Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys.

Many patients with hyperandrogenemia are overweight or obese, which exacerbates morbidities associated with polycystic ovary syndrome (PCOS). To examine the ability of testosterone (T) to generate PCOS-like symptoms, monkeys received T or cholesterol (control) implants (n = 6/group) beginning prepubertally. As previously reported, T-treated animals had increased neuroendocrine drive to the reproductive axis [increased luteinizing hormone (LH) pulse frequency] at 5 yr, without remarkable changes in ovarian or metabolic features. To examine the combined effects of T and obesity, at 5.5 yr (human equivalent age: 17 yr), monkeys were placed on a high-calorie, high-fat diet typical of Western cultures [Western style diet (WSD)], which increased body fat from <2% (pre-WSD) to 15-19% (14 mo WSD). By 6 mo on WSD, LH pulse frequency in the controls increased to that of T-treated animals, whereas LH pulse amplitude decreased in both groups and remained low. The numbers of antral follicles present during the early follicular phase increased in both groups on the WSD, but maximal follicular size decreased by 50%. During the late follicular phase, T-treated females had greater numbers of small antral follicles than controls. T-treated monkeys also had lower progesterone during the luteal phase of the menstrual cycle. Although fasting insulin did not vary between groups, T-treated animals had decreased insulin sensitivity after 1 yr on WSD. Thus, while WSD consumption alone led to some features characteristic of PCOS, T + WSD caused a more severe phenotype with regard to insulin insensitivity, increased numbers of antral follicles at midcycle, and decreased circulating luteal phase progesterone levels.

Elevated androgens during puberty in female rhesus monkeys lead to increased neuronal drive to the reproductive axis: a possible component of polycystic ovary syndrome.

BACKGROUND: Hyperandrogenemia is associated with several clinical disorders in which both reproductive dysfunction and metabolic changes may coexist [i.e. polycystic ovary syndrome (PCOS), obesity and congenital adrenal hyperplasia]. Moreover, there is growing evidence that the elevated levels of circulating androgens in obese girls may lead to an increased neuroendocrine drive to the reproductive axis, similar to that associated with PCOS. METHODS: To test whether androgen exposure in the childhood and adolescent period could lead to pubertal alterations in LH secretory patterns, female rhesus monkeys received subcutaneous testosterone implants prepubertally beginning at 1 year of age, maintaining a 3.7-fold increase (P = 0.001) in circulating testosterone levels over cholesterol-implant controls (n = 6/group) into the post-pubertal period. In early adulthood, pulsatile secretion of LH was measured over 12 h during the early follicular phase of a menstrual cycle, and responsiveness of the pituitary to gonadotrophin-releasing hormone was determined. In addition, ultrasounds were performed to assess ovarian morphology and glucose tolerance testing was performed to assess insulin sensitivity. RESULTS: The timing of menarche was similar between groups. Testosterone-treated animals had a significantly greater LH pulse frequency during the early follicular phase compared with controls (P = 0.039) when measured at 5 years of age. There was a larger LH response to GnRH when testosterone-treated animals were 4 years of age (P = 0.042), but not when the animals were 5 years old (P = 0.57). No differences were seen in insulin sensitivity or ovarian morphology, and the groups showed similar rates of ovulation in early adulthood. CONCLUSIONS: Exposure to increased levels of androgens over the course of pubertal development appears to trigger physiological changes in the neural drive to the reproductive axis that resemble those of obese hyperandrogenemic girls in early adulthood and are characteristic of PCOS.

Prefrontal blood flow dysregulation in drug naive ADHD children without structural abnormalities.

Recent studies suggest a role for prefrontal cortex abnormalities in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). We evaluated young drug-naive ADHD outpatients without MRI structural abnormalities to detect prefrontal cortex regional cerebral blood flow (rCBF) functional dysregulation; correlation between age and rCBF; and correlation between symptoms profile and rCBF. Functional brain activities (i.e. rCBF), neuropsychological attention performance and symptom profile were evaluated respectively by single photon emission computerized tomography (SPECT) scan, Stroop Test and the Child Attention Problem Rating Scale. There was a decreased rCBF in the left dorso lateral prefrontal cortex (DLPFC) compared to the right DLPFC of the subjects. In addition, there were positive correlations between age and relative rCBFs of the dorsolateral and orbital prefrontal cortex, and negative correlations between age and absolute rCBFs of the dorsolateral and orbital prefrontal cortex. Finally, higher levels of right relative rCBF and lower levels of left relative rCBF were predictors of higher severity of clinical symptom expression and neuropsychological attention impairment. The results of this study highlight the role of the DLPFC blood flow impairment in the pathogenesis of ADHD even in young subjects without structural abnormalities.

