Biomedical subjects
Publications and source records attributed to J Clark.
The first solid-phase synthesis of zatebradine 1 and its analogues is reported. This has resulted in the preparation of compounds with increased ability to reduce the spontaneous beating of isolated guinea-pig atria in a concentration-dependent manner. One example, 8g, showed a maximum reduction of beating of 80% at 3 microM compared to a reduction of 40% at 3 microM with zatebradine 1.
BACKGROUND: A modified Phase I/II trial was conducted evaluating the incorporation of three-dimensional conformal radiation therapy into a strategy of sequential and concurrent carboplatin/paclitaxel in Stage III unresectable nonsmall cell lung carcinoma (NSCLC). The dose of thoracic conformal radiation therapy (TCRT) from 60 to 74 gray (Gy) was increased. Endpoints included response rate, toxicity, and survival. METHODS: Sixty-two patients with unresectable Stage III NSCLC were included. Patients received 2 cycles of induction carboplatin (area under the concentration curve [AUC], 6) and paclitaxel (225 mg/m(2) over 3 hours) every 21 days. On Day 43, concurrent TCRT and weekly (x 6) carboplatin (AUC, 2) and paclitaxel (45 mg/m(2)/3 hours) were initiated. The TCRT dose was escalated from 60 to 74 Gy in 4 cohorts (60, 66, 70, and 74 Gy). RESULTS: The response rate to induction carboplatin/paclitaxel was 40%. Eight patients (13%) progressed on the induction phase. No dose-limiting toxicity was observed during the escalation of the TCRT dose from 60 to 74 Gy. The major toxicity was esophagitis, however, only 8% developed Grade 3/4 esophagitis using Radiation Therapy Oncology Group criteria. The overall response rate was 52%. Survival rates at 1, 2, 3, and 4 years were 71%, 52%, 40%, and 36%, respectively, with a median survival of 26 months. The 1-, 2-, and 3-year progression free survival probabilities were 47%, 35%, and 29%, respectively. CONCLUSIONS: Incorporation of TCRT with sequential and concurrent carboplatin/paclitaxel is feasible, and dose escalation of TCRT to 74 Gy is possible with acceptable toxicity. Overall response and survival rates are encouraging. Both locoregional and distant failure remain problematic in this population of patients.
The discovery of Org 24598, one of the first potent and selective inhibitors of the glycine transporter is discussed. In vitro structure-activity relationships (SARs) data for interaction of a ligand with this system is discussed.
Prefrontal cortex plays a central role in mnemonic control, with left inferior prefrontal cortex (LIPC) mediating control of semantic knowledge. One prominent theory posits that LIPC does not mediate semantic retrieval per se, but rather subserves the selection of task-relevant knowledge from amidst competing knowledge. The present event-related fMRI study provides evidence for an alternative hypothesis: LIPC guides controlled semantic retrieval irrespective of whether retrieval requires selection against competing representations. With selection demands held constant, LIPC activation increased with semantic retrieval demands and with the level of control required during retrieval. LIPC mediates a top-down bias signal that is recruited to the extent that the recovery of meaning demands controlled retrieval. Selection may reflect a specific instantiation of this mechanism.
Altered expression of genes can have phenotypic consequences in cancer development and treatment, developmental abnormalities, and differentiation processes. Here we describe a rapid approach, termed comparative expressed sequence hybridization (CESH), which gives a genome-wide view of relative expression patterns within tissues according to chromosomal location. No prior knowledge of genes or cloning is required, and minimal amounts of tissue can be used. Expression profiles are achieved in a manner similar to the identification of chromosomal imbalances by comparative genomic hybridization analysis. The approach is demonstrated to indicate a chromosomal region that harbors overexpressed genes that may be associated with a drug-resistant phenotype. In addition, known and new regions of differential gene expression in both normal tissues and tumor samples from the soft tissue sarcoma group of rhabdomyosarcoma (RMS) are indicated. These regions included 2p24; overexpression of MYCN at 2p24 was confirmed by quantitative reverse transcription-PCR for all of the alveolar RMS cases and did not necessarily correspond to genomic amplification. Evidence including region specific microarray analysis indicated that overexpression of several genes from a region may be required for detection by CESH. This evidence is consistent with clusters of functionally related genes and mechanisms that affect the expression of a number of genes at a particular genomic location. The distinctive CESH profiles demonstrated in different subtypes of RMS show potential for tumor classification.
