Familial psoriasis and HLA-B: unambiguous support for linkage in 97 published families

The existence of a psoriasis susceptibility locus, PSORS1 (HUGO/GDB-approved symbol), in or near the HLA region of chromosome 6 is strongly supported by a lod score analysis of HLA-B and psoriasis in 97 families from 16 published datasets. Families included in the dataset represent all the psoriasis families with usable HLA data that we could find in the published literature through May 1997. The recombination fraction between PSORS1 and HLA-B is estimated to be at or near 0.00, with a maximum two-point lod score of 23.7, assuming a dominant mode of inheritance with low (20%) penetrance at the PSORS1 locus. Although these families are geographically and ethnically diverse, there is no evidence for linkage heterogeneity at the HLA-linked locus in this analysis. We also conclude that the HLA-B17 allele, which is strongly associated with psoriasis, is unlikely itself to contribute directly to psoriasis susceptibility; rather, the HLA-B locus is probably tightly linked to the PSORS1 locus. Finally, we raise the possibility of a two-locus/heterogeneity model as one way to reconcile several findings in the literature.     

Preventing congestive heart failure

The morbidity, mortality and health care costs associated with congestive heart failure make prevention a more attractive public health strategy than treatment. Aggressive management of etiologic factors, including hypertension, coronary artery disease, valvular disease and excessive alcohol intake, can prevent the left ventricular remodeling and dysfunction that lead to heart failure. Early intervention with angiotensin converting enzyme inhibitors in patients with chronic left ventricular dysfunction can prevent, as well as treat, the syndrome. Several intervention strategies in patients with acute myocardial infarction can slow or prevent the left ventricular remodeling process that antedates congestive heart failure. The primary care physician must be alert to the need for aggressive intervention to reduce the burden of heart failure syndrome on the patient and on society.     

Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson's disease family

Recent data suggesting complex I dysfunction in Parkinson's disease (PD) arises from mitochondrial DNA (mtDNA) mutation does not conclusively answer whether the responsible genetic lesion is inherited (primary) or somatic (secondary). To address this question, we identified a family in which multiple members over three generations are affected with PD through exclusively maternal lines. Cytoplasmic hybrids (cybrids) were created for 15 family members over two generations by transferring each individual's mtDNA to mtDNA-depleted human neuroblastoma cells. Eight of the 15 cybrid lines contained mtDNA obtained from maternally descended family members and seven contained mtDNA from paternally descended family members. After 6 weeks of culture, cybrid cell lines were assayed for complex I activity and oxidative stress, and mitochondrial morphology was analyzed by electron microscopy. Compared with the cybrid lines containing mtDNA from paternal descendants, cybrid lines containing mtDNA from maternal descendants had lower complex I activity, increased reactive oxygen species production, increased radical scavenging enzyme activities, and more abnormal mitochondrial morphologic features. These findings were present in cybrid lines containing mtDNA from maternal descendants with PD as well as in currently asymptomatic young maternal descendants, and support a precedent for inherited mtDNA mutation in some persons with PD.     

Toxicity of fotemustine in rat hepatocytes and mechanism-based protection against it

Fotemustine is a relatively novel DNA-alkylating 2-chloroethyl-substituted N-nitrosourea (CENU) drug, clinically used for the treatment of disseminated malignant melanoma in different visceral and non-visceral tissues. Thrombocytopenia has been observed in patients treated with fotemustine and liver and renal toxicities as well. In this study, firstly the metabolism of fotemustine was investigated in vitro and secondly the undesired cytotoxicity of fotemustine as well as different ways of protection against it. In rat hepatocytes, chosen as a model system, fotemustine was shown to cause lactate dehydrogenase (LDH) leakage, glutathione (GSH) depletion, GSSG-formation and lipid peroxidation (LPO). A reactive metabolite, DEP-isocyanate, is most likely responsible for these undesired cytotoxic effects. Based on the observed cytotoxicity mechanisms, chemoprotection with several sulfhydryl-containing nucleophiles and antioxidants was investigated. The sulfhydryl nucleophiles; GSH, N-acetyl-L-cysteine (NAC) and glutathione isopropylester (GSH-IP) protected almost completely against fotemustine-induced LDH-leakage and LPO. NAC and GSH protected partly against fotemustine-induced GSH-depletion. The antioxidant, vitamin E protected completely against fotemustine-induced LPO, but only partly against fotemustine-induced LDH-leakage and not against GSH-depletion. Ebselen, a peroxidase-mimetic organoselenium compound, did not show protective effects against the cytotoxicity of fotemustine, possibly because GSH is required for the bioactivation of ebselen. It is concluded that co-administration of sulfhydryl nucleophiles, in particular NAC and GSH-IP, possibly in combination with antioxidants, such as vitamin E, are effective against the toxicity of fotemustine in vitro. It might, therefore, be worthwhile to investigate the cytoprotective potency of these agents against undesired toxicities of fotemustine in vivo as well.     

