Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial.

BACKGROUND: Patients with ALS commonly exhibit pseudobulbar affect. METHODS: The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140). RESULTS: AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q. CONCLUSIONS: AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.

Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey.

Concern that people who form kidney stones may have reduced bone mineral density (BMD) and increased fracture risk has motivated clinical and population-based studies, but findings are inconsistent. In this cross-sectional study, we use the Third National Health and Nutrition Examination Survey (NHANES III) to determine whether a history of kidney stones (n = 793) is associated with lower femoral neck BMD and whether the association is similar for men and women. We further ask whether dietary calcium modifies the association between kidney stone history and BMD and whether there is an association between kidney stone history and prevalent spine or wrist fracture. We find that men with kidney stone history have lower femoral neck BMD than men without kidney stone history after adjusting for age, body mass index (BMI), race/ethnicity, and other potential confounders. The effect of kidney stone history on BMD is weaker for women. Men with kidney stone history also are more likely to report prevalent wrist and spine fractures. Dietary calcium, represented by usual milk consumption, is associated positively with BMD for both men and women and modifies the effect of kidney stone history on BMD for men. For men who form kidney stones, milk consumption is associated more strongly with femoral neck BMD than for men without such a history. The effect modification is such that the difference in BMD between men with and without kidney stone history is observed only at lower levels of milk consumption.

Impact of interpreter services on delivery of health care to limited-English-proficient patients.

OBJECTIVE: To determine whether professional interpreter services increase the delivery of health care to limited-English-proficient patients. DESIGN: Two-year retrospective cohort study during which professional interpreter services for Portuguese and Spanish-speaking patients were instituted between years one and two. Preventive and clinical service information was extracted from computerized medical records. SETTING: A large HMO in New England. PARTICIPANTS: A total of 4,380 adults continuously enrolled in a staff model health maintenance organization for the two years of the study, who either used the comprehensive interpreter services (interpreter service group [ISG]; N = 327) or were randomly selected into a 10% comparison group of all other eligible adults (comparison group [CG]; N = 4,053). MEASUREMENTS AND MAIN RESULTS: The measures were change in receipt of clinical services and preventive service use. Clinical service use and receipt of preventive services increased in both groups from year one to year two. Clinical service use increased significantly in the ISG compared to the CG for office visits (1.80 vs. 0.70; P <.01), prescriptions written (1.76 vs 0.53; P <.01), and prescriptions filled (2.33 vs. 0.86; P<.01). Rectal examinations increased significantly more in the ISG compared to the CG (0.26 vs. 0.02; P =.05) and disparities in rates of fecal occult blood testing, rectal exams, and flu immunization between Portuguese and Spanish-speaking patients and a comparison group were significantly reduced after the implementation of professional interpreter services. CONCLUSION: Professional interpreter services can increase delivery of health care to limited-English-speaking patients.

Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: A multicenter, randomized, placebo-controlled trial.

BACKGROUND: Recurrent herpes simplex labialis (HSL) occurs in 20% to 40% of the US population. Although the disease is self-limiting in persons with a healthy immune response, patients seek treatment because of the discomfort and visibility of a recurrent lesion. OBJECTIVE: Our purpose was to determine whether docosanol 10% cream (docosanol) is efficacious compared with placebo for the topical treatment of episodes of acute HSL. METHODS: Two identical double-blind, placebo-controlled studies were conducted at a total of 21 sites. Otherwise healthy adults, with documented histories of HSL, were randomized to receive either docosanol or polyethylene glycol placebo and initiated therapy in the prodrome or erythema stage of an episode. Treatment was administered 5 times daily until healing occurred (ie, the crust fell off spontaneously or there was no longer evidence of an active lesion) with twice-daily visits. RESULTS: The median time to healing in the 370 docosanol-treated patients was 4.1 days, 18 hours shorter than observed in the 367 placebo-treated patients (P =.008; 95% confidence interval [CI]: 2, 22). The docosanol group also exhibited reduced times from treatment initiation to (1) cessation of pain and all other symptoms (itching, burning, and/or tingling; P =.002; 95% CI: 3, 16.5); (2) complete healing of classic lesions (P =.023; 95% CI: 1, 24.5); and (3) cessation of the ulcer or soft crust stage of classic lesions (P <.001; 95% CI: 8, 25). Aborted episodes were experienced by 40% of the docosanol recipients versus 34% of placebo recipients (P =.109; 95% CI for odds ratio: 0.95, 1.73). Adverse experiences with docosanol were mild and similar to those with placebo. CONCLUSION: Docosanol applied 5 times daily is safe and effective in the treatment of recurrent HSL. Differences in healing time compared favorably with those reported for the only treatment of HSL that has been approved by the Food and Drug Administration.

