Comparative thrombosis risk of vascular access devices among critically ill medical patients.

BACKGROUND: Central venous catheters (CVC) and peripherally inserted central catheters (PICCs) are central vascular access devices (CVADs) that facilitate administration of medications among critically ill patients. Both are associated with risk of venous thromboembolism (VTE). The relative risk of VTE between these catheter types is not well defined. We report the rate of VTE in intensive care unit (ICU) medical patients receiving PICC, CVC, both, or neither. METHODS: We conducted a single-center, retrospective cohort study of medical-ICU patients between November 2007 and November 2013 grouped by receipt of CVC, PICC, both, or neither. The primary outcome was the rate of 30-day symptomatic venous thrombosis (upper and lower deep vein thrombosis and pulmonary embolism). Cox modeling was used to analyze this population and adjust for comorbidities which could contribute to VTE. Secondary outcomes included VTE location, major bleeding, and all-cause mortality among patients with and without CVADs. RESULTS: We analyzed 5788 patients. CVADs were placed in 2403 (42%) patients (PICC, n = 816; CVC, n = 1153; both, n = 434). Compared with no CVAD, the hazard ratio (HR) for 30-day VTE was 1.81 (95% CI 1.52-2.17) for any CVAD, 1.90 (95% CI 1.52-2.37) for PICC, 1.57 (95% CI 1.26-1.96) for CVC, and 2.70 (95% CI 2.09-3.47) for both. PICCs had a non-significantly higher HR for VTE compared with CVC (1.21; 95% CI 0.94-1.55). For patients with both a CVC and PICC the HR for VTE was 1.72 times that of solitary CVAD (95% CI 1.32-2.23). CONCLUSIONS: Among critically ill medical patients, PICCs and CVCs were associated with increased risk of VTE. Placement of both conferred higher risk of VTE compared with either alone.

Aggregated serum free light chains may prevent adequate removal by high cut-off haemodialysis.

Free light chain (FLC) removal by high cut-off haemodialysis has been described as an adjuvant therapy for the management of patients with severe renal failure complicating multiple myeloma. The two cases reported here are the first patients in whom this treatment did not remove FLCs. In both patient's sera, size-exclusion chromatography identified large FLC aggregates, with molecular weights above the cut-off of the dialyser. It is important for clinicians to be aware of FLC aggregates as a reason for failure to remove FLCs by this new modality.

Risks of Lynch syndrome cancers for MSH6 mutation carriers.

BACKGROUND: Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. METHODS: We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. RESULTS: For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7). CONCLUSION: We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.

The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.

BACKGROUND & AIMS: Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. METHODS: We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. RESULTS: Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. CONCLUSIONS: PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.

The vocational continuum: how to make sense of vocational outcomes after group cognitive behavioural therapy for chronic pain sufferers.

INTRODUCTION: Vocational outcomes following group CBT programmes for patients with chronic pain are scarcely reported within the literature, despite their importance as measures of function. This study reports vocational, physical and psychological outcomes following a group CBT programme for patients suffering chronic pain. The study aimed to examine the vocational situation of chronic pain patients who completed a group CBT programme, using a scale known as the vocational continuum. The scale was developed to measure changes in RTW intention and work status, in an effort to reconceptualise vocational outcomes for this population with respect to the RTW process. METHODS: A group of patients referred to a hospital pain clinic that went on to complete a group CBT programme were retrospectively surveyed about their vocational status at various time points. Physical outcomes measured included the 12-min walk test, 2-min sit to stand test, 2-min stair climb test and timed 20-m walk test. Psychological outcomes measured included pain intensity, self-efficacy, psychological distress (depression, anxiety and stress), catastrophising and disability. Responses to vocational items including work status, hours of work, intention to RTW and barriers to RTW were incorporated into the vocational continuum. RESULTS: Two hundred and nine (58%) of the 360 patients who completed the group CBT programme between 1998 and 2005 completed the vocational survey. Ninety percent of participants reported that their chronic pain was a barrier to RTW or increasing hours of work pre-CBT. According to the vocational continuum, fifty per cent of the study population advanced toward working full-time (chi(2)(2, N = 163) = 28.87, P < 0.01) and this result was associated with a significant reduction in pain as a reported barrier to RTW or increasing participation in work post-CBT. Significant improvements were seen across all physical and psychological measures for study participants at 1, 6 and 12 month intervals post-CBT. CONCLUSIONS: The study demonstrates improvements across physical and psychological measures post-CBT, indicating that participants benefited from reduced levels of pain-related distress and disability. Although retrospective, the study also suggests improvements were made across vocational outcomes. By doing so, the study adds to scant literature reporting on vocational outcomes of group CBT programmes for patients with chronic pain and offers a new scale for measuring and interpreting vocational outcomes for this population.

Cross-talk between histone modifications in response to histone deacetylase inhibitors: MLL4 links histone H3 acetylation and histone H3K4 methylation.

Histones are subject to a wide variety of post-translational modifications that play a central role in gene activation and silencing. We have used histone modification-specific antibodies to demonstrate that two histone modifications involved in gene activation, histone H3 acetylation and H3 lysine 4 methylation, are functionally linked. This interaction, in which the extent of histone H3 acetylation determines both the abundance and the "degree" of H3K4 methylation, plays a major role in the epigenetic response to histone deacetylase inhibitors. A combination of in vivo knockdown experiments and in vitro methyltransferase assays shows that the abundance of H3K4 methylation is regulated by the activities of two opposing enzyme activities, the methyltransferase MLL4, which is stimulated by acetylated substrates, and a novel and as yet unidentified H3K4me3 demethylase.

Human class I histone deacetylase complexes show enhanced catalytic activity in the presence of ATP and co-immunoprecipitate with the ATP-dependent chaperone protein Hsp70.

Antibodies to histone deacetylases (HDACs) have been used to immuno-isolate deacetylase complexes from HeLa cell extracts. Complexes shown to contain HDAC1, HDAC3, HDAC6, and HDAC1+2 as their catalytic subunits have been used in an antibody-based assay that detects deacetylation of whole histones at defined lysines. The class II deacetylase HDAC6 was inactive in this assay, but the three class I enzymes deacetylated all histone lysines tested, although with varying efficiency. In comparison to HDAC1, HDAC3 preferentially deacetylated lysines 5 and 12 of H4 and lysine 5 of H2A. H4 tails in purified mononucleosomes were refractory to deacetylation by both HDAC1 and HDAC3, unless ATP was added to the reaction mix. Surprisingly, ATP also consistently enhanced cleavage of free, non-nucleosomal histones, but not small peptides, by both enzyme complexes. We found no evidence that ATP operates by phosphorylation of components of the HDAC complex, but have shown that HDACs 1, 2, and 3 all co-immunoprecipitate with the ATP-dependent chaperone protein Hsp70. Another common ATP-dependent chaperone, Hsp90, was absent from all HDAC complexes tested, whereas Hsp60 associated with HDAC1 only. We suggest that Hsp chaperone proteins enhance the deacetylase activity of HDAC complexes by ATP-dependent manipulation of protein substrates.