Rapid intravenous loading of levodopa for human research: clinical results

Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2,169 and 1,200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612+/-187 ng/ml, mean+/-S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P<0.0005).     

Limited versus radical parathyroidectomy in familial isolated primary hyperparathyroidism

BACKGROUND: Familial isolated primary hyperparathyroidism (FIHPT) is characterized by earlier onset, higher incidence of multiglandular disease, and higher recurrence rate when compared with sporadic primary hyperparathyroidism. Excision of 3.5 or 4 glands with autotransplantation has been recommended; however, these approaches lead to permanent hypoparathyroidism in 13% to 41% of patients. It is reported that many patients with FIHPT return to normocalcemia after single-gland excision. The use of preoperative localization and intraoperative parathyroid hormone assay permits limited resection of only hypersecreting glands. We report the outcome of this operative approach. METHODS: Fifteen consecutive patients with FIHPT underwent limited parathyroidectomy with resection guided by intact parathyroid hormone secretion in 2 university centers. Patients were followed up postoperatively for serum calcium and intact parathyroid hormone levels. RESULTS: With an operative success of 93%, 14 patients had only single-gland excision and 80% had unilateral neck exploration. All initial patients had their hypercalcemia corrected. In 4 reoperations, permanent hypoparathyroidism occurred in 2 patients. One recurrence was observed in 40 (8-122) months of follow-up. CONCLUSION: Limited parathyroidectomy allows successful single-gland excision in many patients with FIHPT, thus decreasing the risk of hypoparathyroidism. In these patients, a low incidence of hypoparathyroidism may be preferable to the possibility of late recurrence.     

T-cell depletion and graft survival induced by anti-human CD3 immunotoxins in human CD3epsilon transgenic mice

BACKGROUND: Anti-CD3 immunotoxins are broad-spectrum immunosuppressive agents in a wide range of organ transplantation animal models with potential use in eliciting antigen-specific tolerance. However, the anti-CD3 immunotoxins used in animal studies do not cross-react with human T cells, limiting extrapolation to humans and hindering clinical development. METHODS: Three anti-human CD3-directed immunotoxins, DT389-scFv(UCHT1), scFv(UCHT1)-PE38, and UCHT1-CRM9, were compared in vitro and in transgenic mice, tg(epsilon)600+/-, that have T cells expressing both human and murine CD3epsilon antigens. RESULTS: These immunotoxins were extraordinarily potent in vitro against human or transgenic mouse T cells, with IC50 values in cellular assays ranging from pM to fM. Systemic administration of these immunotoxins dose-dependently depleted >99% of tg(epsilon)600+/- lymph node and spleen T cells in vivo. Depletion was specific for T cells. The loss of the concanavalin A-induced, but not the lipopolysaccharide-induced, splenic proliferative response from immunotoxin-treated animals further demonstrated specific loss of T-cell function. Immunotoxin treatment prolonged fully allogeneic skin graft survival in tg(epsilon)600+/- recipients to 25 days from 10 days in untreated animals. T-cells recovered to approximately 50% of normal levels after approximately 22 days in animals with or without skin grafts; T-cell recovery correlated with skin graft rejection. All three immunotoxins elicited >100 day median survival of fully allogeneic heterotopic heart grafts. By 100 days, T cells recovered to normal numbers in these animals, but the grafts showed chronic rejection. CONCLUSION: These immunotoxins profoundly deplete T cells in vivo and effectively prolong allogeneic graft survival.     

Primary in vivo oscillations of metabolism in the pancreas

The role of metabolism in the generation of plasma insulin oscillations was investigated by simultaneous in vivo recordings of oxygen tension (pO(2)) in the endocrine and exocrine pancreas and portal blood insulin concentrations in the anesthetized rat. At the start of the experiment, the blood glucose concentration of seven rats was 6.2 +/- 0.1 mmol/l and the arterial blood pressure was 116 +/- 5 mmHg. These values did not differ from those obtained at the end of the experiment. Islet pO(2) was measured by impaling superficially located islets with a miniaturized Clark electrode. The pO(2) measurements revealed slow (0.21 +/- 0.03 min(-1)) with superimposed rapid (3.1 +/- 0.3 min(-1)) oscillations. The average pO(2) was 39 +/- 5 mmHg. Simultaneous recordings of pO(2) in the exocrine pancreas were significantly lower (16 +/- 6 mmHg), but showed a slow and a rapid oscillatory activity with similar frequencies as seen in the endocrine pancreas. Corresponding measurements of portal insulin concentrations revealed insulin oscillations at a frequency of 0.22 +/- 0.02 min(-1). The results are the first in vivo recordings of an oscillatory islet parameter with a frequency corresponding to that of plasma insulin oscillations; they support a primary role of metabolic oscillations in the induction of plasma insulin oscillations.     

