Identification, prevalence and aspects of molecular biology of hepatitis G virus

Summary. Hepatitis G virus (HGV) is a newly identified member of the Flaviviridae family. The positive-sense RNA genome of the virus contains a single open reading frame that encodes the viral polyprotein. Its genomic organization is similar to that of the hepatitis C virus (HCV) with which it has only 25% homology at the nucleotide level. Nucleotide sequences from the NS-3 helicase region of HCV varied by 10–30%. HGV is therefore much less variable than HCV. Construction of phylogenetic trees, and calculation of mean distances between possible subtypes, indicated one level of variation in NS-3 sequences: the degree of variation between isolates was similar to that observed between HCV subtypes. Thus no evidence for clustering of sequences into multiple genotypes was found. The virus is transmissible through blood transfusion and by exposure to blood products or intravenous drug use, and may result in acute or chronic hepatitis. A causative role of HGV in acute and chronic hepatitis is not yet established. Concurrent infection with hepatitis B virus (HBV) and HCV is common and persistent viraemia has been documented for many years, in many cases, in the absence of transaminase elevations.     

Distal hyperirrigation syndrome. Clinical and physiopathological aspects

In this retrospective study, distal hyperirrigation syndrome was identified by "irrigraphy", a functional exploration method used to define an irrigation index at various levels of the lower limbs as determined by pulse wave amplitude, heart rare and segmental resistances. In 47 lower limbs studied, there were 26 unequivocal, 14 relative and 7 "masked" hyperirrigations. The main etiology was diabetes (24 limbs), but the syndrome was also noted in cases of peripheral neuropathy and chronic venous insufficiency. There was no basic difference between unequivocal and relative hyperirrigations. Some hyperirrigation states were not apparent in irrigraphy because of arterial lesions on upstream axes. The syndrome was also observed in approximately the same number of cases in insulin-dependent and noninsulin-dependent diabetes. The clinical disorders observed were especially peripheral trophic ones, notably perforating ulcers of the foot or various ulcers. Changes in the irrigraphic profile were followed regularly in 20 limbs. The rise in distal irrigation indices was due to a drop in peripheral resistances related to an abnormal opening up of arteriovenous anastomoses. A state of spontaneous sympathectomy was thus constituted, particularly in diabetic patients. The process was similar in syndromes of neurologic origin and in venous stasis. The mechanism was local, with venous hypertension causing the opening up of arteriovenous shunts. However, microangiopathic lesions must also be taken into account, since they can cause or favor arteriovenous shunting. The opening up of arteriovenous anastomoses is in effect the element common to all syndromes of distal hyperirrigation of various origins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serrated polyposis syndrome: molecular, pathological and clinical aspects

Hyperplastic polyps have traditionally been considered not to have malignant potential. New pathological classification of serrated polyps and recent discoveries about the serrated pathway of carcinogenesis have revolutionized the concepts and revitalized the research in this area. Until recently, it has been thought that most colorectal cancers arise from conventional adenomas via the traditional tumor suppressor pathway initiated by a mutation of the APC gene, but it has been found that this pathway accounts for only approximately 70%-80% of colorectal cancer (CRC) cases. The majority of the remaining colorectal cancer cases follow an alternative pathway leading to CpG island methylator phenotype carcinoma with BRAF mutation and with or without microsatellite instability. The mechanism of carcinomas arising from this alternative pathway seems to begin with an activating mutation of the BRAF oncogene. Serrated polyposis syndrome is a relatively rare condition characterized by multiple and/or large serrated polyps of the colon. Clinical characteristics, etiology and relationship of serrated polyposis syndrome to CRC have not been clarified yet. Patients with this syndrome show a high risk of CRC and both sporadic and hereditary cases have been described. Clinical criteria have been used for diagnosis and frequent colonoscopy surveillance should be performed in order to prevent colorectal cancer. In this review, we try to gather new insights into the molecular pathogenesis of serrated polyps in order to understand their possible clinical implications and to make an approach to the management of this syndrome.     

Clinical aspects and molecular genetics of the persistent Müllerian duct syndrome

OBJECTIVE The 5α-reductase inhibitor, finasteride, provides a logical medical treatment for benign prostatic hyperplasia (BPH). However, the effects of chronic finasteride treatment on prostatic androgen levels, 5α-reductase activity and tissue prostatic specific antigen (PSA) have not been studied. We have examined prostate tissue androgen concentrations and 5α-reductase activity of the gland in men with BPH treated with the drug for 3 months. DESIGN AND PATIENTS Twenty-eight patients with clinically diagnosed BPH, awaiting transurethral resection of the prostate, were entered in a double-blind placebo controlled study. Nineteen patients were randomly allocated to treatment with finasteride (5 mg daily) and 9 received placebo for 3 months. MEASUREMENTS Prostate specimens were collected immediately following surgery and analysed for testosterone, dihydrotestosterone (DHT), androstenedione, 5α-reductase activity and PSA. Blood specimens obtained before the start and immediately following treatment were also tested for steroid hormone concentrations and PSA levels. RESULTS There was no significant difference in the median levels of intraprostatic testosterone (P = 0.77), DHT(P= 0.46) and androstenedione (P = 0.09) between the finasteride and placebo groups. However, the 5α-reductase activity of the placebo group (237.9 pmol DHT/g tissue/30 min) was approximately 10 times that of the finasteride group (21.5 pmol DHT/g tissue/30 min; P = 0.0008). Although we were unable to detect any differences in the PSA concentrations of the prostate glands, there was a significant difference (P = 0.0002) in the median percentage change of serum PSA concentrations for the two patient groups. Serum DHT levels were also depleted (P = 0.038) whilst serum testosterone was increased (P = 0.054) in the finasteride patients when compared to the placebo group. Furthermore our study demonstrated no correlation between the in vitro 5α-reductase activity of the gland and tissue DHT concentrations. CONCLUSIONS Whilst finasteride treatment induced a reduction in serum dihydrotestosterone and prostatic specific antigen levels with a concomittant increase in blood testosterone concentrations, the impact of the drug on tissue androgen concentrations varied considerably from one patient to another. The differential effect of the drug on tissue androgen concentrations suggests that in the human prostate there are possibly more than one isoform of 5α-reductase responsible for the accumulation of DHT in the gland.     

Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia.

The eosinophilia-myalgia syndrome, which is associated with the ingestion of L-tryptophan that contained products, occurred as an epidemic in the United States in 1989. Eosinophilia-myalgia syndrome is similar in many ways to the toxic-oil syndrome, which occurred in Spain in 1981, and to diffuse fasciitis with eosinophilia, which has been noted since 1974 to occur sporadically. Recent studies have clarified the epidemiology, histopathology, and clinical features of eosinophilia-myalgia syndrome. These studies are reviewed, and comparisons to the related syndromes, toxic-oil syndrome and diffuse fasciitis with eosinophilia, are made.     

Clinical, laboratory and therapeutics aspects of Sheehan's syndrome

Sheehan's syndrome is characterized by hypopituitarism that occurs as a result of ischemic pituitary necrosis due to severe postpartum hemorrhage. Nowadays it is not usually seen in developed countries because of the improvements in obstetric care. However, in developing countries it is still frequent and probably one of the most common causes of hypopituitarism. Most patients usually present it months to years later, with a history of failure of postpartum lactation, failure to resume menses and other signs of panhypopituitarism. In mild forms of the disease, patients may remain undetected and do not receive treatment for many years. Early diagnosis and appropriate treatment are important to reduce the morbimortality of the patients with Sheehan's syndrome. The aim of this review is to describe clinical, laboratory and therapeutic aspects of Sheehan's syndrome, including our experience in the replacement of recombinant GH in these patients.     

Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes.

Alport syndrome (AS) is a genetically heterogeneous disease arising from mutations in genes coding for basement membrane type IV collagen. About 80% of AS is X-linked, due to mutations in COL4A5, the gene encoding the alpha 5 chain of type IV collagen (alpha 5[IV]). A subtype of X-linked Alport syndrome (XLAS) in which diffuse leiomyomatosis is an associated feature reflects deletion mutations involving the adjacent COL4A5 and COL4A6 genes. Most other patients have autosomal recessive Alport syndrome (ARAS) due to mutations in COL4A3 or COL4A4, which encode the alpha 3(IV) and alpha 4(IV) chains, respectively. Autosomal dominant AS has been mapped to chromosome 2 in the region of COL4A3 and COL4A4. The features of AS reflect derangements of basement membrane structure and function resulting from changes in type IV collagen expression. The primary pathologic event appears to be the loss from basement membranes of a type IV collagen network composed of alpha 3, alpha 4, and alpha 5(IV) chains. While this network is not critical for normal glomerulogenesis, its absence appears to provoke the overexpression of other extracellular matrix proteins, such as the alpha 1 and alpha 2(IV) chains, in glomerular basement membranes, leading to glomerulosclerosis. The diagnosis of AS still relies heavily on histologic studies, although routine application of molecular genetic diagnosis will probably be available in the future. Absence of epidermal basement membrane expression of alpha 5(IV) is diagnostic of XLAS, so in some cases kidney biopsy may not be necessary for diagnosis. Analysis of renal expression of alpha 3(IV)-alpha 5(IV) chains may be a useful adjunct to routine renal biopsy studies, especially when ultrastructural changes in the GBM are ambiguous. There are no specific therapies for AS. Spontaneous and engineered animal models are being used to study genetic and pharmacologic therapies. Renal transplantation for AS is usually very successful. Occasional patients develop anti-GBM nephritis of the allograft, almost always resulting in graft loss.     

Rheumatologic syndrome in gastrointestinal diseases. Clinical and pathogenetic aspects

Patients with reactive arthritis, sacroiliitis, spondylitis or Reiter's syndrome following intestinal infection from Yersinia, Salmonella, Shigella or Campylobacter organisms have been reported from endemic areas and after epidemic dysenteries. Possession of the antigen HLA B27 affects severity and prognosis of the arthritis and is more often associated with spondylitis and Reiter's syndrome. Articular manifestations are also quite common systemic complications of chronic inflammatory bowel disease. The clinical picture, pathogenetical aspects and treatment of arthritis associated with Crohn's disease, ulcerative colitis and Whipple's disease are reviewed. In only few cases, coeliac disease can be complicated by arthritis. In patients undergoing intestinal bypass surgery systemically absorption of intestinal bacterial antigens and immune complex formation may contribute to the development of bypass-arthropathy and dermatologic manifestations.