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K L Davis

Publications and source records attributed to K L Davis.

At least 109 records · Page 6Linked to original sources
PubMed1996

Empirical evaluation of the factorial structure of clinical symptoms in schizophrenia: effects of typical neuroleptics on the brief psychiatric rating scale.

There has been little investigation of the effect of neuroleptic medication on the structure of symptoms in schizophrenia. In this study, 135 male schizophrenic patients were rated with the Brief Psychiatric Rating Scale (BPRS) after 4 weeks of treatment with typical neuroleptic medication and after 2 weeks free of neuroleptics, with the order of assessment varying across patients. Confirmatory factor analyses (CFA) found that there were no differences in symptom structure across medication status and no differences in the structure of symptoms in treatment responders and nonresponders. The typical 5-factor BPRS model fit the data poorly and the fit improved considerably through deletion of items measuring symptoms not associated with schizophrenia, suggesting that some of the symptoms that contribute to a total BPRS score may be adding primarily error variance. Although the sample size in this study is limited, the results suggest that using total BPRS scores to measure severity of schizophrenic symptoms should be reconsidered.

Adult↗
PubMed1996

Functional and structural role of arginine 103 in human erythropoietin.

The identification of amino acid residues essential for function of the hematopoietic growth factor erythropoietin has been approached by several methods, including comparisons of related sequences, immunochemical approaches, mutagenesis, and computer modeling. We have reported previously that mutations within amino acids 100-109 of erythropoietin can have profound effects on the hormone's structure and/or activity and that Arg103 is especially important for function [Y. Chern, T. Chung, and A. J. Sytkowski (1991) Eur. J. Biochem. 202, 225-229; J. Grodberg, K.L. Davis, and A. J. Sytkowski (1993) Eur. J. Biochem. 218, 597-601]. We have now constructed a series of Arg103 substitutions in order to determine the structural features of amino acid 103 required for biological activity. Each of the mutants was expressed and secreted efficiently by transfected COS1 cells. Mutants Arg103Asn, Arg103Gln, and Arg103Glu exhibited no biological activity. In contrast, Arg103His and Arg103Lys had specific activities equal to 2 and 25%, respectively, of that of wild-type erythropoietin, indicating that a positive charge may be required at position 103 but that other constraints necessitate the presence of Arg for full activity. A role for amino acid 103 in the protein's structure was supported by the results of experiments which revealed marked differences in heat stability among the mutants. We hypothesize that an Arg at position 103 may confer sufficient flexibility to the receptor binding domain to facilitate initial binding to the receptor and may then stabilize the binary complex by hydrogen bonding with carbonyls of the receptor protein.

Amino Acid Sequence↗
PubMed1996

Evidence of a locus for schizophrenia and related disorders on the short arm of chromosome 5 in a large pedigree.

We attempted to identify a locus for schizophrenia and related disorders in 24 nuclear families of schizophrenic probands using a predefined classification system for affected cases that included those disorders most clearly identified as sharing a genetic relationship with schizophrenia--schizoaffective disorder and schizotypal personality disorder. Initially, we evaluated 8 markers on chromosome 5 on the first 12 families with available genotyping and diagnostic assessments and, assuming autosomal dominant transmission, found a lod score of 2.67 for the D5S111 locus (5p14.1-13.1) in one large nuclear family (no. 17; sibship: n = 12; schizophrenia: n = 3; schizotypal personality disorder: n = 2); the other 11 families were much smaller, less complete, and provided little additional information. Other branches of no. 17 were then assessed and the 2-point lod score for family 17 rose to 3.72; using multipoint analysis the lod score in 17 was 4.37. When only schizophrenia was used to define affectedness, the positive evidence for linkage to D5S111 was greatly reduced. Sensitivity analysis indicated that the lod score is heavily dependent upon the predefined diagnostic criteria. Our studies of other families of schizophrenic probands eventually totalled 23, but linkage to D5S111 in these yielded a -2.41 lod score. The results provide evidence for genetic linkage of the D5S111 locus to schizophrenia and related disorders in one family. It may be of interest that over several generations, almost all the ancestors of family 17 could be traced back to a small, relatively isolated, hill region of Puerto Rico.

