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Biomedical subjects

C F Howard

Publications and source records attributed to C F Howard.

At least 37 records · Page 2Linked to original sources
PubMed1986

Neutralizing antibody prevents type D retrovirus viremia in Celebes black macaques.

The Celebes black macaque (Macaca nigra) colony at the Oregon Regional Primate Research Center has a high incidence of simian acquired immunodeficiency syndrome (SAIDS-RF) that may be caused by type D retrovirus type 2 (SRV-2). During the spring and autumn screening of the colony, seven monkeys previously aviremic were found to be viremic on the basis of the Raji co-culture assay. These monkeys and control groups were selected for further study, which included titration of neutralizing antibody activity and immunofluorescent antibody (IFA) activity before and at the time that the animals became viremic. Results indicated that neutralizing antibody was not present before or at the time that monkeys became viremic and that control monkeys who were IFA+ and did not become viremic had high levels of neutralizing antibody. The IFA titre did not change significantly or predictably at the time the animals became viremic.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Metabolism of arachidonic acid by macaque platelets. Implications for studies on atherosclerosis.

The metabolism of [1-14C]arachidonic acid [( 1-14C]AA) by washed platelets from macaques and human subjects was investigated. The results were as follows: At substrate levels of 1 microM, similar amounts of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), and thromboxane A2 (TXA2), measured as thromboxane B2 (TXB2), were produced from [1-14C]AA by platelets from rhesus, Celebes black, and cynomolgus macaques and humans. An increase in the AA concentration from 1 microM to 20 microM decreased the TXB2: PGD2 ratio (aggregator: antiaggregator) from greater than 5 to less than 2 in all series. In the human series, the ratio decrease was due to an increase in PGD2 production; in the macaque series, PGD2 production increased and TXB2 production decreased. Under basal conditions and at 1 microM AA concentrations, the amounts of prostaglandins and thromboxanes produced by platelets from male and female rhesus macaques were the same. An increase in substrate concentration from 1 microM to 20 microM AA decreased TXB2 production and increased PGD2 production to the same extent in platelets from male and female rhesus macaques. Imidazole increased prostaglandin production and decreased TXB2 production by platelets from both male and female rhesus macaques. The TXB2: PGD2 ratios were reduced below 1.5; there was no difference between the ratios in the two series. In the presence of 1 mM imidazole, greater amounts of prostaglandins and thromboxanes were produced in the male than in the female series. These data indicate that macaque's platelets are a suitable model for the study of AA metabolism in human platelets.

Animals↗
PubMed1985

Virus-associated deficiencies in the mitogen reactivity in celebes black macaques (Macaca nigra).

Celebes black macaques (Macaca nigra) with a history of diabetes mellitus, recurrent bacterial and protozoal infections, diarrhea, anemia, weight loss, anorexia, and a high mortality were studied to determine their immune status. Two groups of monkeys, healthy and unhealthy, were formed on the basis of a clinical assessment. The proliferative response and the pokeweed-mitogen-induced polyclonal IgG response of peripheral blood mononuclear cells of unhealthy monkeys were significantly less than the responses of healthy monkeys. The percentage of HLA-DR+ cells varied greatly in unhealthy monkeys. The OKT4/OKT8 ratios of unhealthy monkeys were generally greater than the ratios of healthy monkeys. Unhealthy monkeys usually had smaller percentages of OKT8+ cells than did healthy monkeys. The two groups of monkeys were examined for the presence of a syncytial forming retrovirus by a coculture assay involving Raji cells, a human B lymphoblastoid cell line. A type D retrovirus was detected in the unhealthy group but not in the healthy group. Retroperitoneal fibromatosis was detected in several monkeys in the unhealthy group.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Atherosclerosis and insulin in primates with diabetes mellitus.

