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Biomedical subjects

D C Macallan

Publications and source records attributed to D C Macallan.

At least 19 recordsLinked to original sources
PubMed2006

Altered CD45 expression in C77G carriers influences immune function and outcome of hepatitis C infection.

BACKGROUND: A polymorphism in exon 4 (C77G) of CD45 that alters CD45 splicing has been associated with autoimmune and infectious diseases in humans. OBJECTIVE: To investigate the effect of C77G in hepatitis C virus (HCV) infected individuals and study the phenotype and function of peripheral blood mononuclear cells (PBMC) from healthy and hepatitis C infected C77G carriers. RESULTS: C77G individuals showed an increased proportion of primed CD45RA and effector memory CD8 T cells and more rapid activation of the lymphocyte specific protein tyrosine kinase (Lck) following CD3 stimulation. Transgenic mice with CD45 expression mimicking that in human C77G variants had more activated/memory T cells, more rapid proliferative responses, and activation of Lck. CONCLUSIONS: Changes in CD45 isoform expression can alter immune function in human C77G variants and CD45 transgenic mice. The C77G allele may influence the outcome of HCV infection.

Animals↗
PubMed2001

Metabolic syndromes in human immunodeficiency virus infection.

Infection with human immunodeficiency virus (HIV) is associated with marked disturbance of metabolism affecting the metabolism of carbohydrates, fats and proteins. In the first decade of clinical experience of HIV, the primary clinical manifestation of such disturbed metabolism was wasting. Such wasting was often severe and contributed significantly to the morbidity and mortality of AIDS. Mechanistic studies demonstrated that in addition to the effects of altered intermediary metabolism, reduced food intake played a major role in the causation of AIDS-related wasting. More recently, potent anti-retroviral drugs have dramatically changed the clinical consequences of HIV infection. Wasting has become far less frequent among infected patients and occurs in only a small percentage of subjects on effective anti-retroviral therapy. However, a new constellation of metabolic syndromes has become apparent characterized by altered body fat distribution ('lipodystrophy'), lactic acidosis and evidence of mitochondrial dysfunction. The mechanistic basis for such syndromes is currently unclear, but is the subject of ongoing research.

Anti-HIV Agents↗
PubMed2000

Determinants of energy intake and energy expenditure in HIV and AIDS.

To determine the relative importance of various factors in the causation of wasting related to human immunodeficiency virus (HIV), quantitative analysis and linear structural modeling was performed on energy metabolism data collected longitudinally and prospectively from 33 men positive for the human immunodeficiency virus at 105 time points over a 3-y period before the era of highly active antiretroviral therapy. Measured variables included energy intake, total energy expenditure, resting energy expenditure, rate of change in weight, CD4 count, clinical status, appetite, and mood. Derived variables included energy balance, activity-related energy expenditure, and physical activity level. Relative contributions were assessed by linear structural modeling based on multiple regression expressing results as path coefficients for individual relationships. The primary determinant of energy balance was energy intake (r = 0.80). Total energy expenditure made a very minor contribution to energy balance (r = -0.04). Total energy expenditure was primarily determined by activity level (r = 0.91), which itself was negatively related to the presence of opportunistic infection and CD4 count. Energy intake was related to activity level (r = 0.28) and appetite (r = 0.30), which were closely interrelated (r = 0.59). Such linear structural models allow quantitative importance to be apportioned to factors determining weight change in those infected with HIV and represent a powerful tool for future metabolic studies.

AIDS-Related Opportunistic Infections↗
PubMed2000

Is acute appendicitis another inflammatory condition associated with highly active antiretroviral therapy (HAART)?