Positive and sustained effects of highly active antiretroviral therapy on HIV-1-associated neurocognitive impairment.

OBJECTIVES: To determine whether highly active antiretroviral therapy (HAART) is effective in HIV-associated neurocognitive impairment. DESIGN: An open label, prospective, observational study. METHODS: Since April 1996, 116 patients with advanced HIV infection, reverse transcriptase inhibitor (nRTI) experienced but protease inhibitor (PI) naive, were screened for the presence of neurocognitive impairment. Ninety patients with confounding neurological illness, opportunistic infections or drug abuse were excluded. The remaining 26 patients underwent comprehensive neuropsychological testing, and laboratory measures before, after 6 and after 15 months of treatment with one PI plus two nRTI. RESULTS: The prevalence of neurocognitive impairment decreased from 80.8% (baseline) to 50.0% (P<0.05) (sixth month) and to 21.7% (P<0.001) (15th month). Among the functions explored, the impairment of concentration and speed of mental processing decreased from 65.4 to 21.7% (P<0.01) and of memory impairment from 50 to 8.7% (P<0.01). Comparing baseline with the sixth and 15th month raw scores, a statistically significant improvement was seen in measures exploring concentration and speed of mental processing (P<0.05), mental flexibility (P<0.05), memory (P<0.05), fine motor functions (P<0.05) and visuospatial and constructional abilities (P<0.01). After 6 months of HAART patients with a normal neuropsychological examination had lower mean plasma viraemia (2.95 versus 3.97 log copies/ml, P<0.05) and greater mean log plasma HIV RNA changes from baseline (-1.84 versus -0.83 log copies/ml, P<0.05) than neuropsychologically impaired subjects. CONCLUSION: HAART produces a positive and sustained effect on neurocognitive impairment in HIV-infected patients. A reduction of plasma viral load was associated with the regression of neuropsychological test abnormalities.

MACOP-B and involved field radiation therapy is an effective therapy for primary mediastinal large B-cell lymphoma with sclerosis.

PURPOSE: To evaluate the clinical features of presentation and the response to two different third-generation regimens (F-MACHOP and MACOP-B) of primary mediastinal large B-cell lymphoma (MLBCL), a recently defined distinct clinicopathological entity of non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-seven consecutive patients with MLBCL, eight male and 29 female (F/M ratio 1:3.5) with a median age of 35 years, were enrolled in the present study. Thirty-five (94.5%) patients presented disease confined to thorax, with chest symptoms of a rapidly enlarging mass in the mediastinum in 70% and superior vena cava syndrome (SCVS) in 43% of these patients. The first 10 patients received F-MACHOP and the succeeding 27 patients MACOP-B chemotherapy, associated in 24 (88.8%) with involved field radiation therapy (IFRT). 67Gallium scan was routinely performed pre- and post-IFRT in 18 patients. RESULTS: All 37 patients were assessable for response: 10 of 10 (100%) in the F-MACHOP and 26 of 27 (96.3%) in the MACOP-B group achieved overall responses (CR + PR). Three of 24 (12.5%) patients in PR after chemotherapy obtained CR after IFRT. Persistent Gallium avidity was observed in 16 patients after chemotherapy and in only four patients after IFRT. Thus far, four of the 10 F-MACHOP and two of the 26 MACOP-B responders have presented disease progression. The probability of progression-free survival (PFS) was 91% and 60% (P < 0.02) while overall survival (OS) was 93% and 70% (P = n.s.) at a mean follow-up of 27 and 52 months in the MACOP-B + IFRT and F-MACHOP groups, respectively. CONCLUSION: MACOP-B + IFRT has proved to be a highly effective and less toxic therapeutic approach for primary MLBCL and appears to be superior to other third-generation chemotherapy regimens.

[Improvement of postinfarct left myocardial contractile function after administration of diltiazem]. / Ripresa contrattile di asinergie miocardiche postinfartuali indotta dalla somministrazione acuta di diltiazem.