Decreased pulmonary expression of Forkhead Box f1 (Foxf1) transcription factor was associated with lethal alveolar hemorrhage in 55% of the Foxf1 +/- newborn mice. The severity of the pulmonary abnormalities correlates with the levels of Foxf1 mRNA. Defects in alveolarization and vasculogenesis were observed in subsets of the Foxf1 +/- mice with relatively low levels of expression from the normal Foxf1 allele. Lung hemorrhage was coincident with disruption of the mesenchymal-epithelial cell interfaces in the alveolar and bronchiolar regions of the lung parenchyma and was associated with increased apoptosis and reduced surfactant protein B (SP-B) expression. Finally, the lung defect associated with the Foxf1 +/- mutation was accompanied by reduced expression of vascular endothelial growth factor (VEGF), the VEGF receptor 2 (Flk-1), bone morphogenetic protein 4 (Bmp-4), and the transcription factors of the Brachyury T-Box family (Tbx2-Tbx5) and Lung Kruppel-like Factor. Reduction in the level of Foxf1 caused neonatal pulmonary hemorrhage and abnormalities in alveologenesis, implicating this transcription factor in the regulation of mesenchyme-epithelial interaction critical for lung morphogenesis.
Conditional targeted ablation of specific cell populations in living transgenic animals is a very powerful strategy to determine cell functions in vivo. This approach would be of particular value to study the functions of distinct neuronal populations; however, the transgene of choice for conditional cell ablation studies in mice, the herpes simplex virus thymidine kinase gene, cannot be used to ablate neurones as its principal mode of action relies on cell proliferation. Here we report that expression of the E.coli nitroreductase gene (Ntr) and metabolism of the prodrug CB1954 (5-aziridin-1-yl-2-4-dinitrobenzamide) to its cytotoxic derivative can be used to conditionally and acutely ablate specific neuronal populations in vivo. As proof of principal, we have ablated olfactory and vomeronasal receptor neurones by expressing Ntr under the control of the olfactory marker protein (OMP) gene promoter. We demonstrate that following CB1954 administration, olfactory and vomeronasal receptor neurones expressing the transgene were selectively eliminated from the olfactory epithelium (OE), and projections to the olfactory bulb (OB) were lost. The functional efficacy of cell ablation was demonstrated using a highly sensitive behavioural test to show that ablated mice had lost the olfactory ability to discriminate distinct odors and were consequently rendered anosmic. Targeted expression of Ntr to specific neuronal populations using conventional transgenes, as described here, or by "knock-in" gene targeting using embryonic stem cells may be of significant value to address the functions of distinct neuronal populations in vivo.
Andersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.
A cross-correlation method for recording spinal myotatic reflexes has been developed to meet the need for brief test periods in babies and children and subjects with central neurological pathology. In normal adult subjects the method has been validated by comparing excitatory and inhibitory reflexes obtained with cross-correlation with those obtained with conventional signal averaging. In the cross-correlation method a pseudo-random binary sequence of 64 brief tendon taps was delivered in <1.5 s, and in the averaging method 20-150 taps at one per second. The reflexes were expressed as unit impulse responses to enable direct, quantitative comparisons to be made. With cross-correlation the responses were slightly expanded in time, had lower peak amplitudes, and onset latencies advanced by 10 ms, the clock period of the pseudo-random binary sequence. The amplitude of biceps phasic stretch reflex increased with muscle contraction in a similar manner with both methods. In tests for stationarity the amplitude of biceps phasic stretch reflex varied <10% in the first six repeats of the pseudo-random binary sequence. The tap force required at threshold for cross-correlation was approximately half that for averaging, but with both methods the magnitude of biceps phasic stretch reflex varied linearly with tap force over the range of one to two times threshold. The validity of responses obtained with cross-correlation was assessed by a statistical procedure. In conclusion, the cross-correlation method is robust and gives similar results to those obtained with averaging.
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BACKGROUND: In assigning risk of infection, the traditional wound classification system has been replaced by the National Nosocomial Infection Surveillance (NNIS) system. NNIS classification is determined by procedure length, wound cleanliness, and ASA status. To date, no prophylactic antibiotic guidelines have been proposed for the NNIS system. METHODS: Clean general surgery cases were retrospectively reviewed in our hospital for infection and prophylactic antibiotic use. These cases were then stratified per the NNIS system. RESULTS: One thousand twenty-three clean general surgery cases had 16 (1%) surgical site infections. The infection rate in NNIS class 0, 1, and 2 cases not given prophylactic antibiotics was 1.21%, 3.03%, and 0%, respectively. The infection rate in NNIS class 0, 1, and 2 cases given prophylactic antibiotics was 0.94%, 2.44%, and 6.67%, respectively. CONCLUSIONS: No statistically significant decrease in infection rate was demonstrated by us using prophylactic antibiotics, regardless of the NNIS classification in clean general surgery cases.
