Ixodes ricinus tick salivary gland extract inhibits IL-10 secretion and CD69 expression by mitogen-stimulated murine splenocytes and induces hyporesponsiveness in B lymphocytes

Tick saliva contains immunosuppressive factors allowing this blood-feeding ectoparasite to remain on hosts and enhancing pathogen transmission. In this study, we examined the modulation of mitogen-induced activation of naive murine splenocytes by the saliva and salivary gland extract (SGE) of I. ricinus ticks. We found that saliva-specific factors reduced IL-10 production by both concanavalin A (ConA) and lipopolysaccharide (LPS) stimulated splenocytes. The LPS-induced IL-10 production is 10 times more sensitive to SGE than the ConA-induced IL-10 production. Flow cytometric analysis determined that SGE particularly inhibited B (B220+) cell IL-10 production in mitogen-stimulated splenocyte preparations. Moreover, SGE reduced the early activation marker CD69 expression on ConA-activated T cells and also on B cells in presence of ConA or LPS. Annexin V and Via-probe staining demonstrated that SGE did not increase cell death in activated splenocytes and slightly decreased apoptosis in B lymphocytes. By employing assays with isolated B cells, we further showed that SGE had a direct effect on B cells and inhibited LPS-induced B cell proliferation. Taken together, our results indicate that salivary immunomodulators induce hyporesponsiveness to mitogen in both T and B cells, and that a direct B-cell inhibitory activity is present in tick saliva.     

Melorheostosis with ipsilateral nevus sebaceus (didymosis melorheosebacea)

We report an unusual case of unilateral melorheostosis and ipsilateral extensive sebaceous nevus. Because the two conditions affected the same side of the body, we hypothesize that they originated from a common genetic mechanism. The temporal and spatial co-occurrence may represent a further example of non-allelic didymosis (twin spotting). The embryo would carry two different recessive mutations at one gene locus or at linked loci on either of a pair of homologous chromosomes. Postzygotic recombination occurring during early embryonic development would result in two different populations of cells homozygous for either mutation. If this concept holds true, the present case may be described as " didymosis melorheosebacea ".     

New insights into the interactions between T-cell costimulatory blockade and conventional immunosuppressive drugs

OBJECTIVE: To determine the precise in vivo interaction between T-cell costimulatory blockade and conventional immunosuppression in transplantation. SUMMARY BACKGROUND DATA: Blocking B7 or CD154 T-cell costimulatory activation pathways prevents allograft rejection in small and large animal transplant models and is considered a promising strategy for clinical organ transplantation. METHODS: A fully MHC-mismatched vascularized mouse cardiac allograft model was used to test the interactions between anti-CD154 or CTLA4Ig monotherapy and conventional immunosuppressive drugs in promoting long-term graft acceptance. The frequency of alloreactive T cell was measured by ELISPOT. Chronic rejection was examined by histology. RESULTS: Cyclosporine, tacrolimus, and anti-IL-2R monoclonal antibody therapy abrogated the effect of a single-dose protocol of anti-CD154 therapy. In contrast, rapamycin acted synergistically with anti-CD154 therapy in promoting long-term allograft survival. The addition of calcineurin inhibitors did not abolish this synergistic effect. Intense CD154-CD40 blockade by a multiple-dose schedule of anti-CD154 resulted in long-term graft survival and profound alloreactive T-cell unresponsiveness and overcame the opposite effects of calcineurin inhibitors. CTLA4Ig induced long-term graft survival, and the effect was not affected by the concomitant use of any immunosuppressive drugs. CONCLUSIONS: The widespread view that calcineurin inhibitors abrogate the effects of T-cell costimulatory blockade should be revisited. Sufficient costimulatory blockade and synergy induced by CD154 blockade and rapamycin promote allograft tolerance and prevent chronic rejection.     

Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study

Background Modafinil is a unique wake-promoting agent that is chemically distinct from traditional stimulants. Results of a placebo-controlled study showed it to improve fatigue in multiple sclerosis (MS) at a dose of 200 mg daily, but not at a dose of 400 mg daily. Objective To establish the efficacy, safety and appropriate dose of modafinil in the treatment of fatigue and sleepiness in patients with multiple sclerosis. Method A total of 50 patients diagnosed with MS (mean age 40.4 ± 10.3 years, 30 females/20 males; MS type: 36 relapsing remitting, 1 primary progressive, 13 secondary progressive; mean disability level 3.8 ± 1.5 on the Kurtzke EDSS) and complaining of chronic fatigue were enrolled in a prospective 3-month, two-center, open-label study. Efficacy was evaluated with the Fatigue Severity Scale (FSS, score range 0-42), the Epworth Sleepiness Scale (ESS, score range 0-24) and by subjective patient appraisal of change of fatigue, quality of life and overall satisfaction with treatment. Adverse effects (AEs) were recorded throughout the study. Treatment was started with a single daily dose of 100 mg in all patients. In non-responders the dose was increased by 100 mg increments up to a maximum daily dose of 400 mg. Results Three patients discontinued modafinil because of AEs (nervousness, dizziness). Two patients (4 %) were treated with 50 mg, 25 (50 %) with 100 mg, 21 (42 %) with 200 mg and 2 (4 %) with 300 mg daily. No patient required 400 mg daily. Mean FSS scores were 30.3 ± 8.5 at baseline and 25.4 ± 3.7 at 3 months (p < 0.0001). Mean ESS scores were 9.7 ± 3.9 at baseline and 4.9 ± 2.9 at 3 months (p < 0.0001). Self-appraisal of change of fatigue showed clear improvement in 41 patients (87.2 %), some improvement in 4 (8.5 %) and no change in 2 (4.3 %). Overall clinical condition was clearly improved in 43 patients (91.5 %), somewhat improved in 1 patient (2.1 %), and unchanged in 3 patients (6.4 %). No patient reported worsening of overall clinical condition. Conclusions Treatment with modafinil significantly improves fatigue and sleepiness and is well tolerated by patients with MS. Unlike the higher dose regimen required in narcolepsy, a low-dose regimen of modafinil is effective in MS. Received: 10 August 2001 Received in revised form: 22 January 2002 Accepted: 25 January 2002     

