Biomedical subjects

K L Davis

Publications and source records attributed to K L Davis.

At least 91 records · Page 5Linked to original sources

PubMed1998

Association of elevated alpha 1-antichymotrypsin with cognitive impairment in a prospective study of the very old.

OBJECTIVE: The authors investigated the relationships between concentrations of two acute-phase proteins, alpha 1-antichymotrypsin (ACT) and alpha 2-macroglobulin (MAC), and cognitive impairment in the very old. METHOD: Concentrations of ACT and MAC were determined in a prospective study using sera from medically stable elderly nursing home residents. Cognitive impairment was assessed with the Mini-Mental State. RESULTS: Concentrations of ACT were associated with greater cognitive impairment, as reflected by lower Mini-Mental State scores. This relationship did not exist for MAC. CONCLUSIONS: These data extend previous reports that patients with Alzheimer's disease have greater concentrations of ACT in their blood by demonstrating in a diagnostically diverse nursing home population a relationship between serum ACT and mental status. Elevated serum ACT in patients with compromised mental status may reflect a cerebral acute-phase response.

Acute-Phase Proteins↗

PubMed1998

Symptoms, cognitive functioning, and adaptive skills in geriatric patients with lifelong schizophrenia: a comparison across treatment sites.

OBJECTIVE: Although many geriatric patients with schizophrenia have been referred to nursing home care, little is known about their characteristics. Across nursing home and chronic hospital settings, the authors directly assessed poor outcome geriatric patients with schizophrenia and contrasted their cognitive, symptomatic, and adaptive functioning to that of acutely admitted patients with a better outcome over the lifetime course of the illness. METHOD: The subjects were 97 chronically hospitalized patients with schizophrenia, 37 patients with chronic schizophrenia who lived in nursing homes, and 31 acutely admitted geriatric patients with schizophrenia. These patients were rated with the Positive and Negative Syndrome Scale, tested with a neuropsychological battery, evaluated with the Mini-Mental State examination, and rated on a scale of social and adaptive deficits, the Social Adaptive Functioning Evaluation scale. RESULTS: Each group of patients proved discriminable from the other two: nursing home patients displayed the most severe adaptive deficits, and acutely admitted patients were the least cognitively impaired. Cognitive impairment was the strongest predictor of adaptive deficits for all three groups, and negative symptom differences among the groups were smaller than differences in cognitive impairment. Nursing home patients had the least severe positive symptoms, and the acutely ill and chronic hospital patients did not differ on positive symptoms. CONCLUSIONS: Cognitive impairment is a predictor of both overall outcome and specific adaptive deficits. These data suggest that interventions aimed at cognitive impairment may have an impact on overall functional status. In comparison, positive symptom severity is less strongly correlated with overall adaptive outcome and is uncorrelated with specific deficits in adaptive skills.

Age Factors↗

PubMed1998

Future therapeutic approaches to Alzheimer's disease.

As palliative treatments for Alzheimer's disease proliferate, the focus of therapeutics turns to drugs with the potential to alter course. Evidence is reviewed, suggesting that there is biological plausibility to utilizing anti-inflammatory agents, antioxidants, free-radical scavengers, estrogen preparations, and perhaps cholinomimetics. This range of possibilities leads to an optimistic assessment of the likelihood for altering the course or delaying the onset of Alzheimer's disease.

Aged↗

PubMed1997

Validity of the family history method for identifying schizophrenia-related disorders.

We examined the family history method's validity for identifying schizophrenia related disorders (SRD) by comparing family history and family study derived diagnoses. First degree relatives (n = 284) of 48 psychiatrically disordered probands, predominantly with schizophrenia, were diagnosed using the Family History RDC (FH-RDC) which include three psychotic schizophrenia related disorders (P-SRD): schizophrenia, chronic SAD and chronic unspecified functional psychosis (CUFP). Supplementary criteria for schizophrenia related personality disorders (SRP), derived to identify schizotypal and paranoid personality disorders (PD), were also assessed. About two thirds of these relatives (n = 196; 69.0%) were independently diagnosed by RDC and DSM-III-R on both axis I and axis II in a family study. The specificity was 1.0 (178/178) and the sensitivity of the family history derived diagnosis for P-SRD was 0.72 (13/18). Sensitivity for P-SRD was improved, however, by inclusion of SRP which captured three of the five false negative relatives. The sensitivity of SRP for schizotypal or paranoid PD was 0.39 (15/38) and the specificity was 0.92 (127/138). The FH-RDC have moderately good sensitivity and excellent specificity for the psychotic schizophrenia related disorders. While family history criteria for SRP are not a good proxy for schizotypal or paranoid PD, they can enhance the family history method's sensitivity for SRD.

