The structure of enteric human adenovirus 41-A leading cause of diarrhea in children.

Human adenovirus (HAdV) types F40 and F41 are a prominent cause of diarrhea and diarrhea-associated mortality in young children worldwide. These enteric HAdVs differ notably in tissue tropism and pathogenicity from respiratory and ocular adenoviruses, but the structural basis for this divergence has been unknown. Here, we present the first structure of an enteric HAdV-HAdV-F41-determined by cryo-electron microscopy to a resolution of 3.8 Å. The structure reveals extensive alterations to the virion exterior as compared to nonenteric HAdVs, including a unique arrangement of capsid protein IX. The structure also provides new insights into conserved aspects of HAdV architecture such as a proposed location of core protein V, which links the viral DNA to the capsid, and assembly-induced conformational changes in the penton base protein. Our findings provide the structural basis for adaptation of enteric HAdVs to a fundamentally different tissue tropism.

Serotonin syndrome caused by interaction between citalopram and fentanyl.

OBJECTIVE: To report a case of serotonin syndrome associated with interaction between fentanyl and citalopram, as evidenced by medication history, clinical features and reversal following discontinuation of fentanyl. CASE SUMMARY: A 65-year-old patient chronically treated with the selective serotonin reuptake inhibitor (SSRI) citalopram developed confusion, agitation, tachycardia, tremors, myoclonic jerks and unsteady gait, consistent with serotonin syndrome, following initiation of fentanyl, and all symptoms and signs resolved following discontinuation of fentanyl. Based on the Naranjo probability scale, serotonin syndrome was a probable adverse reaction associated with co-administration of citalopram and fentanyl. DISCUSSION: Serotonin syndrome is a potentially lethal pharmacodynamic interaction between medications that increase serotonergic transmission at the synaptic junction. The development of new pharmacological agents with varied properties and actions has increased the risk of serotonin syndrome as a clinical diagnosis. SSRIs and fentanyl are commonly co-administered, especially in the setting of chronic or malignant pain, as underlying depression may contribute to the pathogenesis of pain. CONCLUSION: Healthcare professionals should be aware of the possible development of serotonin syndrome as a complication of initiation of fentanyl and other phenylpiperidine opioids in patients treated with SSRIs.

Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review.

Nicotinic acid has, like the Roman God Janus, two faces. One is the vitamin. The other is the broad-spectrum lipid drug. The Canadian pathologist Rudolf Altschul discovered 50 years ago that nicotinic acid in gram doses lowered plasma levels of cholesterol. From the point of view of treatment of the dyslipidaemias that are risk factors for clinical atherosclerosis nicotinic acid is a miracle drug. It lowers the levels of all atherogenic lipoproteins--VLDL and LDL with subclasses as well as Lp(a)--and in addition it raises more than any other drug the levels of the protective HDL lipoproteins. Trials have shown that treatment with nicotinic acid reduces progression of atherosclerosis, and clinical events and mortality from coronary heart disease. The new combination treatment with statin-lowering LDL and nicotinic acid-raising HDL is reviewed. A basic effect of nicotinic acid is the inhibition of fat-mobilizing lipolysis in adipose tissue leading to a lowering of plasma free fatty acids, which has many metabolic implications which are reviewed. The very recent discovery of a nicotinic acid receptor and the finding that the drug stimulates the expression of the ABCA 1 membrane cholesterol transporter have paved the way for exciting and promising new 50 years in the history of nicotinic acid.

Niaspan, the prolonged release preparation of nicotinic acid (niacin), the broad-spectrum lipid drug.

Niacin (nicotinic acid) is the broad-spectrum lipid drug, which lowers the concentration of all atherogenic plasma lipids/lipoproteins and at the same time raises the levels of the protective HDL (high-density lipoprotein). Niaspan is a prolonged release (PR) formulation of niacin, which has considerable advantages over both immediate release (IR) and slow release (SR) formulations of this drug. The major early side effect of IR niacin, the flush, is reduced with Niaspan. The hepatotoxic effects with SR niacin are not present with Niaspan. It is suitable for once daily prescription at bedtime. Niaspan is effective as monotherapy and in combination with other lipid-lowering drugs such as statins and fibrates. It is particularly useful for treatment of the dyslipidaemia of type 2 diabetes, where IR but not PR niacin may deteriorate the diabetic condition. Overall, niacin, now available as the well-tolerable drug formulation Niaspan, is the unique broad-spectrum lipid drug for the prevention and treatment of clinical atherosclerosis.

Angioplasty or stent placement in the proximal common iliac artery: is protection of the contralateral side necessary?

