The IBD6 Crohn's disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated variants

Genetic studies in inflammatory bowel disease have identified multiple susceptibility loci, whose relevance depends critically on verification in independent cohorts. Genetic variants associated with Crohn's disease have now been identified on chromosomes 5 (IBD5/5q31 risk haplotype) and 16 (IBD1 locus, CARD15/NOD2 mutations). Stratification of genome-wide linkage analyses by disease associated variants is now possible, offering both increased power for identification of other loci and improved understanding of genetic mechanisms. We performed a genome-wide scan of 137 Crohn's disease affected relative pairs from 112 families. Multipoint non-parametric linkage analyses were performed, with further stratification of affection status by common CARD15 mutations and the IBD5 haplotype. We verified linkage of Crohn's disease to regions on chromosome 3 (P=0.0009) and X (P=0.001) in our cohort. Linkage to chromosome 16 (IBD1) was observed in Crohn's disease pairs not possessing common CARD15 mutations (P=0.0007), approximately 25 cM q telomeric of CARD15. Evidence for linkage to chromosome 19 (IBD6) was observed in Crohn's disease pairs not possessing CARD15 mutations (P=0.0001), and in pairs possessing one or two copies of the IBD5 risk haplotype (P=0.0005), with significant evidence for genetic heterogeneity and epistasis, respectively. These analyses demonstrate the complex genetic basis to Crohn's disease, and show that the discovery of disease-causing variants may be used to aid identification of further susceptibility loci in complex disease.     

The mTOR pathway is activated in glial cells in mesial temporal sclerosis

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates basic cellular processes, including development and growth. Mutations in mTOR cause tuberous sclerosis complex (TSC), a condition that is characterized by developmental brain malformations (cortical tubers) and epilepsy. Although considerable insight has been gained recently into the pathologic dysfunction of mTOR in tubers in TSC-related epilepsy, data on the mTOR cascade in mesial temporal lobe epilepsy (MTLE) are lacking. Immunohistochemical investigation with confocal microscopy was performed to evaluate mTOR cascade and to correlate its activity with cellular alterations observed in surgically resected samples of human neocortex and hippocampus in MTLE. We compared results in human tissue to findings in the rat pilocarpine model of sclerotic MTLE. In nonsclerotic and control hippocampus, many neurons in the CA1 subfield expressed high levels of phospho-S6 (p-S6), a reliable marker of mTOR activation. In nonsclerotic and control hippocampus, as well as in magnetic resonance imaging (MRI) normal human neocortex, protoplasmic astrocytes did not express p-S6. In contrast, in sclerotic hippocampus, prominent p-S6 immunostaining was observed mainly in astrocytes and microglia located in the areas of neuronal loss and astrogliosis, whereas neurons in preserved areas of CA1 expressed significantly lower levels of p-S6 immunopositivity than neurons in nonsclerotic or control CA1 subfields. In surgically resected neocortex with chronic astroglial scar tissue, only microglia revealed moderate p-S6 immunoreactivity. Different from human sclerotic epileptic hippocampus, astrogliosis in the chronic rat pilocarpine model of epilepsy was not characterized by glial cells with mTOR activation. The mTOR cascade is activated in astroglial cells in sclerotic MTLE, but not in astrocytes in chronic neocortical scarring or in the pilocarpine model of MTLE. These findings suggest that the astroglial "scar" in sclerotic MTLE has active, ongoing cellular changes. Targeting mTOR in MTLE may provide new pathways for the medical therapy of epilepsy.     

No risk,no gain: invest in women and girls by funding advocacy,organizing, litigation and work to shift culture

The new development framework aspires to merge long-term hopes for environmental, political and financial sustainability with international poverty eradication goals. Central to this agenda is the promotion and protection of the human rights of women and girls. Yet national mechanisms, donors and international development agencies often do not fully tackle these issues or confront the accompanying politically sensitive, complex issues intermingling religion, socioeconomic status, social, cultural and family life. The increasing reliance on private investment may further weaken a women’s rights approach. The proposed framework described in the High-Level Panel of Eminent Persons Report could further systematize this problem, even though it improves on the MDGs by expanding targets related to women. Success will require support for a potent mix of advocacy, movement building and a complex set of ground-based strategies that shift cultural practices, laws and policies that harm women and girls. Funding for advocacy and interventions that hold firm on human rights is imperative, but given the conflicting loyalties of governments and public–private partnerships, reliance on either sector may be risky. An analysis of the status of women’s rights work, infrastructure and donor support in Bangladesh and South Africa shows the need for vigilance and long-term investment in effective work.     

Incidence of malignancy in complex cystic renal masses (Bosniak category III): should imaging-guided biopsy precede surgery?

