2-Chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), a new lead compound for the treatment of human cytomegalovirus infections

Human cytomegalovirus (HCMV) remains one of the major pathogens in immunocompromised patients (AIDS and transplants) and the main cause for congenital infections leading from slight cognitive defects up to severe mental retardation. The drugs that are currently available for the treatment of HCMV infections, i.e. ganciclovir, foscarnet and cidofovir, are all acting at the level of the viral DNA polymerase. Here we describe an entirely new molecule, the 2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), that shows very potent in vitro activity against HCMV. CMV423 is highly active against HCMV reference strains and clinical isolates, but also against those strains, isolated from patients or emerging after in vitro selection, that are resistant to either ganciclovir, foscarnet or cidofovir. CMV423 also showed activity in two ex vivo models, that are both highly relevant for the pathophysiology of HCMV, the retinal pigment epithelial and the bone marrow stromal cell assays. Viral antigen expression analysis by flow cytometry, as well as time of addition experiments, confirmed that CMV423 acts on a step of the viral replicative cycle that precedes the DNA polymerase step and, most likely, coincides with the immediate early (IE) antigen synthesis. Finally, CMV423 combined with either ganciclovir, foscarnet or cidofovir in checkerboard experiments demonstrated a highly synergistic activity.     

Soy protein supplementation increases serum insulin-like growth factor-I in young and old men but does not affect markers of bone metabolism

Recent studies suggest that soy protein (SP) protects bone in women; however, its effects on bone metabolism in men have not been investigated. Healthy men (59.2 +/- 17.6 y) were assigned to consume 40 g of either SP or milk-based protein (MP) daily for 3 mo in a double-blind, randomized, controlled, parallel design. Serum insulin-like growth factor-I (IGF-I), which is associated with higher rates of bone formation, was greater (P < 0.01) in men supplemented with SP than in those consuming MP. Serum alkaline phosphatase and bone-specific alkaline phosphatase activities, markers of bone formation, and urinary deoxypyridinoline excretion, a specific marker of bone resorption, were not different between the SP and MP groups. Furthermore, because substantial reductions in bone density occur in men at approximately 65 y of age, data were analyzed separately for men >/=65 y and those <65 y of age. The response to protein supplementation was consistent in the two age groups. The effects of SP on serum IGF-I levels suggest that SP may positively influence bone in men. Longer-duration studies examining the effects of SP or its isoflavones on bone turnover and bone mineral density and content in men are warranted.     

Interaction of high concentrations of riluzole with recombinant skeletal muscle sodium channels and adult-type nicotinic receptor channels

Riluzole is a neuroprotective drug that modulates glutamergic transmission but also blocks the inactivated state of voltage-gated neuronal sodium channels at very low concentrations (about 0.1 microM). After nausea, the most common adverse effect of riluzole is asthenia, which could be due to a block of muscle sodium channels or acetylcholine receptor channels. Using the patch-clamp technique, we applied riluzole on recombinant voltage-gated skeletal muscle sodium and adult nicotinic acetylcholine receptor channels expressed in a mammalian cell line (HEK 293). Riluzole blocked the inactivated state of voltage-gated skeletal muscle sodium channels, shifting the midpoint of the steady-state inactivation curve to more negative potentials, but only in comparatively high concentrations (> or = 0.1 mM). At these concentrations, riluzole also caused an open-channel block at acetylcholine receptor channels. We conclude that riluzole has only a mild blocking effect on the inactivated state of voltage-gated skeletal muscle sodium channels and nicotinic acetylcholine receptor channels. As the plasma concentration of riluzole in amyotrophic lateral sclerosis (ALS) patients approximates 2 microM, it seems unlikely that asthenia is caused by a block of skeletal muscle sodium channels or acetylcholine receptor channels by riluzole.     

