Activating KIR Haplotype Influences Clinical Outcome Following HLA-Matched Sibling Hematopoietic Stem Cell Transplantation.

Natural killer cells are thought to influence the outcome of hematopoietic stem cell transplant (HSCT), impacting on relapse, overall survival, graft versus host disease and the control of infection, in part through the complex interplay between the large and genetically diverse killer immunoglobulin-like receptor (KIR) family and their ligands. This study examined the relationship between KIR gene content and clinical outcomes including the control of opportunistic infections such as cytomegalovirus in the setting of human leucocyte antigen (HLA)-matched sibling HSCT in an Australian cohort. The presence of the KIR B haplotype which contain more activating receptors in the donor, in particular centromeric B haplotype genes (Cen-B), was associated with improved overall survival of patients with acute myeloid leukemia (AML) undergoing sibling HSCT and receiving myeloablative conditioning. Donor Cen-B haplotype was also associated with reduced acute graft versus host disease grades II-IV whereas donor telomeric-B haplotype was associated with decreased incidence of CMV reactivation. In contrast, we were not able to demonstrate a reduced rate of relapse when the donor had KIR Cen-B, however relapse with a donor Cen-A haplotype was a competing risk factor to poor overall survival. Here we show that the presence of donor activating KIR led to improved outcome for the patient, potentially through reduced relapse rates and decreased incidence of acute GvHD translating to improved overall survival. This article is protected by copyright. All rights reserved.

Heteroligomeric forms of codon 54 mannose binding lectin (MBL) in circulation demonstrate reduced in vitro function.

Mannose binding lectin (MBL) is a pattern recognition molecule that plays a pivotal role in innate immunity. This liver derived, circulating plasma protein binds organisms displaying high-density carbohydrate structures and flags them for destruction via opsonisation and initiation of the lectin pathway of the complement cascade. The present study reveals native, oligomeric forms of human MBL in plasma from healthy blood donors of differing genotypes and correlates the relative abundance of observed molecular weight species with mannan binding activity and C4 deposition in vitro. Wild type (A/A) individuals demonstrate predominately high molecular weight MBL that correlated with high mannan binding capacity and C4 deposition. A/C individuals demonstrated predominantly low molecular weight MBL with decreased mannan binding and C4 deposition activity. A/D individuals demonstrated both high molecular weight and low molecular weight MBL with reduced mannan binding and C4 deposition predominantly seen in combination with LX promoter. We identified A/B individuals as a unique group with large variation in MBL level, mannan binding activity and C4 deposition and propose a model for C4 deposition based on differential binding of MASP.

[Patient education in pre-dialysis -- patient-led forums]. / Die Patientenschulung bei der Prädialyse--Patienten geführte Foren.

In order for patients to make an informed choice about renal replacement therapies, it is important that they are given sufficient and appropriate information, which must include explanations about their condition and likely outcomes with or without treatment. Furthermore information regarding the reality of living with dialysis, its strict regimes and patient's commitment to self care are imperative to enable patients to adapt to a life changing, ongoing, often relentless treatment. Encouraging patients to take control of their chronic illness through the provision of education support and choice is fundamental to the successful outcomes of the patient's journey through the pre-dialysis phase of their illness. This paper describes the implementation of Patient-led Forums designed to offer an education programme for pre-dialysis patients and the benefits gained by those who have attended.

Mannose binding lectin acute phase activity in patients with severe infection.

Mannose Binding Lectin (MBL) is a liver derived, circulating plasma protein that plays a pivotal role in innate immunity. MBL functions as a pathogen recognition molecule, opsonising organisms and initiating the complement cascade. MBL deficiency arising from mutations and promoter polymorphisms in the MBL2 gene is common and has been associated with risk, severity, and frequency of infection in a number of clinical settings. With MBL therapy on the horizon, the usefulness of replacement MBL therapy has been challenged by the notion, that as an acute phase protein, MBL levels may rise under stress to sufficient levels, in individuals who are usually deficient. This report demonstrates that in patients with sepsis and septic shock, the majority of patients do not display an MBL acute phase response: 41.4% of individuals maintained consistent MBL levels throughout hospital stay, 31.3% of individuals demonstrated a positive acute phase response, and a negative acute phase response was observed in 27.3% of individuals studied. Importantly, a positive acute phase response was generally observed in individuals with wild-type MBL2 genes. When a positive acute phase response was observed in individuals with coding mutation, these individuals demonstrated a normal MBL level on admission to hospital. Furthermore, no individual, regardless of genotype who was MBL deficient at admission was able to demonstrate a positive acute phase response into the normal MBL range. These findings indicate MBL demonstrates a variable acute phase response in the clinical setting of sepsis and septic shock.

