Warfarin or Low-Molecular-Weight Heparin Therapy does not Prolong Pig-To-Primate Cardiac Xenograft Function

Microvascular thrombosis is a prominent feature in cardiac delayed xenograft rejection (DXR). We investigated the impact of warfarin or low-molecular-weight heparin (LMWH) anti-coagulation on xenograft function using a heterotopic pig-to-primate model. Donor hearts were from CD46 transgenic pigs and baboon immunosuppression included tacrolimus, sirolimus, anti-CD20 and TPC, an alpha-galactosyl-polyethylene glycol conjugate. Three groups of animals were studied. Group 1 (n = 9) was treated with warfarin, Group 2 (n = 13) with LMWH and Group 3, received no anti-coagulant drugs. The median duration of xenograft function was 20 days (range 3-62 days), 18 days (range 5-109 days) and 15 days (range 4-53 days) in Groups 1 to 3 respectively. Anti-coagulation achieved the targeted international normalized prothrombin ratio (INR) and anti-factor Xa levels consistent with effective in vivo therapy yet, no significant impact on median xenograft function was observed. At rejection, a similar histology of thrombosis and ischemia was apparent in each group and the levels of fibrin deposition and platelet thrombi in rejected tissue was the same. Anti-coagulation with warfarin or LMWH did not have a significant impact on the onset of DXR and microvascular thrombosis. However, a role for specific anti-coagulant strategies to achieve long-term xenograft function cannot be excluded.     

Medizinische Beurteilungskriterien zu bandscheibenbedingten Berufskrankheiten der Lendenwirbelsäule (I)

Occupational diseases Nos. 2108 and 2110 correspond to intervertebral disc-related diseases of the lumbar spine from many years of carrying or lifting heavy loads, occupations in extreme postures of full flexion or oscillation of the whole body when seated, and which compel the cessation of all activities which are or could be the cause for the origin, exacerbation or recurrence of the disease. These occupational diseases came into force at the start of 1993, but there have been considerable problems in their implementation. The present Part I of the contribution is the result of the work of an interdisciplinary study group and contains medical criteria for the assessment of possibly strain-related clinical characteristics and the evaluation of other possible causes. Part II is to be published in Volume 4/2005 and will deal with questions related to forced cessation and to the assessment of the loss of earning ability. Agreement was reached in many areas related to the assessment of occupational claims. This should allow for evidence-based decision making in the future for the occupational diseases Nos. 2108 and 2110.     

Expression of the β‐adhesin part of HRgpA in Sprague Dawley rats induces a specific antibody response

The β‐adhesin part of the Porphyromonas gingivalis W50 (ATCC 53978) protease HRgpA was cloned in an eukaryotic expression vector and expressed in COS‐7 cells. The monoclonal antibody MAb (61BG1.3), specific for the hemagglutinating domain of β‐adhesin, recognized the expressed β‐adhesin in the transfected cells both by immunoblot and immunofluorescence. Sprague Dawley rats were immunized intramuscularly with β‐adhesin encoding expression plasmid and expression plasmid without β‐adhesin insert. Skeletal muscle tissue at the site of immunization in the β‐adhesin immunized animals was shown to express this protein. The immunization induced a β‐adhesin‐specific antibody response. Sera from the immunized animals were tested for hemagglutination inhibiting activity. Due to high natural inhibiting activity in all rat sera tested, no increased hemagglutination inhibition was detected in sera from the β‐adhesin immunized animals.     

Investigation of hearing loss in patients with acute brucellosis by standard and high-frequency audiometry

This study aimed to determine the effect of acute brucellosis on the auditory system. Forty-two patients with acute brucellosis were evaluated clinically, and with serological and audiological tests, before and after treatment. Hearing threshold averages were calculated at 11 different frequencies (250-8000 Hz) of the auditory airway, and statistical analysis was performed. The average hearing thresholds were > 20 dB, with standard audiometry at 6000-8000 Hz, and < 20 dB at all other frequencies. After treatment, the average auditory threshold decreased to < 20 dB at 6000-8000 Hz (p < 0.0001). Pure-tone hearing thresholds were improved at all frequencies after treatment, with statistically significant differences at all frequencies except 12,000, 14,000 and 16 000 Hz (p < 0.05). There was no permanent hearing loss caused by acute brucellosis, and hearing thresholds were restored after treatment. It was concluded that acute brucellosis affects the auditory system, especially at high frequencies, and that patients with all forms of brucellosis should be evaluated for hearing loss.     

