Welding of thin stainless-steel sheets using a QCW green laser source.

Bipolar plates are structured thin metal sheets and are, next to the membrane electrode assembly (MEA), one of the main components of polymer electrolyte membrane fuel cells. One of the production steps of such bipolar plates is the joining process of its two halves. Laser welding is a suitable method for such an application since it is fast, non-contact, automatable, and scalable. Particularly important aspects of the weld seam are the weld seam width and depth. In this paper, welding of stainless-steel material analogous to materials used in bipolar plates is examined. For this purpose, a newly developed quasi continuous wave (QCW) green laser source with higher beam quality is employed to assess the effect of the wavelength and the spot diameter on the welding of stainless-steel material. By using various focusing lens, different sized beam diameters below 20 µm are achieved and their influence on the final welding result-specifically concerning the seam width-are analyzed. With welding speeds starting at 500 mm/s, reduced weld seam widths (≤ 100 µm) are realized, particularly with a focusing lens of 200 mm focal distance. The suitability of such a process for thin channels of under 75 µm width is examined.

Intravesical Bacillus Calmette-Guérin (BCG) treatment's severe complications: A single institution review of incidence, presentation and treatment outcome.

OBJECTIVES: Intravesical Bacillus Calmette-Guérin (BCG) treatment for superficial bladder cancer is interrupted in approximatively 8% of cases as a result of complications. The objective is to report the severe related complications of Bacillus Calmette-Guérin (BCG) following an intravesical instillation for bladder tumor encountered at our institution for the past 5 years. METHODS: Medical records of a tertiary teaching hospital, located in Beirut, Lebanon, were retrospectively analyzed from June 2014 to June 2019 searching for severe related complications of BCG. A comprehensive review of articles on this subject was conducted. RESULTS: The incidence of severe systemic adverse events related to BCG instillation was 1.5% (5 out of 332 patients). A total of five patients were found to have a severe BCG related complication, with fever, chills, and irritative urinary signs being the most frequent symptoms. All patients received antituberculosis therapy (Isoniazid, Rifampin and Ethambutol). Two were put on add-on corticosteroids. Three patients had a computed tomography scan image in favor of an infection. Two patients had a favorable outcome, three patients died. CONCLUSION: BCG severe adverse events were mostly seen in patients with a traumatic instillation. Treatment used at our institution was similar to most cases reported in the literature. A standardized diagnostic and treatment approach should be implemented to help physicians tackle these life-threatening complications.

Role of Macrophage Dopamine Receptors in Mediating Cytokine Production: Implications for Neuroinflammation in the Context of HIV-Associated Neurocognitive Disorders.

Despite the success of combination anti-retroviral therapy (cART), around 50% of HIV-infected individuals still display a variety of neuropathological and neurocognitive sequelae known as NeuroHIV. Current research suggests these effects are mediated by long-term changes in CNS function in response to chronic infection and inflammation, and not solely due to active viral replication. In the post-cART era, drug abuse is a major risk-factor for the development of NeuroHIV, and increases extracellular dopamine in the CNS. Our lab has previously shown that dopamine can increase HIV infection of primary human macrophages and increase the production of inflammatory cytokines, suggesting that elevated dopamine could enhance the development of HIV-associated neuropathology. However, the precise mechanism(s) by which elevated dopamine could exacerbate NeuroHIV, particularly in chronically-infected, virally suppressed individuals remain unclear. To determine the connection between dopaminergic alterations and HIV-associated neuroinflammation, we have examined the impact of dopamine exposure on macrophages from healthy and virally suppressed, chronically infected HIV patients. Our data show that dopamine treatment of human macrophages isolated from healthy and cART-treated donors promotes production of inflammatory mediators including IL-1ß, IL-6, IL-18, CCL2, CXCL8, CXCL9, and CXCL10. Furthermore, in healthy individuals, dopamine-mediated modulation of specific cytokines is correlated with macrophage expression of dopamine-receptor transcripts, particularly DRD5, the most highly-expressed dopamine-receptor subtype. Overall, these data will provide more understanding of the role of dopamine in the development of NeuroHIV, and may suggest new molecules or pathways that can be useful as therapeutic targets during HIV infection.

