Persistent neuropathic pain after inguinal herniorrhaphy depending on the procedure (open mesh v. laparoscopy): a propensity-matched analysis

Background

A greater incidence of persistent pain after inguinal herniorrhaphy is suspected with the open mesh procedure than with laparoscopy (transabdominal preperitoneal), but the involvement of neuropathy needs to be clarified.

Methods

We examined the cumulative incidence of neuropathic persistent pain, defined as self-report of pain at the surgical site with neuropathic aspects, within 6 months after surgery in 2 prospective subcohorts of a multicentre study. We compared open mesh with laparoscopy using different analysis, including a propensity-matched analysis with the propensity score built from a multivariable analysis using a generalized linear model.

Results

Considering the full patient sample (242 open mesh v. 126 laparoscopy), the raw odds ratio for neuropathic persistent pain after inguinal herniorrhaphy was 4.3. It reached 6.8 with the propensity-matched analysis conducted on pooled subgroups of 194 patients undergoing open mesh and 125 undergoing laparoscopy (95% confidence interval 1.5–30.4, p = 0.012). A risk factor analysis of these pooled subgroups revealed that history of peripheral neuropathy was an independent risk factor for persistent neuropathic pain, while older age was protective.

Conclusion

We found a greater risk of persistent pain with open mesh than with laparoscopy that may be explained by direct or indirect lesion of nerve terminations. Strategies to identify and preserve nerve terminations with the open mesh procedure are needed.     

TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region

Treacher Collins Syndrome (TCS) is the most common of the human mandibulofacial dysostosis disorders. Recently, a partial TCOF1 cDNA was identified and shown to contain mutations in TCS families. Here we present the entire exon/intron genomic structure and the complete coding sequence of TCOF1. TCOF1 encodes a low complexity protein of 1,411 amino acids, whose predicted protein structure reveals repeated motifs that mirror the organization of its exons. These motifs are shared with nucleolar trafficking proteins in other species and are predicted to be highly phosphorylated by casein kinase. Consistent with this, the full-length TCOF1 protein sequence also contains putative nuclear and nucleolar localization signals. Throughout the open reading frame, we detected an additional eight mutations in TCS families and several polymorphisms. We postulate that TCS results from defects in a nucleolar trafficking protein that is critically required during human craniofacial development.     

Efficacy of sulfadoxine/pyrimethamine in the treatment of uncomplicated Plasmodium falciparum malaria in Republic of Congo

Congo is facing frequent failures of treatment of Plasmodium falciparum malaria with chloroquine (CQ), which is still recommended and used as a first-line drug. In Pointe-Noire and Brazzaville, the two largest cities that contain approximately 60% of the population of Congo, we compared the efficacy of CQ versus sulfadoxine/pyrimethamine (SP) for treatment of uncomplicated malaria in children 6-59 months old (mean = 33 months) using the standard World Health Organization (WHO) 14-day in vivo test in two phases between 1999 and 2002. Patients enrolled were randomly assigned to receive SP (25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine) or CQ (25 mg/kg). In the first phase of the study, 46 patients were assigned to the CQ (n = 23) or SP (n = 23) groups in Pointe-Noire and 52 children were assigned to the CQ (n = 26) or to SP (n = 26) groups in Brazzaville. Results were interpreted according to the WHO lot quality assurance sampling method, and treatment failure rates for SP versus CQ were < 25% versus > 25% in both cities. In the second phase of the study, we accurately determined the actual proportion of treatment failures for SP in Brazzaville. Thus, in 75 of the 80 children enrolled and followed-up until day 14, no clinical or parasitologic failure was recorded and no serious adverse reaction was observed. Since the CQ treatment failure rate exceeds the unacceptable upper limit, SP seems well to be an appropriate alternative for the first-line treatment of uncomplicated P. falciparum malaria, at least in the settings of the present study.     

