The relationships of anhedonia and the process-reactive dimension to season of birth and infectious disease incidence in schizophrenia

This project was designed to test two hypotheses drawn from a new formulation explaining the exaggerated winter birthrate among hospitalized schizophrenics. The first is that the supposed exaggerated winter birthrate among process schizophrenics actually represents a reduction in spring-fall births caused by prenatal exposure to infectious diseases during the preceding winter--i.e., a high prenatal death rate in process preschizophrenic fetuses. The second is that the level of negative symptoms in survivors at risk for schizophrenia who were born after winters with high infectious disease rates is exaggerated. The findings provided some tentative support for this formulation. Compared with counterparts born after low-disease winters, schizophrenics born after winters with high disease incidences tended to show lower (more reactive) scores on a measure of the process-reaction dimension but higher anhedonia scores.     

3% NaCl and 7.5% NaCl/dextran 70 in the resuscitation of severely injured patients.

Cardiovascular resuscitation of the severely injured patient in the field remains unsatisfactory because large volumes of intravenous fluid are needed to keep up with ongoing blood losses and because only small volumes of fluid can be given. In the first study reported here, small volumes (less than or equal to 12 mL/kg) of 3% NaCl were given to patients who were having surgery for severe injuries. The 3% NaCl restored blood pressure, pH, and urine output with approximately one half of the cumulative fluid requirement of patients who received isotonic fluids (p less than 0.05). In a second study, 7.5% NaCl/dextran 70, 250 mL, was given in a prospective, randomized, and double-blinded trial to injured patients in the field. Blood pressure in the hypertonic/hyperoncotic group increased 49 mmHg during transport (p less than 0.005); blood pressure in patients given lactated Ringer's solution increased 19 mmHg (NS). Survival favored the hypertonic/hyperoncotic group. The 7.5% NaCl/dextran 70 solution appears particularly promising for treatment of injured patients in the field.     

Patients with adult respiratory distress syndrome (ARDS) demonstrate in vivo neutrophil activation associated with diminished binding of neutrophil-specific monoclonal antibody 31D8

Neutrophils (PMNs) from patients with adult respiratory distress syndrome (ARDS) were assessed for light scattering, membrane potential, and phagocytic responses using fluorescent probes and flow cytometry to evaluate individual cells. Qualitative and quantitative oxidant responses were measured by nitroblue tetrazolium (NBT) and cytochromec reduction assays, respectively. The results were correlated with the proportion of cells binding the PMN subset-specific monoclonal antibody 31D8. Despite an increased forward scatter signal (4.3±1.6 vs. 1.3±1.1 ARDS vs. control,P=0.041) and spontaneous NBT test (12.6±4.7% vs. 2.5 ±0.8% positive, ARDS vs. control,P=0.033) indicating in vivo priming of ARDS PMNs, there were no significant differences between ARDS and control PMNs in assays of stimulated membrane potential, NBT, and O·₂ ^– production or phagocytosis. However, positive correlations between the degree of prestimulus forward light scatter and subsequent O·₂ ^– production to FMLP (r=0.673,P=0.006) and between the percentage of bands and the O·₂ ^– response to PMA (r=0.660,P =0.003), suggest that the great variability of the ARDS PMN functional responses may relate to varying degrees of in vivo cell priming and/or deactivation. ARDS PMNs demonstrated a significantly lower percentage of 31D8 positive cells (73.4 ±7.5% vs. 94.5±1.6%,P=0.012) and a lower level of 31D8 staining when compared to normals (60.1±10.4% of control level,P=0.001). The lower 31D8 expression did not directly correlate with any functional parameter tested or with the proportion of immature cells. However, patients receiving an intravenous PGE₂1-infusion demonstrated a significant increase in 31D8 staining relative to controls and inhibition of PMA-stimulated O·₂ ^– production. The data suggest that the function of PMNs from ARDS patients varies widely and reflects great in vivo variation in cell priming. While the mechanism responsible for the lowered expression of the 31D8 antigen and its apparent modulation by PGE₁ is unknown, 31D8 may be an indirect marker for in vivo stress factors that regulate the preferential release of a structurally distinct PMN subset from the bone marrow.This work was supported in part by NIH grant P30-DK35747, a University of California, Davis, Dean's Research Grant, and The Upjohn Company.     

The definition of posttraumatic stress disorder in alcoholic Vietnam veterans. Are the DSM-III criteria necessary and sufficient?

