Evidence of increased excitability in GEPR hippocampus preceding development of seizure susceptibility

3-Benzoylpyridine (3BP) is a major metabolite of HGG-12, and oxime that has been synthesized as a potential antidote to the toxic effects of soman and other anticholinesterases. Structural similarities exist between 3BP, the cytochrome P450 (CYP)-inducer metyrapone (MET) and other 3-substituted pyridines that interact with CYPs. The present study evaluated the regulatory effects of 3BP on CYP expression in rat liver. Both 3BP and MET (100 mg/kg) increased total hepatic microsomal holo-CYP content significantly 24 h after administration to male rats. Pronounced increases in activities mediated by CYP2B (androstenedione 16 beta-hydroxylation and 7-pentylresorufin O-depentylation) were produced by 3BP and MET, which correlated with respective 9- and 14-fold increases in CYP2B immunoreactive protein. In addition, both agents slightly increased rates of microsomal CYP3A-dependent steroid 6 beta-hydroxylation, troleandomycin metabolite complex formation and total CYP3A immunoreactive protein. Induction of the dexamethasone-inducible CYP3A23 mRNA to 4.5- and 2.5-fold of control was detected in liver of MET- and 3BP-induced rats; CYP3A2 mRNA levels were unchanged. Analogous in vitro studies revealed that MET was a preferential inhibitor of CYP3A-mediated steroid 6 beta-hydroxylation activity, but 3BP was inactive against constitutive steroid hydroxylase CYPs. These findings indicate that the structurally related 3BP and MET elicit similar induction effects on CYPs 2B and 3A23 in rat liver after in vivo administration, but differential inhibitory effects of the chemicals on CYP activity in vitro. Recent reports have implicated a microsomal binding site in the induction of CYP3A1/3A23 in rat liver. In light of the present findings, substituted pyridines like 3BP may be useful tools in structure-activity studies to evaluate the physicochemical requirements for binding to this protein.     

Adult reactivity in rats exposed to cocaine during two early postnatal periods

The effects of temperature on the A-B transition of DNA in fibers are determined by fiber X-ray diffraction and measurement of variations of the fiber length with the relative humidity (r.h.). It is observed that the transition from the A to the B helical form occurs at higher r.h. when the temperature is raised. At 7 degrees C, this transition is complete for a r.h. of 88% while the A form remains stable at that same r.h. and is even maintained for r.h. values up to 92% when the temperature is 37 degrees C. The interpretation of the present experimental results is given in terms of hydration effects in which the entropic contribution of the solvent molecules is dominant.     

Impairment of cingulothalamic learning-related neuronal coding in rabbits exposed to cocaine in utero: General and sex-specific effects.

Neuronal activity was recorded in the cingulate cortex and the limbic thalamus in Dutch-belted rabbits (Oryctolagus cuniculus) exposed to cocaine (8 mg/kg/day iv) or saline in utero during acquisition and reversal learning of a discriminative avoidance response. Anterior cingulate cortical excitatory training-induced activity (TIA) was attenuated in cocaine-exposed female rabbits during acquisition and reversal learning, but only during reversal learning in male rabbits. Posterior cingulate cortical excitatory TIA was lessened in cocaine-exposed rabbits during acquisition, whereas discrimination between the positive and negative cues was enhanced. Neuronal firing was attenuated in the anterior ventral thalamus in cocaine-exposed rabbits during acquisition and reversal learning. Behavioral learning was normal in cocaine-exposed rabbits. Other data suggest that rabbits exposed to cocaine in utero exhibit a learning deficit when trained with nonsalient cues. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence for a major gene controlling susceptibility to tegumentary leishmaniasis in a recently exposed Bolivian population

Tegumentary leishmaniasis due to Leishmania braziliensis is a parasitic disease that occurs in two stages after the infected sandfly bite: (1) a primary cutaneous lesion followed by (2) a secondary mucosal involvement generally resulting in severe facial deformities. In order to investigate the genetic and environmental factors involved in the development of the cutaneous lesion, a familial study was performed in a region of Bolivia in which the disease is endemic. Complete selection of 118 nuclear families (703 subjects, with 241 patients), each with at least one cutaneous affected subject, was achieved; 41 families were of native origin, and 77 (herein designated "migrant") recently had settled in the area. For the analysis, the trait under study was the time to onset of the primary cutaneous lesion. The start of the follow-up was birth, for native population, or date of arrival in the endemic area, for migrant population. Segregation analysis was performed by use of a model based on survival analysis methods that allows joint estimation of genetic and environmental effects and accounts for gene x covariate interactions. A significant effect of gender, home-forest distance, and forest-related activity was found. In the 77 migrant families there was evidence for a recessive major gene controlling the onset of the primary cutaneous lesion, with residual familial dependences and age x genotype interaction. Penetrance estimations show that young subjects are genetically more susceptible than older subjects, suggesting that this genetic component could concern mechanisms involved in the development of individual protection during childhood. There was also a significant genetic heterogeneity of the sample according to the native/migrant origin of the families, and no major-gene effect was found in the native subsample.     