Fas gene promoter polymorphisms in primary Sjögren's syndrome.

BACKGROUND: Fas mediated apoptosis may be important in the pathogenesis of primary Sjögren's syndrome (pSS). OBJECTIVE: To examine genetic variation in the promoter region of the Fas gene in pSS. METHODS: Two single nucleotide polymorphisms at positions -1377(G/A) and -670(G/A) in the Fas gene promoter were genotyped by PCR-SSP in 101 patients with pSS and 108 Caucasoid controls. RESULTS: No significant differences in allele or genotype frequencies were detected between the patients with pSS and controls. However, significant associations were observed with Ro/La autoantibody negative patients, who display milder and later onset disease. The -670A allele was more frequent in Ro/La autoantibody negative patients than in Ro/La autoantibody positive patients (p = 0.04). CONCLUSION: This study does not confirm an earlier report of an association between pSS and the Fas promoter -670G allele. However, the results suggest that genetically determined variability in Fas expression may modulate Ro/La autoantibody responses in patients with pSS.

Variation in immune response genes and chronic Q fever. Concepts: preliminary test with post-Q fever fatigue syndrome.

Acute primary Q fever is followed by various chronic sequelae. These include subacute Q fever endocarditis, granulomatous reactions in various organs or a prolonged debilitating post-infection fatigue syndrome (QFS). The causative organism, Coxiella burnetii, persists after an initial infection. The differing chronic outcomes may reflect variations within cytokine and accessory immune control genes which affect regulation of the level of persistence. As a preliminary test of the concept we have genotyped QFS patients and controls for gene variants spanning 15 genes and also examined HLA-B and DR frequencies. QFS patients exhibited a significantly increased frequency of HLA-DR-11 compared with controls and also significant differences in allelic variant frequencies within the NRAMP, and IFNgamma genes. These results indicate a possible genetic role in the expression of overt chronic Q fever. Further studies will be undertaken to increase sample sizes, to survey other forms of chronic Q fever and to examine Q fever patients who have recovered without sequelae.

Analysis of the relationship between mannose-binding lectin (MBL) genotype, MBL levels and function in an Australian blood donor population.

The mannose-binding lectin (MBL) pathway of complement activation is an important component of innate host defence. Numerous studies have described associations between the MBL genotype, MBL levels and disease susceptibility. However, genotyping and quantitative assays used in these studies have frequently been limited, and comprehensive data examining the interaction between structural and coding MBL genetic variants, MBL antigenic levels and MBL functional activity are lacking. Such data may be important for accurate planning and interpretation of studies of MBL and disease. This study has examined MBL in a cohort of 236 Australian blood donors. Five MBL promoter and coding single nucleotide polymorphisms were genotyped using polymerase chain reaction-sequence-specific priming (PCR-SSP). Plasma levels of MBL antigen were quantified using a double-antibody enzyme-linked immunosorbent assay (ELISA), and functional MBL levels were quantified using a mannan-binding assay. Activation of the complement pathway by MBL was measured in a C4-deposition assay. Significant associations were found between both coding and promoter polymorphisms and MBL antigenic and functional levels. There was significant correlation between the results of MBL double-antibody, mannan-binding and C4-deposition assays. Comprehensive MBL genotyping and functional MBL quantitation using mannan-binding and C4-deposition assays have the potential to be highly informative in MBL disease association studies.

Metastatic bone disease and tumour-induced hypercalcaemia: the role of bisphosphonates.

Tumour-induced hypercalcaemia (TIH) is the most common metabolic disorder associated with cancer, and if left untreated is associated with a low survival rate. Bisphosphonates are potent inhibitors of bone resorption. They have emerged as the standard method of treatment for TIH and a new form of medical therapy for bone metastases in addition to current treatments. Newer forms of bisphosphonates are 100-1000 times more potent than pamidronate, the current gold standard. One of these third generation bisphosphonates, zoledronic acid (Zometa, Novartis Pharmaceuticals) has already been shown to provide more effective treatment of TIH than pamidronate. Ongoing research is aimed at choosing the optimum route, type of bisphosphonate and combination therapy to inhibit the development of bone metastases and TIH.

Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease.