Lower C-reactive protein and IL-6 associated with vegetarian diets are mediated by BMI.

BACKGROUND AND AIMS: The mechanism by which vegetarian diets are associated with less inflammation is not clear. We investigated the role of BMI as a mediator in the relationship between vegetarian diet and concentrations of C-reactive protein (CRP), and the cytokines IL-6, IL-10 and TNF-α. METHODS AND RESULTS: We used data from participants of the Adventist Health Study 2 (AHS-2) Calibration (n = 893) and Biological Manifestations of Religion (n = 478) sub-studies. Vegetarian diet variations were determined based on reported intake of animal products assessed by FFQ. Combining all participants, the proportion of non-vegetarians (NVs), partial vegetarians (PVs), lacto-ovo vegetarians (LOVs), and strict vegetarians (SVs) was 44%, 16%, 31%, and 9%, respectively. NV and PV participants were older than other dietary groups, and non-vegetarians had the highest BMI. Mediation analyses supported the mediating effect of BMI in associations of vegetarian diet with CRP (p < 0.001 each for PV, LOV and SV), and with IL-6 (p < 0.05 each for PV, LOV and SV). Mediation by BMI was not evident between vegetarian diet and the biomarkers IL-10 and TNF-α. A direct pathway was significant only in the association between strict vegetarians and CRP (p = 0.017). CONCLUSION: The lower CRP and IL-6 concentrations among vegetarians may be mediated by BMI.

An unusual, deceptive delayed of profuse haemorrhage after mandibular implant dentistry: risk planning and medico-legal instruction.

Mandibular implant placement (MIP) has been accepted and widely used for decades all over the world, and has reached a very high level of therapeutic reliability. MIP is used mostly in elderly edentulous patients who lost their teeth when dentistry was not oriented to fixed or removable prosthetic. Notwithstanding this, every year cases of severe complications during MIP due to haemorrhage causing life-threatening airway's obstruction are reported. These severe complications of MIP need immediate therapy, usually with hospitalization, and may be potentially fatal. A 56-year-old man presented to the private practice requesting the placement of two dental implants at 41 and 31 previously lost for periodontal disease. Two implants of 3.3 mm of diameter, and 10 mm of length were inserted replacing teeth 31 and 41. Two hours after surgery and home delivery, the patient came to the emergency room complaining of dyspnoea and edema at the floor of the mouth. The maxillo-facial surgeon decided to perform tracheostomy and haemostasis under general anaesthesia. Two weeks after demission a complete healing was performed. This is important for dental practitioners to avoid severe bleeding complications during the MIP in the interforaminal region, especially on the midline. Moreover, when mandibles are severely atrophic, practitioners should be aware of this fact and the possible implications. The evaluation of these data is essential in the correct preoperative planning of implant procedures in the mandible, and with the increasing demand for MIP, the variations of the lingual foramen of the mandible should receive more attention.

A Canadian perspective on the use of immunoglobulin therapy to reduce infectious complications in chronic lymphocytic leukemia.

Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (cll), who typically have increased susceptibility because of hypogammaglobulinemia (hgg) related to their disease and its treatment. Immunoglobulin replacement therapy (igrt) has been shown to reduce the frequency of bacterial infections and associated hospitalizations in patients with hgg or a history of infection, or both. However, use of igrt in cll is contentious. Studies examining such treatment were conducted largely before the use of newer chemoimmunotherapies, which can extend lifespan, but do not correct the hgg inherent to the disease. Thus, the utility of igrt has to be re-evaluated in the current setting. Here, we discuss the evidence for the use of igrt in cll and provide a practical approach to its use in the prevention and management of infections.

Relationship of vitamin D levels to blood pressure in a biethnic population.