Changes of blood pressure responsiveness in rats exposed in utero and perinatally to a high-salt environment

We tested the hypothesis that the pressor responses to angiotensin II could be influenced by an early salt exposure. Twenty-five adult female rats were pseudorandomly divided in two groups. Twelve animals underwent a partial ligature of their abdominal aorta (PAL). Once polydipsia and sodium appetite developed, these rats were mated. The other group (13 rats) was sham-operated (Sham) and mated. Throughout pregnancy and lactation, water and 2.7% NaCl solution intakes differed between the two groups of mother rats. PAL offspring (PAL-O; n = 14), and Sham-operated offspring (Sh-O; n = 10), were maintained on a solid diet containing 1% NaCl, tap water and a 2.7% NaCl solution. At 90 days of age, pressor responsiveness to intravenous angiotensin II (50, 100 and 200 ng) was assessed in anesthetized rats. The pressor responses to 50 and 200 ng angiotensin II were significantly greater in PAL-O rats than in Sh-O rats. These results support the hypothesis of a modulation of cardiovascular responsiveness or its underlying mechanisms by an early high salt environment.     

Blood pressure in children exposed prenatally to cocaine

Prenatal exposure to cocaine may alter autonomic nervous system function resulting in hypertension. Blood pressure was measured oscillometrically in a convenience sample of cocaine-exposed (n = 32) and nonexposed (n = 23) children, aged 8 to 26 months, by examiners unaware of exposure status. The exposed and nonexposed groups did not differ in systolic pressure (mean +/- SD 102.3 +/- 9.9 mmHg vs 119.1 +/- 19.4). Prenatal exposure to cocaine does not appear to be associated with elevated blood pressure in young children.     

Prenatal morphine exposure induces age-related changes in seizure susceptibility in male rats

The purpose of this study was to investigate the effects of prenatal exposure to morphine (5-10 mg/kg on days 11-18 of gestation) on flurothyl seizure susceptibility in adult and developing male rats. In adult rats, prenatal morphine exposure increased the threshold to clonic seizures but not to tonic-clonic seizures. The effects of prenatal morphine exposure on clonic seizures were age dependent. At postnatal day (PND) 15, prenatal drug exposure did not alter the seizure threshold. At PND 25, there was a reduction in the threshold but by PND 38, the clonic seizure threshold was increased and this increase persisted into adulthood. Prenatal exposure to morphine did not alter the tonic-clonic seizure threshold in any age group of intact male rats. A group of male rats prenatally exposed to morphine was gonadectomized in adulthood. In gonadectomized rats both clonic and tonic-clonic thresholds were increased. These results suggest that exposure to morphine during mid to late gestation induces age-dependent alterations in the susceptibility to clonic but not tonic-clonic seizures. In adult male rats the threshold to tonic-clonic seizures is influenced by prior gonadectomy in adulthood.     

Intellectual impairment in children exposed to polychlorinated biphenyls in utero

BACKGROUND: In utero exposure to polychlorinated biphenyls, a ubiquitous environmental contaminant, has been linked to adverse effects on neurologic and intellectual function in infants and young children. We assessed whether these effects persist through school age and examined their importance in the acquisition of reading and arithmetic skills. METHODS: We tested 212 children, recruited as newborns to overrepresent infants born to women who had eaten Lake Michigan fish contaminated with polychlorinated biphenyls. A battery of IQ and achievement tests was administered when the children were 11 years of age. Concentrations of polychlorinated biphenyls in maternal serum and milk at delivery were slightly higher than in the general population. A composite measure of prenatal exposure was derived from concentrations in umbilical-cord serum and maternal serum and milk. RESULTS: Prenatal exposure to polychlorinated biphenyls was associated with lower full-scale and verbal IQ scores after control for potential confounding variables such as socioeconomic status (P = 0.02). The strongest effects related to memory and attention. The most highly exposed children were three times as likely to have low average IQ scores (P <0.001) and twice as likely to be at least two years behind in reading comprehension (P = 0.03). Although larger quantities of polychlorinated biphenyls are transferred by breast-feeding than in utero, there were deficits only in associated with transplacental exposure, suggesting that the developing fetal brain is particularly sensitive to these compounds. CONCLUSIONS: In utero exposure to polychlorinated biphenyls in concentrations slightly higher than those in the general population can have a long-term impact on intellectual function.     

