Palo Alto Veterans Institute for Research

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Schizophrenia—its nature, etiology, and the kind of therapy to use for it—remains one of the most puzzling of the mental illnesses. The theory of schizophrenia presented here is based on communications analysis, and specifically on the Theory of Logical Types. From this theory and from observations of schizophrenic patients is derived a description, and the necessary conditions for, a situation called the “double bind”—a situation in which no matter what a person does, he “can't win.” It is hypothesized that a person caught in the double bind may develop schizophrenic symptoms. How and why the double bind may arise in a family situation is discussed, together with illustrations from clinical and experimental data.

ABSTRACT The Stanford Sleepiness Scale (SSS) is a self‐rating scale which is used to quantify progressive steps in sleepiness. The present study investigated whether the SSS cross‐validates with performance on mental tasks and whether the SSS demonstrates changes in sleepiness with sleep loss. Five college student S s were given a brief test of memory and the Wilkinson Addition Test in 2 test sessions and The Wilkinson Vigilance Test in 2 other sessions spaced throughout a 16‐hr day for 6 days. S s made SSS ratings every 15 min during their waking activities. On night 4, S s underwent all night sleep deprivation. On all other nights, S s were allowed only 8 hrs in bed. Mean SSS ratings correlated r = .68 with performance on the Wilkinson Tests. Discrete SSS ratings correlated r = .47 with performance on the memory test. Moreover, mean baseline SSS ratings were found to be significantly lower than corresponding ratings of the deprivation period.

OBJECTIVE: To model in vivo the dynamic interrelations of head size, gray matter, white matter, and cerebrospinal fluid (CSF) volumes from infancy to old age using magnetic resonance imaging (MRI). DESIGN: Cross-sectional, between-subjects using an age-regression model. SETTING: A Veterans Affairs medical center and community hospitals. PARTICIPANTS: There were 88 male and female subjects aged 3 months to 30 years whose clinical MRI film had been read as normal and 73 healthy male volunteers aged 21 to 70 years who had an MRI performed specifically for this study. MAIN OUTCOME MEASURES: These MRI data were quantified using a semiautomated computer technique for segmenting images into gray matter, white matter, and CSF compartments. The cortex was defined geometrically as the outer 45% on each analyzed slice, and the volumes of cortical white matter, gray matter, and CSF were computed. Subcortical (ventricular) CSF volume was computed for the inner 55% of each analyzed slice. RESULTS: In the younger sample, intracranial volume increased by about 300 mL from 3 months to 10 years. The same patterns of change in volume of each compartment across the age range were seen in both sexes: cortical gray matter volume peaked around age 4 years and decreased thereafter; cortical white matter volume increased steadily until about age 20 years; cortical and ventricular CSF volumes remained constant. In the older sample, brain volumes were statistically adjusted for normal variation in head size through a regression procedure and revealed the following pattern: cortical gray matter volume decreased curvilin-early, showing an average volume loss of 0.7 mL/y, while cortical white matter volume remained constant during the five decades; complementary to the cortical gray matter decrease, cortical CSF volume increased by 0.6 mL/y and ventricular volumes increased by 0.3 mL/y. CONCLUSIONS: These patterns of growth and change seen in vivo with MRI are largely consistent with neuropathological studies, as well as animal models of development, and may reflect neuronal progressive and regressive processes, including cell growth, myelination, cell death, and atrophy.

The ability of insulin to stimulate glucose uptake varies widely from person to person, and these differences, as well as how the individual attempts to compensate for them, are of fundamental importance in the development and clinical course of what are often designated as diseases of Western civilization. Evidence is presented that non-insulin-dependent diabetes mellitus (NIDDM) results from a failure on the part of pancreatic beta-cells to compensate adequately for the defect in insulin action in insulin-resistant individuals. In addition, a coherent formulation of the physiological changes that lead from the defect in cellular insulin action to the loss in glucose homeostasis is presented. However, the ability to maintain the degree of compensatory hyperinsulinemia necessary to prevent loss of glucose tolerance in insulin-resistant individuals does not represent an unqualified homeostatic victory. In contrast, evidence is presented supporting the view that the combination of insulin resistance and compensatory hyperinsulinemia predisposes to the development of a cluster of abnormalities, including some degree of glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, high blood pressure, hyperuricemia, smaller denser low-density lipoprotein particles, and higher circulating levels of plaminogen activator inhibitor 1. The cluster of changes associated with insulin resistance has been said to comprise syndrome X, and all of the manifestations of syndrome X have been shown to increase risk of coronary heart disease. Thus it is concluded that insulin resistance and its associated abnormalities are of utmost importance in the pathogenesis of NIDDM, hypertension, and coronary heart disease.

