Nutritional pharmacology and malignant disease: a therapeutic modality in patients with cancer

It is now established that certain nutrients have a significant effect on cellular metabolism and growth, tissue repair and regeneration, and modulation of host defences. So far, however, potential clinical benefits have been difficult to demonstrate. Nevertheless, the use of nutrients in combinations seems to have promise and may be associated with a reduction in infectious complications and length of hospital stay. Nutritional pharmacology in the future may be able to improve tumour response to chemotherapy and may minimize the metabolic effect of cachexia.     

The HMG-CoA reductase inhibitor atorvastatin increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs

We have previously shown in vivo that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin decreases hepatic apolipoprotein B (apoB) secretion into plasma. To test the hypothesis that atorvastatin modulates exogenous triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg body wt) containing retinol (50 000 IU) was given to 6 control miniature pigs and to 6 animals after 28 days of treatment with atorvastatin 3 mg. kg-1. d-1. A multicompartmental model was developed by use of SAAM II and kinetic analysis performed on the plasma retinyl palmitate (RP) data. Peak TRL (d<1.006 g/mL; Sf>20) triglyceride concentrations were decreased 29% by atorvastatin, and the time to achieve this peak was delayed (5.2 versus 2.3 hours; P<0.01). The TRL triglyceride 0- to 12-hour area under the curve was decreased by 24%. In contrast, atorvastatin treatment had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma; however, the TRL RP 0- to 12-hour area under the curve was decreased by 20%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate was increased significantly, 1.4-fold (3.093 versus 2.276 pools/h; P=0.012), with atorvastatin treatment. The percent conversion of TRL RP from the rapid-turnover to the slow-turnover compartment was decreased by 47% with atorvastatin treatment. The TRL RP fractional clearance rate was negatively correlated with very low density lipoprotein apoB production rate measured in the fasting state (r=-0.49). Thus, although atorvastatin had no effect on intestinal TRL assembly and secretion, plasma TRL clearance was significantly increased, an effect that may relate to a decreased competition for removal processes by hepatic very low density lipoprotein.     

1H-magnetic resonance spectroscopy-determined cerebral lactate and poor neurological outcomes in children with central nervous system disease

By using proton magnetic resonance spectroscopy ((1)H-MRS), cerebral lactate has been shown to be elevated in a wide variety of pediatric and adult neurological diseases. In this study we compared 36 newborns, infants, and children with elevated lactate peaks on (1)H-MRS with 61 patients without an identifiable lactate signal. (1)H-MRS was acquired from the occipital gray and parietal white matter (8 cm3 volume, STEAM sequence with echo time = 20 msec, repetition time = 3.0 seconds) and data were expressed as ratios of different metabolite peak areas (N-acetylaspartate [NA]/creatine [Cr], NA/choline [Ch], and Ch/Cr) and the presence of a characteristic lactate doublet peak at 1.3 ppm. Outcomes (Pediatric Cerebral Performance Category Scale score; PCPCS) were assigned 6 to 12 months after injury. Patients with lactate peaks were more likely to have suffered a cardiac arrest, were more often hyperglycemic, and had lower Glasgow Coma Scale scores on admission. They were also more likely to have abnormal metabolite ratios when compared with age-matched controls or with patients without detectable lactate. Of prognostic importance, patients with increased lactate were more likely to be severely disabled (39% vs 10%), survive in a persistent vegetative state (13% vs 2%), or have died (39% vs 7%). In contrast, patients with similar conditions without increased lactate were more likely to have had a good outcome (23% vs 3%) or recovered to a mild (38% vs 6%) or moderate disability (20% vs 0%). Our data suggest that (1)H-MRS is useful in the prediction of long-term outcomes in children with neurological disorders. Patients with elevated cerebral lactate are more likely to die acutely or are at greater risk for serious long-term disability.     

Bidirectional cavopulmonary shunt in patients with anomalies of systemic and pulmonary venous drainage

BACKGROUND: Bidirectional cavopulmonary shunt and Fontan repair are now commonly performed in patients with a variety of forms of complex single ventricle, including those with anomalies of systemic or pulmonary venous return. These anomalies are ideally dealt with during bidirectional cavopulmonary shunt, thereby minimizing the complexity of the eventual Fontan procedure. METHODS: Between March 1990 and December 1995, 36 patients with anomalous systemic or pulmonary venous drainage underwent bidirectional cavopulmonary shunt. A combination of anomalous systemic and pulmonary venous drainage was present in 12 patients, whereas 19 patients had anomalous drainage only from the systemic circulation and 5 patients had isolated anomalies of pulmonary venous return. Visceral heterotaxy syndrome was diagnosed in 18 patients. The median age at operation was 11 months, and bidirectional cavopulmonary shunt was the first surgical procedure performed in 10 of these patients. Techniques of repair are described. RESULTS: There were two early deaths and one bidirectional cavopulmonary shunt was taken down, for mortality and failure rates not significantly different than those for all patients undergoing bidirectional cavopulmonary shunt during this time period (n = 117). At a mean follow-up of 19.9 months, there have been three late deaths and 11 patients have undergone Fontan completion. Actuarial survival was 87% at 1 year and 81% at 3 years. Among all patients undergoing bidirectional cavopulmonary shunt during this time period, neither heterotaxy syndrome nor anomalies of systemic or pulmonary venous return were significantly associated with decreased survival or poor outcome. CONCLUSIONS: Bidirectional cavopulmonary shunt can be performed in patients with anomalous systemic or pulmonary venous drainage, including those with visceral heterotaxy syndrome, with morbidity and mortality rates that do not differ significantly from those achieved in all patients undergoing bidirectional cavopulmonary shunt. In this report, we describe our experience with this group of patients, primarily focusing on outcomes and technical issues that pertain to the use of bidirectional cavopulmonary shunt as a preparatory procedure for the extracardiac conduit Fontan operation.     

Effects of melengestrol acetate on onset of puberty, follicular growth, and patterns of luteinizing hormone secretion in beef heifers

Our objective was to test the hypothesis that short-term (8 days) treatment of prepubertal heifers with melengestrol acetate (MGA) and subsequent steroid withdrawal would stimulate LH secretion and follicular growth. Angus heifers were divided randomly into two groups; MGA-treated (n = 8) or control (CON; n = 9). Puberty was determined by monitoring circulating concentrations of progesterone and ovarian morphology during a 14-day period following MGA withdrawal. LH secretory patterns were assessed upon initiation of MGA (Day 0), during MGA (Day 7), and 1 day after withdrawal of MGA (Day 9). All MGA-treated heifers, versus four CON heifers, exhibited corpora lutea and luteal phase concentrations of progesterone within 10 days after treatment (p = 0.01). Mean LH and LH pulse frequency increased (p = 0.005 and 0.0001, respectively) between Days 0 and 9 in MGA-treated heifers. In CON heifers, mean LH concentrations and pulse frequencies did not change. During the same period, diameter of the largest follicle increased in MGA-treated animals (p = 0.003) but did not change in the CON heifers. On the basis of these results, we suggest that MGA withdrawal enhances onset of puberty by stimulating pulsatile LH secretion that accelerates follicle growth to the preovulatory stage.