Douglas C. Heimburger

Malnutrition Syndromes: A Conundrum vs Continuum

This provocative commentary critically examines historic definitions for adult malnutrition syndromes as they apply to developed countries with modern healthcare. To stimulate further discussion, the authors propose an updated approach that incorporates current understanding of the systemic inflammatory response to help guide assessment, diagnosis, and treatment. An appreciation of a continuum of inflammatory response in relation to malnutrition syndromes is described. This discussion serves to highlight a research agenda to address deficiencies in diagnostics, biomarkers, and therapeutics of inflammation in relation to malnutrition.

Macronutrient Supplementation for Malnourished HIV-Infected Adults: A Review of the Evidence in Resource-Adequate and Resource-Constrained Settings

Access to antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection has expanded rapidly throughout sub-Saharan Africa, but malnutrition and food insecurity have emerged as major barriers to the success of ART programs. Protein-calorie malnutrition (a common form of malnutrition in the region) hastens HIV disease progression, and food insecurity is a barrier to medication adherence. Analyses of patient outcomes have identified a low body mass index after the start of ART as an independent predictor of early mortality, but the causes of a low body mass index are multifactorial (eg, normal anthropometric variation, chronic inadequate food intake, and/or wasting associated with HIV infection and other infectious diseases). Although there is much information on population-level humanitarian food assistance, few data exist to measure the effectiveness of macronutrient supplementation or to identify individuals most likely to benefit. In this report, we review the current evidence supporting macronutrient supplementation for HIV-infected adults, we report on clinical trials in resource-adequate and resource-constrained settings, and we highlight priority areas for future research.

Weight Maintenance 2 Years after Participation in a Weight Loss Program Promoting Low-Energy Density Foods

Objective: Observational study designed to determine weight outcomes and associated dietary intake patterns for a sample of participants ≥1 year after completing the University of Alabama at Birmingham EatRight Weight Management Program.

Simplified severe sepsis protocol: a randomized controlled trial of modified early goal-directed therapy in Zambia.

Objective: To assess the efficacy of a simple, goal-directed sepsis treatment protocol for reducing mortality in patients with severe sepsis in Zambia. Design: Single-center nonblinded randomized controlled trial. Setting: Emergency department, ICU, and medical wards of the national referral hospital in Lusaka, Zambia. Patients: One hundred twelve patients enrolled within 24 hours of admission with severe sepsis, defined as systemic inflammatory response syndrome with suspected infection and organ dysfunction Interventions: Simplified Severe Sepsis Protocol consisting of up to 4 L of IV fluids within 6 hours, guided by jugular venous pressure assessment, and dopamine and/or blood transfusion in selected patients. Control group was managed as usual care. Blood cultures were collected and early antibiotics administered for both arms. Measurements and Main Results: Primary outcome was in-hospital all-cause mortality. One hundred nine patients were included in the final analysis and 88 patients (80.7%) were HIV positive. Pulmonary infections were the most common source of sepsis. In-hospital mortality rate was 64.2% in the intervention group and 60.7% in the control group (relative risk, 1.05; 95% CI, 0.79–1.41). Mycobacterium tuberculosis complex was isolated from 31 of 82 HIV-positive patients (37.8%) with available mycobacterial blood culture results. Patients in Simplified Severe Sepsis Protocol received significantly more IV fluids in the first 6 hours (2.7 L vs 1.7 L, p = 0.002). The study was stopped early because of high mortality rate among patients with hypoxemic respiratory failure in the intervention arm (8/8, 100%) compared with the control arm (7/10, 70%; relative risk, 1.43; 95% CI, 0.95–2.14). Conclusion: Factors other than tissue hypoperfusion probably account for much of the end-organ dysfunction in African patients with severe sepsis. Studies of fluid-based interventions should utilize inclusion criteria to accurately capture patients with hypovolemia and tissue hypoperfusion who are most likely to benefit from fluids. Exclusion of patients with severe respiratory distress should be considered when ventilatory support is not readily available.