Adult↗

PubMed1997

The validity of the family history method for identifying Alzheimer disease.

OBJECTIVE: To examine the validity of the family history method for identifying Alzheimer disease (AD) by comparing family history and neuropathological diagnoses. METHODS: Seventy-seven former residents of the Jewish Home and Hospital for the Aged, New York, NY, with neuropathological evaluations on record were blindly assessed for the presence of dementia and, if present, the type of dementia through family informants by telephone interviews. The Alzheimer's Disease Risk Questionnaire was used to collect demographic information and screen for possible dementia. If dementia was suspected, the Dementia Questionnaire was administered to assess the course and type of dementia, i.e., primary progressive dementia (PPD, likely AD), multiple infarct dementia, mixed dementia (i.e., PPD and multiple infarct dementia), and other dementias based on the modified Diagnostic and Statistical Manual of Mental Disorders, Third Edition, criteria. RESULTS: Sixty (77.9%) of 77 elderly subjects were classified as having dementia and 17 (22.1%) were without dementia by family history evaluation. Of the 60 elderly subjects with dementia, 57 (95%) were found at autopsy to have had neuropathological changes related to dementia. The sensitivity of the family history diagnosis for dementia with related neuropathological change was 0.84 (57 of 68) and the specificity was 0.67 (6 of 9). Using family history information to differentiate the type of dementia, the sensitivity for definite or probable AD (with or without another condition) was 0.69 (36 of 51) and the specificity was 0.73 (19 of 26). The majority (9 of 15) of patients testing false negative for PPD had a history of stroke associated with onset of memory changes, excluding a diagnosis of PPD. CONCLUSIONS: Identifying dementia, in general, and AD, in particular, has an acceptable sensitivity and specificity. As is true for direct clinical diagnosis, the major issue associated with misclassifying AD in a family history assessment is the masking effects of a coexisting non-AD dementia or dementia-related disorders, such as stroke. Including mixed cases, ie, PPD and multiple infarct dementia in estimates of the familial risk for AD can reduce the extent of underestimation of PPD.

Aged↗

PubMed1997

Eye tracking, attention, and schizotypal symptoms in nonpsychotic relatives of patients with schizophrenia.

BACKGROUND: Biological relatives of patients with schizophrenia demonstrate an increased prevalence of schizotypal personality disorder symptoms, eye tracking deficits, and attentional disturbances. We investigated whether these hypothesized components of a schizophrenia-related phenotype are associated with one another or are independent in nonpsychotic relatives of patients with schizophrenia. METHODS: Eighty-three nonpsychotic first-degree relatives of 38 patients with schizophrenia and 45 control subjects without a psychiatric diagnosis underwent clinical evaluation, eye tracking evaluation, and the Continuous Performance Test (CPT) of visual attention. RESULTS: Eye tracking qualitative rating was more powerful than quantitative eye tracking measures or CPT measures in discriminating relatives of patients with schizophrenia from control subjects. Correlations between neurocognitive variables and DSM-III-R schizotypal personality disorder symptom clusters suggested that CPT errors of omission are associated with positive schizotypal symptoms. Eye tracking measures were not significantly correlated with schizotypal symptoms or CPT errors in relatives of patients with schizophrenia. CONCLUSIONS: Eye tracking deficits in the relatives of patients with schizophrenia are unrelated to CPT deficits and schizotypal symptoms. Eye tracking deficits and disturbances in visual attention may be separate components of a schizophrenia-related phenotype and should be considered as independent factors in genetic studies of schizophrenia.

Adult↗

PubMed1997

Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia.

