NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes

Egress of lipoprotein-derived cholesterol from lysosomes requires two lysosomal proteins, polytopic membrane-bound Niemann-Pick C1 (NPC1) and soluble Niemann-Pick C2 (NPC2). The reason for this dual requirement is unknown. Previously, we showed that the soluble luminal N-terminal domain (NTD) of NPC1 (amino acids 25-264) binds cholesterol. This NTD is designated NPC1(NTD). We and others showed that soluble NPC2 also binds cholesterol. Here, we establish an in vitro assay to measure transfer of [(3)H]cholesterol between these two proteins and phosphatidylcholine liposomes. Whereas NPC2 rapidly donates or accepts cholesterol from liposomes, NPC1(NTD) acts much more slowly. Bidirectional transfer of cholesterol between NPC1(NTD) and liposomes is accelerated >100-fold by NPC2. A naturally occurring human mutant of NPC2 (Pro120Ser) fails to bind cholesterol and fails to stimulate cholesterol transfer from NPC1(NTD) to liposomes. NPC2 may be essential to deliver or remove cholesterol from NPC1, an interaction that links both proteins to the cholesterol egress process from lysosomes. These findings may explain how mutations in either protein can produce a similar clinical phenotype.     

The dose-to-mother method to measure milk intake in infants by deuterium dilution: a validation study

A validation study of the dose-to-mother deuterium dilution method to measure breast-milk intake has been carried out on ten infants from a Nutrition Recovery Centre in Santiago, Chile. Formula milk labelled with exponentially decreasing doses of deuterium oxide represented milk from a 'pseudo mother' of these exclusively bottle-fed infants. Unlabelled formula represented milk from other sources. Deuterium levels in the infants' body water were measured on saliva samples by mass spectroscopy. The data were fitted in a two-compartment steady-state model of the mother-child system to estimate the flow of labelled water from the 'mother' to the infant and the 'mother' and infant's water elimination constants. A dose-to-child experiment was also carried out on each infant to determine the deuterium dilution space and total daily water intake. Total and labelled water flows from deuterium dilution were used to calculate total, labelled and unlabelled formula milk intakes which were compared to the same quantities measured by bottle weighing. Water elimination constants calculated from the dose-to-mother experiments underestimated by 17 per cent the initially set mother constant and overestimated by 21 per cent the infant constants calculated from the dose-to-child experiments. Rate constants, however, have little effect on the estimated water flows so that there was good agreement between values from deuterium dilution and from direct weighing. Mean (SD) total formula, labelled formula and unlabelled formula intakes were 865 (129) g/d, 417 (74) g/d and 448 (106) g/d, respectively, when measured by deuterium dilution, compared with 856 (116) g/d, 414 (71) g/d and 441 (68) g/d when measured by direct weighing. The mean per cent differences were 1.1 per cent, 0.7 per cent and 1.6 per cent and the mean absolute differences for individuals, 4.3 (1.9) per cent, 4.8 (3.1) per cent and 9.7 (6.6) per cent, respectively.     

Diet and cancer of the pancreas

A case-control study was carried out in Geneva on the basis of an interview involving 88 new cases of pancreatic cancer and 336 controls. The percentage of histologically confirmed cases was 67 p. 100. Controls were drawn at random from the general population. An excess risk was observed with increased consumption of fatty foods. This excess, however, was only significant for butter; in contrast, margarine was associated with a reduction in risk (relative risk = 0.35, p less than 0.05). Meat intake did not modify the risk, except for lean pork, for which the risk was significantly reduced. For carbohydrates, an excess risk was observed, with a dose-response effect. Fresh fruit and vegetables led to a marked and significant reduction in risk. Among beverages, beer was the only one for which consumption entailed an increased risk (RR = 2.85, p less than 0.05). The results concerning tea and coffee were not significant, but there appeared to be a trend towards an increase in relative risk.     