The authors evaluated the validities of the DSM-III elements defining posttraumatic stress disorder (PTSD) in alcoholic Vietnam veterans by studying the relationships of each to qualification for a PTSD diagnosis under DSM-III standards, the history of a major stressor (3 or more months of combat), and the presence/absence of enough other problems to meet the symptomatic DSM-III requirements for this diagnosis. Elements dealing with the reexperiencing of traumas, diminished pleasure, detachment from others, hyperalertness, sleep disturbance, guilt over behaviors required for survival, and avoidance of stimuli reminiscent of traumas showed substantial correlations with eligibility for a PTSD diagnosis. However, items dealing with emotional expressiveness, response to intimacy, survival guilt, impaired memory, and trouble concentrating either failed to correlate with qualification for a PTSD diagnosis or yielded marginal results. One ("lacking direction") of 10 additional symptoms sometimes termed as "post-Vietnam syndrome" behaviors correlated with eligibility for a PTSD diagnosis as well. The present results and those described in earlier studies suggest that several modifications in the DSM-III definition of PTSD are desirable.     

A receptor guanylyl cyclase expressed specifically in olfactory sensory neurons.

We have cloned an additional member (GC-D) of the membrane receptor guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] family that is specifically expressed in a subpopulation of olfactory sensory neurons. The extracellular, putative ligand-binding domain of the olfactory cyclase is similar in primary structure to two guanylyl cyclases expressed in the retina but diverges considerably from other known guanylyl cyclases. The expression of GC-D RNA is restricted to a small, randomly dispersed population of neurons that is within a single topographic zone in the olfactory neuroepithelium and resembles the pattern of the more diverse seven-transmembrane-domain odorant receptors. These observations suggest that GC-D may function directly in odor recognition or in modulating the sensitivity of a subpopulation of sensory neurons to specific odors.     

The β-secretase, BACE

Evidence suggests that the β-amyloid peptide (Aβ) is central to the pathophysiology of Alzheimer’s disease (AD). Amyloid plaques, primarily composed of Aβ, progressively develop in the brains of AD patients, and mutations in three genes (APP, PS1, and PS2) cause early onset familial AD (FAD) by directly increasing synthesis of the toxic, plaque-promoting Aβ42 peptide. Given the strong association between Aβ and AD, therapeutic strategies to lower the concentration of Aβ in the brain should prove beneficial for the treatment of AD. One such strategy would involve inhibiting the enzymes that generate Aβ. Aβ is a product of catabolism of the large TypeI membrane protein, amyloid precursor protein (APP). Two proteases, called β- and γ-secretase, mediate the endoproteolysis of APP to liberate the Aβ peptide. For over a decade, the molecular identities of these proteases were unknown. Recently, the γ-secretase has been tentatively identified as the presenilin proteins, PS1 and PS2, and the identity of the β-secretase has been shown to be the novel transmembrane aspartic protease, β-site APP cleaving enzyme 1 (BACE1; also called Asp2 and memapsin2). BACE2, a novel protease homologous to BACE1, was also identified, and together the two enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the properties of the β-secretase, and as the key rate-limiting enzyme that initiates the formation of Aβ, BACE1 is an attractive drug target for AD. Here, I review the identification and initial characterization of BACE1 and BACE2, and summarize our current understanding of BACE1 post-translational processing and intracellular trafficking. In addition, I discuss recent studies of BACE1 knockout mice and the BACE1 X-ray structure, and relate implications for BACE1 drug development.     

Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice.

A construct containing approximately 2500 base pairs (bp) of 5' upstream and approximately 700 bp of 3' downstream sequence was used to drive the expression of an intronless human K14 gene in vitro and in vivo. To track the expression of the gene, a small sequence encoding the antigenic portion of neuropeptide substance P was inserted in frame 5' to the TGA translation stop codon of the gene. Surprisingly, this gene was expressed promiscuously in a wide variety of cultured cells transiently transfected with the construct. In contrast, when introduced into the germ line of transgenic mice, the construct was expressed in a fashion analogous to the endogenous K14 gene--namely, in the basal layer of stratified squamous epithelia. Our results suggest that some regulatory mechanism is overridden as a consequence of transient transfection but that sequences that can control proper K14 expression are present in the construct. The appropriate tissue-specific and differentiation-specific expression of K14.P in transgenic mice is an important first step in characterizing a promoter that could be employed to drive the foreign expression of drug-related genes in the epidermis of skin grafts.