BACKGROUND: Cytoarchitectural and neurochemical studies demonstrate disorganization in the cerebral cortex in schizophrenia, which perhaps underlies the severe behavioral disturbances of the disease. This neuronal disarray should be accompanied by synaptic abnormalities. As such, presynaptic proteins have proved valuable indexes of synaptic density and their concentrations have correlated markedly with synaptic loss. Our study sought to determine whether abnormalities exist in the concentrations of presynaptic proteins in the postmortem cerebral cortex of subjects with schizophrenia. METHODS: Presynaptic protein immunoreactivities were assessed in 4 different cerebrocortical regions derived from 16 elderly controls, 19 elderly subjects with schizophrenia, and 24 subjects with Alzheimer's disease. Tissues were assayed with the monoclonal antibodies EP10 and SP4, which recognize synaptophysin, and the monoclonal antibodies SP6 and SP14, which detect syntaxin and synaptosomal-associated protein-25-kd immunoreactivities, respectively. RESULTS: In subjects with schizophrenia relative to controls, presynaptic proteins were increased in the cingulate cortex, but were unchanged in the temporal, frontal, and parietal cortices. In contrast, when cases with Alzheimer's disease were compared with controls, presynaptic proteins were decreased in the frontal, temporal, and parietal samples. CONCLUSIONS: These findings reveal changes in the synaptic organization of the cingulate cortex in schizophrenia relative to other areas examined. These changes are distinct from the deficits in presynaptic proteins observed in Alzheimer's disease.

Alzheimer Disease↗

PubMed1997

Dopamine receptor transcript expression in striatum and prefrontal and occipital cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia.

BACKGROUND: The identification of novel subtypes of the dopamine receptors has renewed interest in the involvement of dopaminergic mechanisms in schizophrenia. We determined the expression of transcripts encoding the dopamine receptors in the brains of schizophrenic patients. METHODS: The levels of the messenger RNA molecules encoding the 5 dopamine receptors were quantified in postmortem brain samples from 16 schizophrenic patients and 9 control subjects. Samples from multiple regions of the prefrontal cortex, primary visual cortex, and striatum were subjected to in situ hybridization followed by quantitative image analysis. RESULTS: Expression of dopamine receptor transcripts did not differ between schizophrenic patients and controls in striatum or visual cortex. Dramatic decreases of dopamine receptor transcripts were found in the prefrontal cortex, but these changes were restricted to the D3 and D4 receptors, and localized to Brodmann area 11 (orbitofrontal cortex). CONCLUSIONS: Cortical dopaminergic neurotransmission may be disrupted in schizophrenia at the level of receptor expression. There appears to be a focal abnormality of D3 and D4 messenger RNA expression in the prefrontal cortex, with down-regulation of both, consistent with prefrontal cortical hypodopaminergia in schizophrenia.

Aged↗

PubMed1997

The Caregiver Activity Survey (CAS): development and validation of a new measure for caregivers of persons with Alzheimer's disease.

BACKGROUND: Most instruments that measure the impairments associated with Alzheimer's disease assess symptom severity. Little attention has been paid to the illness's impact on the time formal and informal caregivers spend caring for Alzheimer's individuals. A tool that measures the time spent caregiving would help to determine the economic impact of the illness. The Caregiver Activity Survey (CAS) was developed to measure the time caregivers spend aiding Alzheimer's patients with their day-to-day activities. METHODS: The test-retest reliability of the CAS was assessed during a 3-week study with 42 Alzheimer's patients and their caregivers. The CAS was validated with the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog), the Mini Mental State Exam (MMSE) and the Physical Self Maintenance Scale (PSMS). RESULTS: The final version of the CAS consists of six items (communicating with the person, using transportation, eating, dressing, looking after one's appearance and supervising the person). The six-item CAS total score has high test-retest reliability, with ICC = 0.88 between weeks 1 and 3. The scale has strong convergent validity with the ADAS-Cog (r = 0.61), MMSE (r = -0.57) and PSMS (r = 0.43). Efforts to include a dimension that reflects caregiver burden were not successful, in part due to the reluctance of caregivers to acknowledge that caregiving is bothersome. CONCLUSIONS: The CAS provides a new tool that measures time spent caring for Alzheimer's individuals. The instrument may be used to augment existing clinical assessments that measure the efficacy of potentially therapeutic agents for persons with Alzheimer's disease.

Activities of Daily Living↗

PubMed1997

Cooling gradients and formation of gaseous microemboli with cardiopulmonary bypass: an echocardiographic study.