OBJECTIVE: Complex indeterminate renal cystic masses (Bosniak type III) can have benign and malignant causes and have been traditionally considered surgical lesions. We sought to determine the incidence of malignancy and to assess a possible role for imaging-guided biopsy for this category of renal masses. MATERIALS AND METHODS: Three hundred ninety-seven renal biopsies were performed at our institution between 1991 and 2000. Between January 1997 and August 2000, 28 Bosniak category III lesions, based on established CT imaging criteria on helical CT scans, were identified for analysis. The incidence of malignancy, based on surgical pathology or imaging follow-up and percentage of lesions proceeding to surgery, among these 28 lesions, was determined. The surgical results were correlated with the biopsy findings. RESULTS: Of the 28 biopsied category III lesions, 17 (60.7%) were malignant (16 renal cell carcinomas and one lymphoma), and 11 (39.3%) were benign (six hemorrhagic cysts, three inflammatory cysts, one metanephric adenoma, and one cystic oncocytoma). Seventeen of the 28 lesions (16 renal cell carcinomas and one inflammatory cyst) had surgical resection after the biopsy. All resected lesions had pathologic diagnoses identical to the percutaneous imaging-guided biopsy results. The remaining 11 patients who had undergone nonsurgical biopsies had radiologic follow-up for a minimum of 1 year, with benign lesions showing no interval change. CONCLUSION: Renal biopsy and radiologic follow-up were useful in identifying nonmalignant lesions in complex cystic renal masses and avoided unnecessary surgery in 39% of patients.     

Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.     

Serious adverse effects of amiodarone

Amiodarone is an effective antiarrhythmic drug which has been used successfully to treat a variety of cardiac arrhythmias. Early reports emphasized both the striking efficacy of this agent and the relative paucity of side effects necessitating discontinuing treatment with this drug. As amiodarone has been used more widely and in more diverse patient populations, reports of serious thyroid, pulmonary, cardiovascular, and other adverse reactions have appeared in the literature. In this paper, we review the serious adverse effects that have been reported to date. The incidence of these reactions varies considerably in different series, and cannot be explained solely by different doses employed or by varying methods of drug administration. The final role of amiodarone in the therapy of cardiac arrhythmias cannot be determined until the long-term toxicity has been more thoroughly investigated.     

Resective epilepsy surgery: assessment of randomized controlled trials

Neurosurgical Review - Epilepsy is the most common form of chronic neurologic disease. Here, we review the available randomized controlled trials (RCTs) that examined the efficacy of resective...     

The influence of surgical hoods and togas on airborne particle concentration at the surgical site: an experimental study

Background

Arthroplasty surgeons are increasingly using personal protection systems with helmets. It is theoretically possible for the fans in these helmets to blow squames, sweat droplets and orobronchial fomites onto the surgical site. A controlled experiment was set up to investigate the effect of different surgical gowns on counts of airborne particles measuring ≥0.3 μm, using a hand-held particle counter.

Methods

The clothing that was sequentially tested included the following:

1. Barrier^® surgical gown (single use) made from nonwoven polypropylene (Mölnlycke Health Care Ltd, Dunstable, UK)
2. Stryker^® T5 Helmet (reusable) covered with a disposable Stryker^® T4/T5 urethane hood worn separate to and enclosed by the Barrier^® surgical gown both at the front and back
3. Stryker^® T5 Helmet (reusable) worn within a disposable Stryker^® T4/T5 urethane zippered toga (Stryker Corporation, Kalamazoo, MI, USA)

Six readings were taken for each of the following three setups in a randomised order:

1. Gown: surgeon with surgical gown and face mask
2. Hood: surgeon with surgical gown and hood, maximum fan speed
3. Toga: surgeon with toga, maximum fan speed

Wilcoxon rank sum tests were applied to assess equality of means between the three occlusive measures (gown, hood, toga). P values were computed based upon one-sided tests and adjusted for multiple comparisons using the Bonferroni correction.

Results

The mean particle counts (over more than 5 L of air) for the three set-ups were: gown: 1178 (least protective), hood: 328, toga: 42 (most protective). There was a significant reduction in particle counts for the toga versus gown (p = 0.007) and toga versus hood (p = 0.037); differences in particle counts were not significant between the hood and gown (p = 0.140).

Conclusions

The fans in the helmets do not increase contaminants by blowing particles from the head area. A significant reduction in surgeon-originated contaminants was seen with the toga compared to both the hood/gown separate ensemble and gowns alone.     

Short-term and long-term outcome in low body mass index patients undergoing cardiac surgery

Objective  We sought to assess the effect of low body mass index (BMI) on short- and long-term outcomes following cardiac surgery. Methods  This is a retrospective review of a prospectively collected departmental database over a 6-year period. Patients were eligible for the study if the BMI was <25 kg/m². All morbidities, length of hospital stay, and short- and long-term mortality were reviewed. Results  There were 704 patients divided into low (n = 71) and normal (n = 633) BMI. Postoperative pulmonary complications were higher in the low BMI group compared to the normal BMI group (24% vs. 11%, P < 0.001) with a higher incidence of in-hospital mortality (10% vs. 5%). Using multiple logistic regression, low BMI was an independent risk factor for in-hospital mortality. The 1-, 3-, and 5-year survivals for the low group were 90%, 78%, and 70% compared to 94%, 86%, and 81% in the normal BMI group. Conclusion  Low BMI is associated with increased morbidity and mortality following cardiac surgery. Risk scoring systems should utilize the BMI in the preoperative risk assessment with special attention to low BMI. This study was presented in poster form at the 7th international congress on coronary artery disease, Venice, Italy, October 2007.