Limiting factors of the anaphylatoxin forming system in plasma from different species

Summary Plasma or serum of various species which do not yield directly measurable amounts of anaphylatoxin (AT) has been investigated with respect to the presence of the anaphylatoxin-forming enzyme (system), anaphylatoxinogen, and the co-factor (PI) which is necessary for the anaphylatoxin-forming enzyme of cobra venom to form anaphylatoxin.The anaphylatoxin-forming enzyme was found in plasma (serum) from man, horse, cow, sheep, pig, dog, cat, rabbit, rat, fowl, and eel. Only in frog plasma could it not be detected. Except for horse and rabbit plasma, it was regularly activated by Sephadex or zymosan. In rabbit plasma Sephadex was inactive and in horse plasma both polysaccharides often failed to activate the formation of AT. Immune precipitates caused activation in horse plasma.The substrate, anaphylatoxinogen was the limiting factor in all species mentioned. After addition of anaphylatoxinogen solutions the plasma of all species formed AT upon activation by contact. The reason for the failure of most mammalian plasmas to show AT activity after contact activation is thus lack of sufficient substrate, not inactivation of AT actually formed.Our thanks are due to Miss Gisa Schmidt for assistance and preparation of serum fractions.     

Serological status: a predictor of response to intensive therapy in rheumatoid arthritis

BackgroundRheumatoid arthritis is the most common chronic inflammatory disease in the UK. Serological status such as rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA) positivity predict poor outcomes. Early intensive treatment regimens targeting remission reduce disease activity, structural damage, and long-term disability. However, we do not know whether all patients with active disease should have such intensive treatment regimens. Can serological status be used to predict the need for intensive therapy?MethodsWe analysed samples from a published randomised controlled trial which compared four treatment regimens in patients with early active rheumatoid arthritis (disease duration <2 years): methotrexate monotherapy, double therapy (methotrexate plus either ciclosporin or prednisolone), and triple therapy (methotrexate plus ciclosporin plus prednisolone). The trial randomised 467 patients (68% female, median age 54 years [IQR 46–63]). Disease activity was assessed with the disease activity score of 28 joints (DAS28). Remission was defined as DAS28 less than 2·6 at 24 months. RF isotypes (IgM and IgA) and ACPA levels were measured with commercial ELISA kits. Statistical analysis used Pearson's chi-squared test.Findings402 (86%) patients were positive for IgM RF, 346 (74%) for IgA RF, and 346 (74%) for ACPA. 98 (21%) patients achieved remission at 24 months. In RF IgM negative cases (n=65) the proportion of patients achieving remission at 24 months was similar in all treatment groups (25%, 22%, and 30% for monotherapy, double therapy, and triple therapy, respectively). In RF IgM positive cases, significantly fewer patients achieved remission with monotherapy (13/65, 17%) and double therapy (24/157, 15%) than with triple therapy (27/80, 34%) (p=0·001). There were similar, consistent findings with IgA RF and ACPA, with significantly more seropositive patients achieving remission with triple therapy than with monotherapy.InterpretationContemporary treatment of rheumatoid arthritis emphasises the use of intensive therapy to achieve remission. However, we have shown that not all patients require such an aggressive approach to therapy. Given the heterogeneity of the diease, treatment should be personalised to the individual, which would minimise costs of treatment as well as potentially toxic side-effects. Our study shows that only seropositive patients with rheumatoid arthritis should be given more intensive therapies.FundingNational Institute for Health Research.     

Germline <Emphasis Type="Italic">MUTYH</Emphasis> gene mutations are not frequently found in unselected patients with papillary breast carcinoma

MUTYH- associated polyposis (MAP) is an autosomal recessive disease, which predisposes to polyposis and colorectal cancer. There is a trend towards an increased risk of breast cancer in MAP patients, with a remarkable proportion of papillary breast cancers. To determine whether MUTYH mutations are associated with this specific and rare type of breast cancer, 53 unselected patients with papillary breast cancer were analyzed for founder mutations in the MUTYH gene. No germline mutations were identified, indicating that biallelic MUTYH mutations are not a frequent underlying cause for the development of papillary carcinomas of the breast.     

Germline MUTYH gene mutations are not frequently found in unselected patients with papillary breast carcinoma

MUTYH-associated polyposis (MAP) is an autosomal recessive disease, which predisposes to polyposis and colorectal cancer. There is a trend towards an increased risk of breast cancer in MAP patients, with a remarkable proportion of papillary breast cancers. To determine whether MUTYH mutations are associated with this specific and rare type of breast cancer, 53 unselected patients with papillary breast cancer were analyzed for founder mutations in the MUTYH gene. No germline mutations were identified, indicating that biallelic MUTYH mutations are not a frequent underlying cause for the development of papillary carcinomas of the breast.     

