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R Grossman

Publications and source records attributed to R Grossman.

At least 19 recordsLinked to original sources
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials.

The International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) supported an international panel tasked with reviewing the methodology for clinical trials in spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the first of four papers. Here, we examine the spontaneous rate of recovery after SCI and resulting consequences for achieving statistically significant results in clinical trials. We have reanalysed data from the Sygen trial to provide some of this information. Almost all people living with SCI show some recovery of motor function below the initial spinal injury level. While the spontaneous recovery of motor function in patients with motor-complete SCI is fairly limited and predictable, recovery in incomplete SCI patients (American spinal injury Association impairment scale (AIS) C and AIS D) is both more substantial and highly variable. With motor complete lesions (AIS A/AIS B) the majority of functional return is within the zone of partial preservation, and may be sufficient to reclassify the injury level to a lower spinal level. The vast majority of recovery occurs in the first 3 months, but a small amount can persist for up to 18 months or longer. Some sensory recovery occurs after SCI, on roughly the same time course as motor recovery. Based on previous data of the magnitude of spontaneous recovery after SCI, as measured by changes in ASIA motor scores, power calculations suggest that the number of subjects required to achieve a significant result from a trial declines considerably as the start of the study is delayed after SCI. Trials of treatments that are most efficacious when given soon after injury will therefore, require larger patient numbers than trials of treatments that are effective at later time points. As AIS B patients show greater spontaneous recovery than AIS A patients, the number of AIS A patients requiring to be enrolled into a trial is lower. This factor will have to be balanced against the possibility that some treatments will be more effective in incomplete patients. Trials involving motor incomplete SCI patients, or trials where an accurate assessment of AIS grade cannot be made before the start of the trial, will require large subject numbers and/or better objective assessment methods.

Clinical Trials as Topic↗
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures.

An international panel reviewed the methodology for clinical trials of spinal cord injury (SCI), and provided recommendations for the valid conduct of future trials. This is the second of four papers. It examines clinical trial end points that have been used previously, reviews alternative outcome tools and identifies unmet needs for demonstrating the efficacy of an experimental intervention after SCI. The panel focused on outcome measures that are relevant to clinical trials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are of three main classes: (1) those that provide an anatomical or neurological assessment for the connectivity of the spinal cord, (2) those that categorize a subject's functional ability to engage in activities of daily living, and (3) those that measure an individual's quality of life (QoL). The American Spinal Injury Association impairment scale forms the standard basis for measuring neurologic outcomes. Various electrophysiological measures and imaging tools are in development, which may provide more precise information on functional changes following treatment and/or the therapeutic action of experimental agents. When compared to appropriate controls, an improved functional outcome, in response to an experimental treatment, is the necessary goal of a clinical trial program. Several new functional outcome tools are being developed for measuring an individual's ability to engage in activities of daily living. Such clinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measures often do not correlate tightly with the above outcome tools, but may need to form part of Phase 3 trial measures.

Activities of Daily Living↗
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

Clinical Trials as Topic↗
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.

Clinical Trials as Topic↗
PubMed2005

Haemorrhagic complications and the incidence of asymptomatic bleeding associated with stereotactic brain biopsies.