Update on medical therapy for obscure gastrointestinal hemorrhage]

The development of capsule endoscopy and double-balloon enteroscopy has increased diagnostic and therapeutic rates in obscure gastrointestinal hemorrhage, where angiodysplasia of the small bowel is the most frequent cause. Nevertheless, almost 25-40% of patients who are not candidates or do not respond to endoscopic, angiographic, or surgical management may be at high risk of rebleeding, and therefore lack a clearly effective medical therapy. The utility of hormonal therapy remains unclear and is burdened by adverse effects. Subcutaneous octreotide usually controls bleeding but does not seem adequate for maintenance therapy. Non-selective beta-blockers alone or in combination with other treatments, as in the prophylaxis of portal hypertension variceal bleeding, may be helpful. Recently, octreotide LAR, a depot formulation administered once a month intramuscularly, and oral thalidomide, a powerful inhibitor of angiogenesis, have demonstrated their effectiveness and safety for long-term therapy in anecdotal case reports and deserve further investigation.     

Inflammation-related genes and the risk of Parkinson's disease: a multilocus approach

For the first time, the multilocus approach by the set-association method has been applied for the analysis of a cluster of five genes [tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-8, IL-1α and IL-10] involved in the brain neuroinflammatory pathway in Parkinson's disease (PD), in a well-defined group of 197 PD patients and 173 control subjects from Spain. Set-association analysis did not reveal an independent or an interactive effect of these inflammatory genes on the PD risk.     

Pain relief after low back surgery: the efficacy of transcutaneous electrical nerve stimulation

Transcutaneous electrical nerve stimulation (TENS) was used for the relief of post-operative pain following low back surgery in a consecutive series of over 157 patients. A comparative study of the use of post-operative narcotic analgesics by 52 of these patients (26 in each of two groups) was made to determine the effectiveness of TENS in relieving post-operative pain. Fifty per cent of the sample used analgesics only; 50% used TENS in addition to analgesics. The data collected included its frequency of post-operative analygesic use, a rank order of analgesic potency, and a post-operative "pain score" derived from the combination of analgesic potency and frequency of use. Data analysis revealed significant differences between the groups in the use of analgesics. TENS decreased the need for narcotics in the relief of post-operative pain following low back surgery, although it is not a replacement for post-operative medication.     

Projections of leukemia risk associated with occupational exposure to benzene

In 1982, White et al published an assessment of quantitative leukemia risk associated with lifetime occupational exposure to benzene. At about the same time, IARC (1982) published estimates of quantitative cancer risk associated with industrial chemicals. Benzene was one of the two chemicals selected by IARC for its risk estimation. This paper presents a summary of these assessments along with new study results demonstrating adverse effects on bone marrow and peripheral blood cells as a result of low-level benzene exposure. Mathematical extrapolations based on epidemiologic studies are consistent with a finding of significant risk of dying from leukemia under the current occupational permissible exposure limit of 10 ppm. Although a significant reduction of risk could be expected to be achieved by reducing exposure to 1 ppm, a significant risk may still remain. The uncertainty of the dose-response projections rests on the underlying estimates of relative risk of death from leukemia, the estimates of benzene exposure (dose), and the appropriateness of the mathematical model. Recent findings in experimental animals demonstrate chromosomal damage to bone marrow cells, significant depression of the bone marrow, and disturbances of immune system function as a result of less than 1 week of exposure to the current permissible benzene exposure limit of 10 ppm. This was the lowest dose tested. These experimental findings provide further evidence of a potentially significant risk of bone marrow proliferative cancer (leukemia) as a result of low-dose benzene exposure.     

Output pathway for turning behavior from the neostriatum and substantia nigra in cats

The goal of the present work was to study the output pathway of the information for turning behavior originating in the striatum and coursing through the substantia nigra pars reticulata (SNR). In 45 adult cats distributed in 3 groups, Ni-Cr electrodes were implanted in the caudate nucleus and substantia nigra pars reticulata and depending on the animal group in the superior colliculus (SC), nucleus ventralis lateralis/nucleus ventralis medialis (VL/VM) complex or nucleus tegmenti pedunculopontinus (TPP) of one cerebral hemisphere. The threshold current required to evoke turning behavior was determined in each animal for each implantation site. An electrolytic lesion of the superior colliculus, the VL/VM complex or the nucleus tegmenti pedunculopontinus was carried out in each group of cats. The effects of the lesions on behavior and on the electrical threshold currents were determined and compared with the prelesion values. Finally the extent of the lesions and electrode positions were analyzed. The results show that the substantia nigra pars reticulata is the structure with the lowest thresholds for turning and that the superior colliculus appears to be more relevant for carrying the information for turning than either the VL/VM complex or the nucleus tegmenti pedunculopontinus.