BACKGROUND: The impairment of intracellular calcium homeostasis is an important biochemical alteration in stunned and hibernating myocardium. These different forms of viable myocardium frequently occur after myocardial infarction and their recognition may modify the therapeutic program and prognosis. Experimental studies and experiences on male subjects have demonstrated that calcium-channel blockers exert a protective action on myocardial reperfusion injury and reduce infarct size. OBJECTIVES: The aim of the present study was to evaluate the efficacy of i.v. diltiazem (i.e. a calcium-channel blocker with negative inotropic effect) in enhancing the contractility of viable akinetic myocardium in patients after myocardial infarction. METHODS: Sixty patients (52 males and 8 females, age 57 +/- 10 years) with the first acute myocardial infarction were evaluated with dobutamine-echocardiography 9 +/- 2 days after admission and on the following day with diltiazem-echocardiography. Diltiazem was administered i.v. using repeated boluses of 0.25 mg/kg up to the maximum dose of 1 mg/kg. Before and during the infusion, left ventricular regional function was scored and the Wall Motion Score Index (WMSI) was calculated; ECG and arterial blood pressure were also monitored. Results were compared with low-dose dobutamine-echocardiography. In a subset of 13 patients who underwent myocardial revascularization (7 coronary artery by-pass graftings and 6 percutaneous transluminal angioplasties), post-procedure echocardiograms were performed to evaluate whether regional left ventricular function had improved. RESULTS: Low-dose dobutamine and diltiazem enhanced regional left ventricular contractility in 28 and 31 patients, respectively; both tests were positive in 26 cases. Conversely, dobutamine-test was negative in 32 patients and diltiazem in 29, with concordance in 27. A good correlation was found between diltiazem and dobutamine WMSI at the basal evaluation (r = 0.91; p < 0.000) as well as during the pharmacological test (r = 0.86; p < 0.000). In patients who underwent myocardial revascularization, the same good correlation was found between diltiazem-WMSI and WMSI evaluated after the procedure (r = 0.91; p < 0.000). CONCLUSIONS: Acute i.v. administration of diltiazem about ten days after myocardial infarction may enhance the contractility of viable akinetic ventricular wall segments, as evaluated with echocardiography. The results of this study may have some physiopathological and therapeutical implications that could lead to reconsidering the use of calcium-channel blockers, particularly diltiazem, in selected patients after myocardial infarction.

Dipyridamole echocardiography and 99mTc-MIBI spect dipyridamole scintigraphy for cardiac evaluation prior to peripheral vascular surgery.

Coronary artery disease accounts for most of the early and late mortality and morbidity associated with vascular surgery. Cardiac pre-operative evaluation is mandatory for the assessment of cardiac risk. The aim of this study is to compare dipyridamole scintigraphy with 99mTc-MIBI (MIBI-dipy) and dipyridamole echocardiography (ECHO-dipy) and to evaluate their capability in identifying cardiac risk for strong events such as death, unstable angina or myocardial infarction. METHODS. Sixty consecutive patients (mean age 67 +/- 7) were enrolled. 52 performed ECHO-dipy, 51 MIBI-dipy. 40 patients went to aorto-femoral or aorto-iliac graft replacement and 15 to vascular angioplasty. Five patients did not undergo surgery. RESULTS. Eighteen patients (30%) had stress defects and 9 patients also rest defects with MIBI-dipy. Six patients new asinergic areas at ECHO-dipy. Three pts died in the first year follow-up for a cerebrovascular event, a myocardial infarction and a sudden death respectively. Sensitivity and specificity, positive and negative predictive value were 100%, 69%, 16%, 100% for MIBI-dipy and 66%, 94%, 40%, 98% for ECHO-dipy. CONCLUSIONS. As other authors reported, stress scintigraphy is a pre-operative test showing high sensitivity but with no satisfying specificity. Stress echocardiography, in our population, can produce a good negative predictive value. It is a less expensive and widespread clinical tool useful in the evaluation of preoperative patients. Its positive predictive power is not satisfying but it is shared with all non-invasive pre-operative tests available now.

Effects of zidovudine in 30 patients with mild to end-stage AIDS dementia complex.

