Response of adolescent bonnet macaques to an acute fear stimulus as a function of early rearing conditions.

When primate infants are reared during the first half-year of life in an environment in which their mothers face uncertain requirements for food procurement (variable foraging demand [VFD]), long-lasting behavioral and neurodevelopmental consequences ensue, including increases in timidity and social subordinance as well as alterations in stress-related neuroendocrine profiles. We examined the nature and persistence of the effects of VFD rearing by exposing VFD-reared and normally reared adolescent bonnet macaques to a mild fear-provoking stimulus 2 years after the end of differential rearing. VFD-reared subjects at baseline were less gregarious than normally reared monkeys. VFDs also were considerably less responsive to the fear stimulus, and their behavior and affect returned to baseline levels more quickly than normally reared subjects. The extent and persistence of the sequelae of VFD rearing suggest parallels with predisposing factors in human anxiety disorders.

Effects of LY354740, a novel glutamatergic metabotropic agonist, on nonhuman primate hypothalamic-pituitary-adrenal axis and noradrenergic function.

The search for novel anxiolytics and antidepressants has focused on compounds with the potential to reduce excessive hypothalamic-pituitary-adrenal (HPA) axis activity. L-glutamate, an excitatory neurotransmitter ubiquitously present within the central nervous system, conceivably plays an important role in activating the neural sites involved in stress modulation. Deactivation of the HPA axis by glutamatergic neurotransmission modulation may represent a novel therapeutic approach. Accordingly, the acute intravenous effects of the novel metabotropic (mGlu2/3) agonist LY354740 were tested on bonnet macaques (Macaca radiata) undergoing acute infusions of yohimbine, a noradrenergic stimulant. Dependent measures were the magnitude of the increase of plasma cortisol and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) customarily elicited by yohimbine. Next, the effects of 6 weeks of chronic oral administration of LY354740 on baseline (postcapture) plasma cortisol and MHPG levels in comparison to the identical measure in untreated controls were assessed. Subjects chronically treated with LY354740 received yohimbine infusions which were compared to yohimbine infusions and saline infusions in non-LY354740-treated subjects. Preliminary evidence supports the view that acute LY354740 infusion resulted in a marked diminution of yohimbine-induced stress response, as manifest by a substantial attenuation of cortisol and MHPG response observed in comparison to the saline-treated yohimbine condition. Chronic oral administration of LY354740 led to postcapture baseline cortisol levels which were markedly reduced (approximately 50 percent) in comparison to untreated control subjects; however, there were no significant parallel differences in MHPG levels. Yohimbine infusions elicited an increase in cortisol and MHPG levels in both LY354740-treated and non-LY354740-treated subjects, in comparison to declines in cortisol values observed following vehicle infusions (group X time interaction; P<.0001). Chronic LY354740-treated subjects failed to achieve cortisol levels comparable in range to those of untreated subjects primarily because of their low baseline cortisol levels. In contrast, despite equivalent baselines, yohimbine-induced MHPG values were increased overall in the chronically treated group compared to the saline and yohimbine-alone groups. Thus, LY354740 markedly reduced the acute corticoid and noradrenergic response elicited by yohimbine infusion. Chronic administration of LY354740 appears to present a safe and effective mechanism to markedly down-modulate the HPA axis while retaining noradrenergic responsivity.

Growth hormone response to clonidine in adversely reared young adult primates: relationship to serial cerebrospinal fluid corticotropin-releasing factor concentrations.

A reduction of the growth hormone (GH) response to the alpha(2) adrenergic agonist clonidine is a neuroendocrine abnormality observed with reasonable consistency among human patients with mood and anxiety disorders. In previous primate studies, in comparison to predictably reared controls, monkeys exposed as infants to maternal variable foraging demand (VFD) rearing exhibited persistent elevations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF), as well as other biological disturbances. As CRF has been demonstrated to inhibit GH release, the authors hypothesized that within VFD-reared subjects, animals with relatively high CRF concentrations would exhibit relatively diminished GH responses to clonidine. The current study examined the relationship between the GH response to clonidine in VFD-reared adult primates in relation to a range of both juvenile and follow-up CSF CRF concentrations. Nine bonnet macaques (Macaca radiata) were given ascending dosages of clonidine under ketamine anesthesia. Plasma samples for GH-like immunoreactivity were obtained throughout the session. A significant positive correlation was noted between juvenile CSF CRF concentrations and the levels of the neuropeptide observed in young adults. The mean of the serial CSF CRF concentrations exhibited a significant inverse relationship towards the GH response to clonidine in young adulthood, with relatively high CSF CRF associated with relatively attenuated GH responses to clonidine. These data raise the possibility that a reduced GH response to clonidine may inversely reflect trait-like increases of central nervous system (CNS) CRF activity.

