Bariatric Surgery for Congestive Heart Failure Patients Improves Access to Transplantation and Long-term Survival.

INTRODUCTION: Obese patients with congestive heart failure (CHF) are often denied access to heart transplantation until they obtain significant weight loss to achieve a certain BMI threshold, often less than 35 kg/m2. It is unknown whether the rapid weight loss associated with bariatric surgery leads to improved waitlist placement, and as such improved survival for morbidly obese patients with CHF. METHODS: A decision analytic Markov state transition model was created to simulate the life of morbidly obese patients with CHF who were deemed ineligible to be waitlisted for heart transplantation unless they achieved a BMI less than 35 kg/m2. Life expectancy following medical weight management (MWM), Roux-en-Y gastric bypass (RYGB), and sleeve gastrectomy (SG) was estimated. Base case patients were defined as having a pre-intervention BMI of 45 kg/m2. Sensitivity analysis of initial BMI was performed. Markov parameters were extracted from literature review. RESULTS: RYGB improved survival compared with both SG and MWM. RYGB patients had higher rates of transplantation, leading to improved mean long-term survival. Base case patients who underwent RYGB gained 2.1 additional years of life compared with patient's who underwent SG and 7.4 additional years of life compared with MWM. SG patients gained 5.3 years of life compared with MWM. CONCLUSIONS: When strict waitlist criteria were applied, bariatric surgery improved access to heart transplantation and thereby increased long-term survival compared with MWM. Morbidly obese CHF patients who anticipate need for heart transplantation should be encouraged to pursue surgical weight management strategies, necessitating discussion between bariatric surgeons, cardiologists, and cardiac surgeons for appropriate perioperative risk management.

Sirolimus reduces the risk of significant hepatic fibrosis after liver transplantation for hepatitis C virus: a single-center experience.

INTRODUCTION: Hepatitis C virus (HCV) recurrence following orthotopic liver transplantation is an expected outcome in all patients transplanted for a primary diagnosis of HCV. HCV recurrence has been shown to be associated with graft fibrosis and graft loss. Recent studies suggest that sirolimus (SRL) therapy may slow or inhibit hepatic fibrosis following liver transplant in patients positive for HCV at the time of transplant. METHODS: Among 313 patients who underwent orthotopic liver transplantation for HCV between 2000 and 2009, 251 qualified for inclusion in the study. Per protocol liver biopsies were performed on all patients at 1 year following liver transplantation and/or at the time of a clinical diagnosis of HCV recurrence. Biopsies were scored for fibrosis using the Batts-Ludwig staging system (0-4); significant fibrosis was defined as fibrosis ≥ stage 2. RESULTS: Overall, there was no difference in overall survival or graft loss in the SRL compared with the control group. Multivariate analysis revealed SRL therapy to be associated with decreased odds of significant hepatic fibrosis at year 1 postoperatively and over the study duration. CONCLUSIONS: This retrospective, single-center study showed sirolimus-based immunosuppression to be associated with a lower risk of significant graft fibrosis, both at year 1 and throughout the study period, following liver transplantation in HCV-infected recipients.

A prospective study of immunisation for a cohort of children.

AIMS: To determine rates of immunisation by 24 months of age, the number of times children were recalled and the cost of immunisation for a cohort of children in general practices in Wellington. METHODS: A prospective study of 979 children registered with 27 general practices. Children in the cohort were followed from 9-24 months old. Data collected included immunisation status, the number of times children were recalled and demographic data. RESULTS: At the end of the study period (when children reached 24 months of age) 803 (82%) remained with the practices and 176 (18%) had left. At 24 months 724 (74%) of the total cohort and 685 (85.3%) of registered children who stayed with the practice were fully immunised for the early childhood vaccinations. 54% of the cohort were fully immunised after a standard recall process. The average cost per child immunised was $13.33. CONCLUSION: It is possible to achieve high rates of full immunisation in children registered with a general practice using an effective system of facilitation and support.

Mutations in specific I-A(k) alpha(2) and beta(2) domain residues affect surface expression.

A previous investigation demonstrated that several mutations in class II dimer-of-dimers contact residues interfere with antigen presentation by transfectants but not with plasma membrane expression of the mutant class II. In the present study we examined other class II mutations in this region that did inhibit plasma membrane expression of mutant class II molecules. Molecules containing both mutations H alpha 181D in the alpha(2) domain and E beta 170K in the beta(2) domain exhibited low plasma membrane expression, but molecules with only one of these mutations were expressed normally. The mutant class II molecules were transported to organelles that were accessible to a fluid-phase protein, hen egg lysozyme (HEL). Culture of transfectants with lysozyme enhanced the amount of class II compact dimer (alpha beta plus peptide; CD), and this was especially marked for the class II mutant H alpha 181D/E beta 170K and for other molecules possessing both mutations. Formation of class II CD was not paralleled by an increase in class II surface expression. Thus the joint mutation of H alpha 181 and E beta 170 has two effects. In the absence o high concentrations of exogenous peptide, it prevents efficient CD formation, possibly by affecting invariant chain (Ii) proteolysis and/or the stability of the class II after Ii/CLIP is removed. At high peptide concentrations supplied by exogenous HEL, the mutations allow CD formation, but not expression of class II on the plasma membrane. Molecular modeling of the possible interaction of class II and Ii suggests that the mutant amino acids H alpha 181D and E beta 170K, besides affecting the overall stability of class II, might also interact with Ii via two loops in class II's alpha(2) and beta(2) domains respectively.

