Prognostic Utility of Disproportionately Enlarged Subarachnoid Space Hydrocephalus in Idiopathic Normal Pressure Hydrocephalus Treated with Ventriculoperitoneal Shunt Surgery: A Systematic Review and Meta-analysis.

BACKGROUND: Disproportionately enlarged subarachnoid space hydrocephalus is a specific radiologic marker for idiopathic normal pressure hydrocephalus. However, controversy exists regarding the prognostic utility of disproportionately enlarged subarachnoid space hydrocephalus. PURPOSE: Our aim was to evaluate the prevalence of disproportionately enlarged subarachnoid space hydrocephalus in idiopathic normal pressure hydrocephalus and its predictive utility regarding prognosis in patients treated with ventriculoperitoneal shunt surgery. DATA SOURCES: We used MEDLINE and EMBASE databases. STUDY SELECTION: We searched for studies that reported the prevalence or the diagnostic performance of disproportionately enlarged subarachnoid space hydrocephalus in predicting treatment response. DATA ANALYSIS: The pooled prevalence of disproportionately enlarged subarachnoid space hydrocephalus was obtained. Pooled sensitivity, specificity, and area under the curve of disproportionately enlarged subarachnoid space hydrocephalus to predict treatment response were obtained. Subgroup and sensitivity analyses were performed to explain heterogeneity among the studies. DATA SYNTHESIS: Ten articles with 812 patients were included. The pooled prevalence of disproportionately enlarged subarachnoid space hydrocephalus in idiopathic normal pressure hydrocephalus was 44% (95% CI, 34%-54%). The pooled prevalence of disproportionately enlarged subarachnoid space hydrocephalus was higher in the studies using the second edition of the Japanese Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus compared with the studies using the international guidelines without statistical significance (52% versus 43%, P = .38). The pooled sensitivity and specificity of disproportionately enlarged subarachnoid space hydrocephalus for prediction of treatment response were 59% (95% CI, 38%-77%) and 66% (95% CI, 57%-74%), respectively, with an area under the curve of 0.67 (95% CI, 0.63-0.71). LIMITATIONS: The lack of an established method for assessing disproportionately enlarged subarachnoid space hydrocephalus using brain MR imaging served as an important cause of the heterogeneity. CONCLUSIONS: Our meta-analysis demonstrated a relatively low prevalence of disproportionately enlarged subarachnoid space hydrocephalus in idiopathic normal pressure hydrocephalus and a poor diagnostic performance for treatment response.

Chronic psychosocial stress impairs learning and memory and increases sensitivity to yohimbine in adult rats.

BACKGROUND: It is well known that intense and prolonged stress can produce cognitive impairments and hippocampal damage and increase noradrenergic activity in humans. This study investigated the hypothesis that chronic psychosocial stress would affect behavior, drug sensitivity, and hippocampal-dependent learning and memory in rats. The work provides a novel connection between animal and human studies by evaluating the effects of stress on a rat's response to yohimbine, an alpha(2) adrenergic receptor antagonist. METHODS: Rats were exposed to a cat for 5 weeks and randomly housed with a different group of cohorts each day (psychosocial stress). The effects of the stress manipulations were then assessed on open field behavior, spatial learning and memory in the radial arm water maze and the behavioral response to a low dose of yohimbine (1.5 mg/kg). RESULTS: Stressed rats displayed impaired habituation to a novel environment, heightened anxiety, and increased sensitivity to yohimbine. In addition, the stressed rats exhibited impaired learning and memory. CONCLUSIONS: There are commonalities between the current findings on stressed rats and from studies on traumatized people. Thus, psychosocial stress manipulations in rats may yield insight into the basis of cognitive and neuroendocrine disturbances that commonly occur in people with anxiety disorders.

Structural characteristics of size-controlled self-aggregates of deoxycholic acid-modified chitosan and their application as a DNA delivery carrier.