Fos-immunoreactive responses in inferior colliculi of rats with experimental audiogenic seizure susceptibility

Quantitative ultrasound (QUS) is a simple, inexpensive and non-invasive measure of bone which has been used in research settings for the prediction of osteoporosis. This review summarizes the current status of the epidemiology of QUS analysis, including its relationship with bone mineral density (BMD), risk of osteoporotic fracture and risk factors for osteoporosis. Although only moderately correlated with BMD, QUS appears to be as strong a predictor of osteoporotic fracture as BMD and may predict fracture independent of BMD. Risk factors for low QUS, including age, menopause, body composition and physical inactivity, seem to parallel those of low BMD. More longitudinal research is needed to confirm the clinical utility of QUS and more experimental and population-based studies are needed to determine whether the etiology of low QUS values is different from that of low bone mass.     

Management of the adolescent girl exposed in utero to DES

Attention in this discussion of the management of the adolescent girl exposed "in utero" to diethylstilbestrol (DES) is directed to the following: history; scope of the problem; pathogenesis/embryology; management; future fertility; squamous cell carcinoma; and male factors. In the late 1940s and early 1950s, estrogen deficiency was thought to play a role in the high fetal death rate among pregnant diabetic women. DES was 1st used in diabetics and soon thereafter in patients who were threatening to miscarry, who had previous stillbirths, and previous spontaneous abortions. Estrogens were used by some physicians through the late 1960s. In 1970 Herbst and Scully reported 7 carcinomas of the vagina in young women. On careful review, it was found that the mothers of these young women with clear-cell cancer had been treated with DES at various stages of their pregnancies. Subsequent investigation led to the discovery of the condition of vaginal adenosis in many young women exposed "in utero" to DES. It is estimated that 80-90% of patients exposed to intrauterine DES will show gross and microscopic evidence of vaginal and cervical adenosis. It is now felt by most authorities that adenosis coexists with the clear-cell cancer rather than preceding the tumor. A clear-cell tumor registry has been established and, to date, over 400 cases have been registered. The age-range of DES-exposed clear-cell carcinoma is between 7 and 31 years of age. The care of a girl exposed to DES begins when the physician is informed that the patient's mother either received the medication or there was any possibility of such medication. If bleeding occurs before the menarche, the patient should be hospitalized and examined under anesthesia. In the women of menstrual age, management has been somewhat controversial. The use of the colposcope has allowed careful initial examination of the cervix and vagina as well as providing an excellent means of follow-up. The colposcope has been very helpful in delineating the changes caused by DES. There are numerous gross findings that represent adenosis. These include the cervical changes of the "cockscomb" or anterior cervical ridge or "hood," a cervix within a cervix, and a hermicervix. With the colposcope, the areas of adenosis are seen as grape-like projections which, on biopsy, represent columnar epithelium. Areas of metaplastic squamous tissue are easily identified. On occasion dysplasia can occur in areas of adenosis. Of equal importance is the digital examination of the vagina. At this time it is felt that adenosis requires no other treatment than observations. The treatment of clear-cell carcinoma of the vagina or cervix is best determined by a gynecologic oncologist. 80% of DES patients have had live births.     

X-Y chromosome dissociation in mice and rats exposed to increased testicular or environmental temperatures

Heating the testes, scrota and tails of mice and rats by immersion in a water bath at 42 degrees C for 20 min caused an increased percentage of X-Y univalents in meiotic preparations made after 6 and 12 days respectively. It was also confirmed that exposing mice of a cool-adapted strain to an environment at 33 degrees C for 5 days resulted in an increase in the percentage of X-Y and autosomal univalents in meiotic preparations made after a recovery period of 2 days. Mice of a strain adapted to living at 33 degrees C also showed a higher rate of X-Y dissociation than control cool-adapted mice, but a lower frequency of autosomal univalents than cool-adapted mice exposed to the hot environment. The testes of the heat-adapted mice were even more sensitive than the testes of cool-adapted mice to the effects of local heating, as judged by the fall in testis weight 21 days afterwards.     

