Adapted MMSE and TYM cognitive tests: how much powerful in screening for Alzheimer's disease in Iranian people.

Alzheimer's disease (AD) is a major global health priority and providing an efficient way for early diagnosis of people developing dementia is important. The Mini-Mental State Examination (MMSE, total score = 30) and Test Your Memory (TYM, total score = 50) are widely used as screening tests for cognitive function. In the present study 174 subjects including healthy people (CON group) and those having Alzheimer's disease (AD group) were introduced to MMSE and TYM cognitive tests adjusted to Iranian population. Sensitivities and specificities with optimal cut-off scores, area under curve (AUC), positive predictive value (PPV) and negative predictive value (NPV) were measured for both tests. The MMSE scores of the CON and AD groups were 23.77 ± 0.327 and 10.88 ± 0.762, respectively. The TYM scores were 44.32 ± 0.389 and 14.37 ± 1.368 in the CON and AD participants, respectively. Findings in the MMSE test were: AUC = 0.962, optimal cut-off score = 18.5, sensitivity = 0.90 and specificity = 0.96. Values in the TYM test were: AUC = 0.991, optimal cut-off score = 31, sensitivity = 0.90 and specificity = 1. We found no correlation between the cognitive performance and age in the CON group but a positive correlation in the AD patients. On the other hand, t-test analysis indicated that achievement of the test scores are significantly sex dependent, with more scores attained by the females. Taken together, in regard to correct classification rate (CCR); the TYM test seems to be more appropriate for cognitive screening in our study. However, considering an analogous AUC, both tests are comparable and have high sensitivity and specificity for discriminating between people with and without AD.

THE EFFECTS OF OPIUM ADDICTION ON THYROID AND SEX HORMONES IN DIABETIC AND NON-DIABETIC MALE AND FEMALE RATS.

OBJECTIVE: Opium is a narcotic drug that is commonly abused. The prescription of pharmaceutical derivatives of opium is limited due to their possible harmful effects on the body's metabolism and tolerability by patients. The aim of the present study was to evaluate the effects of chronic opium consumption on some sexual and thyroid hormones in diabetic and non-diabetic male and female rats. MATERIAL AND METHODS: This experimental study was conducted on 56 Wistar rats. The animals were divided into diabetic addicted (DA), diabetic non-addicted (DNA), non-diabetic addicted (NDA) and non-diabetic non-addicted (NDNA) groups of male and female rats. Peripheral blood samples were collected to measure the thyroid and sex hormone levels. Student's t-test was used to compare the mean values of the hormones between two groups. RESULTS: T3 serum level in male addicted groups significantly increased in comparison with non-addicted ones in both diabetic and non-diabetic groups. The testosterone level of male rats decreased due to the consumption of opium while it was significantly increased in diabetic and NDNA female rats in comparison with non-addicts. In DNA female animals, the mean level of 17-hydroxyprogesterone increased significantly compared with non-diabetic groups, however, it decreased in addicted females (diabetic and non-diabetic) in comparison with non-addicts. The level of DHEA-S increased significantly in diabetic and NDA male rats as compared with the non-addicted group. CONCLUSION: Opium affects the endocrine system in a sex-dependent manner, and opium could have different effects in diabetic and non-diabetic conditions.

Estimation of influenza and severe acute respiratory illness incidence (burden) in three provinces of the Islamic Republic of Iran, 2012 and 2013.

There are few estimates of influenza burden in the WHO Region for the Eastern Mediterranean. In this study we estimated the burden of severe acute respiratory infection (SARI) and influenza-associated SARI (F-SARI) in selected provinces of Islamic Republic of Iran, the trends of SARI and confirmed cases of influenza (F-SARI) over 12 months (seasonality), and the age groups most at risk. Using the electronic Iranian influenza surveillance system and data of cases in sentinel hospitals of 3 selected provinces, we estimated the monthly trend (seasonality) of incidence for SARI and F-SARI, overall incidence of SARI and F-SARI and their disaggregation by age with the aid using the Monte Carlo technique. The age groups most at-risk were children aged under 2 years and adults older than 50 years.

Historical cohort study of shift work and blood pressure.