Precise control of the size and structure is one critical design parameter of micellar systems for drug delivery applications. To control the size of self-aggregates, chitosan was depolymerized with various amounts of sodium nitrite, and hydrophobically modified with deoxycholic acid to form self-aggregates in aqueous media. Formation and physicochemical characteristics of size-controlled self-aggregates were investigated using dynamic light scattering, fluorescence spectroscopy, and computer simulation method. The size of self-aggregates varied in the range of 130-300 nm in diameter, and their structures were found to depend strongly on the molecular weight of chitosan ranging from 5 to 200 kDa. Due to the chain rigidity of chitosan molecule, the structure of self-aggregates was suggested to be a cylindrical bamboolike structure when the molecular weight of chitosan was larger than 40 kDa, which might form a very poor spherical form of a birdnestlike structure. To explore the potential applications of self-aggregates as a gene delivery carrier, complexes between chitosan self-aggregates and plasmid DNA were prepared and confirmed by measuring the fluorescence intensity of ethidium bromide and electrophoresis on agarose gels. The complex formation had strong dependency on the size and structure of chitosan self-aggregates and significantly influenced the transfection efficiency of COS-1 cells (up to a factor of 10). This approach to control the size and structure of chitosan-derived self-aggregates may find a wide range of applications in gene delivery as well as general drug delivery applications.

Cognitive effects of insulin in the central nervous system.

Evidence has been accumulating recently that the hormone insulin may modulate cognitive activity by acting in the central nervous system. Initially derived from the observation that insulin and insulin receptors are found in specific brain areas, this evidence also includes cognitive assessments of humans in insulin-deficient and insulin-resistant disease states and experimental manipulation of rodent models. Additional support is derived from in vivo and in vitro systems that are used to investigate the neurophysiological basis of learning and memory. This article is a brief review of the literature that suggests a connection between insulin and memory and draws together some of the findings relevant to possible physiological mechanisms for this cognitive effect.

Intracerebroventricular insulin enhances memory in a passive-avoidance task.

Previous studies have indicated a possible enhancing effect of hyperinsulinemia on certain cognitive tasks in human subjects. Further, brain areas important in these tasks have high concentrations of insulin receptors, suggesting that insulin might modulate memory by activity at specific central sites. Extending this observation to the laboratory rat would provide a convenient model system for determining factors important for this possible cognitive effect. The present experiment determined whether intracerebroventricular administration of insulin improves memory formation in rats. Long-Evans rats were trained on a step-through passive-avoidance task, in which they were either shocked or not after entering a darkened compartment. After training, the animals received an intracerebroventricular injection of 4 mU insulin, heat-deactivated insulin or saline vehicle. After 24 h, the animals were tested for retention of the task. Rats receiving insulin after being shocked had an increased latency to enter the dark compartment, compared to those rats that had received saline or heat-deactivated insulin after shock. This difference is consistent with an enhanced memory for the negative consequences of entering.

Preparation and solubility in acid and water of partially deacetylated chitins.

Partially deacetylated chitins with different degrees of deacetylation (DD) were prepared by alkaline treatment under homogeneous conditions, and the effect of DD on their solubility was discussed in terms of crystal structure and mode of hydrogen bonding. With an increase in the treatment time, the DD of chitin increased proportionally. The chitin became soluble in dilute acetic acid at the DD of ca. 28% or over and soluble in water at the DD of ca. 49%. The solubility of the partially deacetylated chitins had a close relationship with their crystal structure, crystallinity, and crystal imperfection as well as the glucosamine content. The wide-angle X-ray diffractometry (WAXD) revealed that the chitin with ca. 28% DD retained the crystal structure of alpha-chitin with significantly reduced crystallinity and perfection of the crystallites. The water-soluble chitin of ca. 49% DD had a new crystal structure similar to that of beta-chitin rather than either alpha-chitin or chitosan, suggesting that the homogeneous deacetylation transformed the crystal structure of chitin from the alpha to the beta form. Some hydrogen bonds existing in raw alpha-chitin were found to be missing at a DD of ca. 49%.

Exposing rats to a predator impairs spatial working memory in the radial arm water maze.

