The impact of serum sodium concentration on mortality after liver transplantation: a cohort multicenter study.

Modification of the current allocation system for donor livers in the United States to incorporate recipient serum sodium concentration ([Na]) has recently been proposed. However, the impact of this parameter on posttransplantation mortality has not been previously examined in a large risk-adjusted analysis. We assessed the effect of recipient [Na] on the survival of all adults with chronic liver disease who received a first single organ liver transplant in the UK and Ireland during the period March 1, 1994 to March 31, 2005 (n=5,152) at 3 years, during the first 90 days, and beyond the first 90 days, adjusting for a wide range of recipient, donor, and graft characteristics. Compared to those with normal [Na] (135-145 meq/L; n=3,066), severely hyponatremic recipients ([Na]<130 meq/L, n=541), had a higher risk-adjusted mortality at 3 years (hazard ratio [HR] 1.28; 95% confidence interval [CI], 1.04-1.59; P<0.02). The excess mortality was, however, confined to the first 90 days (HR 1.55; 95% CI, 1.18-2.04; P<0.002) with no significant difference thereafter. This was also true for hypernatremic recipients ([Na]>45 meq/L, n=81), who had an even greater risk-adjusted mortality compared to normonatremic recipients (overall: HR 1.85; 95% CI, 1.25-2.73; P<0.002; 90 days: HR 1.12; 95% CI, 0.55-2.29; P=0.8), whereas mildly hyponatremic recipients ([Na] 130-134 meq/L, n=1,127) had similar risk-adjusted mortality to those with normal [Na] at the same time points. In conclusion, recipient [Na] is an independent predictor of death following liver transplantation. Attempts to correct the [Na] toward the normal reference range are an important aspect of pretransplantation management.     

Tumor necrosis factor-alpha-induced changes in insulin-producing beta-cells

The migration of macrophages and lymphocytes that produce cytokines such as tumor necrosis factor-alpha (TNF-alpha) causes beta-cell death, leading to type 1 diabetes. Similarly, in type 2 diabetes, the adipocyte-derived cytokines including TNF-alpha are elevated in the circulation, causing inflammation and insulin resistance. Thus, the studies described in this article using TNF-alpha are relevant to furthering our understanding of the pathogenesis of diabetes mellitus. We used RINr1046-38 (RIN) insulin-producing beta-cells, which constitutively express calbindin-D(28k), to characterize the effect of TNF-alpha on apoptosis, replication, insulin release, and gene and protein expression. Western blots of TNF-alpha-treated RIN cells revealed a decrease in calbindin-D(28k). By ELISA, TNF-alpha-treated beta-cells had 47% less calbindin-D(28k) than controls. In association with the decline in calbindin-D(28k), TNF-alpha treatment of RIN cells led to a 73% greater increase in changes in intracellular calcium concentration (Delta[Ca(2+)](i)) in TNF-alpha-treated cells as compared to that in control RIN cells upon treatment with 50 mM KCl; caused a greater increase in the [Ca(2+)](i) following the addition of 5.5 microM ionomycin; increased by more than threefold the apoptotic rate, expressed as the percentage of TUNEL-positive nuclei to total nuclei; decreased the rate of cell replication by 36%; and increased and decreased selectively the expression of specific genes as determined by microarray analysis. The subcellular localizations of Bcl-2, an antiapoptotic protein, and Bax, a proapoptotic protein, within RIN cells were altered with TNF-alpha treatment such that the two were colocalized with mitochondria in the perinuclear region. We conclude that the proapoptotic action of TNF-alpha on beta-cells is manifested via decreased expression of calbindin-D(28k) and is mediated at least in part by [Ca(2+)](i).     

A novel autosomal recessive non-syndromic deafness locus (DFNB35) maps to 14q24.1-14q24.3 in large consanguineous kindred from Pakistan

Autosomal recessive nonsyndromic deafness is one of the most frequent forms of inherited hearing impairment. Over 30 autosomal recessive nonsyndromic hearing loss loci have been mapped, and 15 genes have been isolated. Of the over 30 reported autosomal recessive nonsyndromic hearing loss (NSHL) loci, the typical phenotype is prelingual non-progressive severe to profound hearing loss with the exception of DFNB8, which displays postlingual onset and DFNB13, which is progressive. In this report we describe a large inbred kindred from a remote area of Pakistan, comprising six generations and segregating autosomal recessive nonsyndromic prelingual deafness. DNA samples from 24 individuals were used for genome wide screen and fine mapping. Linkage analysis indicates that in this family the NSHL locus, (DFNB35) maps to a 17.54 cM region on chromosome 14 flanked by markers D14S57 and D14S59. Examination of haplotypes reveals a region that is homozygous for 11.75 cM spanning between markers D14S588 and D14S59. A maximum two-point LOD score of 5.3 and multipoint LOD score of 7.6 was obtained at marker D14S53. The interval for DFNB35 does not overlap with the regions for DFNA9, DFNA23 or DFNB5.     