BACKGROUND: There is considerable debate as to the optimum schedule of bisphosphonate treatment in advanced malignancy. Short term studies using symptomatic response and biochemical markers of bone resorption may provide useful insight into differences between agents. PATIENTS AND METHODS: Fifty-one patients with metastatic bone disease were randomly allocated to either oral clodronate 1,600 mg daily (group 1), intravenous clodronate followed by the same schedule of oral clodronate (group 2). or intravenous pamidronate 90 mg monthly (group 3). No radiotherapy was delivered or other systemic anticancer treatments were allowed except for long term endocrine therapy. Bone resorption was assessed by measurement of urinary collagen crosslinks. At each visit a pain score was recorded. RESULTS: Symptomatic response was more frequent in the pamidronate group than in patients receiving clodronate. Nine of sixteen patients experienced a sustained improvement in pain score in the pamidronate-treated group, in contrast to only 4 of 16 and 2 of 11 patients in groups 1 and 2, respectively. There was a significant improvement in pain scores in the pamidronate arm compared with the clodronate treated patients after both three months of treatment (P <0.01) and at the last measurement (P <0.05). Biochemical changes correlated with changes in the pain score (P = 0.01). CONCLUSION: Intravenous pamidronate appears to be more effective than oral clodronate in both controlling symptoms and suppressing bone resorption.

Restricted polymorphism of the mannose-binding lectin gene of indigenous Australians.

Mannose-binding lectin (MBL) is an important complement-activating protein of the human innate immune system. Deficiency of MBL is associated with an increased risk of various infections and arises from three structural gene mutations in exon 1 (variants B, C and D) and/or the presence of a low efficiency promoter. The C allele is found in sub-Saharan Africa whereas the B allele is found elsewhere, suggesting that these mutations occurred after the suggested hominid migration out of Africa [100-150 000 years before present (BP)]. Paradoxically, these alleles may have a selective advantage in protection against intracellular pathogens and occur at particularly high frequencies in sub-Saharan Africa (C variant) and South America (B variant). Since hominids reached Australia at least 50 000 years ago, a study of MBL polymorphisms in the indigenous population was of interest. Using heteroduplex technology we found a paucity of MBL structural gene mutations in two population groups from geographically distinct regions. Of 293 individuals tested, 289 were wild-type and four were heterozygous for either the B or D allele. In each individual with an MBL mutation the HLA haplotype profile suggested some Caucasian admixture. We also found a restricted range of MBL promoter haplotypes and the serum MBL levels were higher than those of any other ethnic group studied to date (median 3.07 microg/ml). Our data suggest that the B mutation probably arose between 50 000 and 20 000 BP. Its absence from the founder gene pool of indigenous Australians may also partly explain their vulnerability to intracellular infections such as tuberculosis.

The DD genotype of the angiotensin-converting enzyme gene occurs in very low frequency in Australian Aboriginals.

BACKGROUND: The DD genotype of the angiotensin-converting enzyme (ACE) gene appears to be an independent risk factor for myocardial infarction, left ventricular hypertrophy and an increased incidence and rate of progression of renal disease. The high incidence of renal disease and end-stage renal failure in the Australian Aboriginal population has prompted investigation of ACE genotypes in these people. METHODS: ACE genotypes were determined in four groups: (i) normal Australian Caucasian blood donors (n = 100), (ii) Caucasian renal transplant recipients (n = 173), (iii) normal Australian Aboriginals from a single tribe (n = 184), and (iv) Australian Aboriginals included in the renal-transplant programme (n = 94). FINDINGS: The D allele frequency in the normal Australian Caucasian (54.5%) and renal transplant groups (57.2%) was similar. However, the D allele frequency in the normal Australian Aboriginal (3%) and Aboriginal renal patient group (14.4%) was significantly lower than both Caucasian groups. INTERPRETATION: The D allele of the ACE gene has little or no influence on the renal disease of Australian Aboriginals.

The smoking cessation efficacy of varying doses of nicotine patch delivery systems 4 to 5 years post-quit day.

BACKGROUND: This study was undertaken to evaluate the long-term smoking cessation efficacy of varying doses of transdermal nicotine delivery systems 4 to 5 years post-quit day. METHODS: A follow-up study was conducted 48 to 62 months after quit day among patients who were enrolled in the Transdermal Nicotine Study Group investigation. The latter study included group smoking cessation counseling and randomized assignment to 21, 14, or 7 mg nicotine patches or placebo patches. Seven of nine smoking cessation research centers participated in the long term follow-up investigation. RESULTS: The self-reported continuous quit rate among patients originally assigned 21 mg (20.2%) was significantly higher than rates for patients assigned 14 mg (10.4%), 7 mg (11.8%), or placebo patches (7.4%). Log rank survival analysis found no difference in relapse rates after 1 year postcessation. Smokers under age 30 years were significantly less likely to be abstinent at long term follow-up compared to smokers > or = 30 years of age (3 vs 13%, respectively). Mean weight gain in confirmed continuous quitters was 10.1 kg in men and 8.0 kg in women. Of the 63 continuous abstainers surveyed, 30 respondents (48%) reported that they no longer craved cigarettes, and no individual reported daily craving for cigarettes. CONCLUSIONS: Nicotine patch therapy with 21 mg/day patches resulted in a significantly higher long-term continuous abstinence rate compared to lower dose patches and placebo. Relapse rates among the various treatment conditions were similar after 1 year postcessation.

