Chronic disulfiram treatment effects on intranasal cocaine administration: initial results

BACKGROUND: Simultaneous abuse of cocaine and alcohol is common. Alcohol decreases negative stimulant effects and potentiates "high." Disulfiram (Antabuse) is being studied in outpatient trials as a cocaine pharmacotherapy with the rationale that inability to modulate cocaine effects with alcohol may decrease cocaine use. METHODS: We examined the interaction of disulfiram and cocaine in a randomized, double-blind, placebo-controlled study where subjects were chronically treated with disulfiram and then participated in intranasal cocaine administration studies. RESULTS: Disulfiram 250 mg/day treatment significantly increased plasma cocaine concentrations (p = .013), heart rate (cocaine 1 mg/kg, p = .046), and systolic (cocaine 2 mg/kg p = .003) and diastolic (cocaine 2 mg/kg, p = .022) blood pressure. "High" and "nervous" ratings were nonsignificantly increased. CONCLUSIONS: The combination of "high" with increased anxiety in the context of inability to lessen negative effects with alcohol may be an effective treatment in selected patients. The significant pharmacokinetic interaction must be considered in the decision regarding use of disulfiram.     

Three-dimensional ultrasonography of the fetal distal lower extremity: normal and abnormal

The objective of this study was to compare two-dimensional and three-dimensional ultrasonographic evaluation of fetal distal lower extremities. Data from two-dimensional and three-dimensional ultrasonographic examinations from 40 distal lower extremities in 33 fetuses from a predominantly high-risk patient population were compared. Three-dimensional ultrasonography routinely provided three orthogonal planes (coronal, sagittal, and axial) for distal lower extremity evaluation. Specific features of distal lower extremity evaluation were not different using two-dimensional and three-dimensional ultrasonography. Rotation of the rendered volume provided assistance in assessing all but one of 40 distal lower extremities. Time from image acquisition to assessment for two views (coronal and sagittal) was longer with three-dimensional ultrasonography (8.2 min) than with two-dimensional ultrasonography (3.2 min). Confidence in the diagnosis of abnormal distal lower extremities was slightly improved using three-dimensional ultrasonography compared to two-dimensional ultrasonography. Pregnancy management was assisted in three of the four cases with isolated limb anomalies. In conclusion, three-dimensional ultrasonography improves the ability to evaluate the fetal distal lower extremity because of the multiplanar nature of volume assessment and the ability to rotate volume data sets. In addition, it provides assistance in counseling families, particularly for cases involving isolated limb anomalies.     

Antagonistic roles for phospholipase D activities in B cell signaling: while the antigen receptors transduce mitogenic signals via a novel phospholipase D activity, phosphatidylcholine-phospholipase D mediates antiproliferative signals

Cross-linking of the Ag receptors on B cells induces DNA synthesis and proliferation. Butanol trap experiments suggest that one or more phospholipase D activities play a key role in this process. Although phosphatidylcholine-phospholipase D has been shown to play a central role in the transduction of proliferative responses for a wide variety of calcium-mobilizing receptors, we show that the Ag receptors are not coupled to this phospholipase. In addition, phosphatidylcholine-phospholipase D is not stimulated under conditions that mimic T cell-dependent B cell activation. In contrast, ATP, which inhibits surface Ig (sIg)-mediated DNA synthesis in murine B cells via P2-purinoceptors, activates phosphatidylcholine-phospholipase D. Phosphatidylcholine-phospholipase D is therefore associated with antiproliferative signal transduction in mature B cells, but it does not transduce early signals associated with sIg-mediated growth arrest or apoptosis in immature B cells. Mitogenic stimulation of sIg is, however, coupled to a novel nonphosphatidylcholine-hydrolyzing phospholipase D activity. The resultant sIg-generated phosphatidic acid, unlike the phosphatidylcholine-derived phosphatidic acid generated via the purinoceptors, is converted to diacylglycerol. These data provide the first evidence that while the novel sIg-coupled phospholipase D and resultant diacylglycerol generation may play a role in B cell survival and proliferation, phosphatidylcholine-phospholipase D may transduce, via phosphatidic acid, negative immunomodulatory signals in mature B lymphocytes.     