Chromosome Mapping↗
PubMed1996

Neuropeptide deficits in schizophrenia vs. Alzheimer's disease cerebral cortex.

Neuropeptide concentrations were determined in the postmortem cerebral cortex from 19 cognitive-impaired schizophrenics, 4 normal elderly subjects, 4 multi-infarct dementia (MID) cases, and 13 Alzheimer's disease (AD) patients. Only AD patients met criteria for AD. The normal elderly and MID cases were combined into one control group. Somatostatin concentrations were reduced in both schizophrenia and AD. Neuropeptide Y concentrations were reduced only in schizophrenia, and corticotropin-releasing hormone concentrations were primarily reduced in AD. Concentrations of vasoactive intestinal polypeptide and cholecystokinin also were reduced in schizophrenia, although not as profoundly as somatostatin or neuropeptide Y. In AD, cholecystokinin and vasoactive intestinal peptide were unchanged. Neuropeptide deficits in schizophrenics were more pronounced in the temporal and frontal lobes than in the occipital lobe. The mechanisms underlying these deficits in schizophrenia and AD are likely distinct. In schizophrenia, a common neural element, perhaps the cerebral cortical gaba-aminobutyric acid (GABA)-containing neuron, may underlie these deficits.

Aged↗
PubMed1996

Apolipoprotein E-epsilon 4 allele and familial risk in Alzheimer's disease.

Recent studies have found an association between presence of apolipoprotein E (APOE) epsilon 4 allele and Alzheimer's disease (AD). The present study compared the cumulative risk of primary progressive dementia (PPD) in relatives of AD probands carrying at least one copy of the epsilon 4 allele with the relatives of AD probands not carrying epsilon 4 and with relatives of non-demented controls. Our aim was to determine whether the familial aggregation of PPD in relatives of AD probands is primarily due to those carrying epsilon 4. Seventy-seven neuropathologically diagnosed AD patients were obtained as probands through our Alzheimer's Disease Research Center Brain Bank. AD probands were genotyped for APOE. As a comparison group, 198 non-demented probands were also included. Through family informants, demographic and diagnostic data were collected on 382 first-degree relatives (age > or = 45 years) of AD probands and 848 relatives of the controls. We found that the cumulative risk of PPD in both relatives of AD probands with and without the epsilon 4 allele was significantly higher than that in the relatives of non-demented controls. However, the increased risk in the relatives of AD probands with the epsilon 4 allele was marginally, but not significantly, lower than the risk in the relatives of probands without epsilon 4. A greater likelihood of death by heart diseases over developing PPD in relatives of AD probands with epsilon 4 (3.1-fold increase) was found compared to relatives of probands without epsilon 4 (1.7-fold increase), especially prior to age 70, although the difference was not statistically significant. The increased familial risk for PPD in the relatives of AD probands with the APOE-epsilon 4 allele relative to controls suggests that familial factors in addition to APOE-epsilon 4 are risk factors for AD. Differential censorship from increased mortality of heart diseases may have prevented a higher incidence of PPD among the relatives of probands with epsilon 4.

Age of Onset↗
PubMed1996

Cardiac surgical conditions induced by beta-blockade: effect on myocardial fluid balance.

BACKGROUND: Both crystalloid and blood cardioplegia result in cardiac dysfunction associated with myocardial edema. This edema is partially due to the lack of myocardial contraction during cardioplegia, which stops myocardial lymph flow. As an alternative, acceptable surgical conditions have been created in patients undergoing coronary artery bypass operations with esmolol-induced minimal myocardial contraction. We hypothesized that minimal myocardial contraction during circulatory support using either standard cardiopulmonary bypass (CPB) or a biventricular assist device would prevent myocardial edema by maintaining cardiac lymphatic function and thus prevent cardiac dysfunction. METHODS: We placed 6 dogs on CPB and 6 dogs on a biventricular assist device and serially measured myocardial lymph flow rate and myocardial water content in both groups and preload recruitable stroke work only in the CPB dogs. In all dogs we minimized heart rate with esmolol for 1 hour during total circulatory support. RESULTS: Although myocardial lymph flow remained at baseline level during CPB and increased during biventricular assistance, myocardial water accumulation still occurred during circulatory support. However, as edema resolved rapidly after separation from circulatory support, myocardial water content was only slightly increased after CPB and biventricular assistance, and preload recruitable stroke work was normal. CONCLUSIONS: Our data suggest that minimal myocardial contraction during both CPB and biventricular assistance supports myocardial lymphatic function, resulting in minimal myocardial edema formation associated with normal left ventricular performance after circulatory support. The concept of minimal myocardial contraction may be a useful alternative for myocardial protection, especially in high-risk patients with compromised left ventricular function.