The most commonly available primate models of diabetes mellitus are of the insulin-dependent type and are attained through beta cell ablation techniques. Noninsulin-dependent primate models are less common since the animals must have a genetic predisposition to diabetes. Few studies have been conducted on lipid or vascular abnormalities associated with diabetes in primates. Diabetes develops spontaneously in Macaca nigra as the result of a lesion in the islets of Langerhans. As secretory cells are gradually lost, mild to moderate hyperglycemia, impaired glucose clearance, acute insulin release, hyperglucagonemia, and chronic hypoinsulinemia develop. Overtly diabetic monkeys require insulin therapy and thus alternate between hypoinsulinemia and hyperinsulinemia. The development of aortic atherosclerosis correlates positively with the severity of metabolic impairment. Lipid deposition is primarily extracellular and there is a paucity of foam cells. The very low density and intermediate-density lipoprotein fractions increase significantly, the low-density lipoprotein fraction increases slightly, and the high-density lipoprotein fractions remain essentially unchanged. Because these monkeys are maintained on a nonatherogenic chow ration, the effects of diabetes, per se, on vascular sclerosis can be evaluated.

Animals↗
PubMed1985

Gestational diabetes mellitus and impaired glucose tolerance in an aged Macaca mulatta.

Gestational diabetes mellitus was diagnosed in an aged (21-year-old) pregnant rhesus monkey (Macaca mulatta); she was hyperglycemic and had minimal glucose clearance in an intravenous glucose tolerance test (iv-GTT). An overweight (840 g) dead full-term fetus was delivered by cesarean section. A second iv-GTT conducted 3 months later revealed impaired glucose tolerance. While pregnant, the monkey was hyperinsulinemic and showed minimal secretory response to the glucose load. When tested postpartum, the fasting insulin was only slightly elevated, but the insulin response to glucose was still lacking.

Aging↗
PubMed1984

Correlations of aortic histology with gross aortic atherosclerosis and metabolic measurements in diabetic and nondiabetic Macaca nigra.

We studied the aortic histology of 28 Macaca nigra males and females, from 6 to more than 20 years old, normal and manifesting various degrees of spontaneous diabetes. Correlations of several metabolic and hormonal indicators of diabetes severity with gross and microscopic findings in the aortas demonstrated direct associations with the severity of atherosclerosis. Mild to relatively severe aortic lesions were present. These monkeys showed many changes similar to those observed in medium and large arteries of diabetic humans. Intimal proliferation, prominent extracellular fibers as part of the intimal thickening, and lipid deposition--mostly in extracellular locations--were particularly evident. Significant relationships were observed when glucose clearance, insulin secretion, and fasting glucose levels were correlated with all aortic microscopic findings. Cholesterol concentrations had no correlation with the histological state of the aortas, and triglyceride levels correlated only with aortic lipid content and intimal thickness. Aortic pathologic changes increased with age; diabetics had significantly greater changes than nondiabetics. Macaca nigra can be useful in the study of how diabetes affects the development of atherosclerosis without the influence of an atherogenic diet.

Animals↗
PubMed1984

Diabetes mellitus: relationships of nonhuman primates and other animal models to human forms of diabetes.