CAR2 displays unique ligand binding and RXRalpha heterodimerization characteristics.

The constitutive androstane receptor (CAR; NR1I3) regulates the expression of genes involved in xenobiotic metabolism. Alternative splicing of the human CAR gene yields an array of mRNAs that encode structurally diverse proteins. One form of CAR, termed CAR2, contains an additional four amino acids (SPTV) that are predicted to reshape the ligand-binding pocket. The current studies show a marked, ligand-independent, CAR2-mediated transactivation of reporters containing optimal DR-3, DR-4, and DR-5 response elements, and reporters derived from the natural CYP2B6 and CYP3A4 gene promoters. Overexpression of the RXRalpha ligand binding domain was critical for achieving these effects. CAR2 interaction with SRC-1 was similarly dependent on the coexpression of RXRalpha. Mutagenesis of Ser233 (SPTV) to an alanine residue yielded a receptor possessing higher constitutive activity. Alternatively, mutating Ser233 to an aspartate residue drastically reduced the transactivation capacity of CAR2. The respective abilities of these mutagenized forms of CAR2 to transactivate a DR-4 x 3 reporter element correlated with their ability to interact with RxRalpha and to recruit SRC-1 in a ligand-regulated manner. Together, these results demonstrate a robust RXRalpha-dependent recruitment of coactivators and transactivation by CAR2. In addition, CAR2 displays novel dose responses to clotrimazole and androstanol compared with the reference form of the receptor while at the same time retaining the ability to bind CITCO. This result supports a hypothesis whereby the four-amino-acid insertion in CAR2 structurally modifies its ligand binding pocket, suggesting that CAR2 is regulated by a set of ligands distinct from those governing the activity of reference CAR.     

B-Lynch sutures for major primary postpartum haemorrhage at caesarean section.

This was a retrospective observational study of 11 consecutive patients of major primary postpartum haemorrhage (PPH) who had the B-Lynch suture at the time of caesarean section, performed between 1 March 2001 and 31 March 2004 at a teaching hospital in Scotland. Case-note review was performed in 123 patients, who had major primary PPH to identify patients who had B-Lynch sutures at the time of caesarean section. The patient's age, parity, gestation of pregnancy at which the B-Lynch suture was performed, the indication for caesarean section and the cause of primary major PPH were recorded. The operative details, intraoperative and immediate postoperative complications and the need for subsequent hysterectomy were noted. The patients were followed-up with clinic visits at 6 weeks and any further hospital referral for late postoperative complications and whether subsequent successful pregnancy was achieved, were documented. The incidence of major PPH in our centre was 0.5% of the total deliveries, of which 11 cases had the B-Lynch suture applied at the time of caesarean section. The patients were aged between 25 and 38 years old (mean 31 years). Parity ranged from 0 to 1 and the gestational age at which the procedure was performed ranged from 34 to 41 weeks (mean 38 weeks). Ten operations (91%) were performed by senior registrars supervised by the consultant on call and one (9%) case was performed by a consultant on call. All cases had the B-Lynch sutures performed for major primary PPH caused by uterine atony at the time of caesarean section. The weight of the babies delivered ranged between 2,110 - 4,820 g (mean 3,500 g). The total blood loss at surgery ranged from 2,000 - 10,000 ml (mean 3,500 ml). Only three patients (28%) required hysterectomy. All the patients made a good postoperative recovery. The hospital stay ranged from 4 - 24 days (mean 8 days). The patient who remained in hospital for 24 days did so because her baby was admitted into the neonatal unit. All the patients were reviewed 6 weeks postnatally. There was no significant morbidity. A subsequent successful pregnancy has been achieved in one patient.