OBJECTIVE: To report the occurrence of acute appendicitis as a possible manifestation of the immune restoration inflammatory syndrome (IRIS) following the commencement of highly active antiretroviral therapy (HAART) in HIV patients. DESIGN: Case-note review of HIV patients on HAART with acute appendicitis. METHODS: Review of HIV markers, antiretroviral therapy and abdominal ultrasound results of four HIV patients with acute appendicitis and the histopathology reports on the appendix in two of the patients. RESULTS: From a population of approximately 350 HIV patients on HAART, we found four patients who developed acute appendicitis within 6 months of commencing or changing HAART. CONCLUSION: Acute appendicitis occurring in HIV patients on HAART may represent a variant of IRIS. Further immunohistopathological and epidemiological evaluation will be needed to define this relationship fully.

Acute Disease↗
PubMed2000

Tuberculosis, malnutrition and wasting.

Malnutrition predisposes to tuberculosis, and tuberculosis causes 'consumption'. Starting from current advances and historic findings in epidemiology and immunology, we can hope to decipher the effects of macro- and micronutrient deficiency upon tuberculosis, the contribution of immune response to the pathogenesis of wasting, and the best approach to its treatment.

Diet, Vegetarian↗
PubMed1999

Short-term growth hormone administration at the time of opportunistic infections in HIV-positive patients.

OBJECTIVES: A 12-week course of recombinant human growth hormone is an effective but expensive therapy for established HIV-related wasting. Wasting in HIV disease is often episodic, coinciding with bouts of acute opportunistic infection. We hypothesized that a short course of growth hormone, targeted at the time of opportunistic infection, might improve protein metabolism thereby reducing lean tissue loss. METHODS: HIV-infected men with acute opportunistic infections, who received standard antimicrobial treatment for their infection as well as intensive nutritional counselling and oral energy supplements, were randomized to receive growth hormone or placebo for 14 days. Principal assessments were protein metabolism (measured by 13C-leucine infusion), body composition (measured by DEXA) and safety. RESULTS: There were no significant changes in outcome parameters in the placebo group (n = 11). In the growth hormone group (n = 9), protein catabolic rate decreased by 60% in the fasted state (P = 0.02 versus placebo), lean body mass increased by 2.2 kg (P = 0.03 versus baseline) and fat mass decreased by 0.7 kg (P = 0.002 versus baseline). There was no increase in adverse or serious adverse events in the growth hormone as compared with the placebo group. CONCLUSIONS: A two-week course of growth hormone at the time of acute opportunistic infection in HIV-infected patients improves protein metabolism and body composition during therapy and appears to be safe. This may represent a rational and economical approach to the use of growth hormone therapy.

AIDS-Related Opportunistic Infections↗
PubMed1999

Automated erythrocytapheresis in the treatment of severe falciparum malaria.

Removal of parasitized erythrocytes is generally considered to be of value as adjunctive therapy in severe falciparum malaria with high parasitaemia. This is commonly achieved by exchange transfusion. We describe three cases of severe falciparum malaria treated by automated erythrocytapheresis (red cell exchange) in addition to quinine and conventional supportive therapy. Erythrocytapheresis consists of removal of the red-cell fraction by apheresis. Plasma, leukocyte and platelet fractions are returned to the patient. In all cases, dramatic reduction in parasitaemia was achieved within 2 h with subsequent complete clinical recovery. Erythrocytapheresis has significant advantages over exchange transfusion in terms of speed, efficiency, haemodynamic stability and retention of plasma components such as clotting factors and may thus represent an improvement in adjunctive therapy for severe malaria.

Adult↗
PubMed1999

Malnutrition in tuberculosis.

Tuberculosis has a dramatic effect on nutritional state and this has been borne out in all the studies that have investigated body composition in affected patients. I have included some of the key studies in this review; those I have not cited generally reach the same conclusions. Such malnutrition undoubtedly contributes to the morbidity of the disease and may also contribute to mortality, particularly in resource-poor settings where nutritional state, even in the "healthy," may be parlous. The extent to which such malnutrition also contributes to pathology remains unclear. Certainly, in other models, nutritional depletion has a major impact on immune function (Chandra, 1997) and depression of lymphocyte function cannot be a desirable commodity in an individual fighting invasive mycobacterial infection. Considering the reverse relationship, there is good evidence, both at the population level and at the clinical level, for the effect of primary malnutrition on tuberculosis, both to increase frequency of occurrence and to exacerbate clinical manifestations. It has not been possible to explore this relationship within the context of this paper but it is clearly an important aspect of the bi-directional relationship between tuberculosis and malnutrition. There is still more to be understood about the pathophysiology of the wasting seen in chronic infections such as tuberculosis but it is clear that, in addition to good anti-tuberculous therapy, such patients need a good supply of nutrition during the treatment/recovery phase. In the developed world, this may include medical measures to achieve nutritional support whereas in resource-poor settings, nutritional intake may have more to do with equitable resource distribution and community involvement in health care.