BACKGROUND: Previous studies demonstrated gas emboli formation during rewarming from hypothermia on cardiopulmonary bypass when the temperature gradient exceeded a critical threshold. It also has been suggested that formation of arterial gas emboli may occur during cooling on cardiopulmonary bypass when cooled oxygenated blood exiting the heat exchanger is warmed on mixture with the patient's blood. The purpose of this study was to determine under what circumstances gas emboli formation would occur during cooling on cardio-pulmonary bypass. METHODS: Eight anesthetized mongreal dogs were placed on cardiopulmonary bypass using a roller pump, membrane oxygenator, and arterial line filter. For emboli detection, we positioned a transesophageal echocardiographic probe at the aortic arch distal to the aortic cannula and Doppler probes at the common carotid artery and the arterial line. Cooling gradients between normothermic blood and cooled arterial perfusate of 5 degrees, 10 degrees, 15 degrees, 20 degrees, and 0 degree C (isothermal controls) were investigated. In addition to preestablished temperature gradients, we investigated the effect of rapid cooling (maximal flow through the heat exchanger at a water bath temperature of 4 degrees C) after the initiation of normothermic cardiopulmonary bypass. RESULTS: Minimal gas emboli were detected at the aortic arch at gradients of 10 degrees C or greater. The incidence of emboli was related directly to the magnitude of the temperature gradient (p < 0.01). No emboli were detected at the carotid artery. During rapid cooling, no emboli were observed either at the aorta or at the carotid artery. CONCLUSIONS: Cooling gradients of 10 degrees C or greater may be associated with gas emboli formation, but they may be of limited clinical significance because no emboli were detected distal to the aortic arch. During the application of rapid cooling, no emboli formation was observed.

Animals↗

PubMed1997

Pharmacological modulation of Alzheimer's beta-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions.

Abnormal deposition and accumulation of Alzheimer's amyloid beta-protein (A beta) and degeneration of forebrain cholinergic neurons are among the principal features of Alzheimer's disease. Studies in rat model systems have shown that forebrain cholinergic deficits are accompanied by induction of cortical beta-amyloid precursor protein (beta-APP) mRNAs and increased levels of secreted beta-APP in the CSF. The studies reported here determined whether the CSF levels of secreted beta-APP could be altered pharmacologically. In different experiments, rats with lesions of the forebrain cholinergic system received injections of vehicle, a muscarinic receptor antagonist scopolamine, or one of two cholinesterase inhibitors - diisopropyl phosphorofluoridate (DFP) or phenserine. Scopolamine was administered to determine whether the levels of beta-APP in the CSF could be increased by anticholinergic agents. The cholinesterase inhibitors were administered to determine whether the forebrain cholinergic system lesion-induced increases in CSF beta-APP could be reduced by cholinergic augmentation. Scopolamine administration led to a significant increase in the CSF levels of secreted beta-APP in sham-lesioned rats. Phenserine, a novel, reversible acetyl-selective cholinesterase inhibitor, significantly decreased the levels of secreted beta-APP in the CSF of forebrain cholinergic system-lesioned rats whereas DFP, a relatively non-specific cholinesterase inhibitor, failed to affect CSF levels of secreted beta-APP. These results suggest that the levels of secreted beta-APP in the CSF can be pharmacologically modulated but that this modulation is dependent upon the status of the forebrain cholinergic system and the pharmacological properties of the drugs used to influence it.

Alzheimer Disease↗

PubMed1997

Augmenting cardiac contractility hastens myocardial edema resolution after cardiopulmonary bypass and cardioplegic arrest.

UNLABELLED: Although myocardial edema is associated with cardiopulmonary bypass (CPB) and cardioplegic arrest (CPA), interventions to expedite edema removal have not been investigated. The primary mechanism for the removal of excess interstitial fluid in the heart is myocardial lymphatic drainage, but lymphatic function can be impaired by decreased contractility because of edema. The purpose of this study was to determine whether enhancing cardiac contractility would increase myocardial lymphatic function and hasten edema resolution after CPB. Sixteen dogs were subjected to CPB and 1 h of hypothermic CPA. After weaning from CPB, 10 dogs received an intravenous dobutamine infusion and 6 dogs received no inotropic support. We determined myocardial lymph driving pressure from the major cardiac lymphatic, myocardial water content by using microgravimetry, and the peak rate of left ventricular pressure increase (dP/dmax) by using micromanometry. Measurements were taken at baseline, during CPA, and 60 min after CPB. Compared with controls, dobutamine-treated dogs had an increased dP/dmax (P < 0.05), which was associated with higher lymph driving pressures (P < 0.05), resulting in lower myocardial water gain 1 h after CPB (P < 0.05). We conclude that the resolution of myocardial edema after CPB was hastened by dobutamine. Organized ventricular contraction and myocardial contractility seem to be important determinants of myocardial lymphatic function and myocardial edema removal. These findings suggest that the administration of inotropic drugs after CPB may hasten cardiac recovery. IMPLICATIONS: Myocardial edema, which develops during cardiopulmonary bypass and cardioplegic arrest, contributes to cardiac dysfunction after heart surgery. This study demonstrated that enhancement of cardiac contractility by the administration of dobutamine after cardiopulmonary bypass and cardioplegic arrest was associated with increased myocardial lymphatic function and hastened edema resolution in dogs.