OBJECTIVE: Zidovudine (ZDV) is an inhibitor of HIV replication that may have a beneficial effect on patients with AIDS dementia complex (ADC). However, little is known about the association between long-term ZDV treatment and severity of ADC, ZDV dose or clinical and laboratory response to therapy. DESIGN: An open study on ZDV administration in 30 consecutive patients with ADC. SETTING: An infectious diseases hospital. PATIENTS: Thirty consecutive patients followed-up for 12 months. INTERVENTIONS: Three oral ZDV doses were used: 1000 mg (nine patients), 750 mg (eight patients) and 500 mg (13 patients) per day, depending on haematological status. MAIN OUTCOME MEASURES: Clinical and neurological examinations, neuropsychological evaluations, high-field brain magnetic resonance imaging (MRI) and 99mTc-HM-PAO single photon emission computerized tomography (SPECT). RESULTS: A favourable clinical response, defined as reversal to a less severe ADC stage (Price and Brew's criteria), was observed after 1, 3, 6, 9 and 12 months in 15, 22, 25, 19 and 14 patients, respectively. Neither severity of ADC at entry nor ZDV dose correlated with response to treatment. Seven patients died during the 12-month follow-up. The only factor associated with longer survival was ADC severity at entry (12-month survival, 0.94 and 0.53, in patients in stages 1 or 2 and in stages 3 or 4, respectively; P < 0.01). After 6-12 months of ZDV treatment six patients who initially responded to therapy showed a relapse in initial ADC stage, and two patients a less severe neurological deterioration. Neuropsychological evaluations showed significant improvement in the Wisconsin Card-Sorting test (P = 0.006 for categories, P = 0.029 for perseverative errors), which is particularly sensitive to cognitive and frontal-lobe type functions. Brain MRI revealed a reduction of the extent of white matter lesions in six out of 13 patients, who also showed clinical improvement. SPECT scanning revealed a reduction in the extent of uptake defects concomitant with clinical response in nine out of 14 patients. CONCLUSIONS: ZDV is effective in most patients with mild to end-stage ADC, although the benefit is sometimes only transient; several relapses and deaths occurred after the sixth month of treatment.

Methods for detecting early signs of AIDS dementia complex in asymptomatic HIV-1-infected subjects.

OBJECTIVES: To determine the optimal diagnostic procedures for identifying early signs of AIDS dementia complex (ADC) in asymptomatic HIV-1-infected individuals, in order to prevent further cognitive function impairment by early treatment. DESIGN: Study patients had been referred electively and consecutively to hospital; all had been referred for the first time and gave informed consent. Inclusion criteria were (1) lack of history and/or symptoms of psychosis and neurological disorders; (2) lack of active viral, protozoan or fungal pathology; (3) abstinence from heroin and/or cocaine for at least 6 months before baseline evaluation. SETTINGS: Subjects were seen at the L. Spallanzani Hospital for Infectious Diseases, Rome, Italy between March 1989 and March 1991. PARTICIPANTS: Eighty-two asymptomatic HIV-1-infected subjects: 41 drug users, 27 homosexuals and 14 heterosexuals. MAIN OUTCOME MEASURES: All subjects were evaluated using Wechsler-Bellevue I, Benton C form and Bender tests. Thirty-nine subjects underwent single-photon emission computed tomography (SPECT) and 12 magnetic resonance imaging (MRI). The immunological status of each subject was determined. RESULTS: On psychometric testing, 23 out of the 82 (28%) asymptomatic subjects had a mental decay percentage (MD%) > or = 20%. Cerebral perfusion abnormalities were detected in 31 out of 39 (79.48%) subjects who underwent SPECT; MRI abnormalities were observed in seven out of 12 (58%) subjects. Twelve out of 23 subjects with MD% > or = 20, 15 out of 29 subjects with SPECT abnormalities and four out of seven patients with MRI abnormalities had total CD4+ lymphocyte counts > or = 500 x 10(6)/l. CONCLUSIONS: The high incidence of abnormal SPECT and of MD% > or = 20 in asymptomatic HIV-1-infected patients, and the lack of correlation between immunological status and degree of mental decay, SPECT and MRI abnormalities raise many questions about subclinical HIV-1 neurological disease.

Prediction of postoperative pulmonary function following thoracic surgery for bronchial carcinoma.

At present surgery is accepted as the most effective mode of therapy for carcinoma of the lung. Because the lack of respiratory reserve is the major determinant of postoperative function, it is useful to identify the patient, who is at significant risk. Eighteen patients with lung cancer (mean age = 56 +/- 6.5 years) were studied preoperatively (preop) and postoperative (postop) (three to four months after lung resection) by spirometry, measurement of arterial blood gases, and quantitative lung scanning (99mTc). A predicted postoperative value of some variables was calculated by the formula: postop value = preop value x % function of regions of lung not resected. The correlation coefficient between the predicted (pred) and postoperatively observed (observ) values VC = vital capacity, FEV1 = forced expiratory volume in 1 second) is: VC pred/VC observ r = 0.83 p less than 0.001 FEV1 pred/FEV1 observ r = 0.82 p less than 0.001. The authors' results agree with earlier reports and show that the method used can accurately predict the postoperative respiratory function in patients undergoing lung resection (pneumonectomy or lobectomy). A predicted FEV1 of 0.8 L does not permit a surgical program, because, below this level, carbon dioxide retention becomes more frequent and exercise intolerance is increasingly severe (poor quality of life). The method proposed to predict the postoperative respiratory function is simple and routinely useful. The authors choose a perfusion instead of ventilation scan, because the former provides similar predicted postoperative data, and can be done routinely.

