Genetic factors affecting the consistency and magnitude of changes in plasma cholesterol in response to dietary challenge

We examined the role of common genetic variation in determining the consistency and magnitude of change in plasma total cholesterol (TC) levels in response to two separate changes from a high-saturated (SFA) to a low-saturated/high-polyunsaturated-fat (PUFA) diet, in a group of free-living healthy men and women. Consistent responders were defined as those whose mean difference in the change in TC was within one SD of the mean for all participants, and the remainder were defined as variable responders. DNA was obtained from 55 individuals and genotype determined at the apolipoprotein (apo) B locus (signal peptide, SP), apoCIII (C1100-T) and lipoprotein lipase (LPL) gene loci (HindIII). In the 38 consistent responders, the apoBSP24 allele was significantly more common than in the 17 individuals with a variable response (0.29 vs. 0.12; p < 0.05). No other polymorphism showed a significant frequency difference between groups. In the group as a whole, the correlation between the change in TC level in response to the first and second dietary change was 0.28 (p = 0.05), but those with one or more apoB SP24 alleles and those with the apoCIII genotype CC had a significantly higher correlation than those with other genotypes (0.46 (p = 0.05) vs. 0.12 (NS) and 0.31 (p = 0.05) vs. 0.02 (NS), respectively). In the group as a whole, mean response left TC 10% higher on the SFA than on the PUFA diet, and neither apoB nor apoCIII genotypes affected the magnitude of this response. However, individuals with the LPL HindIII genotype H+ H+ had a significantly smaller change in mean TC in response to diet than those with one or more H- allele (9.3% vs. 14.4%; p = 0.03). Thus variation at the apoB and apoCIII loci affects the consistency of response to change in dietary fat content, while variation at the LPL gene locus affects magnitude of response.      

High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia

Lipid targets can be difficult to attain in familial hypercholesterolaemia. To compare atorvastatin with simvastatin- fenofibrate and simvastatin-cholestyramine therapy, we studied 54 patients with familial hypercholesterolaemia over periods of 2-6 months on each therapeutic regimen. The atorvastatin regimen reduced total cholesterol by 41.2 +/- 11.2%, LDL by 45.6 +/- 15.5%, triglycerides by 33.8 +/- 24.8%, and increased HDL by 2.3 +/- 37.0%. Simvastatin- fenofibrate therapy achieved reductions of 33.9 +/- 8.5% in cholesterol, 42.0 +/- 12.2% in LDL, 34.7 +/- 38.3% for triglycerides, and a 25.4 +/- 55.1% increase in HDL. Simvastatin-cholestyramine gave a reduction of 31.3 +/- 11.8% in cholesterol, 36.0 +/- 14.4% in LDL, 13.7 +/- 36.3% in triglycerides, and a 1.1 +/- 30.3% rise in HDL. The atorvastatin regimen was marginally but not significantly better than simvastatin-fenofibrate in improving the LDL:HDL ratio, LDL:apoB and and apolipoprotein B:A1 ratios. Eleven patients (20.4%) had side- effects: two discontinued atorvastatin due to side-effects; two patients had rashes; six had myalgia and two had diarrhoea. Gastrointestinal side-effects were described in 16 (30.1%) patients on simvastatin-cholestyramine therapy and four cases of myalgia (11.2%) were seen with simvastatin-fenofibrate. In nine patients on atorvastatin (20.4%) a 30% or greater fall in HDL was observed, compared to five patients with resin therapy (9.2%) and two with fibrate therapy (5.5%). There were no significant differences in liver or muscle biochemistry between the regimens, but atorvastatin did raise transaminase and creatine kinase concentrations significantly compared to pre-treatment values (p = 0.001). Atorvastatin significantly improves the lipid profile in most patients compared with other regimens. It has a comparable incidence of side-effects to combination therapy regimens.      

H-2 effects on cell-cell interactions in the response to single non-H-2 alloantigens. II. H-2 D region control of H-7.1-specific stimulator function in mixed lymphocyte culture and susceptibility to lysis by H-7.1- specific cytotoxic cells

