Effect of neoadjuvant chemoradiation on postoperative fecal continence and anal sphincter function in rectal cancer patients

Background and aims Neoadjuvant chemoradiation (nCRT) followed by curative surgery has gained acceptance as the therapy of choice in locally advanced rectal cancer. This prospective study evaluates the effect of nCRT on postoperative anorectal function and continence. Patients and methods Group A consisted of 12 patients (59.8 ± 11.9 years, male:female = 8:4) who received nCRT (5-FU, CPT-11. 45 + 5.4 Gy boost) before surgery and Group B of 27 patients (61.9 ± 10.6 years, male:female = 16:11) who were treated by surgery alone. All patients received a questionnaire to evaluate stool continence and anorectal function before as well as after surgery. Anorectal function was further analyzed by perfusion manometry pre- and postoperatively. Results Preoperatively, none of the patients had signs or symptoms of fecal incontinence, and preoperative measurements showed values within normal limits. Postoperatively, fecal continence was impaired in both groups, but no significant difference was found between patients with or without nCRT. Anorectal manometry revealed an impairment of anorectal function after low anterior resection regardless of the treatment regime. Conclusion nCRT does not impair anorectal function and fecal continence. The deterioration of continence and anal sphincter function after sphincter preserving surgery is solely caused by the surgical procedure.     

Do antibiotic-impregnated shunts in hydrocephalus therapy reduce the risk of infection? An observational study in 258 patients

Background  

Shunt infection in hydrocephalus patients is a severe, even life-threatening complication. Antibiotic-impregnated shunts (AIS) have been developed in an attempt to reduce rate of shunt infection. The study was performed to analyze if AIS can diminish the rate of shunt infection. The pathogenic nature of shunt infection in patients with AIS systems and those without antibiotic impregnated shunts (non-AIS) was compared.     

Coronary collateral function long after drug-eluting stent implantation.

OBJECTIVES: This study was designed to compare coronary collateral function in patients after bare-metal stent (BMS) or drug-eluting stent (DES) implantation. BACKGROUND: Drug-eluting stents have an inhibitory effect on the production of cytokines, chemotactic proteins, and growth factors, and may therefore negatively affect coronary collateral growth. METHODS: A total of 120 patients with long-term stable coronary artery disease (CAD) after stent implantation were included. Both the BMS group and the DES group comprised 60 patients matched for in-stent stenosis severity of the vessel undergoing collateral flow index (CFI) measurement at follow-up and for the duration of follow-up. The primary end point of the investigation was invasively determined coronary collateral function 6 months after stent implantation. Collateral function was assessed by simultaneous aortic, coronary wedge, and central venous pressure measurements (yielding CFI) and by intracoronary electrocardiogram during balloon occlusion. RESULTS: There were no differences between the groups regarding age, gender, body mass index, frequency of cardiovascular risk factors, use of cardiovascular drugs, severity of CAD, or site of coronary artery stenoses. Despite equal in-stent stenosis severity (46 +/- 34% and 45 +/- 36%) and equal follow-up duration (6.2 +/- 10 months and 6.5 +/- 5.4 months), CFI was diminished in the DES versus BMS group (0.154 +/- 0.097 vs. 0.224 +/- 0.142; p = 0.0049), and the rate of collaterals insufficient to prevent ischemia during occlusion (intracoronary electrocardiographic ST-segment elevation > or =0.1 mV) was higher with 50 of 60 patients in the DES group and 33 of 60 patients in the BMS group (p = 0.001). CONCLUSIONS: Collateral function long after coronary stenting is impaired with DES (sirolimus and paclitaxel) when compared with BMS. Considering the protective nature of collateral vessels, this could lead to more serious cardiac events in the presence of an abrupt coronary occlusion.     

The intron 6 G/T polymorphism of c-myb oncogene and the risk for coronary in-stent restenosis

BACKGROUND: The principle mechanisms leading to the development of atherosclerosis are long-term accumulation of lipids and cell proliferation. We have recently shown that a single nucleotide polymorphism in the c-myb gene is associated with the development of coronary artery disease in humans and intracellular lipid accumulation. C-myb expression has been further shown to be up-regulated during cell proliferation. The development of in-stent restenosis is predominantly driven by smooth muscle cell proliferation. METHODS: To study a possible association of c-myb with neointima formation in humans we genotyped 485 consecutive patients undergoing coronary stenting for a G/T-single nucleotide polymorphism in intron 6 of the cmyb gene. Restenosis was assessed by quantitative coronary angiography and angiographic follow-up after 6 months. To study the effect of c-myb on smooth muscle cell proliferation primary human smooth muscle cells were infected with recombinant adenovirus expressing c-myb, a dominant negative myb-engrailed fusion protein or control virus. RESULTS AND CONCLUSION: Restenosis > 50% occurred in 27.6% of patients with at least one G-allele and in 20.8% of those without (p = 0.10). Even after adjustment for the independent risk factors diabetes mellitus, reference lumen diameter, smoking, dyslipidemia and number of diseased vessels, the observed difference in the distribution of the c-myb alleles did not reach statistical significance (p = 0.08). Adenoviral gene transfer of c-myb did not increase proliferation of cultured smooth muscle compared to control virus or untransfected cells, while the expression of the dominant negative mutant reduced proliferation of VSMC as previously shown. Our results indicate that expression of c-myb, while being important for cell cycle is not sufficient to induce smooth muscle cell proliferation. The G/T-nucleotide transversion polymorphism in intron 6 of the c-myb oncogene that has been associated with atherosclerosis and lipid accumulation is not a risk factor for human in-stent restenosis.     

