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.

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.

The effect of endotoxin on skeletal muscle protein gene expression in the rat.

Sepsis is associated with net breakdown of skeletal muscle protein, mediated partly by reduced rates of muscle protein synthesis. This study investigated the role of altered gene expression for specific muscle proteins in mediating reduced protein synthesis in a rat model of acute severe sepsis. Adult rats were given a single sublethal intraperitoneal dose of endotoxin (bacterial lipopolysaccharide). Protein, RNA and DNA contents of muscle were measured and changes in expression of mRNA in tibialis anterior and extensor digitorum longus muscles were detected by quantification of Northern blots at 6, 24, 48 and 72 hr after endotoxin and in animals starved for 24 hr. Results showed that at 24 hr after endotoxin there was a loss of about 14% of muscle protein content. No reduction in mRNA was found at any time point for beta-myosin heavy chain (MHC), fast-MHC, alpha-actin, skeletal muscle troponin or carbonic anhydrase III (CA III); rather, at 48 hr there was increased expression of beta-MHC (224 +/- 123% control) and CA III (202 +/- 56%). Blocking TNF-alpha by pre-treatment with a monoclonal antibody did not appear to influence this. Total RNA content of muscle was reduced to 67% of the control values 24 hr after LPS, although this was no different to pair-fed animals starved for 24 hr. It is concluded that reduced protein synthesis in skeletal muscle in early acute sepsis is not primarily associated with reduced muscle protein gene expression.

Prospective analysis of patterns of weight change in stage IV human immunodeficiency virus infection.

Weight loss is a major manifestation of infection with the human immunodeficiency virus (HIV). Prospective analysis of weight change was performed in 30 male subjects with stage IV HIV infection over a period of 9-49 mo and weight change events (> 4 kg) related to contemporaneous clinical events. Two distinct patterns of weight loss were observed: episodes of acute severe weight loss and episodes of chronic unremitting progressive weight loss. Thirty-three acute episodes (median 9.1 kg in 1.7 mo) and 23 chronic episodes (13.2 kg in 9.5 mo) were identified. Twenty-seven of 33 (82%) acute weight-loss episodes were associated with nongastrointestinal opportunistic infections and 15 of 23 (65%) chronic episodes with gastrointestinal disease (P < 0.01). Weight loss was neither inevitable nor unremitting. Periods of weight stability (> 4 mo) occurred in 13 individuals (43%); 35 episodes of weight gain were identified, mostly related to recovery from opportunistic infection. These findings have important implications for our understanding of the natural history of weight loss in HIV infection.

Whole-body protein turnover from leucine kinetics and the response to nutrition in human immunodeficiency virus infection.

Whole-body protein metabolism was investigated in human immunodeficiency virus (HIV) infection by primed constant infusion of L-[1-13C]leucine in 8 control and 22 HIV-infected subjects (8 stage II; 14 stage IV disease), in postabsorptive and fed states. Postabsorptive leucine flux was increased 25% in subjects with stage IV HiV infection vs that in control subjects (130 +/- 13 vs 103 +/- 10 mumol leucine.kg-1.h-1, P < 0.001); both leucine disposal by protein synthesis (111.6 +/- 12.1 vs 82.3 +/- 9.2, P < 0.001) and release by protein degradation (129.7 +/- 13.1 vs 103.4 +/- 10.2, P < 0.001) were increased. No difference in leucine balance or oxidation was found but fat oxidation was greater in subjects with HIV infection (61.1 +/- 13.0% of energy) than in control subjects (47.6 +/- 13.7% of energy, P < 0.025). Stage II subjects had intermediate values of leucine flux, not significantly different from those of control subjects. Provision of parenteral nutrition for 4 h increased leucine flux with a switch in leucine balance from net loss to net gain; this response was quantitatively similar in all groups. HIV infection increases whole-body protein turnover but does not quantitatively impair the acute anabolic response to intravenous nutrition.

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.

Red cell exchange, erythrocytapheresis, in the treatment of malaria with high parasitaemia in returning travellers.

In severe falciparum malaria with high parasitaemia, removal of parasitized erythrocytes is generally considered to be of value as adjunctive therapy in addition to standard chemotherapy. Such removal is commonly achieved by exchange transfusion but this procedure is time-consuming and may be associated with haemodynamic disturbance. Current-generation automated cell-separator hardware and software allows prompt red cell exchange, erythrocytapheresis, in a single continuous-flow isovolaemic procedure. We describe the application of this procedure to 5 cases of severe falciparum malaria in travellers returning to the UK from the tropics. All patients also received quinine and conventional supportive therapy. 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.

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.

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.

