Gene therapy of Duchenne muscular dystrophy.
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Adenoviridae↗
Biomedical subjects
S Murphy
Publications and source records attributed to S Murphy.
Orthodromic activation of peptidergic cells in the medial amygdala.
Electrical recordings from vasopressin-containing cells in the medial amygdala were obtained. Electrical stimulation of one major afferent structure, the accessory olfactory bulb, invariably elicited single unit discharge in the peptidergic cells and set up a field potential indicating widespread excitation in the structure. Pheromonal stimuli, normally borne into the brain by the accessory olfactory bulb, were ineffective in activating the medial amygdala. These results in combination with preexisting research suggest that the accessory olfactory bulb is an important influence, but not the only influence, on the activity of the peptidergic cells.
Action Potentials↗
Thalamic NMDA receptors modulate inflammation-produced hyperalgesia in the rat.
The effects of inhibition of thalamic NMDA receptor function and synthesis on thermal and mechanical hyperalgesia induced by hindlimb intraplantar injection of carrageenan in the rat were studied in the 'acute' phase (within 3-5 h) and the 'subacute' phase (24 h) after carrageenan administration. Blockade of NMDA receptors was produced by intrathalamic injection of D,2-amino-5-phosphonovaleric acid (D-APV) and NMDA receptor synthesis was decreased (or not) by pretreatment of rats with intrathalamic (hindlimb representation area) injections of antisense, sense or missense oligodeoxynucleotides (ODNs) directed against the NR1 subunit of the NMDA receptor complex. Treatment with D-APV, but not saline, in the contralateral (but not ipsilateral) thalamus significantly reduced both the acute thermal and mechanical hyperalgesia in the injected paw; these same rats demonstrated significantly less thermal and mechanical hyperalgesia in the sub-acute phase than rats that had received saline or D-APV in the ipsilateral thalamus. None of the treatments had any effect on withdrawal responses of the uninjected hindpaw. Rats pretreated with NR1 sense or missense ODNs developed both thermal and mechanical hyperalgesia that was equivalent in magnitude and duration to rats that received intrathalamic saline injections. In contrast, rats pretreated with NR1 antisense ODN did not develop either acute or subacute thermal hyperalgesia; they developed less mechanical hyperalgesia than saline, sense or missense ODN-treated rats. Antisense ODN-treated rats also displayed a decrease in the number of thalamic NMDA receptors as determined by receptor binding assay. These results suggest an involvement of thalamic NMDA receptors in the development and maintenance of hyperalgesia associated with neurogenic inflammation in a model of tonic pain.
2-Amino-5-phosphonovalerate↗
Paramyotonia congenita and hyperkalemic periodic paralysis associated with a Met 1592 Val substitution in the skeletal muscle sodium channel alpha subunit--a large kindred with a novel phenotype.
Paramyotonia congenita (PC) and Hyperkalemic periodic paralysis (HyperPP) are caused by amino acid substitutions in the alpha subunit of the human skeletal muscle sodium channel. One such substitution, methionine for valine at position 1592, has been associated with HyperPP with myotonia and cold sensitivity. We report clinical, electromyographic (EMG), genetic and pathological features of a large kindred with the Met1592Val substitution. Affected members were phenotypically heterogenous and had episodic potassium-sensitive paralysis, and stiffness and weakness induced by exercise and cold, which was confirmed by EMG studies. These features indicate a combined PC-HyperPP phenotype not previously described with this mutation.
Adult↗
Health locus of control and value for health in smokers and nonsmokers.
A representative sample of 11,401 persons completed a questionnaire, including measures of health locus of control, value for health, and smoking frequency. Smokers held stronger internal, chance, and powerful others beliefs than never smokers. Ex-smokers had lower scores on internal and chance dimensions and placed a higher value on their health than smokers. The interaction between chance health locus of control and value for health was a significant predictor of smoking status, suggesting that health value may moderate the relationship between health locus of control and smoking status. Within smokers, the health locus of control dimensions and value for health explained less than 1% of the variance in smoking frequency, with only the chance dimension emerging as a significant predictor.
Adolescent↗
The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia.
Sixty-six adults with refractory acute lymphocytic leukemia received salvage therapy with the 'hyper-CVAD' regimen, consisting of eight courses of alternating intensive chemotherapy with growth factor support, followed by oral maintenance chemotherapy. Their outcome was compared with 63 prognostically similar historical control patients treated with high-dose Ara-C plus mitoxantrone with or without GM-CSF. Overall, the complete response rates were similar in the treatment and control groups (29 of 66 (44%) vs 24 of 63 (38%)). There were more patients in the current study with primary resistant disease (10 of 66 (15%) vs one of 63 (2%), P = 0.006), and conversely fewer patients with secondary resistance (19 of 66 (29%) vs 28 of 63 (44%), P = 0.06). Recovery of granulocyte counts above 500/microl was significantly faster in the current study when compared to high-dose Ara-C-treated patients who were given GM-CSF (20 vs 25 days, P = 0.04). Survival was prolonged in the hyper-CVAD-treated patients, with most of the benefit seen in first salvage patients (42 vs 20 weeks, P = 0.016). When only first salvage patients were considered, there was a significant difference in disease-free survival in favor of hyper-CVAD (52 vs 20 weeks, P = 0.008). The hyper-CVAD regimen is a more effective and less toxic salvage regimen for relapsed acute lymphocytic leukemia than high-dose Ara-C-based regimens.