Tissue Doppler imaging in patients with moderate to severe aortic valve stenosis: clinical usefulness and diagnostic accuracy

Background

Mitral annular velocities derived from tissue Doppler imaging (TDI) provide information about left ventricular (LV) long-axis function and allow for the assessment of LV filling pressures in selected subsets of patients. It was the aim of this study to assess the usefulness of TDI in patients with moderate to severe aortic valve stenosis (AS).

Methods

Twenty-three patients with moderate to severe AS (mean aortic valve area 0.8 ± 0.4 cm²), in whom coronary artery disease had been ruled out, and 36 asymptomatic age-matched control subjects underwent assessment of ejection fraction, fractional shortening, and mitral inflow (E, A, E/A ratio). TDI velocities (S', E', A') were derived from the septal mitral annulus. In patients with AS, LV pressure before atrial contraction (LV pre-A pressure), LV end-diastolic pressure, and cardiac index were measured during cardiac catheterization.

Results

In patients with AS, systolic (S') and early diastolic mitral annular velocities (E') were significantly reduced in comparison to control subjects (systolic, 5.5 ± 1.2 vs 8.3 ± 1.3 cm/s; early diastolic, 5.6 ± 1.6 vs 10.2 ± 3.0 cm/s, P < .001 for both comparisons), but ejection fraction, fractional shortening, and cardiac index were normal. In patients with AS, LV pre-A pressures (14 ± 4 mm Hg) and end-diastolic pressures were high (19 ± 7 mm Hg). In such patients, the mitral E/E' ratio was significantly related to LV pre-A pressure (r = 0.75, P < .001) and to LV end-diastolic pressure (r = 0.78, P < .001). In patients with AS, an E/E' ratio ≥13 identified an LV end-diastolic pressure >15 mm Hg, with a sensitivity of 93% and a specificity of 88%.

Conclusions

In patients with moderate to severe AS, TDI allows for a reliable, noninvasive estimation of filling pressures. In such patients, systolic long-axis function is impaired even in the presence of normal ejection fraction and cardiac index. Thus, TDI integrates information about systolic and diastolic performance and may be a useful addition in the echocardiographic workup and care of patients with AS.     

Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.     

Immunophenotypic and genetic characterization of a CD8 positive mantle cell lymphoma in a patient with concomitant Mycosis fungoides

Mantle cell lymphoma (MCL) is immunophenotypically characterized by cell surface co-expression of CD19, CD20, CD5, IgM and FMC7. However, the concomitant presence of other antigens distinctive of a particular leukocyte subset, e.g. T-lymphocytes, is an exceptional finding in MCL. Here, the first case of a blastic MCL in leukaemic phase with aberrant expression of the T-cell associated antigen CD8 occurring in a patient with concomitant Mycosis fungoides is described. Comprehensive immunophenotypic analysis showed that the MCL cells expressed the typical B-lymphocytic markers, were CD5 and CD8 positive, but did not express other T-cell proteins, such as CD2, CD3, CD4, CD7, TCRalphabeta and TCRgammadelta. The MCL cells expressed both CD8alpha and CD8beta chains indicating cell surface presence of CD8alphabeta heterodimers. Intriguingly, expression of the cytotoxic enzymes perforin and granzyme A was detected by RT-PCR. Cytogenetic and molecular genetic analysis of the lymphoma cells confirmed cyclin D1 overexpression secondary to the t(11;14)(q13;32) chromosomal translocation. Furthermore, trisomy 11, trisomy 14 and extra copies of t(11;14) translocated chromosomes were detected in sub clones of the analyzed MCL cells. Clinically, an aggressive course of disease including cerebral lymphoma involvement was noted in the reported patient. Hence, systematic studies addressing the incidence, biology and clinical behavior of this form of MCL seem to be justified in future.     

Hepatitis C-associated autoimmunity in patients coinfected with HIV.