OBJECT: Stereotactic brain biopsy is a routinely used technique for the diagnosis of brain lesions. Due to its minimally invasive nature, the potential risks associated with this procedure are sometimes underestimated. We have retrospectively analyzed the incidence of symptomatic and asymptomatic haemorrhagic complications associated with stereotactic biopsies. Various variables that may contribute to such complications have been retrospectively analyzed. METHODS: Medical and radiological records of 355 consecutive patients who underwent a diagnostic stereotactic brain biopsy were reviewed. The incidence of haemorrhage was derived from a routine post-operative CT scan done within 90-120 minutes of the biopsy. Demographic, radiographic, pathological, and clinical data were also extracted and evaluated for their possible association with haemorrhagic complications. RESULTS: Twenty-five patients (7%) experienced haemorrhagic complications associated with stereotactic biopsy, about half of whom (3.4%) were asymptomatic with no impact on the clinical course. Thirteen (3.6%) complications were symptomatic and two patients (0.6%) died. Lesions located in the brainstem were found to have a significantly higher rate of complications compared to other locations. No other variables, such as location, edema, number of biopsy specimens, or pre-existing neurological deficit showed a statistically significant impact on the incidence or severity of haemorrhage. Seven of the symptomatic complications occurred immediately post biopsy, but in six patients they developed within several hours and even days. The overall diagnostic yield of the biopsies was 93.8%, but was somewhat lower in patients experiencing a haemorrhagic complication. CONCLUSIONS: Stereotactic brain biopsy was associated with a low incidence of symptomatic haemorrhagic complications, morbidity and mortality, and a high diagnostic yield. About half of the haemorrhagic complications were asymptomatic. Lesions located in the brainstem had a higher rate of complications. No other clinical, radiographic, or pathological variables were found as predictors of increased risk for haemorrhage.

Adolescent↗
PubMed2003

Increase in peripheral benzodiazepine receptors and loss of glutamate NMDA receptors in a mouse model of closed head injury: a quantitative autoradiographic study.

Increases in peripheral type benzodiazepine receptors (PTBR) have been utilized for the detection of neuroinflammation and neurotoxicity in the brain. We have investigated the relationship between PTBR and NMDA receptor binding density in mice with closed head injury (CHI) using quantitative autoradiography. CHI was induced by a weight drop in nine mice, four of which received a single injection of the rat sarcoma (Ras) inhibitor famesyl thiosalicylate (FTS) 1 h after the insult. Sham controls received anesthesia but no contusion. The neurological status of the mice was evaluated at 1 h, and hence up to 7 days using a neurological severity score (NSS). Animals were killed 7 days after CHI and consecutive brain sections were incubated with [3H]PK11195, a PTBR antagonist, or [3H]MK801, an n-methyl-d-aspartate receptor (NMDAR) use-dependent antagonist. CHI produced large (two- to threefold), widespread increases in PK11195 binding in the traumatized hemisphere and a significant decrease (20%-40%) in NMDAR binding limited to regions at close proximity to the lesion. Histologically, these regions were characterized by glial proliferation and neuronal loss. Significant increases in PTBR binding, but no concomitant decrease in NMDAR, were identified in several regions remote from the lesion, including the contralateral ventrolateral striatum and the ipsilateral ventral thalamus. Drug treatment significantly improved the neurological deficits but had only a marginal effect on PTBR. These results support a complex role for glial activation and PTBR increases in the context of CHI.

Animals↗
PubMed2002

Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain.

Following induction of acute neuroinflammation by intracisternal injection of endotoxin (lipopolysaccharide) in rats, quantitative autoradiography was used to assess the regional level of microglial activation and glutamate (NMDA) receptor binding. The possible protective action of the antioxidant phenyl-tert-butyl nitrone in this model was tested by administering the drug in the drinking water for 6 days starting 24 hafter endotoxin injection. Animals were killed 7 days post-injection and consecutive cryostat brain sections labeled with [3H]PK11195 as a marker of activated microglia and [125I]iodoMK801 as a marker of the open-channel, activated state of NMDA receptors. Lipopolysaccharide increased [3H]PK11195 binding in the brain, with the largest increases (two- to threefold) in temporal and entorhinal cortex, hippocampus, and substantia innominata. A significant (> 50%) decrease in [125I]iodoMK801 binding was found in the same brain regions. Phenyl-tert-butyl nitrone treatment resulted in a partial inhibition (approx. 25% decrease) of the lipopolysaccharide-induced increase in [3H]PK11195 binding but completely reversed the lipopolysaccharide-induced decrease in [125I]iodoMK80 binding in the entorhinal cortex, hippocampus, and substantia innominata. Loss of NMDA receptor function in cortical and hippocampal regions may contribute to the cognitive deficits observed in diseases with a neuroinflammatory component, such as meningitis or Alzheimer's disease.