Adult↗
Regulation of astrocyte nitric oxide synthase type II expression by ATP and glutamate involves loss of transcription factor binding to DNA.
Pretreatment of astrocytes with either glutamate or ATP, acting via specific receptors, suppresses subsequent cytokine-induced expression of type II nitric oxide synthase (NOS). This effect is downstream from the activation and translocation of nuclear factor (NF)-kappaB, as western blotting revealed no difference in accumulation of the p50 subunit in nuclear extracts from agonist-treated vs. nontreated cells. However, evidence from gel-shift assay suggests that the binding of nuclear protein from agonist-treated cells to NF-kappaB and activator protein-1 consensus oligonucleotides is markedly reduced. Selective inhibitors of protein kinases A and C could not restore either binding of transcription factors to DNA or type II NOS mRNA expression in agonist-pretreated cells. The modulation of proinflammatory cytokine-evoked type II NOS expression by ATP and glutamate may play an important role in CNS pathologies associated with stroke and trauma.
Adenosine Triphosphate↗
Fat embolism with the use of intraosseous infusion during cardiopulmonary resuscitation.
The objective of this prospective study was to assess the incidence and magnitude of fat emboli after cardiopulmonary resuscitation and intraosseous infusions. An animal laboratory at a university center was used to study 33 mixed-breed piglets. The piglets underwent hypoxic cardiac arrest followed by chest compressions and mechanical ventilation for a minimum of 30 minutes. The animals were divided in groups: group 1 (n = 5), which had no intraosseous cannulas, group 2 (n = 6), which had intraosseous cannulas with infusion, groups 3 (n = 6), 4 (n = 6), and 5 (n = 8), which had intraosseous cannulas with infusion of epinephrine, normal saline, and sodium bicarbonate respectively, and group 6 (n = 2), which was a sham group with no intraosseous cannulas and no cardiopulmonary resuscitation. At cessation of cardiopulmonary resuscitation, representative lung samples were collected from upper and lower lobes of each lung and observed for fat globules and bone marrow elements. Fat globules were seen in the peribronchial blood vessels and intravascular areas throughout all lung fields of groups 1 through 5. There was no difference in appearance or distribution of fat globules among the 5 treatment groups. Analysis of variance showed no statistical significance (P < 0.05) within or among groups 1 through 5. The use of the intraosseous cannula for infusion of emergency drugs and fluids did not increase the magnitude of fat embolization over cardiopulmonary resuscitation alone in this animal model. The benefits of using this procedure in critically ill children as a means of rapid vascular access for resuscitation is well established. However, the risk of fat embolism in this population needs further study.
Analysis of Variance↗
Intraosseous and central venous blood acid-base relationship during cardiopulmonary resuscitation.
OBJECTIVE: The objectives of this study were: 1) to determine whether obtaining intraosseous (IO) blood samples was practical during cardiopulmonary resuscitation (CPR), and 2) to compare the acid-base status (pH and partial pressure of CO2 (PCO2) of venous and IO blood during CPR. DESIGN: A prospective repeated measure study. SETTING: An animal laboratory at a university medical center. INTERVENTIONS: Nine mixed breed piglets (mean weight 43 kg) were anesthetized, tracheotomized, and placed on a ventilator (Siemens 900C Elema, Sweden). Placement of a pulmonary artery catheter was done via a surgical incision in the neck. An IO cannula was then placed in the tibial marrow cavity. The animals were positioned under a mechanical thumper (Thumper, Michigan Instruments, Grand Rapids, MI) for chest compressions. Blood gases were analyzed during steady state (baseline) after five minutes of ventricular fibrillation and during CPR at seven, nine, 11, 13, 15 and 18 minutes. MAIN RESULTS: Blood samples for acid-base analysis were easily obtained from the IO sites during all sampling times. Mixed venous blood was slightly more acidic than IO blood, especially at 13, 15, and 18 minutes. However, there were no significant differences in pH and Pco2 values between IO and central venous (CV) gases at all time intervals except the PCO2. At nine minutes, a significant difference (P < 0.006) was found in PCO2 (59 +/- 4 vs 47 +/- 5 torr) for the CV versus IO sample, respectively. As the duration of CPR progressed, the differences in PCO2 between IO and CV sites were clinically relevant (though not statistically significant). CONCLUSION: Obtaining blood from the IO site is practical during CPR. The divergence in values as CPR progresses suggests that, during longer periods of CPR, IO blood may reflect local acidosis and yield lower PCO2 and higher pH values that CV blood. This finding may limit the usefulness of IO blood to judge acid base status as CPR progresses.