Anti-GBM nephritis in the mouse: severe proteinuria in the heterologous phase

Summary Highly reproducible anti glomerular basement membrane (GBM) nephritis has been induced in the mouse after a single injection of rabbit or goat antibody against purified homologous GBM. The severity of albuminuria was closely related to the amount of antibody given. With doses of 4 mg or more, low serum albumin concentrations, sometimes accompanied by ascites and oedema, were observed after 1 week. Glomerular injury was characterized by an initial accumulation of polymorphonuclear granulocytes followed by thrombosis and necrosis, the extent of which defined the outcome of the glomerulonephritis. With high doses of antibody the exudative lesions entered a chronic phase, while at doses lower than 2 mg remission of the lesions occurred. Immunofluorescence studies showed prompt linear fixation of the injected anti-bodies to the glomerular capillary wall, accompanied by immediate binding of C3 in a fine granular pattern. Fibrin deposits appeared at 2 h in some glomeruli, increased thereafter, and were present after one day in more than 90% of the glomeruli in mice that had received 4 mg of antibody. This new reproducible model in the mouse is suited for the study of the relationship between activation of mediator systems, histological lesions, and proteinuria.     

Psychiatric disorders,acne and systemic retinoids: comparison of risks

Background: The link between isotretinoin, treatment of a severe form of acne, and psychiatric disorders remains controversial, as acne itself could explain the occurrence of psychiatric disorders. This study aims at assessing the disproportionality of psychiatric adverse events reported with isotretinoin in the French National PharmacoVigilance Database, compared with other systemic acne treatments and systemic retinoids.

Materials and methods: Data were extracted from the French National PharmacoVigilance Database for systemic acne treatments, systemic retinoids and drugs used as comparators. Each report was subjected to double-blind analysis by two psychiatric experts. A disproportionality analysis was performed, calculating the number of psychiatric ADRs divided by the total number of notifications for each drug of interest.

Results: Concerning acne systemic treatments: all 71 reports of severe psychiatric disorders involved isotretinoin, the highest proportion of mild/moderate psychiatric adverse events was reported with isotretinoin (14.1%). Among systemic retinoids, the highest proportion of severe and mild/moderate psychiatric events occurred with isotretinoin and alitretinoin.

Conclusion: Our study raises the hypothesis that psychiatric disorders associated with isotretinoin are related to a class effect of retinoids, as a signal emerges for alitretinoin. Complementary studies are necessary to estimate the risk and further determine at-risk populations.     

Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion

Chronic rejection accounts for most renal allograft losses after the first year posttransplantation. On March 24 and 25, 1997, a roundtable of five transplant surgeons, two nephrologists, and one pathologist assembled in Dallas, Texas, to review critical issues surrounding chronic renal allograft rejection. This article summarizes the presentations and relevant discussions of this meeting regarding the cause of chronic rejection, clinical diagnoses, risk factors, future prospects for intervention strategies, and general recommendations for the transplant community. Growing evidence indicates that chronic rejection is the aggregate sum of irreversible immunologic and nonimmunologic injuries to the renal graft over time. A history of acute rejection episodes and inadequate immunosuppression, likely attributable to inconsistent cyclosporine exposure or poor patient compliance, are among the most recognizable immunologic risk factors for chronic rejection. Donor organ quality, delayed graft function, and other donor and recipient variables leading to reduced nephron mass are nonimmunologic factors that contribute to the progressive deterioration of renal graft function. Clinical management of renal transplant recipients should incorporate both immunologic- and nonimmunologic-based intervention strategies aimed at minimizing risk factors to thwart the progression of chronic rejection and improve long-term allograft and patient survival.     

Sutured point-fixation versus Jaboulay fixation for salvaged testicular torsion in children

BackgroundSurgical techniques for fixation of the testis are varied and subject to ongoing debate. Non-sutured techniques may avoid the theoretical morbidities of sutured fixation of the testis yet are criticized for insufficient prophylaxis against future torsion. This study aims to compare outcomes between sutured (point-fixation) versus Jaboulay fixation.MethodsEmergency scrotal explorations performed at a tertiary hospital in the state of South Australia between February 2002 and December 2017 were analyzed to identify cases of testicular torsion. Primary outcome measures included future testicular torsions and return to theater episodes following initial testicular fixation. Secondary outcome measures included re-presentations and post-operative complications.ResultsA total of 482 scrotal compartments were explored in 244 boys with acute testicular torsion. Testis fixation was performed using sutured point-fixation in 58.4% and Jaboulay tunica plication in 41.6%. No future testicular torsion occurred regardless of fixation technique. There were no significant differences in returns to theater (0.4% versus 1.2%, p = 0.12), re-presentations (6.9% versus 6.0%, p = 0.83), and post-operative complications (1.7% versus 1.8%, p = 1.0) in testes that previously underwent sutured or Jaboulay fixation, respectively.ConclusionJaboulay testicular fixation techniques are comparable with sutured point-fixation techniques in effectiveness and morbidity.Type of StudyTreatment Study.Level of EvidenceLevel III.