BACKGROUND: It has been suggested that shift work (SW) is associated with changes in blood pressure (BP). However, studies have reported contradictory results. AIMS: To prospectively examine the association between SW and BP among male workers. METHODS: A historical cohort study, involving workers of Esfahan's Mobarakeh Steel Company, in Iran, was conducted over 14 years. The association between SW, systolic BP (SBP) and diastolic BP (DBP) was investigated after adjusting for body mass index, age, work experience, marriage, smoking and education based on the Bayesian multilevel modelling approach. RESULTS: The study sample included 5331 male workers. The mean age (standard deviation, SD) was 34.8 (6.6) years and mean work (SD) experience was 9.4 (6.1) years. Among these subjects, 2348 (44%), 340 (6%) and 2643 (50%) were day workers, weekly rotating shift workers and routinely rotating shift workers, respectively. The mean SBP (SD) and DBP (SD) of these workers were 118.7 (8.1) and 73.1 (6.7) mmHg, respectively. After controlling for several confounding variables, there was no significant relationship between SBP and DBP and SW. CONCLUSIONS: No significant association between SW and BP was observed among these three groups (day workers, weekly rotating shift workers and routinely rotating shift workers). Prospective studies, which control for confounding factors, such as the healthy worker effect, occupational history, family history and psychological factors (e.g. occupational stress and job satisfaction), are required to evaluate this further.

What do we need to eradicate rubella in the Islamic Republic of Iran?

To evaluate the need for congenital rubella syndrome prevention in our national health programme we aimed to determine the rate of anti-rubella positivity in umbilical cord blood samples 8 years after measles-rubella mass vaccination in the Islamic Republic of Iran. In a cross-sectional study we tested umbilical cord blood samples for anti-rubella IgG and IgM by ELISA in 154 deliveries at a university hospital in Tehran. Overall 72.7% of umbilical cord blood samples were positive for anti-rubella lgG and 27.3% were negative. All of the samples were negative for anti-rubella IgM. In the samples with a history of mothers' rubella vaccination, only 87.5% were positive for anti-rubella IgG. The results suggest the need for another mass vaccination for rubella in women of child-bearing age and continuation of routine vaccination of infants, plus consideration of obligatory anti-rubella IgG testing before pregnancy in women who were not vaccinated and vaccination of women before marriage.

Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome.

BACKGROUND: Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene. METHODS AND RESULTS: A consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers. CONCLUSIONS: A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations.

How physical activity behavior affected well-being, anxiety and sleep quality during COVID-19 restrictions in Iran.

OBJECTIVE: The Islamic Republic of Iran has displayed one of the highest rates of COVID-19 infection in the world and the highest rate of mortality in the Middle East. Iran has used a stringent package of preventive health measures to mitigate the spread of infection, which however has negatively affected individuals' physical and psychological health. This study aimed at examining whether physical-activity (PA) behavior, anxiety, well-being, and sleep-quality changed in response to the COVID-19-related public health restrictions enforced in Iran. PATIENTS AND METHODS: An online questionnaire was disseminated to adults residing in Iran from November 17, 2020, to February 13, 2021 (~88 days), during Iran's strictest public health restrictions. Main outcome measures included Godin-Shephard Leisure-Time Exercise Questionnaire, General Anxiety Disorder-7, Mental Health Continuum-Short Form, and Pittsburgh Sleep Quality Index. RESULTS: A total of 3,323 adults (mean age 30±11 years, 54.3% female) participated in the survey. Firstly, the restrictions generally reduced PA behavior: (a) among inactive participants (IPs), 60.6% became less active vs. 5.1% who became more active; and (b) among active participants (APs), 49.9% became less active vs. 22.8% who became more active. Secondly, PA behavior was associated with higher well-being and sleep quality during the restrictions: (a) APs reported higher (or lower) levels of well-being and sleep quality (or anxiety) than did IPs; and (b) among IPs as well as among APs, the more active the participants, the greater (or lower) the levels of well-being and sleep quality (or anxiety). CONCLUSIONS: This study showed the beneficial role of PA behavior for well-being, anxiety, and sleep quality during the COVID-19 restrictions, whereas such restrictions appeared to decrease PA participation. Active lifestyle should be then encouraged during the COVID-19 outbreak while taking precautions.

Limitations of 64-detector-row computed tomography coronary angiography: calcium and motion but not short experience.