The relative immunogenicity of the H-7.1 alloantigen has been shown in a previous communication to be regulated by a gene in the D region of the mouse major histocompatibility (H-2) complex. The level of relative immunogenicity was inferred from survival times of H-7.1-incompatible skin grafts donated by donors with different H-2 haplotype origins of H-2D region genes. In this communication we report the results of an extension of these previous investigations into the possible role of H-2D region genes in controlling the capacity of H-7.1-incompatible lymphocytes to stimulate H-7.1-speciflc mixed lymphocyte culture proliferation and generation of cytotoxic effector cells. The results reported herein demonstrate that the H-2D genotype of H-7.1-incompatible stimulator cells determines the relative H-7.1-specific capacity of those lymphocytes to stimulate H-7.1-specific proliferation of in vivo primed responder T cells in secondary mixed lymphocyte culture. H-2D(b)-bearing, H-7.l-incompatible stimulators were significantly more effective in stimulating H-7.1-specific proliferation than H-2D(d)-bearing stimulators. As expected, H-2D(b), H-7.1-in-compatible stimulators were also more effective than H-2D(d) a stimulators in generating H-7.1- specific cytotoxic effector cells. Further, the susceptibility of (51)Cr- labeled, H-7.1-incompatible lymphoblast targets to H-7.1-specific lysis was similarly regulated by an H-2D gene. Reciprocal H-2 restriction (F(1) cells are capable of killing only the cells bearing the immunizing cell parental H-2 haplotype) observed by other investigators for cytolysis of non-H-2-incompatible targets was not observed. H-2D a-bearing, H-7.1- incompatible stimulators stimulated generation of cytotoxic effectors capable of detectably lysing H-2D(b) but not H-2D(a)-bearing, H-7.1- incompatible targets. The impact of these observations on the proposed models for H-2 restriction of non-H-2 histocompatibility antigen-specific cytolysis is discussed.     

Short-term outcomes of a simple and effective approach to aortic root and arch repair in acute type A aortic dissection

Objective

To evaluate short-term outcomes following direct aortic root and arch repair in patients with acute type A aortic dissection (ATAAD) without technical adjuncts.

Treatment of Type 1 Gaucher's Disease Affecting Bone with Aminohydroxypropylidene Bisphosphonate (Pamidronate)

Two patients with Type 1 (adult) Gaucher's disease and majorskeletal involvement with multiple fractures have been treatedwith the second generation bisphosphonate pamidronate for extensiveperiods. There was evidence of an immediate reduction in boneresorption, with increased calcium absorption (delayed in Patient1), improved calcium balance and maintained or improved bonedensity indices in the axial and peripheral skeleton. Therewas no evidence of immediate relapse on treatment cessation.No toxic effects of pamidronate treatment were identified andsubjective skeletal pain diminished in both patients. Histomorphometryof transiliac bone biopsies obtained before the start of treatment,after double in vivo tetracycline labelling, represents oneof the earliest reports of the quantitative findings in iliacbone invaded by Gaucher cells.     

Identification of alpha-enolase as a nuclear DNA-binding protein in the zona fasciculata but not the zona reticularis of the human adrenal cortex

In order to establish whether there are differences in DNA-binding proteins between zona fasciculata (ZF) and zona reticularis (ZR) cells of the human adrenal cortex, we prepared nuclear extracts from separated ZF and ZR cells. The formation of DNA-protein complexes was studied using an element in the first intron of the type I and type II 3beta-hydroxysteroid dehydrogenase genes (HSD3B1 and HSD3B2). Using the element in the HSD3B2 gene as a probe, a complex (C1) was formed with extracts from ZF cells but was formed only at a low level with ZR cell extracts. Another pair of complexes (C2/C3) was formed with both ZF and ZR cell extracts. The ZF-specific protein forming C1 was enriched by column chromatography on DEAE-Sepharose and carboxymethyl-Sepharose. Oligonucleotide competition analysis on the enriched fraction gave results consistent with those obtained on the unfractionated material. A further enrichment was brought about by passing the protein over an oligonucleotide affinity column based on the HSD3B2 element. The protein bound to the column was identified as alpha-enolase by mass spectrometry. Although alpha-enolase is a glycolytic enzyme, it binds to specific DNA sequences and has been found to be present in nuclei of various cell types. We performed immunohistochemistry on sections of adult human adrenal cortex and found alpha-enolase to be located in nuclei of ZF cells but to be predominantly cytoplasmic in ZR cells. Transfection of an alpha-enolase expression vector into NCI-H295R human adrenocortical cells increased HSD3B2 promoter activity, suggesting a possible functional role for this protein in regulation of HSD3B2 expression.     

