The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA.

Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.

The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: synergism with the benzodiazepine diazepam.

Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA(A)) receptors. However, seizure activity itself causes the endocytosis of GABA(A) receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-d-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20mg/kg, im) and DZP (10mg/kg, sc), administered both separately and in combination, at 10, 20 or 30min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD(50); 132µg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20-30min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity.

Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period.

Kinetics of osmotically controlled indomethacin delivery systems after repeated dosing.

Two osmotically driven, controlled-release dosage forms of indomethacin were evaluated in a multiple-dose crossover study in 12 healthy subjects. Following equivalent daily doses, less frequent dosing of both controlled-release forms resulted in plasma concentration profiles that are more uniform than those following capsule regimens. After the first day, morning predose plasma levels wer significantly higher for the controlled-release treatments. Renal clearances were similar between days and among treatments. Total urinary recoveries were comparable for all regimens.

Effects of diflunisal on platelet function and fecal blood loss.

The effects of diflunisal, a nonacetylated difluorinated salicylate, on platelet function were compared with those of aspirin and placebo. In a randomized, double-blind trial, normal subjects were given diflunisal, 250, 500, or 1,000 mg twice daily; aspirin, 650 or 1,300 mg twice daily; or placebo for 8-day periods. Difunisal, 250 mg, had no effect on platelet function, whereas 500 mg induced minimal inhibition of colagen-induced release of platelet serotonin, and 1,000 mg inhibited platelet malondialdehyde production, moderately prolonged template bleeding times (P = NS), and increased fecal blood loss (P less than 0.05). In contrast, aspirin, 650 mg, markedly inhibited collagen-induced platelet aggregation and serotonin release, and 1,300 mg prolonged bleeding time (P less than 0.01) and increased fecal blood loss (P less than 0.01). The effects of aspirin lasted for up to 5 days, whereas changes induced by diflunisal had returned to baseline 24 hr after the drug was discontinued. We conclude that in doses in the same range as those of aspirin diflunisal inhibits platelet function less.

Pharmacology of enantiomers and (-) p-OH metabolite of indacrinone.

Indacrinone, a racemic mixture, is a loop-blocking diuretic with effects on uric acid elimination that differ from those of furosemide. A series of studies in healthy men was undertaken to characterize the pharmacologic activity of the positive (+) and negative (-) enantiomers (E) of indacrinone and its (-) p-OH metabolite, (-) MET. All subjects were on sodium- and potassium-controlled diet; each experiment was similar in design and included placebo and positive controls. Oral (-)E and (-)MET exerted dose-related natriuretic and diuretic effects; intravenous doses of (-)E were more effective than (-)MET. The effects of (-)E and (-)MET on serum uric acid were the same as those reported with indacrinone. After (-)E, both (-)E and generated (-)MET appeared to contribute to the natriuresis. (+)E induced dose-related decreases in serum uric acid up to 24 hr after dosage; at the higher doses of (+)E, the hypouricemic effects were of the order of those after 500 mg of probenecid. Thus, indacrinone is a novel loop diuretic with enantiomers and a (-)MET, each of which has a different pharmacologic profile.

Cognitive screening examinations for silent cerebral infarcts in sickle cell disease.

OBJECTIVE: In children with sickle cell disease (SCD), silent cerebral infarcts are the most frequent cause of neurologic injury. We determined the sensitivity and specificity of selective neurocognitive measures when separating children with silent cerebral infarcts and SCD from sibling controls. Additionally, we tested the validity of the same cognitive measures to identify patients with overt strokes. METHODS: We examined performance on a neuropsychologic battery containing measures of attention/executive, spatial, language, memory, and motor functioning for seven children with SCD and silent cerebral infarct, 21 children with SCD and overt stroke, and 17 normal siblings. Diagnosis of cerebral infarct was based on results of MRI. RESULTS: Measures from the attention and executive domains were the most useful for identifying children with silent cerebral infarct. The Test of Variables of Attention was the most robust measure and yielded a sensitivity rate of 86% and a specificity rate of 81%. This measure also showed a sensitivity rate of 95% in identifying overt stroke. CONCLUSIONS: Brief cognitive screening measures, if properly constructed, may be an effective means of identifying children with silent cerebral infarct. Future prospective studies should be pursued to assess the utility of cognitive screening for silent cerebral infarcts in SCD.