Antitubercular Agents↗
PubMed1999

Nutrition and immune function in human immunodeficiency virus infection.

The triad of human immunodeficiency virus (HIV) infection, nutritional status and immune function are intimately related, each factor having effects on the others. The dominant effect in this three-way relationship is the effect of HIV infection on nutritional status, an effect which, until the advent of potent anti-retroviral drugs, has been manifest primarily as wasting. Recently, more complex metabolic abnormalities have become apparent, particularly fat redistribution syndromes, hyperlipidaemia and hypercholesterolaemia. For the converse effect, the effect of nutritional state on HIV disease progression, there is good evidence that clinical outcome is poorer in individuals with compromised nutrition. However, the beneficial effects of nutritional support have been more difficult to demonstrate. For macronutrients, effective macronutrient supply improves survival in severely-malnourished individuals and may have beneficial effects in less-severely-affected individuals. Micronutrient deficiencies appear to be involved in modifying clinical HIV disease and may also be associated with enhanced mother-to-child transmission of virus, particularly in developing countries. Intervention trials in this setting are currently under way. In conclusion, the interaction of HIV infection and nutrition is of great importance not just because of the major impact that HIV infection has on nutritional state, but also because strategies to improve nutritional status, both quantitatively and qualitatively, may have a beneficial effect on the clinical and immunological course of the disease.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Wasting in HIV infection and AIDS.

AIDS wasting is not characterized by a single pathophysiological process but by a variety of processes that operate at different times. Acute wasting tends to be associated with secondary infections; chronic wasting is associated with gastrointestinal disease. Although resting energy expenditure is increased, total energy expenditure is reduced in individuals who are losing weight and it is usually reduced intake that commonly drives wasting. However, reduced intake is not an adequate explanation for the metabolic abnormalities that are seen in HIV infection. In particular, protein metabolism and lipid metabolism are abnormal, possibly representing inappropriate utilization of substrates. The response to nutrition may be impaired, particularly in terms of accrual of lean tissue but nutritional support may prolong survival. The impact of protease inhibitors on wasting in HIV infection is yet to be fully ascertained but despite antiviral therapy it seems that wasting is likely to remain a problem at least in some patients.

Anti-HIV Agents↗
PubMed1998

Measurement of cell proliferation by labeling of DNA with stable isotope-labeled glucose: studies in vitro, in animals, and in humans.

A method for measuring DNA synthesis and, thus, cell proliferation, in vivo is presented. The technique consists of administering [6,6-2H2]Glc or [U-13C]Glc, isolating genomic DNA, hydrolyzing enzymatically to free deoxyribonucleosides, and derivatizing for GC-MS analysis of dA or dG isotopic enrichments, or both. Comparison of dA or dG to extracellular Glc enrichment (with a correction for intracellular dilution) reveals the fraction of newly synthesized DNA, by application of the precursor-product relationship. Thus, the technique differs from the widely used [3H]thymidine or BrdUrd techniques in that the de novo nucleotide synthesis pathway, rather than the nucleoside salvage pathway, is used to label DNA; the deoxyribose rather than the base moiety is labeled; purine rather than pyrimidine deoxyribonucleosides are analyzed; and stable isotopes rather than radioisotopes are used. The method is applied here in vitro to the growth of HepG2 and H9 cells in culture; in animals to proliferation of intestinal epithelium, thymus, and liver; and in humans to granulocyte turnover in blood. In all instances, measured cell proliferation kinetics were consistent with expected or independently measured kinetics. The method has several advantages over previously available techniques for measuring cell turnover, involves no radioactivity or potentially toxic metabolites, and is suitable for use in humans. The availability of a reliable and safe method for measuring cell proliferation in humans opens up a number of fundamental questions to direct experimental testing, including basic problems related to cancer, AIDS, and other pathologic states.