BACKGROUND: Recently, 64-detector-row computed tomography coronary angiography (CTA) has been introduced for the noninvasive diagnosis of coronary artery disease. PURPOSE: To evaluate the diagnostic capacity and limitations of a newly established CTA service. MATERIAL AND METHODS: In 101 outpatients with suspected coronary artery disease, 64-detector-row CTA (VCT Lightspeed 64; GE Healthcare, Milwaukee, Wisc., USA) was performed before invasive coronary angiography (ICA). The presence of >50% diameter coronary stenosis on CTA was rated by two radiologists recently trained in CTA, and separately by an experienced colleague. Diagnostic performance of CTA was calculated on segment, vessel, and patient levels, using ICA as a reference. Segments with a proximal reference diameter <2 mm or with stents were not analyzed. RESULTS: In 51 of 101 patients and 121 of 1280 segments, ICA detected coronary stenosis. In 274 of 1280 (21%) segments, CTA had non-diagnostic image quality, the main reasons being severe calcifications (49%), motion artifacts associated with high or irregular heart rate (45%), and low contrast opacification (14%). Significantly more women (43%) had non-diagnostic scans compared to men (20%). A heart rate above 60 beats per minute was associated with significantly more non-diagnostic patients (38% vs. 18%). In the 1006 diagnostic segments, CTA had a sensitivity of 78%, specificity of 95%, positive predictive value (PPV) of 54%, and negative predictive value (NPV) of 98% for detecting significant coronary stenosis. In 29 patients, CTA was non-diagnostic. In the remaining 72 patients, sensitivity was 100%, specificity 65%, PPV 79%, and NPV 100%. The use of a more experienced CTA reader did not improve diagnostic performance. CONCLUSION: CTA had a very high negative predictive value, but the number of non-diagnostic scans was high, especially in women. The main limitations were motion artifacts and vessel calcifications, while short experience in CTA did not influence the interpretation.

Is training essential for interpreting cardiac computed tomography?

BACKGROUND: Cardiac computed tomography (CT) has gained increasing acceptance for diagnosing obstructive coronary artery disease (CAD). Several guidelines have been published on required education for proficiency in the interpretation of these examinations. PURPOSE: To describe the learning-curve effect of the interpretation of 100 consecutive cardiac CT examinations aimed at diagnosing CAD. The diagnostic accuracy of radiologists and radiographers was also compared. MATERIAL AND METHODS: Two radiologists and two radiographers, all with no prior experience in evaluation of cardiac CT, independently underwent a dedicated training program of 100 examinations randomized into 10 blocks (sessions), with 10 cases in each. They independently evaluated the coronary arteries regarding significant obstructive CAD. After every session, individual feedback on diagnostic accuracy and comparison with the corresponding invasive coronary angiography (currently regarded as the gold standard to detect coronary lesions) was given. The time required for interpretation was recorded. RESULTS: The mean review time decreased (P<0.0001) successively during the 10 sessions for all the observers together. The first session had a mean review time of 32 min, and the last session 16 min. No significant improvement in sensitivity, specificity, or negative predictive value (NPV) was observed. For positive predictive value (PPV), there was an improvement for the radiologists (P<0.05), but not for the radiographers. The radiographers had a higher total specificity compared to the radiologists (P<0.01). CONCLUSION: The review time for novices in cardiac CT was approximately halved during the first 100 cases, with maintained accuracy. There was a learning-curve effect in PPV for the radiologists. The diagnostic accuracy of dedicated radiographers indicates that they might be considered to be included as part of the evaluation team.

The Incidence of Cytomegalovirus Glycoprotein B Genotypes in Kidney Transplant Recipients in Iran.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic viral infection in kidney transplant recipients. CMV classification is usually based on its glycoprotein B (gB) genotypes, which divides the virus into 4 strains (gB1-4). OBJECTIVE: To determine the incidence of CMV genotypes in Iran and their relation to various clinical factors. METHODS: We studied 80 renal transplant recipients admitted to our transplant referral center between 2014 and 2015. All of the studied patients were monitored every 1-2 weeks for CMV infection by immunofluorescence method. There were 34 CMV-infected patients whose sera were studied with sequencing technique to identify the 4 CMV genotypes. All patients were followed up to 6 months after transplantation. RESULTS: gB1 was the most common genotype (35.3%); it was followed by gB3 and gB4 (each with 17.6 %), gB2, and mixed gB1,3 and gB1,2 (each with 14.7%). Age (p=0.037), time of infection after transplantation (p=0.011), and biopsy-proven rejection (p=0.012) were associated with CMV genotype. After adjusting for covariates, significant associations were found between genotype gB1 and family relationship (p=0.047) as well as HLA mismatch (p=0.014); genotype gB3 and family relationship (p=0.011); and genotype gB4 and age (p=0.019). CONCLUSION: The most common CMV gB genotype in CMV-infected kidney transplant recipients in Iran was gB1. We recommend considering related therapeutic applications in the management of such patients.

