Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate.

BACKGROUND: Hereditary angioedema (HAE) due to C1 inhibitor deficiency manifests as recurrent swelling attacks that can be disabling and sometimes fatal. Long-term prophylaxis with twice-weekly intravenous injections of plasma-derived C1-inhibitor (pdC1-INH) has been established as an effective treatment. Subcutaneous (SC) administration of pdC1-INH has not been studied in patients with HAE. METHODS: This open-label, dose-ranging, crossover study (COMPACT Phase II) was conducted in 18 patients with type I or II HAE who received two of twice-weekly 1500, 3000, or 6000 IU SC doses of highly concentrated volume-reduced CSL830 for 4 weeks each. The mean trough plasma levels of C1-INH functional activity, C1-INH and C4 antigen levels during Week 4, and overall safety and tolerability were evaluated. The primary outcome was model-derived steady-state trough C1-INH functional activity. RESULTS: After SC CSL830 administration, a dose-dependent increase in trough functional C1-INH activity was observed. C1-INH and C4 levels both increased. The two highest dose groups (3000 and 6000 IU) achieved constant C1-INH activity levels above 40% values, a threshold that was assumed to provide clinical protection against angioedema attacks. Compared with intravenous injection, pdC1-INH SC injection with CSL830 showed a lower peak-to-trough ratio and more consistent exposures. All doses were well tolerated. Mild-to-moderate local site reactions were noted with pain and swelling being the most common adverse event. CONCLUSIONS: Subcutaneous volume-reduced CSL830 was well tolerated and led to a dose-dependent increase in physiologically relevant functional C1-INH plasma levels. A clinical outcome study of SC CSL830 in patients with HAE warrants further investigation.

Risk factors for mediastinitis following cardiac surgery: the importance of managing obesity.

BACKGROUND: Mediastinitis is a devastating complication of cardiac surgery. Previous studies have often observed small populations, been retrospective in design, and used a variety of definitions for mediastinitis. AIM: To identify risk factors for mediastinitis, and strategies to minimize its incidence. METHODS: A prospective cohort study of 4883 adult patients who underwent cardiac surgery between October 2003 and February 2009, comparing pre- and peri-operative risk factors, microbial aetiology, requirement for re-admission, length of stay and mortality between patients with and without mediastinitis. FINDINGS: Ninety (1.8%) patients were diagnosed with mediastinitis. Microbial aetiology was defined for 75 patients. Staphlyocococcus aureus was the most common isolate (30 episodes; 15 due to meticillin-resistant S. aureus). Univariate analysis revealed the following pre-operative factors associated with mediastinitis: age; body mass index; diabetes; modified logistic European System for Cardiac Operative Risk Evaluation score; urgent admission; and longer pre-operative stay (P < 0.05). Associated peri-operative factors were: combined coronary artery bypass grafting plus aortic valve replacement; longer aortic cross-clamp time; and longer cardiopulmonary bypass time (P < 0.005). Multi-variate analysis revealed that higher body mass index, combined coronary artery bypass grafting plus aortic valve replacement, and older age were associated with mediastinitis (P < 0.05). Mediastinitis was associated with re-admission to hospital, longer inpatient stay and reduced long-term survival (P < 0.05). CONCLUSION: Mediastinitis is associated with worse short-term outcomes (re-admission, length of stay) and reduced long-term survival. Obesity is the only modifiable pre-operative risk factor for mediastinitis. It may be possible to reduce risk through pre-operative weight loss programmes before elective surgery.

Sensitizing undergraduate medical students to consultation skills: A pilot study.

BACKGROUND: Good consultation skills help physicians to diagnose the problems of the patient more accurately, and foster a therapeutic relationship. We describe a pilot study that used role-play with peers as a method to sensitize first clinical year medical students to consultation skills Methods. Students were divided into groups of three where one acted as a doctor, the second as a patient and the third as an observer. Students were asked to perform a role-play of a prepared clinical scenario where the patient had a hidden fear of malignancy. Observations were recorded in a simplified Calgary-Cambridge consultation checklist. Students' feedback and their emotions written after the role-play were analysed and discussed. Assessment of their learning was done with an objective structured clinical examination. RESULTS: Students' feedback revealed that they were sensitized to the importance of starting the consultation with an open question, listening to the opening statement, non-verbal.

Study of methyl transferase (G9aMT) and methylated histone (H3-K9) expressions in unexplained recurrent spontaneous abortion (URSA) and normal early pregnancy.

