Abnormal regulation of corticopetal cholinergic neurons and impaired information processing in neuropsychiatric disorders

Cholinergic neurons originating in the basal forebrain innervate all cortical areas and participate in the gating of cortical information processing. Aberrations in the excitability of cortical cholinergic inputs fundamentally alter the processing of sensory stimuli and higher processes, thereby advancing the development of major neuropsychiatric disorders. Cortical cholinergic deafferentation has been considered to be a major neuropathological variable that contributes to the development of age- and dementia-associated impairments in cognition. Conversely, it has been suggested that increases in the excitability of cortical cholinergic inputs mediate the abnormal cognitive processes that escalate into psychotic symptoms and contribute to addictive-drug-seeking behavior, anxiety and phobia. Abnormal regulation of the excitability of cortical cholinergic afferents represents a 'final common pathway' that mediates the manifestation of major neuropsychiatric disorders.     

Activation of A(1) adenosine or mGlu3 metabotropic glutamate receptors enhances the release of nerve growth factor and S-100beta protein from cultured astrocytes.

Pharmacological activation of A(1) adenosine receptor with 2-chloro-N6-cyclopentyladenosine (CCPA) or mGlu3 metabotropic glutamate receptors with (2S,2'R,3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine (DCG-IV) or aminopyrrolidine-2R, 4R-dicarboxylate (2R,4R-APDC) enhanced the release of nerve growth factor (NGF) or S-100beta protein from rat cultured astrocytes. Stimulation of release by CCPA and DCG-IV or 2R,4R-APDC was inhibited by the A(1) adenosine receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine and by the mGlu2/3 receptor antagonist (2S,1'S, 2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-4), respectively. Time-course studies revealed a profound difference between the release of S-100beta protein and the release of NGF in response to extracellular signals. Stimulation of S-100beta protein exhibited rapid kinetics, peaking after 1 h of drug treatment, whereas the enhancement of NGF release was much slower, requiring at least 6 h of A(1) adenosine or mGlu3 receptor activation. In addition, stimulation of NGF but not S-100beta release was substantially reduced in cultures treated with the protein synthesis inhibitor cycloheximide. In addition, a 6-8 h treatment of cultured astrocytes with A(1) or mGlu3 receptor agonists increased the levels of both NGF mRNA and NGF-like immunoreactive proteins, including NGF prohormone. We conclude that activation of A(1) adenosine or mGlu3 receptors produces pleiotropic effects in astrocytes, stimulating the synthesis and/or the release of protein factors. Astrocytes may therefore become targets for drugs that stimulate the local production of neurotrophic factors in the CNS, and this may provide the basis for a novel therapeutic strategy in chronic neurodegenerative disorders.     

Multivariate Analysis of Left Ventricular Mass Determinants in Adults: Different Patterns in Men and Women

Echocardiographic left ventricular mass (LVM) estimates are strong predictors of subsequent mortality and cardiovascular events. It is known that blood pressure (BP), weight (WT), and age are significantly correlated with LVM. We hypothesized that stroke volume (SV) measured by Doppler echocardiography would also be correlated with LVM. Two hundred and thirteen patients referred for routine echocardiography had determination of LVM, cuff BP, and Doppler SV. Those with localized LV disease, valvular disease, or cor pulmonale were excluded. In both men and women, systolic BP (SBP) was more closely correlated with LVM than was diastolic blood pressure or mean arterial pressure, and SV was more closely correlated with LVM than cardiac output or cardiac index. Stepwise regression, followed by multiple regression showed that four variables (WT, SV, SBP, and AGE) explained 32.3% of the variability in LVM in men and 48.5% of the variability in LVM in women. WT and SV were significant determinants of LVM in both men and women. Age was also significant in men and SBP was also significant in women. For both men and women, SV was more significantly correlated with LVM than was SBP. The changes in LVM associated with 1 SD increments of SV and SBP, respectively, were 8 and 5 g for men and 13 and 11 g for women. We conclude that men and women have different patterns of variables influencing LVM. Doppler echocardiographic SV is a newly described determinant of LVM that has a greater correlation with LVM than does SBP. This study reemphasizes the importance of WT as the major determinant of LVM. (ECHOCARDIOGRAPHY, Volume 13, January 1996)     

Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma

Summary The relationship between tumor proliferative activity and response to first-line chemotherapy and survival was investigated in 76 advanced breast cancer patients. Proliferative activity was determined by means of Ki-67 immunohistologic staining on primary tumors (55 patients) or at the relapse site (21 patients), and was classified as low ( 25% of stained cells) or high (> 25% of stained cells). The usual WHO response criteria were used. The median duration of follow-up was 18 months (range 3–58).Forty-seven patients (62%) had tumors with low, and 29 (38%) had tumors with a high rate of proliferative activity. The two groups were well balanced in terms of important variables such as disease-free survival, performance status, age, menopausal status, and the type of first-line chemotherapy (anthracycline-based regimens versus cyclophosphamide-methotrexate-5-fluorouracil). The estrogen receptor (ER) content, measured by means of immunohistochemical assay, was markedly different in the two groups, with 27/47 tumors with low proliferative activity (57%) and 6/29 with high-proliferative activity (21%) being ER positive ( 45% of stained cells) (p = 0.003). Moreover, a significant difference in the metastatic pattern was also evident, with a higher incidence of bone and a lower incidence of soft tissue metastases in the group of patients with tumors with low proliferative activity (p = 0.004). Overall, 10/47 responses (21%: PR = 7, and CR = 3) were observed in the group with a low rate of proliferative activity, versus 14/29 (48%: PR = 9, and CR = 5) in the group with highly proliferative tumors, the difference being statistically significant (p = 0.03). When a multivariate analy-sis was performed, the only factor that retained independent prognostic significance was the predominant site of disease, particularly soft tissues (p = 0.003). Despite the difference in response rate, when survival analysis was performed according to the Kaplan-Meier method, no significant difference was observed in the two groups, but when the analysis was limited to responsive patients, the median survival observed in those with a low and those with a high rate of proliferation was 35 and 19 months respectively (p = 0.02). The same results were obtained when multivariate survival analysis was carried out using Cox's regression model. These data suggest that there is a link between tumor proliferative activity and response to chemotherapy in advanced breast cancer, and may indicate the need to use more intensive treatments in selected patients with highly proliferative tumors.Presented in part at the Annual Meeting of the American Society of Clinical Oncology, May 14–17, 1994, Dallas, TX, USA     

Insulin resistance in the aged: a quantitative evaluation of in vivo insulin sensitivity and in vitro glucose transport

It has recently been made clear that reduced sensitivity to exogenous insulin can be demonstrated in the course of aging. This phenomenon has been further investigated with the aid of sophisticated techniques, such as the euglycemic clamp, which, when coupled with the measurement of hepatic glucose production, showed that "impaired tissue sensitivity to insulin is the primary factor responsible for the decrease of glucose tolerance in advancing age." Nevertheless, this study did not establish whether such impairment reflects reduced sensitivity (receptor deficiency) or reduced response (postreceptor or receptor plus postreceptor defect), as shown in other diseases. Evidence in favor of the view that receptor deficiency is responsible can be seen in our observation of an approximately 50% reduction in receptors in a study of insulin binding on isolated human fat cells. Two aspects of this question appeared to require further investigation: tissue sensitivity to receptor-saturating insulin concentration (euglycemic clamp at about 1000 microU/mL plasma insulin), and the glucose transport system coupled to the receptor. A decrease in receptors alone should shift the insulin sensitivity curve to the right, both in vivo (euglycemic clamp) and in vitro (glucose transport), with no reduction of the maximum effect. A solution to this question is proposed in the light of a study conducted on young volunteers and subjects over 65 years old.     

