Liver transplantation in the treatment of bleeding esophageal varices

From March 1980 to July 1987, 1000 patients with various end-stage liver diseases received orthotopic liver transplants. Of the 1000 patients, three hundred two had definite histories of bleeding from esophageal varices before transplantation. There were 287 patients with nonalcoholic liver diseases and 15 patients with alcoholic cirrhosis. All patients had very poor liver function, which was the main indication for liver transplantation. One- through 5-year actuarial survival rates of the 302 patients were 79%, 74%, 71%, and 71%, respectively. These survival rates are far better than those obtained with other available modes of treatment for bleeding varices when liver disease is advanced. Long-term sclerotherapy is the treatment of primary choice for bleeding varices. Patients in whom sclerotherapy fails should be considered for liver transplantation unless clear contraindications exist

Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality, Ventricular Dilatation and Deranged Matrix during Cardiac Pressure Overload

RATIONALE: Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. OBJECTIVE: We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. METHODS AND RESULTS: Mice harboring a systemic knockout of the CXCR5 (CXCR5(-/-)) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5(-/-) developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5(-/-) compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5(-/-) mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. CONCLUSIONS: Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly

The selective post-translational processing of transcription factor Nrf1 yields distinct isoforms that dictate its ability to differentially regulate gene expression

Upon translation, the N-terminal homology box 1 (NHB1) signal anchor sequence of Nrf1 integrates it within the endoplasmic reticulum (ER) whilst its transactivation domains [TADs, including acidic domain 1 (AD1), the flanking Asn/Ser/Thr-rich (NST) domain and AD2] are transiently translocated into the ER lumen, whereupon the NST domain is glycosylated to yield an inactive 120-kDa glycoprotein. Subsequently, these TADs are retrotranslocated into extra-luminal subcellular compartments, where Nrf1 is deglycosylated to yield an active 95-kDa isoform. Herein, we report that AD1 and AD2 are required for the stability of the 120-kDa Nrf1 glycoprotein, but not that of the non-glycosylated/de-glycosylated 95-kDa isoform. Degrons within AD1 do not promote proteolytic degradation of the 120-kDa Nrf1 glycoprotein. However, repositioning of AD2-adjoining degrons (i.e. DSGLS-containing SDS1 and PEST2 sequences) into the cyto/nucleoplasm enables selective topovectorial processing of Nrf1 by the proteasome and/or calpains to generate a cleaved active 85-kDa Nrf1 or a dominant-negative 36-kDa Nrf1γ. Production of Nrf1γ is abolished by removal of SDS1 or PEST2 degrons, whereas production of the cleaved 85-kDa Nrf1 is blocked by deletion of the ER luminal-anchoring NHB2 sequence (aa 81–106). Importantly, Nrf1 activity is positively and/or negatively regulated by distinct doses of proteasome and calpain inhibitors

The epidemiology of infantile hypertrophic pyloric stenosis in Sweden 1987-96

AIMS—To find out whether the incidence of infantile hypertrophic pyloric stenosis (IHPS) has changed over the past decade, and if so, to investigate possible contributory factors.
METHODS—All infants undergoing pyloromyotomy for IHPS in Sweden between 1987 and 1996 were studied. Using the national patient registers the yearly incidence was determined and evaluated in relation to sex, latitude, urbanisation, and type of surroundings by use of a Poisson model.
RESULTS—There was a substantial decline from 2.7/1000 to 0.85/1000 over the time period. The incidence in the south was almost three times greater than in the north.
CONCLUSION—The declining incidence and geographical difference suggest that environmental factors are of importance in this disorder.


A Decade Followup in Early Cases of Renal Homotransplantation

Sixty-four consecutive patients underwent renal homotransplantation 10 1/6 to 11½ years ago, 46 from related and 18 from nonrelated living donors. Thirty-six of these recipients were alive when this series was presented to the American Surgical Assocation in 1965. Now, nine years later, 26 (72%) of the 36 still survive, in 22 instances with function of their original grafts. The 10 who died in the interim tended to have subnormal renal function or graft failure. However, the actual causes of death included 2 or more examples each of myocardial infarction, hepatitis, or other systemic infections. The prognosis for achieving a one decade survival was not obviously related to HL-A tissue match. The best results were with related kidneys, within which subgroup 24 (52%) of the original recipients are still alive. However, there was no particular category of consanguineous donor that had a marked superiority. Only 2 of 18 nonrelated recipients are still alive. All 36 patients who were alive in 1965 had a biopsy of their renal homograft. Kidneys that were destined to function for a decade tended to have relatively minor histopathologic abnormalities. If serious glomerular lesions were found, the outlook for long graft survival was grave. Vascular lesions had a somewhat less serious import. Mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis proved prognostically to be the least significant. Long-term followup of these early cases has shown the durability of chronic renal homografts, particularly if these are from related donors, and has demonstrated the very high degree of rehabilitation that could be achieved even in the early days of renal homotransplantation