Motivated behavior and the estrous cycle in rats

(1) The estrous cycle in the rat may be used to study recurrent changes in motor behaviors and motivation which are strongly related to cyclic hormonal and CNS changes. (2) The peak in motivated behaviors occurs during a sharply defined period on the night between proestrus and estrus and is evident in facilitated wheel-running, lordosis, and intracranial self-stimulation. (3) Behaviors without a clearly motivated character do not show an estrous cyclicity. (4) The estrous cyclic variation in intracranial self-stimulation was observed at a specific locus — the pars campacta of the substantia nigra. (5) A neurochemical link between sexually motivated behavior, wheel running and intracranial self-stimulation is suggested. This link is in part dopaminergic but is probably also activated by many other systems.     

State and output feedback design for robust tracking of linear systems with rate limited actuators

A design technique (Control of Uncertain Systems with Bounded Inputs, Tarbouriech S, Garcia G, (Eds), Lecture Notes in Control and Information Sciences, vol. 227 , Springer: Berlin, 1997; 173–186) recently proposed for stabilization of a linear system with rate‐limited actuators is utilized to design feedback laws that cause the system output to track a desired command signal. This design technique combines two design techniques recently developed for linear systems with position limited actuators, piecewise‐linear LQ control (Automatica, 1994; 30 : 403–416) and low‐and‐high gain feedback (IEEE Trans. Automat. Control, 1996; 41 : 368–378), and hence takes advantage of both design techniques, while avoiding their disadvantages. In the case that only the output is available for feedback, the performance of the state feedback law is preserved by the use of a fast observer. An open‐loop exponentially unstable fighter aircraft is used to demonstrate the effectiveness of the proposed control design method. Copyright © 2002 John Wiley & Sons, Ltd.     

Pharmacokinetics of a valpromide isomer,valnoctamide, in healthy subjects

Summary The pharmacokinetics of a single 400 mg oral dose of valnoctamide (VCD) has been investigated in seven healthy, adult, male volunteers. VCD was not biotransformed rapidly to its corresponding acid valnoctic acid (VCA), unlike its isomer valpromide (VPD). It had a mean residence time of 13.2 h and a terminal half-life of 9.3 h. Throughout the study, only low plasma levels of VCA could be detected. Thus, unlike VPD, which is a prodrug of the corresponding acid, (valproic acid, VPA). VCD appears to act as a drug in its own right, and it does not undergo similar hydrolysis. The pharmacokinetic difference may account for the different pharmacological activities of the two isomers.     

The logical structure and validity of experimental designs in pharmacokinetics and clinical pharmacology

Much of the literature on research design in clinical pharmacology and pharmacokinetics emphasizes statistical concerns, thus suggesting that a primary ingredient of a valid research design is an appropriate plan for statistical analysis of data. However, statistical validity is only one of several ways to evaluate an experimental study. The present paper reviews the underlying logic and sources of invalidity of experimental drug research suggesting influences and factors which may deceive or lure an experimenter into erroneous conclusions.     

Plasma C-peptide and cognitive performance in older men without diabetes.

BACKGROUND: Emerging evidence suggests that type 2 diabetes may be related to diminished cognition, but little data are available directly regarding the role of insulin levels. OBJECTIVE: The objective of this prospective cohort study was to examine the relation of insulin secretion to cognitive function among men without diabetes. SETTING: The study setting was the Physicians' Health Study-U.S. male physicians. PARTICIPANTS: Three hundred sixty-seven men who provided blood samples in 1982, when they had no lifetime history of diabetes and ranged in age from 47-65 years (mean age: 57 years). MEASUREMENTS: The authors assayed plasma C-peptide, reflecting insulin secretion, in the stored blood samples. Beginning in 2001, an average 18 years after blood collection, the authors administered telephone interviews, including tests of general cognition (Telephone Interview of Cognitive Status [TICS]), verbal memory, and category fluency. The authors used regression models to estimate mean differences in cognitive performance across levels of C-peptide controlling for a wide variety of potential confounding factors. RESULTS: On the TICS, men in the top tertile of C-peptide performed significantly worse than those in the bottom (multivariable-adjusted mean difference: -1.01 points, 95% confidence interval: -1.78 to -0.24); this apparent impact of C-peptide on cognition was equivalent to the cognitive differences the authors observed between men 6 years apart in age. Performance on the global score (combining results from all the individual tests) and verbal memory score (combining results from four tests of verbal memory) appeared lower among men in the highest C-peptide tertile, but results were not statistically significant. CONCLUSION: Higher midlife insulin secretion may be related to decreased later-life cognitive function, even among men without diabetes.     