The impact of contralateral breast cancer on the outcome of breast cancer patients treated by mastectomy.

PURPOSE: To evaluate the clinical and pathological features of breast cancer patients who develop contralateral breast cancer (CBC) and assess the impact of the second breast cancer on their prognosis. PATIENTS AND METHODS: This retrospective study includes 2136 women with stage I-III breast cancer treated between 1927 and 1987 at the University of Chicago Hospitals. A total of 132 (6.2%) developed CBC during a median follow-up period of 14.2 years; all of them were treated with mastectomy for both breast cancers. We compare the prognostic characteristics, treatments, and outcomes of patients who developed bilateral breast cancer with those who had only unilateral breast cancer (UBC). We also compare the features of the first and the second tumors among patients with bilateral breast cancer (BBC). RESULTS: The annual incidence rate for CBC remained constant at an average rate of 0.23%, resulting in a cumulative incidence rate of 6.2%. Patients with BBC were significantly younger than those with UBC (median age, 51 years vs 54 years). No other significant differences were observed between BBC and UBC patients. Among BBC patients, the second cancer was smaller (2.0 cm vs 3.0 cm) and was associated with a lower incidence of axillary node involvement (29% vs 52%). The development of CBC was associated with worse survival (hazard ratio = 1.46 in comparison with patients who did not develop CBC, 95% CI of 1.09-1.95). On multivariate analysis, factors that decreased the disease-specific survival (DSS) in patients with BBC were a higher number of positive lymph nodes of the first and second cancers, a larger size of the second cancer, and a shorter interval between the two primaries. DISCUSSION: At the time of diagnosis of first breast cancer, BBC patients were significantly younger than UBC patients. The second cancer among the BBC patients was at an earlier stage than the first one; however, no difference was noticed in the pathological feature between the cancer in the UBC patients and the first cancer of BBC patients. There is an indication that the longer the interval between the two cancers, the better the survival of the BBC patients.

A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis.

OBJECTIVES: Therapeutic trials in left-sided ulcerative colitis (L-UC) and ulcerative proctitis (UP) have lacked control for medication type, dose, delivery, and duration of therapy. METHODS: All published therapeutic articles and abstracts in L-UC or UP from 1958-1997 were reviewed. Improvement, remission rates, and adverse events were recorded for all (ALL), placebo-controlled (PC) studies, and for PC studies passing quality assessment (QA) scoring. Meta-analysis was used where appropriate. RESULTS: Left-sided UC: For active disease, 67 studies (17 PC; 10 QA) were identified. Mesalamine enemas achieved remission in a duration but not a dose response (QA), with higher remission rates than steroid enemas (ALL) and clinical improvement rates superior to oral therapies (QA, ALL). Remission maintenance: 17 (six PC, six QA) studies were identified. Mesalamine therapies had comparable remission rates at 6 months, with a possible dose but not delivery effect. Mesalamine enema dosing intervals between QHS to Q3 days maintained efficacy. Reported adverse events were most common with oral sulfasalazine and dose-independent for mesalamine. Withdrawals from therapy were less than placebo, or < or =3%. Ulcerative proctitis: For active disease, 18 (nine PC, three QA) studies were identified. Mesalamine suppositories achieved clinical improvement and remission in a duration but not dose response, with higher rates of remission than topical steroids (ALL). Remission maintenance: three (three PC, two QA) studies were identified. Remission ranged from 75% to 90% (6 months) and 61-90% (12 months) for mesalamine agents. Reported adverse events were most common for mesalamine foam (8%). Withdrawals from therapy were <2%. CONCLUSIONS: In L-UC and UP, the efficacy and side-effect profile of topical mesalamine are dose independent and superior to oral therapies and topical steroids. Economic analysis suggests that use of these agents will also result in an overall decrease in patient costs.