Animals↗
A 200 kDa protein is associated with haemagglutinating isolates of Moraxella (Branhamella) catarrhalis.
Moraxella catarrhalis adheres to human erythrocytes by means of a proteinaceous, trypsin sensitive, heat modifiable haemagglutinin. A 200 kDa protein was found to be associated with haemagglutinating isolates of M. catarrhalis. This protein was present on all haemagglutinating isolates (n = 17), but was absent on the non-haemagglutinating isolates (n = 23) examined. This protein demonstrated heat-modifiable properties in sodium dodecyl sulfate and was degraded by trypsin. Immunoblot assays with polyclonal antiserum indicated that the 200 kDa protein was associated exclusively with haemagglutinating isolates and antibodies to this protein did not recognise epitopes on non-haemagglutinating isolates. This protein, which appears to be a surface expressed protein may be a haemagglutinin of M. catarrhalis.
Bacterial Proteins↗
Intracranial hypertension in Africans with cerebral malaria.
The causes of death and neurological sequelae in African children with cerebral malaria are obscure. Intracranial pressure (ICP) was monitored and cerebral perfusion pressure (CPP) calculated in 23 Kenyan children with cerebral malaria. Four children had severe intracranial hypertension (ICP > 40 mm Hg, CPP < 40 mm Hg): two died, one with an ICP of 158 mm Hg and signs of transtentorial herniation, the other one with an ICP of 42 mm Hg and cardiorespiratory arrest. The other two survived with severe neurological sequelae. Nine had intermediate intracranial hypertension (ICP > 20 mm Hg, CPP < 50 mm Hg) and 10 had mild intracranial hypertension (maximum ICP 10-20 mm Hg); all survived without severe sequelae. Mannitol controlled the ICP in children with intermediate intracranial hypertension, but it did not prevent the development of intractable intracranial hypertension in children with severe intracranial hypertension. Intracranial hypertension is a feature of Kenyan children with cerebral malaria and severe intracranial hypertension is associated with a poor outcome.
Child↗
The British Journal of Social Medicine: what was in a name?
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Community Medicine↗
Diagnosis of neurosyphilis: appraisal of clinical caseload.
OBJECTIVES: To review the management of a cohort of patients with positive treponemal serology and psychiatric and/or neurological disorders. METHODS: A retrospective case note review of 172 patients with positive treponemal serology attending the Patrick Clement's Clinic, Central Middlesex Hospital between December 1990 and November 1995 was performed. RESULTS: 101 men and 71 women were new attenders diagnosed with positive treponemal serology. A neurological problem was identified in 27 patients (12 women and 15 men) with psychiatric and/or neurological disorders, of whom 20 (six women and 14 men) underwent investigation of the cerebrospinal fluid (CSF). With the medical history and results of CSF-RPR and FTA tests, white cell count (WCC), and total protein level in the CSF, 10 patients (eight men and two women) were diagnosed with likely neurosyphilis and 17 with neurological disorders not thought to be caused by syphilis. The clinical features in those having neurosyphilis were sensorineural hearing loss (n = 5) and tabes dorsalis (n = 5). In the seven patients diagnosed with neurosyphilis who underwent CSF examination one patient had a reactive CSF-FTA, elevated protein, and elevated WCC; one patient had a reactive CSF-FTA and RPR with elevated protein; the total protein only was elevated in three cases and the WCC elevated in one case. Nine of the 10 patients with neurosyphilis received adequate neurosyphilitic treatment; one patient was lost to follow up. CONCLUSIONS: The management of patients with positive treponemal serology and psychiatric and/or neurological disorders was consistent. Patients with suspected neurosyphilis or patients with neurological signs compatible with neurosyphilis (who did not undergo CSF examination) were treated with adequate neurosyphilitic therapy.
Adult↗
Studies on haemagglutination and serum resistance status of strains of Moraxella catarrhalis isolated from the elderly.
A total of 40 strains of Moraxella catarrhalis, isolated from the sputum of elderly persons with respiratory tract infections and from nasopharyngeal swabs from healthy elderly, were examined for haemagglutination of human red blood cells and resistance to bactericidal activity in normal human serum (NHS). 15 of 20 strains isolated from the infected elderly and 3 of 20 strains isolated from the healthy elderly showed haemagglutinating properties (p < 0.001). Similarly, 13 of 20 strains from the infected group and 2 of 20 strains from the healthy group were found to be resistant to the bactericidal activity of NHS (p < 0.001). Strains of M. catarrhalis which were associated with respiratory tract infections in the elderly, in contrast to strains colonizing the healthy elderly, were found to be predominantly haemagglutinating for human red blood cells and resistant to complement killing in NHS.