Results from studies with M. nigra allow some conclusions and predictions about the etiology and development of diabetes relative to the islet lesion in monkeys and human beings. Some factor or factors must initiate the lesion; whether this is genetic, environmental, or a combination of both is not known. Amyloid is not the initiating factor to the islet lesion, but appears later as there is deterioration of cells. Sufficient evidence does not yet exist to choose from among the alternatives regarding the source of amyloid. With gradual deterioration of cells and replacement by amyloid, secretion of insulin is impaired and concentrations of glucagon increase. Sufficient circulating insulin is probably chronically available to the cells in this moderately impaired state, so that an acute decrease in delta IRI in response to glucose in an iv-administered GTT does not cause significant impairment in glucose clearance. The increase in circulating glucagon is probably due to a loss of controls on alpha-cell secretion or synthesis of glucagon. Fasting glucose levels increase but remain within the nondiabetic range. Eventually there is sufficient accretion of amyloid, usually greater than 50%, so that substantial beta-cell loss occurs and the monkey can no longer maintain fasting normoglycemia. The monkey then is hyperglycemic and hypoinsulinemic. Only at this time are the impairments detectable by the usual diagnostic clinical criterion of hyperglycemia. The ICAs arise in response to secretory cell deterioration and are present until there no longer are sufficient cells to elicit an immune response. Results from M. nigra can give insight into a similar condition that probably exists in a subpopulation of older diabetic humans. Humans probably pass through stages similar to those discerned in monkeys. Nondiabetic humans with sufficient beta cells to sustain adequate secretion of insulin, but with moderate amyloid infiltration, probably would be in a category equivalent to BD monkeys; since these people are not overtly hyperglycemic, they are not clinically recognizable as diabetic and would be classified retrospectively as nondiabetic. Continued loss of cells with concomitant amyloid deposition would eventually lead to hyperglycemia; if examined at autopsy, these people would have visible islet amyloid as well as a retrospective diagnosis of diabetes. Older type II diabetic humans with ICA usually proceed to insulin therapy more rapidly than do those who are ICA negative (Irvine et al., 1977; Del Prete et al., 1977; Gray et al., 1980).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Islet cell cytoplasmic antibodies in Macaca nigra.

Islet cell antibodies (ICA) have been measured in mature Macaca nigra. Of 30 nondiabetic monkeys, 26 (87%) were ICA-negative; of 43 monkeys with evidence of mild to severe hormonal or glycemic abnormalities, 39 (91%) were ICA-positive. Pancreatic islets were examined from biopsy and autopsy sections to assess cell deterioration and amyloid infiltration. No ICA were found in 13 of 18 (72%) monkeys with no evidence of amyloid, whereas 30 of 35 (86%) monkeys with islet amyloid and concurrent cell deterioration were ICA-positive. Association of ICA with metabolic and islet abnormalities was significant at P less than or equal to 0.001. ICA were specific for the islet cells in pancreatic sections; plasma preincubated with insulin, glucagon, or acetone extracts of tissues retained their ICA-positive reaction. The relationships of ICA in older monkeys to the islet lesion and to metabolic abnormalities could be relevant to similar situations in aging diabetic persons.

Adult↗
PubMed1982

Nonhuman primates as models for the study of human diabetes mellitus.

Nonhuman primates have been used for a variety of studies on diabetes mellitus. Spontaneous, natural forms of diabetes have been well documented in several species; there are limited data on numerous other species that indicate diabetes or a diabetes-like syndrome. The causes and manifestations of spontaneous diabetes, their prevalence, and their severity vary among species. Diabetes has also been induced in nonhuman primates with streptozotocin, alloxan, hypothalamic lesions, or pancreatectomy. The extent and severity of metabolic and hormonal abnormalities vary according to the method of induction, the individual monkey, and the species. Metabolic, hormonal, and pathologic abnormalities present in human diabetics also occur in monkeys with either spontaneous or induced diabetes. Hyperglycemia and impaired glucose clearance are common, lipid concentrations are elevated, and hemoglobin A1c concentrations are increased in hyperglycemic monkeys. Monkeys may have fasting hypo- or hyperinsulinemia; insulin responses are often impaired in glucose tolerance tests. Glucagon concentrations may be increased. Aortic atherosclerosis, muscle capillary microangiopathies, cataracts, and glomerulosclerosis have been documented. Primate size and longevity allow longitudinal studies with procedures that may not be feasible in smaller animals or in human beings. Nonhuman primates may be the models of choice for studies on selected aspects of diabetes and its secondary complications.

Animals↗
PubMed1982

Metabolic and underlying causes of diabetes mellitus.

