Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8-deficient mice.

The cAMP/protein kinase A pathway regulates methamphetamine (METH)-induced neuroplasticity underlying behavioral sensitization. We hypothesize that adenylyl cyclases (AC) 1/8 mediate these neuroplastic events and associated striatal dopamine regulation. Locomotor responses to METH (1 and 5 mg/kg) and striatal dopamine function were evaluated in mice lacking AC 1/8 (DKO) and wild-type (WT) mice. Only 5 mg/kg METH induced an acute locomotor response in DKO mice, which was significantly attenuated versus WT controls. DKO mice showed a marked attenuation in the development and expression of METH-induced behavioral sensitization across doses relative to WT controls. While basal and acute METH (5 mg/kg)-evoked accumbal dialysate dopamine levels were similar between genotypes, saline-treated DKO mice showed elevated tissue content of dopamine and homovanillic acid in the dorsal striatum (DS), reflecting dysregulated dopamine homeostasis and/or metabolism. Significant reductions in DS dopamine levels were observed in METH-sensitized DKO mice compared to saline-treated controls, an effect not observed in WT mice. Notably, saline-treated DKO mice had significantly increased phosphorylated Dopamine- and cAMP-regulated phosphoprotein levels, which were not further augmented following METH sensitization, as observed in WT mice. These data indicate that AC 1/8 are critical to mechanisms subserving drug-induced behavioral sensitization and mediate nigrostriatal pathway METH sensitivity. Calcium/calmodulin-stimulated adenylyl cyclase (AC) isoforms 1 and 8 were studied for their involvement in the adaptive neurobehavioral responses to methamphetamine. AC 1/8 double knockout (DKO) mice showed heightened basal locomotor activity and dorsal striatal dopamine responsivity. Conversely, methamphetamine-induced locomotor activity was attenuated in DKO mice, accompanied by reductions in dopamine and HVA content and impaired DARPP-32 activation. These findings indicate AC 1/8 signaling regulates the sensitivity of the nigrostriatal pathway subserving stimulant and neuroadaptive sensitizing effects of methamphetamine. 3-MT, 3-methoxytyramine; Ca(2+), calcium; CaM, calmodulin; cdk5; cyclin-dependent kinase 5; DA, dopamine; DARPP-32, dopamine- and cAMP-regulated phosphoprotein; D1R, dopamine D1 receptor; HVA, homovanillic acid; PKA, protein kinase A.

Impact of September 11 World Trade Center disaster on children and pregnant women.

BACKGROUND: Children are uniquely sensitive to toxic exposures in the environment. This sensitivity reflects children's disproportionately heavy exposures coupled with the biologic vulnerability that is a consequence of their passage through the complex transitions of early development. METHODS AND RESULTS: To assess effects on children's health associated with the attacks on the World Trade Center (WTC) of September 11, 2001, research teams at the Mount Sinai School of Medicine and other academic health centers in New York City launched a series of clinical and epidemiologic studies. Mount Sinai investigators undertook a prospective analysis of pregnancy outcomes in 182 women who were pregnant on September 11, 2001, and who had been either inside or within 0.5 miles of the WTC at the time of the attacks; they found a doubling in incidence of intrauterine growth retardation (IUGR) among infants born to exposed mothers as compared to infants born to unexposed women in northern Manhattan. A Columbia research team examined pregnancy outcomes in 329 women who lived, worked or gave birth in lower Manhattan in the 9 months after September 11; they found that these women gave birth to infants with significantly lower birth weight and shorter length than women living at greater distances from Ground Zero. NYU investigators documented increased numbers of new asthma cases and aggravations of preexisting asthma in children living in lower Manhattan. Mount Sinai mental health researchers documented a significant increase in mental health problems in children who directly witnessed the attacks and subsequent traumatic events; these problems were most severe in children with a past history of psychological trauma. The New York City Department of Health and Mental Hygiene established a WTC Registry that has enrolled over 70,000 persons of all ages in lower Manhattan and will follow the health of these populations to document on a continuing basis the health consequences of September 11.

Grand rounds: nephrotoxicity in a young child exposed to uranium from contaminated well water.

