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M Bernstein

Publications and source records attributed to M Bernstein.

At least 73 records · Page 4Linked to original sources
PubMed1998

Ex vivo liposome-mediated gene transfer to lung isografts.

OBJECTIVE: Gene therapy is a promising strategy to modify ischemia-reperfusion injury and rejection after transplantation. We evaluated variables that may affect ex vivo gene transfer to rat lung isografts. METHODS: Left lungs were harvested and perfused via the pulmonary vein with chloramphenicol acetyltransferase complementary deoxyribonucleic acid complexed with cationic liposomes. Several variables were examined: (1) Influence of temperature: In group I (n = 4), grafts were stored for 4 hours at 23 degrees C and transplanted. Chloramphenicol acetyltransferase activity was assessed on postoperative day 2. In groups II and III (n = 4), grafts were stored at 10 degrees and 4 degrees C, respectively. Arterial oxygen tension and inflammatory infiltrate were also determined. (2) Influence of storage time: Grafts were preserved at 10 degrees C for 1, 2, 3, 4 (n = 4), and 10 hours (n = 5). chloramphenicol acetyltransferase activity was assessed on postoperative day 2. (3) Rapidity and duration of transgene expression: Grafts were preserved at 10 degrees C for 1 hour and then transplanted. Chloramphenicol acetyltransferase activity was assessed 2, 4, 6, 12, and 24 hours and 2, 7, 14, 21, and 28 days after implantation. RESULTS: Chloramphenicol acetyltransferase expression was apparently less in lungs transfected at 4 degrees C than in those transfected at 10 degrees and 23 degrees C. Storage for 1 hour at 10 degrees C was sufficient to yield significant expression. Increasing the exposure time to 10 hours did not increase toxicity. There were no differences in arterial oxygen tension between transfected and nontransfected lungs. Chloramphenicol acetyltransferase expression was detected for at least 28 days. CONCLUSION: Ex vivo liposome-mediated transfection of lung isografts can be achieved after a short time of cold storage, with minimal toxicity.

Animals↗
PubMed1998

Pharmacological characterisation of metabotropic glutamatergic and purinergic receptors linked to Ca2+ signalling in hippocampal astrocytes.

Intracellular Ca2+ ([Ca2+]i) signals induced by metabotropic glutamate receptor (mGluR) agonists and by purinergic agonists in cultured hippocampal astrocytes were investigated using [Ca2+]-sensitive fluorophores. The mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) and (R,S)-3,5-dihydroxyphenylglycine (DHPG) induced [Ca2+]i responses in 76 and 93% of the cells, respectively. The broad-spectrum mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) and the mGluR1 antagonists (S)-4-carboxy-3-hydroxyphenylglycine (4C3HPG) and (S)-4-carboxyphenylglycine (4CPG) suppressed the agonist-evoked [Ca2+]i response in about 25% of the cells completely and in about 60% partially, depending on the agonist concentration employed. Together with immunohistochemical receptor localisations these results suggest the presence of at least two subpopulations of class I mGluRs recruited from the truncated splice variants of mGluR1 (mGluR 1b, 1c, 1d) and/or hitherto unknown glial-specific class I mGluRs. Of the hippocampal astrocytes 88, 92 or 83% of the cells responded with a [Ca2+]i elevation (mostly oscillations) to application of ATP, ADP, or 2-methylthio-ATP (2-MeS-ATP), respectively, whereas only 14 and 5% responded to AMP and adenosine, respectively, indicating the predominance of P2 receptors. The ATP-induced [Ca2+]i signal was suppressed by suramin. Release of Ca2+ from intracellular stores was involved in the response to ATP because the cells also exhibited [Ca2+]i elevations in Ca2+-free medium. Cells did not respond to 10 microM UTP. We conclude that the P2Y subtype represents the main [Ca2+]i-linked purinoceptor in hippocampal astrocytes. Sequential application of ATP and DHPG in Ca-free medium showed that metabotropic glutamate and purinergic receptors initiate release of Ca2+ from subsets of cyclopiazonic acid-sensitive Ca2+ stores which are partly independent.