Nonconvulsive status epilepticus in the critically ill elderly

PURPOSE: To describe the electrographic and clinical features of nonconvulsive status epilepticus (NCSE) in the critically ill elderly and to identify potential predictors of outcome. METHODS: We prospectively identified 25 episodes of altered mentation and NCSE in 24 critically ill elderly patients associated with generalized, focal, or bihemispheric epileptiform EEG patterns. Patients with anoxic encephalopathy were excluded. RESULTS: Of 25 hospitalizations, 13 (52%) resulted in death, and 12 (48%) patients survived to discharge. Death was associated with the number of acute, life-threatening medical problems on presentation (survivors, 1.8; fatalities, 2.8; p = 0.013) and with generalized EEG pattern (p = 0.017). Higher doses or greater number of antiepileptic drugs (AEDs) did not improve outcome. Treatment with intravenous benzodiazepines was associated with increased risk of death (p = 0.033). Ten patients with advance directives were managed outside the intensive care unit (ICU). Mean hospitalization was 39 days in the ICU group and 22 for those with advance directives (p = 0.017). CONCLUSIONS: Severity of illness correlates with mortality in critically ill elderly patients with NCSE. Treatment with intravenous benzodiazepines may increase their risk of death. Aggressive ICU management may prolong hospitalization at considerable cost, without improving outcome. It is unclear whether NCSE affects outcome in the critically ill elderly or is merely a marker for severity of disease in predisposed patients. The benefits of aggressive therapy are unclear. Carefully controlled, prospective trials will be necessary to determine the best therapies for NCSE in the critically ill elderly and the appropriate role of the ICU in their management.     

Improved survival in congenital diaphragmatic hernia with evolving therapeutic strategies

OBJECTIVE: To compare the survival rates for 3 therapeutic eras, each using different treatment strategies for the management of newborns with congenital diaphragmatic hernia (CDH). DESIGN: Retrospective review of all infants with CDH from 1970 through 1997. SETTING: Tertiary care children's hospital. PARTICIPANTS: A total of 203 newborns with CDH. INTERVENTIONS: Extracorporeal membrane oxygenation (ECMO) was performed with arterial and venous cannulation connected to a membrane oxygenatorroller pump perfusion apparatus, using systemic heparinization. Delayed operative therapy involved operative repair 2 to 5 days after birth using preoperative ventilation support only. Since 1970, 203 newborns with CDH were managed in 3 therapeutic eras: era 1 (1970-1983, 102 patients) was immediate CDH repair with postoperative ventilator and pharmacologic support; era 2 (1984-1988, 45 patients) was immediate repair with postoperative ventilator support (18 patients), immediate ECMO with CDH repair on ECMO (4 patients), or immediate repair with postoperative ECMO (23 patients); and era 3 (1989-1997, 56 patients) was immediate ECMO with repair on ECMO (23 patients), immediate repair with postoperative ECMO (9 patients), or delayed (2-5 days) CDH repair (24 patients). MAIN OUTCOME MEASURES: Survival, defined as discharge from the hospital, and morbidity. RESULTS: Survival was 42% (43/102 patients) in era 1, 58% (26/45 patients) in era 2, and 79% (44/56 patients) in era 3 (P<.02 vs eras 1 and 2). In era 3, the survival for immediate ECMO with repair on ECMO was 57% (13/23 patients), 89% (8/9 patients) for immediate repair with postoperative ECMO, and 96% (23/24 patients) for delayed repair. Eight late deaths were caused by pulmonary hypertension (1 death), sudden infant death syndrome (1 death), and other causes (6 deaths). Morbidity in survivors included mild neurologic deficit (5 patients) and pulmonary disease (3 patients). CONCLUSION: These data demonstrate a significant improvement in survival in CDH with preoperative ECMO and with delayed repair with and without ECMO support and suggest that immediate repair of CDH without the availability of ECMO support should be abandoned.     

Angiographic methods to assess human coronary angiogenesis

It is unclear how agents designed to promote angiogenesis in the human heart affect the arteriographic appearance of the collateral circulation. Possible changes in collateral vessels include new collateral vessels arising from epicardial arteries, new branches emanating from existing collateral vessels, wider or longer collateral vessels, and higher dye transit rates that result in improved recipient vessel filling. Given the multiple mechanisms by which these new agents may improve myocardial perfusion, a rigorous, systematic, and comprehensive analysis of coronary arteriograms is required to discern the true mechanism of benefit. The method of analysis must account for potential changes in collateral blood flow, number, branching pattern, and length as well as changes in recipient vessel filling. The ability to detect differences between intricate networks of vessels in an angiographic study is dependent on maintaining consistency in cinefilming as well as the core laboratory methods between time points. In this report, we describe the methodology our angiographic core laboratory has found to be most effective to evaluate these very complex angiograms and attempt to capture all the possible modalities of angiogenesis.     

