Perioperative infection prophylaxis and risk factor impact in colon surgery

Background: A prospective observational study was undertaken in 2,481 patients undergoing elective colon resection in 114 German centers to identify optimal drug and dosing modalities and risk factors for postoperative infection. Methods: Patients were pair matched using six risk factors and divided into 672 pairs (ceftriaxone vs, other cephalosporins, group A) and 400 pairs (ceftriaxone vs. penicillins, group B). End points were local and systemic postoperative infection and cost effectiveness. Results: Local infection rates were 6.0 versus 6.5% (group A) and 4.0 versus 10.5% (group B); systemic infection rates in groups A and B were 4.9 versus 6.3% and 3.3 versus 10.5%, respectively. Ceftriaxone was more effective than penicillins overall (6.8 vs. 17.8%, p < 0.001). Length of postoperative hospital stay was 16.2 versus 16.9 days (group A) and 15.8 versus 17.6 days (group B). Of the six risk factors, age and concomitant disease were significant for systemic infection, and blood loss, rectum resection and immunosuppressive therapy were significant for local infection. Penicillin was a risk factor compared to ceftriaxone (p < 0.0001). Ceftriaxone saved Q160.7 versus other cephalosporins and O416.2 versus penicillins. Conclusion: Clinical and microbiological efficacy are responsible for the cost effectiveness of ceftriaxone for perioperative prophylaxis in colorectal surgery. Copyright (C) 2000 S. Karger AG, Basel

Cryopyrin-Associated Periodic Fever Syndrome and the Nervous System

PURPOSE OF REVIEW: The purpose of this review is to highlight the molecular and clinical characteristics of the cryopyrin-associated periodic fever syndrome (CAPS) and its management. CAPS is an autosomal dominantly inherited autoinflammatory disorder associated with mutations in the NLRP3 gene, which ultimately lead to excessive production of interleukin-1β (IL-1β) and systemic inflammation. Typical systemic features include fever, urticarial rash and arthralgia, and ultimately amyloidosis. There are also multiple neurological manifestations including, but not restricted to, headache, sensorineural hearing loss, aseptic meningitis, myalgia and optic nerve involvement. RECENT FINDINGS: Since the recognition of CAPS as a single disease entity and discovery of the underlying causative gene, there has been a major breakthrough in terms of its treatment by pharmacological IL-1β inhibition. Highly targeted therapies against IL-1 have been shown to be remarkably effective in the treatment of CAPS and make early diagnosis of this condition crucial. It is hoped that starting pharmacological intervention in a timely manner will prove neuroprotective. There are three drugs licensed for treatment of CAPS; canakinumab, anakinra and rilonacept. The former two are widely used: canakinumab is a fully humanised anti-IL-1β monoclonal antibody administered as a subcutaneous injection once every 8 weeks starting at a dose of 150 mg in patients weighing more than 40 kg. Anakinra is a recombinant form of the IL-1 receptor antagonist and the adult daily dose is 100 mg subcutaneously. CAPS is a highly debilitating disorder characterised by unregulated IL-1β production driven by autosomal dominantly inherited mutations in the NLRP3 gene. Effective therapies targeted against IL-1 are now available and are vital to prevent long-term complications

White matter integrity correlates with cognition and disease severity in Fabry disease

Cerebral white matter pathology is a common CNS manifestation of Fabry disease, visualized as white matter hyperintensities on MRI in 42-81% of patients. Diffusion tensor imaging (DTI) MRI is a sensitive technique to quantify microstructural damage within the white matter with potential value as a disease biomarker. We evaluated the pattern of DTI abnormalities in Fabry disease, and their correlations with cognitive impairment, mood, anxiety, disease severity and plasma lyso-Gb3 levels in 31 patients with genetically proven Fabry disease and 19 age-matched healthy control subjects. We obtained average values of fractional anisotropy and mean diffusivity within the white matter and performed voxelwise analysis with tract-based spatial statistics. Using a standardized neuropsychological test battery, we assessed processing speed, executive function, anxiety, depression and disease severity. The mean age (% male) was 44.1 (45%) for patients with Fabry disease and 37.4 (53%) for the healthy control group. In patients with Fabry disease, compared to healthy controls the mean average white matter fractional anisotropy was lower in [0.423 (standard deviation, SD 0.023) versus 0.446 (SD 0.016), P = 0.002] while mean average white matter mean diffusivity was higher (749 × 10-6 mm2/s (SD 32 × 10-6) versus 720 × 10-6 mm2/s (SD 21 × 10-6), P = 0.004]. Voxelwise statistics showed that the diffusion abnormalities for both fractional anisotropy and mean diffusivity were anatomically widespread. A lesion probability map showed that white matter hyperintensities also had a wide anatomical distribution with a predilection for the posterior centrum semiovale. However, diffusion abnormalities in Fabry disease were not restricted to lesional tissue; compared to healthy controls, the normal appearing white matter in patients with Fabry disease had reduced fractional anisotropy [0.422 (SD 0.022) versus 0.443 (SD 0.017) P = 0.003] and increased mean diffusivity [747 × 10-6 mm2/s (SD 26 × 10-6) versus 723 × 10-6 mm2/s (SD 22 × 10-6), P = 0.008]. Within patients, average white matter fractional anisotropy and white matter lesion volume showed statistically significant correlations with Digit Symbol Coding Test score (r = 0.558, P = 0.001; and r = -0.633, P ≤ 0.001, respectively). Average white matter fractional anisotropy correlated with the overall Mainz Severity Score Index (r = -0.661, P ≤ 0.001), while average white matter mean diffusivity showed a strong correlation with plasma lyso-Gb3 levels (r = 0.559, P = 0.001). Our findings using DTI confirm widespread areas of microstructural white matter disruption in Fabry disease, extending beyond white matter hyperintensities seen on conventional MRI. Moreover, diffusion measures show strong correlations with cognition (processing speed), clinical disease severity and a putative plasma biomarker of disease activity, making them promising quantitative biomarkers for monitoring Fabry disease severity and progression