Cerebral blood flow in AIDS-related neurotoxoplasmosis: a preliminary 99mTc-HMPAO SPECT study.

Cerebral blood flow (CBF) was evaluated by gamma camera 99mTc-HMPAO SPECT in 11 patients with AIDS-related neurotoxoplasmosis and correlated with neurological findings and the results of CT and MRI. Evident CBF abnormalities were observed in all patients with involvement of at least two cerebral lobes. In 10 patients the abnormalities were bilateral and in 8 patients basal ganglia were involved; no specific hypoperfusion pattern was however evident. Focal lesions were found in 7 patients by CT (sensitivity: 63.6%) and in 10 patients by MRI (sensitivity: 90.9%). It may be concluded that neurotoxoplasmosis in AIDS patients is associated with a high prevalence of focal cortical and subcortical hypoperfusion but that the scintigraphic findings are not specific; that HMPAO SPECT may show focal hypoperfusion in patients with normal CT studies and/or non-focal MRI abnormalities; that the hypoperfusion may be more extensive than the corresponding MRI lesion(s) and that it may be present even in areas with normal MRI signals; and that more experience and longitudinal studies are needed to assess the possible impact of HMPAO SPECT on follow-up and therapy monitoring.

Cortical cerebral blood flow in HIV-1-related dementia complex.

Dementia complex is a syndrome that affects a high percentage of AIDS patients. Neuroradiological findings may be non-specific and the diagnosis can be difficult in its earlier stages. Preliminary radionuclide studies have recently reported derangements of regional cerebral blood flow (CBF) which may be present before overt anatomical injury. This study reports on cortical and cerebellar CBF changes in 26 patients studied with 99Tcm-HM-PAO and single photon emission computed tomography (SPECT). Extensive cortical CBF derangements were observed in all patients and an evident cerebellar hypoperfusion was also present in three. The prevalence of hypoperfusion was highest in the frontal and parietal lobes. The extension of the hypoperfusion showed a highly significant correlation with the severity of the dementia complex (P less than 0.01 by chi 2 test). The SPECT also showed hypoperfused areas in three patients with normal CT scans and in two patients with normal MRI scans. These results confirm previous preliminary reports on the high prevalence of cortical hypoperfusion in dementia complex and suggest the use of this radionuclide technique to assist in the early diagnosis and follow-up of AIDS patients, especially when CT and MRI are still normal.

The influence of age on the pulmonary clearance of 99Tcm-DTPA radioaerosol.

Age-dependent changes of 99Tcm-DTPA radioaerosol transpulmonary clearance have been investigated in 49 healthy volunteers with an age range of 21-63 years. The clearance was uniformly increased in all smokers irrespective of age, but it showed a highly significant (p less than 0.001) decrease in non-smoking patients over 50 years. Several age-related changes in the ageing lung can contribute to this decreased clearance, but the reduced alveolar-capillary surface area available for the transport is probably the key factor. The practical implication of the results is the need to use age-related normal ranges when interpreting 99Tcm-DTPA radioaerosol clearance studies.

Plasma carcinoembryonic antigen and tissue polypeptide antigen levels in lung cancer: correlation with cell types and stage.

This investigation was carried out to evaluate the plasma CEA and TPA levels in normal subjects and in 140 patients with lung cancer: 116 patients with nonsmall cell lung cancer (NSCLC) and 24 patients with small cell carcinoma (SCLC). The CEA and TPA levels were determined simultaneously by radioimmunoassay. The cutoff limit of CEA was found to be 17 U/SORIN, and the cutoff of TPA was 99 U/L. TPA has shown a sensitivity almost twice that of CEA. The relationship between the mean values of CEA and TPA and the stages of NSCLC was statistically significant (P less than 0.01), whereas only the mean values of TPA significantly (P less than 0.05) correlated with extensive and limited disease in SCLC. The determinations of combined CEA and TPA levels (CEA X TPA) (P less than 0.001) correlated significantly with the stage of disease in patients with NSCLC; conversely, the use of CEA X TPA did not correlate with the stage of SCLC.