Adrenergic beta-Antagonists↗
PubMed1996

Dopamine receptor mRNA expression in human striatum and neocortex.

The distributions of the transcripts encoding the five dopamine receptors have been determined in the human striatum and selected regions of the neocortex. In the striatum significant levels of dopamine receptor expression are restricted to the D1, D2, and D3 receptors. D1 and D2 receptor messenger ribonucleic acids (mRNAs) are homogeneously distributed throughout the caudate, putamen, and nucleus accumbens. D3 receptor mRNA is particularly enriched in the nucleus accumbens, with moderate levels in the ventral putamen. In the prefrontal cortex D1 and D4 receptor mRNAs are the most abundant, although the other three transcripts are seen at lower levels. A similar pattern is seen in the temporal neocortex. In the occipital cortex, D1 receptor mRNA is the most abundant, D3 the rarest, while the other three transcripts are present at modest levels of expression. These data add to a growing understanding of the neuroanatomical distribution of these transcripts in the human brain. They are essential to understand in the context of the limbic circuitry of the brain, as new hypotheses of dysfunction of dopaminergic neurotransmission are advanced in psychiatry and as these receptor subtypes are targeted for development of novel pharmacological treatments.

Aged↗
PubMed1996

Issues in accelerating the pace of development for neuroprotective agents.

Accelerating the pace of development for neuroprotective agents requires a number of advances in the therapeutics of Alzheimer disease. Identification of patients who are presymptomatic, by discovering early markers of Alzheimer disease will be essential. Clinical trials methodology must be devised to accommodate atypical outcome measures, prolonged trials, and large sample sizes without posing serious ethical considerations regarding placebo administration. Finally, regulatory issues that discourage development of drugs that will be in complicated, expensive and lengthy clinical trials need to be addressed. This paper reviews these issues, and offers some suggestions.

Alzheimer Disease↗
PubMed1996

Regulation of microvascular filtration in the myocardium by interstitial fluid pressure.

We hypothesized that myocardial microvascular filtration rate (Jv) could be manipulated by varying end-diastolic myocardial interstitial hydrostatic (P(int)) pressure. Dogs under general anesthesia were instrumented with intramyocardial capsules to measure P(int) and with prenodal myocardial lymphatic trunk cannulas and superior vena caval balloon-tipped catheters to manipulate myocardial lymph flow. Because, for a given surface area, the lymph-to-plasma protein concentration ration (CL/CP) varies inversely with JV, CL/CP was utilized as an index of changes in JV. When lymphatic outflow pressure (P0) was elevated to abolish lymph flow and force myocardial interstitial fluid volume to expand, P(int) rose significantly from 15.0 +/- 0.8 to 27.6 +/- 1.0 mmHg and CL/CP increased significantly from 0.75 +/- 0.04 to 0.85 +/- 0.04, indicating a decrease in JV. When P0 was lowered and lymph flow resumed, P(int) and CL/CP decreased significantly to 15.3 +/- 0.9 mmHg and 0.75 +/- 0.04, respectively, indicating an increase in JV. We conclude that myocardial microvascular filtration rate may be modulated by changes in P(int) resulting from alterations in myocardial interstitial fluid volume secondary to variations in lymph flow from the heart.

Animals↗
PubMed1996

Clinical characteristics of Kraepelinian schizophrenia: replication and extension of previous findings.

