Increased production of vascular endothelial growth factor in peritoneal macrophages of cirrhotic patients with spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) is a common complication of cirrhotic patients with ascites that usually results in renal failure and death despite the efficacy of the current antibiotic therapy. The pathogenesis of these phenomena is poorly known but it has been related to the production of vasoactive cell mediators locally acting on the splanchnic vasculature. Because previous studies showed that peritoneal macrophages of cirrhotic patients may produce high quantities of vascular endothelial growth factor (VEGF), a powerful vessel permeabilizing agent, when stimulated by cytokines and bacterial lipopolysaccharide, the present study was aimed to seek whether peritoneal macrophages of SBP patients are induced to produce increased amounts of VEGF. Our results indicate that the production rate and the messenger RNA (mRNA) and protein expression of this substance are increased in macrophages of patients with SBP in comparison with those of noninfected cirrhotic patients. This characteristic feature is absent in circulating monocytes of these patients. Moreover, enhanced endothelial cell proliferation induced by conditioned medium of macrophages isolated from the ascites of patients with SBP is abolished by anti-VEGF antibody, and peritoneal tissue of cirrhotic patients expresses both VEGF receptors, Flt-1 and KDR. These results, therefore, are consistent with the concept that locally released macrophage-derived VEGF may result in increased vascular permeability and plasma leakage in the peritoneal vessels of cirrhotic patients with SBP.     

Growing teratoma syndrome in intracranial non-germinomatous germ cell tumors (iNGGCTs): a risk for secondary malignant transformation—a report of two cases

Purpose

About 5 % of pediatric intracranial germ cell tumors and 20 % of non-germinomatous germ cell tumors (NGGCT) progress to growing teratoma syndrome (GTS) following chemoradiotherapy. The growing teratoma is thought to arise from the chemotherapy-resistant, teratomatous portion of a germ cell tumor and is commonly benign but may undergo malignant transformation.

Methods

Two pediatric patients whose intracranial NGGCTs progressed to growing teratomas during chemotherapy and later transformed to secondary malignant tumors after partial resection and radiation therapy (RT).

Results

Both tumors were diagnosed by MRI scans and elevated serum and CSF markers. Following normalization of tumor markers with chemotherapy and initial decrease in tumor volume, subsequent imaging showed regrowth during chemotherapy with pathology revealing benign teratoma. RT was administered. Several years following this treatment, further growth was seen with pathology indicating malignant carcinoma in one patient and malignant rhabdomyosarcoma in the other. The patient with carcinoma received palliative care while the patient with the sarcoma received further resection, intensive chemotherapy, and an autologous stem cell transplant and is currently in remission, 36 months since malignant transformation.

Conclusion

Malignant transformation of presumed residual teratoma has been seldom reported. Treatment of NGGCT involves platinum-based chemotherapy with craniospinal RT and boost to the primary site, with cure rates of around 80 %. Teratomas are characteristically chemotherapy and RT resistant and are treated surgically. In the event that residual or growing teratoma is suspected, a complete resection should be considered early in the management as there is a risk of malignant transformation of residual teratoma.     

Correction to: Serum microRNA is a biomarker for post-operative monitoring in glioma

Journal of Neuro-Oncology - We performed a systematic review and meta-analysis of clinical outcomes for patients with acromegaly treated with stereotactic radiosurgery (SRS). Primary outcomes were...     

STD-Dependent and Independent Encoding of Input Irregularity as Spike Rate in a Computational Model of a Cerebellar Nucleus Neuron

Neurons in the cerebellar nuclei (CN) receive inhibitory inputs from Purkinje cells in the cerebellar cortex and provide the major output from the cerebellum, but their computational function is not well understood. It has recently been shown that the spike activity of Purkinje cells is more regular than previously assumed and that this regularity can affect motor behaviour. We use a conductance-based model of a CN neuron to study the effect of the regularity of Purkinje cell spiking on CN neuron activity. We find that increasing the irregularity of Purkinje cell activity accelerates the CN neuron spike rate and that the mechanism of this recoding of input irregularity as output spike rate depends on the number of Purkinje cells converging onto a CN neuron. For high convergence ratios, the irregularity induced spike rate acceleration depends on short-term depression (STD) at the Purkinje cell synapses. At low convergence ratios, or for synchronised Purkinje cell input, the firing rate increase is independent of STD. The transformation of input irregularity into output spike rate occurs in response to artificial input spike trains as well as to spike trains recorded from Purkinje cells in tottering mice, which show highly irregular spiking patterns. Our results suggest that STD may contribute to the accelerated CN spike rate in tottering mice and they raise the possibility that the deficits in motor control in these mutants partly result as a pathological consequence of this natural form of plasticity.     