Exogenous psychosis induced by cobalamin-deficiency

The case of a 69 years old female patient is reported, who developed paranoid behaviour due to cobalamin-deficiency without megaloblastosis based on a chronic gastric atrophy. The psychosis showed complete remission after vitamin B 12 supplementation. The discussion leads to the question, whether or not chronic use of tricyclic antidepressants may be one cause of atrophic gastritis. Furthermore, differentialdiagnostic reflections consider the role of cobalamine and folate in the synthesis of monoamine neurotransmitters in the brain.     

Clinical comparison of the efficacy and tolerability of once daily Canesten with twice daily Nizoral (clotrimazole 1% cream vs. ketoconazole 2% cream) during a 28-day topical treatment of interdigital tinea pedis

The effects of two topical cream formulations containing clotrimazole 1% and ketoconazole 2%, respectively, were clinically compared in a double-blind, randomized manner for a 28-day therapy of interdigital tinea pedis in 106 treated patients. Ketoconazole was to be used twice daily whereas clotrimazole was administered only once daily. The primary response criterion defined as the number of patients with cure or improvement after 28 treatment days was comparable with 62.0% vs. 64.0% (clotrimazole vs. ketoconazole) for the full analysis set of 100 (50 vs. 50) patients. The mycological response revealed a negative culture and microscopy in 53.1% vs. 52.1% of the patients after 14, in 76.0% vs. 79.2% after 28, and in 83.7% vs. 76.9% after 56 days of observation, indicating a possibly better long-term efficacy of clotrimazole. The development of the overall score of tinea-related signs and symptoms did not show relevant differences between the two drugs and continuously decreased from 11+/-5 in both groups at baseline to 2+/-2 vs. 2+/-1 at day 56. As to the remission and improvement rates of single symptoms, better results were obtained under clotrimazole than under ketoconazole particularly for pruritus (97.8 vs. 89.6%) and burning/stinging (97.5 vs. 89.4%) which both are perceived as most bothersome by the patients. Furthermore, both substances appeared as comparably safe and well tolerable (8 vs. 7 adverse events with only 1 vs. 3 drug related). In conclusion, a successful therapy of tinea pedis can be achieved with both clotrimazole and ketoconazole within 28 days of treatment and once-daily clotrimazole is equally effective as twice-daily ketoconazole with favourable influences on the most irritating symptoms of the disease. Mycological and reliable clinical cure cannot be observed during two weeks after start of treatment.     

Round-table-talk on patient education in rheumatology

Primarily the discussion group focused on obtaining current information about the existing patient education programs for different rheumatic diseases developed by a working group of the German Society of Rheumatology, about the institutions running the patient education courses, the train-the-trainer seminars, the costs and the problems of fund raising from the health insurance companies. As a successful example for running patient education courses in an outpatient setting, the cooperation between the Arthritis Center of Hannover and the League against Rheumatism in Lower Saxony was illustrated. Then the group defined three important future tasks: to reach a standard of funding patient education by every health insurance company in Germany, to increase the efforts to inform the public about patient education and to establish a nation-wide network of patient education centers. A meeting of all Collaborative Arthritis Centers in Germany was proposed to discuss the necessary steps to reach these aims.     

Sleep loss and fatigue in residency training: a reappraisal

Reduced sleep time is commonplace for many interns and residents. Recent studies, however, suggest that sleep loss and fatigue result in significant neurobehavioral impairments in healthy young adults. We reviewed studies addressing the effects of sleep loss on cognition, performance, and health in surgical and nonsurgical residents. We describe the effectiveness of countermeasures for sleepiness, including recent work-hour restrictions. A more complete understanding of the issues of sleep loss during residency training can inform innovative strategies to minimize the effects of sleepiness and fatigue on patient care and resident safety.      

Ifosfamide-induced subclinical nephrotoxicity and its potentiation by cisplatinum

Renal function was assessed in 72 children and adolescents 3.5 to 123 months after completion of chemotherapy employing ifosfamide (n = 39) or ifosfamide plus cisplatinum (n = 33). No patient had preexisting renal parenchymal disease. Whereas reduction in glomerular filtration rate was present in six of 69 patients (8.7%), impairment of tubular transport for phosphate, glucose, and amino acids was more frequent: 32.8% of the patients showed reduction in phosphate reabsorption, and glucose and amino acid reabsorption was lowered in 16.4% and 55.0%, respectively. Elevated sodium excretion was found only occasionally, and there was no evidence of renal tubular acidosis. Proximal tubular damage is related to ifosfamide chemotherapy, but correlation between ifosfamide dose and phosphate reabsorption was not linear. The most severe depletion of phosphate reabsorption was seen in patients treated with both ifosfamide and cisplatinum. On reexamination of phosphate reabsorption after a median interval of 8 months, the majority of patients with initially reduced values showed further deterioration of this function. © 1994 Wiley-Liss, Inc.