New scoring system identifies kidney outcome with radiation therapy in acute renal allograft rejection.

PURPOSE: To evaluate the role of radiation therapy for acute refractory renal rejection after failure of medical intervention, and to identify risk factors that influence graft survival following radiation therapy. METHODS: Between June 1989 and December 1995, 53 renal transplant recipients (34 men and 19 women) were treated with localized radiation therapy for acute renal allograft rejection. Graft rejection was defined as an increase in serum creatinine with histologic evidence of rejection on renal biopsy. Ninety-one percent were cadaveric transplant recipients. The majority of patients who experienced acute graft rejection initially received corticosteroid therapy, except for 25% who were referred for radiation therapy and steroids for the first rejection. In more recent years, patients with moderate or severe steroid-resistant or recurrent rejection received OKT3, a polyclonal antilymphocyte antibody (ATGAM), tacrolimus (FK506), or mycophenolate mofetil (MMF). Patients who failed to respond to medical treatment were then referred for radiation therapy. Ultrasound was performed for kidney localization. Treatment consisted of a dose of 600 cGy given in 3 or 4 fractions using 6 MV photons, delivered AP or AP/PA. RESULTS: The overall actuarial graft survival from the initiation of RT was 83% at 1 month, 60% at 1 year, and 36% at 5 years. The median follow-up from the date of transplant to the last follow-up was 22 months. The median time from the date of transplant to the initiation of radiotherapy was 3 months, and the median time from the initiation of radiotherapy to the last follow-up was 10 months. Variables evaluated were as follows: human leukocyte antigen matching on HLA-A, HLA-B, and HLA-DR, the transplant panel-reactive antibodies (PRA) at transplantation, number of acute rejection episodes, interval from the date of the transplant to the first rejection, serum creatinine levels at the time of the first radiation treatment, number of transplants, and concomitant immunosuppressive therapy. Independent factors examined by Cox regression modeling were: gender (p = 0.005), creatinine levels (p = 0.000), HLA-DR (p70% (p = 0.014). Each factor was scored using integral coefficients to generate four different groups. The Kaplan-Meier survival analyzed by group produces an interpretable separation of the risk factors for graft loss. CONCLUSIONS: The outcome in patients treated with radiation therapy for acute renal graft rejection can be predicted by a novel scoring system. Patients with scores of three or less are able to achieve 100% renal graft salvage, while patients who have scores of 12 or higher are not able to be salvaged with the current radiation therapy regimen. Future studies should be directed toward identifying more effective treatment for patients who have a high score based on our criteria. The scoring system should be utilized to identify patients at risk who could benefit from radiation therapy. Further study with a randomized trial utilizing this scoring system is needed to confirm the validity of the scoring system in predicting graft survival and the efficacy of radiation in patients who receive radiation therapy for acute graft rejection.

Clinical trials in general surgical journals: are methods better reported?

BACKGROUND: Reports of clinical trials often lack adequate descriptions of their design and analysis. Thus readers cannot properly assess the strength of the findings and are limited in their ability to draw their own conclusions. A review of 6 surgical journals in 1984 revealed that the frequency of reporting 11 basic elements of design and analysis in clinical trials was only 59%. This study attempted to identify areas that still need improvement. METHODS: Eligible studies published from July 1995 through June 1996 included all reports of comparative clinical trials on human subjects that were prospective and had at least 2 treatment arms. A total of 68 articles published in 6 general surgery journals were reviewed. The frequency that the previously identified 11 basic elements of design and analysis were reported was determined. RESULTS: Seventy-four percent of all items were reported accurately (a 15% increase from the previous study), 4% were reported ambiguously, and 23% were not reported; improvement was seen in every journal. The reporting of eligibility criteria and statistical power improved the most. For 3 items, reporting was still not adequate; 32% of reports provided information about statistical power, 40% about the method of randomization, and 49% about whether the person assessing outcomes was blind to the treatment assignment. CONCLUSIONS: Improvements have been made in reporting surgical clinical trials, but in general methodologic questions poorly answered in the 1980s continue to be answered poorly in the 1990s. Editors of surgical journals are urged to provide authors with guidelines on how to report clinical trial design and analysis.