Cerebrospinal fluid concentrations of somatostatin and biogenic amines in grown primates reared by mothers exposed to manipulated foraging conditions.

BACKGROUND: In an earlier study, infant primates were nursed by mothers randomly assigned to variable foraging demand (VFD) or nonvariable foraging conditions (non-VFD). A group of grown VFD-reared subjects demonstrated elevations of cisternal cerebrospinal fluid (CSF) corticotropin-releasing factor concentrations and decreased CSF cortisol levels vs non-VFD counterparts. To further characterize neurobiological sequelae of disturbed early rearing, CSF concentrations of serotonin, dopamine, and norepinephrine metabolites (5-hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol [MHPG], respectively) and of somatostatin were determined. METHODS: Second CSF taps were obtained from the previously studied cohort of 30 subjects and from 28 age-matched ad libitum-reared control subjects. Relevant assays were performed. RESULTS: All neurochemicals assayed except MHPG were elevated in the VFD-reared compared with non-VFD subjects. In the VFD group, statistically significant positive correlations between corticotropin-releasing factor and each neurochemical was found, except for MHPG. In the non-VFD subjects, no significant correlations with corticotropin-releasing factor were observed. No effect of age was evident. CONCLUSIONS: Reducing the predictability of maternal foraging demand during early rearing was associated with elevations of cisternal somatostatin and of serotonin and dopamine metabolite concentrations in grown offspring. The corticotropin-releasing factor elevations reported previously were positively correlated with all the elevated CSF parameters of the current study. The findings support the notion that adverse early rearing experiences in primates have longstanding and complex effects on a range of neurochemicals relevant to emotional regulation. Replication in prospective age-controlled studies is warranted.

Cholesterol screening using the school as a worksite.

This article illustrates the appropriateness of the school as a worksite for health promotion programs and demonstrates how cholesterol screening is an effective tool to introduce such a program into a school system. Of 1,639 employees, 1,217 elected to have their cholesterol measured (74% response rate). Forty-five percent had elevated cholesterol according to the NIH Consensus Panel. Of these, 12% were in the "high" category (greater than or equal to 240 mg/dl) while 33% had levels that placed them in the "borderline high" risk category (200-239 mg/dl). Cholesterol screening can be incorporated easily into most school systems due to the presence of nursing staff and health educators. Systematic planning is essential for success and must include a counseling and educational intervention coupled with an active referral and follow-up program. This type of screening should be part of a multicomponent health promotion program.

Multivariate statistics in oncology: a review.

In recent years multivariate analysis has been applied to the study of prognosis, diagnosis, and treatment in cancer patients. This form of analysis has provided investigators with a method to interpret increasingly complex data sets. In the current review, multivariate procedures such as the Cox proportional hazards model, logistic regression, and stepwise regression analysis are examined and compared with emphasis on the advantages and disadvantages of each procedure. Guidelines for the proper usage and interpretation of results are presented.

Anonymous human immunodeficiency virus surveillance and clinically directed testing in a Newark, NJ, hospital.

From September 1988 to August 1989, in a university hospital in Newark, NJ, 3529 serum and plasma specimens from patients with admitting conditions presumably not associated with human immunodeficiency virus (HIV) infection (Centers for Disease Control, Atlanta, Ga, Sentinel Hospital Surveillance System criteria) were tested anonymously for the presence of type 1 HIV (HIV-1) antibody. Of these specimens, 269 (7.6%) were confirmed HIV-1 seropositive. Overall, 10.3% of male patients and 4.8% of female patients were seropositive. Persons 25 to 44 years old had the highest HIV-1 seroprevalence- 20.9% for male and 7.5% for female patients. Based on this anonymous testing, the number of HIV-infected hospitalized patients discharged in 1988 was estimated. Data on hospital-confirmed HIV-infected patients tested on the basis of clinical suspicion suggest that only 40% of HIV-infected patients were actually tested for HIV-1 infection as part of their medical care in this hospital. These data demonstrate a high prevalence of HIV infection in this patient population and suggest that hospitals serving populations with a high HIV seroprevalence offer routine screening for HIV infection as part of good medical care.