We investigated the expression of methyl transferase G9a and methylated histone H3-K9 in fresh human decidual/endometrial tissue of 12 normal early pregnancies and 15 unexplained recurrent spontaneous abortions (URSA). The samples were obtained through dilatation and curettage and collected as per strict inclusion-exclusion criteria. The tissue was subjected to immunohistochemical analysis (IHC), western blotting (WB) and RT-PCR analysis. The results demonstrated methyl transferase G9a to have a lower expression in abortions when compared with that in normal pregnancy (P < 0.05). The sensitivity of RT-PCR, IHC and WB were respectively 66.67, 75 and 71.43%, while specificity of the same were 66.67, 60 and 78.92%, respectively. Methylated histone H3-K9 was significantly lower (P < 0.0001) in URSA tissues than in controls. This study suggests that methylation may cause URSA and indicates the need for further work to explore the role of methylation in URSA and its possible prevention through locally acting methylating/demethylating agents.

Persistent Müllerian duct syndrome with transverse testicular ectopia presenting as an incarcerated inguinal hernia.

The presence of both of the testes in one scrotal sac is one of the very rare presentations of testicular ectopia, which is known as transverse testicular ectopia (TTE) and is also known as crossed testicular ectopia. The presence of the uterus and fallopian tubes in a normally virilized male is termed as persistent Müllerian duct syndrome (PMDS). We report a case of an adult male who had a unique combination of both TTE and PMDS presenting as an incarcerated inguinal hernia.

Neutralizing human monoclonal antibodies to conformational epitopes of human T-cell lymphotropic virus type 1 and 2 gp46.

Ten human monoclonal antibodies derived from peripheral B cells of a patient with human T-cell lymphotropic virus (HTLV)-associated myelopathy are described. One monoclonal antibody recognized a linear epitope within the carboxy-terminal 43 amino acids of HTLV gp21, and two monoclonal antibodies recognized linear epitopes within HTLV type 1 (HTLV-1) gp46. The remaining seven monoclonal antibodies recognized denaturation-sensitive epitopes within HTLV-1 gp46 that were expressed on the surfaces of infected cells. Two of these antibodies also bound to viable HTLV-2 infected cells and immunoprecipitated HTLV-2 gp46. Virus neutralization was determined by syncytium inhibition assays. Eight monoclonal antibodies, including all seven that recognized denaturation-sensitive epitopes within HTLV-1 gp46, possessed significant virus neutralization activity. By competitive inhibition analysis it was determined that these antibodies recognized at least four distinct conformational epitopes within HTLV-1 gp46. These findings indicate the importance of conformational epitopes within HTLV-1 gp46 in mediating a neutralizing antibody response to HTLV infection.

Metallothionein induction and deinduction in human prostatic carcinoma cells: relationship with resistance and sensitivity to adriamycin.

Human prostate carcinoma cell line DU-145 was used to examine the relationship between the intracellular levels of cysteine-rich metallothionein (MT) and the sensitivity or resistance of cells to Adriamycin (ADR). The basis for the poor response of human prostate carcinomas to ADR was studied. Cadmium-resistant (Cdr) cells, capable of growth in 10(-5) M cadmium, were derived from DU-145 cadmium-sensitive (Cds) cells, by exposure to increasing concentrations of cadmium. The relative rates of MT synthesis were measured by L-[35S]cysteine incorporation and MT separation by high-performance liquid chromatography. Cdr cells, continuously exposed to cadmium, show a steady-state rate of MT synthesis (designated as control = 100%) which is 3.5 times the basal rate in Cds cells (29%). Dose-response curves, using clonal and cell count assays, show that the dose levels required to produce inhibition of growth to 50% and 90% of control, respectively, of ADR for Cdr cells (19.00 and 132.0 ng/ml) are 1.5 to 1.7 times those for Cds cells (12.5 and 77.5 ng/ml). In the absence of cadmium, deinduction of MT occurs with MT synthesis declining, after 70 and 118 h, to 29% and 19% of control. Correspondingly, in such deinduced cells (Cdr minus cadmium), the 50% inhibitory doses of ADR in clonal and growth assays are 3.5 and 4.8 ng/ml, respectively. Thus, deinduced cells are 3 and 4 times more sensitive to ADR than Cds and Cdr cells. This increased sensitivity is explained by the rapid and marked inhibition of MT synthesis upon exposure to ADR, even in the presence of cadmium, so that after 6 and 10 h in the presence of 10 ng/ml of ADR, the rates drop to 62% and 19% of control. On the basis of these results, we propose that: (a) the increased levels of MT increase the resistance of Cdr cells to ADR and that this may be partly responsible for the poor response of prostate carcinomas to ADR; (b) MT deinduction results in increased sensitivity to ADR; and (c) ADR inhibits MT synthesis. Thus, it is suggested that a treatment regimen consisting of ADR exposure followed by a second exposure, during increased ADR sensitivity, may be effective for growth inhibition of slow-growing prostatic carcinomas.