Is geographic variation in hip fracture rates related to current or former region of residence?

This study examines geographic variation in male and female age-adjusted hip fracture rates in white elderly Medicare enrollees. We assembled a cohort of more than 2 million 1992 enrollees and followed them passively through record linkage for 2 years for a hospitalization containing a diagnostic code indicating hip fracture. We simultaneously estimated rate ratios by region of residence early (inferred from the Social Security number) and late in life. Residence region early in life is associated with substantial variation in hip fracture rates. Conversely, current region has little relation with hip fracture risk.

SPECT brain imaging in epilepsy: a meta-analysis.

UNLABELLED: A meta-analysis of SPECT brain imaging in epilepsy was performed to derive the sensitivity and specificity of interictal, postictal or ictal rCBF patterns to identify a seizure focus in medically refractory patients. METHODS: Papers were obtained by pooling all published articles identified by two independent literature searches: (a) Dialnet (EMBASE) or Radline by CD-ROM and (b) Current Contents searched manually. Literature inclusion criteria were: (a) patients had a localization-related epileptic syndrome; (b) more than six patients were reported; and (c) patients had at least an interictal EEG-documented epileptiform abnormality. Of 46 papers meeting these criteria, 30 contained extractable data. SPECT results were compared to localization by standard diagnostic evaluation and surgical outcome. Meta-analytic sensitivities for SPECT localization in patients with temporal lobe seizures relative to diagnostic evaluation were 0.44 (interictal), 0.75 (postictal) and 0.97 (ictal). Similar results were obtained relative to surgical outcome. False-positive rates were low relative to diagnostic evaluation (7.4% for interictal and 1.5% for postictal studies) and surgical outcome (4.4% for interictal and 0.0% for postictal studies). RESULTS: The results were not dependent on tracer used (or dose), the presence of CT-identified structural abnormalities, blinding of image interpretation or camera quality (although data were more variable with low-resolution cameras). There were insufficient data for conclusions regarding extratemporal-seizure or pediatric epilepsy populations. CONCLUSION: Insights gained from reviewing this literature yielded recommendations for minimal information that should be provided in future reports. Additional recommendations regarding the nature and focus of future studies also are provided. The most important of these is that institutions using SPECT imaging in epilepsy should perform ictal, preferably, or postictal scanning in combination with interictal scanning.

Postcesarean analgesia with both epidural morphine and intravenous patient-controlled analgesia: neurobehavioral outcomes among nursing neonates.

UNLABELLED: Among nursing parturients after cesarean delivery, intravenous patient-controlled analgesia (PCA) with meperidine is associated with significantly more neonatal neurobehavioral depression than PCA with morphine. A single dose of epidural morphine (4 mg) decreases postcesarean opioid analgesic requirements and may reduce or prevent neonatal neurobehavioral depression associated with PCA meperidine. Prospectively, 102 term parturients underwent cesarean delivery with epidural anesthesia, 2% lidocaine and epinephrine 1:200,000. After umbilical cord clamping, each patient received epidural morphine 4 mg and was randomly allocated to receive either PCA meperidine or PCA morphine. Initial neonatal characteristics, included gestational age, Apgar scores, weight, and umbilical cord gas partial pressures. Brazelton Neonatal Behavioral Assessment Scale (NBAS) examinations were performed on each of the first 4 days of life. Nursing infants (n = 47) were grouped according to maternal PCA opioid in breast milk (meperidine [n = 24] or morphine [n = 23]); bottle-fed infants (n = 56) served as the control group. The three infant groups were equivalent with respect to initial characteristics and NBAS scores on the first 2 days of life. On the third day of life, infants in the morphine group were significantly more alert and oriented to animate human cues compared with infants in the meperidine or control group. On the fourth day of life, infants in the morphine group remained significantly more alert and oriented to animate human auditory cues than infants in the meperidine group. Average PCA opioid consumption through 48 h postpartum was equivalent (0.54 mg/kg morphine and 4.7 mg/kg meperidine); however, even with these small doses, meperidine was associated with significantly poorer neonatal alertness and orientation than morphine. Morphine is the PCA opioid of choice for postcesarean analgesia among nursing parturients. IMPLICATIONS: Among nursing parturients after cesarean delivery, intravenous patient-controlled analgesia with meperidine is associated with more neonatal neurobehavioral depression than patient-controlled analgesia with morphine. In this study, we found that nursing infants exposed to morphine were more alert and oriented to animate human cues than those exposed to meperidine.

Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis.

OBJECTIVE: We investigated the disease-specific and metastasis-free survival rates in men with locally advanced (clinical stage T3) prostate cancer who were treated surgically. METHODS: A retrospective, multi-institutional pooled analysis of the results of surgical treatment in 345 men with clinical stage T3 disease was performed. Survival curves were generated using the Kaplan-Meier method. RESULTS: Among 298 evaluable patients, pelvic lymphadenectomy alone was performed in 56 men (19%), while 242 men (81%) underwent node dissection and radical prostatectomy. In total, 122 of 298 patients (41%) had nodal metastases and/or seminal vesicle tumor spread. Pathologically organ-confined disease was noted in 27 men (9%). The actuarial 10-year disease-specific and metastasis-free survival rates for all patients managed surgically were 57 and 32%, respectively. For patients with well, moderately and poorly differentiated tumors, cancer-specific survival rates at 10 years were 73, 67 and 29%, respectively. CONCLUSIONS: A large number of men with clinical stage T3 prostate cancer have advanced disease and are unlikely to achieve improved long-term survival with surgery alone. Although there may be a role for radical prostatectomy in selected patients with low to intermediate grade tumors, such treatment appears unlikely to result in long-term survival in men with high grade disease. A prospective study is necessary to determine the optimal treatment approach in men with locally advanced prostate cancer.

Eye injuries after nonocular surgery. A study of 60,965 anesthetics from 1988 to 1992.

BACKGROUND: Eye injuries after anesthesia, although infrequent, may result in visual impairment. Previous studies have not defined the risk factors associated with these injuries. To study the cause of these injuries and to determine incidence data, the authors reviewed the records from a 4.5-y period of patients who sustained eye injuries after anesthesia and nonocular surgery. METHODS: The records were surveyed of 60,965 patients who underwent anesthesia for nonocular surgery at our institution from January 1988 to July 1992. Eye injuries were identified by examining several sources of information, including quality improvement data, postoperative visits or telephone calls, and examination of medical records of postoperative patients who required an ophthalmology consultation. Records were reviewed to determine the types and causes of eye injuries. Logistic regression, with univariate and multivariate analysis, was used to identify the importance of possible risk factors. RESULTS: Of 34 patients who sustained eye injuries (0.056%), the most common was corneal abrasion (n = 21). Other injuries were conjunctivitis, blurred vision, red eye, chemical injury, direct trauma, and blindness. Independent factors associated with a higher relative risk of eye injury were long surgical procedures (odds ratio, 1.16 per hour of anesthetic care; CI, 1.1 to 1.3), lateral positioning during surgery (odds ratio, 4.7; CI, 2 to 11), operation on the head or neck (odds ratio, 4.4; CI, 2.2 to 9.0), general anesthesia (odds ratio, 3.0; CI, 2.2 to 38), and surgery on a Monday (odds ratio, 2.7; CI, 1.4 to 5.3). In only 21% of cases was a specific cause of injury identified. CONCLUSIONS: For reasons not understood, eye injuries are more common in patients who are older or who undergo lengthier procedures. The cause of injury was usually not determined by the authors' methods. Until the mechanisms producing perioperative eye injuries are better understood, it is difficult to identify strategies to prevent this type of injury.

Results of radical prostatectomy in men with clinically localized prostate cancer.