Adenosine↗
PubMed1998

Iatrogenic seeding of anaplastic astrocytoma following stereotactic biopsy.

We present a case of probable tumor seeding along the needle tract following computer tomography-guided stereotactic biopsy of an anaplastic astrocytoma in a 23 year old male. Six months after the initial biopsy and 3 months following a second stereotactic procedure for cyst aspiration, a second lesion appeared directly along the biopsy trajectory at a distance from the primary tumor. This lesion is presumed to be recurrent tumor and appears to have been spread iatrogenically following the biopsy of the initial tumor and the subsequent cyst aspiration along the same tract.

Adult↗
PubMed1998

Conduct of phase I trials in children with cancer.

PURPOSE AND METHODS: Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. RESULTS AND CONCLUSION: Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect the relative unavailability of appropriate patients. The application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.

Antineoplastic Agents↗
PubMed1998

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

PURPOSE: A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS: A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS: Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION: The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Adolescent↗
PubMed1998

Incidence of silent hemorrhage and delayed deterioration after stereotactic brain biopsy.

OBJECT: Many neurosurgeons routinely obtain computerized tomography (CT) scans to rule out hemorrhage in patients after stereotactic procedures. In the present prospective study, the authors investigated the rate of silent hemorrhage and delayed deterioration after stereotactic biopsy sampling and the role of postbiopsy CT scanning. METHODS: A subset of patients (the last 102 of approximately 800 patients) who underwent stereotactic brain biopsies at the Toronto Hospital prospectively underwent routine postoperative CT scanning within hours of the biopsy procedure. Their medical charts and CT scans were then reviewed. A postoperative CT scan was obtained in 102 patients (aged 17-87 years) who underwent stereotactic biopsy between June 1994 and September 1996. Sixty-one patients (59.8%) exhibited hemorrhages, mostly intracerebral (54.9%), on the immediate postoperative scan. Only six of these patients were clinically suspected to have suffered a hemorrhage based on immediate postoperative neurological deficit: in the remaining 55 (53.9%) of 102 patients, the hemorrhage was clinically silent and unsuspected. Among the clinically silent intracerebral hemorrhages, 22 measured less than 5 mm. 20 between 5 and 10 mm, five between 10 and 30 mm, and four between 30 and 40 mm. Of the 55 patients with clinically silent hemorrhages, only three demonstrated a delayed neurological deficit (one case of seizure and two cases of progressive loss of consciousness) and these all occurred within the first 2 postoperative days. Of the neurologically well patients in whom no hemorrhage was demonstrated on initial postoperative CT scan, none experienced delayed deterioration. CONCLUSIONS: Clinically silent hemorrhage after stereotactic biopsy is very common. However, the authors did not find that knowledge of its existence ultimately affected individual patient management or outcome. The authors, therefore, suggest that the most important role of postoperative CT scanning is to screen for those neurologically well patients with no hemorrhage. These patients could safely be discharged on the same day they underwent biopsy.

Adolescent↗
PubMed1998

Complete hydatidiform mole. Comparison of clinicopathologic features, current and past.

OBJECTIVE: To investigate whether changes have occurred in the pathologic and clinical features of complete molar gestation in recent years. STUDY DESIGN: Twenty-three contemporary complete hydatidiform moles (1994-1997) and 20 historical complete moles (1969-1975) were compared regarding clinical features (gestational age at evacuation, maternal age, preevacuation diagnosis and persistence) and pathologic findings (volume of tissue, presence of gross cisterns, maximal villous size, percent of cavitated villi, percent of villi exhibiting circumferential trophoblast hyperplasia, and presence of necrosis and primitive stromal features). RESULTS: Contemporary complete moles were evacuated at an earlier mean gestational age (8.5 vs. 17.0 weeks, P = .00008). Histologically, contemporary complete moles had less circumferential trophoblastic hyperplasia (39% vs. 75% of villi, P = .03), a smaller mean maximal villous diameter (5.7 vs. 8.2 mm, P = .001), more primitive villous stroma (70% vs. 10% of cases, P = .0003) and less global necrosis (22% vs. 54% of cases, P = .02). CONCLUSION: These striking morphologic differences indicate that pathologic findings in complete molar gestations have changed significantly over the past several decades due to the current practice of very early uterine evacuation. Contemporary complete moles are often characterized by subtle morphologic alterations that may result in their misclassification as partial moles or nonmolar spontaneous abortions. It is important for pathologists to recognize the distinctive histopathologic features of early complete hydatidiform mole.