Changes in the retinal ganglion cell layer and optic nerve of rats exposed neonatally to cocaine

In a study of 452 ex-prisoners in England in 1990, 66 people reported that they were tested for HIV antibodies when last in prison. The circumstances under which many of those who were tested were difficult: 36% found it an unpleasant experience, 17% had not taken the test voluntarily and 55% said they received no counselling. Further information was gathered about the experiences of those who were HIV positive or assumed to be. Most were accommodated in a 'special location', not allowed to associate with other prisoners and denied access to work or recreational facilities. These data highlight the difficulties arising from the policy of Viral Infectivity Restrictions, a set of regulations applied to the management of prisoners with HIV in English prisons. This policy created a distressing situation for those tested for HIV or identified as being HIV positive in prison. For the prison environment, these conditions may create a vicious circle reinforcing inaccurate beliefs and anxieties.     

Evidence for lower susceptibility to multiple sclerosis in Japanese-Americans

A search for cases of multiple sclerosis (MS) was carried out among the 120,066 Japanese-American residents and the 3,060,366 Caucasian residents native to state of residence in King and Pierce Counties, Washington, and Los Angeles County, California. Although 48 cases would have been expected among Japanese-Americans in both areas (on the basis of the prevalence among Caucasians in these two areas), only eight cases were found who were residents on prevalence day -- all were American-born residents of Los Angeles County. The age-, sex-adjusted prevalence of MS among Japanese-Americans in both areas was 5.9 per 100,000. The lower prevalence of multiple sclerosis among Japanese-Americans than among Caucasians has been interpreted as evidence of a lower susceptibility to factors causing multiple sclerosis.     

Reactivity and regulation in children prenatally exposed to cocaine.

Children prenatally exposed to cocaine may be at elevated risk for adjustment problems in early development because of greater reactivity and reduced regulation during challenging tasks. Few studies have examined whether cocaine-exposed children show such difficulties during the preschool years, a period marked by increased social and cognitive demands and by rapid changes in reactivity and regulation. The authors addressed this question by examining frustration reactivity and regulation of behavior during a problem-solving task in cocaine-exposed and -unexposed preschoolers. Participants were 174 4.5-year-olds (M age = 4.55 years, SD = 0.09). Frustration reactivity was measured as latency to show frustration and number of disruptive behaviors, whereas regulation was measured as latency to approach and attempt the problem-solving task and number of problem-solving behaviors. Results indicated that cocaine-exposed children took longer to attempt the problem-solving task but that cocaine-exposed boys showed the most difficulties: They were quicker to express frustration and were more disruptive. Effect sizes were relatively small, suggesting both resilience and vulnerabilities. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Multiple birth defects in a newborn exposed to Mycoplasma pneumoniae in utero

A newborn baby girl with progressive hydrocephalus and congenital defects of the skin and eyes was born to a mother who experienced bilateral bronchopneumonia in her first trimester. At the time of her infection, the mother's serum cold agglutinin titer was 1:128 and at delivery the mother's and baby's serum samples had complement-fixation titers to Mycoplasma pneumoniae of 1:1,024 and 1:256, respectively. At 1 week of age the baby's serum IgM value was 44 mg/100 ml (98% of cord IgM values in normal newborns range from 0 to 20 mg/100 ml). The baby died of progressive hydrocephalus, which may have had an inflammatory basis in view of the cerebrospinal fluid (CSF) protein level of 192 mg/100 ml. We realize that the significance of this association is questionable, but we believe that it is worthwhile to call the coincidence of events to the attention of others.     

Effects of proposed treatments for cocaine addiction on hemodynamic responsiveness to cocaine in conscious rats