The control of spermathecal contractions in Locusta migratoria via a neural loop was demonstrated using mechanical stimulation and electrophysiological recordings. Extracellular electrophysiological recordings from the receptaculum seminis nerve (N2B2), which innervates the spermathecal sac, were conducted during mechanical stimulation of the genital chamber sensory cells. Activation of the genital chamber sensory cells, using a glass probe approximating the shape and size of an egg, was found to increase the action potential frequency and initiate bursts of action potentials if a tonic frequency of action potentials was present prior to stimulation. If the motor pattern initially consisted of bursts of action potentials, then mechanical stimulation of the genital chamber sensory cells resulted in an increase in firing frequency, in most preparations, with the bursting remaining. Removal of the probe from the genital chamber always returned the motor activity to that noted prior to sensory cell stimulation. Simultaneous electrophysiological recordings from both the left and right receptaculum seminis nerves (N2B2) revealed that the bursts of action potentials were coordinated, although individual action potentials were not coupled one to one. Activation of the genital chamber sensory cells also resulted in increases in spermathecal contraction frequency, an effect which was coordinated with the changes in motor activity. It is proposed that an egg in the genital chamber activates the sensory cells resulting in increases in spermathecal contraction frequency and the subsequent release of spermatozoa onto the micropyle of the egg for fertilization.
BACKGROUND AND PURPOSE: To update and summarize the experience at the Massachusetts General Hospital of a treatment program of high-dose preoperative irradiation, surgical re-resection, and intraoperative radiation therapy (IORT) as a salvage treatment for patients with recurrent rectal or rectosigmoid carcinoma. PATIENTS AND METHODS: From June 1978 to February 1997, the records of 69 patients with locally recurrent rectal carcinomas or rectosigmoid carcinomas without metastases referred for consideration of IORT were reviewed. Forty-nine patients received IORT and local control and disease-free survival curves were calculated using the actuarial method of Kaplan-Meier. RESULTS: The 5-year overall survival, local control and disease-free survival rates of 49 patients receiving IORT were 27, 35, and 20%, respectively. Thirty-four patients who underwent a macroscopic complete resection had a significantly better 5-year overall survival than the remaining 15 patients with gross residual disease (33 vs. 13%, P=0.05, log rank). For those patients, local control and disease-free survival rates were 46 and 27%, respectively. Patients with a microscopic complete resection had a superior 5-year overall survival than partially resected patients (40 vs. 14%, P=0.0001, log rank). Chemotherapy had no significant influence on overall or disease-free survival. CONCLUSION: The current analysis shows the importance of a microscopic complete resection in a multi-modality approach with IORT for survival and local control. Salvage is rare for patients undergoing subtotal resection.
BACKGROUND: Outcome evaluations can be useful for reassuring patients that their time and effort are well spent on treatment and for providing staff with confidence in their treatment provision. Outcome evaluations were carried out in 1997 and 1999 to assess two initiatives for the treatment of patients within the Regina Health District (RHD), Saskatchewan, Canada-the Chronic Pain Team Evaluation and Management (CP TEAM) Service and the Acute Injury Management (AIM) Program. STUDY 1: The CP Team Service was an individualized interdisciplinary treatment program intended to serve patients with chronic pain. Of 47 eligible chronic pain patients, 36 participants completed treatment within 15 months, and 27 completed follow-up questionnaires on discharge; the comparison group was composed of the remaining 11 nontreated participants, 8 of whom responded to follow-up questionnaires. Only patients in the treatment group reported a decrease in pain and a decrease in interference in activities. Overall, satisfaction with treatment received was high. STUDY 2: The AIM Program was intended to aid employees with acute musculoskeletal injuries who could not perform regular job duties. Following injury, employees were contacted by an occupational health nurse and informed of the program. If the employee was interested, the AIM coordinator carried out an assessment and designed an individualized treatment package, including physical therapy, exercise therapy, and/or occupational therapy. Treatment was expected to continue until the employee returned to normal duties. Of 72 eligible employees, 43 employees participated and 29 opted not to participate-15 of whom agreed to participate as control participants for this study. Of the employees receiving AIM, 20 agreed to participate in this study. Of the employees not participating in AIM, 15 agreed to participate as control participants. Although pain and interference were greater among AIM participants before commencing treatment, by the end of treatment participants had improved more in level of pain severity and interference compared with controls. All participants reported improved job function over time. AIM participants, however, reported lower job function before treatment than control participants and similar job function after treatment- and indicated they were highly satisfied with the service they received. SUMMARY AND CONCLUSIONS: Evaluations are not only used to assess program outcomes but are an important aspect of program validation and development. Data collection was incorporated, as much as possible, into routine treatment protocols and staff focused on obtaining essential information regarding patient outcomes rather than the whole scope of information.