Circulating lymphocytes are recruited from the blood to the tissue by rolling along the endothelium until being stopped by a signaling event linked to the Gialpha subunit of a heterotrimeric GTP-binding protein; that event then triggers rapid integrin-dependent adhesion. Four chemokines are now shown to induce such adhesion to intercellular adhesion molecule-1 and to induce arrest of rolling cells within 1 second under flow conditions similar to those of blood. SDF-1 (also called PBSF), 6-C-kine (also called Exodus-2), and MIP-3beta (also called ELC or Exodus-3) induced adhesion of most circulating lymphocytes, including most CD4+ T cells; and MIP-3alpha (also called LARC or Exodus-1) triggered adhesion of memory, but not naïve, CD4+ T cells. Thus, chemokines can regulate the arrest of lymphocyte subsets under flowing conditions, which may allow them to control lymphocyte-endothelial cell recognition and lymphocyte recruitment in vivo.

We report the complete nucleotide sequence of a human beta actin cDNA. Both the 5' and 3' untranslated regions of the sequence are similar (greater than 80%) to the analogous regions of the rat beta-actin gene reported by Nudel et al (1983). When a segment of the 3' untranslated region is used as a radiolabelled probe, strong hybridization to chick beta actin mRNA is seen. This conservation of sequences suggests that strong selective pressures operate on non-translated segments of beta actin mRNA.

The present study investigates the hypothesis that endothelium-dependent relaxation of vascular smooth muscle may be mediated through the formation of cGMP. Relaxation of the rat thoracic aorta to acetylcholine, histamine, and Ca++ ionophore A23187 was associated with increased levels of cGMP in a time- and concentration-dependent manner, whereas cAMP levels were unaltered. Removal of the endothelium prevented relaxation to these agents and prevented the increased levels of cGMP. Removal of the endothelium after exposure to acetylcholine only partially decreased the elevated levels of cGMP, suggesting that the changes in cGMP occurred within the smooth muscle cells. Eicosatetraynoic acid, an inhibitor of lipoxygenase and cyclooxygenase, and quinacrine, an inhibitor of phospholipase, prevented and reversed acetylcholine-induced relaxation, respectively, and inhibited acetylcholine-induced increased levels of cGMP. In contrast, sodium nitroprusside-induced relaxation and increased levels of cGMP were independent of the presence of the endothelium, exposure to eicosatetraynoic acid, and quinacrine. The present results support the hypothesis that vascular smooth muscle relaxation induced by some agents is dependent on the presence of the endothelium and is mediated through the formation of an endothelial factor that increases cGMP levels in smooth muscle.

One of the most remarkable characteristics of astrocytes is their vigorous response to diverse neurologic insults, a feature that is well conserved across a variety of different species. The astroglial response occurs rapidly and can be detected within one hour of a focal mechanical trauma (Mucke et al., 1991). Prominent reactive astrogliosis is seen; in AIDS dementia; a variety of other viral infections; prion associated spongiform encephalopathies; inflammatory demyelinating diseases; acute traumatic brain injury; neurodegenerative diseases such as Alzheimer's disease. The prominence of astroglial reactions in various diseases, the rapidity of the astroglial response and the evolutionary conservation of reactive astrogliosis indicate that reactive astrocytes fulfill important functions of the central nervous system (CNS). Yet, the exact role reactive astrocytes play in the injured CNS has so far remained elusive. This chapter summaries the various experimental models and diseases that exhibit astrogliosis and increase in glial fibrillary acidic protein (GFAP). Recent in vitro studies to inhibit GFAP synthesis are also presented.