PURPOSE: To determine if protection of the contralateral common iliac artery is necessary when performing angioplasty or stent placement in a proximal common iliac artery. MATERIALS AND METHODS: A retrospective review of all patients undergoing endovascular treatment for unilateral common iliac artery stenosis or occlusion from 1979 to 2000 was performed. All angiograms were reviewed independently by three experienced vascular interventional radiologists who evaluated both common iliac arteries before and after angioplasty or stent placement. RESULTS: The medical records or angiograms of 514 patients were located. Of these, complete records and angiograms were found for 175 patients who underwent proximal (within 2 cm of its origin) common iliac artery angioplasty or stent placement without treatment or protection of the contralateral common iliac artery. Treatment of proximal common iliac stenosis in 160 patients resulted in luminal compromise of the contralateral common iliac in two patients (17% and 24% reduction in luminal diameter). No contralateral compromise was noted in 15 patients treated for iliac occlusion. CONCLUSION: The data reported herein suggest that protection of the contralateral common iliac artery during angioplasty or stent placement in a proximal common iliac artery is not mandatory.

Using spatial terms to select an object.

Our interactions with the world often involve selecting one object from a cluttered array of objects. One way to accomplish this is with language. For example, spatial terms, such as above, guide selection by specifying the position of one object (the located object) with respect to a second object (the reference object). Most of the work on the apprehension of spatial terms has examined displays that contain only these two objects. In the present paper, we examine how the presence of an extra object (a distractor) in the display impacts apprehension. Consistent effects of distractor presence were obtained across acceptability-rating and speeded sentence/picture verification tasks. Importantly, these effects were independent of the placement of the distractor. These results suggest that the distractor has its influence during processes that spatially index and identify the located and reference objects and that processes involved in computing the spatial term operate only on these objects.

Grounding spatial language in perception: an empirical and computational investigation.

The present paper grounds the linguistic cdategorization of space in aspects of visual perception; specifically, the structure of projective spatial terms such as above are grounded in the process of attention and in vector-sum coding of overall direction. This is formalized in the attentional vector-sum (AVS) model. This computational model accurately predicts linguistic acceptability judgments for spatial terms, under a variety of spatial configurations. In 7 experiments, the predictions of the AVS model are tested against those of 3 competing models. The results support the AVS model and disconfirm its competitors. The authors conclude that the structure of linguistic spatial categories can be partially explained in terms of independently motivated perceptual processes.

Actualización sobre hiperlipidemia

Colesterol

HDL

Lípidos

Triglicéridos

Actualización sobre hiperlipidemia

Colesterol

HDL

Lípidos

Triglicéridos

Circulator boot therapy alters the natural history of ischemic limb ulceration.

Despite numerous advances in interventional radiology and vascular surgery, the clinician continues to be confronted with inoperable vascular disease. Previous studies have shown that ulceration associated with a transcutaneous oxygen pressure (tcPO2) of <20 mmHg is refractory to all attempts at healing. External pneumatic compression for the treatment of peripheral vascular disease has been available for several years, although there is a relative paucity of data regarding its role in clinical practice as well as its efficacy. The objective of this study was to examine the experience with circulator boot therapy in the treatment of ischemic ulcers in the absence of osteomyelitis, and specifically to determine whether such therapy can be of benefit in ischemic limb ulceration associated with a tcPO2 of <20 mmHg. A retrospective chart review was undertaken of ail patients with a lower limb ulcer who, in the absence of osteomyelitis, underwent circulator boot therapy at the Gonda Vascular Center. A total of 98 patients was identified. Two patients died within 1 month of commencing therapy and were not included in further analysis. The tcPO2 data were unavailable in five patients. Outcome in the patient population was classified as favorable if (1)healing was achieved, (2)the ulcer decreased in size, or (3) the affected limb improved sufficiently to allow successful revascularization. An unfavorable outcome was one where a major amputation was performed or where the ulcer increased in size. Out of a total of 29 patients with a tcPO2 <20 mmHg at the area of ulceration, 19 had a favorable outcome following circulator boot therapy. Of the remaining 62 patients with a tcPO2 >20 mmHg, 54 had a favorable outcome. Circulator boot therapy is associated with improved outcomes in limb ulceration due to peripheral vascular disease. Complete ulcer healing as well as preservation of the affected limb can be achieved in most cases.

Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol transport in humans.

