CCI-779 plus cisplatin is highly effective against human melanoma in a SCID mouse xenotranplantation model.

BACKGROUND: This study set out to investigate the antitumor effects of a treatment strategy combining the mTOR inhibitor CCI-779 with cisplatin in vitro and in a human melanoma SCID mouse model. METHODS: In vitro 518A2, Mel-JUSO or 607B cell lines were incubated with CCI-779, cisplatin and CCI-779 plus cisplatin. Based on these results, a 4-group, parallel, controlled experimental study design was initiated in vivo. SCID mice were injected with melanoma cells, and after the development of tumors the mice received daily injections of CCI-779 or solvent. On treatment days 2 and 6 cisplatin or mock solution were administered. RESULTS: In vitro a synergistic antitumor effect was observed for the treatment regimen of CCI-779 plus cisplatin. In SCID mice after 2 weeks of therapy with CCI-779 plus cisplatin 4 of 6 tumors of the 518A2 cell line were completely eradicated. In the two remaining 518A2 xenografts this treatment strategy reduced the tumor weight by 94 +/- 9% compared to solvent. CCI-779 plus cisplatin also exerted a significant antitumor effect in Mel-JUSO and 607B xenografts compared to mock-treated animals. CONCLUSION: We provide circumstantial evidence that the use of CCI-779 plus cisplatin might qualify as a promising strategy in the treatment of human melanoma.

Isolation and polymerase chain reaction typing of Borrelia afzelii from a skin lesion in a seronegative patient with generalized ulcerating bullous lichen sclerosus et atrophicus.

A 64-year-old woman presented with bullous and ulcerating lichen sclerosus et atrophicus (LSA) on the neck, trunk, genital and perigenital area and the extremities. Histology of lesional skin showed the typical manifestations of LSA; in one of the biopsies spirochaetes were detected by silver staining. Despite treatment with four courses of ceftriaxone with or without methylprednisone for up to 20 days, progression of LSA was only stopped for a maximum of 1 year. Spirochaetes were isolated from skin cultures obtained from enlarging LSA lesions. These spirochaetes were identified as Borrelia afzelii by sodium dodecyl sulphate--polyacrylamide gel electrophoresis and polymerase chain reaction (PCR) analyses. However, serology for B. burgdorferi sensu lato was repeatedly negative. After one further 28-day course of ceftriaxone the lesions stopped expanding and sclerosis of the skin was diminished. At this time cultures for spirochaetes and PCR of lesional skin for B. afzelii DNA remained negative. These findings suggest a pathogenetic role for B. afzelii in the development of LSA and a beneficial effect of appropriate antibiotic treatment.

Cardiovascular autonomic function, autoantibodies, and esophageal motor activity in patients with systemic sclerosis and mixed connective tissue disease.

OBJECTIVE: To study cardiovascular autonomic nerve function and presence of autoantibodies in relation to esophageal motor activity in patients with systemic sclerosis (SSc) and mixed connective tissue disease (MCTD). METHODS: Twenty-five patients with SSc (13 limited, 12 diffuse cutaneous disease; disease duration 1-19 yrs) and 6 patients with MCTD (disease duration 1-10 yrs) were studied. Cardiovascular autonomic function was assessed using 5 standard tests and autoantibody status determined. Esophageal motor activity and lower and upper esophageal sphincter pressures were recorded manometrically. RESULTS: Five patients with SSc had definite, 7 borderline, and 13 no autonomic dysfunction; 23 had antinuclear. 9 anti-Sc170, 4 anticentromere, and 1 U1snRNP antibodies. Contraction amplitudes in the smooth muscle as well as the striated muscle esophagus and lower esophageal sphincter pressures were significantly lower and autonomic dysfunction more frequent in patients with than in those without anti-Sc170 (6 of 9 vs 6 of 16 patients); upper esophageal sphincter pressures did not differ. All patients with MCTD had antinuclear antibodies, 5 had definite autonomic dysfunction; their lower esophageal sphincter pressures were significantly lower than in SSc patients without anti-Sc170 and anti-U1snRNP. CONCLUSION: Esophageal motor dysfunction may be associated with the presence of anti-Sc170 and anti-U1snRNP autoantibodies and prevail in patients with cardiovascular autonomic neuropathy.