BACKGROUND AND AIMS: Accumulating epidemiological and clinical studies have suggested that vitamin D insufficiency may be associated with hypertension. Blacks tend to have lower vitamin D levels than Whites, but it is unclear whether this difference explains the higher blood pressure (BP) observed in Blacks in a population with healthy lifestyle practices. METHODS AND RESULTS: We examined cross-sectional data in the Adventist Health Study-2 (AHS-2), a cohort of non-smoking, mostly non-drinking men and women following a range of diets from vegan to non-vegetarian. Each participant provided dietary, demographic, lifestyle and medical history data. Measurements of weight, height, waist circumference, percent body fat and blood pressure and fasting blood samples were obtained from a randomly selected non-diabetic sample of 284 Blacks and 284 Whites aged 30-95 years. Multiple regression analyses were used to assess independent relationships between blood pressure and 25(OH)D levels. Levels of 25(OH)D were inversely associated with systolic BP in Whites after control for age, gender, BMI, and use of BP-lowering medications (ß-coefficient -0.23 [95% CI, -0.43, -0.03; p = 0.02]). This relationship was not seen in Blacks (ß-coefficient 0.08 [95% CI, -0.14, 0.30; p = 0.4]). Results were similar when controlling for waist circumference or percentage body fat instead of BMI. No relationship between serum 25(OH)D and diastolic BP was seen. CONCLUSION: Systolic BP is inversely associated with 25(OH)D levels in Whites but not in Blacks. Vitamin D may not be a major contributor to the White-Black differential in BP.

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc- mouse model.

The efficacy of IVIG in preventing GvHD has not been definitely demonstrated clinically. Using a xenogeneic model of GvHD in NOD/SCID/γc- (NSG) mice, we showed that weekly administration of IVIG significantly reduced the incidence and associated mortality of GvHD to a degree similar to CsA. Unlike CsA and OKT3, IVIG were not associated with inhibition of human T-cell proliferation in mice. Instead, IVIG significantly inhibited the secretion of human IL-17, IL-2, IFN-γ and IL-15 suggesting that IVIG prevented GvHD by immunomodulation. Furthermore, the pattern of modification of the human cytokine storm differed from that observed with CsA and OKT3. Finally, in a humanized mouse model of immune reconstitution, in which NSG mice were engrafted with human CD34(+) stem cells, IVIG transiently inhibited B-cell reconstitution, whereas peripheral T-cell reconstitution and thymopoiesis were unaffected. Together these in vivo data raise debate related to the appropriateness of IVIG in GvHD prophylaxis. In addition, this model provides an opportunity to further elucidate the precise mechanism(s) by which IVIG inhibit GvHD.

Acute effect of nut consumption on plasma total polyphenols, antioxidant capacity and lipid peroxidation.

BACKGROUND: Nuts have been shown to have beneficial effects on human health due to the healthy fat content; however, the effect of antioxidants (i.e. polyphenols) in nuts have not been fully investigated. The present study aimed to assess the immediate effect of a polyphenol-rich meal (75% of energy from nuts: walnuts or almonds) and a polyphenol-free meal on plasma polyphenol content, antioxidant capacity and lipid peroxidation in healthy volunteers. METHODS: Thirteen subjects participated in a randomized, crossover, intervention study. After an overnight fast, walnuts, almonds or a control meal in the form of smoothies were consumed by study subjects. Each subject participated on three occasions, 1 week apart, consuming one of the smoothies each time. Blood samples were obtained at fasting and then at intervals up to 3.5 h after consumption of the smoothies. RESULTS: There was a significant increase in plasma polyphenol concentration following both nut meals, with peak concentrations being achieved at 90 min, and with a walnut meal having a more sustained higher concentration than an almond meal. The plasma total antioxidant capacity reached its highest point at 150 min postconsumption of the nut meals, and was higher after the almond compared to walnut meal. A gradual significant (P < 0.05) reduction in the susceptibility of plasma to lipid peroxidation was observed 90 min after ingestion of the nut meals. No changes were observed following consumption of control meal. CONCLUSIONS: Consumption of both nuts increased plasma polyphenol concentrations, increased the total antioxidant capacity and reduced plasma lipid peroxidation.