Canakinumab reverses overexpression of inflammatory response genes in tumour necrosis factor receptor-associated periodic syndrome

OBJECTIVE: To explore whether gene expression profiling can identify a molecular mechanism for the clinical benefit of canakinumab treatment in patents with tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Blood samples were collected from 20 patients with active TRAPS who received canakinumab 150 mg every 4 weeks for 4 months in an open-label proof-of-concept phase II study, and from 20 aged-matched healthy volunteers. Gene expression levels were evaluated in whole blood samples by microarray analysis for arrays passing quality control checks. RESULTS: Patients with TRAPS exhibited a gene expression signature in blood that differed from that in healthy volunteers. Upon treatment with canakinumab, many genes relevant to disease pathogenesis moved towards levels seen in the healthy volunteers. Canakinumab downregulated the TRAPS-causing gene (TNF super family receptor 1A (TNFRSF1A)), the drug-target gene (interleukin (IL)-1B) and other inflammation-related genes (eg, MAPK14). In addition, several inflammation-related pathways were evident among the differentially expressed genes. Canakinumab treatment reduced neutrophil counts, but the observed expression differences remained after correction for this. CONCLUSIONS: These gene expression data support a model in which canakinumab produces clinical benefit in TRAPS by increasing neutrophil apoptosis and reducing pro-inflammatory signals resulting from the inhibition of IL-1β. Notably, treatment normalised the overexpression of TNFRSF1A, suggesting that canakinumab has a direct impact on the main pathogenic mechanism in TRAPS. TRIAL REGISTRATION NUMBER: NCT01242813

Cytotoxic polyfunctionality maturation of cytomegalovirus-pp65-specific CD4 + and CD8 + T-cell responses in older adults positively correlates with response size

Cytomegalovirus (CMV) infection is one of the most common persistent viral infections in humans worldwide and is epidemiologically associated with many adverse health consequences during aging. Previous studies yielded conflicting results regarding whether large, CMV-specific T-cell expansions maintain their function during human aging. In the current study, we examined the in vitro CMV-pp65-reactive T-cell response by comprehensively studying five effector functions (i.e., interleukin-2, tumor necrosis factor-α, interferon-γ, perforin, and CD107a expression) in 76 seropositive individuals aged 70 years or older. Two data-driven, polyfunctionality panels (IL-2-associated and cytotoxicity-associated) derived from effector function co-expression patterns were used to analyze the results. We found that, CMV-pp65-reactive CD8 + and CD4 + T cells contained similar polyfunctional subsets, and the level of polyfunctionality was related to the size of antigen-specific response. In both CD8 + and CD4 + cells, polyfunctional cells with high cytotoxic potential accounted for a larger proportion of the total response as the total response size increased. Notably, a higher serum CMV-IgG level was positively associated with a larger T-cell response size and a higher level of cytotoxic polyfunctionality. These findings indicate that CMV-pp65-specific CD4 + and CD8 + T cell undergo simultaneous cytotoxic polyfunctionality maturation during aging

Spectrum of cardiac disease in maternity in a low-resource cohort in South Africa

Background: Lack of evidence-based data on the spectrum of cardiovascular disease (CVD) in pregnancy or in the postpartum period, as well as on maternal and fetal outcome, provides challenges for treating physicians, particularly in areas of low resources. The objectives of this study were to investigate the spectrum of disease, mode of presentation and maternal and fetal outcome of patients referred to a dedicated Cardiac Disease and Maternity Clinic (CDM). Methods: The prospective cohort study was conducted at a single tertiary care centre in South Africa. Two hundred and twenty-five women presenting with CVD in pregnancy, or within 6 months postpartum, were studied over a period of 2 years. Clinical assessment, echocardiography and laboratory tests were performed at baseline and follow-up visits. Prepartum, peripartum and postpartum complications were grouped into cardiac, neonatal and obstetric events. Results: Ethnicity was black African (45%), mixed ethnicity (32%), white (15%), Indian/others (8%) and 12% were HIV positive. Of the 225 consecutive women (mean age 28.8±6.4), 196 (86.7%) presented prepartum and 73 in modified WHO class I. The 152 women presenting in a higher risk group (modified WHO class II-IV) were offered close follow-up at the CDM clinic and were diagnosed with congenital heart disease (32%, 15 operated previously), valvular heart disease (26%, 15 operated previously), cardiomyopathy (27%) and other (15%). Women presenting with symptoms of CVD or heart failure postpartum (n=30) presented in a higher New York Heart Association, had higher heart rates (p42 days postpartum. Perinatal death occurred in 1/152 (0.7%) - translating to a perinatal mortality rate of 7/1000 live births. Conclusions: Disease patterns were markedly different to that seen in the developed world. However, joint obstetric-cardiac care in the low-resource cohort was associated with excellent survival outcome rates of pregnant mothers (even with complex diseases) and their offspring and was similar to that seen in the western world. Mortality typically occurred in the postpartum period, beyond the standard date of recording maternal death