Animals↗
PubMed1998

Whole body protein metabolism in human pulmonary tuberculosis and undernutrition: evidence for anabolic block in tuberculosis.

1. Differing patterns of protein metabolism are seen in wasting due to undernutrition and wasting due to chronic infection. 2. We investigated whole body energy and protein metabolism in nine subjects with pulmonary tuberculosis, six undernourished subjects (body mass index < 18.5 kg/m2) and seven control subjects from an Indian population. Fasting subjects were infused with L-[1-13C]leucine (2.3 mumol.h-1.kg-1) for 8 h, 4 h fasted then 4 h fed. Leucine kinetics were derived from 13C-enrichment of leucine and alpha-ketoisocaproic acid in plasma and CO2 in breath. 3. Undernourished subjects, but not tuberculosis subjects, had higher rates of whole body protein turnover per unit lean body mass than controls [163.1 +/- 9.4 and 148.6 +/- 14.6 mumol compared with 142.8 +/- 14.7 mumol leucine/h per kg, based on alpha-ketoisocaproic acid enrichment (P = 0.039)]. 4. In response to feeding, protein oxidation increased in all groups. Tuberculosis subjects had the highest fed rates of oxidation (47.0 +/- 10.5 compared with 37.1 +/- 5.4 mumol.h-1.kg-1 in controls), resulting in a less positive net protein balance in the fed phase (controls, 39.7 +/- 6.2; undernourished subjects, 29.2 +/- 10.6; tuberculosis subjects, 24.5 +/- 9.3; P = 0.010). Thus fed-phase tuberculosis subjects oxidized a greater proportion of leucine flux (33.2%) than either of the other groups (controls, 24.0%; undernourished subjects, 24.0%; P = 0.017). 5. Tuberculosis did not increase fasting whole body protein turnover but impaired the anabolic response to feeding compared with control and undernourished subjects. Such 'anabolic block' may contribute to wasting in tuberculosis and may represent the mechanism by which some inflammatory states remain refractory to nutrition support.

Adolescent↗
PubMed1997

Longitudinal changes in body composition measured with a variety of methods in patients with AIDS.

We test the hypothesis that human immunodeficiency virus (HIV)-related weight loss is accompanied by inappropriately large losses of fat-free mass (FFM). Our secondary aims were to examine whether FFM increases during weight gain and to compare several techniques for measuring FFM change. FFM was measured at intervals averaging 5 months in 21 AIDS patients by means of skinfold thickness (SF), dual-energy x-ray absorptiometry (DEXA), total body water (TBW), and bioelectrical impedance using the equation of the manufacturer of the equipment (BIA(EZComp)) and a published prediction equation (BIA(Segal)). The FFM content of weight loss was similar for SF (57%), DEXA (60%), TBW (55%) and BIA(EZComp) (65%), but the result from BIA(Segal) (78%) was higher. The results were close to predicted starvation values apart from the results with BIA(Segal), which were significantly higher than predicted values. Weight gain was also composed of a large proportion of FFM. There were large intermethod differences in measurements of absolute FFM, but for measuring changes in FFM, the bias between SF, DEXA, and TBW was minimal. The results of BIA vary with the prediction equation used. In this group of patients with the acquired immune deficiency syndrome (AIDS), weight loss was composed of a large proportion of FFM, but in general this is compatible with undernutrition as the underlying cause and does not support the hypothesis of excessive FFM catabolism in HIV disease. SF, DEXA, TBW, and BIA(Segal) show reasonable agreement for measuring body composition changes. This information should be considered in the design of future intervention studies for HIV-related wasting.

Absorptiometry, Photon↗