Nuclear morphometry as a prognostic indicator in colorectal carcinoma resected for cure.

The prognostic value of nuclear morphometry in addition to clinical and pathologic features was retrospectively studied in 64 cases of colorectal carcinoma resected for cure with a minimum of five years of follow-up. By univariate analysis, patient outcome was found to correlate with the presence of serosal involvement (P = .003), the presence of lymph node involvement (P = .01), the number of involved lymph nodes (P = .0001) and the mean nuclear area (P = .02). With multivariate analysis, only the number of involved lymph nodes significantly correlated with the survival (P = .0001). In a subsequent multivariate model expressing lymph node status as the presence or absence of metastasis, the presence or absence of serosal involvement and the mean nuclear area were both found to independently correlate with the outcome (P = .003 and P = .02, respectively). Linear regression analysis revealed significant colinearity between the mean nuclear area and the number of involved lymph nodes (P = .03). Accelerated failure time models based on determination of serosal involvement and then either specification of the number of involved lymph nodes or calculation of the mean nuclear area were of comparable predictive value to the determination of the number of involved lymph nodes alone. The former appeared to be better at identifying a subgroup of patients with good prognosis. This study demonstrates that two or more models based on pathologic features may be of comparable predictive value in colorectal carcinoma resected for cure, including models that incorporate mean nuclear area.

Cellularity in breast carcinoma.

Tumor cellularities were observed in 23 consecutive cases of infiltrating ductal carcinoma of the breast and correlated with other morphometric, pathologic, and clinical features. The cellularity mean index (CMI), defined as the percentage of tumor volume occupied by invasive tumors cells, was found to correlate with lymph node involvement by tumor (P = 0.03) and the number of mitotic figures per ten high-power fields (P = 0.0002). The CMI also correlated with mitotic activity (P = 0.01) when the latter was expressed as the percentage of tumor cells actively in mitosis, thus correcting for differences in cellularity between individual tumors. The relationship between cellularity and mitotic activity is discussed.

Prognostic value of morphometry in papillary thyroid carcinoma.

The value of morphometric analysis in addition to standard prognostic indicators was studied in 28 cases of papillary thyroid carcinoma. Standard features included age, sex, lymph node status, tumor size, and encapsulation. The mean follow-up was 47 months (maximum, 140 months). Recurrences were documented in six patients at a mean time of 34 months; five patients recurred with distal metastases and one patient recurred with local disease. Univariate analysis most closely associated tumor recurrence with nuclear anisotropism (the standard deviation of the estimated nuclear area [ENASD]) and tumor size. With forward stepwise incremental analysis, the value of tumor size was lost and only the ENASD and the cellularity mean index (CMI), defined as the percentage of tumor volume composed of tumor cells, significantly correlated with recurrence. Fifty-five percent of patients with an ENASD greater than 17 microns2 and a CMI greater than 40% developed recurrence as compared with 5% of patients with lesser values (P = .0001). Morphometric analysis may significantly contribute to the role of histopathology in the evaluation of papillary thyroid carcinoma and may also provide information regarding prognosis not obtained by standard methods.

A pilot study on cholesterol screening in the school environment.

A newly-developed analyzer measures total cholesterol from a single drop of blood and gives results within minutes. This procedure has made mass cholesterol screening inexpensive and less invasive than methods requiring a venipuncture blood sample, and it offers the opportunity for on-the-spot counseling and referral. In a pilot study, 610 high school students in the Victoria (Tex.) School District were screened for elevated cholesterol. Eighteen percent were found to have cholesterol levels above 180 mg/dl. Mean cholesterol values were higher for females than males, and higher for blacks and Hispanics than whites. Follow-up questionnaires indicated students and their parents understood the basic relationship between cholesterol and cardiovascular disease and how to modify their diet to reduce cholesterol intake. Telephone contact with parents of students with elevated cholesterol showed only about 27% of students with elevated cholesterol had visited a physician subsequent to the cholesterol testing.

