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Biomedical subjects

A J Becker

Publications and source records attributed to A J Becker.

8 recordsLinked to original sources

Role of the nitric oxide donor linsidomine chlorhydrate (SIN-1) in the diagnosis and treatment of erectile dysfunction.

OBJECTIVES: Recently, nitric oxide was shown to be a mediator of penile erection in men and the nitric oxide donor linsidomine chlorhydrate (SIN-1) was introduced as a novel treatment option in patients with erectile dysfunction. We now present our follow-up results with the intracavernous application of SIN-1. METHODS: One hundred thirteen patients with erectile dysfunction of various etiologies and 10 normal control subjects underwent intracavernous pharmacotesting with 1 mg SIN-1. Of the 113 patients, 71 (62.8%) underwent additional pharmacotesting with a mixture of papaverine (15 mg/mL) and phentolamine (0.5 mg/mL) (P/P). Forty-eight responders to SIN-1 were enrolled in an autoinjection program with this substance. RESULTS: All normal control subjects had full rigid erections lasting 40 to 70 minutes. Of 113 patients, 78 (69%) had responses sufficient for intercourse with SIN-1, and the other 35 patients (31%) demonstrated inadequate responses. All 44 responders to SIN-1 who also received P/P had erections sufficient for intercourse with P/P in doses of 0.25 to 2 mL (mean, 0.6 +/- 0.3 mL). Six patients (13.6%) had prolonged erections with minimal to moderate doses of P/P. From the total of 27 patients who had erections insufficient for intercourse with SIN-1, 20 (74.1%) had good responses with 0.25 to 2.0 mL P/P (mean, 1.5 +/- 0.5 mL). One patient (4%) had a prolonged erection with 1.0 mL P/P: After 10 to 150 injections/patient (total of 1160 injections; mean, 24.1 injections), no significant side effects were noted with SIN-1. CONCLUSIONS: Our data suggest that intracavernous SIN-1 is safe and efficacious in the majority of patients with erectile dysfunction; however, it has a lower smooth muscle relaxing effect than a combination of P/P. The absence of severe side effects, including priapisms, may be explained by the use of a physiologic pathway for induction of the erectile response and the rapid intracavernous decomposition of SIN-1.

Adult

Intracavernous calcitonin gene-related peptide plus prostaglandin E1: possible alternative to penile implants in selected patients.

The implantation of a penile prosthesis is still the ultima ratio for patients with erectile dysfunction who fail other treatment options such as pharmacotherapy and penile venous surgery. Despite mostly favorable results regarding restoration of erectile capacity, penile allografts are often not accepted for various reasons. Therefore, pharmacotesting with a mixture of calcitonin gene-related peptide and prostaglandin E1 (CGRP/PGE1) was offered to different selected patients populations: 28 patients with erectile dysfunction and venous leakage who failed penile venous surgery, 28 patients with erectile dysfunction and venous leakage (who refused penile venous surgery) and 12 patients without venous leakage, but poor response to maximum doses of papaverine/phentolamine, received 5 micrograms CGRP plus 10 micrograms PGE1. Erections sufficient for intercourse were noted in 19/28 (67.9%), 20/28 (71.4%) and 11/12 (91.7%) patients, respectively. Our data show that a combination of CGRP and PGE1 may be an alternative to penile implants in selected patients.

Alprostadil

A physical map around the retinoblastoma gene.

The gene predisposing to retinoblastoma, RB1, has been mapped to 13q14 and a cDNA clone has been isolated. Alterations of this chromosomal region are found not only in retinoblastoma, but in other tumor types including bone and soft tissue sarcomas, gastric tumors, small cell lung cancer, hematologic malignancies, rhabdomyosarcoma, and breast cancer. Genetic alterations implicating RB1 in some of these cancers have been observed. A long-range, overlapping restriction map around RB1 has been derived to provide a basis for study of rearrangements in tumors. Putative CpG islands closely linked to RB1 were identified, the effect of methylation was investigated, and RB1 transcriptional direction was determined. Using data in the literature, the map was oriented with respect to the centromere and it was determined that the distance between esterase D, a nearby gene, and RB1 was greater than 200 kb.