Cyclosporin versus tacrolimus for liver transplanted patients.

BACKGROUND: Most liver transplant recipients receive either cyclosporin or tacrolimus to prevent rejection. Both drugs inhibit calcineurin phosphatase which is thought to be the mechanism of their anti-rejection effect and principle toxicities. The drugs have different pharmacokinetic profiles and potencies. Several randomised clinical trials have compared cyclosporin and tacrolimus in liver transplant recipients, but it remains unclear which is superior. OBJECTIVES: To evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, and conference proceedings were searched (August 2005) to identify relevant randomised clinical trials. Our search included scanning of reference lists in relevant articles and correspondence with investigators and pharmaceutical companies. SELECTION CRITERIA: All randomised clinical trials where tacrolimus was compared with cyclosporin for the initial treatment of first-time liver transplant recipients. We included randomised trials irrespective of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: The primary outcome measure was all-cause mortality. Data were synthesised (fixed-effect model) and results expressed as relative risk (RR), values less than 1.0 favouring tacrolimus, with 95% confidence intervals (CI). Two authors assessed trials for eligibility, quality, and extracted data independently. MAIN RESULTS: We included 16 randomised trials. The number of deaths was 254 in the tacrolimus group (1899 patients) and 302 in the cyclosporin group (1914 patients). At one year, mortality (RR 0.85, 95% CI 0.73 to 0.99) and graft loss (RR 0.73, 95% CI 0.61 to 0.86) were significantly reduced in tacrolimus-treated recipients. Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75 to 0.88), and steroid-resistant rejection (RR 0.54, 95% CI 0.47 to 0.74) in the first year. Differences were not seen with respect to lymphoproliferative disorder or de-novo dialysis rates, but more de-novo insulin-requiring diabetes mellitus (RR 1.38, 95% CI 1.01 to 1.86) occurred in the tacrolimus group. More patients were withdrawn from cyclosporin therapy than from tacrolimus (RR 0.57, 95% CI 0.49 to 0.66). AUTHORS' CONCLUSIONS: Tacrolimus is superior to cyclosporin in improving survival (patient and graft) and preventing acute rejection after liver transplantation, but it increases the risk of post-transplant diabetes. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid acute rejection and steroid-resistant rejection in nine and seven patients, respectively, and graft loss and death in five and two patients, respectively, but four additional patients would develop diabetes after liver transplantation.

Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis.

A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato-Biliary Group Controlled Trials Registers were searched. Using fixed and random effects model, relative risk (RR), values <1 favoring tacrolimus, with 95% confidence intervals (CI) were calculated. Of 717 potentially relevant references, 16 RCTs were eligible for inclusion. Mortality and graft loss at 1 year were significantly reduced in tacrolimus-treated recipients (Death: RR 0.85, 95% CI 0.73-0.99; graft loss: RR 0.73, 95% CI 0.61-0.86). Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75-0.88) and steroid-resistant rejection (RR 0.54, 95% CI 0.47-0.74) in the first year. Lymphoproliferative disorder or dialysis rates were not different but more de novo diabetes (RR 1.38, 95% CI 1.01-1.86) occurred with tacrolimus. More patients stopped cyclosporin than tacrolimus (RR 0.57, 95% CI 0.49-0.66). Treating 100 recipients with tacrolimus instead of cyclosporin would avoid rejection and steroid-resistant rejection in nine and seven patients respectively, graft loss and death in five and two patients respectively, but four additional patients would develop diabetes after liver transplantation.

[Management of gynecomastia induced by bicalutamide]. / Prise en charge des gynécomasties induites par le bicalutamide.

