When aliens invade: multiple mechanisms for dissociation between will and action.
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Biomedical subjects
Publications and source records attributed to G Goldberg.
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Although gap junction channels are still widely viewed as large, non-specific pores connecting cells, the diversity in the connexin family has led more attention to be focused on their permeability characteristics. We summarize here the current status of these investigations, both published and on-going, that reveal both charge and size selectivity between gap junction channels composed of different connexins. In particular, this review will focus on quantitative approaches that monitor the expression level of the connexins, so that it is clear that differences that are seen can be attributed to channel properties. The degree of selectivity that is observed is modest compared to other channels, but is likely to be significant for biological molecules that are labile within the cell. Of particular relevance to the in vivo function of gap junctions, recent studies are summarized that demonstrate that the connexin phenotype can control the nature of the endogenous traffic between cells, with consequent effects on biological effects of gap junctions such as tumor suppression.
Hip Arthroplasty to alleviate pain related to arthritic degeneration has become one of the most common orthopedic procedures performed. As the elderly population expands, the number of such procedures can be expected to continue to increase. An electrodiagnostic evaluation can aid in localization, help identify the mechanism of injury, and be used as a tool to identify the nature and severity of the nerve pathology. Electrodiagnosis can also be used to generate a prognosis for recovery from nerve damage following hip surgery.
Evoked potentials (EPs) have been shown to have useful prognostic value during the acute phase of traumatic and anoxic coma. We have hypothesized that EPs obtained in the subacute phase can be used to assess prognosis for functional recovery in minimally responsive patients with diffuse brain damage due to either brain trauma or anoxia. This pilot study correlated graded brainstem auditory evoked potentials (BAEPs) and upper extremity somatosensory evoked potentials (UESSEPs) with outcome grade based on the discharge Disability Rating Scale (DRS) score of 33 patients admitted to a responsiveness assessment program of a brain injury rehabilitation unit with an initial DRS score of 22 or greater. Results indicated a significant correlation with outcome grade for both the BAEP grade (P < .02) and the UESSEP grade (P < .02). The BAEP had a higher sensitivity and lower specificity, as false-positive exceeded false-negative predictions. The UESSEP tended to predict outcome more accurately and with a balanced number of false-positive and false-negative predictions. EPs were also found to be useful for detecting occult impairment of sensory function. This pilot study demonstrates that EPs performed near the time of admission to the rehabilitation unit can be useful in guiding the rehabilitation management of the minimally responsive patient by helping to predict functional recovery and to detect occult impairment of sensory systems.
OBJECTIVE: To evaluate the utility and neuropsychological correlates of serially performed recordings of event-related potentials (ERPs) in patients recovering from a severe closed head injury (CHI). DESIGN: Prospective longitudinal study. SETTING: Brain injury rehabilitation unit based in a national rehabilitation hospital. SUBJECTS: Sixteen patients with severe CHI (significant degree of impaired consciousness greater than 24 hours) subclassified into two severity groups according to initial Glasgow Coma Scale (GCS) score: those with initial GCS score < 9, consistent with a more severe injury; and those with initial GCS score > 8, indicating a less severe injury. METHODS: ERPs were elicited using the standard auditory P300 "oddball" detection paradigm. ERP recordings were carried out three times: 2 months after injury, 1 month later, and 2.5 months or more after the initial study. Parameters analyzed included latencies and amplitudes of the P3, N2, P2, and N1 components of the ERPs. Correlations between changes in these ERP parameters and specific neuropsychological test results were evaluated. RESULTS: Initial P3 latencies in the more severely injured group were significantly longer (P < .05) than those recorded in the less severely injured patients. In subsequent recordings, P3 latency was found to be significantly shorter compared with the initial P3 latency, and the difference in P3 latency between the two patient groups was no longer statistically significant by the time of the third recording. For the group as a whole, P3 latency decreased significantly on each repeated recording. N2 latency was found to be significantly shorter (P < .05) between the first and third recordings. Cognitive performance significantly improved between the first and third recordings. P3 latency shortening was correlated with improvement in neuropsychological test scores for short-term and long-term story recall and for word recall. N2 latency shortening was correlated with improvement in the neuropsychological test scores for word recall only. CONCLUSION: ERP recordings performed in the subacute stage after CHI may assist in evaluating injury severity. Moreover, serially performed recordings of P3 latency may be used as a physiologic index of brain activity that correlates with recovery from CHI.