Isolation of Borrelia afzelii from circumscribed scleroderma.

A 45-year-old man presented with circumscribed scleroderma (CS) on the extremities. Histology of lesional skin showed the typical manifestations of scleroderma including a perivascular and interstitial infiltrate of lymphocytes and plasma cells; in one of the biopsies spirochaetes could be detected. Despite treatment with penicillin, progression of CS was observed and spirochaetes were isolated from skin cultures obtained from active scleroderma lesions. These spirochaetes were identified as Borrelia afzelii by sodium dodecyl sulphate-polyacrylamide gel electrophoresis of outer surface proteins and polymerase chain reaction (PCR) analysis of their chromosome. After two courses with ceftriaxone the lesions stopped expanding and sclerosis of the skin was diminished. At this time cultures for spirochaetes and PCR of lesional skin for Borrelia afzelii DNA remained negative. The pathogenetic role of Borrelia afzelii in the development of CS is discussed.

Assessment of pain in herpes zoster: lessons learned from antiviral trials.

Pain typically accompanies acute herpes zoster and, in a proportion of patients, it persists well beyond rash healing. Pain must therefore be analyzed in trials of antiviral agents in herpes zoster, but different methods have been used to analyze pain in recent published trials. These reports are reviewed and their methodological strengths and weaknesses examined. Based on this review, recommendations for the design and analysis of future trials of antiviral agents in herpes zoster are proposed. The principal recommendation is that antiviral efficacy should be evaluated both by distinguishing post-herpetic neuralgia from acute pain and by considering pain as a continuum. The primary endpoint should address both the prevalence and duration of post-herpetic neuralgia and should be examined in those patients who have post-herpetic neuralgia. Adopting the proposed recommendations in design and analysis of future trials should facilitate comparison across trials of the efficacy of antiviral agents in the treatment of herpes zoster.

[Familial lupus erythematosus with partial C4 deficiency]. / Familiärer Lupus erythematodes bei partiellem C4-Mangel.

A report is presented of a family with selective partial C4-deficiency in 3 members, two of whom suffer from systemic lupus erythematosus (SLE). C4-allotyping showed the presence of one "silent gene" for the C4B-locus (C4BQO) in these three cases. Presumably it is not the reduced C4-content per se that plays the essential role in the pathogenesis of familial SLE, but the combination of the C4BQO-allele with the HLA-DR2, which was also present in all three affected persons. However, it is of practical relevance that strikingly low C4-levels in comparison with the C3-levels in patients with early onset of SLE should initiate an investigation of the whole family. Furthermore, the C4-level in this form of familial SLE is not a suitable parameter for ganging disease activity on follow-up control investigations.

Necrobiosis lipoidica: treatment with systemic corticosteroids.

In an attempt to find an effective therapy for necrobiosis lipoidica, we have treated six patients with this disease with a 5-week course of systemic corticosteroids. This treatment resulted in complete cessation of disease activity in all patients and no recurrence in a mean follow-up period of 7 months; however, restitution of atrophic skin lesions could not be achieved. The therapy was well tolerated and did not pose problems, even in diabetic patients. These results strongly suggest that short-course therapy of necrobiosis lipoidica with corticosteroids is of lasting benefit to these patients and should probably be considered early in the course of their skin disease.

Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis.