Usability for genetic evaluations of records from herds participating in progeny test programs of artificial insemination organizations

Thirteen AI organizations provided identification of herds that participated in their progeny test programs in 1989 and 1990; 15% of those herds participated in programs of more than one AI organization, but only 2.6% participated in programs of more than two AI organizations. Of the 19,589 participating herds, 82 and 76% were enrolled in DHI test plans that were considered to be usable for genetic evaluations during 1991 and 1992. For herds that had participated in AI progeny test programs, mean percentages of usable records were 77% in 1991 and 78% in 1992; the mean percentages of usable records for nonparticipating herds were 62% in 1991 and 60% in 1992. Participating herds had larger mean herd sizes, higher means and standard deviations of milk yields, younger cows, and a lower percentage of registered cows than did nonparticipating herds. Analysis of variance was used to explain the variation in the percentage of records that were usable for genetic evaluations. Herds that participated in AI progeny test programs or that had smaller herd sizes, higher mean milk yields, younger cows, or larger percentages of registered cows had higher percentages of records that were usable for genetic evaluations. Improved usability of records for genetic evaluations would increase the efficiency of AI progeny testing, and consideration of herd characteristics associated with higher percentages of usable records should aid AI organizations in evaluating prospective herds for progeny test programs.     

The painful shoulder: can consultants agree?

As a two-phase exercise in inter-district audit, with the emphasis on critical evaluation of routine clinical practice, three rheumatologists each examined the same 44 patients with shoulder pain, and recorded their diagnosis and the investigations and treatment they would carry out. In the first phase, 26 patients were seen by each rheumatologist separately; there was complete diagnostic agreement in only 46%, with wide variation in the frequency of requests for standard investigations, but all three rheumatologists recommended steroid injections for most patients. In the second phase, all three rheumatologists examined a further 18 patients together, discussed the symptoms and signs, and recorded their diagnoses separately. There was complete agreement in 78%. The presence of more than one lesion, and differences in the interpretation of certain physical signs, partly explain the lack of agreement in Phase 1. Treatment of specific shoulder lesions is highly concordant, with injection the major treatment modality, followed by physiotherapy. Perhaps the different diagnoses reached, and the fact that treatment might therefore be administered for the wrong diagnosis, may explain some treatment failures. Also, recruitment of patients for studies of the treatment of shoulder lesions requires care to avoid selection of a heterogeneous group.     

Survey of changes in the provision of vascular surgical services in the Oxford Region over 5 years

AIM: This study aimed to examine changes in the provision of vascular services in the Oxford region over 5 years. METHODS: A questionnaire was sent to all general surgeons in the region asking of their involvement in vascular surgery. Data were obtained from the Department of Health concerning vascular procedures and inpatient codes for each district in the Oxford Region from 1990-1991 to 1994-1995. Office of Population Censuses and Surveys (OPCS) data for abdominal aortic aneurysm repair and femoral artery reconstruction were validated against data collected prospectively for West Berkshire. RESULTS: Eighteen of 45 surgeons who replied to the questionnaire carried out elective and emergency arterial work. All were members of the Vascular Surgical Society of Great Britain and Ireland (VSS). All but one took part in the general surgical rota. Eight surgeons carried out emergency arterial surgery only; only two of these were members of the VSS. Of 19 surgeons undertaking no arterial surgery, 15 operated on primary and 11 on recurrent varicose veins. The number of arterial reconstructions rose from 20.8 per 100000 population to 28 per 100000 throughout the study. The greatest increase occurred in districts where a new vascular consultant had been appointed. Similar results were obtained with endovascular procedures. The number of major amputations remained fairly constant at approximately 11 per 100000 population. The number of inpatient episodes for arterial disease also rose, from 35.7 to 47.6 per 100000. In validating OPCS codes against prospectively collected data, discrepancies for individual years were noted but the annual trend was reflected fairly accurately by the codes. CONCLUSION: There has been an increase in vascular activity in the region, but variations still exist between different districts.