BACKGROUND: The tetravalent rhesus rotavirus vaccine (RV-TV) has been administered to several thousand children in multiple settings throughout the world. It has been proved safe and efficacious, resulting in an application for licensure in 1997. However, only limited information has been reported on viral shedding after RV-TV vaccination. METHODS: Stool specimens were collected between Days 3 and 5 after administration of each of 3 doses of RV-TV to 248 subjects 6 to 12 weeks of age in 8 centers across the United States. Rotavirus antigen was measured by an enzyme-linked immunosorbent assay to determine the number of subjects who shed after each dose. The relative quantities of vaccine strains shed were then determined by plaque purification and serotype analysis. RESULTS: Rotavirus shedding was detected in 125 (50.4%) subjects, and 19 shed after more than 1 dose. Although fewer subjects shed rotavirus after Dose 2 (14.5%), shedding after Doses 1 (26.0%) and 3 (22.5%) were comparable. After plaque purification and serotyping, most viruses shed (76.2%) were identified as G3 after Dose 1, but a major shift to G2 strains was found after Doses 2 (61.3%) and 3 (69.0%). CONCLUSIONS: Sequential RV-TV administrations caused no overall significant decrease in the number of vaccinees who experienced detectable shedding. A major shift in shedding was found from the serotype G3 vaccine strain (RRV) after the first dose of vaccine to the serotype G2 reassortant after Doses 2 and 3.
Traumatic brain injury is one of the leading causes of injury and death among the young in the United States. Severity can range from the brief confusion of a football player who has had his "bell rung" to the complete loss of voluntary behavior seen in the vegetative state. In this article, Dr Goldberg reviews the rehabilitation process used to restore the fullest function possible within the limits of the patient's injury, with emphasis on innovative assessment and treatment techniques. He also describes an approach to evaluation of minimally conscious patients that can be used to detect and confirm the presence of active cognition.
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BACKGROUND: Recent clinical trials with a combination of interferon (IFN alpha) and 13 cis-retinoic acid resulted in high response rates among women with locally advanced and metastatic carcinoma of the uterine cervix. The authors sought to amplify these observations by employing the isomer of 13 cis-retinoic acid, all-trans retinoic acid (tRA), in combination with IFN alpha. METHODS: Sequential clinical trials were initiated by the New York Gynecologic Oncology Group to test the combination of tRA and IFN alpha in women with metastatic or recurrent carcinoma of the cervix who had failed primary therapy. IFN alpha was administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was administered at 50 mg/m2 orally 3 times per day on a daily schedule (daily regimen), whereas in the second trial, tRA was administered at the same dose 3 times per day, but only on Days 1-3 each week (intermittent schedule). Clinical outcomes included response to therapy and survival. Plasma pharmacokinetic studies of tRA were performed in both trials to assess the effects of different schedules on plasma levels of the drug. RESULTS: Fourteen women with metastatic or recurrent squamous cell carcinoma of the cervix were enrolled in the daily trial and 12 women in the intermittent trial. There was no clinical activity for either regimen, and both studies were terminated according to an early stopping rule. Because tRA has been reported to induce its own metabolism, plasma levels of tRA were measured on Days 1, 8, and 28. The change in the area under the time versus tRA concentration curve (AUC) was significantly different between the two groups. The average AUC on Day 8 was 14% of that observed on Day 1 for the daily treatment group; in contrast, it was 107% on Day 1 in the intermittent treatment group. In 6 of 8 patients studied in the daily trial, the AUC decreased at least 60% by either Week 2 or Week 4. In contrast, in the intermittent trial, only 3 of 9 patients experienced >60% decrease in plasma levels of the drug at either Day 8 or Day 28. CONCLUSIONS: The combination of tRA + IFN alpha was inactive in patients with advanced carcinoma of the cervix when employed at these doses on either the daily or intermittent schedule. The failure of activity of this regimen did not result from induction of metabolism of tRA, suggesting that intrinsic mechanisms of resistance to tRA at the cellular level may be of greater importance.
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OBJECTIVE: To document the use of statistical methods in the recent rehabilitation research literature. DESIGN: Descriptive survey study. METHODS: All 1,039 articles published between January 1990 and December 1993 in the American Journal of Physical Medicine and Rehabilitation and the Archives of Physical Medicine and Rehabilitation were reviewed for the use of statistical methods. RESULTS: There were 682 (66%) research articles in the sample that included systematic data collection and analysis. The most frequently encountered analytic tests and techniques included: (1) analysis of variance, (2) t tests, (3) correlation analysis, (4) contingency table analysis, (5) regression, and (6) nonparametric tests. Results were compared with results of a review of the 1982 rehabilitation literature by Wainapel and Kayne. Our study showed an increased sophistication in statistical methodology as well as a more intense use of such methods. In addition, there was a large number of relatively obscure and poorly documented tests encountered in the more recent literature. There was also a lack of adherence to a standardized format for describing statistical methods. CONCLUSIONS: The following recommendations are made: (1) Training curricula for rehabilitation professionals should provide instruction in the most commonly-encountered statistical methods and should be revised as needed to reflect changes in statistical method usage. (2) When less common statistical tests are applied, the responsibility of the authors to fully describe and justify their methods should be recognized. (3) Critical assessment of the literature is facilitated when statistical methods are reported in a standardized format.