Adult↗
PubMed1998

Reproductive outcome after methotrexate treatment of tubal pregnancies.

OBJECTIVE: To evaluate subsequent pregnancy outcomes in women who have been treated with methotrexate for tubal pregnancies. METHODS: Descriptive study of subsequent pregnancy outcomes in 170 women who were treated with methotrexate for tubal pregnancy at Brigham and Women's Hospital during 1989-1994. Patients who agreed to participate were administered a telephone interview. Fertility rates and outcomes were calculated for patients who tried to conceive after receiving methotrexate. RESULTS: One hundred four of the 170 women with tubal pregnancies identified during the study period returned their consent forms. The other 66 patients were either unable to be reached by phone, and/or their consent form was returned without a forwarding address. Ninety-four patients (90%) agreed to participate in the study. Eighty-two (87%) women tried to conceive after receiving methotrexate for their tubal pregnancies, and 57 (70%) were successful. Forty-six (81%) of the 57 women experienced intrauterine pregnancies, and 11 (19%) had recurrent tubal pregnancies. When the first subsequent postmethotrexate outcome was examined, there were 26 (46%) term births, 5 (9%) preterm births, 11 (19%) recurrent ectopics and 15 (26%) spontaneous abortions. Over the six-year study period, 42 (74%) women had at least one live birth. There were no congenital anomalies or stillbirths in the subsequent pregnancies. CONCLUSION: Pregnancy outcomes after methotrexate treatment for tubal pregnancy are comparable to reported experience with surgical therapy. Patients who are treated with methotrexate for tubal pregnancies can be assured that their methotrexate exposure should have no untoward effects on subsequent pregnancies.

Female↗
PubMed1998

Oral contraceptive use in relation to smoking.

BACKGROUND: Use of OC simultaneous with smoking in older women remains a concern for prescribing physicians, in light of current guidelines for OC use and evidence from recent studies about risks and benefits of different OC agents. It is useful to look at prevalence of OC use simultaneously with smoking after age of 35, as an indication of the effectiveness of these guidelines. METHODS: Survey of OC use in relation to smoking on a representative sample of 1138 urban women aged 40-54, from Geneva, Switzerland. History of exposure to both OC and smoking is analyzed up to the age of 40. RESULTS: Seventy-six percent of women had ever used OC, and 49% had ever smoked by age 40. Fifty-four percent of women reported OC exposure simultaneous to smoking at some time, and simultaneous exposure accounted for 48% of woman-years of use. But simultaneous use decreased with age, such that simultaneous users during age 36-40 accounted for 37% of OC users during that age period, and for only 13% of all ever OC users. Similarly, woman-years of OC use simultaneous with smoking fell after age 25, and woman-years during age 36-40 accounted for 36% of woman-years during that age period, such that only 5% of woman-years of OC use overall. CONCLUSIONS: OC use simultaneous with smoking after age 35 is not typical. Results suggest that a physician today may prescribe a type of OC that fits a young woman's current risk profile, confident of being able to change OC use or smoking by the time the woman enters an older risk profile. Prescribing OC to a young smoker does not generally lead to simultaneous exposure at a later age.

Adult↗
PubMed1997

Is there a genetic susceptibility locus for Parkinson's disease on chromosome 22q13?

