Immunomodulatory effects of voriconazole on monocytes challenged with Aspergillus fumigatus: differential role of Toll-like receptors

Voriconazole (VRC) has activity against Aspergillus fumigatus, the most frequent cause of invasive aspergillosis in immunocompromised patients. The combination of VRC and A. fumigatus hyphae induced a more pronounced profile of expression of genes encoding inflammatory molecules in human monocytes than Aspergillus alone did. Herein, we provide further evidence of the potential mechanism underlying this immunomodulatory effect of VRC on human monocytes in response to A. fumigatus hyphae. A significant additive antifungal effect was shown when VRC was combined with monocytes against A. fumigatus hyphae. Both A. fumigatus hyphae and VRC induced pronounced profiles of mRNA and protein expression of Toll-like receptor 2 (TLR2) as well as tumor necrosis factor alpha (TNF-α) in THP-1 monocytic cells compared to untreated cells. The VRC-induced increase was greater than that induced by hyphae. The combination of VRC and hyphae increased mRNA and protein expression of TLR2 and TNF-α to even higher levels than did either VRC or hyphae alone. In contrast, TLR4 expression, both at the mRNA and protein levels, was not increased by either VRC or hyphae or their combination. In addition, significantly more NF-κB was translocated to the nuclei of THP-1 cells treated with VRC than untreated cells. While VRC induced more NF-κB than hyphae did, treatment with the combination of the two factors induced the greatest NF-κB expression. The pronounced profile of TLR2 signaling, TNF-α expression, and NF-κB activation in the presence of VRC suggests an immunomodulatory effect leading to a more efficient response to A. fumigatus.     

Clinical significance of nuclear factor (NF)-κB levels in urothelial carcinoma of the urinary bladder

Nuclear factor (NF)-kappaB has been reported to be constitutively activated in various human neoplasms. However, its clinical significance in bladder urothelial carcinoma (UC) remains an unresolved issue. We conducted this study trying to elucidate the role of NFkappaB in bladder UC and its potential prognostic significance, by quantifying immunohistochemically the levels of p65/RelA expression in paraffin-embedded tissue from 116 patients. Some of the cases had previously been stained for cellular FLICE-like inhibitory protein (c-FLIP) and bcl-2. Seventy-four cases displayed concurrent cytoplasmic and nuclear immunoreactivity, whereas 18 only nuclear immunoexpression and 21 only cytoplasmic immunoexpression, and the remaining three cases were negative for p65/RelA. Nuclear p65/RelA expression was positively associated with tumour grade and T-category (p=0.0001 in both cases). In addition, cytoplasmic p65/RelA expression was lower in advanced T-category (p=0.0030). Moreover, p65/RelA nuclear expression was positively correlated with c-FLIP (p=0.0109) and bcl-2 (p=0.0452). p65/RelA nuclear expression adversely affected survival in both univariate and multivariate analysis in superficial (Ta-T1; p=0.0010 and p=0.0008) as well as in muscle-invasive carcinomas (T2-T4; p=0.0004 and p=0.0003). Our results demonstrate that NF-kappaB nuclear expression is correlated with histologic grade and T category in bladder UC. Moreover, NF-kappaB nuclear expression emerges as an independent prognosticator of adverse significance, conveying information beyond that obtained by standard clinicopathological prognosticators.     

Ductal plate malformation and congenital hepatic fibrosis Clinical and histological findings in four patients.

Congenital hepatic fibrosis belongs to the fibrocystic diseases of the liver and represents ductal plate malformation of interlobular bile ducts, along with a destructive cholangiopathy associated with fibrosis. Four patients with congenital hepatic fibrosis are described. Their median age at presentation was 25 years; none of them had a family history of liver or renal disease. Variceal bleeding was the initial manifestation in three patients. All of them required frequent endoscopic variceal ligation sessions and distal splenorenal shunting was also performed in two, almost obviating the need for further variceal ligation. Variceal bleeding did not recur during follow-up. One of these three patients rarely exhibited acute cholangitis; administration of ursodeoxycholic acid resulted in complete remission. In contrast, the fourth patient showed frequent severe episodes of acute cholangitis but normal cholangiographic findings. He underwent liver transplantation but died 2 months later. Laboratory findings disclosed pancytopenia in all patients whereas hepatic synthetic capacity was well preserved. Renal function was unaffected despite the presence of polycystic kidneys in two patients. In summary, congenital hepatic fibrosis can also be diagnosed in older ages, might have strikingly different manifestations and is associated with prominent portal hypertension necessitating aggressive management in order to prevent variceal bleeding.     

Healing of colonic anastomoses after immediate postoperative intraperitoneal administration of oxaliplatin

Aim  The aim of this experimental study was to investigate the effect of intraperitoneal administration of oxaliplatin on the healing of colonic anastomoses when injected immediately after colon resection. Materials and methods  Thirty male Wistar rats were used. During the operation, the rats were randomized to two groups of 15 rats each. Immediately after colonic anastomoses were performed, the rats were injected intraperitoneally with either 3 ml of 0.9% NaCl solution or oxaliplatin (2.4 mg/kg body weight) depending on their group. All rats were killed on the eighth postoperative day. The anastomoses were examined macroscopically. The anastomotic bursting pressures were recorded, the anastomoses graded histologically, and the hydroxyproline tissue contents determined. Results  Anastomotic leakage was noted in four rats (26.7%) of the oxaliplatin group, whereas no anastomotic dehiscence was detected among rats of the control group (p = 0.016). The adhesion formation at the anastomotic sites and the inflammatory cell infiltration were significantly higher in the oxaliplatin group than in the control group (p = 0.001). The bursting pressures (p = 0.001), the hydroxyproline tissue content (p = 0.001), the neoangiogenesis (p = 0.033), the fibroblast activity (p = 0.001), and the collagen deposition (p = 0.001) were significantly lower in the oxaliplatin group in comparison to the control group. Conclusion  The immediate postoperative intraperitoneal administration of oxaliplatin seems to impair healing of colonic anastomoses in rats.     