Prevalence of Transfusion-transmitted Virus (TTV) Infection and its Association with Renal Post-transplantation Complications in Iran.

BACKGROUND: Transfusion-transmitted virus (TTV) is a single-stranded DNA virus. Renal transplant patients have a higher risk of TTV infection. OBJECTIVE: To evaluate the prevalence of TTV and its correlation with post-renal transplantation complications in a population of Iranian patients. METHODS: A cross-sectional study was performed on 120 renal transplant recipients. TTV infection in the peripheral blood samples was detected by semi-nested polymerase chain reaction (semi-nested PCR). Then, the relationship between TTV and renal post-transplant complications was examined. RESULTS: 34.2% renal transplant recipients were positive for TTV. There was a significant correlation between the presence of TTV and diabetes, acute transplant rejection, and urinary tract infection. We did not find any direct correlation between the presence of TTV infection and hypertension, hyperlipidemia, respiratory tract infection, and cytomegalovirus infection. CONCLUSION: We found an increased rate of TTV infection in renal transplant recipients associated with post-transplantation complications. TTV may be an important risk factor for some post-renal transplantation complications.

Survey and evidence based review of probiotics used in very low birth weight preterm infants within the United States.

OBJECTIVE: Data from multiple clinical trials, mostly conducted outside the US, indicate that probiotic prophylaxis is an effective intervention for prevention of necrotizing enterocolitis (NEC) in preterm infants. Probiotics are routinely used in many countries. However, in the US, probiotic use in preterm infants is limited (6.7% of very low birth weight (VLBW) infants in the US were exposed to probiotics in 2014, Vermont Oxford Network (VON)). Probiotic products are often considered in 'generic' terms, but considerable variation exists between commercially available probiotics in terms of their quantity and quality. The study objectives were to identify the probiotic products used in VLBW infants within the US, and to determine whether their use was supported by reliable evidence. STUDY DESIGN: A phone survey of all neonatal intensive care units (NICU) participating in VON within the US was conducted between May and September 2015 to identify NICUs that are using probiotics in VLBW infants. Data was collected regarding specific probiotic brands, timing, dose and duration of probiotic use. An evidence based literature search, limited to randomized controlled trials in VLBW infants, was conducted to determine whether the use of identified probiotics were supported by reliable evidence. RESULTS: There was a 70.3% (500/711) response rate to the phone survey. During the survey period, 14.0% of NICUs were using probiotics in VLBW infants (70/500). Probiotics were routinely given to all VLBW infants in 8.8% (44/500) NICUs, while it was given in selected VLBW infants in 5.2% (26/500) of NICUs. The common indications for selective use of probiotics were feeding intolerance and antibiotic use. Sixteen commercial probiotics products were identified through the phone survey. Probiotic products most commonly used were Culturelle (27.1%), Biogaia (14.3%), Gerber Soothe (14.3%) and Florababy (8.6%). The literature search identified evidence that evaluated 4/16 probiotic products identified (Culturelle, Align, Biogaia and ABC Dophilus). Only ABC Dophilus was reported to have a protective effect against NEC, but is used sparingly in US NICUs (2.9%). CONCLUSIONS: The probiotics use in VLBW infants within the US is increasing, but is still limited. There was no evidence for safety or efficacy of 90% of the probiotics currently used in US NICUs, and therefore, caution is warranted.

Sequential magnetic resonance monitoring of pulmonary flow with endovascular stents placed across the pulmonary valve in growing Swine.

BACKGROUND: Patients with endovascular stent implantation for the treatment of right ventricular outflow tract obstruction are often left with incomplete relief of the obstruction and significant pulmonary regurgitation. A noninvasive and reproducible method for monitoring such patients is desirable. MRI in the presence of a stent, however, has to overcome the problem of potential metallic artifacts. METHODS AND RESULTS: Under x-ray fluoroscopic guidance, endovascular nitinol stents were placed across the pulmonary valve in 6 young pigs to induce pulmonary regurgitation. Five additional pigs served as controls. Initial MRI was performed after 2 days (13.5+/-1.8 kg) and follow-up after 3 months (32+/-2.9 kg). Pulmonary flow volumes and regurgitant fraction were quantified by velocity-encoded cine (VEC) MRI through (VEC-TS) and distal to (VEC-DS) the stent. VEC-TS was compared with VEC-DS and volumetric measurements of left and right ventricular stroke volumes provided by cine MRI ("gold standard"). Antegrade and retrograde pulmonary flow volumes by VEC-TS were slightly but significantly less than those with VEC-DS and cine MRI. Excellent correlations (r>0.97) for phasic pulmonary flow volumes as measured by VEC-TS and VEC-DS were shown. Pulmonary regurgitant fraction increased from 32.8+/-15% to 49.6+/-17% (P<0.05) over the course of 3 months with VEC-TS. CONCLUSIONS: MRI demonstrates the progression of pulmonary regurgitation in growing swine. VEC MRI has the ability to quantify pulmonary blood flow inside the lumen of nitinol stents. MRI appears to be ideally suited for monitoring patients with endovascular nitinol stents in the pulmonary artery or pulmonary valve position.