Tumor necrosis factor, or cachectin (TNF-alpha), a protein with a wide range of biological activities, is produced mainly by macrophages and may be important in inflammatory processes. The role of TNF-alpha in the pathogenesis of cerebral malaria was investigated in a murine model. Most CBA mice infected with Plasmodium berghei anka die between days 6 and 14 with acute neurological manifestations unrelated to the level of parasitemia, whereas mice of some other strains have malaria of the same severity that ends in death after 3 to 4 weeks without neurological manifestations. The activity of serum TNF-alpha was considerably increased in CBA/Ca mice with cerebral malaria but not in Plasmodium berghei-infected mice that did not develop this complication. One injection of rabbit antibody to TNF-alpha on day 4 or 7 fully protected infected mice from cerebral malaria without modifying the parasitemia, whereas immunoglobulins from normal rabbit had no effect. In mice with cerebral malaria, the cerebral vessels showed focal accumulations of packed macrophages often containing infected erythrocytes; this lesion was not seen in mice treated with antibody to TNF-alpha or in untreated mice without cerebral malaria. These findings indicate that TNF-alpha has an important role in the pathogenesis of cerebral malaria in this murine model and suggest that local accumulation and activation of macrophages may lead to the predominance of lesions in the central nervous system.

We studied the acquisition of bone mineral in 45 healthy prepubertal and pubertal girls and related changes in bone mass to age, body mass, pubertal status, calcium intake, and exercise. A subgroup of 12 girls was followed longitudinally. Bone mineral content (BMC) of the lumbar spine, whole body, and femoral neck was measured by dual energy x-ray absorptiometry and that at the midradius by single photon absorptiometry. For comparison, spine and whole body mineral contents were also measured by dual photon absorptiometry. Bone mass was expressed in conventional terms of BMC and area density (BMD). However, we show that BMD fails to account for differences in bone thickness. Since bone size increases during adolescence, we present a new expression, bone mineral apparent density (BMAD), which is BMC normalized to a derived bone reference volume. This term minimizes the effect of bone geometry and allows comparisons of mineral status among bones of similar shape but different size. BMC increased with age at all sites. These increases were most rapid in the early teens and plateaued after 16 yr of age. When bone mineral values at all sites were regressed against age, height, weight, or pubertal stage, consistent relationships emerged, in which BMC was most strongly correlated, BMD was correlated to an intermediate degree, and BMAD correlated only modestly or without significance. Dietary calcium and exercise level did not correlate significantly with bone mass. From these relationships, we attribute 50% of the pubertal increase in spine mineral and 99% of the change in whole body mineral to bone expansion rather than to an increase in bone mineral per unit volume. In multiple regressions, pubertal stage most consistently predicted mineral status. This study emphasizes the importance of pubertal development and body size as determinants of bone acquisition in girls. BMAD may prove to be particularly useful in studies of bone acquisition during periods of rapid skeletal growth.

The effects on guanylate cyclase and cyclic GMP accumulation of a synthetic peptide containing the amino acid sequence and biological activity of atrial natriuretic factor (ANF) were studied. ANF activated particulate guanylate cyclase in a concentration- and time- dependent fashion in crude membranes obtained from homogenates of rat kidney. Activation of particulate guanylate cyclase by ANF was also observed in particulate fractions from homogenates of rat aorta, testes, intestine, lung, and liver, but not from heart or brain. Soluble guanylate cyclase obtained from these tissues was not activated by ANF. Trypsin treatment of ANF prevented the activation of guanylate cyclase, while heat treatment had no effect. Accumulation of cyclic GMP in kidney minces and aorta was stimulated by ANF activation of guanylate cyclase. These data suggest a role for particulate guanylate cyclase in the molecular mechanisms underlying the physiological effects of ANF such as vascular relaxation, natriuresis, and diuresis.

The nonextensivity parameter q occurring in some of the applications of Tsallis statistics (known also as index of the corresponding Levy distribution) is shown to be given, in the q>1 case, entirely by the fluctuations of the parameters of the usual exponential distribution.

