Micronutrients and infection: interactions and implications with enteric and other infections and future priorities

Symposium presentations have focused on the elegant molecular science and the biologic mechanisms by which micronutrients play critical roles in cellular and humoral immune responses, cellular signaling and function, and even in the evolution of microbial virulence. The concluding session examined the practical issues of how best to evaluate the nutritionally at-risk host, especially in the areas of greatest need-an analytical model of nutrient-immune interactions, implications of nutritional modulation of the immune response for disease, and the implications for international research and child health. This overview illustrated how malnutrition may be a major consequence of early childhood diarrhea and enteric infections, as enteric infections may critically impair intestinal absorptive function with potential long-term consequences for growth and development. The potentially huge, largely undefined DALY (disability-adjusted life years) impact of early childhood diarrheal illnesses demonstrates the importance of quantifying the long-term functional impact of largely preventable nutritional and infectious diseases, especially in children in developing areas.     

ERCP and MRCP--when and why

Since the introduction of endoscopic retrograde cholangiopancreatography (ERCP) in the 1970s, gastroenterologists have a wide spectrum of diagnostic and therapeutic options in the biliopancreatic ductal system at their disposal. With its arrival in the 1990s, magnetic resonance cholangiopancreatography (MRCP) developed as a potent diagnostic tool in biliopancreatic pathology. Currently, MRCP is widely replacing diagnostic ERCP and thereby avoiding complications related to endoscopic technique.We summarize evidence-based data and demonstrate indications and differential indications for MRCP and ERCP in pancreatic disease. Complications related to the procedures and possible medical prevention are discussed. The feasibility of interventional endoscopy in pancreatic disease is reported in detail. The role of gastroenterologists in performing MRCP is outlined on the basis of practical examples.     

Convection and permeation and albumin between plasma and interstitium.

Nonequilibrium thermodynamics is combined with compartmental analysis to interpret albumin sieving and tracer experiments in terms of a permeability-surface product PS (permeation) and a solvent drag reflection coefficient σ_f (convection) for various blood-tissue barriers. The human whole-body albumin data of Lassen, Parving, and Rossing (Lassen, Parving, and Rossing, Microvasc. Res.7, i–iv (1974)), modified for nonliver tissues by Johnson and Levitt (Johnson &; Levitt, Microvasc. Res.9, 141 (1975)) lead to P ～ 1.8 × 10^?8 cm sec^?1 (based on a surface area per unit plasma volume of 700 cm^?1) and to σ_f ～ 0.9, which imply, in agreement with Johnson and Levitt, that permeation is the dominant nonliver blood-tissue transport mechanism for albumin in the normal resting human. Similar values are derived from the dog paw muscle data of Garlick and Renkin (Garlick and Renkin, Amer. J. Physiol.219, 1595–1605 (1970)). The Casley-Smith (Casley-Smith, Microvasc. Res.9, 43–48 (1975)) mechanism of uphill albumin transport is verified as possible. It is tentatively inferred that lymph formation in resting tissue does not result from a small difference between a large fluid (volumetric) filtration and an almost equally large fluid reabsorption, either in the same capillary (Starling) or between different capillaries (Zweifach) (Zweifach, Circ. Res.34, 858–866 (1974)). Rather, reabsorption is negligibly small relative to filtration, and lymph flow is comparable to volumetric filtration.     

Leucine and alpha-ketoisocaproate metabolism and interconversions in fed and fasted sheep

Fed and three-day-fasted sheep were infused with [1-14C] alpha-ketoisocaproate (KIC), L-[1-14C] leucine, and [14C] bicarbonate for determination of their whole-body turnovers, interconversions, and oxidation. Protein synthesis (PS), protein degradation (PD), net tissue metabolism, unidirectional utilization, and production rates also were estimated for the portal-drained viscera, liver, and hindquarters. KIC and leucine arterial concentrations (6.5 and 95 mumol X L-1) both increased with fasting. KIC turnover (9 mumol X min-1) also increased but leucine turnover (108 mumol X min-1) decreased. About 40% of KIC and 15% of leucine were oxidized, but they contributed less than 1% of whole-body CO2 production. The portal-drained viscera released KIC and leucine into the blood only in fed sheep. Hepatic net utilization of KIC and leucine (approximately 2 and 12 mumol X min-1) changed only little with fasting; thus, total splanchnic tissues utilized both in fasted sheep. Net metabolism by the hindquarters (representative of skeletal muscle) was always opposite to splanchnic metabolism. Thus, muscle must produce both KIC and leucine during fasting. In fed sheep whole-body PS, expressed as mumol X min-1 of leucine, was 92 +/- 6 and PD was 71 +/- 5. After fasting, PS decreased by 27%. Calculated liver protein metabolism was unaffected by the fast; PS (fixed and plasma) remained at about 25 and PD at about 15 mumol X min-1. However, protein metabolism by the hindquarters was sensitive to fasting; PS decreased from 30 +/- 4 in fed sheep to 20 +/- 3 mumol X min-1 after fasting and PD increased from 27 +/- 2 to 35 +/- 6 mumol X min-1. Thus, hepatic PS was maintained at the expense of muscle. If the total muscle mass of the body is considered, muscle PS contributed more than one half of whole-body PS.     

