cells, without the need for growth factor stimulation, which could potentially lead to differentiation of these cells before transplantation.     

Pharmacokinetic and pharmacodynamic effects of vaginal rings releasing levonorgestrel at a rate of 27 micrograms/24 hours: a pilot study

The pharmacokinetic and pharmacodynamic effects of vaginal rings releasing levonorgestrel (L-NOG) at an initial rate of 27 micrograms/24 h were studied in a group of 12 normally menstruating women during 90 days of continuous use (i.e., during three 30-day treatment segments). Blood samples were drawn immediately before insertion, 15 and 30 min, as well as 1, 2, 4, 8, 12 and 24 h after insertion of the rings, and thereafter three times weekly throughout the study for the analysis of L-NOG, estradiol, progesterone and sex hormone-binding globulin (SHBG). Endometrial biopsies were obtained for a morphometric analysis in a pre-treatment (control) cycle and in the 6th and 10th weeks of treatment. The peak of average L-NOG levels was reached within two hours after the insertion of rings. Until 24 h after insertion, the levels did not change significantly. Thereafter, a decrease at a rate of 0.2% per day was initiated. The L-NOG and SHBG levels were highly correlated. This was seen for both the pre-treatment SHBG vs L-NOG (r = 0.96) and the treatment SHBG vs L-NOG levels (r = 0.92). There was a significant (p < 0.001) decrease of SHBG levels due to treatment. During the total of 36 treatment segments, a normal ovarian function was seen in 47% of the segments. The women were anovulatory and had an inadequate lutal function in 28% and 25% of segments, respectively. No correlation between the L-NOG levels and ovarian reaction to treatment was found. The use of L-NOG induced significant changes in the endometrium; the number of glands/mm2 decreased after 6 (p < 0.02) and 10 weeks of use (p < 0.01). Also, the diameter of glands and the occurrence of vacuolated cells decreased significantly (p < 0.02 and p < 0.005, respectively). None of the endometrial parameters or dating was correlated with the ovarian reaction to treatment, indicating independent endometrial effects of L-NOG.