Experimental hyperlipidemia induces insulin resistance in sheep.

This study aimed to evaluate the effects of intravenous infusion of a soybean-based lipid emulsion on some blood energy-related metabolites and insulin sensitivity indexes in sheep. Four clinically healthy ewes were assigned into a 2-treatment, 2-period cross-over design. Either normal saline (NS) or lipid emulsion (LE) was intravenously introduced at a rate of 0.025 mL·kg(-1) min(-1) for 6 h. The concentrations of blood nonesterified fatty acid (NEFA), beta-hydroxybutyrate, triglyceride, cholesterol, urea, creatinine, cortisol, glucose, and insulin were measured at different time points. After 6 h, intravenous glucose tolerance test was performed. Lipid infusion elicited an increase (P < 0.05) in the NEFA, beta-hydroxybutyrate, and triglyceride concentrations compared with the baseline value and NS infusion. Infusion of NS did not influence blood glucose concentration; however, LE infusion increased plasma glucose concentration (P < 0.05). At time point 12 h, serum insulin concentrations were increased (P < 0.05) in NS treatment; however, such an increase was not observed in the LE treatment. Insulin sensitivity index for the LE infusion was lower (P < 0.05) than that for the NS treatment. The glucose effectiveness was not (P > 0.05) different among treatments. In the LE treatment, acute-phase insulin responses increased (P < 0.05) and disposition index decreased (P < 0.001) compared with NS treatment. The results showed that experimentally induced NEFA in blood could cause insulin resistance in sheep. The current model could be used to evaluate the pathogenesis of conditions associated with increased lipid mobilization and insulin resistance.

Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist.

BACKGROUND AND PURPOSE: The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the µ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH: We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS: Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg(-1) ), unmasked etorphine (3 mg·kg(-1) ) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg(-1) ) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg(-1) ) and diazepam (1 mg·kg(-1) ). CONCLUSIONS AND IMPLICATIONS: Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Antipeptide antibodies against the 5-HT1A receptor.

The availability of the primary amino acid sequence for a large number of molecules provides a fruitful opportunity for their cellular localization by utilizing the procedure of antipeptide antibody formation. This procedure permits a synthetic peptide sequence to be attached to a carrier molecule for the purpose of inoculating an animal to raise specific antibodies against the selected protein sequence. In this report we describe a number of steps that can be taken to increase the likelihood that the selected peptide sequence will be specific and antigenic. In addition, we describe how the peptides are synthesized, purified and coupled to keyhold limpet hemocyanin. The preparation of the antibody and its characterization are also presented in this method report. The immunocytochemical staining at both the light and ultrastructural level with serotonin (5-HT1A) receptor antipeptide antibodies is discussed. The advantages and disadvantages of this procedure are summarized.

Neonatal ACTH administration elicits long-term changes in forebrain monoamine innervation. Subsequent disruptions in hypothalamic-pituitary-adrenal and gonadal function.