Are higher doses of nicotine replacement more effective for smoking cessation?

This study determined whether higher dose nicotine patches are more efficacious than lower dose patches among heavy smokers. A randomized double-blind study compared 0, 21, 35, and 42 mg/day of a 24-h patch in 1039 smokers (> or = 30 cigarettes/day) at 12 clinical sites in the USA and one in Australia. Daily patches were used for 6 weeks followed by tapering over the next 10 weeks. Weekly group therapy occurred. Biochemically validated self-reported quit rates at 6, 12, 26, and 52 weeks post-cessation were measured. Quit rates were dose-related at all follow-ups (p < 0.01). Continuous, biochemically verified abstinence rates for the 0, 21, 35, and 42 mg doses at the end of treatment (12 weeks) were 16, 24, 30, and 39%. At 6 months, the rates were 13, 20, 20, and 26%. Among the 11 sites with 12 month follow-up (n = 879), the quit rates were 7, 13, 9, and 19%. In post-hoc tests, none of the active doses were significantly different from each other at any follow-up. The rates of dropouts due to adverse events for 0, 21, 35, and 42 mg were 3, 1, 3, and 6% (p = n.s.). Our results are similar to most prior smaller studies; i.e., in heavy smokers higher doses increase quit rates slightly. Longer durations of treatment may be necessary to show greater advantages from higher doses.

[Effects of transdermal nicotine as an adjunct in smoking cessation therapy. A double-blind randomized study controlled with placebo]. / Effetti del rilascio transdermico di nicotina come terapia di supporto per lo svezzamento dal fumo di sigaretta. Uno studio randomizzato in doppio cieco con controlli trattati con placebo.

To assess the smoking cessation efficacy of transdermal nicotine patches an adjunct to low-intervention therapy, we conducted a double-blind, placebo-controlled trial in 158 smokers. Participants were randomly assigned to one of the following three study regimens that required daily application of two 15-cm2 patches: 1) 24-hour nicotine delivery, 2) nicotine delivery during wakeful hours only, and 3) placebo. The impact of the three regimens on smoking cessation rates and tobacco withdrawal symptoms was examined. During the last 2 weeks of the trial, 39% of the 24-hour nicotine regimen delivery group, 35% of those on wakeful hour nicotine regimens, and 13.5% of the placebo treatment group achieved abstinence. Self-reported quit rates for the two nicotine patch-wearing regimens, as compared with that for the placebo group, continued to be significantly higher at 6 months. Moreover, compared with placebo, the transdermal nicotine patches significantly reduced tobacco withdrawal symptoms during the first few weeks of quitting. The differences in quit rates and tobacco withdrawal symptoms between the to active groups were not statistically significant. The patches were well tolerated both topically and systemically. We concluded that transdermal nicotine, when used as an adjunct to low-intervention therapy, significantly reduced tobacco withdrawal symptoms and enhanced smoking cessation rates.

Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy. A randomized, placebo-controlled, double-blind study.

To assess the smoking cessation efficacy of transdermal nicotine patches as an adjunct to low-intervention therapy, we conducted a double-blind, placebo-controlled trial in 158 smokers. Participants were randomly assigned to one of the following three study regimens that required daily application of two 15-cm2 patches: (1) 24-hour nicotine delivery, (2) nicotine delivery during wakeful hours only, and (3) placebo. The impact of the three regimens on smoking cessation rates and tobacco withdrawal symptoms was examined. During the last 2 weeks of the trial, 39% of the 24-hour nicotine regimen delivery group, 35% of those on wakeful hour nicotine regimens, and 13.5% of the placebo treatment group achieved abstinence. Self-reported quit rates for the two nicotine patch-wearing regimens, as compared with that for the placebo group, continued to be significantly higher at 6 months. Moreover, compared with placebo, the transdermal nicotine patches significantly reduced tobacco withdrawal symptoms during the first few weeks of quitting. The differences in quit rates and tobacco withdrawal symptoms between the two active groups were not statistically significant. The patches were well tolerated both topically and systemically. We concluded that transdermal nicotine, when used as an adjunct to low-intervention therapy, significantly reduced tobacco withdrawal symptoms and enhanced smoking cessation rates.