OBJECTIVE: Subtypologies of schizophrenia based on cross-sectional criteria, such as the nomenclature of the DSMs, have not been successful in identifying valid diagnostic subgroups among patients with schizophrenia. A subtypology that uses criteria to classify individuals on the basis of longitudinal deficits in self-care may identify a more valid subgroup of schizophrenic patients. METHOD: This study describes the clinical characteristics of a group of schizophrenic patients identified on the basis of a longitudinal criterion: at least 5 years of continuous and complete dependence on others for obtaining and maintaining the basic necessities of life, including food, clothing, and shelter. RESULTS: Sixty-one "Kraepelinian" schizophrenic inpatients, when compared to 80 non-Kraepelinian schizophrenic inpatients who were similar in years of illness, age, and education, demonstrated more severe negative symptoms and more severe formal thought disorder; yet the severity of their delusions, hallucinations, and bizarre behavior did not differ significantly. None of the Kraepelinian patients and eight non-Kraepelinian patients met DSM-III-R criteria for schizoaffective disorder. CONCLUSIONS: Data from this replication study suggest that Kraepelinian schizophrenic patients, identified on the basis of a longitudinal course characterized by severe dysfunctions in self-care, may represent an alternative, and possibly more valid, method of subtyping schizophrenia.

Activities of Daily Living↗
PubMed1996

Myocardial fluid balance in acute hypertension.

OBJECTIVES: We hypothesized that (1) acute arterial hypertension increases myocardial microvascular fluid filtration and (2) the combination of acute arterial hypertension and coronary sinus pressure elevation may increase myocardial microvascular filtration sufficiently to estimate the osmotic reflection coefficient of the myocardial exchange vessels. METHODS: In nine mechanically ventilated dogs we cannulated the prenodal major cardiac lymph trunk. With the use of central venous phenylephrine infusion, mean arterial pressure (MAP) was raised progressively to 120, 160, and 180 mm Hg. In five dogs we additionally raised coronary sinus pressure (CSP) to 20 and 40 mm Hg. At each manipulation of MAP and/or CSP, we measured indexes of myocardial lymphatic function and lymph-to-plasma concentration ratios for total protein (CL(TP)/CP(TP) and albumin (CL(alb)/CP(alb)). RESULTS: Myocardial lymph flow rate (QL; microL/min) increased exponentially (QL = 10.9.e0.014.(MAP) and myocardial lymph driving pressure (PL; mm Hg) increased linearly (PL = 2.30 + 0.20 + 0.20 . MAP) following increases, whereas CL(TP)/CP(TP) and CL(alb)/CP(alb) decreases from 0.67 +/- 0.07 (SD) to 0.56 +/- 0.10 and from 0.91 +/- 0.05 to 0.75 +/- 0.11, respectively. Adding CSP elevation increased QL up to 12 times control associated with further CL(TP)/C(TP) and CL(alb)/CP(alb) decreases to 0.49 +/- 0.05 and 0.59 +/- 0.02, respectively. CONCLUSIONS: We conclude that hypertensive arterial pressures are, at least in part, transmitted to the myocardial microvascular exchange vessels in the intact animal leading to increased microvascular fluid filtration. However, the combination of acute arterial hypertension and coronary sinus pressure elevation is not sufficient to produce filtration independence required for myocardial osmotic reflection coefficient determination.

Animals↗
PubMed1996

Ventricular enlargement associated with linkage marker for schizophrenia-related disorders in one pedigree.

We previously obtained evidence indicating a genetic linkage marker for schizophrenia and related disorders (two-point lod score = 3.72, P = 0.01) on the short arm of chromosome 5(5p14.1-13.1) in one large pedigree. Automated computer algorithms were used to edge the brain and measure the volume of the ventricles, regional sulcal atrophy, and skull size and shape in the original nuclear family members. Of the 11 subjects who underwent computed tomography, six (three schizophrenic, two with schizotypal personality disorder, and one unaffected) carried the marker allele that co-segregated with schizophrenia-related disorders, while five (all unaffected) did not. The family members with the marker allele linked to schizophrenia-related disorders (n = 6) had significantly (P < 0.05) larger ventricle-brain ratios (VBRs) and more fronto-parietal atrophy (controlling for age) than the family members lacking the schizophrenia-related marker allele (n = 5). The three individuals with the largest VBRs all carried the marker, although they received diagnoses of no schizophrenia-related disorder, schizotypal personality disorder, and schizophrenia. Regional cortical values indicative of cerebrospinal fluid content were higher in the frontal and parietal regions of family members carrying the marker. The hypothesis that genetic linkage is associated with structural brain pathology is difficult to test because of all the potential compounding factors. Our findings suggest the possibility that, in this family, relatively enlarged VBR and fronto-parietal atrophy, as determined by computed tomograph, may be associated with a schizophrenia-related gene and present susceptibility to schizophrenia-related disorders. In addition to a replication of these findings in other similarly linked families yet to be identified, further studies using higher resolution structural and functional neuroimaging techniques will be required.