Several agents may treat cocaine addiction and toxicity including bromocriptine, desipramine, GBR 12909 [1-(2-(bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl) piperazine], diazepam, buprenorphine and dizocilpine. In this study, we sought to determine whether these specific therapeutic agents alter cardiovascular responses to cocaine in conscious rats. Arterial pressure responses to cocaine (5 mg/kg, i.v.) were similar in all rats whereas cardiac output responses varied widely. In 26 of 33 rats (named vascular responders), cocaine induced a decrease in cardiac output of 8% or more. The remaining rats with little change or an increase in cardiac output were classified as mixed responders. Pretreatment with bromocriptine (0.1 mg/kg) or desipramine (1 mg/kg) increased cardiac output in mixed responders and increased systemic vascular resistance in vascular responders similar to the differential effects noted with cocaine. GBR 12909 (0.5-10 mg/kg) elicited a decrease in cardiac output at higher doses. Diazepam (0.1 and 0.5 mg/kg) had small, short-lasting effects on cardiovascular parameters. Buprenorphine (0.3 mg/kg) or the NMDA (N-methyl-D-aspartic acid) receptor antagonist, dizocilpine (0.05 mg/kg), increased arterial pressure, heart rate and cardiac output in vascular responders. Bromocriptine and desipramine prevented the difference in cardiac output responses in vascular and mixed responders by reducing the cocaine-induced decrease in cardiac output in vascular responders. Pretreatment with GBR 12909 (1 mg/kg) had little effect on cardiovascular responses to cocaine except to depress the increase in cardiac output noted in mixed responders. Buprenorphine selectively enhanced the increase in systemic vascular resistance whereas dizocilpine enhanced the pressor response. These data suggest that several treatment regimens for cocaine addiction alter the cardiovascular responses to cocaine and that dopamine D2 receptor activation may be necessary for the decrease in cardiac output noted in vascular responders.     

Semantic development of African-American children prenatally exposed to cocaine

Semantic content categories were described for the single word, multiple word, and verb relation utterances of 22 African-American 2-year-olds during a 90-min laboratory session. Half of the toddlers had been exposed prenatally to cocaine and half were unexposed, as documented by biological assay in the newborn period. The exposed and unexposed groups were carefully matched on demographic, medical, and proximal caregiving variables. Children's spontaneous utterances were transcribed from audio- and videotapes during the laboratory session and scored for semantic features by a team of reliable coders who were masked to child exposure status. General productive language features (utterance length, verbosity, and intelligibility) were also assessed. To evaluate general language and cognitive skills, the toddlers were evaluated with the Sequenced Inventory of Communicative Development-Revised (SICD-R) and the Bayley Scales of Infant Development (BSID). Although exposed and nonexposed toddlers exhibited similar sequences of semantic development, the exposed toddlers were more restricted and delayed in their semantic representations. No significant group differences were observed, however, for structural features of language (e.g., utterance length, distribution of utterance types) or for children's general language and cognitive functioning as assessed by standardized assessments (i.e., SICD-R, BSID). Thus, a history of prenatal cocaine exposure and associated risk factors (e.g., prenatal exposure to alcohol, diminished birth weight) are related to delays in early semantic development. Proposed diagnostic and treatment strategies are discussed.     

Brain dopamine and seizure susceptibility in mice

In electroshock test apomorphine appeared without effect, D, L-amphetamine and L-DOPA (in a high dose) elevated the convulsive threshold, while amantadine decreased it. Among investigated dopamine (DA) receptor blockers spiperone, pimozide and fluphenazine lowered the threshold, haloperidol being without effect. The convulsive threshold elevated by L-DOPA was not affected by neuroleptics and phentolamine but on the other hand DA receptor blockers and phentolamine anatagonized the effect of D, L-amphetamine. The effect of amantadine was not influenced by neuroleptics. In pentylenetetrazol (PTZ) test only amantadine and L-DOPA (in high doses) affected the threshold, increasing seizure susceptibility; the above effect was not abolished by pimozide. Our results seem to indicate that the activity of brain DA system seems not to be involved directly in the susceptibility to electrogenic or PTZ-induced seizures in mice.     

Impaired male sexual development in perinatal Sprague-Dawley and Long-Evans hooded rats exposed in utero and lactationally to p,p''-DDE

The evolution of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a multi-stage process, comprising the sequential development of chronic H. pylori-associated gastritis, low grade and high grade lymphoma. The genesis of MALT lymphoma embodies the mechanisms of both physiological immune responses and the acquisition of genetic abnormalities. The tumour probably originates from an autoreactive MALT marginal zone B cell, which is generated during H. pylori infection. As a consequence of a genotoxic insult induced by H. pylori infection, the progenitor tumour cell may become genetically unstable and develop genetic abnormalities such as the t(11;18) translocation, trisomy three, c-myc and p53 mutations during a phase of expansion, which lead to partial transformation. With the growth help from H. pylori specific T cells, this abnormal B cell clone may undergo clonal expansion and gradually form a low grade MALT lymphoma. Additional genetic abnormalities including the t(1;14) translocation and other uncharacterised events could completely transform this abnormal B cell clone and result in escape from T cell dependency. Finally, further genetic events such as complete inactivation of the tumour suppressor genes p53 and p16, and possible activation of c-myc oncogene by translocation or other undetermined abnormalities can result in high grade transformation