Adult↗
Onset of myasthenia gravis in a patient with multiple sclerosis during interferon-1b treatment.
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Adjuvants, Immunologic↗
Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment.
This report suggests modest changes in the criteria used for the diagnosis of ET and allows tentative recommendations concerning therapy. As outlined in Table I, we believe that absent stainable marrow iron does not necessarily indicate iron deficiency in these patients and that the serum ferritin and RBC mean corpuscular volume should be incorporated in this assessment. Normal values speak strongly against iron-deficient erythropoiesis. A search for the bcr/abl gene rearrangement should be included with the marrow karyotype to exclude CML. Finally, cytogenetic data and morphologic study of the marrow should be used to be certain that a MDS should not be considered. It may be that measurements of serum thrombopoietin levels may be useful in the future. Nonetheless, in principle, ET remains a diagnosis of exclusion as we have originally suggested. For therapy, HU remains an excellent choice for the older patient at risk for thrombosis. Nonetheless, no myelosuppressive therapy remains a perfectly viable option, particularly for the young patient and the older with low thrombotic risk. The roles of anagrelide and alpha interferon in this setting have not been fully defined. Experience with both has still been relatively short. It would be ideal if prospective, randomized trials could be mounted to address these questions. We conclude with confidence that return to older approaches such as 32P and AA in patients who fail on HU is to be discouraged. The use of anagrelide or interferon alfa seems to be a much more appropriate approach. We have not investigated the role of antithrombotic agents such as aspirin in ET. In PV, the combination of aspirin, 300 mg three times daily, and dipyridamole, 75 mg three times daily, failed to reduce the rate of thrombosis and was associated with an increased rate of hemorrhage. It is rational to suggest that lower doses of aspirin (ie, < 325 mg daily) might be associated with less hemorrhage and, perhaps, a beneficial effect on thrombosis. This remains to be shown.
Humans↗
Biology and treatment of acute lymphocytic leukemia in children.
Biological factors and therapy interact in complex ways to affect prognosis of children with acute lymphocytic leukemia. Therefore, it is important that trials prospectively collect data on potential prognostic factors (such as age, white blood cell count, DNA index, cytogenetics, immunophenotype, central nervous system status, and early treatment response) in all patients. As results of treatment improve, subsequent trials must be large enough to detect small differences in outcomes. Results should be reported after sufficient follow-up, using multivariate analyses, and in a format that permits comparison with outcomes at other centers. Attention to the above will permit an approach to treatment that adapts the intensity of therapy to the risk of relapse.
Age Factors↗
Therapeutic dilemmas: balancing the risks of bleeding, thrombosis, and leukemic transformation in myeloproliferative disorders (MPD).
With these uncertainties, which patients with ET and PV should receive myelosuppressive therapy and accept its possible risks? Remembering the generalization from the literature that most patients with ET who are to have a catastrophic thrombosis either have it at the time of diagnosis or after preceding, less severe thrombotic symptoms, it is acceptable to omit myelosuppressive therapy in asymptomatic patients with ET. Young patients with PV and no thrombotic manifestations can similarly be managed with phlebotomy alone. There is no evidence in the literature to show that myelosuppressive therapy should be used simply because the platelet count is high or to prevent transition to myeloid metaplasia. In patients with ET or PV with previous thrombotic manifestations, the risk/benefit ratio probably favors myelosuppressive therapy. The PVSG studies also suggest that patients over the age of 70 with PV are at particular risk for thrombosis and should be treated with myelosuppression. No myelosuppressive agent has been shown to be superior to hydroxyurea. Patients who fail on hydroxyurea should not be treated with 32P or alkylating agents. Anagrelide or interferon would be more appropriate. The PVSG-05 study suggests that high doses of aspirin, i.e. approximately 1.0 grams per day, are not indicated. Trials of low dose aspirin to prevent thrombosis are encouraged. There is no way to predict which patients will have hemorrhagic complications and, as mentioned, one study suggests that there will be few (44). Patients with thrombocytosis and pathological bleeding, i.e. hemorrhagic thrombocythemia, generally improve with myelosuppressive therapy. This syndrome is to be distinguished from patients who bleed with normal or low platelet counts, generally in the setting of myeloid metaplasia (14). These patients have an acquired disorder of platelet function due to platelet production from abnormal megakaryocytes. An occasional patient will benefit from increasing the platelet count by splenectomy.
Cell Transformation, Neoplastic↗