It is emphasized that animal models should be used to study specific genotypic or phenotypic expressions associated with diabetes rather than assuming a single animal model can reflect diverse forms of the human disease. Diabetic and normal animals are reviewed on the basis of their usefulness as models of genetic, viral, and chemically induced diabetes, including the often associated immune phenomena. Characteristics of spontaneously diabetic animals with and without obesity are also described with an emphasis on both genetics and metabolic derangements. Recommendations for future animal experimentation include: more longitudinal studies evaluating the role of sex, prenatal environment, diet, and viral or chemical attack on B-cell function; characterization of the immune phenomena associated with B-cell lesions (and insulitis) in diabetic and immunologically incompetent lines; clarification of relationships between obesity and islet-cell function with emphasis on the role of fuel metabolism, vitamins, and minerals; and, finally, the development of new models with specific genetic aberrations placed in normal or diabetic lines.

Alloxan↗
PubMed1982

Cardiovascular complications.

This report summarizes the current state of knowledge concerning the cardiovascular system in various animal models of diabetes and presents their major strengths and weaknesses for studying the important research questions in the field. Nonhuman primates have many desirable features for studies on the macrovascular and cardiac complications of the disease as well as risk factor alterations, but their availability, cost, and maintenance present practical disadvantages. The spontaneous rodent models of diabetes currently are not considered very useful for cardiovascular research, but they have not been well characterized with respect to most aspects of their cardiovascular system. Alloxan-diabetic rabbits offer some promise for examining the effects of diabetes on atherogenesis, lipoprotein metabolism, and cardiomyopathy, but additional research is required to validate their usefulness. Insufficient data are available on canine and swine models of diabetes to judge their merits for cardiovascular research. The Task Force recommends: (1) additional longterm investigations to determine the extent and severity of cardiovascular complications in the well-characterized rodent models and in diabetic rodents with multiple risk factor abnormalities; (2) further studies on the macrovascular disease and lipoprotein abnormalities of the alloxan-diabetic rabbit and the development of rabbit colonies with spontaneous diabetes; (3) increased emphasis on such potentially important but neglected areas of research in diabetic animals as the intramyocardial circulation, adventitial blood vessels, blood pressure, platelet function, blood coagulation, blood rheology, and autonomic nervous function; (4) long-term studies on the influence of control of hyperglycemia and of insulin therapy on cardiovascular complications in diabetic animals; and (5) encouragement of use of diabetic nonhuman primates for cardiovascular research and institution of measures to increase their supply and availability by expanding current colonies, screening newly imported animals for diabetes, and establishing a visiting scientist's program allowing investigators to study diabetic primates at resource centers.

Animals↗
PubMed1982

Correlations of hemoglobin A1c and metabolic status in nondiabetic, borderline diabetic, and diabetic Macaca nigra.

Glycosylated hemoglobin A1c (HbA1c) increases from 2.6% in nondiabetic Macaca nigra to 7.9% in diabetic monkeys. Monkeys without overt hyperglycemia but with impaired glucose clearance, impaired insulin secretion, and increased postprandial glucose have a significant increase in glycosylation to 3.5%. HbA1c. Two different forms of hemoglobin are electrophoretically distinguishable in this species due to an amino acid change in the globin beta-chain. Colorimetric analysis established that glycosylation of the different hemoglobin forms was related only to metabolic status. Percentages of glycosylated hemoglobins indicate the inability of monkeys with varying severity of metabolic abnormalities to adequately maintain glucose homeostasis.

Animals↗
PubMed1982

Insular amyloidosis in spontaneously diabetic nonhuman primates.

Sections of pancreas from 21 nonhuman primates with diabetes mellitus were examined by light and electron microscopy. All monkeys showed amyloid accumulation in the islets of Langerhans. Amyloid was identified by its dichroism with three different stains: Congo red, changing from red to yellowish-green; standardized toluidine blue, changing from blue to red; and sulfated alcian blue, changing from blue-green to pink. Sulfated alcian blue was a rapid and effective means of detecting amyloid. The characteristic fibrillar structure of amyloid was seen with transmission electron microscopy. Deposition of islet amyloid was independent of the presence or absence of amyloid in other organs. Results indicate that nonhuman primates offer a model for studying the sequential development of insular amyloidotic diabetes mellitus.