Background: Hepatitis C virus (HCV) infection is associated with multiple extrahepatic manifestations. It is unclear to what extent extrahepatic manifestations occur in HIV/HCV coinfection. Methods: We prospectively assessed cross-sectional frequencies of autoimmune manifestations in HIV/HCV-coinfected patients (n=98), HIV-mono-infected (n=45) and HCV-mono-infected patients (n=78). Diagnostic vasculitis scores, HCV and HIV loads, CD4 cell counts, thyroid-, cardiolipin-, non-organ-specific tissue antibodies (nuclear, smooth muscle, anti-liver-kidney-microsome, neutrophil-cytoplasmic) and cryoglobulins were determined. Results: Synergistic effects of HCV and HIV infection were observed with respect to the prevalence of antibodies against thyroglobulin (HCV infection 15.4%, HIV infection 8.8%, HIV/HCV coinfection 30.6%; P<0.001) and cardiolipin antibodies (HCV infection 9.0%, HIV infection 31%, HIV/HCV coinfection 46%; P<0.001). Cryoglobulinemia type III, was significantly associated with HCV infection (HCV, 25.6%; HIV/HCV, 20.4%) but not with HIV infection (4.4%, P<0.05). Rheumatoid factor was commonly detected in patients with HCV infection (48%), but occurred considerably less frequently in patients with HIV infection (4.4%) or HIV/HCV coinfection (9.5%, P<0.01). Conclusion: HIV coinfection appears to differentially modulate the frequency of HCV-related autoimmunity. However, autoimmunity is rarely accompanied by clinical manifestations.     

Vascular remodeling in mice lacking the cytoplasmic domain of tissue factor

Tissue factor (TF), the cell surface receptor for the serine protease FVIIa supports cell migration by interaction with the cytoskeleton. Intracellular signaling pathways dependent on the cytoplasmic domain of TF modify cell migration and may alter vascular remodeling. Vascular remodeling was analyzed in a femoral artery injury and a blood flow cessation model in mice with a targeted deletion of the 18 carboxy-terminal intracellular amino acids of TF (TF(Deltact/Deltact)) and compared with TF wild-type mice (TF(wt/wt)). Morphometric analysis revealed a decrease in the intima/media ratio after vascular injury in arteries from TF(Deltact/Deltact) compared with TF(wt/wt) mice (femoral artery injury: 2.4+/-0.3 TF(wt/wt) versus 0.6+/-0.3 TF(Deltact/Deltact), n=9 to 10, P=0.002; carotis ligation: 0.45+0.11 TF(wt/wt) versus 0.22+0.03 TF(Deltact/Deltact), n=12 to 14, P=0.09). This was caused by an increase in the media by 54% (P=0.04) in the femoral artery model and by 32% (P=0.03) after carotis ligation and was associated with an increased number of proliferating cells. Isolated aortic smooth muscle cells (SMCs) of TF(wt/wt) mice showed an increased migratory response toward the TF ligand active site-inhibited FVIIa that was abolished in TF(Deltact/Deltact) SMC. In contrast, the unstimulated proliferation rate was increased in TF(Deltact/Deltact) SMC compared with TF(wt/wt) SMCs. Thus, retention of SMCs attributable to a migratory defect and increased proliferation results in thickening of the media and in decrease in neointima formation after arterial injury. TF cytoplasmic domain signaling alters vascular remodeling and, thereby, may play a role in the development of restenosis, atherosclerotic disease, and neovascularization.     

An opposing time‐dependent immune‐modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen–induced arthritis

Objective

The sympathetic nervous system (SNS) seems to play a proinflammatory role in the early asymptomatic phase of arthritis, but its role in the late stages of chronic arthritis is not well known. The purpose of this study was to examine the effects of the SNS on late‐stage chronic arthritis in mice with type II collagen–induced arthritis (CIA).

Methods

We tested the effects of the SNS by ablating sympathetic nerves at different time points in mice with CIA. Early sympathectomy was performed 7 days before immunization. Late sympathectomy was performed on day 56. Cytokine stimulation assays were performed on local lymph node cells and spleen cells, and levels of interleukin‐10 (IL‐10), IL‐4, tumor necrosis factor α (TNFα), and interferon‐γ (IFNγ) were determined.

Results

Animals with CIA that underwent early sympathectomy showed significantly lower arthritis scores than the controls. In contrast, animals that underwent late sympathectomy had significantly increased arthritis scores compared with controls. On day 0, lymph node cells from animals subjected to early sympathectomy had increased levels of IL‐10 and IL‐4 and unchanged levels of TNFα and IFNγ compared with those from untreated animals. This indicates an immune‐stimulating property of the SNS in draining lymph nodes. On day 80, lymph node cells and spleen cells from animals subjected to late sympathectomy showed increased levels of TNFα and IFNγ compared with those from nonsympathectomized controls with CIA. This indicates an immune‐depressing property of the SNS in draining lymph nodes and spleen. Arthritis per se largely diminished sympathetic nerve fiber density in synovium on day 80 (P < 0.01).

Conclusion

The effect of the SNS is bimodal, enhancing or depressing levels of proinflammatory and antiinflammatory cytokines. This feature is dependent on the time point of immune system activation and the respective compartment. The SNS supports inflammation during the asymptomatic phase of CIA, whereas it inhibits inflammation during the chronic symptomatic phase.