Acute choroidal closure caused by hemodialysis accident in an amyloidosic patient

Background We report the case of a 43-year-old man haemodialysed for 20 years for systemic amyloidosis who underwent an acute choroidal occlusion after a haemodialysis accident.Case report The patient had cardiac, pulmonary, neurovegetative and renal localizations of amyloidosis. He complained during a haemodialysis session of uncomfort with abdominal pain, headache, bradycardia, vomiting, confusion and blurred vision. Acute haemolytic anemia was confirmed. In the following days, eyes were red and the vision was still altered.Results Examination showed decreased visual acuity (VA) to 20/80 OU, low intraocular pressure (IOP), major vitritis and pigmentary alterations of the fundus with yellow retinal deposits. Fluorescein and indocyanine green angiographies showed amyloid retinal deposits, pigmentary alterations, normal retinal perfusion and massive choroidal hypoperfusion persisting in the late sequence. Steroid therapy was tried unsuccessfully. The situation slowly improved within 3 months with complete clearing of the vitreous opacities and stabilisation of the pigmentary alterations. VA progressively recovered to 20/30, 1 year after the onset of the disease, but IOP remained low and choroidal perfusion did not improve 2 years after the accident.Conclusion Choroidal complications of amyloidosis have never been described so far. The acute occlusion observed here was the consequence of an intravascular haemolytic event that completed the preexisting amyloid vascular infiltration.     

Major dietary patterns and risk of renal cell carcinoma in a prospective cohort of Swedish women

Links between specific foods and the risk of renal cell carcinoma (RCC) are not well established. Dietary patterns may be a better predictor of RCC risk. Our aim was to identify and examine major dietary patterns and their relation to the risk of RCC in a large prospective cohort study of Swedish women. Complete dietary information was available from a FFQ from 46,572 women aged 40-76 y at baseline. We conducted factor analysis to identify dietary patterns. Cox proportional hazard models were used to estimate rate ratios (RRs) and 95% CIs. During a mean of 14.3 y of follow-up, we identified 93 cases of RCC. We observed 3 major dietary patterns in the cohort: Healthy (vegetables, tomato, fish, fruits, poultry, whole grains), Western (sweets, processed meat, refined grains, margarine/butter, high-fat dairy products, fried potato, soft drinks, meat) and Drinker (wine, hard liquor, beer, snacks) pattern. Higher Healthy pattern scores were not significantly associated with decreased risk of RCC (highest vs. lowest tertile RR = 0.81; 95% CI 0.45-1.48 and RR = 0.54; 95% CI 0.27-1.10 among women < or = 65 y). There was a suggestion of an inverse association between the Drinker pattern and RCC risk (RR comparing the 2nd and 3rd with the first tertile, 0.56; 95% CI, 0.34-0.95; and 0.72; 95% CI, 0.42-1.22, respectively, P = 0.08 by Wald test); the association was clearer among women < or = 65 y (P = 0.02 by Wald test). Our data suggest an inverse association between Drinker pattern and the risk of RCC.     

Lower abdominal bulge after deep inferior epigastric perforator flap (DIEP) breast reconstruction

The etiology of lower abdominal bulge following breast reconstruction with the DIEP flap is uncertain. Most studies report an incidence that ranges from 0.7% to 5%. The purpose of this study was to review a set of factors that may predispose to a lower abdominal bulge. This was a retrospective review of 123 women who had breast reconstruction with the DIEP flap over a 4-year period. The reconstruction was unilateral in 93 women and bilateral in 30 women, totaling 153 flaps. Etiologic factors that were evaluated included patient age, diabetes mellitus, tobacco use, previous abdominal operations, unilateral or bilateral reconstruction, previous childbirth, aponeurotic plication to improve the natural abdominal contour, and use of Marlex mesh. A lower abdominal bulge occurred in 5 of the 123 women (4%), 2 following 30 bilateral reconstructions (6.6%) and 3 following 93 unilateral reconstructions (3.2%). Analysis of the factors for all women demonstrated diabetes mellitus in 1 (0.8%), tobacco use in 9 (7.3%), a prior abdominal operation in 55 (44.7%), previous childbirth in 95 (77%), aponeurotic plication in 49 (40%), and use of Marlex mesh in 4 (3.3%). Statistical analysis did not show any significant association between the explanatory factors and the occurrence of a lower abdominal bulge, except for a weak trend in women who had not been pregnant (P = 0.08). The results of this study demonstrate that the occurrence of a lower abdominal bulge following the DIEP flap is a random event that can occur in anyone. Pregnancy may confer a preventative effect as the collagen fibers strengthen to overcome the stretching forces. Techniques for prevention and treatment include intraoperative assessment of the anterior rectus sheath, use of an adjuvant material for reinforcement if unstable, and vertical plication for bulge repair.     