Animals↗

PubMed1997

Effect of body repositioning after venous air embolism. An echocardiographic study.

BACKGROUND: Current therapy for massive venous air embolism (VAE) may include the use of the left lateral recumbent (LLR) position, although its effectiveness has been questioned. This study used transesophageal echocardiography to evaluate the effect of body repositioning on intracardiac air and acute cardiac dimension changes. METHODS: Eighteen anesthetized dogs in the supine position received a venous air injection of 2.5 ml/kg at a rate of 5 ml/ s. After 1 min the dogs were repositioned into either the LLR, LLR 10 degrees head down (LLR-10 degrees), right lateral recumbence, or remained in the supine position. RESULTS: Repositioning after VAE resulted in relocation of intracardiac air to nondependent areas of the right heart. Peak right ventricular (RV) diameter increase and mean arterial pressure decrease were greater in the repositioned animals compared with those in the supine position (P < 0.05). Right ventricular diameter and mean arterial pressure showed an inverse correlation (r = 0.81). Peak left atrial diameter decrease was greater in the LLR and LLR-10 degrees positions compared with the supine position (P < 0.05). Repositioning did not influence peak pulmonary artery pressure increase, and no correlation was found between RV diameter and pulmonary artery pressure. All animals showed electrocardiogram and echocardiographic changes reconcilable with myocardial ischemia. CONCLUSIONS: In dogs, body repositioning after VAE provided no benefit in hemodynamic performance or cardiac dimension changes, although relocation of intracardiac air was demonstrated. Right ventricular air did not appear to result in significant RV outflow obstruction, as pulmonary artery pressure increased uniformly in all groups and was not influenced by the relocation of intracardiac air. The combination of increased RV afterload and arterial hypotension, possibly with subsequent RV ischemia rather than RV outflow obstruction by an airlock appeared to be the primary mechanism for cardiac dysfunction after VAE.

Animals↗

PubMed1997

Noncognitive disturbances in Alzheimer's disease: frequency, longitudinal course, and relationship to cognitive symptoms.

OBJECTIVE: To investigate the frequency and longitudinal course of symptoms of depression, agitation, and psychosis in a longitudinally studied sample of patients with Alzheimer's disease (AD). DESIGN: Longitudinal study of AD patients with follow-up assessments at 6-month intervals for an average of more than 3 years. SETTING: Alzheimer's Disease Research Center of the Mount Sinai Medical Center and the Bronx VA Medical Center, New York. PARTICIPANTS: A total of 153 AD patients. MEASUREMENTS: Blessed Test of Information, Memory and Concentration (BIMC) and the Alzheimer's Disease Assessment Scale cognitive (ADAS-Cog) and noncognitive (ADAS-NC) subscales. RESULTS: At entry into the study, more than 90% of patients had a behavioral disturbance that was rated as mild or worse on one of the 10 ADAS noncognitive items; and 40% had at least one rating that was moderate or severe. Correlational analyses indicated that, with the exception of the two mood-related items, noncognitive symptoms on the ADAS were not highly correlated with one another. Only one of the noncognitive items, concentration, was strongly correlated with the severity of cognitive impairment. On average, patients showed progressively worse cognitive functioning over time as measured both by the ADAS-Cog and the BIMC. The mean severity of noncognitive symptoms did not change during the course of a 5-year follow up. The severity of behavioral disturbance at any one evaluation was negatively correlated with change in behavior during the next 6 months and was not correlated with cognitive decline. CONCLUSION: Mild behavioral disturbances are common, whereas moderate to severe behavioral symptoms are less frequent in this population of AD patients. Disturbances in mood and manifestations of agitation and psychotic symptoms are not closely related to one another and show little progressive worsening over time. Rather, they tend to be episodic such that increasing severity at one time is usually followed by improvement later. Concentration problems are a manifestation of cognitive dysfunction rather than behavioral disturbance in AD. Implications of these results for treatment of noncognitive disturbances in AD are discussed.

