The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel.

Inherited predisposition occurs in 5-10% of all prostate cancer (CaP) patients, but the genes involved in conferring genetic susceptibility remain largely unknown. Several lines of evidence indicate that germline mutations in BRCA1 and BRCA2 might be associated with an increased risk for CaP. Three mutations in these two genes (185delAG and 5382InsC (BRCA1) and 6174delT (BRCA2) occur in about 2.5% of the general Ashkenazi population, and the 185delAG BRCA1 mutation, in up to 1% of non-Ashkenazi Jews. In order to assess the contribution of these germline mutations to prostate cancer in Jewish Israeli patients, we tested 174 unselected prostate cancer patients (95 of Ashkenazi origin) for these mutations by PCR amplification and modified restriction enzyme digests. Patient's age range was 45-81 years (median 66), and in 24 (14.4%) the disease was diagnosed prior to 55 years of age. Nineteen (11%) and 12 (6.9%) patients had a first or second degree relative with CaP or breast cancer, respectively. Overall, five mutation carriers were detected: 2/152 (1.3%) 185delAG, 2/104 (2%) 5382InsC, and 1/158 (0.6%) 6174delT. In all carriers, the disease was diagnosed after the age of 55, and only one of them had a family history of breast and CaP. In addition, no allelic losses at the BRCA1 locus were demonstrated in 17 patients with a family history of CaP, using seven microsatellite markers. We conclude that the rate of the predominant Jewish BRCA1 and BRCA2 mutations in CaP patients does not significantly differ from that of the general population, and that mutational inactivation of the BRCA1 is rare in familial CaP. Thus, germline BRCA1 and BRCA2 mutations probably contribute little to CaP occurrence, to inherited predisposition, and to early onset disease in Jewish individuals.

Prevention of postoperative pericardial adhesions using tissue-protective solutions.

Repeat cardiac surgical procedures are associated with increased technical difficulty and risk because of the previous formation of dense adhesions between the heart and the surrounding tissues. Dilute solutions of sodium hyaluronic acid (NaHA) and carboxymethyl cellulose (CMC) have been shown to prevent postoperative abdominal and pelvic adhesions and could therefore potentially inhibit adhesion formation following cardiac surgery. Adhesion prevention using 0.1% NaHA, 0.4% NaHA, or 0.1% CMC solutions was examined in a canine abrasion/desiccation pericardial adhesion model (5 animals/group) and compared to 10 animals treated with Ringer's lactate (RL) solution alone. The pericardium and heart were coated with 25 ml of test or control solution prior to and after pericardiotomy, after controlled gauze abrasion, after 30 min of desiccation, and prior to closure. At 6 weeks, animals were reexplored and adhesions were scored in a blinded manner by three to four surgeons using a 0-4 scale. Scores of 2 or greater were considered clinically significant. Mean adhesion scores from the left epicardium were 0.0 in animals treated with 0.1% NaHA, 0.6 in animals treated with 0.4% NaHA or 1% CMC, and 2.3 in animals treated with RL (P < 0.05 Duncan's ANOVA). In addition, none of the animals treated with 0.1% NaHA, 20% of the animals treated with 0.4% NaHA, and 20% of the animals treated with 1% CMC had clinically significant adhesions, whereas 80% of animals treated with RL had such adhesions. Sodium hyaluronic acid and CMC solutions, used as tissue coatings during cardiac surgery, inhibit the formation of undesired postoperative adhesions. Application of these biocompatible polymer solutions during surgery could reduce the technical difficulty and risk of repeat cardiac surgical procedures.

Prevention of tissue injury and postsurgical adhesions by precoating tissues with hyaluronic acid solutions.

The effectiveness of inhibiting serosal tissue damage and preventing surgical adhesions by precoating tissues with dilute solutions of hyaluronic acid (HA) was evaluated in a rat cecal abrasion model. This study was performed at three independent laboratories using the same protocol. Three hundred and seventy-five adult rats were divided into five treatment groups (125 animals at each study site): 0.1% HA, 0.25% HA, 0.4% HA, phosphate-buffered saline solution (PBS), and no solution. The abdominal cavity of each animal was precoated with 4 ml of test solution or no solution, prior to a controlled abrasion of the cecum. One week later, the animals were sacrificed and adhesions were scored on a 0-4 scale. The data were pooled because no statistical difference was found in the trends at the three study sites. The PBS precoating and no tissue precoating treatment groups had the same high incidence of cecal adhesions, which was significantly higher than the incidence of adhesions in the HA treatment groups. As the HA concentration in the precoating solution increased from 0% (PBS group) to 0.4% HA, the mean incidence of cecal adhesions decreased in a concentration-dependent manner from 1.6 +/- 0.11 to 0.7 +/- 0.09 (P < 0.001). The percentage of animals with no cecal adhesions increased from 11% in the PBS group to 50% in the 0.4% HA treatment group (P < 0.001). In a separate histological study employing 150 rats, HA solutions significantly inhibited serosal tissue damage and ameliorated the inflammatory response due to abrasion and desiccation compared to that with no coating or precoating with buffered saline. Together, these studies demonstrate that tissue precoating with dilute HA solutions reduces damage to serosal tissues during surgery and thereby limits formation of postsurgical adhesions.

Prevention of postoperative abdominal adhesions by tissue precoating with polymer solutions.

Polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC) solutions were evaluated in a rat cecal abrasion model to test the effect of these high-molecular-weight hydrophilic polymer solutions on postoperative adhesion formation when used as tissue precoating solutions. Eleven groups of 5-20 animals each were studied including 25 control animals treated with Ringer's lactate (RL) solution. Animals were reoperated at 2 weeks and adhesions were scored according to a 0-4 grading scale. Tissue coating following cecal abrasion failed to inhibit adhesion formation. However, tissue coating with polymer solutions prior to cecal abrasion significantly reduced the formation of post-operative adhesions. Solutions of 1.5% CMC and 5% of a unique gamma-polymerized PVP in RL exhibited the greatest tissue-protective behavior compared to RL controls (P < 0.002). Both CMC and gamma-PVP solutions warrant further investigation as tissue precoatings to inhibit surgical adhesions.

Prevention of postoperative adhesions by precoating tissues with dilute sodium hyaluronate solutions.

Postoperative adhesions (POA), the collagenous connective tissues which form in response to surgical trauma, can be a severe and life threatening surgical complication. However, no generally applicable methods are currently available to mitigate this often serious problem. We have investigated the use of dilute aqueous solutions of sodium hyaluronate (HA) as protective tissue coatings applied prior to surgical manipulation. In a random/blind rat cecal adhesions study conducted at three separate research centers, 0.4 wt% HA in buffered saline gave a three center average of 24% significant adhesions (n = 74) versus 87% for phosphate buffered saline (PBS) controls (n = 69). Histological data suggest that hyaluronic acid tissue precoating minimizes surgical trauma thereby inhibiting POA formation. Clinical studies have been initiated to evaluate the efficacy of tissue precoating with HA solutions in human surgery.

Reduction of postoperative adhesions secondary to strabismus surgery in rabbits.

The efficacy of tissue coating with sodium hyaluronate solution or oxidized regenerated cellulose (Interceed) sleeves in reducing the occurrence and severity of postoperative adhesions following strabismus surgery was tested in rabbits in vivo and compared with the efficacy in this regard of treatment with balanced salt solution. The use of Interceed sleeves significantly increased formation of postoperative adhesions, but coating with sodium hyaluronate solution prior to and during surgery significantly reduced such formation.

Effect of Ringer's lactate irrigation on the formation of postoperative abdominal adhesions.

Intraabdominal adhesions continue to pose a potentially serious postoperative clinical problem. Reported here is an experiment designed to study any effect that balanced Ringer's lactate (RL) solution may have on intraabdominal adhesion formation. Surgical trauma was induced in mice by controlled gauze abrasion of one side of the abdominal wall; the opposite side was used as a control. RL irrigation was compared with no irrigation. Adhesions were scored on the basis of incidence (%) and severity (on a 0-10 scale). The abraded right peritoneum exhibited 100% adhesions for both the RL group and the nonirrigated group. However, on the side that was not abraded, the nonirrigated group showed only 30% incidence of adhesions and 1.7 +/- 3.3 severity as compared with 100% adhesions and 7.7 +/- 2.2 severity for the RL group. These results suggest the need for further studies to establish the extent to which irrigation with solutions such as Ringer's lactate or saline may enhance formation of postoperative adhesions.

Prevention of postoperative pericardial adhesions with hydrophilic polymer solutions.

Pericardial adhesions subject patients requiring cardiac reoperation to potential injuries of the heart, great vessels, and extracardiac grafts during resternotomy. We evaluated polyvinylpyrrolidone (PVP) and a methlycellulose derivative (MCD) as intraoperative irrigating solutions in the prevention of postoperative pericardial adhesions. Fifteen dogs weighing 15 to 20 kg were divided into three equal cohorts and subjected to left thoracotomy with pericardiotomy. Prior to surgical manipulation, the pericardial cavity was irrigated with either PVP, MCD, or Ringer's lactate (RL). Serosal injury stimulating intraoperative trauma was induced by gauze sponge abrasion of the epicardium and inner surface of the pericardium and by allowing desiccation of serosal surfaces for 30 min. The pericardial cavity was evaluated for adhesion formation 6 weeks postoperatively by reoperation. Two independent observers, unaware of the study solution, evaluated the extent and severity of pericardial adhesions on a 0-4 scale. All dogs in the RL control group had surgically significant adhesions and a mean adhesion score of 3.2 +/- 1.1. In contrast, no PVP- or MCD-treated dog had surgically significant adhesions. The mean adhesion scores were 0.2 +/- 0.4 for PVP and 0.5 +/- 0.7 for MCD. Our results indicate that PVP (P less than 0.004) and MCD (P less than 0.024) significantly reduce pericardial adhesion formation when compared to RL. Clinical application of PVP or MCD for the prevention of pericardial adhesions should reduce morbidity and mortality of cardiac reoperation.

A mechanistic model for the enzymic degradation of synthetic biopolymers.

The degradation pathway of a synthetic biopolymer, poly-N5-(2-hydroxyethyl)-L-glutamine, by papain under physiological conditions, was extensively investigated. The enzymic reaction was found to be rather complex: it progressively slows down, and comes to an end when the degradation fragments are tetrapeptides. In order to account for this phenomenon, a modified Michaelis-Menten kinetic model is proposed, in which Km is assumed to be dependent on the degree of polymerization of the macromolecular substrate, and therefore varies as the degradation reaction proceeds. The new model accurately describes all the experimental data, and allows one to predict the entire course of the reaction. The behaviour of the system considered is interpreted to represent a model of biological recognition at the molecular level.