Adjuvant bicalutamide monotherapy after radical prostatectomy improves the overall survival in patients with locally advanced prostate cancer. The main adverse event of the nonsteroidal antiandrogen is the development of gynecomastia against which prophylactic breast irradiation can be administered. Therapeutic local radiotherapy using a very small number of fractions is a well-tolerated management option. Symptom improvement is observed in about half of the patients. Radiotherapy-related adverse effects are often mild (erythema, skin irritation) and transient. Tamoxifen has been also shown to be effective in prevention and treatment of gynecomastia induced by adjuvant therapy by bicalutamide in two-third of patients. Long-term safety of this prophylactic and therapeutic approach needs to be investigated through appropriate trials. Further evaluation of the optimal dose and duration of treatment with tamoxifen in this setting is required.

[Percutaneous computed tomography-guided thermal ablation of osteoid osteoma]. / Thermocoagulation percutanée scannoguidée de l'ostéome ostéoïde.

PURPOSE OF THE STUDY: Progress in medical imaging has improved recognition and management of osteoid osteoma. The purpose of this study was to assess the efficacy of computed tomography (CT)-guided percutaneous thermal ablation and discuss the advantages and disadvantages. MATERIAL AND METHODS: We reviewed retrospectively 33 consecutive patients with osteoid osteoma who had undergone CT-guided radiofrequency ablation. The diagnosis was established on the basis of the clinical presentation and pathognomonic radiographic findings (CT and bone scintigram) without histological proof. We recorded patient age and gender, tumor location, clinical signs and duration, imaging findings, duration of the ablation procedure, type of anesthesia, hospital stay, and complications. We evaluated their effect on final outcome. RESULTS: Weight-bearing was possible in all patients with a lesion of the lower limb a few hours after surgery. Patients resumed their normal activities in 24-48 hours. Pain resolved immediately after radiofrequency ablation in 26 patients and limping, when present, disappeared within 24 hours. At mean follow-up of 34 months (minimum 12 months) there was one case of recurrent pain. Clinical cure was confirmed by CT and bone scintigraphy in twelve patients. DISCUSSION AND CONCLUSION: This precise and minimally invasive method is an effective and safe way to reduce healthcare expenditures. It can be recommended as the primary treatment for osteoid osteoma.

Impact of HLA matching on outcome of hematopoietic stem cell transplantation in children with inherited diseases: a single-center comparative analysis of genoidentical, haploidentical or unrelated donors.

SUMMARY: Hematological inherited diseases can be cured by hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-identical sibling donor (MSD), but the outcome of unrelated donors (URD) or haploidentical donors (HMD) has been a cause of concern. In all, 94 children affected with inherited diseases underwent HSCT at a single center using MSD (group A, n=31), URD (group B, n=23) or HMD (group C, n=40). There was no difference in the rate of engraftment or in the incidence of grades III-IV acute graft-versus-host disease (GVHD) between the groups. Survival rate was 80.6% in group A, 62.5% in group B and 47.5% in group C (P=0.023). In group B, survival rate was 73.7% in the subgroup with zero or one class I mismatch, and 25% in the subgroup with two or more class I mismatches (P=0.04). In group C, survival rate was 83.3% in the 9/10-identical subgroup, 64.3% in the seven or 8/10 subgroup, and 25% in the five or 6/10 subgroup (P=0.0007). Thus, engraftment, incidence of GVHD and survival are similar in recipients of grafts from MSD, URD with 0-1 class I-mismatch, or HMD with at least 7/10 HLA matches. The low success of HSCT using more disparate donors suggests reserving them for patients with very poor prognosis.

Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial).