This series of studies investigated the effects of predator exposure on working memory in rats trained on the radial arm water maze (RAWM). The RAWM is a modified Morris water maze that contains four or six swim paths (arms) radiating out of an open central area, with a hidden platform located at the end of one of the arms. The hidden platform was located in the same arm on each trial within a day and was in a different arm across days. Each day rats learned the location of the hidden platform during acquisition trials, and then the rats were removed from the maze for a 30-min delay period. During the delay period, the rats were placed either in their home cage (nonstress condition) or in close proximity to a cat (stress condition). At the end of the delay period, the rats were run on a retention trial, which tested their ability to remember which arm contained the platform that day. The first experiment confirmed that the RAWM is a hippocampal-dependent task. Rats with hippocampal damage were impaired at learning the location of the hidden platform in the easiest RAWM under control (non-stress) conditions. The next three experiments showed that stress had no effect on memory in the easiest RAWM, but stress did impair memory in more difficult versions of the RAWM. These findings indicate that the capacity for stress to impair memory is influenced not only by the brain memory system involved in solving the task (hippocampal versus nonhippocampal), but also by the difficulty of the task. This work should help to resolve some of the confusion in the literature regarding the heterogeneous effects of stress on hippocampal-dependent learning and memory.

Taste aversion learning in fyn mutant mice.

Conditioned taste aversion (CTA) learning is a robust form of classical conditioning in which animals rapidly associate a flavor with aversive internal symptoms. The present study assessed CTA learning in transgenic mice deficient in a specific nonreceptor tyrosine kinase (the fyn mutant). Fyn mutants show impaired long-term potentiation and marked deficits in acquisition of spatial learning tasks. To assess whether they are also impaired in CTA learning, fyn mutant and wild-type mice received 2 conditioning trials consisting of access to a flavored solution followed by administration of LiCl. Fyn mutant mice acquired significant CTAs following a single conditioning trial and these aversions were comparable to those seen in wild-type mice. These results indicate that the fyn mutation does not interfere with the acquisition of CTAs and hence that this mutation is not associated with a global learning deficit.

A comparison of the effects of food deprivation and 2,5-anhydro-D-mannitol on metabolism and ingestion.

Using respiratory quotient as an index of metabolic state, we compared the effects of administrations of the fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) at a dose of 300 mg/kg with the effect of 10 h of food deprivation. We measured behavioral and physiological responses of the animals receiving the two treatments, including food intake, energy expenditure, rates of carbohydrate and fatty acid utilization, and plasma levels of glucose, insulin, corticosterone, epinephrine, and norepinephrine. A vehicle-treated control group was also included. Fasting produced a greater food intake than 2,5-AM administration. Although plasma glucose, insulin, and norepinephrine levels were similar between the two treatments, plasma corticosterone and epinephrine levels were significantly elevated in animals receiving 2,5-AM. We conclude that although 2,5-AM can produce a metabolic state similar to fasting, as measured by an index of whole body metabolic state (respiratory quotient), there remain factors that influence food intake that are not similar in the two conditions.

The evaluation of insulin as a metabolic signal influencing behavior via the brain.

The intent of this paper is to evaluate decreases of food intake and body weight that occur when a peptide is administered to an animal. Using the pancreatic hormone insulin as an example, the case is made that endogenous insulin is normally secreted in response to circulating nutrients as well as in proportion to the degree of adiposity. Hence, its levels in the blood are a reliable indicator of adiposity. A further case is then made demonstrating that insulin is transported through the blood-brain barrier into the brain, where it gains access to neurons containing specific insulin receptors that are important in the control of feeding and metabolism. Finally, experimentally-induced changes of insulin in the brain cause predictable changes of food intake and body weight. Given these observations, the question is then asked: since endogenous insulin, acting within the brain, appears to decrease food intake, can a decrease of food intake caused by exogenous insulin administered into the same area of the brain be ascribed to the same, naturally-occurring response system, or should it be attributed to malaise or a non-specific depression of behavior? Arguments are presented supporting the former position that exogenous insulin, when administered in small quantities directly into the brain, taps into the natural caloric/metabolic system and hence influences food intake and body weight.

Whole body energy expenditure and fuel oxidation after 2,5-anhydro-D-mannitol administration.