The findings from this study demonstrated that the manipulation of the HPA system resulting from ACTH administration during neonatal development produces long-term, differential effects, not only on adrenocortical activity, but also on the activity and integrity of the forebrain monoamine systems. Increased concentrations of the monoamines within the forebrain regions studied at days 7 and 15, suggest a hastened maturation of these neural systems in animals neonatally treated with ACTH. The observed neurochemical alterations in these animals at one year are suggestive of an accelerated aging in the monoamine systems. A further consequence of these disturbances during development is an altered functioning of the HPG axis, as demonstrated by a delayed onset of puberty as previously reported, as well as significantly decreased proestrus plasma estradiol. Although deficits in sexual behavior also existed, it seems probable that these behavioral changes are a manifestation of altered neural systems regulating the ability to cope with a novel stimulus or situation, rather than a disruption of the "feminization" of the brain during sexual differentiation. This is in contrast to the male rat which exhibits permanent deficits in male typical sexual behavior following developmental ACTH treatment. The clinical relevance of these findings may be extensive. Perinatal exposure to events or agents that markedly increase ACTH and the corticosteroids may cause significant immediate and long-term changes in central monoamine functioning. These changes may constitute some of the most deleterious effects of stress exposure in infants and children. The alterations may be especially devastating in individuals with predispositions to stress-sensitive disorders such as anxiety, depression, and Tourette's syndrome. Finally, the use of ACTH in the treatment of infantile spasms may need to be reassessed in light of the possible long-term effects of ACTH on central monoamine functioning.

Neonatal ACTH and corticosterone alter hypothalamic monoamine innervation and reproductive parameters in the female rat.

Female Sprague-Dawley rat pups were injected SC with either ACTH(1-24) (0.5 mg/kg) or saline vehicle once daily from postnatal day 1 (day of birth) to day 7. Plasma corticosterone (CORT) levels were recorded via radioimmunoassay (RIA) on day 4 to measure adrenal response to these treatments. Hypothalamic 5-HT and DA fiber densities were assessed using high-affinity specific 3H-5-HT and 3H-DA uptake at days 7, 25, and at adulthood (80-90 days). Animals were checked daily for vaginal opening (starting on day 30) as a sign of sexual maturation and later tested for sexual behavior as virgins (60-70 days of age). Plasma estradiol and progesterone levels were measured via RIA. Plasma CORT levels were greatly increased among ACTH-treated animals during the treatment period. The 5-HT uptake was significantly increased in ACTH-treated animals at day 7 (p < 0.01) and at adulthood (p < 0.02) compared to controls. The DA uptake was significantly higher among ACTH-treated animals at day 7 (p < 0.01). The sexual maturation of ACTH-treated animals was delayed when compared to control animals (p < 0.01). The ACTH-treated animals displayed slight deficits in female sexual behavior compared to control animals (p < 0.05). No significant changes in plasma sex steroid levels were found. Based on this study, we suggest that monoamine innervation into the developing female hypothalamus is susceptible to early postnatal manipulation with ACTH and CORT, and that the resulting changes in these monoamine fiber densities may be responsible for the observed deficits in reproductive maturation and behavior.

Prenatal cocaine exposure disrupts the development of the serotonergic system.

Prenatal cocaine exposure has been found to result in a number of neurobehavioral abnormalities in both clinical and laboratory studies. We have previously shown that cocaine inhibits the growth of developing serotonin neurons in culture. This study examines the effects of cocaine on the developing serotonin system in vivo. Pregnant rats were injected with cocaine (40 mg/kg s.c.) from gestational day 13 to parturition. One group of rats was additionally injected on postnatal days 1-5 with cocaine (10 mg/kg s.c.). [3H]Paroxetine, a selective ligand for the serotonin uptake carrier, was used to quantify serotonin terminal fiber density at one day, one week, and four weeks postnatal. Cocaine exposure was found to significantly decrease [3H]paroxetine-labelled sites and thus the density of serotonin fibers in the cortex and hippocampus at one day and one week postnatal. By four weeks postnatal, no significant effect was observed, indicating that a recovery had occurred. Serotonin immunocytochemistry performed at one month revealed normal fiber distribution in the cortex but a loss of fibers in the CA1 and CA2 hippocampal fields. Postnatal treatment alleviated the effects of prenatal cocaine exposure, resulting in [3H]paroxetine binding levels at one week which were comparable to and, in the cortex, even higher than those of saline controls. We conclude that cocaine delays the maturation of the serotonin system when administered prenatally but may accelerate maturation when administered both pre- and postnatally.

Increased tyrosine hydroxylase immunoreactivity in the rat cortex following prenatal cocaine exposure.

Cocaine has been found to be a neurobehavioral teratogen in both animals and humans. In this study the effects of cocaine on the developing catecholamine systems were examined. Rats were treated gestationally with cocaine (40 mg/kg s.c.) or saline from gestational day 13 until parturition. On postnatal day 28, tyrosine hydroxylase immunocytochemistry was performed. Increases in catecholamine fiber densities were observed in the hippocampus, anterior cingulate cortex, and parietal cortex in cocaine-treated animals. These findings may explain some of the behavioral alterations seen following prenatal cocaine exposure.