Israel Medical Association Journal

Background: The role of prostatic fossa radiation as salvage therapy in the setting of a rising prostate-specific antigen following radical prostatectomy is not well defined.

Objectives: To study the efficacy and safety of pelvic and prostatic fossa radiation therapy following radical prostatectomy for adenocarcinoma.

Methods: A retrospective review of 1,050 patient charts treated at the Sheba Medical Center for prostate cancer between 1990 and 2002 identified 48 patients who received post-prostatectomy pelvic and prostatic fossa radiotherapy for biochemical failure. Two patients were classified as T-1, T2A-9, T2B-19, T3A-7 and T3B-11. Gleason score was 2–4 in 9 patients, 5–6 in 22 patients, 7 in 10 patients and 8–10 in 7 patients. Positive surgical margins were noted in 28 patients (58%) of whom 18 had single and 10 had multiple positive margins. Radiation was delivered with 6 mV photons using a four-field box to the pelvis followed by two lateral arcs to the prostatic fossa.

Results: At a median follow-up of 34.3 months (25th, 75th) (14.7, 51,3) since radiation therapy, 32 patients (66%) are free of disease or biochemical failure. Exploratory analysis revealed that a pre-radiation PSA[1] less than 2 ng/ml was associated with a failure rate of 24% compared with 66% in patients with a pre-radiation PSA greater than 2 ng/ml (chi-square P < 0.006).

Conclusions: For patients with biochemical failure following radical prostatectomy early salvage radiation therapy is an effective and safe treatment option.

Background: Dysphagia is a common disorder among the elderly population. As many as 50% of nursing home residents suffer from dysphagia. It is important to identify patients at increased risk for colonization of dental and denture plaque by pathogenic organisms for prevention of associated disease.

Objectives: To quantify the prevalence and evaluate the effect of dental and denture plaque colonization by Candida albicans in hospitalized elderly dysphagic patients as a complication of stroke, as well as the effect of systemic antimicrobial therapy on C. albicans colonization in these patients.

Methods: We evaluated dysphagia and antibiotic therapy as risk factors for dental and denture plaque colonization by C. albicans in elderly stroke rehabilitating patients with dysphagia, as compared to elderly non-dysphagic stroke and non-stroke rehabilitating patients on days 0, 7 and 14 following admission to the Fliman Geriatric Rehabilitation Hospital.

Results: The risk of C. albicans colonization of dental plaque was greater in dysphagic patients than in those without dysphagia on day 0 (50% vs. 21%, P = 0.076), day 7 (58 vs. 15.2%, P = 0.008) and day 14 (58 vs. 15.2%, P = 0.08). Similarly, patients on antibiotic therapy were at greater risk for C. albicans colonization of dental plaque on day 0 (56 vs. 11%, P = 0.002), day 7 (44 vs. 14.8%, P = 0.04) and day 14 (39 vs. 19%, P = 0.18). The risk of C. albicans colonization of denture plaque as opposed to dental plaques in non-dysphagic patients was significantly greater on day 0 (45.7 vs. 21.2%, P = 0.03), day 7 (51.4 vs. 15.1%, P = 0.0016) and day 14 (54.3 vs. 15.1%, P = 0.0007). Dysphagia did not increase the risk of denture plaque colonization by C. albicans.

Conclusiona: Both dysphagia and antibiotic therapy are risk factors for C. albicans colonization of dental plaque, and although dysphagia does not significantly increase colonization of denture plaque, denture wearers are at greater risk of such colonization.

Since both major forms of diabetes involve inadequate function of pancreatic beta cells, intensive research is ongoing to better understand how beta cells perform their complex role of secreting the hormone insulin in response to physiologic needs. Identification and characterization of pancreatic transcription factors has revealed that they play a crucial role not only in maintenance of mature beta-cell function but also at multiple stages in pancreatic development. Furthermore, recent reports have revealed their potential to convert non-beta cells into insulin-producing cells, which in some cases can function to ameliorate diabetes in experimental animals. The ability to translate these successes to the clinic will require a detailed mechanistic understanding of the molecular basis of action of these proteins. Specific gene regulation in beta cells involves the action of multiple transcription factors recruited to the promoter and functioning synergistically to activate transcription, in part through recruitment of co-activator proteins and components of the basal transcriptional machinery. In addition, the process involves modification of chromatin structure, the details of which are beginning to be elucidated. Our ability to modulate gene expression patterns may lead to developing ways to provide an unlimited supply of functional beta cells for transplantation, permitting a dramatic improvement in therapeutic options for diabetes.

Type 1 diabetes mellitus is caused by an autoimmune destruction of pancreatic islet beta cells, leading to insulin deficiency. Beta-cell replacement is considered the optimal treatment for type 1 diabetes, however it is severely limited by the shortage of human organ donors. An effective cell replacement strategy depends on the development of an abundant supply of beta cells and their protection from recurring immune destruction. Stem/progenitor cells, which can be expanded in tissue culture and induced to differentiate into multiple cell types, represent an attractive source for generation of cells with beta-cell properties: insulin biosynthesis, storage, and regulated secretion in response to physiologic signals. Embryonic stem cells have been shown to spontaneously differentiate into insulin-producing cells at a low frequency, and this capacity could be further enhanced by tissue culture conditions, soluble agents, and expression of dominant transcription factor genes. Progenitor cells from fetal and adult tissues, such as liver and bone marrow, have also been shown capable of differentiation towards the beta-cell phenotype in vivo, or following expression of dominant transcription factors in vitro. These approaches offer novel ways for generation of cells for transplantation into patients with type 1 diabetes.

