High frequency of cholestasis in generalized pustular psoriasis: Evidence for neutrophilic involvement of the biliary tract

Generalized pustular psoriasis is a rare form of psoriasis that is sometimes associated with extracutaneous manifestations. Evidence for biliary involvement has been suggested in isolated cases. We investigated the prevalence and nature of liver abnormalities occurring in this disease. Twenty-two patients consecutively admitted for generalized pustular psoriasis who underwent liver biological tests at the time of the attack and during the following weeks were included. Twenty patients (90%) had at least one abnormal biological liver parameter. Eleven patients (50%) had pronounced abnormalities: jaundice (4/22), gammaglutamyl transferase higher than 5 times the normal value (10/22), alkaline phosphatase higher than twice the normal value (7/22), and/or aminotransferases higher than 3 times the normal value (7/22). These abnormalities returned to normal range at the time of remission of pustular psoriasis, suggesting that severe liver abnormalities could be associated with severe cutaneous disease. Neutrophilic cholangitis was observed on liver biopsy. Persistent magnetic resonance cholangiopancreatography features similar to those observed in sclerosing cholangitis were found in 3 of the 4 patients studied. No causal factor other than pustular psoriasis could be identified. In conclusion, our results demonstrate the high frequency of liver abnormalities in patients with generalized pustular psoriasis. Biliary involvement related to neutrophilic cholangitis should be added to the spectrum of extracutaneous manifestations of this disease, and physicians should be aware of such a complication.     

Incidence,consequences, and risk factors for anastomotic dehiscence after colorectal surgery: a prospective monocentric study

Background Anastomotic dehiscence is the most severe surgical complication after large bowel resection. This study was designed to assess the incidence, to observe the consequences, and to identify the risk factors associated with anastomotic leakage after colorectal surgery. Materials and methods All procedures involving anastomoses of the colon or the rectum, which were performed between November 2002 and February 2006 in a single institution, were prospectively entered into a computerized database. Results One thousand eighteen colorectal resections and 811 anastomoses were performed over this 40-month period. The most frequent procedures were sigmoid (276) and right colectomies (217). The overall anastomotic leak rate was 3.8%. The mortality rate associated with anastomotic leak was 12.9%. In univariate analysis, the following parameters were associated with an increased risk for anastomotic dehiscence: (1) ASA score ≥ 3 (p = 0.004), (2) prolonged (>3 h) operative time (p = 0.02), (3) rectal location of the disease (p < 0.001), (4) and a body mass index > 25 (p = 0.04). In multivariate analysis, ASA score ≥ 3 (OR = 2.5; 95% CI 1.5–4.3, p < 0.001), operative time > 3 h [OR = 3.0; 95% CI 1.1–8.0, p = 0.02), and rectal location of the disease (OR = 3.75; 95% CI 1.5–9.0 (vs left colon), p = 0.003; OR = 7.69; 95% CI 2.2–27.3 (vs right colon), p = 0.001] were factors significantly associated with a higher risk of anastomotic dehiscence. Conclusions Three risk factors for anastomotic leak have been identified, one is patient-related (ASA score), one is disease-related (rectal location), the third being surgery-related (prolonged operative time). These factors should be considered in perioperative decision-making regarding defunctioning stoma formation.     

Nylon-fiber-induced neutrophil fragmentation

We have investigated the effects of mechanical elution of neutrophils from nylon-wool fiber (NWF) using the scanning electron microscope and biochemical analysis of elution fractions. We have determined that mechanical removal of neutrophils from nylon-wool fiber disrupts neutrophils adherent to nylon-wool fiber and augments release of granules, release of peripheral cytoplasmic fragments, and release of lactic dehydrogenase, a soluble cytoplasmic enzyme. Mechanical shearing of the adherent cell, and not adherence per se, causes the fragmentation. The extent of fragmentation is proportional to the NWF surface area available to neutrophils and is maximal at the temperature for optimal adherence and spreading. Agents that decrease cell spreading (n-ethylmaleimide and cold) diminish fragmentation. Cytochalasin B, an agent that destabilizes the neutrophil cortex, increases fragmentation. Fragmentation may be an important contributing cause of the abnormal morphology, function, and in vivo survival of nylon-wool-fiber procured human neutrophils. The prevention of fragmentation would appear to be necessary to insure the procurement of optimally functioning cells. Elution of NWF-adherent neutrophils in the cold might be a practical way to diminish neutrophil damage during clinical filtration leukapheresis.     