BACKGROUND: Mesna is used to abolish urotoxicity of cyclophosphamide and related compounds in immunosuppressive and antineoplastic treatment schedules. Adverse reactions to this drug have been reported only rarely. OBSERVATIONS: Drug eruptions to mesna have developed in seven of 15 patients with autoimmune disorders treated with monthly pulses of intravenous cyclophosphamide. Two different types of drug eruptions were observed: five patients had development of a macular and partly papular or urticarial rash and angioedema and two patients had a generalized fixed drug eruption, primarily and predominantly at the sites of previous skin lesions of their underlying condition. The results of prick, patch, and intradermal tests were similar in both types of rash; however, the two patients with fixed drug eruption had developed a generalized eruption upon prick testing with mesna. CONCLUSIONS: Two distinct eruptions to mesna have been induced in these patients during cyclophosphamide/corticosteroid therapy; these eruptions are not thought to share a common pathogenic mechanism. The results of skin and challenge tests do not support the hypothesis that a type 1 or a type 4 immune reaction may be responsible for these eruptions. The unusually high incidence (about 50%) of these reactions and their clinical presentation make it important to distinguish them from an exacerbation of the preexistent autoimmune disorder.

[Allergy to topical antihistamines--discrepancy between the literature and clinical practice]. / Allergie gegen topische Antihistaminika--Diskrepanz zwischen Literatur und Praxis.

In a prospective study, 100 patients suffering from allergic contact dermatitis were tested for allergy to antihistamines. Diphenhydramine was chosen as test substance because it is the most widely used topical antihistamine in Europe and is, moreover, prescribed for several indications. Not one of the 100 patients proved to react positively on patch testing. The bad reputation among allergists of topically administered antihistamines, which is based on reports in the American literature claiming a high risk of epicutaneous sensitization, thus appears unjustified on the basis of our own data and the lack of European reports of this problem. The adverse findings in the USA may be due to their frequent use of a particularly potent contact sensitizer as emulsifier in topical preparations in general and antihistamines in particular.

[Toxoplasma infection in dermatomyositis]. / Toxoplasmoseinfektion bei Dermatomyositis.

A 31-year-old woman with long-standing amyopathic dermatomyositis developed a maculopapular rash resembling erythema multiforme in some areas, accompanied by lymphadenopathy and malaise. An acute infection with Toxoplasma gondii was found to be the cause of clinical symptoms that mimicked an exacerbation of the underlying condition.

[Acquired epidermolysis bullosa. A clinico-pathologic study]. / Epidermolysis bullosa acquisita. Eine klinisch-pathologische Studie.

Epidermolysis bullosa acquisita is an immunologically mediated mechano-bullous dermatosis presenting with a variety of clinical appearances. In mild cases the skin lesions, serous blisters, erosions and scars are restricted to the extremities. Scarring alopecia, dystrophy and even loss of nails as well as extensive erosions of mucous membranes may complicate severe cases. The characteristic histopathological feature is a subepidermal blister, which is located within the dermis by electron microscopy. Linear deposits of IgG and C3 along the basement membrane zone have been found on the dermal side of the lamina densa by immunoelectron microscopy. This close anatomical relationship with anchoring fibrils strongly suggests a functional disturbance of these anatomical structures, leading to dermolytic blistering. Treatment with sulphones, in combination with cortico-steroids in the more severe cases, has resulted in long-term improvement in two of our three patients.

Inherited deficiency of the fourth component of human complement.

The highly polymorphic fourth component of human complement (C4) is usually encoded by two genes, C4A and C4B, adjacent to the 21-hydroxylase (21-OH) genes, and is also remarkable by the high frequency of the null alleles, C4A*Q0 and C4B*Q0. Despite considerable structural homology, the gene products of the two loci differ in hemolytic activities, antigenic reactivities and covalent binding affinities to antigens and antibodies. Complete C4 deficiency is exceptional because this condition appears only in homozygotes for the very rare double-null haplotype C4AQ0,BQ0. In contrast, partial C4 deficiency is a common immune protein defect in all human populations as a consequence of the high frequency of the C4 half-null haplotypes. Complete C4 deficiency in most cases gives rise to SLE and an increased susceptibility to infections, and partial C4 deficiencies predispose to different auto-immune diseases related to extended HLA haplotypes bearing the C4 half-null haplotypes. Studies at the DNA level have shown that about half of the null alleles are due to deletions involving C4A and 21-OHA, C4B and 21-OHA or C4B and 21-OHB. Larger deletions including both C4A and C4B genes have never been observed. Partial C4 deficiency may be observed in combination with other complement deficiencies or immune defects, and allo- or auto-anti-C4 immunization is also a possible consequence of this genetic abnormality. Although the pathogenesis of the diseases related to complete and partial C4 deficiencies is not yet clearly understood, it is evident that C4 null alleles represent interesting markers and additive risk factors for autoimmune phenomena.