Lymphocyte recirculation through different organs is thought to be regulated by adhesion molecules ("homing receptors") recognizing tissue-specific vascular addressins on endothelium. Here we show that the alpha 4/beta 7-integrin has a key role in the migration of mouse lymphocytes to mucosal sites. Homing to Peyer's patches but not to peripheral lymph nodes is inhibited by Fab fragments of mAb PS/2 against the alpha 4-integrin chain, by mAb DATK32 recognizing a combinatorial epitope on the alpha 4/beta 7-integrin, and by mAb FIB30 against the beta 7-chain. The Abs significantly reduce homing of lymphocytes to the intestine, as well. The migration of immunoblasts to gut and gut-associated lymphoid tissue also involves the alpha 4/beta 7-integrin heterodimer. Another anti-alpha 4 Ab, R1-2, which blocks lymphocyte binding to Peyer's patches in the Stamper-Woodruff frozen section assay and lymphocyte adhesion to VCAM-1 and fibronectin, has only minor effects on lymphocyte traffic in vivo. Anti-VCAM-1 Ab as well as the fibronectin peptide CS-1 are without influence on the migration to Peyer's patches or intestine, in contrast to Ab against the mucosal addressin MAdCAM-1. Thus, homing to gut-associated sites is regulated by the alpha 4/beta 7-integrin heterodimer interacting with the vascular addressin, MAdCAM-1, and not with fibronectin or VCAM-1 as counterstructures. Inhibition of homing to Peyer's patches and intestine by the anti-integrin Abs studied was only partial. L-selectin also participates in the homing of small lymphocytes to mucosal sites, especially Peyer's patches, but does not contribute substantially to the localization of blasts into the intestinal wall. The results support a major, but not exclusive role of the alpha 4/beta 7-integrin in lymphocyte traffic to mucosal sites.

BACKGROUND: Metabolic abnormalities associated with human immunodeficiency virus (HIV) infection, including dysglycemia and hyperlipidemia, are increasingly prevalent, and there is concern about the possibility of an association with accelerated cardiovascular and cerebrovascular disease. METHODS: We conducted a retrospective study of the risk of cardiovascular and cerebrovascular disease among the 36,766 patients who received care for HIV infection at Veterans Affairs facilities between January 1993 and June 2001. RESULTS: For antiretroviral therapy, 70.2 percent of the patients received nucleoside analogues, 41.6 percent received protease inhibitors, and 25.6 percent received nonnucleoside reverse-transcriptase inhibitors for a median of 17 months, 16 months, and 9 months, respectively. Approximately 1000 patients received combination therapy with a protease inhibitor for at least 48 months, and approximately 1000 patients received combination therapy with a nonnucleoside reverse-transcriptase inhibitor for at least 24 months. Between 1995 and 2001, the rate of admissions for cardiovascular or cerebrovascular disease decreased from 1.7 to 0.9 per 100 patient-years, and the rate of death from any cause decreased from 21.3 to 5.0 deaths per 100 patient-years. Patient-level regression analyses indicated that there was no relation between the use of nucleoside analogues, protease inhibitors, or nonnucleoside reverse-transcriptase inhibitors and the hazard of cardiovascular or cerebrovascular events, but the use of antiretroviral drugs was associated with a decreased hazard of death from any cause. CONCLUSIONS: Use of newer therapies for HIV was associated with a large benefit in terms of mortality that was not diminished by any increase in the rate of cardiovascular or cerebrovascular events or related mortality. Fear of accelerated vascular disease need not compromise antiretroviral therapy over the short term. However, prolonged survival among HIV infected patients means that longer-term observation and analysis are required.