Brain↗
PubMed1995

L-deprenyl and physostigmine for the treatment of Alzheimer's disease.

The present study evaluated the safety of and obtained preliminary data on the cognitive effects of L-deprenyl and physostigmine in patients with Alzheimer's Disease. Seventeen outpatients with Alzheimer's Disease participated in a double-blind crossover study in which they received 4 weeks of L-deprenyl at a dose of 10 mg p.o., q.d., and 4 weeks of placebo in random order. During both the L-deprenyl and placebo periods, patients received cognitive assessments during physostigmine (0.5 mg) and placebo infusions separated by 2 days. The cognitive effects of these agents alone and in combination were measured with digit span, verbal fluency, list learning, praxis, delayed recall, and delayed recognition tasks. Fifteen patients completed the study. The two drugs, used alone or in combination, were safe and well tolerated. Analyses of variance demonstrated that neither physostigmine nor L-deprenyl, whether given alone or in combination, significantly improved cognition, when compared with the double placebo condition.

Administration, Oral↗
PubMed1995

Normothermic continuous antegrade blood cardioplegia does not prevent myocardial edema and cardiac dysfunction.

BACKGROUND: Normothermic continuous blood cardioplegia (BC) has been proposed to completely protect the myocardium during cardiac surgery. However, previous work from our laboratory suggests that BC could cause myocardial edema that produces cardiac dysfunction. The purpose of this present study was to evaluate the impact of BC on myocardial fluid balance and left ventricular function. METHODS AND RESULTS: In 11 dogs, myocardial water content (MWC) was determined by microgravimetry. Myocardial lymph flow rate was measured after cannulation of the major prenodal cardiac lymphatic. Preload recruitable stroke work (PRSW) was calculated by sonomicrometry and micromanometry. The dogs were placed on normothermic cardiopulmonary bypass (CPB), and BC was delivered at either 80 to 90 mm Hg (BChigh; n = 6) or 40 to 50 mm Hg (BClow; n = 5) for 1 hour. Coronary sinus lactate and oxygen saturation monitoring demonstrated ischemia avoidance. BC was associated with substantial myocardial lymph flow rate decrease (P < .05) and myocardial edema development in both groups. MWC increased from 76.0 +/- 1.9% to 79.2 +/- 1.7% (P < .05) after 10 minutes of BChigh and from 75.9 +/- 0.6% to 78.9 +/- 1.4% (P < .05) after 30 minutes of BClow. PRSW decreased to 63 +/- 19% (BChigh) and 69 +/- 15% of control (BClow) at 30 minutes after CPB (P < .05). Myocardial lymph flow rate increases of threefold to fourfold that of control (P < .05) resulted in significant myocardial edema reduction associated with PRSW improvement to 71 +/- 17% (BChigh) and to 78 +/- 11% (BClow) at 2 hours after CPB. CONCLUSIONS: We conclude that BC is associated with compromised cardiac function despite ischemia avoidance. This cardiac dysfunction is due to myocardial edema caused by the combination of increased myocardial microvascular fluid filtration and decreased myocardial lymph flow rate during BC.

Animals↗
PubMed1995

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and clinical symptoms in Alzheimer's disease.

Postmortem findings point to significant abnormalities in central noradrenergic function in Alzheimer's disease (AD) which may be associated with changes in peripheral markers. In this study, the relationship between the peripheral noradrenergic marker, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), and clinical symptoms was examined in 23 patients with probable AD. Basal MHPG levels correlated significantly with increased cognitive impairment (r = .58, p = .005), controlling for age, age at onset, gender, and time interval between plasma MHPG determination and cognitive testing. These results suggest that plasma MHPG increases as cognitive function in AD deteriorates, further supporting preliminary evidence for increases in noradrenergic indices in association with disease severity in AD.

Affective Symptoms↗