The cytochrome P450 mono-oxygenase gene, CYP2D6 on chromosome 22q13 (ch22q13), has been inconsistently associated with Parkinson's disease. Associations with CYP2D6 have either been absent altogether or have involved more than one polymorphism, many of which have the same metabolic effect on gene expression. We examined the association between CYP2D6 polymorphisms and Parkinson's disease in a case-control study and included 10 polymorphic dinucleotide repeat markers linked to CYP2D6 to determine whether the association was present or due to linkage disequilibrium. There was no association between any polymorphism of CYP2D6 and Parkinson's disease, but two of 10 dinucleotide repeat markers linked to CYP2D6 were associated with the disease. These results provide evidence to suggest that there may be an unidentified locus for susceptibility to Parkinson's disease that is in linkage disequilibrium with dinucleotide repeat markers mapping near CYP2D6 on ch22q13.

Adult↗
PubMed1997

Mechanical bowel preparation for elective colorectal surgery. A prospective, randomized, surgeon-blinded trial comparing sodium phosphate and polyethylene glycol-based oral lavage solutions.

AIM: The aim of this study was to compare the cleansing ability, patient compliance, and safety of two oral solutions for elective colorectal surgery. METHODS: All eligible patients were prospectively randomized to receive either 4 l of standard polyethylene glycol (PEG) solution or 90 ml of sodium phosphate (NaP) as mechanical bowel preparation for colorectal surgery. A detailed questionnaire was used to assess patient compliance. In addition, the surgeons, blinded to the preparation, intraoperatively evaluated its quality. Postoperative septic complications were also assessed. The calcium serum level was monitored before and after bowel preparation. Statistical analysis was performed using the Wilcoxon's rank-sum test and Fisher's exact test. RESULTS: Two hundred patients, well matched for age, gender, and diagnosis, were prospectively randomized to receive either PEG or NaP solutions for elective colorectal surgery. All patients completed all phases of the trial. There was a significant decrease in serum calcium levels after administration of both NaP (mean, 9.3-8.8 mg/dl) and PEG (9.2-8.9 mg/dl), respectively (P < 0.0001), with no clinical sequelae. However, patient tolerance to NaP was superior to PEG: less trouble drinking the preparation (17 vs. 32 percent; P < 0.0002), less abdominal pain (12 vs. 22 percent; P = 0.004), less bloating (7 vs. 28 percent), and less fatigue (8 vs. 17 percent), respectively. Additionally, 65 percent of patients who received the NaP preparation stated they would repeat this preparation again compared with only 25 percent for the PEG group (P < 0.0001). Ninety-five percent of patients who received the NaP solution tolerated 100 percent of the solution compared with only 37 percent of the PEG group (P < 0.0001). For quality of cleansing, surgeons scored NaP as "excellent" or "good" in 87 compared with 76 percent after PEG (P = not significant). Rates of septic and anastomotic complications were 1 percent and 1 percent for NaP and 4 percent and 1 percent for PEG, respectively (P = not significant). CONCLUSION: Both oral solutions proved to be equally effective and safe. However, patient tolerance of the small volume of NaP demonstrated a clear advantage over the traditional PEG solution.

Colonic Diseases↗
PubMed1997

Liposome-mediated gene transfer to lung isografts.

OBJECTIVES: Our objective were to determine the feasibility, efficacy, and safety of in vivo and ex vivo liposome-mediated gene transfer to lung isografts. METHODS: Fischer rats were divided into three main groups: (1) Nontransplant setting: Liposome-chloramphenicol acetyl transferase cDNA was intravenously injected, and lungs were harvested at different time points: 2, 6, 12, and 24 hours; 2, 5, 8, and 21 days (n = 3). Chloramphenicol acetyl transferase activity was determined in lungs, hearts, livers, and kidneys. The distribution and type of transfected cells were evaluated by in situ hybridization. Lung toxicity was assessed by arterial oxygen tension, histology, and tumor necrosis factor-alpha levels. (2) In vivo graft transfection: Left lungs were transplanted 6 hours, 4 hours, and 15 minutes after intravenous injection and were assessed for chloramphenicol acetyl transferase activity and arterial oxygen tension on postoperative day 2. (3) Ex vivo graft transfection: Grafts were infused ex vivo with either 660 micrograms (n = 3) or 330 micrograms (n = 3) of DNA complexed to liposomes and stored at 10 degrees C for 4 hours. Chloramphenicol acetyl transferase activity was assessed 44 hours after transplantation. RESULTS: Transgene expression was detected in endothelial cells, macrophages, and interstitial cells. Chloramphenicol acetyl transferase activity was present as early as 2 hours, increased significantly between 6 hours and 8 days, and then decreased to minimal levels by 21 days. Chloramphenicol acetyl transferase activity was greatest in donor lungs and hearts and minimal in livers and kidneys. Arterial oxygen tension was normal in treated animals. Inflammation was minimal, and tumor necrosis factor-alpha levels increased only sevenfold in treated animals. CONCLUSION: In vivo and ex vivo liposome-mediated gene transfer to lung isografts allows significant transgene expression with minimal effects on graft function.