Primary tuberculosis of the thyroid gland: report of three cases.

We report on three cases with rapidly increasing thyroid masses who were referred with the provisional diagnosis of thyroid carcinoma. In the two cases, the diagnosis of tuberculosis was established after thyroidectomy, but in the third case diagnosis was made pre-operatively with acid fast bacilli (AFB) staining and culture from fine needle aspiration (FNA) material. Although rare, tuberculosis of the thyroid gland should be included in the differential diagnosis of thyroid masses. FNA, AFB staining and culture of the aspirate are important diagnostic tools in these cases.     

The impact of psychological functioning upon systemic sclerosis patients' quality of life

OBJECTIVE: To access health-related quality of life (HRQOL) in systemic sclerosis (SSc) patients using the World Health Organization Quality of Life Instrument, Short-Form (WHOQOL-BREF), and to identify the association between clinical, psychopathological, and personality parameters and SSc patients' HRQOL. METHODS: Fifty-six patients with SSc were compared with 72 patients with rheumatoid arthritis (RA), 43 with systemic lupus erythematosus (SLE), 34 with Sj?gren syndrome (SS), and 74 healthy controls. A wide range of clinical information was collected and the following self-report instruments were used: the WHOQOL-BREF, the General Health Questionnaire, the Symptom Distress Check List, the Hostility and Direction of Hostility Questionnaire, the Defense Style Questionnaire, and the Sense of Coherence scale. RESULTS: HRQOL perceived by SSc patients was significantly impaired compared with healthy controls. Initial examination of HRQOL across groups of rheumatology patients revealed similar HRQOL, but when age, pain, psychopathology, and coping strategies were taken into account, SSc patients had impaired physical health QOL in comparison with RA, SLE, and SS patients. Arthritis-related pain was closely associated with SSc patients' HRQOL. Elevated psychological distress symptoms as well as certain personality traits, such as maladaptive defenses and lower sense of coherence, were also associated with diminished HRQOL. CONCLUSIONS: Impaired psychological functioning is associated with diminished HRQOL in SSc, and consequently, treatment of depressive symptoms should be considered a priority. Moreover, assessment of HRQOL should only be used in conjunction with specific psychological distress measurements, to detect the influence of psychopathology on HRQOL.     

Lamivudine/pegylated interferon alfa-2b sequential combination therapy compared with lamivudine monotherapy in HBeAg-negative chronic hepatitis B

BACKGROUND AND AIM: Monotherapy has been proven insufficient in achieving sustained control of chronic hepatitis B. We aimed to assess the efficacy of combined sequential administration of lamivudine and pegylated interferon alfa-2b in patients with hepatitis Be antigen (HBeAg)-negative chronic hepatitis B. METHODS: Eighteen patients were given sequential combination treatment starting with 3 months of lamivudine monotherapy followed by 9 months of pegylated interferon alfa-2b (after a 3-month period of concomitant administration of the two drugs) and 24 patients received lamivudine monotherapy. RESULTS: At the end of treatment, 88.9% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy had hepatitis B virus (HBV) DNA levels below 400 copies/mL (P = not significant). At the end of treatment, 72.2% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy achieved alanine aminotransferase normalization (P = not significant). After 12 months of follow up, 33.3% of the patients who received sequential combination treatment and 16.7% of those who received lamivudine monotherapy had HBV-DNA levels below 400 copies/mL (P = 0.4). After 12 months of follow up, 72.2% of the patients who received sequential combination treatment and 25.0% of those who received lamivudine monotherapy had normal alanine aminotransferase levels (P < 0.01). Twenty-five percent of the patients in the lamivudine monotherapy group had virological breakthrough compared to none in the sequential combination treatment group (P = 0.06). CONCLUSIONS: Sequential combination treatment is able to improve sustained biochemical response rates and prevent the emergence of lamivudine-resistant mutants in patients with HBeAg-negative chronic hepatitis B.     

Effects of combined deferiprone and deferoxamine chelation therapy on iron load indices in beta-thalassemia

The benefits of combined deferoxamine (DFO) and deferiprone (L1) chelation therapy, focusing on reducing myocardial iron loading, have been widely reported. Herein, we present the efficacy of combined chelation and its effects on iron load indices. Five thalassemia major (TM) patients who were undergoing chelation monotherapy with DFO were enrolled. Inclusion criteria were magnetic resonance imaging (MRI) T2* values, indicating serious heart and/or liver transfusional hemosiderosis. Combined therapy was started with the same dose of DFO and the addition of L1. The MRI T2* studies were repeated 18 months later. An Echo-Doppler study was performed in order to further evaluate the left ventricular (LV) systolic function. Within the 18 months' follow-up period, there was a significant statical decrease in mean serum ferritin levels. All patients increased their MRI T2* liver values, while two patients with very low MRI T2* also increased their myocardial values. The MRI ejection fraction (EF) and Echo-Doppler study measurements confirmed the improvement of systolic function. No adverse effects were reported. Combined L1 and DFO therapy seems to be effective in reducing iron excess in organ iron overloaded thalassemic patients. Magnetic resonance imaging can accurately quantify iron load, while echocardiography remains a reliable monitoring technology.