We tested the hypothesis (McNamara 1996; Zborowski and McNamara 1998) that dream recall and dream content would pattern with interpersonal attachment styles. In study I, college student volunteers were assessed on measures of attachment, dream recall, dream content and other psychologic measures. Results showed that participants who were classified as 'high' on an 'insecure attachment' scale were significantly more likely to (a) report a dream, (b) dream 'frequently', and (c) evidence more intense images that contextualize strong emotions in their dreams as compared with participants who scored low on the insecure attachment scale. In study II, 76 community dwelling elderly volunteers completed measures of attachment, and dream recall. Participants whose attachment style was classified as 'preoccupied' were significantly more likely to report a dream and to report dreams with higher mean number of words per dream as compared with participants classified as 'securely' attached or as 'avoidant' or as 'dismissing.' Dream recall was lowest for the avoidant subjects and highest for the preoccupied subjects. These data support the view that rapid eye movement (REM) sleep and/or dreaming function, in part, to promote attachment.
We assessed cardiogenic pulmonary edema (CPE) patient response to full mask pressure support noninvasive positive pressure ventilation (NPPV). Adult patients presenting to the emergency department (ED) in acute respiratory failure who clinically required endotracheal intubation (ETI) were studied. In addition to routine therapy consisting of oxygen, nitrates, and diuretics, patients were started on full mask NPPV using a Puritan Bennett 7200 ventilator delivering pressure support 10 cm H(2)O, PEEP 5 cm H(2)O, FiO(2) 100%. Pressure support was titrated to achieve tidal volumes of 5 to 7 mL/kg, and PEEP titrated to achieve oxygen saturation (SaO(2)) > 90%. Outcome measures included arterial blood gas (ABG), Borg dyspnea score, vital signs, and need for ETI. Twenty patients mean age 74.7 +/- 14.3 years were entered on the study. Initial mean values on FiO(2) 100% by nonrebreather mask: pH 7.17 +/-.13, paCO(2) 65.5 +/- 19.4 mmHg, paO(2) 73.8 +/- 27.3 mm Hg, SaO(2) 89.7 +/- 10.0%, Borg score 8.1 +/- 1.4, and respiratory rate(RR) 38 +/- 6.3. At 60 minutes of NPPV, improvement was statistically significant: pH 7.28 (difference.11; 95% CI.04-.19), paCO(2) 45 (difference 20.5; 95% CI 8-33), Borg score 4.1 (difference 4.0; 95% CI 3-5), and RR 28.2 (difference 9.8; 95% CI 5-14). NPPV duration ranged from 30 minutes to 36 hours (median 2 hours, 45 minutes). Eighteen patients (90%) improved allowing cessation of NPPV. Two patients with concomitant severe chronic obstructive pulmonary disease (COPD) required ETI. There were no complications of NPPV. NPPV using full face mask and pressure support provided by a conventional volume ventilator is an effective treatment for CPE and may help prevent ETI.
Reflex sympathetic dystrophy (RSD) or complex regional pain syndrome type 1, is characterized by spontaneous pain or allodynia and hyperalgesia disproportionate to the inciting event, multiperipheral nerve involvement, edema, vasomotor or sudomotor change, and possible loss of function. It has been described in relation to various insults, including a number of infectious and inflammatory conditions. We report a case of a patient who developed RSD 1 week after an exacerbation of hidradenitis suppurativa, a rare chronic inflammatory disease of apocrine sweat glands. The patient responded well to a combination of range-of-motion exercises, thermal modalities, and oral steroids. Hidradenitis suppurativa should be considered when searching for an etiology of new onset RSD.
AIMS: The radial artery, increasingly used for coronary artery bypass grafting (CABG). has a potential for spasm which may increase peri-operative risk. Increased alpha-adrenoceptor activation is a key candidate for the spasm. We studied the effects of vasoconstriction in a radial artery, which had undergone brief exposure to the alpha-adrenoceptor antagonist phenoxybenzamine vs the opioid derivative papaverine. METHODS AND RESULTS: Using standard classical organ bath techniques, concentration responses were obtained to norepinephrine in segments of radial artery from 12 CABG patients pre- and post-incubation for 20 min in either phenoxybenzamine 10(-6) M or papaverine 3 x 10(-3) M. Responses were reassessed 2, 4 and 18 h after washout of phenoxybenzamine and 2, 4, 8 and 18 h after washout of papaverine. There was concentration-dependent constriction to norepinephrine (maximum response 0.89 +/- 0.20 (SEM) g x mm(-1), n=6). Constriction to norepinephrine was abolished immediately after incubation in phenoxybenzamine and remained completely inhibited for at least 18 h (P<0.0001 ANOVA phenoxybenzamine pre-treated vs controls). Most of the inhibition of concentration-dependent constriction to norepinephrine following pre-treatment with papaverine was lost 8 h later. CONCLUSION: Radial artery vasoconstriction induced by a clinically relevant agonist, norepinephrine, may be prevented for at least 18 h by pre-incubation in phenoxybenzamine, in contrast to the brief inhibition achieved by pre-treatment with papaverine. Adding phenoxybenzamine to radial artery graft bathing solution may improve early outcome following CABG.