Magnetic resonance imaging (MRI) was used to study in vivo the brains of 49 patients with chronic alcoholism, 3 to 4 weeks post-withdrawal, and 43 normal healthy controls, all right-handed male veterans between the ages of 23 and 70 years. MRI scans were analyzed using a semi-automated procedure, which allowed the subcortical regions to be segmented into cerebrospinal fluid (CSF) and brain tissue and the cortical regions to be segmented into CSF, gray matter, and white matter. An age regression model was used to examine the effects of alcohol on brain structure, over and above that expected from the normal aging process. The alcoholics exhibited decreased tissue and increased CSF after correcting for aging. In the cortex, there was significant loss of both gray matter and white matter volume. In this sample of alcoholics, no particular cortical region was preferentially affected or spared. Furthermore, brain tissue volume loss increased with advanced age in the alcoholics. In this group of alcoholics there was no relationship between length of illness and age, i.e., the younger alcoholics had as heavy alcohol use histories as did the older alcoholics. Thus, the increased brain tissue loss with advanced age is interpreted as evidence for age-related increase in brain vulnerability to chronic alcohol abuse.

A time-dependent approach for emulating bone modeling and remodeling in response to the daily loading history is presented. We postulate that genotype, systemic metabolic conditions, and local tissue interactions establish the level of local tissue mechanical stimulation (attractor state) appropriate for the maintenance of bone tissue. The net daily rate of apposition or resorption on a bone surface is determined by the difference between the actual stimulus and the tissue attractor state and can be modulated by other biologic factors. In calculating the net change in local bone apparent density, the technique takes into account the bone surface area available for osteoblastic and osteoclastic activity. Endosteal, periosteal, haversian, and cancellous bone modeling and remodeling are thereby treated in a consistent, unified fashion.

Abstract— Gangliosides were isolated from purified human myelin in a yield of 62 μg of lipid‐bound sialic acid per 100 mg of dry myelin. Sialosylgalactosyl ceramide (G 7 ) was found to be a major component of the ganglioside fraction, amounting to 15 per cent of the total sialic acid. It accounted for 10 per cent of lipid‐bound sialic acid in adult human white matter, making it the third most abundant ganglioside on a molar basis. These results were obtained with an improved method for isolating total gangliosides in high yield, by employing DEAE‐Sephadex column chromatography. Myelin from other mammalian species had considerably less G 7 , and there were also indications of maturational changes. Both 2‐hydroxy and unsubstituted fatty acids were components of the ceramide unit, in a ratio of 3:2, respectively. The overall fatty acid pattern was very similar to that for myelin cerebroside and sulphatide. Long‐chain bases included only C 18 species, with sphingosine predominating (>90 per cent). These observations suggest a metabolic relationship between G 7 and either cerebroside or sulphatide.

Eukaryotic cells rely on long-lived microtubules for intracellular transport and as compression-bearing elements. We considered that long-lived microtubules are acetylated inside their lumen and that microtubule acetylation may modify microtubule mechanics. Here, we found that tubulin acetylation is required for the mechanical stabilization of long-lived microtubules in cells. Depletion of the tubulin acetyltransferase TAT1 led to a significant increase in the frequency of microtubule breakage. Nocodazole-resistant microtubules lost upon removal of acetylation were largely restored by either pharmacological or physical removal of compressive forces. In in vitro reconstitution experiments, acetylation was sufficient to protect microtubules from mechanical breakage. Thus, acetylation increases mechanical resilience to ensure the persistence of long-lived microtubules.

DESCRIPTION: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the diagnosis of obstructive sleep apnea in adults. METHODS: This guideline is based on published literature on this topic that was identified by using MEDLINE (1966 through May 2013), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular mortality, nonfatal cardiovascular disease, stroke, hypertension, type 2 diabetes, postsurgical outcomes, and quality of life. Sensitivities, specificities, and likelihood ratios were also assessed as outcomes of diagnostic tests. This guideline grades the evidence and recommendations by using ACP's clinical practice guidelines grading system. RECOMMENDATION 1: ACP recommends a sleep study for patients with unexplained daytime sleepiness. (Grade: weak recommendation, low-quality evidence). RECOMMENDATION 2: ACP recommends polysomnography for diagnostic testing in patients suspected of obstructive sleep apnea. ACP recommends portable sleep monitors in patients without serious comorbidities as an alternative to polysomnography when polysomnography is not available for diagnostic testing. (Grade: weak recommendation, moderate-quality evidence).