Animals↗
PubMed2001

A plague on your city: observations from TOPOFF.

The United States Congress directed the Department of Justice to conduct an exercise engaging key personnel in the management of mock chemical, biological, or cyberterrorist attacks. The resulting exercise was called "TOPOFF," named for its engagement of top officials of the United States government. This article offers a number of medical and public health observations and lessons discovered during the bioterrorism component of the exercise. The TOPOFF exercise illuminated problematic issues of leadership and decision-making; the difficulties of prioritization and distribution of scarce resources; the crisis that contagious epidemics would cause in health care facilities; and the critical need to formulate sound principles of disease containment. These lessons should provoke consideration of future directions for bioterrorism planning and preparedness at all levels of government and among the many communities and practitioners with responsibilities for national security and public health.

Bioterrorism↗
PubMed2001

Childhood trauma and risk for PTSD: relationship to intergenerational effects of trauma, parental PTSD, and cortisol excretion.

Among the adverse mental health consequences of childhood trauma is the risk related to the development of posttraumatic stress disorder (PTSD) in adulthood. Other risk factors for PTSD. including parental trauma exposure and parental PTSD, can also contribute to the experience of child trauma. We examined associations between childhood trauma and PTSD in 51 adult children of Holocaust survivors and 41 comparison subjects. in consideration of parental trauma exposure and parental PTSD. We also examined these variables in relation to 24-hr urinary cortisol levels. Adult offspring of Holocaust survivors showed significantly higher levels of self-reported childhood trauma, particularly emotional abuse and neglect. relative to comparison subjects. The difference was largely attributable to parental PTSD. Self-reported childhood trauma was also related to severity of PTSD in subjects, and emotional abuse was significantly associated with 24-hr mean urinary cortisol secretion. We conclude that the experience of childhood trauma may be an important factor in the transmission of PTSD from parent to child.

Adult↗
PubMed2001

A preliminary double-blind, placebo-controlled trial of divalproex sodium in borderline personality disorder.

BACKGROUND: Borderline personality disorder is characterized by affective instability, impulsivity, and aggression and is associated with considerable morbidity and mortality. Since anticonvulsant agents may be helpful in such symptomatology, we compared divalproex sodium with placebo in patients with borderline personality disorder. METHOD: A 10-week, parallel, double-blind design was conducted. Sixteen outpatients meeting Structured Clinical Interview for DSM-IV Axis II Personality Disorders criteria for borderline personality disorder were randomly assigned to receive placebo (N = 4) or divalproex sodium (N = 12). Change was assessed in global symptom severity (Clinical Global Impressions-Improvement Scale [CGI-I]) and functioning (Global Assessment Scale [GAS]) as well as in specific core symptoms (depression, aggression, irritability, and suicidality). RESULTS: There was significant improvement from baseline in both global measures (CGI-I and GAS) following divalproex sodium treatment. A high dropout rate precluded finding significant differences between the treatment groups in the intent-to-treat analyses, although all results were in the predicted direction. CONCLUSION: Treatment with divalproex sodium may be more effective than placebo for global symptomatology, level of functioning, aggression, and depression. Controlled trials with larger sample sizes are warranted to confirm these preliminary results.

Adolescent↗
PubMed2001

[Neurological manifestations in West Nile fever].

The West Nile fever is a viral disease transferred by a mosquito bite. It is well known in the world for the last 70 years. Recently, there was an outbreak of this disease in Israel. We will describe case reports of 2 patients who were afflicted by the disease. The first one was hospitalized with an unusual presentation including paralysis to the lower limbs, while the second one was admitted with meningitis. In both, the course was quite dramatic, and one of them expired. Reviewing the literature revealed that neurological manifestations are quite frequent among these patients (90%), while in elder people, they were fatal.

Adult↗
PubMed2001

Tretinoin cream 0.02% for the treatment of photodamaged facial skin: a review of 2 double-blind clinical studies.