Usefulness of radionuclide angiocardiography in predicting stenotic mitral orifice area

Fifteen patients with pure mitral stenosis (MS) underwent high-temporal-resolution radionuclide angiocardiography for calculation of the ratio of peak left ventricular (LV) filling rate divided by mean LV filling rate (filling ratio). Whereas LV filling normally occurs in 3 phases, in MS it is more uniform. Thus, in 13 patients the filling ratio was below the normal range of 2.21 to 2.88 (p < 0.001). In 11 patients in atrial fibrillation, filling ratio divided by mean cardiac cycle length and by LV ejection fraction provided good correlation (r = 0.85) with modified Gorlin formula derived mitral area and excellent correlation with echocardiographic mitral area (r = 0.95). Significant MS can be detected using radionuclide angiocardiography to calculate filling ratio. In the absence of the confounding influence of atrial systole calculation of 0.14 (filling ratio ÷ cardiac cycle length ÷ LV ejection fraction) +0.40 cm² enables accurate prediction of mitral area (±4%). Our data support the contention that the modified Gorlin formula, based on steady-state hemodynamics, provides less certain estimates of mitral area for patients with MS and atrial fibrillation, in whom echocardiography and radionuclide angiocardiography may be more accurate.     

Prophylactic effect of recombinant factor VIIa in factor VII deficient patients

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder associated with a bleeding tendency. We describe three patients with congenital FVII deficiency who have been treated with activated recombinant factor VII (rVIIa). Two patients had novel mutations and were treated prophylactically with 1.2 mg rVIIa two to three times a week. Patients 1 and 2 had a severe bleeding tendency. The frequency and severity of bleeding decreased by treatment with rVIIa compared with similar treatment with plasma-derived FVII. The third patient with a moderate bleeding phenotype was treated on demand and showed no change in the frequency of bleeding upon treatment with rVIIa or plasma products. The beneficial effect of rVIIa cannot be explained by the rVIIa half-lives. Pharmacokinetical analysis showed rVIIa activity half-lives of 35, 50 and 54 min for patients 1, 2 and 3, respectively. In conclusion, prophylactic treatment of FVII deficient patients with rVIIa appears to be applicable, safe and successful, although the mechanism of action remains to be elucidated.     

CXCL13 antibody for the treatment of autoimmune disorders

Background

Homeostatic B Cell-Attracting chemokine 1 (BCA-1) otherwise known as CXCL13 is constitutively expressed in secondary lymphoid organs by follicular dendritic cells (FDC) and macrophages. It is the only known ligand for the CXCR5 receptor, which is expressed on mature B cells, follicular helper T cells (Tfh), Th17 cells and regulatory T (Treg) cells. Aberrant expression of CXCL13 within ectopic germinal centers has been linked to the development of autoimmune disorders (e.g. Rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosis). We, therefore, hypothesized that antibody-mediated disruption of the CXCL13 signaling pathway would interfere with the formation of ectopic lymphoid follicles in the target organs and inhibit autoimmune disease progression. This work describes pre-clinical development of human anti-CXCL13 antibody MAb 5261 and includes therapeutic efficacy data of its mouse counterpart in murine models of autoimmunity.

Results

We developed a human IgG1 monoclonal antibody, MAb 5261 that specifically binds to human, rodent and primate CXCL13 with an affinity of approximately 5 nM and is capable of neutralizing the activity of CXCL13 from these various species in in vitro functional assays. For in vivo studies we have engineered a chimeric antibody to contain the same human heavy and light chain variable genes along with mouse constant regions. Treatment with this antibody led to a reduction in the number of germinal centers in mice immunized with 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Keyhole Limpet Hemocyanin (NP-KLH) and, in adoptive transfer studies, interfered with the trafficking of B cells to the B cell areas of mouse spleen. Furthermore, this mouse anti-CXCL13 antibody demonstrated efficacy in a mouse model of Rheumatoid arthritis (Collagen-Induced Arthritis (CIA)) and Th17-mediated murine model of Multiple Sclerosis (passively-induced Experimental Autoimmune Encephalomyelitis (EAE)).

Conclusions

We developed a novel therapeutic antibody targeting CXCL13-mediated signaling pathway for the treatment of autoimmune disorders.     

The stratification of cirrhosis

Cirrhosis is traditionally seen as an irreversible stage of chronic liver disease although its clinical course may last several years. Overall, the clinical management of patients with cirrhosis is based on the observation of clinical events mostly related to complications of portal hypertension. Each event of cirrhosis decompensation has clear prognostic implications although it is not precisely predictable. In practice, the advancement in the knowledge of the mechanisms responsible for disease progression is not yet translated in clinical tools allowing the stratification of the cirrhotic stage according to pathophysiological mechanisms. This article provides a review of the main clinical and histopathological features of liver cirrhosis that are relevant for its clinical stratification together with the advancements provided by the introduction of non‐invasive measures of portal hypertension. Other clinical aspects that have a major impact on the quality of life and the possibility of liver transplantation are also discussed.