Carboxylesterase

Evaluation of a Bayesian regression program for predicting warfarin response.

The ability of a Bayesian regression program (Warfcalc) to predict warfarin response was evaluated retrospectively in 48 inpatients and prospectively in 10 inpatients. The prothrombin ratio (PR) on the last day of inpatient therapy was predicted using zero (naive) to five sequential, daily PR feedbacks. Bias and precision were measured using mean error (ME) and mean absolute error (MAE), respectively. Root mean squared error (RMSE) was used as a combined measure of bias and precision. In the retrospective group, the use of five PR feedbacks yielded the lowest ME, MAE, and RMSE (0.22, 0.30, and 0.45, respectively). The use of two and three daily PR feedbacks resulted in larger prediction errors compared with the use of naive parameters. Further evaluation of the retrospective patient data indicated that deletion of PR feedbacks associated with an activated partial thromboplastin time greater than 100 s and exclusion of metabolic inhibitors in the estimation of warfarin clearance resulted in more reliable predictions (ME = 0.07, MAE = 0.20, RMSE = 0.28). Similarly, deletion of such PR feedbacks and metabolic inhibitors from the prospective data and use of PRs for the first 5 days of therapy yielded ME, MAE, and RMSE values of 0.07, 0.21, and 0.27, respectively. The variance for prothrombin complex activity (PCA) as a function of the variance in the prothrombin time (PT) was investigated using Monte Carlo simulation assuming four different random error models for the PT measurements. These error models yielded functions that exhibit a maximum coefficient of variation at PCA values of 40-70%.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged

Identification of germline and somatic mutations affecting the retinoblastoma gene.

Retinoblastoma (RB) is a malignant tumor of developing retina that arises when abnormalities resulting in loss of function affect both alleles of the gene at the retinoblastoma locus (RB1) on chromosome 13q. The majority of RB tumors do not show gross alterations in a 4.7-kb fragment (4.7R), which is a candidate RB1 gene. To search for more subtle mutations, the ribonuclease protection method was used to analyze 4.7R messenger RNA from RB tumors. Five of 11 RB tumors, which exhibit normal 4.7R DNA and normal-sized RNA transcripts, showed abnormal ribonuclease cleavage patterns. Three of the five mutations affected the same region of the messenger RNA, consistent with an effect on splicing involving an as yet unidentified 5' exon. The high frequency of mutations in 4.7R supports the identification of 4.7R as the RB1 gene. However, the unusual nature of some of the abnormalities of 4.7 R alleles indicates that the accepted sequence of genetic events involved in the genesis of RB may require reevaluation.

Base Sequence

Cloning of the esterase D gene: a polymorphic gene probe closely linked to the retinoblastoma locus on chromosome 13.

The study of recessive oncogenes such as those responsible for retinoblastoma and Wilms tumor is difficult because the gene products involved are unknown and because the diseases are not associated with unique cellular or molecular phenotypes suitable for genetic manipulation. Since the gene for esterase D (ESD) is known to be tightly linked to the retinoblastoma locus (RB1) in the q14.1 band of chromosome 13, we have cloned the ESD gene from a human cDNA library by using oligonucleotides specific for a partial amino acid sequence of the purified enzyme to provide a genetic marker for further studies on retinoblastoma. The putative ESD gene codes for a message of 1.2 kilobases, which is present in all cell types examined, and maps to 13q14.1, thus confirming that it is the ESD gene. Restriction enzyme analysis reveals a restriction fragment length polymorphism with Apa I; this polymorphism results from the heterozygosity of 32% of the individuals tested and is shown to be useful in identifying carriers of the mutation responsible for retinoblastoma. A preliminary screen of 24 retinoblastoma tumors by Southern blot did not reveal any homologous deletions or rearrangements of the ESD locus.

Carboxylesterase