The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) increases food intake in nondeprived rats. Several lines of evidence indicate that vagal signals arising from the liver are critical for this effect. In addition, 2,5-AM decreases plasma glucose and increases lipolysis, resulting in an increase in plasma free fatty acids and ketone bodies. In these respects 2,5-AM produces a state analogous to that observed after food deprivation. Using an indirect calorimeter, we determined that 2,5-AM (300 mg/kg ip) causes a potent and long-lasting decrease in respiratory quotient, indicating a decrease in the fraction of total energy derived from carbohydrate oxidation and an increase in the fraction derived from fatty acid oxidation. These metabolic variables were altered without affecting total metabolic rate. This dose of analogue also stimulated significantly greater food intake than injections of vehicle. These results support the continued use of 2,5-AM as a tool to probe the metabolic controls of food intake.

Chronic alcohol consumption increases sensitivity to the anorexic effect of cholecystokinin.

In this study we examined the ability of intraperitoneal cholecystokinin COOH-terminal octapeptide (CCK-8; 0.2, 0.6, and 2.0 micrograms/kg) to suppress food intake in rats that had consumed a control diet, 6-8 g.kg-1.day-1 of ethanol (EtOH) in sucrose, or sucrose alone for 6 mo. Both the EtOH- and sucrose-fed rats developed significant dietary obesity. After 3 mo, the EtOH group was significantly more sensitive to CCK-8 than the sucrose and control groups, while the responses of the sucrose and control groups were comparable. In contrast, after 6 mo the EtOH and sucrose groups' response to CCK-8 was no longer significantly different. After 6 mo there were no significant differences in basal or postprandial plasma CCK-8 levels. The sucrose group had significantly higher basal insulin levels than the control and EtOH groups, and postprandial insulin levels, relative to basal, were significantly elevated in the EtOH group. Basal glucose levels did not differ among groups. Postprandial glucose levels (relative to baseline) were significantly lower in the EtOH group compared with the other groups and in fact never rose above baseline levels. These results are consistent with the hypothesis that EtOH, when taken on a chronic basis, increases the sensitivity to CCK-8.

Effect of meal pattern during food restriction on body weight loss and recovery after refeeding.

The present study was designed to assess whether the pattern of meal feeding and the degree of caloric restriction have an effect on the body weights and refeeding patterns of restricted 4-month-old Long-Evans rats, relative to ad lib-fed controls. Four experimental groups of rats (n = 6 each) were put on different paradigms of food restriction, and a fifth group fed ad lib throughout served as controls. Twelve rats were restricted to receiving 50% of their mean baseline food intake, and 12 rats received only 70% of their baseline food intake. Each experimental group was further subdivided with one subgroup receiving all of their calories in one meal/day and the other with caloric intake equally divided into two meals/day. There was no statistical difference in the final body weights of the restricted groups. Although there appeared to be identical patterns of weight regain, none of the restricted groups ever reached the mean body weight of the controls because of an asymptotic leveling off of rate of body weight regain. Rats that had received 50% of baseline calories as two meals/day had significantly more adipose mass than did any other group. The present findings suggest that in the rat, refeeding and, hence, regulation, occurs to normalize rate of weight gain rather than absolute body weight.

Effect of diet-induced obesity and experimental hyperinsulinemia on insulin uptake into CSF of the rat.

We examined the hypothesis that the uptake of plasma insulin into cerebrospinal fluid (CSF) is saturable in two rat models. Dietary obese and control female Osborne Mendel rats received 24-h infusions of vehicle or insulin. CSF insulin levels in cafeteria- and chow-fed rats were comparable at all levels of plasma insulin (4.5 +/- 2.8, 7.6 +/- 2.4, and 23.9 +/- 6.4 microU/ml in cafeteria diet vs. 4.5 +/- 0.9, 6.8 +/- 1.1, and 17.0 +/- 4.0 microU/ml in chow rats). CSF insulin uptake as a percentage of plasma insulin decreased with increased plasma insulin in both groups. A similar relationship was observed in Wistar rats receiving 6-day infusions of vehicle or insulin (plasma insulin = 55 +/- 12 vs. 365 +/- 98 microU/ml; CSF/plasma insulin ratio = 0.022 +/- .007 vs. 0.013 +/- .006, respectively). Hyperinsulinemic Wistar rats did not demonstrate decreased brain capillary insulin binding vs. vehicle-infused controls. The results suggest that a saturable transport process contributes insulin transport into CSF in normal rats and that this process is not altered by moderate diet-induced obesity or hyperinsulinemia per se.