Cocaine as a discriminative stimulus for responding maintained by food in squirrel monkeys.

Squirrel monkeys were trained in a choice procedure to discriminate a dose of 100 micrograms/kg cocaine from saline. Following an injection of cocaine, responding on the right lever was reinforced with food, whereas following an injection of saline, responding on the left lever was reinforced with food. A high degree of stimulus control (100% correct) was established within 20 experimental sessions. The dose-response function of cocaine on lever choice was then determined. When intermediate doses (10, 25 and 50 micrograms/kg) were administered prior to test sessions, a dose-dependent generalization decrement was seen. One monkey was found to discriminate as low as 25 microgram/kg cocaine from saline.

Relationship between plasma lipid concentrations and coronary artery disease in 496 patients.

The relationship between fasting plasma cholesterol and triglyceride concentrations and the frequency and extensiveness of coronary artery disease (CAD) was studied in 496 subjects evaluated for chest pain by coronary arteriography at The Methodist Hospital. One hundred six of the patients had no CAD while 390 had 25% or greater stenosis of one or more major vessels. Ninety-one percent had 75% or greater stenosis of at least one major vessel. Mean age for the group with CAD was 55.7 +/- 8.7 and without disease 49.4 +/- 11.6 (P less than 0.01). Both cholesterol and triglyceride concentrations were higher (P less than 0.001) in the group with CAD. Mean cholesterol concentration in males increased from 195 +/- 36 mg/dl in the group without CAD to 219 +/- 41 in the group with three vessel disease and in females from 207 +/- 40 to 252 +/- 42. A progressive increase in triglyceride values was also detected but was less consistent. At the level of 25% and greater obstruction, the partial correlation coefficients between the number of vessels involved and the cholesterol and triglyceride concentrations, respectively, were +0.201 and +0.181.

A dipole plus quadrupole lead system for human electrocardiography.

A lead system was constructed to extract dipole and quadrupole components of cardiac sources from surface electrocardiograms (ECGs) recorded at 16 sites. The lead system was based on an analysis of a computerized model of a multipole equivalent cardiac generator in a homogeneous torso. The model was previously determined from extensive geometric and electrocardiographic data obtained from one subject. Dipole components estimated with the lead system were 89% accurate for the original subject. Evaluation of the lead system on this subject and in 59 other subjects included calculation of the effect of non-dipolar sources on the values of the estimated dipole components, comparison of the consistency of equivalent sources found independently at two origins in the heart region, and reconstruction of ECGs from lead system components. Dipole consistency at the origins was maintained over the wide range of age, weight, and body shape which characterized the subject population. Whereas quadrupole terms did not agree as well as the dipole terms, inclusion of the quadrupole reduced ECG reconstruction errors by a factor of about three compared to errors for the dipole alone. Together, the dipole and quadrupole accounted for almost 90% of the electrocardiographic information measured on the body surface with the D/Q lead system.

Effect of praseodymium nitrate on hepatocytes and Kupffer cells in the rat.

Intravenous administration of the rare earth metal salt, praseodymium nitrate, induced hepatic damage in the rat, as assessed by morphologic examination (light and electron microscopy) and biochemical parameters (serum glutamic-pyruvic transaminase (EC 2.6.1.2) and glutamic-oxalacetic transaminase (EC 2.6.1.1) activity as well as hepatic triglyceride content). Praseodymium hepatotoxicity was only attained with lower doses (10, 20, or 40 mg/kg), whereas a larger dose (80 mg/kg) was inactive in this respect. As detected by electron microscopy, lower doses of the metal salt caused hepatocytic alterations consisting of degranulation and dilatation of rough endoplasmic reticulum, accumulation of smooth endoplasmic reticulum as well as numerous lipid droplets. No abnormalities were detected in the cell organelles following administration of a large dose of the metal salt; however, vacuoles containing markedly electron-dense material were seen in the cytoplasm of the hepatocytes and the sinusoidal Kupffer cells.