Folate Is Associated with the Natural History of High-Risk Human Papillomaviruses

Several micronutrients have been implicated in cervical carcinogenesis. However, their mode of action is still a matter of speculation. In particular, it is unclear whether certain nutrients reduce the probability of acquiring high-risk human papillomavirus (HPV) or whether they facilitate the clearance of high-risk HPV. We conducted a 24-month prospective follow-up study to test the hypothesis that systemic concentrations of folate are associated with the occurrence and duration of high-risk HPV infections after controlling for other micronutrients (vitamins B12, A, E, and C, total carotene) and known risk factors for high-risk HPV infections and cervical cancer. Circulating concentrations of these micronutrients and risk factors for cervical cancer were determined in a cohort of 345 women who were at risk of developing cervical intraepithelial neoplasia. Using the hybrid capture 2 (HC-2) assay, high-risk HPV status was evaluated at 6-month intervals up to 24 months. All women had at least three consecutive visit high-risk HPV test results. Higher folate status was inversely associated with becoming HC-2 test-positive [odds ratio (OR): 0.27; 95% confidence interval (CI), 0.08–0.91; P = 0.04]. Women with higher folate status were significantly less likely to be repeatedly HC-2 test-positive (OR: 0.33; 95% CI, 0.13–0.86; P = 0.02) and more likely to become test-negative during the study (OR: 2.50; 95% CI, 1.18–5.30; P = 0.02). To our knowledge, this is the first long-term prospective follow-up study reporting an independent protective role of higher folate status on several aspects of the natural history of high-risk HPV after controlling for known risk factors and other micronutrients. Improving folate status in subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer.

Nutritional aspects of HIV-associated wasting in sub-Saharan Africa

The twin global epidemics of HIV infection and food scarcity disproportionately affect sub-Saharan Africa, and a significant proportion of patients who require antiretroviral therapy (ART) are malnourished because of a combination of HIV-associated wasting and inadequate nutrient intake. Protein-calorie malnutrition, the most common form of adult malnutrition in the region, is associated with significant morbidity and compounds the immunosuppressive effects of HIV. A low body mass index (BMI), a sign of advanced malnutrition, is an independent predictor of early mortality (<6 mo) after ART initiation in several analyses, and recent studies show an association between early weight gain when receiving ART and improved treatment outcomes. The cause of the observed increase in mortality is uncertain, but it is likely due in part to malnutrition-induced immune system dysfunction, a higher burden of opportunistic infections, and metabolic derangements. In this article, we describe the epidemiology of HIV infection and malnutrition in sub-Saharan Africa, potential causes of increased mortality after ART initiation among patients with a low BMI, recent studies on post-ART weight gain and treatment outcome, and trials of macronutrient supplementation from the region. We close by highlighting priority areas for future research.

Metabolic complications of total parenteral nutrition : Effects of a nutrition support service

BACKGROUND The effectiveness of Nutrition Support Services in optimizing parenteral nutrition has not been evaluated since the 1980s. METHODS We prospectively monitored medical and surgical patients on total parenteral nutrition (TPN) in a university hospital who did not receive Nutrition Support Service recommendations to compare the incidence of metabolic complications in 1979 (group 1, n = 100) with that in 1992 (group 2, n = 106). The Service provided automatic recommendations on a subsequent group of medical service patients (group 3, n = 128) and compared them with the patients in group 2 who were on the medical service (group 2B, n = 29). RESULTS Statistically significant changes between 1979 and 1992 included a decline in the incidence of hyperglycemia from 47% to 22% and in hypokalemia from 12% to 3% of surgical patients and an increase in hypomagnesemia from 0% to 23% of surgical patients and from 2% to 14% of medical patients. The incidence of hypophosphatemia remained > 20% in both medical and surgical patients. Within 1992, the addition of automatic recommendations had little impact on metabolic abnormalities and was associated with slightly but insignificantly lower TPN costs (not counting Service personnel costs). CONCLUSIONS Factors such as the general integration of parenteral nutrition into tertiary medical care, standard protocols and order forms, automatic Nutrition Support Service consultations in an affiliated hospital, and nutrition curricula may be responsible for the improvements seen since 1979. However, the addition of automatic Service consultation in 1992 had only a marginal effect on metabolic complications and costs of parenteral nutrition.