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BACKGROUND: Increasing incidence and mortality rates from cutaneous melanoma are a major public health concern. As part of a national effort to enhance early detection of melanoma/skin cancer, the American Academy of Dermatology (AAD) has sponsored an annual education and early detection program that couples provision of skin cancer information to the general public with almost 750,000 free skin cancer examinations (1985-1994). OBJECTIVE: To begin to evaluate the impact of this effort, we determined the final pathology diagnosis of persons attending the 1992-1994 programs who had a suspected melanoma at the time of examination. METHODS: We directly contacted all such persons by telephone or mail and received pathology reports from those who had a subsequent biopsy. RESULTS: We contacted 96% of the 4458 persons with such lesions among the 282,555 screenings in the 1992-1994 programs. We obtained a final diagnosis for 72%, and the positive predictive value for melanoma was 17%. Three hundred seventy-one melanomas were found in 364 persons. More than 98% had localized disease. More than 90% of the confirmed melanomas with known histology were in situ or "thin" lesions (< or = 1.50 mm thick). The median thickness of all melanomas was 0.30 mm. The 8.3% of AAD cases with advanced melanoma (metastatic disease, regional disease, or lesions > or = 1.51 mm) is a lower proportion than that reported by the 1990 Surveillance, Epidemiology and End Result Registry. The rate of thickest lesions (> or = 4 mm) and late-stage melanomas among all participants was 2.83 per 100,000 population. Of persons with a confirmed melanoma, 39% indicated (before their examination) that without the free program, they would not have considered having a physician examine their skin. CONCLUSION: The 1992-1994 free AAD programs disseminated broad skin cancer educational messages, enabled thousands to obtain a free expert skin cancer examination, and found mostly thin, localized stage 1 melanomas (usually associated with a high projected 5-year survival rate). Because biases impose possible limitations, future studies with long-term follow-up and formal control groups should determine the impact of early detection programs on melanoma mortality.
There has been growing evidence that maternal obesity is associated with an increased risk of congenital malformations, particularly of neural tube defects. Two new studies confirm this relationship and indicate that it is independent of possible covariant confounders such as maternal age, socioeconomic status, education, smoking, and vitamin intake, including folic acid. There is a suggestion that folic acid loses its protective benefit in overweight and obese mothers. These new findings add to a long list of obstetric morbidities, and show a steep gradient with increasing maternal fatness and point to the urgent need to prevent excess weight gain in young women.
The treatment of locally advanced carcinoma of the cervix with radiation therapy as a single modality is inadequate, specifically for stage III and IVA disease. While chemotherapy as single-modality therapy is ineffective in advanced cervical cancer, there is some evidence of efficacy when used in combination with radiation therapy. A recently conducted phase II trial from the Albert Einstein College of Medicine used standard whole pelvic radiation therapy with concurrent cisplatin 20 mg/m(2)/d X 5 days for four courses in women with stage IB to IVA cervical cancer. Toxicities, mainly hematologic and soft tissue, were acceptable in this trial. There was only a modest impact on disease-free survival among women with stage III disease. A subsequent phase I trial conducted by the New York Gynecologic Oncology Group tested the addition of amifostine to the combination of cisplatin plus radiation therapy using the Albert Einstein College of Medicine regimen. Amifostine at doses escalated from 340 to 910 mg/m(2) was administered immediately before cisplatin. The dose-limiting toxicity was hypotension. Amifostine should be tested in future clinical trials either as a cytoprotective agent in patients receiving cisplatin plus radiation therapy or, alternatively, to assess dose intensification of cisplatin in combination with radiation therapy.
Demographic and clinical information and referral outcome were systematically collected from 347 alcoholics who telephoned to inquire about treatment on alcoholism clinical research protocols over a 1-year period. The ratio of male to female callers was 7:3, with 2:1 scheduling appointments, 3:2 keeping appointments, and 3:2 actually enrolling in a treatment study. These data indicate that although a smaller ratio of female alcoholics initially called for treatment, those who did call were more likely to actually enter treatment than were male callers. A ratio of 2:1 non-minority to minority alcoholics called the clinic, with 7:3 scheduling appointments, 8:1.6 keeping appointments, and 8:1 actually entering the study. These data suggest that minority alcoholics were less likely than non-minority alcoholics to enter treatment protocols. However, discriminant function analysis found income to be a better predictor of entry into treatment than race, age, or gender, and analysis of covariance found non-minorities and minorities did not differ in rate of entry into treatment when income was used as covariate.
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