OBJECTIVE: To assess the results of radical prostatectomy in men with early prostate cancer. DESIGN: Retrospective, nonrandomized, multi-institutional pooled analysis. SETTING: Eight university medical centers in the United States and Europe. PATIENTS: A total of 2758 men with stage Tl and T2 prostatic cancer. MAIN OUTCOME MEASURES: Disease-specific and metastasis-free survival rates. RESULTS: Tumor grade was the most important preoperative factor in determining outcome. Disease-specific survival 10 years following surgery and associated 95% confidence intervals were 94% (range, 87%-98%), 80% (range, 74%-85%), and 77% (range, 65%-86%) for those men with grade 1, 2, and 3 tumors, respectively. Metastasis-free survival at 10 years was 87% (range, 78%-92%), 68% (range, 62%-73%), and 52% (range, 38%-64%) for patients with grade 1, 2, and 3 cancers, respectively. CONCLUSIONS: Radical prostatectomy leads to high 10-year disease-specific survival rates in men with all tumor grades. However, caution is needed in comparing these results with similar studies of alternative treatment strategies, such as watchful waiting, due to the inherent potential biases in uncontrolled trials. Nevertheless, these results offer the best currently available estimates of 10-year outcome of radical prostatectomy in men with clinically localized prostate cancer and may be useful in counseling patients with early malignancy.

Short-term outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy.

OBJECTIVES: Cryosurgical ablation of the prostate represents a possibly efficacious method of treating prostate carcinoma in men failing radiation therapy. In addition to eradicating the disease, cryosurgery has the potential to avoid some of the morbidity associated with other treatment modalities. Therefore, a prospective Phase II trial was conducted to determine the safety and efficacy of cryosurgery following radiation therapy in men with local recurrence. METHODS: Cryosurgical ablation of the prostate was performed in men with prostate cancer previously treated by radiation therapy. All patients had biopsy-proven recurrent disease and no evidence of metastases. Initial follow-up occurred at approximately 3 months and included repeat biopsy and serum prostate-specific antigen (PSA) determinations. Biochemical disease-free survival defined as a PSA value less than 0.3 ng/mL was assessed using the Kaplan-Meier method. RESULTS: Thus far, 23 patients have been treated with cryosurgery with follow-up ranging between 12 and 23 months. Approximately 3 months after treatment, sextant biopsies revealed no cancer in 19 of 22 (86%) of the specimens; however, 10 of 22 (45%) showed small amounts of benign glandular tissue. The PSA at 3 months postoperatively declined in 18 of 22 (82%) patients but reached female levels in only 8 men (36%). Nineteen of 22 (86%) patients followed up a minimum of 1 year after cryotherapy have a PSA level equal to or greater than 0.3 ng/mL. Complications occurred in 100% of the patients with 12 of 22 (55%) requiring at least one transurethral resection of sloughed, necrotic tissue. CONCLUSIONS: Our preliminary results suggest that the current cryosurgical technique used in men failing radiation therapy has a low probability of biochemical cure and a high complication rate. Until more data are available, cryosurgery for men with locally recurrent disease after radiation therapy should be considered strictly experimental.

Prospective, randomized, double-blind trial of BQ-123 and bosentan for prevention of vasospasm following subarachnoid hemorrhage in monkeys.

Thirty-one monkeys were randomly divided into three groups to undergo baseline cerebral angiography followed by induction of subarachnoid hemorrhage by placement of autologous blood clot along the right-sided arteries of the anterior circle of Willis (Day 0). The monkeys were then given drug vehicle or one of two endothelin (ET) antagonists, BQ-123 (6 mg/kg/day) or bosentan (5 mg/kg/day) intracisternally. The BQ-123 was administered by continuous infusion from a subcutaneous pump and the bosentan was given by twice-daily injections into an Ommaya reservoir in the subcutaneous space with a catheter along the right middle cerebral artery (MCA). Seven days later (Day 7), angiography was repeated and the animals were killed. Comparison of arterial diameters shown on angiograms between Day 0 and Day 7 groups given placebo and bosentan showed significant reductions in the diameters of the right intradural internal carotid (28% +/- 6% and 30% +/- 6%, respectively, paired t-test, p < 0.05), anterior cerebral artery (29% +/- 8% and 32% +/- 6% respectively +/- 6%, respectively) and MCA (34% +/- 6% and 46% +/- 4%, respectively). Animals injected with BQ-123 had significant narrowing of the right extradural internal carotid artery (7% +/- 6%) and the basilar artery (11% +/- 3%), but not of the right MCA. Comparison of arterial diameters between groups at Day 7 showed significant variance in the right extradural internal carotid, both intradural internal carotid, right middle cerebral, and left anterior cerebral arteries; the animals injected with BQ-123 developed significantly less arterial narrowing these those receiving bosentan and placebo. Bosentan was not detected in the cerebrospinal fluid aspirated from the cisterna magna on Day 7, whereas BQ-123 was detected in two animals. We can infer from these results that BQ-123 prevents vasospasm following subarachnoid hemorrhage in monkeys, that further investigations of ET antagonists are warranted, and that ET may be an important pathophysiological mediator of vasospasm. The lack of efficacy of bosentan may be related to inadequate cerebrospinal fluid levels obtained by administration twice-daily through an Ommaya reservoir.