New and unusual O alleles at the ABO locus are implicated in unexpected blood group phenotypes

BACKGROUND: In the ABO blood group system mutations in the A gene may lead to weak A subgroups owing to a dysfunctional 3-alpha-N-acetylgalactosaminyltransferase. STUDY DESIGN AND METHODS: Blood and DNA were investigated to correlate weak A phenotypes with genotype, and an overrepresentation of the infrequent O2 allele was observed. Consequently, 57 available O2 alleles were examined in detail. RESULTS: Two new O2 alleles were identified having mutations resulting in Gly229Asp with or without Arg217Cys. A recently described O2 variant (488C>T; Thr163Met) was also found. Surprisingly, both the original and the variant O2 alleles were associated with either O or Aweak phenotypes. Three novel O alleles surfaced in six other samples with suspected A subgroups. These were A1-like alleles having nonsense mutations causing premature truncation at codons 56, 107, or 181. A second example of the rare O3 allele was also identified. A newly described O1 allele having 768C>A was found to be the third most frequent O allele among Swedish donors. Of the five novel O alleles, three were incorrectly interpreted as A1 following routine ABO genotyping. CONCLUSION: Apparent O alleles lacking 261delG may cause weak A expression on red blood cells and/or inhibit anti-A production. A hypothesis that exchange of genetic material between principally dissimilar O alleles during mitosis ("autologous chimerism") restores glycosyltransferase activity in some cells would explain this interesting phenomenon.     

THE SOLID PHASE SYNTHESIS OF PORCINE SECRETIN WITH FULL BIOLOGICAL ACTIVITY

The solid phase synthesis of porcine secretin is described. The C-terminal residue was attached to a polymeric amino support and all the Boc-amino acids, including Boc-glutamine, were coupled by a modified carbodiimide method. A preliminary test synthesis showed that the couplings of several amino acids of the N-terminal section were unsatisfactory. This problem was overcome in the main synthesis by executing all the major reactions twice. Cleavage of the peptide from the resin as well as the removal of all the side chain protecting groups was achieved with liquid HF. The product was purified by ion-exchange chromatography on SP-Sephadex to obtain a highly purified heptacosapeptide amide with full biological activity.     

Vitellogenesis in two spathebothriidean cestodes

Vitellogenesis in two spathebothriidean tapeworms, dixenous adult Cyathocephalus truncatus and monoxenous progenetic Diplocotyle olrikii, has been examined using transmission electron microscopy and cytochemical staining with periodic acid-thiosemicarbazide-silver proteinate for glycogen. Each vitelline follicle consists of vitellocytes at various stages of development and one irregularly shaped interstitial cell. Projections of the interstitial cell enclose the vitellocytes and extend as a cytoplasmic sheath on the follicular periphery. An outer thin fibrous layer (= extracellular lamina) covers the cytoplasmic sheath in C. truncatus, but lacks in D. olrikii. Maturing and mature vitellocytes contain vitelline material in the form of single small shell globules that gradually fuse and give rise to the large shell globule clusters. Morphology of shell globule clusters differs slightly in both species. In addition, single lamellar granules are present in the cytoplasm of vitellocytes of C. truncatus, but not in D. olrikii. Both electron lucent and electron dense lipid droplets are present in the vitellocytes of C. truncatus, whereas only electron dense lipids occur in D. olrikii. A single lipid droplet turns up occasionally in the nuclei of some of the vitellocytes of C. truncatus. The ultrastructural features of vitellogenesis in spathebothriideans resemble those reported previously in lower cestodes, especially in pseudophyllideans.