Intraventricular insulin reduces food intake and body weight of marmots during the summer feeding period.

The study presented below describes experiments that investigate the ability of insulin to inhibit food intake in awake, active marmots during the summer season. Our results suggest that increasing intraventricular insulin concentration during the summer active feeding period will cause a decrease in food intake and body weight of marmots. When infused with insulin into their lateral ventricles (Alzet #2002 minipumps), animals had significantly lower food intake as compared to their food intake during the control period. In addition, these animals lost body weight during the period of the insulin infusion. We suggest that during the summer when marmots are not hibernating and are actively feeding, brain insulin levels may play a role in regulating food intake.

Energy metabolism of the untrained muscle of elite runners as observed by 31P magnetic resonance spectroscopy: evidence suggesting a genetic endowment for endurance exercise.

The purpose of this study was to investigate whether genetically determined properties of muscle metabolism contribute to the exceptional physical endurance of world-class distance runners. ATP, phosphocreatine, inorganic phosphate, and pH were quantitatively determined by 31P nuclear magnetic resonance spectroscopy in the wrist flexor muscles of elite long-distance runners and sedentary control subjects. These muscles had not been exposed to any specific program of exercise training in either group of subjects. The "untrained" muscles were examined at rest, during two cycles of three grades of exercise, and in recovery. The flexor muscles of the athletes had higher concentrations of phosphocreatine and ATP than did those of the control subjects at rest and during exercise. The athletes' muscles possessed a higher capacity for generation of ATP by oxidative metabolism than did control subjects' muscles according to the following criteria: (i) high force output, 60% of maximum voluntary contraction, was more easily reached and better maintained in both exercise cycles; (ii) the ratio of inorganic phosphate to phosphocreatine rose less during exercise and recovered faster in the postexercise period; (iii) there was no loss of adenine nucleotides or total phosphate from the athletes' muscles but significant losses from the control subjects' muscles; and (iv) the pH decreased no more than 0.1 unit in the athletes' muscles during exercise, attesting to a relatively slow glycolysis and/or a rapid oxidation of lactate. In the muscles of the control subjects, on the other hand, the pH decreased nearly 0.4 unit early in the first exercise cycle, indicating a relatively fast glycolysis and/or slower oxidation of lactate. In the second exercise cycle, the pH returned to near normal in the control subjects' muscles, reflecting diminished lactate formation because of glycogen depletion and lactate washout by the high blood flow induced by exercise. By the end of the exercise program, the maximum voluntary contractile force for the control subjects had declined to less than 60% of the initial value. This decline could be explained best by exhaustion of the glycolytic contribution to muscle contraction. Therefore, the residual maximum strength provided a measure of the oxidative capacity to support contraction, as is discussed. In conclusion, we suggest that a greater oxidative capacity relative to glycolytic capacity for support of contraction in untrained muscle of world-class runners reflects a genetic endowment for physical endurance. Additional systemic effects of training cannot be completely excluded. 31P magnetic resonance spectroscopy provides a noninvasive method for assessing this endowment.

Functional pools of oxidative and glycolytic fibers in human muscle observed by 31P magnetic resonance spectroscopy during exercise.