BACKGROUND: The purpose of this study was to evaluate the tolerance and efficacy of combining i.v. irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) with hepatic arterial infusion (HAI) of pirarubicin in non-resectable liver metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-one patients were included in a phase II trial with i.v. irinotecan/5-FU/LV administered every 2 weeks, combined with HAI pirarubicin 60 mg/m(2) on day 1 every 4 weeks. In most cases HAI was administered via a percutaneous catheter. RESULTS: The main grade 3/4 toxicity was neutropenia, encountered in 78% of the patients. When all patients were considered in the analysis, tumour response rate was 15 out of 31 [48%; 95% confidence interval (CI) 32% to 65%]. Liver resection was made possible in 11 patients (35%; 95% CI 21% to 53%). There were no toxic death. Median overall survival was 20.5 months, and median progression-free survival was 9.1 months. In patients with completely resected metastases, median overall survival was not reached and median progression-free survival was 20.2 months. CONCLUSION: The multimodality approach used in the present study was well-tolerated and yielded dramatic responses. An aggressive approach combining i.v. and HAI chemotherapy deserves further investigation.

Chronic intestinal graft-versus-host disease: clinical, histological and immunohistochemical analysis of 17 children.

Graft-versus-host disease (GVHD) can be acute or chronic. The pathogenesis of chronic GVHD is unclear. Chronic GVHD affects mainly skin, liver and digestive tract. Intestinal involvement is uncommon and histological features are poorly described. We report here the clinical, histological and immunohistochemical features of chronic GVHD with intestinal involvement. Intestinal biopsies from children with chronic GVHD (n=17) were compared to control children (n=21: 10 non-transplant cases, four non-GVHD transplant cases, seven acute GVHD). We evaluated clinical outcome, histological features and characterized immunohistochemically the immune cells involved locally. Chronic GVHD with intestinal involvement was usually multisystemic (88.2%) and preceded by acute GVHD in 88.2% of cases. The outcome was severe with complete recovery in only 58.8% of cases, and death related to chronic GVHD in 17.6% of cases. Histological features were characterized by (1) villous atrophy and (2) glandular lesions, mainly apoptotic with variable intensity and (3) lamina propria infiltrate with cytotoxic T lymphocytes (CD3+, CD8+, TiA1+, granzyme B-) which were significantly (P<0.001) increased compared to non-GVHD transplant and non-transplant controls. Therefore in chronic intestinal GVHD, the apoptotic process could be related to cytotoxic T lymphocytes.

The effect of menopause on the relation between weight gain and mortality among women.

OBJECTIVE: To examine the effect of menopause on the relation between weight gain and all-cause mortality. DESIGN: Prospective cohort study of 6,030 adults (ages 25-82 years) who never smoked cigarettes, had no history of coronary heart disease, cancer, or stroke, and were enrolled in a 29-year follow-up in which anthropometric data were given at baseline and at 17 years after baseline. RESULTS: Weight gain that occurred over a 17-year interval (baseline to 17 years after baseline) increased the mortality risk of men and middle-aged women, but decreased the mortality risk of older women. Further study of the women revealed that a strong protective effect of weight gains was only evident among the leanest (25 kg/m2) postmenopausal women [HR (95% CI) = 0.81 (0.41, 1.58)] or for premenopausal women [HR (95% CI) = 1.05 (0.49, 2.25) for 25 kg/m2]. We found that the protective effect of weight gain among the leanest postmenopausal women was primarily due to a more than threefold decrease in cardiovascular disease mortality risk. One possible explanation for these findings is that weight gain increases the level of adipose-tissue-derived estrogen among lean postmenopausal women. CONCLUSION: Moderate menopausal weight gain may be well tolerated in lean women.

Role of p38 MAP kinase in LPS-induced airway inflammation in the rat.