Amyloid↗
PubMed1982

Insular amyloidosis in spontaneously diabetic nonhuman primates.

Sections of pancreas from 21 nonhuman primates with diabetes mellitus were examined by light and electron microscopy. All monkeys showed amyloid accumulation in the islets of Langerhans. Amyloid was identified by its dichroism with three different stains: Congo red, changing from red to yellowish-green; standardized toluidine blue, changing from blue to red; and sulfated alcian blue, changing from blue-green to pink. Sulfated alcian blue was a rapid and effective means of detecting amyloid. The characteristic fibrillar structure of amyloid was seen with transmission electron microscopy. Deposition of islet amyloid was independent of the presence or absence of amyloid in other organs. Results indicate that nonhuman primates offer a model for studying the sequential development of insular amyloidotic diabetes mellitus.

Amyloidosis↗
PubMed1981

Immunoreactive glucagon in nondiabetic and diabetic Macaca nigra.

The primary form of immunoreactive glucagon (IRG) in Macaca nigra has been identified as pancreatic, alpha-cell-size glucagon (IRG3500), with a molecular weight of about 3500. Assays with 30K and K-964 glucagon antibodies gave virtually identical results. Column chromatography of plasma on Bio-Gel P-30 indicated ony minimal amounts of high-molecular-weight IRG. Levels of IRG decrease during a glucose infusion, a response expected of IRG3500. IRG concentrations apparently greater than human values appear to be characteristic of nonhuman primates. Nondiabetic Macaca nigra average 641 pg of IRG3500/ml. Borderline diabetic monkeys with moderately increased glucose and impaired glucose clearance average 2,938 pg/ml. Diabetic monkeys with hyperglycemia and diminished glucose clearance have 375 pg of IRG3500/ml. Changes in IRG3500 are related to a lesion in the islets of Langerhans.

Animals↗
PubMed1981

Diabetes mellitus in the chimpanzee (Pan troglodytes).

Glucose intolerance was found in four adult chimpanzees. The response of glucose, insulin, C-peptide, and glucagon to intravenous glucose and tolbutamide stimulations revealed impaired glucose clearance, deficient pancreatic secretion of insulin and C-peptide, and elevated glucagon levels. Pancreatic islets in a diabetic chimpanzee were hypercellular, possible due to alpha-cells. Minimal or no insulin was observed in beta-cells. Results are consistent with the occurrence of noninsulin-dependent diabetes mellitus, which may be more prevalent in chimpanzees than heretofore suspected.

Animals↗
PubMed1979

Aortic atherosclerosis in normal and spontaneously diabetic Macaca nigra.

Aortic atherosclerosis is minimal in normal Macaca nigra; development of atherosclerosis correlates with increasing severity of diabetes mellitus. The extent of aortic involvement (plaque plus sudanophilia) was quantified and compared with metabolic and clinical parameters. Increasing atherosclerosis correlated with decreasing ability to clear glucose in a tolerance test (P less than 0.01), decreasing insulin (P = 0.02), and increasing glucose (P less than 0.01) and triglycerides (P less than 0.01). A diabetic index, established as a summation of several metabolic measurements, correlated with atherosclerosis at P less than 0.001. On the average, involvement of the thoracic aorta was about 3-fold greater than in the abdominal portion; involvement reached over 40% in severely diabetic monkeys. Atherosclerosis development is unique in these monkeys since they consume a natural ration low in fat and cholesterol. Serum cholesterol did not correlate with diabetes or artherosclerosis. Increasing age alone was associated with slight sudanophila, some intima-media thickening, and occasional small lesions. However, only with increasing severity of diabetes was there significant atherosclerosis.

Age Factors↗