Prognostic significance of allelic losses in primary melanoma

Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine whether allelic loss is of prognostic importance in melanoma, disease-free survival was related to loss of heterozygosity on 6q, 9p and 10q in 83 individuals with sporadic primary cutaneous melanoma. Loss of chromosome arms 6q and 10q were each significantly associated with a poorer clinical outcome (P=0.013 and P=0.001 respectively). In a subgroup of 41 subjects whose primary tumours were allelotyped, the fractional allelic loss (FAL) at 39 autosomal arms also significantly correlated with disease-free survival (P=0.013), with an increase in FAL associated with a poorer outcome; this association remained significant when controlled for tumour thickness (P=0.035). In addition, a greater proportion of cells were immunopositive for Ki67 antigen, p53 and p21WAF1 protein in the primary melanomas than in the benign melanocytic nevi, however, only p53 over-expression was significantly associated with improved survival (P=0.041).     

Sex identification of turkey embryos using a multiplex polymerase chain reaction

A considerable portion of the W chromosome in Gallinaceous birds consists of tandem repetitive DNA. In the turkey, a 0.4-kb PstI element is repeated about 10,000 times in the female diploid genome but is undetectable as such a unit in males. In this study a multiplex polymerase chain reaction was developed to identify the sex of turkeys based upon the PstI repeat. The technique utilized two pairs of primers, the first pair was designed to amplify a region of the PstI repetitive element, resulting in the production of a 177-bp fragment in females. The other pair was designed to amplify a region of the adenosine triphosphate (ATP) synthase gene, present in both males and females. The simultaneous use of all four primers in the same reaction resulted in the coamplification of a 177-bp and a 250-bp fragment in females and a 250-bp fragment in males. This technique was used to verify the sex of 45 adults of known sex and to identify the sex of 74 embryos from Day 5 to hatch. This procedure is rapid and permits the sexing of many embryos in a short time. The ability to sex early embryos can facilitate studies on avian sex determination.     

Seroprevalence of Borrelia burgdorferi sensu lato infection in blood donors and park rangers in relation to local habitat

Serum samples were obtained from blood donors in eleven selected locations in Ireland and tested for antibodies to Borrelia burgdorferi s.l. by enzyme immunoassay (EIA) and immunoblot (IB). The highest seroprevalence (8.7%) was found in Portumna, an area rated as high risk because of the presence of public access woodland harbouring both ticks and spirochaete reservoir hosts. The lowest seroprevalence (0.0%) was found in Ballina, an area where there is no suitable woodland though ticks are common on pastures grazed by cattle and sheep. These results support the findings of an earlier less extensive study and suggest that infection with B. burgdorferi s.l. in Ireland is mainly associated with mixed woodland containing deer and a variety of spirochaete reservoir hosts. The lack of association of tick-infested farmland with seropositive samples suggests that exposure to ticks alone is not a reliable indicator of risk of Lyme borreliosis. This is supported by the fact that none of 38 park rangers, all of whom are regularly bitten by ticks, were seropositive for B. burgdorferi s.l. The low overall seroprevalence of 3.4% in Ireland correlates with the rarity of clinical cases compared with continental European countries, and is due in part to the scarcity of high risk Lyme borreliosis habitat.     

Synthesis and in vitro antimalarial activity of sulfone endoperoxides

A series of 4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]+ ++nonanes, carrying a variety of substituents at position-8 (4) were prepared by a short and efficient method from R-(+)-limonene. Key reactions include thiol oxygen cooxidation, and alkylation and acylation of a sterically hindered tertiary alcohol compatible with the endoperoxy functionality. Some of compounds 4, which are structurally related to yingzhaosu A (2), were found to exhibit in vitro antimalarial activity comparable to that of artemisinin (1) and superior to that of arteflene (3).