Quantitative probing of heterogeneous regions in muscle is feasible with phosphorus-31 magnetic resonance spectroscopy because of the differentiation of metabolic patterns of glycolytic and oxidative fibers. A differential recruitment of oxidative and glycolytic fibers during exercise was demonstrated in 4 of 10 untrained young men by following changes in phosphate metabolites. Concentrations of inorganic phosphate (Pi), phosphocreatine, and ATP were estimated in the wrist flexor muscles of the forearm at rest, during two cycles of three grades of exercise, and in recovery. At high work levels (40% of maximum strength), two distinct Pi peaks were observed and identified with Pi pools at pH 6.9 and pH 5.9-6.4, respectively. These could be accounted for as follows. At the lowest level of work (using 20% of maximum strength), early recruitment primarily of oxidative (type I) and possibly some intermediate (type IIA) muscle fibers occurs with relatively little net lactate production and consequently little decrease in pH. At higher work loads, however, primarily glycolytic (type IIB) muscle fibers are recruited, which have relatively high net lactate production and therefore generate a second pool of Pi at low pH. ATP depletion (35-54%) and Pi losses accompanied the reduction in ability to perform during the first exercise cycle. When the cycle of graded exercise was repeated immediately, the total Pi remained high but gave rise to only one peak at pH 6.8-7.0. These observations indicated exhaustion of glycolytic type IIB fibers, removal of lactate by high local blood flow, and sustained contractions largely by oxidative type I and IIA fibers. A functional differentiation of fiber types could also be demonstrated during recovery if exercise was stopped while two pools of Pi were still apparent. In the first 3 min of recovery, the Pi peak at pH 6.8-6.9 disappeared almost entirely, whereas the Pi peak at pH 6.0 remained unaltered, reflecting the faster recovery of oxidative type I fibers. The potential of magnetic resonance spectroscopy to characterize oxidative and glycolytic fibers, predict capacity for aerobic performance, and signal the presence of muscle pathology is discussed.

Interactions of vitamin E and penicillamine in the treatment of hereditary avian muscular dystrophy.

Our prior work demonstrated that penicillamine treatment of dystrophic chickens delayed the onset of symptoms, partially alleviated contractures, improved muscle function, and lowered serum creatine kinase. Penicillamine, a sulfhydryl compound with reducing properties, also prevented inactivation of glycolytic enzymes by protecting thiol groups. The present study shows that vitamin E enhances the therapeutic effects of penicillamine. Interaction of these two reductants is dose related. With vitamin E as adjunct therapy, the dosage level of penicillamine could be lowered by 50%, thereby minimizing side effects. The therapeutic rationale for two antioxidants is that penicillamine may act primarily in the cytoplasm to prevent oxidative damage, whereas the more hydrophobic vitamin E may protect membrane bilayers. Additionally, penicillamine may prevent collagen cross-linking and, deposition of insoluble collagen in muscle and thus decrease contracture formation. General applications of combined penicillamine and vitamin E therapy are discussed regarding prevention of free radical and oxidative damage in Duchenne dystrophy and a wide range of human diseases.

Catecholamine activation of the membrane transport of long chain fatty acids in adipocytes is mediated by cyclic AMP and protein kinase.

Membrane transport of long chain fatty acids in the isolated adipocyte can be stimulated 5-10-fold by epinephrine (Abumrad, N. A., Perry, P. R., and Whitesell, R. R. (1985) J. Biol. Chem. 260, 9969-9971). This study shows that isoproterenol and norepinephrine are more potent than epinephrine in activating the transport process. The stimulatory effect on transport is mediated by beta-receptor interaction and cAMP. This was shown by the following. alpha-Receptor agonists and antagonists were ineffective; methylisobutylxanthine at low concentration (3 microM) potentiated the effect of a suboptimal dose (0.01 microgram/ml) of epinephrine and was stimulatory at high concentration (100 microM) in the absence of epinephrine; and cAMP analogs were very effective activators. Involvement of the cAMP-dependent protein kinase was indicated by two lines of evidence. 1) Combinations of cAMP analogs which are specific for sites 1 and 2 of the protein kinase, respectively, had synergistic effects on fatty acid transport. Combinations of analogs specific for the same site were only additive in their effects. This is similar to the pattern of protein kinase activation in vitro and to that of lipolysis activation in the intact adipocyte (Beebe, S. J., Holloway, R., Rannels, S. R., and Corbin, J. D. (1984) J. Biol. Chem. 259, 3539-3547). 2) Treatment of cells with various metabolic poisons abolished the stimulatory effect of norepinephrine. The response of fatty acid transport to catecholamines showed multiple parallels with that documented for lipolysis except that it was much more rapid. This suggested that the transport process was a regulatory step in fatty acid mobilization. This interpretation is supported by the observation that basal Vmax for transport is much too slow to accommodate the rate of fatty acid release which is observed following stimulation of intact cells with adrenergic hormones.