Paraganglioma of the ampulla of Vater: a potentially malignant neoplasm

Paragangliomas are rare tumours originating from neuroectodermic remnants and are usually considered as benign. We present two cases of paraganglioma of the ampulla of Vater that were treated surgically by pancreaticoduodenectomy. In one case, histopathology revealed malignant characteristics of the tumour with invasion of the pancreas and simultaneous duodenal lymph-node metastases. Both patients had a favourable outcome without disease recurrence at 40 and 44 months postoperatively. Only 21 cases of ampullary paraganglioma have been reported in the literature, 7 of them with malignant characteristics. In conclusion, paragangliomas of the ampulla of Vater have malignant potential. Surgical therapy of these tumours should not be limited to local resection, as disease recurrence and lymph node involvement have been reported. We propose that paragangliomas of the ampulla of Vater should be operated by cephalic pancreaticoduodenectomy, which allows long-term and disease-free survival.     

Treatment of acetaminophen-induced acute liver failure in the mouse with conditionally immortalized human hepatocytes

BACKGROUND/AIMS: Liver failure is a life threatening condition currently treated by palliative measures and, when applicable, organ transplantation. The use of a bioartificial organ capable of fulfilling the main functions of the liver would represent an attractive alternative. However, the shortage of suitable donor cells, and their limited growth ability have impeded the development of this strategy. We investigated whether lentiviral vectors allow for conditional immortalization of human hepatocytes and whether these immortalized hepatocytes could reverse lethal acute liver failure. METHODS: We exposed primary human hepatocytes to Cre-excisable lentiviral vectors coding for SV40T Antigen, telomerase, and/or Bmi-1 and tested the functionality of the resulting cell lines. Therapeutic potential of immortalized hepatocytes were tested in a murine model of acetaminophen-induced hepatic injury. RESULTS: The immortalized hepatocytes grew continuously yet were non-tumorigenic, stopped proliferating when exposed to Cre recombinase, and conserved defining properties of primary hepatocytes, including the ability to secrete liver-specific proteins and to detoxify drugs. The implantation of encapsulated immortalized human hepatocytes rescued mice from lethal doses of acetaminophen. CONCLUSIONS: Lentiviral vectors represent tools of choice for immortalization of non-dividing primary cells, and lentivirally immortalized human hepatocytes are promising reagents for cell-based therapy of acute liver failure.     

Enhancement of chemotactic factor-stimulated neutrophil oxidative metabolism by leukotriene B4

Leukotriene B4 (LTB4) is a potent primary stimulator of neutrophil chemotaxis, aggregation, and degranulation and induces superoxide production at higher concentrations. In order to determine whether LTB4 modulates neutrophil responses to oxidative stimuli, human neutrophils (PMNs) were incubated with LTB4 prior to stimulation with f-Met-Leu-Phe (fMLP, 10(-7) mol/L), opsonized zymosan (OZ, 250 micrograms/mL), or phorbol myristate acetate (PMA, 32 nmol/L). Superoxide (O2-) production by stimulated PMNs was assessed by the superoxide dismutase-inhibitable reduction of cytochrome c. LTB4 alone did not stimulate O2- production in concentrations below 10(-7) mol/L and had no effect on the O2- assay. In the concentration range of 10(-12) to 10(-8) mol/L, LTB4 did not alter O2- release induced by OZ or PMA. In contrast, LTB4-treated cells demonstrated enhanced O2- production following exposure to fMLP, and in the presence of 10 nmol/LLTB4, generated 180% +/- 41% of O-2 quantities produced by control cells (n = 23). Enhancement was LTB4 dose-dependent, was maximal in the range of 1 to 10 nmol/L LTB4, was not reversed by removal of the lipid from the medium prior to fMLP stimulation, and was not dependent on the presence of Ca++ or Mg++ in the suspending medium. Chemiluminescence of fMLP-stimulated neutrophils was increased to 323% of controls in neutrophils preincubated with 10 nmol/L LTB4. Unlike augmentation of oxidative responses to fMLP seen with other degranulating stimuli, enhancement by LTB4 was not correlated with an increase in 3H-fMLP receptor binding. These results indicate that, in addition to its primary effects on neutrophil function, LTB4 modulates PMN oxidative responses to the chemotactic peptide and, thus, may amplify the release of oxygen metabolites at inflammatory foci.     