Race- and age-dependent alterations in global methylation of DNA in squamous cell carcinoma of the lung (United States)

Objective: The current study investigated the race- and age-dependent alterations in global DNA methylation on the development and progression of squamous cell carcinomas (SCCs) of the lung. Methods: Methylation status was evaluated in SCC and in the associated uninvolved bronchial mucosa (UBM) and epithelial hyperplasia (EH) of 53 Whites and 23 African Americans by using an antibody specific for 5-methylcytosine (5-mc). A low 5-mc score indicates global hypomethylation of DNA. Results: 5-mc scores of SCC were significantly lower compared to 5-mc scores of UBM and EH in Whites (p < 0.05). In African Americans, 5-mc scores of SCCs were not significantly different from 5-mc scores of UBM and EH, suggesting an involvement of methylation in the development of SCCs in Whites, but not in African Americans. 5-mc scores were lower in younger subjects compared to older subjects in Whites. Since cancers in younger subjects tend to be more aggressive than cancers in older subjects, these observations may suggest that hypomethylation may have contributed to aggressiveness cancers of younger Whites. Hypomethylation of SCCs in White men was associated with shorter survival from the disease. Conclusions: These preliminary results suggest that the methylation status of DNA may affect the development, aggressiveness, and prognosis of SCCs in Whites.

Effects of Small-Peptide and Whole-Protein Enteral Feedings on Serum Proteins and Diarrhea in Critically III Patients: A Randomized Trial

BACKGROUND It has been proposed that enteral feeding formulas containing small peptides are more efficacious and better tolerated than whole-protein formulas in critically ill patients. METHODS Intensive care unit patients were stratified with regard to treatment with antibiotics and serum albumin and randomized to treatment with a small-peptide enteral diet or an isoenergetic, isonitrogenous whole-protein diet for 10 days. To assess efficacy, we measured serum prealbumin and fibronectin, and to assess tolerance, we monitored the incidence of diarrhea. A protocol was followed to ascertain all causes of diarrhea (defined as > 200 g stool or > or = 3 liquid stools on 2 consecutive days). RESULTS Fifty subjects completed the trial. Serum prealbumin and fibronectin increased between 21% and 36% in both groups, but the increase was significant only in the small-peptide group. The change in fibronectin between days 5 and 10 was significantly greater in the small-peptide group (p = .02). Diarrhea occurred in 10 subjects (17.8% of days) receiving small-peptide feeding and 4 subjects (7.5% of days) receiving whole-protein feeding (P = .07 for incidence and 0.03 for prevalence), but the difference was explained by the coincidental use of more diarrhea-causing medications in the former. Only one case of diarrhea could be attributed to tube feeding. CONCLUSIONS During 10 days of feeding, the small-peptide diet produced slightly greater increases in serum rapid-synthesis proteins than did the whole-protein diet, especially between days 5 and 10. The clinical implications of this difference between the diets are unknown. Both small-peptide and whole-protein diets were well tolerated.

Immunohistochemical Evaluation of Global DNA Methylation: Comparison with in Vitro Radiolabeled Methyl Incorporation Assay

The in vitro radiolabeled methyl incorporation assay, a commonly used technique to evaluate global methylation of DNA, has some disadvantages and limitations. The purpose of the present study was to compare the results of global DNA methylation evaluated by radiolabeled methyl incorporation (CPM/μg of DNA) with immunohistochemical staining of the same tissue sections with a monoclonal antibody developed against 5-methylcytosine (5-mc). We used archival specimens of squamous cell cancer (SCC) of the human lung with a matched uninvolved specimen (n = 18 pairs) and 18 lung specimens from subjects without lung cancer (noncancer specimens) to make this comparison. The immunostaining for 5-mc was reported as a percentage of cells positive for staining as well as a weighted average of the intensity score. The results suggested that both radiolabeled methyl incorporation assay and immunostaining for 5-mc can be used to demonstrate hypomethylation of DNA in SCC tissues compared to matched uninvolved tissues. An advantage of immunostaining, however, is its ability to demonstrate hypomethylation of SCC compared to adjacent bronchial mucosa on the same archival specimen, obviating the need to use sections from both SCC and matched uninvolved tissues. Only by using the immunostaining technique were we able to document a statistically significant difference in DNA methylation between SCC and noncancer tissues. We conclude that the immunostaining technique has advantages over the radiolabeled methyl incorporation assay and may be best suited for evaluation of global DNA methylation when the methylation status of cancer cannot be normalized by methyl incorporation of normal tissues or when the number of samples available for evaluation is small.