Chronic hepatitis D in intravenous drug addicts and non-addicts. A comparative clinico-pathological study

In recent years chronic infection by the hepatitis delta virus (HDV) has become an important cause of chronic liver disease among drug addicts. To evaluate the influence of addiction to i.v. drugs on the course of this disease we have analyzed the clinical, histopathological, virological and evolutive features in 18 addicts and 11 non-addicts with chronic delta infection. Recent acute hepatitis D, documented as HDV superinfection, was observed in 14 addicts (77%) and in 2 non-addicts (18%) (P less than 0.02). At the time of evaluation for chronic liver disease, the frequency of symptoms, the degree of biochemical disturbances and the histopathological severity were similar in the two groups but the duration of HDV infection was probably shorter in drug addicts. HBV replication, as indicated by the presence of HBeAg and HBV-DNA in serum and HBcAg in liver, was more frequent in addicts. The amount of HDAg in liver tissue was also greater in addicts (P less than 0.005). Antibodies against the human immunodeficiency virus were detected in all of the addicts (P less than 0.001). Although most patients remained asymptomatic, significant histological worsening occurred in one half of the cases after a relatively short period of follow-up (25.1 +/- 16.3 months). The tendency to deteriorate in addicts (61% of cases) was greater than in non-addicts (36%). These observations suggest that the prognosis of chronic HDV infection is particularly poor in drug addicts in whom rapid deterioration may be related to simultaneous and inadequately controlled replication of hepatotropic viruses.     

Esophageal dysfunction in primary biliary cirrhosis

To investigate esophageal involvement of scleroderma in primary biliary cirrhosis, esophageal, manometry was performed in 18 patients (16 females, two males) with primary biliary cirrhosis and in a control group of 18 subjects matched by age and sex. All patients were screened for clinical manifestations of scleroderma and for the presence of Sj?gren's syndrome. Four patients had scleroderma (all of them with Sj?rgren's syndrome), nine had Sj?gren's syndrome without scleroderma, and five had neither scleroderma nor Sj?gren's syndrome. Three patients with scleroderma had aperistalsis and diminished lower sphincter pressure. Five patients with Sj?rgren's syndrome without scleroderma also had esophageal manometric disturbances. Furthermore, lower esophageal sphincter pressure (LESP) and distal mean wave pressure (DMWP) were significantly reduced in patients with scleroderma (LESP: 7.5 +/- 1.4 mmHg; DMWP: 29.5 +/- 5.9 mmHg) and in patients with Sj?gren's syndrome without scleroderma (LESP: 14.8 +/- 0.8 mmHg; DMWP: 54.3 +/- 7.5 mmHg) compared to controls (LESP: 18.0 +/- 0.7 mmHg; DMWP: 83.9 +/- 5.1 mmHg). By contrast, LESP and DMWP were similar in patients without Sj?gren's syndrome (LESP: 17.6 +/- 0.9 mmHg; DMWP: 78.2 +/- 10.9 mmHg) and controls. These results indicate that esophageal motility dysfunction is often present in patients with primary biliary cirrhosis who have scleroderma, and also in those with Sj?gren's syndrome without scleroderma, suggesting that some esophageal motor disturbances could be related to association with Sj?gren's syndrome.     

Hyperglucagonism and glucagon resistance in cirrhosis. Paradoxical effect of propranolol on plasma glucagon levels

Propranolol, a non-selective beta-blocker, is known to decrease glucagon release in normal subjects. The present study was aimed at investigating the effects of propranolol on the hyperglucagonism commonly observed in patients with cirrhosis. Eight cirrhotic patients and 6 matched healthy controls were studied. The plasma concentrations of glucagon, insulin, c-peptide and glucose were measured in basal conditions and after stimulating glucagon secretion by an i.v. infusion of arginine (0.4 g/kg/30 min). The study was repeated 24 h later after inducing beta-blockade by the i.v. infusion of propranolol (10 mg). In baseline conditions, patients with cirrhosis, despite normal levels of insulin and glucose, had a marked hyperglucagonism (654 +/- 303 pg/ml vs. 269 +/- 90 in controls, P less than 0.01). Prior to propranolol, arginine infusion caused greater glucagon release in cirrhotics (71 +/- 31 ng.h.ml-1) than in controls (33 +/- 17 ng.h.ml-1, P less than 0.02), but despite a similar insulin secretion (assessed from c-peptide), blood glucose did not increase. After propranolol, glucagon secretion decreased as expected in controls (29 +/- 12 ng.h.ml-1, P less than 0.05) but experienced a paradoxical increase in cirrhotics (113 +/- 64 ng.h.ml-1, P less than 0.05). Again, despite the marked increase in glucagon release, there was no increase in glucose production, providing further evidence of the glucagon resistance that accompanies hyperglucagonism in cirrhosis. Our results suggest that hyperglucagonism with glucagon resistance might be the initial disturbance in carbohydrate metabolism in patients with cirrhosis. Contrary to what could be expected, propranolol does not correct but further accentuates this disturbance.