CONTEXT: Private wells that tap groundwater are largely exempt from federal drinking-water regulations, and in most states well water is not subject to much of the mandatory testing required of public water systems. Families that rely on private wells are thus at risk of exposure to a variety of unmeasured contaminants. CASE PRESENTATION: A family of seven--two adults and five children--residing in rural northwestern Connecticut discovered elevated concentrations of uranium in their drinking water, with levels measured at 866 and 1,160 microg/L, values well above the U.S. Environmental Protection Agency maximum contaminant level for uranium in public water supplies of 30 microg/L. The uranium was of natural origin, and the source of exposure was found to be a 500-foot well that tapped groundwater from the Brookfield Gneiss, a geologic formation known to contain uranium. Other nearby wells also had elevated uranium, arsenic, and radon levels, though concentrations varied widely. At least one 24-hr urine uranium level was elevated (> 1 microg/24 hr) in six of seven family members (range, 1.1-2.5 microg/24 hr). To assess possible renal injury, we measured urinary beta-2-microglobulin. Levels were elevated (> 120 microg/L) in five of seven family members, but after correction for creatine excretion, the beta-2-microglobulin excretion rate remained elevated (> 40 microg/mmol creatinine) only in the youngest child, a 3-year-old with a corrected level of 90 microg/mmol creatinine. Three months after cessation of well water consumption, this child's corrected beta-2-microglobulin level had fallen to 52 microg/mmol creatinine. SIGNIFICANCE: This case underscores the hazards of consuming groundwater from private wells. It documents the potential for significant residential exposure to naturally occurring uranium in well water. It highlights the special sensitivity of young children to residential environmental exposures, a reflection of the large amount of time they spend in their homes, the developmental immaturity of their kidneys and other organ systems, and the large volume of water they consume relative to body mass.

Impaired Brain Dopamine and Serotonin Release and Uptake in Wistar Rats Following Treatment with Carboplatin.

Chemotherapy-induced cognitive impairment, known also as "chemobrain", is a medical complication of cancer treatment that is characterized by a general decline in cognition affecting visual and verbal memory, attention, complex problem solving skills, and motor function. It is estimated that one-third of patients who undergo chemotherapy treatment will experience cognitive impairment. Alterations in the release and uptake of dopamine and serotonin, central nervous system neurotransmitters that play important roles in cognition, could potentially contribute to impaired intellectual performance in those impacted by chemobrain. To investigate how chemotherapy treatment affects these systems, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to measure dopamine and serotonin release and uptake in coronal brain slices containing the striatum and dorsal raphe nucleus, respectively. Measurements were taken from rats treated weekly with selected doses of carboplatin and from control rats treated with saline. Modeling the stimulated dopamine release plots revealed an impairment of dopamine release per stimulus pulse (80% of saline control at 5 mg/kg and 58% at 20 mg/kg) after 4 weeks of carboplatin treatment. Moreover, Vmax, the maximum uptake rate of dopamine, was also decreased (55% of saline control at 5 mg/kg and 57% at 20 mg/kg). Nevertheless, overall dopamine content, measured in striatal brain lysates by high performance liquid chromatography, and reserve pool dopamine, measured by FSCV after pharmacological manipulation, did not significantly change, suggesting that chemotherapy treatment selectively impairs the dopamine release and uptake processes. Similarly, serotonin release upon electrical stimulation was impaired (45% of saline control at 20 mg/kg). Measurements of spatial learning discrimination were taken throughout the treatment period and carboplatin was found to alter cognition. These studies support the need for additional neurochemical and behavioral analyses to identify the underlying mechanisms of chemotherapy-induced cognitive disorders.

Prevalence of previously unknown elevation of glycosylated hemoglobin in spine surgery patients and impact on length of stay and total cost.

BACKGROUND: Elevated levels of glycosylated hemoglobin (HbA1c) among spine surgery patients may have an impact on length of stay (LOS) and healthcare cost. MATERIALS AND METHODS: We retrospectively reviewed the charts of 556 spine surgery patients who underwent 1 of 3 types of surgery: lumbar microdiscectomy (LMD), anterior cervical decompression and fusion (ACDF), and lumbar decompression and fusion (LDF). Information was collected about their diabetes mellitus (DM) history and HbA1c levels. We used HbA1c 6.1% as the screening cutpoint. Percentages of nondiabetic patients, those with subclinical elevation of HbA1c and those with already known DM were calculated and statistical analysis was applied. RESULTS: After excluding the small group of well-controlled DM (n = 14), 72.4% of patients were nondiabetic, 14.3% were subclinical patients with previously unknown HbA1c elevation, and 13.3% were already known, confirmed DM patients. There were significant differences in the LDF group between the "No DM" and "Subclinical" groups (P < 0.05) in terms of cost and LOS (P < 0.05). Age and body mass index (BMI) were very significant predictors of total cost in spine surgery patients (P 0.05) in determining cost. CONCLUSIONS: There is a significant segment of spine surgery patients who were unaware of their elevated HbA1c status before their preoperative visit. These patients seem to utilize more healthcare resources, which is especially evident in the LDF group. We believe that HbA1c should be considered in the routine preoperative workup of spine surgery patients.