BACKGROUND: Apolipoprotein (apo) A-I is the major protein component of HDL, a cholesterol transport particle that protects against atherosclerosis. Apo A-I is believed to promote reverse cholesterol transport, transferring cholesterol from peripheral cells to the liver for subsequent elimination. To test this hypothesis in humans, we measured fecal steroid excretion before and after the intravenous infusion of human proapo A-I (precursor of apo A-I) liposome complexes. METHODS AND RESULTS: Four subjects with heterozygous familial hypercholesterolemia w re studied under standardized conditions. The fecal excretion of bile acids and neutral sterols was determined for 9 days before and 9 days after an intravenous infusion of recombinant human proapo A-I (4 g protein) liposome complexes. Plasma apoA-I and HDL cholesterol levels increased transiently (mean peak concentrations were 64% and 35% above baseline, respectively) during the first 24 hours. Mean lipoprotein lipid and apolipoprotein levels were not different during the 2 collecting periods, however. Serum lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, was also unchanged. The fecal excretion of cholesterol (neutral sterols and bile acids) increased in all subjects (mean increase, +39% and +30%, respectively), corresponding to the removal of approximately 500 mg/d excess cholesterol after infusion. Control infusions with only liposomes in 2 of the patients did not influence lipoprotein pattern or cholesterol excretion. CONCLUSIONS: Infusion of proapoA-I liposomes in humans promotes net cholesterol excretion from the body, implying a stimulation of reverse cholesterol transport. This mechanism may prove useful in the treatment of atherosclerosis.

Studies in hypertriglyceridaemia. VI: Serum lathosterol concentration is raised in hypertriglyceridaemic non-diabetic males with hyperinsulinaemia.

OBJECTIVES: To assess the cholesterol synthesis rate in primary hypertriglyceridaemia using the serum unesterified lathosterol concentration as an indicator. DESIGN: A cross-sectional, case-control study. SETTING: The Karolinska Hospital, Stockholm. SUBJECTS: Randomly selected hyper- (n = 53) and normotriglyceridaemic (n = 57) males, 40-50 years, with a fasting serum triglyceride concentration (mean +/- SD) of 3.81 +/- 1.65 and 1.28 +/- 0.53 mmol L-1, respectively. The exclusion criterion was diabetes mellitus, defined according to the World Health Organization (WHO) guidelines. MAIN OUTCOME MEASURES: To compare the fasting serum concentration distributions of lathosterol, a cholesterol precursor, in hyper- and normotriglyceridaemic groups. RESULTS: Thirty-six per cent of the hypertriglycerdaemic group had raised serum lathosterol concentrations, based on the 90th percentile of the lathosterol distribution of the normotriglyceridaemic group. In the hyper- but not in the normotriglyceridaemic group, lathosterol concentration was directly correlated with serum insulin responses to oral (r = 0.38; P = 0.007) and intravenous (r = 0.41; P = 0.005) glucose challenges. CONCLUSIONS: One-third of a randomly selected non-diabetic hypertriglyceridaemic population had an increased serum lathosterol concentration and this might indicate an increased cholesterol synthesis rate compatible with increased production of VLDL particles, possibly as the result of chronic hyperinsulinaemia.

Nicotinic acid treatment shifts the fibrinolytic balance favourably and decreases plasma fibrinogen in hypertriglyceridaemic men.

BACKGROUND: Nicotinic acid in gram doses decreases cholesterol and triglyceride concentrations in plasma, but the effect on haemostatic function is not known. METHODS: Twenty-three men with hypertriglyceridaemia were treated with 4 g nicotinic acid daily for 6 weeks. Tests for haemostatic function and serum lipoproteins were performed before and at the end of the period of treatment. RESULTS: Treatment with nicotinic acid had the expected effect on lipoprotein concentrations: it reduced the serum concentrations of triglyceride and the three major density fractions of triglyceride (very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL)). The VLDL cholesterol concentration was reduced, but that of HDL cholesterol was increased (all P<0.0001). The lipoprotein(a) (Lp(a)) concentration decreased significantly (P<0.01). The total fibrinolytic activity was increased by nicotinic acid treatment as indicated by decreases in plasminogen activator inhibitor-1 activity from 34.3 to 23.8 U/ml (P<0.01) and in alpha2-antiplasmin activity from 1.10 to 0.97 U/ml (P<0.01). The plasma fibrinogen concentration decreased from 3.55 to 3.01 U/ml (P<0.01). Multvariate analysis showed that the changes in alpha2-antiplasmin and Lp(a) concentrations could explain 53% of the change in plasma fibrinogen, suggesting that increased plasmin mobilization could be responsible for the decrease in plasma fibrinogen. CONCLUSION: This study of hypertriglyceridaemic men has shown that long-term treatment with nicotinic acid not only corrects serum lipoprotein abnormalities, but also reduces the fibrinogen concentration in plasma and stimulates fibrinolysis.