We investigated the effect of the p38 kinase inhibitor SB 203580 on airway inflammation induced by aerosolized lipopolysaccharide (LPS) in male Wistar rats. SB 203580 significantly inhibited (ED(50)=15.8 mg kg(-1)) plasma levels of TNF-alpha in rats challenged with LPS (1.5 mg kg(-1), i.p.). Aerosolized LPS induced a peak in TNF-alpha levels and the initiation of a neutrophilic response in bronchoalveolar lavage (BAL) fluid at the 2 h time point. Furthermore, the 4 h time point was associated with the peak in IL-1beta levels and the initial plateau of neutrophilia observed in the BAL fluid. SB 203580 (100 mg kg(-1)), had no effect on peak TNF-alpha levels or the associated neutrophilia in the BAL. Interestingly, the PDE 4 inhibitor RP 73401 (100 mg kg(-1)) significantly reduced both TNF-alpha levels and neutrophilic inflammation. However, the BAL fluid from rats pre-treated with either compound significantly inhibited TNF-alpha release from cultured human monocytes 18 h after LPS treatment (83.6 and 44.5% inhibition, respectively). Alternatively, SB 203580 (100 mg kg(-1)) produced dose-related inhibition of BAL IL-1beta levels (67.5% inhibition, P<0.01) and BAL neutrophilia (45.9% inhibition, P<0.01) 4 h after LPS challenge. P38 protein was present in lung tissue and the level of expression was not affected by LPS treatment. P38 kinase appears to be involved in the release of IL-1beta and the sustained neutrophilic response in the BAL fluid. This data may suggest a role for p38 inhibitors in the treatment of airway inflammatory diseases in which neutrophilia is a feature of the lung pathology.

Defective granule exocytosis in Rab27a-deficient lymphocytes from Ashen mice.

Because mutations in Rab27a have been linked to immune defects in humans, we have examined cytotoxic lymphocyte function in ashen mice, which contain a splicing mutation in Rab27a. Ashen cytotoxic T lymphocytes (CTLs) showed a >90% reduction in lytic activity on Fas-negative target cells compared with control C3H CTLs, and ashen natural killer cell activity was likewise diminished. Although their granule-mediated cytotoxicity pathway is profoundly defective, ashen CTLs displayed a normal FasL-Fas cytotoxicity pathway. The CD4/8 phenotype of ashen T cells and their proliferative responses were similar to controls. Ashen CTLs had normal levels of perforin and granzymes A and B and normal-appearing perforin-positive granules, which polarized upon interaction of the CTLs with anti-CD3-coated beads. However, rapid anti-CD3-induced granule secretion was drastically defective in both CD8(+) and CD4(+) T cells from ashen mice. This defect in exocytosis was not observed in the constitutive pathway, as T cell receptor-stimulated interferon-gamma secretion was normal. Based on these results and our demonstration that Rab27a colocalizes with granzyme B-positive granules and is undetectable in ashen CTLs, we conclude that Rab27a is required for a late step in granule exocytosis, compatible with current models of Rab protein function in vesicle docking and fusion.

Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial.

Severe T-cell immunodeficiency after solid organ or bone marrow transplantation may result in the uncontrolled outgrowth of latently Epstein-Barr virus-infected B cells, leading to B-lymphoproliferative disorder (BLPD). Given the potentially important pathogenic role of IL-6 in BLPD, it was tested whether the in vivo neutralization of IL-6 by a monoclonal anti-IL-6 antibody could contribute to the control of BLPD. Safety and efficacy were assessed in 12 recipients of transplanted organs who had BLPD refractory to the reduction of immunosuppression over 8 days. Five patients received 0.4 mg/kg per day. The next 7 patients received 0.8 mg/kg per day. Treatment was scheduled to last 15 days. It was completed in 10 patients, and in the other 2 patients was discontinued early (days 10 and 13, respectively) because of disease progression. Treatment tolerance was good, and no major side effects were observed. High C-reactive protein levels were found in 9 patients before treatment but were normalized under treatment in all patients, demonstrating efficient IL-6 neutralization. Complete remission (CR) was observed in 5 patients and partial remission (PR) in 3 patients. Relapse was observed in 1 of these 8 patients in whom remission was observed. This relapse was unresponsive to treatment. Disease was stable in 1 patient, but it progressed in 3 patients. Seven patients are alive and well. Two patients died because of disease progression, and 3 patients died while in CR (chronic rejection in 2 patients and BLPD sequelae in 1 patient). These data suggest that the anti-IL-6 antibody is safe and should be further explored in the treatment of BLPD.