Validation of a soy food frequency questionnaire with plasma concentrations of isoflavones in US adults

OBJECTIVE: To validate assessment of soy intake using food frequency questionnaires (FFQs) compared with plasma isoflavone (genistein and daidzein) concentrations. DESIGN: Cross-sectional analysis of soy isoflavone intake and plasma analysis of isoflavones. SUBJECTS: 77 men and women, age range 20 to 40 years, recruited from the Seattle metropolitan area. MAIN OUTCOME MEASURES: Isoflavone intake was determined from responses to a 40-item soy FFQ and from tofu and soymilk intake assessed as part of a comprehensive FFQ used for the Women's Health Initiative (WHI FFQ). Isoflavone concentrations in fasting blood samples were determined by liquid chromatography-mass spectrometry. STATISTICAL ANALYSES: Correlation coefficients were calculated for: a) isoflavone intake assessed by the soy FFQ and the WHI FFQ, b) intake assessed by the soy FFQ and plasma isoflavone concentrations, and c) intake assessed by the WHI FFQ and plasma isoflavone concentrations. RESULTS: Isoflavone intake was highly correlated between the soy FFQ and the WHI FFQ (r = 0.84). Genistein and daidzein intakes determined by the soy FFQ were significantly correlated with plasma concentrations (r = 0.53 and 0.45, respectively). Isoflavone intake assessed from the WHI FFQ was also correlated with plasma concentration (r = 0.46 and 0.45). Soymilk and tofu were the two major contributors to isoflavone intake (38.6%). CONCLUSIONS: A soy-specific, 40-item FFQ assessed isoflavone intake with good validity. Isoflavone intake assessed by the WHI FFQ (tofu and soymilk) had lower correlations with plasma concentrations compared with the soy FFQ. Nonetheless, assessment of the two foods is a reasonably good marker for soy food consumption in this sample.     

Olive oil increases the number of triacylglycerol-rich chylomicron particles compared with other oils: an effect retained when a second standard meal is fed

BACKGROUND: Compared with the postprandial events after a single meal, different events occur when a second meal is ingested 4-6 h after a first meal. There is a rapid appearance of chylomicrons in the circulation carrying fat ingested with the first meal, with a peak 1 h after the second meal. OBJECTIVE: Our goal was to examine whether different dietary oils have effects on the storage of triacylglycerol as a result of differences in their digestion, absorption, and incorporation into chylomicrons. DESIGN: A single-blind, randomized, within-subject crossover design was used to study the effects of palm oil, safflower oil, a mixture of fish and safflower oil, and olive oil on postprandial apolipoprotein (apo) B-48, retinyl ester, and triacylglycerol in the S(f) > 400 fraction with the use of a sequential meal protocol. RESULTS: For triacylglycerol, retinyl ester, and apo B-48, the time to reach peak concentration was significantly earlier after the second meal than after the first meal (P < 0.005). This was apparent with each of the dietary oils. The pattern of the apo B-48 response differed significantly among the dietary oils, with olive oil resulting in higher concentrations after both meals (P = 0.003). The ratio of triacylglycerol to apo B-48 was significantly lower after olive oil feeding than after feeding with the other oils (P = 0.02). CONCLUSIONS: The rapid entry of chylomicrons after the ingestion of a second meal 5 h after a first meal was seen with all of the oils investigated. The short-term ingestion of olive oil produced more chylomicrons than did the other dietary oils, which may have been due to differences in the metabolic handling of olive oil within the gut.     

Timing of vagal stimulation affects postprandial lipid metabolism in humans

BACKGROUND: Vagal stimulation combined with an oral fat load enhances postprandial lipemia in animals and humans. OBJECTIVE: We assessed whether the observed postprandial increase in plasma lipids could be explained by changes in exogenous (chylomicron) or endogenous (VLDL) lipid metabolism and whether the timing of vagal stimulation in relation to fat intake was important. DESIGN: Vagal stimulation was achieved by using the modified sham feeding (MSF) technique, in which food is tasted and chewed but not swallowed. Seven healthy men consumed an oral fat load (50 g) on one occasion (control protocol). On 2 other occasions, they consumed an oral fat load combined with MSF of an appetizing meal. MSF was performed for either 1 h before or 1 h after the oral fat load. Blood was collected for 7 h and was analyzed for hormones and metabolites. RESULTS: The postprandial triacylglycerol response differed significantly (P < 0.001) between the 3 protocols. Both MSF studies resulted in significantly higher plasma pancreatic polypeptide concentrations compared with the control. Compared with MSF for 1 hour after fat intake, MSF for 1 h before fat intake resulted in significantly higher plasma insulin concentrations (P = 0.013), a more rapid rise in chylomicron triacylglycerol concentrations (P = 0.04), and higher VLDL triacylglycerol and apoliprotein B-100 concentrations. CONCLUSIONS: Vagal stimulation enhanced postprandial lipemia via effects on both chylomicron and VLDL metabolism. MSF before fat intake had more dramatic effects on postprandial lipemia than did MSF after fat intake, possibly because of increased parasympathetic activity at the time of ingestion.     

Quality of life of patients with chronic renal insufficiency in hemodialysis treatment

This is a convergent-assistance research, which has as its objective the identification of the factors affecting the quality of life of people suffering from Chronic Kidney Failure and who are undergoing hemodialysis. Data were collected in a health education program, developed for a companionship group, across hemodialysis sessions. During the analysis, four categories were identified, representing the elements that are considered as causes for the life quality conditions of those people: health assistance; acceptance and coping with the health condition; support received, and hoping for a better future. In spite of living with an illness which has important consequences on the physical well-being and social roles, persons referred to a life where quality can be achieved, although sometimes it may be difficult to perceive or conquer such quality.