Background: The management of diabetes in preschool children poses unique difficulties for both the families and the medical team.

Objective: To test the feasibility and safety of insulin pump therapy in the 1–6 year age group in order to improve quality of life and metabolic control.

Methods: The study group comprised 15 type 1 diabetic children aged 1–6 years old (mean ± SD, 3.8 ± 1.2 years) from three diabetes centers. Insulin pump therapy was applied for 12 months. Data, including insulin dose, hemoglobin A1c, hypoglycemic events, as well as scores on the Diabetes Quality of Life Measure Questionnaire and the Diabetes Treatment Satisfaction Questionnaire, were collected and compared with the multiple daily injections treatment prior to entry into the study.

Results: HbA1c[1] was measured at the beginning of the study and at 2, 4, 8 and 12 months later; the respective levels (mean ± SD) were 8.82 ± 0.98, 8.45 ± 1.05, 8.37 ± 0.85, 8.32 ± 0.71, 8.18 ± 0.90%. HbA1c measurements after 12 months were significantly lower than at the beginning of the study (P < 0.05). There were no significant differences in insulin dose and the total number of hypoglycemic events. In both the DQOL[2] and DTSQ[3] scales there were significant differences in scores in favor of the insulin pump period (43.7 ± 8.0 versus 33.7 ± 7.9, P < 0.001; and 10.9 ± 2.3 versus 14.5 ± 2.3, P < 0.001), respectively.

Conclusions: For very young diabetic children, insulin pump therapy improves quality of life and is feasible and safe. It should be considered as an optional mode of therapy for this age group.

Background: Intravenous recombinant tissue plasminogen activator therapy within 3 hours of stroke onset is a proven effective treatment for acute ischemic stroke.

Objectives: To assess the feasibility and safety of rt-PA[1] therapy for reperfusion in routine clinical practice in Israel, in a setting of a dedicated stroke unit.

Methods: Consecutive patients presenting within less than 3 hours of stroke onset were evaluated by an emergency physician and the neurology stroke team. After brain computerized tomography eligible patients were treated with intravenous rt-PA (0.9 mg/kg; maximum dose 90 mg) according to an in-hospital protocol corresponding to recommended criteria. Patients were admitted to the acute stroke unit. Safety and clinical outcome were routinely assessed. Re-canalization was assessed by serial transcranial Doppler.

Results: The study group comprised 16 patients, mean age 61 years (range 47–80 years), male to female ratio 10:6, whose median baseline National Institutes of Health stroke scale was 13 (range 6–24). They were treated within a mean door-to-CT time of 39 minutes (range 17–62 min), door-to-drug time 101 minutes (range 72–150), and stroke onset-to-drug time 151 minutes (range 90–180). There was an early improvement within 24 hours (of ≥ 4 points in the NIHSS[2] score) in 7 patients (44%) and no early deteriorations. There were no protocol deviations, no symptomatic intracranial hemorrhages, and no major systemic hemorrhage within 36 hours of rt-PA treatment. Three asymptomatic hemorrhagic transformations of the infarct were noted on routine follow-up brain CT associated with neurologic improvement. Outcome data were comparable to the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study.

Conclusion: Intravenous rt-PA treatment within 3 hours of stroke onset in routine clinical practice in Israel is feasible and appears safe in the setting of a neurology stroke unit and team. Careful implementation of rt-PA therapy for selected patients in Israel is encouraged.

Background: The humanized SCID mouse model is an attractive tool for testing gene therapy to combat human immunodeficiency virus infection in vivo.

Objectives: To devise a more specific gene therapy directed against HIV, replacing the formerly used interferon with either soluble CD4 molecule immunoadhesin (sCD4-IgG) and/or anti-gp41 monoclonal antibody (2F5), or negative transdominants (Tat, Rev).

Methods: Human monocytoid cell line (U937) was transfected with IFNa[1], b or g genes. 3T3 murine fibroblastic cell line was transfected with sCD4-IgG or 2F5, or both genes, and a human T4 cell line (CEM) was grafted to SCID mice. Negative transdominant genes (Tat, Rev or both) were also transduced in CEM T cell line. Animals were then challenged with HIV-1[2]. Viral load was followed.

Results: IFNa or b were potent anti-HIV, reducing viral load in vivo and inhibiting reverse transcriptase activity in human-removed cells from animals. sCD4-IgG immunoadhesin and gp41 monoclonal antibody resulted in a dramatic reduction of HIV-1 cellular and plasmatic viral load in humanized SCID mice. The simultaneous introduction of negative Tat and Rev genes resulted in a synergistic inhibition of HIV-1 replication in vivo.

Conclusions: Despite the marked reduction of HIV-1 propagation by IFN genes or by negative Tat and Rev transdominants, the gene therapy using soluble CD4 immunoadhesin or anti-gp41 was a more efficient preventive treatment against HIV infection.