Using Department of Veterans Affairs Administrative databases to examine long-term care utilization for men and women veterans.

We examined long-term care (LTC) utilization by male and female veterans using administrative databases maintained by VA. Research questions included: (1) Which LTC services are utilized? (2) Do utilization patterns of older veterans differ from those of elderly persons in the general U.S. population? (3) Do LTC needs of veterans vary by gender? We were unable to track LTC utilization of individuals across administrative databases. Some databases could only provide information at the national level, or alternatively, were available only at local facilities, or only at the patient or program-level data--making it impossible to get a clear picture of all the services received by an individual. Those planning to use administrative databases to conduct research must: (1) take more time than expected; (2) be flexible/willing to compromise, (3) "ferret out" information, and (4) recognize that because of dynamism inherent in information systems, results may change over time.

Salt bridge residues between I-Ak dimer of dimers alpha-chains modulate antigen presentation.

Class II dimers of dimers are predicted to have functional significance in antigen presentation. The putative contact amino acids of the I-Ak class II dimer of dimers have been identified by molecular modeling based on the DR1 crystal structure (Nydam et al., Int. Immunol. 10, 1237,1998). We have previously reported the role in antigen presentation of dimer of dimers contact amino acids located in the C-terminal domains of the alpha- and beta-chains of class II. Our calculations show that residues Ealpha89 and Ralpha145 in the alpha2-domain form an inter alpha-chain salt bridge between pairs of alphabeta-heterodimers. Other residues, Qalpha92 and Nalpha115, may be involved in close association in that part of the alpha-chain. We investigated the role of these amino acids on class II expression and antigen presentation. Class II composed of an Ealpha89K substituted alpha-chain paired with a wt beta-chain exhibited inhibited antigen presentation and expression of alpha-chain serologic epitopes. In contrast, mutation of Ralpha145E had less affect on antigen presentation and did not affect I-Ak serologic epitopes. Interchanging charges of the salt bridge residues by expressing both Ralpha145E and Ealpha89K on the same chain obviated the large negative effect of the Ealpha89K mutation on antigen presentation but not on the serologic epitopes. Our results are similar for those reported for mutation of DR3's inter-chain salt bridge with the exception that double mutants did not moderate the DR3 defect. Interestingly, the amino acids differences between I-A and DR change the location of the inter-chain salt bridges. In DR1 these residues are located at positions Ealpha88 and Kalpha111; in I-Ak these residues are located at position Ealpha89 and Ralpha145. Inter alpha-chain salt bridges are thus maintained in various class II molecules by amino acids located in different parts of the alpha2-domain. This conservation of structure suggests that considerable functional importance may attach to the ionic interactions.

Mutations in MHC class II dimer of dimers contact residues: effects on antigen presentation.

The recent solutions of the MHC class II crystal structure reveal dimerization of the alphabeta heterodimers. These dimer of dimers structures may also exist either on resting cells or after engagement by TCR, and may be involved in B cell signaling and up-regulation of co-stimulatory molecules such as B7 which facilitate T cell activation. By combining crystallographic data on HLA-DR1 with the sequence of murine I-Ak and refining the resulting structure through energy minimization calculations, we have predicted the contact amino acids expected to stabilize the I-Ak dimer of dimers structure. As in HLA-DR1, three salt bridges in I-Ak (D alpha62-Hbeta112, H alpha181-E beta163, E alpha183-Hbeta113) appear to provide the main interaction. Guided by this structural data, we prepared 45 B cell transfectants representing 20 different class II mutation phenotypes in the contact region containing these salt bridges. We examined their abilities to activate three T cell hybrids. Antigen-specific h4Ly50.5 cells were not greatly affected by changes in the dimer of dimer contact residues. In contrast, autoreactive C8.A3 T cells were very sensitive to changes in this region but presentation of class II of many mutation phenotypes could be rescued by treatments that up-regulate B7-1. The alloreactive hybridoma 2H40.2.5 was less sensitive to changes in the contact residues. A simple model was developed that summarizes the effects of the mutations for the T cells tested. Mutations at D alpha162, E alpha183, H alpha181 and Rbeta106 had the largest negative impact, while D alpha166, E alpha185, Hbeta112, Hbeta113 and E beta163 were less disruptive. Results are consistent with mutations interfering with class II interaction with another molecule which might or might not be another class II heterodimer. However, the larger negative impact of alpha chain mutations in salt bridge pairs suggests that these sites also help maintain some essential conformation of the alpha chain apart from any possible impact on dimer of dimers stability.