In vitro reverse cholesterol transport from THP-1-derived macrophage-like cells with synthetic HDL particles consisting of proapolipoprotein A1 or apolipoprotein A1 and phosphatidylcholine.

The human monocytic leukaemia cell line THP-1 was induced to differentiate to macrophage-like cells by the addition of phorbol myristoyl acetate (PMA). Subsequently, the cells were enriched in cholesterol and these cholesterol laden cells were used to study the capability of reconstituted discoidal complexes (RDCs), consisting of either human apolipoprotein A1 (apo A1) or recombinant human proapolipoprotein A1 (proapo A1) and phosphatidylcholine (PC), to promote cholesterol efflux. RDCs containing apo A1 and proapo A1 were both effective in the mobilization of intracellular cholesterol, whether this was measured by intracellular cholesterol mass or by the appearance of radiolabelled cholesterol in the supernatant. Using the radiolabelling technique, the activity was saturable and followed Michaelis-Menten kinetics. For both types of complexes and for native HDL the maximum rate of cholesterol removed was approximately 0.5 nmol h-1 per 10(6) cells. For RDCs of proapo A1 and apo A1 and for native HDL the Km values were 3.7, 2.9 and 64.8 micrograms ml-1 respectively. A significant in vitro cholesterol efflux could only be achieved with protein-lipid complexes; no significant export was observed with either free proapo A1 or multilamellar PC liposomes without apolipoprotein. Both RDCs were found to be more active in the mobilization of intracellular cholesterol than HDL isolated from human plasma. The combined results demonstrate that synthetic complexes consisting either of apo A1 or proapo A1 and PC are both active in the in vitro reverse transport of cholesterol.

Studies in hypertriglyceridaemia. 1. Serum triglyceride distribution and its correlates in randomly selected Swedish middle-aged men.

OBJECTIVES: To obtain a randomly selected hypertriglyceridaemic population for detailed further characterization. DESIGN: Study of randomly selected males. SETTING: Subjects examined and blood sampled at Sollentuna Primary Health Care Centre. SUBJECTS: Men aged 40-50 years (n = 1564), living in the Stockholm area, who were screened for hypertriglyceridaemia, January 1990-June 1992. MAIN OUTCOME MEASURES: Fasting concentrations of serum triglycerides. RESULTS: The serum triglyceride concentration distribution showed the expected skew distribution with the 90th and the 95th percentile at 2.51 and 3.05 mmol L-1, respectively. The mean serum triglyceride level compared well with several population values reported from this laboratory over the last 30 years, indicating stable triglyceride levels over time. There was no significant age-trend for the triglyceride concentration. Lower mean values for triglyceride, insulin and waist-to-hip (W/H) ratio were observed during the summer, whilst apolipoprotein A-I levels were higher. There was a linear relation between the number of cigarettes smoked and the serum triglyceride concentration. In stepwise multiple linear regression analysis with the triglyceride concentration as the dependent variable the following variables appeared as significant (P < 0.01) contributors: insulin, cholesterol, glucose, apolipoprotein A-I, number of cigarettes smoked, BMI, W/H ratio and diastolic blood pressure. The regression coefficient for apolipoprotein A-I was negative; all the others were positive. The multiple regression (R) was 0.68, suggesting that up to 47% of the variation of the serum triglyceride concentration could be predicted by these factors. CONCLUSIONS: A group of randomly selected hypertriglyceridaemic men has been recruited for further clinical, metabolic and genetic studies. Basic characteristics of the population for their recruitment are described.

Efflux of cholesterol from cholesterol loaded macrophages by incubation with synthetic HDL-particles.

Cells from the mouse monocyte/macrophage cell line J774A.1 were incubated with acetylated human low density lipoprotein for 2 days, resulting in an intracellular accumulation of mainly cholesteryl esters. These in vitro foam cell models were used to study the capability of synthetic HDL-particles to promote efflux of cholesterol. The synthetic HDL-particles were prepared from recombinant human pro-apolipoprotein A-I or human apolipoprotein A-I and phosphatidylcholine. Both types of reconstituted complexes were found to have a discoidal structure. A 24 h incubation of lipid loaded J774A.1 cells with these two types of discoidal complexes resulted in an equivalent and marked egress of cholesterol. The effect was the same whether the origin of phosphatidylcholine was egg yolk or soybean.