Detection of disease-specific restriction fragment length polymorphisms in pemphigus vulgaris linked to the DQw1 and DQw3 alleles of the HLA-D region.

Pemphigus vulgaris in Israeli Ashkenazi and non-Ashkenazi Jews and in Austrian non-Jewish patients is strongly associated with the DR4 and DRw6 alleles of the HLA-D region class II genes. Restriction fragment length polymorphism analysis was undertaken with DQ beta, DQ alpha, and DR beta cDNA probes. Hybridization with the DQ beta probe identifies Pvu II, BamHI, and EcoRV fragments that absolutely discriminate pemphigus vulgaris patients from healthy DR-, DQ-, and ethnic-matched controls. In contrast the DQ alpha and DR beta probes failed to identify disease-specific restriction fragment length polymorphism fragments. These studies indicate that DQw1 and DQw3 polymorphisms carried by pemphigus vulgaris patients may be directly involved in predisposition to the disease or may be tightly linked to the susceptibility gene itself. To our knowledge, this is the first example of an HLA restriction fragment length polymorphism that is highly associated with susceptibility to autoimmune disease.

[South African tick bite fever]. / Südafrikanisches Zeckenbissfieber.

Two male patients developed South African tick bite fever after visits to South Africa. The clinical and laboratory findings in this condition, which is rarely seen in central Europe, are presented and its differential diagnosis to other rickettsial diseases is discussed.

Genetic deficiency of C4, C2 or C1q and lupus syndromes. Association with anti-Ro (SS-A) antibodies.

Sera from 15 patients with genetically determined complement component deficiencies were studied for the presence of antibodies to various nuclear antigens. One of three patients with C2 deficiency presented with systemic lupus erythematosus (SLE); all eight patients with C4 deficiency had either SLE or a lupus-like syndrome, and two of four patients with functional C1q deficiency had SLE. Five of nine complement deficiency patients with SLE studied had measurable antinuclear antibody titres, but only two had antibodies against native DNA. Precipitating antibodies against extractable nuclear antigens were found in sera from seven of the 11 complement deficient patients with SLE; one had only antibodies against antigens extracted from calf thymus (ECT), six patients (one with C2 deficiency, four with C4 deficiency and one with C1q deficiency) had anti-Ro (SS-A) antibodies with or without anti-ECT antibodies. The frequency of anti-Ro antibodies in the complement deficient population with SLE (55%) was significantly higher (P less than 0.02) than that of a control population of SLE patients without genetically determined complement deficiencies (27%).

[Systemic lupus erythematosus in hereditary complement 4 deficiency]. / Systemischer Lupus erythematodes bei hereditärer Defizienz der vierten Komplementkomponente.

A genetically determined complete absence of the fourth component of complement, C4, associated with systemic lupus erythematosus has been detected in one member of another family. Observations made in this patient, the ninth described so far in whom systemic lupus erythematosus and C4 deficiency occur have confirmed that this condition presents with a characteristic clinical picture: there is pronounced sensitivity to sunlight and to cold with Raynaud's phenomenon; skin lesions are found predominantly in locations typical for subacute cutaneous lupus erythematosus and, remarkably, on the palms and soles. As was the case in two families described earlier, the C4-deficient gene was associated with the HLA-haplotype AW30, B18, DR7; BfS1.