Platelet and leukocyte adhesion and activation in unstable angina and post-PTCA

BACKGROUND: Unstable atherosclerotic plaques activate blood cells which may adhere to the coronary endothelium causing vessel occlusion. However, it is unknown if different clinical syndromes associated with plaque rupture induce similar blood cell activation and adhesion to the endothelium. METHODS: We studied changes in adhesion molecule expression of platelets (GPIIb/IIIa), neutrophils--CD18, CD11b and L-selectin--and monocytes (CD14) after interaction with active lesions of patients with stable angina subjected to PTCA and patients with unstable angina (UA). Generation of superoxide (SO) radicals from PMNs and PMN sequestration in the coronary circulation were also assessed. Blood samples were collected from the aorta (Ao) and coronary sinus (CS) before and 15 min after PTCA (n=13) and within the first 48 h of UA (n=12). RESULTS: PTCA induced a marked up-regulation of CD18, CD11b, CD14 and GPIIb/IIIa with L-selectin shedding and reduced SO formation, whereas only minor L-selectin down-regulation and decreased SO production indicated activation in UA. However, a significant decrease in neutrophil count in the CS compared to the Ao was only observed in UA. CONCLUSIONS: The magnitude of cellular activation depends on the underlying clinical setting and just partially contributes to cell adhesion to the endothelium which might be modulated by different extent of vascular occlusion and shear forces.     

Serum Alkaline Phosphatase and Phosphate and Risk of Mortality and Hospitalization

Background and objectives: Elevated alkaline phosphatase (AlkPhos) and phosphate levels are associated with cardiovascular morbidity and mortality in patients receiving dialysis. A retrospective cohort study was conducted to test these associations in outpatients with an estimated GFR ≥60 ml/min/1.73 m².Design, setting, participants, & measurements: Patients with serum AlkPhos and phosphate levels measured between 2000 and 2002 (n = 10,743) at Montefiore Medical Center (MMC) clinics were followed through September 11, 2008 (median 6.8 years). Mortality data were obtained via Social Security Administration records (n = 949 deaths). Hospitalization data were obtained from MMC records.Results: The mean age was 51 years, 64% were women, 22% were white, 26% were non-Hispanic black, 16% were Hispanic, 13% had a diagnosis of hypertension, 9% had diabetes mellitus, and 8% had cardiovascular disease at baseline. AlkPhos and phosphate were independently associated with mortality and cardiovascular-related hospitalization after multivariable adjustment. Comparing patients in the highest (≥104 U/L) versus lowest quartile of AlkPhos (≤66 U/L), the adjusted hazard ratio (HR) for mortality was 1.65 (P trend across quartiles <0.001). For the highest compared with the lowest quartile of serum phosphate (≥3.8 mg/dl versus ≤3.0 mg/dl), the adjusted HR for mortality was 1.29 (P trend across quartiles = 0.008). High AlkPhos but not phosphate levels were also associated with all-cause, infection-related, and fracture-related hospitalization.Conclusions: Higher levels of serum AlkPhos and phosphate were associated with increased mortality and cardiovascular-related hospitalization in an inner-city clinic population. Further studies are needed to elucidate mechanisms underlying these associations.Individuals with ESRD experience increased cardiovascular morbidity and mortality compared with the general population (1). ESRD patients are at high risk for vascular calcification, a highly regulated process that appears to be partially mediated by disorders of mineral metabolism (2). In response to various stimuli, vascular smooth muscle cells undergo a phenotypic change characterized by expression of proteins that promote bone formation, including alkaline phosphatase (AlkPhos) (3). Phosphate induces this phenotypic change in vitro (2) and upregulates AlkPhos activity (4). Thus AlkPhos and phosphate have been directly implicated in the pathogenesis of vascular calcification and subsequent cardiovascular disease (CVD).In patients with ESRD and in the general population, higher serum levels of AlkPhos and phosphate are associated with increased all-cause and cardiovascular mortality (5–13). Recent studies support the hypothesis that these associations are mediated by vascular calcification (14,15), although medial calcification is seen almost exclusively in patients with advanced kidney disease and diabetes and not in the general population (16). These findings are clinically relevant because medial and intimal vascular calcification have been shown to predict cardiovascular risk in dialysis patients (17) and the general population (18). In addition, several studies have demonstrated an association between vascular calcification and low bone density (19–21), suggesting a role for bone mineral parameters as a marker of both processes.On the basis of these data, we evaluated the association between AlkPhos and phosphate and subsequent mortality and hospitalizations in patients with an estimated GFR (eGFR) ≥60 ml/min/1.73 m² in a large medical system in the Bronx, New York.     