A comparison of intraarticular morphine and bupivacaine for pain control after outpatient knee arthroscopy. A prospective, randomized, double-blinded study.

To determine the duration of pain relief and efficacy of intraarticular morphine compared with bupivacaine after outpatient knee arthroscopy under local anesthesia, we gave patients one of three postoperative intraarticular injections: 4 mg morphine, 0.25% bupivacaine, or 0.9% saline. Visual analog scale scores and supplemental pain medication use were recorded at 0 to 30 minutes, 2, 4, 6, 8 to 12, and 24 hours after surgery. The score on the visual analog scale at 24 hours was significantly lower in the morphine group than in the bupivacaine or control groups. The cumulative amount of pain medication used was significantly lower in the morphine and bupivacaine groups at 2 to 6 hours after surgery than in the saline control group. The morphine group used the least supplemental pain medication during the 12 to 24 hour interval (P = 0.06). We found that the use of intraarticular morphine or bupivacaine after outpatient knee arthroscopy will decrease the amount of narcotic medication needed for pain relief during the early postoperative period. In addition, morphine provided prolonged pain relief up to 24 hours when compared with bupivacaine or placebo, and the patients in the morphine group tended to take less supplemental pain medication during the first postoperative day.

Estimation of the association between desipramine and the risk for sudden death in 5- to 14-year-old children.

BACKGROUND: Four cases of sudden death in children 12 years or younger during desipramine treatment were identified between 1986 and 1992. We evaluated whether these events support the hypothesis that exposure to therapeutic doses of desipramine contributes to the risk for sudden death in otherwise healthy children. METHOD: The National Center for Health Statistics provided the baseline number of sudden unexplained deaths in children 5 to 14 years old. Data from the National Disease and Therapeutic Index were used to estimate the exposure to desipramine in children in the same age group. Since two of the four deaths were identified by 1987, we used the post-1987 experience as if it were a prospective period in which a causal association could be examined. RESULTS: The number of sudden deaths in desipramine-exposed children did not increase from 1986 to 1992 despite a marked increase in exposure. By using 4 to 6 months as the average lifetime of a desipramine prescription and a baseline rate of sudden death of 4.2 deaths/million/year in this population, the post-1987 period would account for 162,000 to 242,000 person-years of desipramine exposure. Although not statistically significant, this level of exposure corresponds to a relative risk of 2.1 (95% CI = 0.5 to 15) to 3.1 (95% CI = 0.8 to 22). CONCLUSION: Although, based on our estimates, the evidence for an association between desipramine and sudden death in children aged 5 to 14 years appears weak, replication of our findings is needed with a more precise numerator (total number of deaths) and denominator (the appropriate conversion from drug appearance to actual exposure) before a firm conclusion on this subject can be drawn. Until then, even if remote, the possibility of an association between desipramine and sudden death in children stresses the importance of assessing risks and benefits when desipramine is used in pediatric patients.

Mucosal allergy in the absence of systemic allergy in nasal polyposis and rhinitis: a meta-analysis.

To better determine the role of allergy in rhinitis and nasal polyposis, we assessed the prevalence of nasal mucosal allergy in the absence of systemic allergy. After a thorough literature search we compiled and analyzed data from nine studies (287 patients) that tested for specific immunoglobulin E both intranasally and systemically. When meta-analysis was applied to the different populations, 19% of those who demonstrated specific immunoglobulin E manifested nasal mucosal allergy but no systemic allergy. We suggest that there is an important segment of rhinitis and nasal polyp patients who have nasal mucosal allergy.