FcR gamma-chain is essential for both surface expression and function of human Fc gamma RI (CD64) in vivo

Most Ig receptors exist as hetero-oligomeric complexes with separate ligand binding (alpha) and signal transducing (beta, gamma, or zeta) subunits. For Fc gamma RIIIa and Fc epsilon RI, association with the FcR gamma-chain is essential for surface expression. However, the human high affinity IgG receptor, hFc gamma RI, was found to be surface- expressed by itself in transient transfection models. We have now analyzed the integrity of hFc gamma RI expression in more detail in stable transfectants. In vitro we noted that, in the absence of FcR gamma-chain, surface expression of hFc gamma RI rapidly declined to background levels, in both IIA1.6 B cells and NIH3T3 fibroblasts. The effect of FcR gamma-chain on hFc gamma RI surface expression in vivo was evaluated by using two newly generated transgenic mouse lines, selectively expressing hFc gamma RI on myeloid cells. These transgenic mice were crossed with FcR gamma-chain-deficient mice. Analysis of blood monocytes and peritoneal macrophages showed that surface expression of hFc gamma RI was reduced by approximately 80%. The remaining approximately 20% of receptors were still capable of binding IgG-opsonized RBC, suggesting FcR gamma-chain not to be critical for hFc gamma RI ligand-binding capacity. Importantly, however, hFc gamma RI signaling capacity was lost in FcR gamma-chain-deficient cells. No phagocytosis could be observed using either ligand sensitized (EA- IgG2a) or CD64-targeted erythrocytes (using a bispecific antibody) in both hFc gamma RI transgenic lines. This documents the FcR gamma-chain to be indispensable for both surface membrane expression and function of human Fc gamma RI in vivo.     

Mycobacterial Infections After Renal Transplantation

Mycobacterial infections occurred in 11 of 633 (1.7 per cent)recipients of successful renal transplants. There were no casesof tuberculosis in patients receiving chemoprophylaxis, butamongst those who did not receive prophylaxis disease occurredin six of the 27 (22 per cent) high-risk patients. The majorcause of morbidity during treatment was renal allograft rejection,largely due to reduction in immunosuppressive drug therapy.     

Conservative management of rectal perforation after nerve sparing endoscopic extraperitoneal radical prostatectomy (NS EERPE) in a patient with a past history of polypectomy

Introduction

Rectal polypectomy causes thinning (or even perforation) of the rectal wall in addition to thermic injury at the polypectomy site.

Case report

We present a rare case of spontaneous rectal perforation after uncomplicated nerve sparing endoscopic extraperitoneal radical prostatectomy in a patient with a previous history of rectal polypectomy at the perforation site. The patient could be treated conservatively. There was complete healing of the fistula without any effect on functional results. This Conservative therapy for such rectal perforations is indicated if the patient''s general condition remains stable without any signs of infection.

Conclusions

Polypectomy is an important risk factor for rectal perforation during nsEERPE. Adequate time interval should be given to allow healing and avoid adding further thermal wall damage which may obscure healing leading to complications like fistula. Conservative therapy for small missed rectal perforations constitutes an attractive, feasible and non invasive treatment entity. Following this principle we have not faced this complication in following similar cases.     

Effect of exercise training on peak oxygen consumption in patients with cancer: a meta-analysis

Background.

We conducted a meta-analysis to determine the effects of supervised exercise training on peak oxygen consumption (VO_2peak) in adults with cancer.

Methods.

A literature review using Ovid MEDLINE (1950–2010), the Cochrane Central Register of Controlled Trials (1991–2010), AMED (1985–2010), Embase (1988–2010), PubMed (1966–2010), Scopus (1950–2010), and Web of Science (1950–2010) was performed to identify randomized controlled trials examining the effects of supervised exercise training on measurement of VO_2peak (via gas exchange analysis) in adults with cancer. Studies were selected using predetermined criteria, and two independent reviewers extracted data. Weighted mean differences (WMDs) were calculated using random effect models.

Results.

Six studies evaluated VO_2peak involving a total of 571 adult cancer patients (exercise, n = 344; usual care control, n = 227). Pooled data indicated that exercise training was associated with a statistically significant increase in VO_2peak (WMD, 2.90 ml·kg⁻¹·min⁻¹; 95% confidence interval [CI], 1.16–4.64); however, significant heterogeneity was evident in this estimate (I², 87%). Usual care (control) was associated with a significant decline in VO_2peak from baseline to postintervention (WMD, −1.02 ml·kg⁻¹·min⁻¹; 95% CI, −1.46 to −0.58; I², 22%). Sensitivity analyses indicated superior improvements in VO_2peak for studies conducted for a shorter duration (<4 months) and following the completion of adjuvant therapy (p-values < .001). Exercise training was not associated with a higher incidence of adverse events, although safety was not rigorously monitored or reported.

Conclusions.

Supervised exercise training is associated with significant improvements in VO_2peak following a diagnosis of early-stage cancer, with minimal adverse events.