Activities of Daily Living↗

PubMed1997

Age-related differences in formal thought disorder in chronically hospitalized schizophrenic patients: a cross-sectional study across nine decades.

OBJECTIVE: This study used a cross-sectional design to examine the frequency of occurrence and severity of 10 different signs of thought disorder in schizophrenic patients across the lifespan. METHOD: Schizophrenic patients, who ranged in age from 19 to 96 years (N = 392), were examined with the Scale for Assessment of Thought, Language, and Communication. The cognitive functioning of the geriatric patients (patients over the age of 64, N = 120) was also assessed. RESULTS: Poverty of speech was more common and more severe in geriatric patients, while four different signs of thought disorder that reflect disconnected speech were less common and less severe in geriatric patients. Analysis of covariance found that the lower severity of disconnection thought disorders in the older patients was not attributable to differences in the amount of speech produced. CONCLUSIONS: Aspects of disconnected speech were less severe in older patients, while the severity and frequency of poverty of speech were greater. These findings suggest that the two previously identified separate dimensions of communication disorder in schizophrenia vary differently with age and possibly in their cognitive and biological underpinnings.

Adult↗

PubMed1997

The search for disease-modifying treatment for Alzheimer's disease.

As a result of advances in the understanding of neurodegenerative mechanism in Alzheimer's disease, several strategies for the development of disease-modifying treatment are being investigated. Nerve growth factor and other neurotrophins may improve neuronal survival, although targeted delivery remains an obstacle. Modulation of protein processing has the potential to decrease the formation of plaques and tangles. Pharmacologic reduction of oxidative stress and destructive inflammation may slow the rate of neurodegeneration. Continued research into basic mechanisms, along with therapeutic trials of promising drugs, are improving the likelihood that it will soon be possible to slow the progression of this disease.

Alzheimer Disease↗

PubMed1997

A risk-benefit assessment of tacrine in the treatment of Alzheimer's disease.

Tacrine, the first drug specifically approved for Alzheimer's disease, produces symptomatic improvement. The theoretical rationale behind treating Alzheimer's disease with tacrine is based on central cholinergic depletion. Tacrine is centrally acting, uncompetitive reversible inhibitor of acetylcholinesterase and butyrylcholinesterase. Multiple clinical trials support the effectiveness of tacrine in Alzheimer's disease. High dosages of tacrine are required for efficacy, with the potential for hepatic and mild gastrointestinal adverse effects. However, the benefits of tacrine currently outweigh its risks, and a trial of the drug should be offered to patients. As clinical experience with tacrine increases, the long term risk-benefit equation may be refined.

Alzheimer Disease↗

PubMed1996

Protein kinase C-epsilon is necessary for erythropoietin's up-regulation of c-myc and for factor-dependent DNA synthesis. Evidence for discrete signals for growth and differentiation.

Erythropoietin regulates the transcription of the protooncogenes c-myc and c-myb by discrete protein kinase C (PKC)-dependent and protein serine/threonine phosphatase-dependent pathways, respectively (Spangler, R., Bailey, S. C., and Sytkowski, A. J. (1991) J. Biol. Chem. 266, 681-684; Patel H. R, Choi H.-S, and Sytkowski A. J. (1992) J. Biol. Chem. 267, 21300-21302). In the present study we demonstrate that up-regulation of c-myc requires the PKC-epsilon isoform and that this pathway is required for erythropoietin-induced DNA synthesis (growth) but apparently not for beta-globin expression (differentiation). Treatment of Rauscher murine erythroleukemia cells resulted in phosphorylation of phospholipase C-gamma1 and activation of PKC-epsilon as evidenced by its translocation from soluble to particulate subcellular fractions. Artificial down-regulation of PKC-epsilon with antisense oligodeoxynucleotides blocked erythropoietin's up-regulation of c-myc in a concentration-dependent manner. In contrast, antisense oligodeoxynucleotides to PKC-alpha, -beta, -gamma, -delta, and -zeta had no effect. Although down-regulation of PKC-epsilon blocked the increase in c-myc expression, it did not inhibit erythropoietin induction of beta-globin expression, a marker of erythroid differentiation. However, down-regulation of PKC-epsilon did block factor-dependent DNA synthesis quantified by measurement of [3H]thymidine incorporation into newly synthesized DNA of normal murine erythroid cells. The results are consistent with discrete intracellular signals regulating erythroid cell growth and differentiation.

Animals↗