Experimental brain tumors by transplacental ENU

Summary Experimental cerebral tumors have been induced by transplacental ENU. The morphologic study of the brains of treated rats revealed that cellular hyperplasias appear at the 30th day of extrauterine life in the paraventricular white matter, i.e., before the already known early neoplastic proliferations. Cytofluorimetric investigations failed to demonstrate differences between treated and control rats during the 1st month. On the contrary, adenylate cyclase activity is very high in that period. The duration of the latency period is discussed.This research was supported by Grants No. 79.00678.96 and No. 79.00664.96 of Progetto Finalizzato Control of Neoplastic Growth, Consiglio Nazionale delle Ricerche (C.N.R.), Rome     

Home health audit tool--at last!

Dissatisfied with the use of an audit tool not applicable to home health nursing, administrators of the Missoula Home Health Agency formed a special audit committee to review audits used by agencies around the country. After examining 50 audit tools, the committee agreed that the Phaneuf public health nursing audit did not adequately emphasize nursing care and charting specific to home health agencies but did fit most of their criteria. After redesigning the Phaneuf audit and testing it through two quarterly audits, the new Missoula Home Health Audit tool has been found very satisfactory. The Missoula Audit emphasizes: 1. home health's goal of independent living and/or self-care; 2. service provider-family-patient relationship; 3. nurse-physician relationship; 4. charting and recording; 5. coordination of careproviders. Unlike many existing audit tools, the Missoula Audit is specific to home health nursing, covers the spectrum of home health services, has sensitive scoring which reflects true differences in quality of care, and initially, at least, appears to be consistent from audit to audit.     

Systolic arterial pressure determination by a new pulse monitor technique

The Doppler ultrasound (DUS) technique is a widely accepted non-invasive technique to estimate systolic blood pressure (SBP) accurately in paediatric patients. The DUS has a number of limitations. A new pulse monitor, Mr Pulse (MP), operating on the principle of a finger plethysmograph, was developed to offer an alternative technique to estimate SBP. From 104 paired SBP measurements taken in 16 paediatric patients undergoing general anaesthesia, SBP determined by the MP technique correlated closely with that by the standard DUS technique (r2 = 0.98). Analysis of degree of agreement performed indicated that there was good agreement between SBP obtained by the MP and the DUS techniques. The mean +/- standard deviation of differences in paired SBP values between the two measurement techniques was 0.55 +/- 3.59 mmHg. Mr Pulse is as accurate as the DUS technique in estimating SBP and has the advantage of less critical sensor positioning as it is not subject to electrical interference. It has no electrical hazard.     

The role of spontaneous portosystemic shunts in the course of orthotopic liver transplantation

Spontaneous portosystemic shunts are commonly found in cirrhotic patients. Not yet established is their role after orthotopic liver transplantation (OLTx), especially when an increase in portal pressure develops, as during early acute rejection. In this study, 34 cirrhotic patients in a series of 70 OLTx are considered. Each patient had preoperative angiographic assessment, and, in 21 (62%), large spontaneous portosystemic shunts were evident. In 12 cases the shunts were not affected by the surgical procedure and were present during the postoperative period; in 9 the hepatectomy itself involved interruption of the shunts. The patient population was divided into two groups: patients with postoperative shunts (n=12) and those without (n=22). The two groups were similar in age, sex, Child's stage, transplantation variables, and number and grade of rejection episodes. However, mean transaminases (AST) values in the first 2 weeks were significantly higher levels in shunt versus nonshunt patients (421±335 vs 183±126; P<0.025), and this was even more evident when rejection occurred (626±375 vs 195±129; P<0.001). Furthermore, during an acute rejection reaction, three cases showed a true steal phenomenon through the large reopened shunts with ischemic damage to the grafts. The data indicate a possible detrimental effect of the spontaneous shunts on graft perfusion and suggest the prophylactic surgical interruption of the residual shunts during the transplantation.