Animals↗
PubMed1997

Screening for neuroblastoma is ineffective in reducing the incidence of unfavourable advanced stage disease in older children.

Neuroblastoma exhibits many characteristics which would suggest that preclinical detection may improve outcome. The Quebec Neuroblastoma Screening Project was initiated to determine whether mass screening could reduce mortality in a large cohort of infants. All 476,603 children born in the province of Quebec during a 5-year period of time (1 May 1989 to 30 April 1994) were eligible for determinations of urinary catecholamine metabolites at 3 weeks and 6 months of age. Children with positive screening were referred to one of four paediatric cancer centres in Quebec for uniform evaluation and treatment. Standardised incidence ratios (SIRs) were calculated for neuroblastoma in Quebec and two comparable population-based controls during the same period of time using similar ascertainment procedures. Compliance with screening in Quebec was 91% at 3 weeks (n = 425,816) and 74% at 6 months (n = 349,706). Up to 31 July 1995 with a follow-up of the birth cohort of 15-75 months, 118 cases of neuroblastoma were diagnosed, 43 detected preclinically by screening, 20 detected clinically prior to screening at 3 weeks of age and 55 detected clinically after 3 weeks of age having normal screens (n = 52) or never screened (n = 3). Based on data from concurrent control populations, 54.5 cases of neuroblastoma would have been expected in Quebec during the study period for an SIR of 2.17 (95% CI 1.79-2.57, P < 0.0001). For the two control groups, the overall SIR was 1.00 (NS). SIRs for Quebec by age at diagnosis in yearly intervals show a marked increased incidence under 1 year of age (SIR = 2.85, 95% CI 2.26-3.50), with no reduction in incidence in subsequent years. We conclude that screening for neuroblastoma markedly increases the incidence in infants without decreasing the incidence of unfavourable advanced stage disease in older children. It is unlikely that screening for neuroblastoma in infants will reduce the mortality of this disease.

Canada↗
PubMed1997

Lhermitte-Duclos disease: literature review and novel treatment strategy.

BACKGROUND: Lhermitte-Duclos disease (LDD) is a rare pathologic entity involving the cerebellum. The fundamental nature of the entity and its pathogenesis remain unknown, and considerable debate has centered on whether it represents a neoplastic, malformative or hamartomatous lesion. The cell or cells of origin remain incompletely defined. Previous reports of cases in the English literature have dealt predominantly with the clinical and pathological aspects yet few address issues of treatment. METHODS: A case of Lhermitte-Duclos disease (LDD) in a 54-year-old female leading to local compressive symptoms and obstructive hydrocephalus is presented. A craniectomy, in addition to a C1 laminectomy followed by a decompressive duroplasty (using autologous fascia lata graft) was performed. RESULTS: The patient clinically improved and follow-up MRI 11 months post-operatively revealed improvement in hydrocephalus. CONCLUSION: The histological and immunohistochemical features of the lesion are described, emphasizing the role of an abnormal dysplastic granule cell layer. The evidence in favor of each of the major theories of pathogenesis, malformative and neoplastic is discussed. Based on these facts a form of surgical intervention involving decompressive duroplasty is proposed.

Cerebellar Diseases↗