A preliminary investigation into the long-term injury consequences reported by retired baseball players

Seventy-five retired baseball players participated in a survey (37.8% response rate) in order to establish the long-term consequences of injuries sustained during their playing careers. Respondents had a mean age of 55.8 (+/-11.4) years with a mean age of 41.3 (+/-11.4) years at retirement from play. The mean overall rate of injury suffered per player/playing career was 5.6 (+/-7.1). 54.7% of respondents experienced a major injury (i.e. injury resulting in 5 or more consecutive weeks absence from training and play) with a mean major injury per player/playing career of 1.5 (+/-2.2). The rate for significant injuries (i.e. injury resulting in more than 1 week but less than 5 weeks absence from training and play) was 4.1 (+/-6.5) per player/playing career. Catchers had significantly less injuries than all other positions (p=0.027). 18.7% of all respondents reported suffering from arthritis, 24% from restricted joint mobility and 4% from chronically stiff fingers; all of these conditions were associated with their participation in baseball based on medical examination by their GP or medical specialist. 29.3% of respondents indicated that they had incurred additional medical costs and 12% reported significant loss of income associated with their injuries. Some injuries were severe enough that they resulted in extended stays in hospital producing costs carried by the health care system.     

MRI demonstration and CT correlation of the brain in patients with idiopathic intracerebral calcification

Twenty-two patients aged 36–63 years were diagnosed as having Fahr's syndrome on the basis of the presence on CT of unexpected extensive calcification of the basal ganglia. Even when associated with calcification of other brain areas, the main diagnostic criterion remained basal ganglia calcification larger than 800 mm². Normal values of parathormone, serum calcium and phosphorus excluded hypercalcaemia and hypoparathyroidism. Mitochondrial CNS disease was excluded clinically. MRI and repeated CT and neurological examination were performed in all of the patients. The patients were divided into two groups: neurologically asymptomatic (group 1) and neurologically symptomatic (group 2). T2-weighted sequences demonstrated hyperintense areas in all of the patients involving the white and the grey matter of the brain. In group 1 the hyperintense lesions were significantly smaller than in group 2. The neurological symptoms correlated better with the hyperintensities on T2-weighted MR images than with the calcification demonstrated on CT. Hyperintensities in T2-weighted MRI and the areas shown by CT to have calcification had different locations. In 15 patients with dementia, the white matter of the entire centrum semiovale was bilaterally hyperintense. In another 3 patients with hemiparesis, hyperintense areas in the internal capsule, contralateral to the side of hemiparesis, were demonstrated in the T2-weighted sequence. The hyperintense T2 signals may reflect a slowly progressive, metabolic or inflammatory process in the brain which subsequently calcifies and are probably responsible for the neurological deficit observed.     

Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma

Glioblastoma (GBM) has explosive biologic properties with rapid clinical progression leading to death. Its distinguishing pathologic features, necrosis with surrounding pseudopalisades and microvascular hyperplasia, are believed to be instrumental to its accelerated growth. Microvascular hyperplasia arises in response to the secretion of proangiogenic factors by hypoxic pseudopalisades and allows for peripheral neoplastic expansion. Mechanisms underlying necrosis and hypoxia remain obscure, but vaso-occlusive and prothrombotic contributions could be substantial. Recent investigations on the origin of pseudopalisades suggest that this morphologic phenomenon is created by a tumor cell population actively migrating away from a central hypoxic region and that, in at least a significant subset, hypoxia-induced migration appears due to vaso-occlusion caused by intravascular thrombosis. Both vascular endothelial growth factor induced vascular permeability to plasma coagulation factors and the increased neoplastic expression of tissue factor likely contribute to a prothrombotic state favoring intravascular thrombosis. In addition to prothrombotic mechanisms, vaso-occlusion could also result from angiopoietin-2-mediated endothelial cell apoptosis and vascular regression, which follows neoplastic co-option of native vessels in animal models of gliomas. Vaso-occlusive and prothrombotic mechanisms in GBM could readily explain the presence of pseudopalisades and coagulative necrosis in tissue sections, the emergence of central contrast enhancement and its rapid peripheral expansion on neuroimaging, and the dramatic shift to an accelerated rate of clinical progression. Since the hypoxic induction of angiogenesis appears to support further neoplastic growth, therapeutic targeting of the underlying vascular pathology and thrombosis could provide a new means to prolong time to progression.