In extensive clinical studies and practical use since its US Food and Drug Administration approval in 1995, tretinoin emollient cream 0.05% has been shown to be safe and effective in the treatment of fine facial wrinkles, mottled hyperpigmentation, and skin roughness. To provide additional prescribing flexibility for various patient needs, a new lower concentration formulation, tretinoin cream 0.02% was chosen for further development. Two multicenter, randomized, double-blind, vehicle-controlled clinical., studies were conducted to evaluate the safety and efficacy of the lower concentration tretinoin formulation in the treatment of moderate-to-severe facial photodamage. Results indicate statistically significant improvement in fine wrinkling, coarse wrinkling, and yellowing with the use of tretinoin cream 0.02% at week-24 end point, compared with placebo. Therapy with tretinoin cream 0.02% was well tolerated overall and demonstrated a favorable safety profile. Both studies demonstrated that tretinoin cream 0.02% is safe and effective for the treatment of moderate-to-severe photodamaged facial skin.

Administration, Topical↗
PubMed2000

Identification of alpha3, alpha4, and alpha5 chains of type IV collagen as alloantigens for Alport posttransplant anti-glomerular basement membrane antibodies.

BACKGROUND: Alport syndrome is a hereditary disorder of basement membranes especially affecting the kidneys, ears, and eyes. Some patients who undergo renal transplantation lose their kidneys as a result of posttransplant anti-glomerular basement membrane (anti-GBM) disease. METHODS: In the present study, we analyzed serum from 21 unselected Alport patients who underwent renal transplantation. Eleven samples were from patients without posttransplant anti-GBM nephritis, and 10 were from patients with this disease. RESULTS: Thirteen serum samples [10 alport posttransplant nephritis serum (APTN) and three Alport posttransplant serum (APT)] revealed linear binding to the GBM by indirect immunofluorescence. By using direct ELISA and immunoblotting with GBM constituents and type IV collagen NC1 domains from bovine, human, and recombinant sources, we detected anti-GBM antibodies in all Alport patients in varying titers. Five samples showed specific reactivity to the alpha3 chain, four to the alpha5 chain, six to both alpha3 and alpha5 chains, one to the alpha3 and alpha4 chains, and two to the alpha3, alpha4, and alpha5 chains of type IV collagen. The varied spectrum of reactivities was present equally in nephritic and non-nephritic sera. Ten control samples from non-Alport transplant patients did not exhibit specific binding to the GBM. CONCLUSIONS: These results suggest that the absence of alpha3, alpha4, and alpha5 chains of type IV collagen in the Alport kidney leads to alloantibodies in all Alport patients who receive transplants, irrespective of whether they develop nephritis or not. Although all Alport transplant patients develop this humoral response, only a select few develop anti-GBM disease. We suggest that this difference could be attributable to a genotypic effect on the ability of some individuals to launch a cell-mediated immune response.

Animals↗
PubMed2000

Mycophenolic acid area under the curve values in African American and Caucasian renal transplant patients are comparable.

The possibility of an effect of ethnicity on the pharmacokinetics of mycophenolic acid, the immunosuppressive metabolite of the prodrug mycophenolate mofetil, was studied over 90 days following renal transplantation in African American (n = 13) and Caucasian patients (n = 20). Since renal dysfunction and time after transplant surgery are two factors known to alter mycophenolic acid pharmacokinetics, two-way analysis of variance of the data at each time point with ethnicity and renal function status as covariates was used to evaluate the possibility of an ethnicity effect on the pharmacokinetic parameters. No statistically significant difference based on ethnicity was detected for the primary pharmacokinetic parameters, abbreviated mycophenolic acid area under the concentration-time curve (MPA AUC), or the predose trough concentration on study days 4, 7, 14, 28, or 90. A statistically significant decrease in MPA AUC and increase in oral apparent clearance were observed in renally impaired patients regardless of ethnicity on days 4, and 4 and 7, respectively. The suggested mechanism for these differences is uremia-induced increased MPA free fraction, leading to a temporary increased clearance for this restrictively cleared drug.

Adult↗