Immunization with a polyprotein vaccine consisting of the T-Cell antigens thiol-specific antioxidant, Leishmania major stress-inducible protein 1, and Leishmania elongation initiation factor protects against leishmaniasis

Development of an effective vaccine against Leishmania infection is a priority of tropical disease research. We have recently demonstrated protection against Leishmania major in the murine and nonhuman primate models with individual or combinations of purified leishmanial recombinant antigens delivered as plasmid DNA constructs or formulated with recombinant interleukin-12 (IL-12) as adjuvant. In the present study, we immunized BALB/c mice with a recombinant polyprotein comprising a tandem fusion of the leishmanial antigens thiol-specific antioxidant, L. major stress-inducible protein 1 (LmSTI1), and Leishmania elongation initiation factor (LeIF) delivered with adjuvants suitable for human use. Aspects of the safety, immunogenicity, and vaccine efficacy of formulations with each individual component, as well as the polyprotein referred to as Leish-111f, were assessed by using the L. major challenge model with BALB/c mice. No adverse reactions were observed when three subcutaneous injections of the Leish-111f polyprotein formulated with either MPL-squalene (SE) or Ribi 529-SE were given to BALB/c mice. A predominant Th1 immune response characterized by in vitro lymphocyte proliferation, gamma interferon production, and immunoglobulin G2A antibodies was observed with little, if any, IL-4. Moreover, Leish-111f formulated with MPL-SE conferred immunity to leishmaniasis for at least 3 months. These data demonstrate success at designing and developing a prophylactic leishmaniasis vaccine that proved effective in a preclinical model using multiple leishmanial antigens produced as a single protein delivered with a powerful Th1 adjuvant suitable for human use.     

Cloning and characterization of a gene encoding an immunoglobulin-binding receptor on the cell surface of some members of the family Trypanosomatidae

Several members of the Trypanosomatidae family, when freshly isolated from their mammalian hosts, have immunoglobulins adsorbed to their cell surfaces. However, a significant portion of these antibody molecules is not parasite specific, i.e., the immunoglobulins are bound to the parasite's cell surface molecules via noncognitive interactions. It has been proposed that this noncognitive adsorption of immunoglobulins to the parasite is mediated by an Fc-like receptor present in several members of the Trypanosomatidae family. However, the molecular identification of this receptor has never been defined. Here, we describe the cloning of a gene encoding a protein that might represent this molecule. The gene, named Lmsp1, was cloned by screening a Leishmania major cDNA expression library using a rabbit antiserum. Lmsp1 is present in both Leishmania and Trypanosoma and is expressed in all developmental stages of these parasites. The predicted protein has a molecular mass of 16.6 kDa and contains an RGD sequence starting at residue 104 and three cysteine residues at positions 55, 74, and 116. The purified recombinant protein strongly binds to normal immunoglobulins of various animal species (humans, rabbits, sheep, goats, guinea pigs, donkeys, rats, and mice) and the binding to human immunoglobulins appears to be immunoglobulin G (IgG) and IgM isotype specific. Moreover, Lmsp1 binds to both purified Fc and Fab fragments of IgG from both humans and rabbits. The mapping of the Lmsp1 epitopes that bind human IgG revealed that different sequences of the molecule bind to Fc or Fab. In addition, fluorescence-activated cell sorter analyses with a specific rabbit anti-Lmsp1 antiserum showed that Lmsp1 is associated with the parasite's cell surface. Finally, inhibition experiments point to an active role of this molecule in the immunoglobulin-mediated attachment and penetration of Trypanosoma cruzi in its macrophage host cells, thus suggesting that Lmsp1 is a putative Trypanosomatidae immunoglobulin receptor.     

Telomeric fusion as a mechanism for the loss of 1p in meningioma

Characteristic cytogenetic aberrations are found in the various histopathological designations of meningioma. These aberrations range from the loss of 22q in histologically benign tumors to complex hypodiploid karyotypes in atypical and malignant tumors. This progression is characterized by increasing chromosome loss and instability, with a critical step being the loss of 1p. We report a detailed cytogenetic investigation of chromosome aberrations in a series of 88 meningiomas using Giemsa banding and multicolor spectral karyotyping (SKY). Clonal chromosome aberrations were identified in 46 (52%) tumors by G banding. Thirty-five tumors showing complex chromosome aberrations not fully characterized by G banding were subsequently reanalyzed by SKY. The SKY technique refined the G-band findings in 18 (51%) of the tumors on which it was applied. The most common features of cytogenetic progression in the complex karyotypes were chromosome arm-specific losses relating to the formation of deletions and dicentric chromosomes involving 1p. Part or all of 1p was lost in 19 tumors. Five tumors showed evidence for the loss of 1p in a progressive step-wise series of telomeric fusions involving the formation of unstable intermediates. Five recurring dicentric chromosomes were identified, including dic (1;11)(p11;p11), dic(1;12)(p12 approximately p13;p11), dic(1;22)(p11;q12 approximately q13), dic(7;19)(p11;p11), and dic(19;22)(p11 approximately p13;q11 approximately q13). These findings provide evidence that telomeric fusions play a role in the formation of clonal deletions, dicentrics, and unbalanced translocations of 1p. The loss of 1p has possible diagnostic and prognostic implications in the management of meningioma.     

Urachal malignant fibrous histiocytoma: a case report and review of the literature

Pathologic processes involving the urachus are usually related to inflammatory or sinofistular conditions. Neoplasms rarely arise within this structure, and when they do occur, they are typically epithelial, with mucinous adenocarcinoma being the most common. Mesenchymal lesions, both benign and malignant, have rarely been described in this location. We report the case of a 66-year-old white man who presented with a primary urachal malignant fibrous histiocytoma and died of metastatic disease 20 months after the initial diagnosis. This is an unusual case of malignant fibrous histiocytoma arising in a urachal remnant.     

Accumulation of allelic losses on chromosome 10 in human gliomas at recurrence

Aims—To elucidate the implications of allelic loss on chromosome 10 in the malignant progression of human gliomas.