Life-style and serum lipids and lipoproteins

In reviewing the trends and influences of life-style in this country on health and disease in the latter half of 20th century, we focused our attention on 4 major habits of smoking, drinking, exercise and diets, and collected data on the Japanese to conduct a meta-analysis of their relationship with serum lipids and lipoproteins, which are the metabolic risk factors most closely related to atherosclerosis. 1) The percentage of smokers was 54.0% in adult males and 14.5% in adult females in 1999. In the data of 7,256 subjects (mean age 47 years) in 16 papers, smoking increased triglycerides by 13 mg/dl (0.15 mmol/L) or in 559 non-drinkers with a mean age of 49 years in 3 papers by 18 mg/dl (0.20 mmol/L), and decreased HDL-cholesterol by 3.5 mg/dl (0.09 mmol/L) with every 20 cigarettes smoked according to the regression equation. 2) As for drinking, the annual ethanol consumption per adult was 8.5L in 1996. The effects of alcohol on serum lipids were analyzed in 27,035 males (mean age 47 years) in 24 studies. Drinking elevated triglycerides by a mean of 10 mg/dl (0.11 mmol/L), and also HDL-cholesterol by 2.5 mg/dl (0.06 mmol/L) per 23 g of alcohol intake (corresponding to 1 go of sake or 1 large bottle of beer). 3) Concerning exercise habit, 25% of males and 21% of females (mean age 47 years) regularly performed exercise such as jogging, swimming, aerobics, and tennis. However, walking was regarded as an easy exercise to be practiced by subjects of all ages. The effects of walking on serum lipids were studied in a total of 46,074 subjects (mean age 47 years) in 8 populations. Triglycerides were significantly lower by 10 mg/dl (0.11 mol/L), and HDL-cholesterol higher by 3 mg/dl (0.08 mmol/L) in those who walked 6,000 or more steps/day than in those who walked less than 2,000 steps/day. The effects of harder exercise like jogging or swimming were analyzed in 2,242 subjects in 14 papers (mean age 44 years). Triglycerides decreased by 10 mg/dl (0.11 mmol/L), and HDL-cholesterol elevated by 5 mg/dl (0.13 mmol/L) with an increase in the exercise intensity by one level of about 300 kcal. In exercise therapy, triglycerides were decreased by a mean of 20 mg/dl (0.23 mmol/L), and HDL cholesterol increased by a mean of 10 mg/dl (0.26 mmol/L) by exercise at a mean heart rate of about 135 bpm, which is equivalent to 50% VO2max for 30 minutes x 3 times/week. 4) In nutritional trends, the mean energy intake in 52 postwar years averaged 2,116+/-84 kcal with no marked changes according to nutritional surveys. However, the percentage of fat in total energy intake was lowest at 7% in 1946, increased thereafter until it exceeded 20% in 1973, and surpassed 25% in 1988. The mean total cholesterol level of the Japanese increased by 28 mg/dl (0.72 mmol/L) in the past 30 years and reached 204 mg/dl (5.28 mmol/L) in a survey in 1990. 5) Concerning dietary habits, total cholesterol was lower by a mean of 13 mg/dl (0.34 mmol/L), triglycerides lower by 40 mg/dl (0.45 mmol/L), and HDL-cholesterol higher by 5 mg/dl (0.13 mmol/L) in the group who ate 7 or more Japanese-style meals in the 9 meals during 3 days than in the group who ate 3 or less Japanese-style meals in the 9 meals. When serum lipids were compared among individuals living in cities (8 groups; 3,613 subjects; mean age 51 years), agricultural villages (13 groups; 5,364 subjects; mean age 51 years), and fishing villages (9 groups; 1,071 subjects; mean age 52 years). Total cholesterol was lower by a mean of 10 mg/dl (0.26 mmol/L) in fishing villages than in cities, and triglycerides lower by a mean of 15 mg/dl (0.17 mmol/L) in fishing villages than in cities and agricultural villages. HDL-cholesterol was 5 mg/dl (0.13 mmol/L) higher in agricultural villages and 3 mg/dl (0.08 mmol/L) higher in fishing villages than in cities. 6) The effects of dietary therapy or guidance were evaluated in 585 subjects (mean age, 53 years) in 12 papers. Total cholesterol was reduced by 20 mg/dl (0.52 mmol/L), triglycerides by a mean of 40 mg/dl (0.45 mmol/L), and HDL-cholesterol was increased by 5 mg/dl (0.13 mmol/L) by restriction of fat intake or restriction of the intake of saturated fat and dietary cholesterol. The results of these meta-analyses are considered to indicate the extent to which abnormalities of serum lipids are caused by a distorted life-style and the extent to which they are improved by correction of the life-style and exercise or dietary therapy. Correction of the life-style as a non-drug therapy may clearly improve hyperlipidemias or hypo-HDL-cholesterolemia so that this approach should be aggressively employed as part of the prevention and treatment for hyperlipidemias.