In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin's disease

The B-lymphocyte/accessory-cell activation antigen B7 (BB1) has been shown in vitro to stimulate T-lymphocyte proliferation and cytokine production via CD28 present on the latter cells. In this study, benign lymphoid tissues, lymphomas, and extralymphoid inflammatory sites were examined immunohistochemically using anti-B7 and other relevant monoclonal antibodies. B7 was expressed by benign transformed germinal center B cells, as it was by B cells of follicular lymphomas. B7 was also expressed by a subpopulation (a mean of 31% to 65%) of macrophages and dendritic cells in a variety of lymphoid tissues. It was present in abundance on all macrophages constituting sarcoid granulomas in lymph nodes. In extralymphoid inflammation, 17% to 35% of macrophages expressed B7 only weakly. Cases of Hodgkin's disease showed expression of B7 by the majority of Reed-Sternberg cells or malignant mononuclear variants, a phenomenon that potentially contributes to the lymphocytic accumulation that is a feature of this condition. CD28+ T cells were seen in all areas where T cells were present. B7+ and CD28+ cells colocalized in, for example, lymphoid follicles, lymph node paracortex, sarcoid granulomas, and Hodgkin's disease tissue, indicating a potential for cellular interaction via these molecules at these sites.     

Normal synthesis and expression of endothelial IIb/IIIa in Glanzmann's thrombasthenia

Glanzmann's thrombasthenia is a bleeding disorder, inherited in an autosomal recessive way and characterized by an absence or deficiency of the platelet glycoprotein (GP) IIb/IIIa complex. Recently, we and others demonstrated that cultured human umbilical vein endothelial cells synthesized a membrane protein complex similar to the platelet GP IIb/IIIa complex. In this article, we demonstrate that endothelial cells isolated from the umbilical vein of a newborn with Glanzmann's thrombasthenia, as compared with normal endothelial cells, show no difference in their ability to synthesize and express this GP IIb/IIIa complex. Our results indicate that Glanzmann's thrombasthenia is not accompanied by an "endotheliopathy."     

Role of hemodynamics in initiation/growth of intracranial aneurysms

Background

Intracranial aneurysm (IA) is a disease of the vascular wall resulting in abnormal enlargement of the vessel lumen. It is a common pathology with a prevalence of 2%‐3% in the adult population. IAs are mostly small, quiescent and asymptomatic; yet, upon rupture, severe brain damage or even death is frequently encountered. In addition to clinical factors, hemodynamic forces, mainly wall shear stress (WSS), have been associated with the initiation of IAs and possibly with their risk of rupture. However, the mechanism by which WSS contributes to aneurysm growth and rupture is not completely understood.

Design

PubMed and Ovid MEDLINE databases were searched. In addition, key review articles were screened for relevant original publications.

Results

Current knowledge about the relation between WSS and IA has been obtained from both computational fluid dynamic studies in patients and experimental models of IA formation and growth. It is increasingly recognized that a high wall shear stress (gradient) participates to IA formation and that both low and high WSS can drive IA growth. Primary cilia (PC) play an important role as mechanosensors as patients with polycystic kidney disease, which is characterized by the absence or dysfunction of PC, have increased risk to develop IAs as well as increased risk of rupture.

Conclusion

Wall shear stress is a key player in IA initiation and progression. It is involved in vascular wall remodelling and inflammation, processes underlying aneurysm pathophysiology.