Total contractile protein contents and gene expression in skeletal muscle in response to chronic ethanol consumption in the rat.

An investigation was carried out to determine changes in the contents of skeletal muscle myofibrillary proteins (i.e., the contractile fraction composed principally of actin and myosin) and gene expression in skeletal muscle in response to ethanol feeding. Male Wistar rats were fed a nutritionally complete liquid diet, which contained 35% of total calories as ethanol. Controls were pair-fed isocaloric amounts of the same diet, in which ethanol was replaced by isocaloric glucose. Total mixed and contractile protein contents of the gastrocnemius in ethanol-fed rats were rapidly reduced by ethanol feeding: a response was discernible as early as 1 week after the commencement of the ethanol feeding regimen (approx. -10%, p < 0.025 and p = 0.05 for mixed and myofibrillary proteins, respectively). At 2, 4, and 6 weeks, mixed and myofibrillary protein contents were further reduced in alcohol-fed rats, by between 12% and 22%, compared to pair-fed controls. Similar changes occurred in the soluble (i.e., sarcoplasmic) protein fractions of skeletal muscle. At 2 weeks the composition of total messenger RNA and individual messenger RNA species was measured. Total messenger RNA content per muscle was reduced by 35% (p < 0.05). Messenger RNA levels for alpha-actin, beta-myosin heavy chain, and carbonic anhydrase III were not significantly altered. In conclusion, skeletal muscle protein contents are rapidly reduced by ethanol feeding, compared to pair-fed controls, though mRNA species encoding specific isoforms of myosin and actin are not affected. It is possible that chronic ethanol feeding may significantly alter the stability of mRNAs encoding other contractile proteins, or alternatively, defects in translation may predominate.

Polyarteritis nodosa presenting as bilateral sudden onset cochleo-vestibular failure in a young woman.

Sudden onset sensorineural hearing loss is an otological emergency. Although deafness is recognised as being associated with polyarteritis nodosa (PAN) only very rarely does it herald the disease. We describe a case of bilateral, sudden onset vestibulo-cochlear failure which with thorough investigation proved to be the presenting complaint of PAN. This diagnosis enabled definitive management of a multi-system disorder and resulted in an improvement of the initial symptom with the chemotherapeutic regime discussed. We review the involvement of PAN in deafness and hope this case will remind otolaryngologists of the need for full investigation of the above mentioned emergency, in an attempt to discover and hence direct management towards a specific underlying pathology.

The electrocardiogram in general practice: its use and its interpretation.

General practitioners in one health district were surveyed by postal questionnaire (including 15 sample electrocardiogram tracings) to assess their usage and competence in interpretation of the electrocardiogram. A response rate of 60% was achieved, of whom 40% said they used the electrocardiogram at least monthly and 43% used it 'always' or 'usually' in patients with suspected myocardial infarction at home. Overall competence in recognizing a variety of abnormalities was felt to be good. Recent qualification, the possession of a higher qualification (MRCP/MRCGP) and frequency of usage were associated with better performance. Even so, unequivocal acute myocardial infarction was misdiagnosed by 20% of respondents. These findings have implications for the provision of electrocardiographic services in primary care and the management of patients in the home with suspected myocardial infarction, particularly with the advent of thrombolytic therapy.

Evaluation of a pro-active strategy for managing tuberculosis-HIV co-infection in a UK tertiary care setting.

Management of tuberculosis (TB)-HIV co-infection is complicated by interactions between the diseases and their therapies. We developed and evaluated a strategy to (i) treat co-infected patients in a single co-infection clinic, (ii) maximize use of first-line drugs, (iii) delay antiretroviral therapy (ART) until two months post-TB treatment except in severe immunosuppression, (iv) commence efavirenz at 600 mg daily with therapeutic drug monitoring (TDM) and (v) target treatment completion. We conducted a prospective cohort review over 5.5 years in a UK tertiary referral center where 56 HIV-positive patients treated for TB were followed-up for a median 30 months. Main outcome measures were treatment completion, adverse events, immune reconstitution inflammatory syndrome, immunological and virological parameters, and TDM for efavirenz. Treatment completion rates were 88% (49/56); four patients were lost to local follow-up and three (5.4%) died during treatment; no deaths were TB-related. Adverse events were common (55%), but caused no treatment interruptions. Standard doses (600 mg daily) of efavirenz with rifampicin achieved or exceeded therapeutic levels in 25/28 (89%). This study supports combined management for TB-HIV co-infected patients. Delaying ART to two months post-TB treatment did not seem to result in poor clinical outcomes in this well-resourced context. Although efavirenz 600 mg daily usually achieved satisfactory levels, TDM is recommended.

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.

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.