From the Cover: The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy

Infection with the hepatitis C virus (HCV) has a huge impact on global health putting more than 170 million people at risk of developing severe liver disease. The HCV encoded p7 ion channel is essential for the production of infectious viruses. Despite a growing body of functional data, little is known about the 3-dimensional (3D) structure of the channel. Here, we present the 3D structure of a full-length viroporin, the detergent-solubilized hexameric 42 kDa form of the HCV p7 ion channel, as determined by single-particle electron microscopy using the random conical tilting approach. The reconstruction of such a small protein complex was made possible by a combination of high-contrast staining, the symmetry, and the distinct structural features of the channel. The orientation of the p7 monomers within the density was established using immunolabeling with N and C termini specific F_ab fragments. The density map at a resolution of ≈16 Å reveals a flower-shaped protein architecture with protruding petals oriented toward the ER lumen. This broadest part of the channel presents a comparatively large surface area providing potential interaction sites for cellular and virally encoded ER resident proteins.     

Arterial compliance in patients on long-treatment-time dialysis

Arterial compliance is found to be reduced in haemodialysis patients. It is not clear whether decreased arterial compliance in uraemic patients is a consequence of long-standing increased mean arterial blood pressure or a consequence of the uraemic state. An adequate blood pressure can be achieved by long-treatment-time dialysis of 8 h three times a week. We studied femoral and carotid artery wall properties in 24 normotensive patients on long-treatment-time dialysis and 4 normal controls matched for mean arterial pressure, age, sex, and body mass index. Arterial distensibility coefficient and compliance coefficient were determined with a vessel wall movement detector system, 24 h after dialysis in the supine position. The patients were 5.9±6.6 years on long-treatment-time dialysis at a Kt/V of 1.8±0.4. We found no significant differences in mean arterial pressure or pulse pressure between patients (85±13, 55±17 mmHg) and controls (84±6, 50±13 mmHg). Femoral distensibility coefficient and compliance coefficient were lower in patients (6.0±2.4 10^-3/kPa; P <0.05, 0.52±0.28 mm²/kPa; n.s.) compared to the controls (8.8±4.0 10^-3/kPa, 0.67±0.38 mm²/kPa). No differences in carotid distensibility coefficient and compliance coefficient were found between patients (12.8±4.6 10^-3/kPa, 0.72±0.30 mm²/kPa) and controls (14.1±4.4 10^-3/kPa, 0.70±0.23 mm²/kPa). We conclude that patients on long-treatment-time-dialysis have an increased stiffening of the muscular femoral artery but not of the more elastic carotid artery. Results suggest that the uraemic state itself has a deleterious effect on the elastic properties of the muscular femoral artery.     

Immune and hormonal changes in early-stage chronic lymphocytic leukemia patients

Summary Fifty-six previously untreated stage-I (according to Rai) chronic lymphocytic leukemia (CLL) patients were examined for their clinical data, immunological characteristics, and hormonal values. Dysfunction of T and B lymphocytes was demonstrated by changed lymphocyte blastogenic response to stimulation with phytohemagglutinin (PHA), concanavalin A (ConA), pisum sativatum agglutinin (PSA), wheat germ agglutinin (WGA), recombinant interleukin 2 (IL 2), and dextran sulfate (DxS); also by decreased immunoglobulin levels (IgG, IgA, IgE) and increased 2-microglobulin (2-M) values. Simultaneously, dysregulation of the hypothalamic-pituitary-adrenal axis, immune system integration, imbalance of sex hormones, and changes in thyroid hormones were observed in the same group of patients. Disturbed immunohormonal interactions in early-stage CLL may be responsible for the pathogenetic mechanisms in this lymphoproliferative malignancy.     

Biological Activity of Some Stereoisomeric Arginine-Containing Peptides

Pharmaceutical Chemistry Journal -     

Fluid state and blood pressure control in patients treated with long and short haemodialysis.

BACKGROUND: Patients treated at the haemodialysis (HD) centre in Tassin, France have been reported to have superior survival and blood pressure (BP) control. This control has been ascribed to maintenance of an adequate fluid state, antihypertensive drugs being required in < 5% of the patients, although it could not be excluded that a high dose of HD regarding removal of uraemic toxins might also have been of value. METHODS: The aim of the study was to assess the fluid state and BP in normotensive patients on long HD (8 h) in Tassin (group TN) using bioimpedance to measure extracellular volume (ECV), ultrasound for determining the inferior vena cava diameter (IVCD), and 'on-line' monitoring of the change in blood volume (BV), and to compare them with normotensive (group SN) and hypertensive (group SH) patients on short HD (3-5 h) at centres in Sweden. ECV was normalized (ECVn) by arbitrarily setting the median ECV (in % of body weight) in SN patients at 100% for each gender, recalculating the individual values and combining the results for male and female patients in each group. RESULTS: The dose of HD (Kt/V urea) was higher for TN patients than for Swedish patients who had a similar Kt/V, whether hypertensive or not. SH patients had significantly higher ECVn and IVCD than TN and SN patients. TN and SN patients did not differ significantly regarding ECVn and IVCD before and after HD. However, in a subgroup of eight TN patients, ECVn was below the range of that in SH and SN patients, due to obesity with a high body mass index. Another subgroup of 14 TN patients had a higher ECVn than most of the SN patients and also higher than the median ECVn in the SH group, without any difference in body mass index, but they were nevertheless normotensive. The fall in BV was greater in SN than in TN patients, presumably due to a higher ultrafiltration rate in SN patients. However, SH patients had a smaller change in BV than SN patients, presumably because their state of overhydration facilitated refilling of BV from the interstitial fluid. CONCLUSIONS: Normotension can be achieved independently of the duration and dose (Kt/V urea) of HD, if the control of post-dialysis ECV is adequate. However, this is more difficult to achieve with short than with more prolonged HD during which the ultrafiltration rate is lower, BV changes are smaller and intradialysis symptoms less frequent. The results in the subgroup of patients with high ECVn at Tassin suggest that normotension may also be achieved in patients with fluid overload provided that the dialysis time is long enough to ensure more efficient removal of one or more vasoactive factors that cause or contribute to hypertension.     

Inhaled insulin: a new route in the optimisation of glucose regulation

The lungs constitute an attractive route for the administration of insulin in view of their large surface area and the permeability for proteins. Inhaled insulin may greatly reduce the daily nuisance of subcutaneous injections for millions of patients. The acceptance of insulin therapy may therefore be increased, so that better metabolic control can be achieved. For optimal efficacy it is essential that the insulin be precipitated in the alveoli and it is precisely the reproducibility of this process that is variable and dependent upon a variety of factors. Thus, the properties of the particles, technique of respiration, administration system and the presence of pulmonary disease (smoking) all play a role. The pharmacokinetics make inhaled insulin suitable for preprandial administration: the absorption is very rapid, so that it can be taken a very short time before meals. The duration of action, however, is short, so that the use of long-acting insulin usually remains necessary. The biological availability of inhaled insulin is < 20%, so that the required dose is larger. The long-term effects of the intra-alveolar administration of insulin and its immunological consequences are still insufficiently clear, although no permanent negative effects have been demonstrated so far. Partly in view of the favourable pharmacodynamic properties, the use of inhaled insulin is an attractive therapeutic option, not only for the group of patients with a fear of injections but for all diabetics that require insulin therapy.