Role of transesophageal echocardiography in the management of patients with bronchogenic carcinoma invading the left atrium.

TEE played a significant role in the management of 2 patients by defining the extent of cardiac invasion. We believe TEE would be helpful in patients presenting with thoracic tumors believed to be encroaching on cardiac structures, where consideration is being given to surgical resection of the tumor.

Pathologic findings in lung volume reduction surgery.

PURPOSE: Lung volume reduction surgery (LVRS) has re-emerged as an alternative in the management of patients with chronic, debilitating, emphysematous lung disease. This has permitted the formal evaluation of pathologic pulmonary changes present in these patients. This study seeks to describe systematically the pathologic findings present in patients undergoing LVRS. METHODS: Tissue sections stained with hematoxylin-eosin, as well as special stains, were retrospectively reviewed from the specimens of 65 nonconsecutive LVRS patients (male patients, 66%; female patients, 31%; mean age, 63.2+/-6.76 yr). All operations were conducted via an open technique (bilateral, 83%; unilateral, 17%). RESULTS: Histologic emphysema grade was mild in 9%, moderate in 72%, and severe in 19% of patients. Microscopic bullae were noted in 75% of specimens. Three patients, each with radiographic evidence of a lesion preoperatively, had small (1.1 to 2.8 cm) adenocarcinomas. Granulomatous bronchiolitis and pneumonitis were noted in one patient who postoperatively developed progressive respiratory compromise. An old, inactive aspergilloma was found in the specimen of another patient. Additional findings of potential clinical significance included bronchiolitis (54), bronchiolectasis (6), and bronchoalveolar metaplasia (1). Incidental findings included interstitial fibrosis and scar (55), interstitial inflammation (20), calcification (20), and ossification (11), bone marrow emboli (4), chemodectoma (2), and carcinoid tumorlets (1). CONCLUSION: This systematic analysis of the resected specimens from patients undergoing LVRS describes a wide range of pathologic findings, including those clinically relevant, as well as incidental. As the application of LVRS continues to expand, the likelihood of discovering clinically significant pathologic lesions (eg, carcinoma) will undoubtedly increase.

The surgical spectrum of pulmonary neuroendocrine neoplasms.

OBJECTIVES: The purpose of this study is to review our experience with the spectrum of neuroendocrine neoplasms of the lung with emphasis on the histopathologic classification and surgical therapy of each class of neoplasm. DESIGN: This retrospective review covers the entire spectrum of neuroendocrine neoplasms of the lung over an 11-year period (January 1985 to December 1995) in a university hospital setting. Only patients who underwent surgical resection were included in this review. PATIENTS: During this period, a total of 77 patients underwent lung resection for the following neuroendocrine neoplasms: typical carcinoid (TC), 50 patients; atypical carcinoid (AC), 5 patients; large cell neuroendocrine carcinoma (LCNEC), 9 patients; mixed large-small cell neuroendocrine carcinoma (LSNEC), 4 patients; or small cell neuroendocrine carcinoma (SCC), 9 patients. There were 37 men (48.1%) and 40 women (51.9%) among the patients, with a mean age of 57.9 years (range, 14 to 87 years). INTERVENTIONS: Primary surgical resection consisted of the following procedures: 52 lobectomies (67.5%); 10 pneumonectomies (13%); 13 limited resections (16.9%); 1 left main bronchus sleeve resection; and 1 carinal resection. Six patients had the following concomitant procedures: pericardiectomy, 2 patients; mediastinoscopy, 1 patient; chest wall resection, 1 patient; stapling blebs, 1 patient; and transdiaphragmatic liver biopsy, 1 patient. Four patients underwent bilobectomies, and two patients underwent multiple wedge resections. RESULTS: The hospital mortality rate was 2.6% (2 of 77 patients), and both patients died of pulmonary failure. Follow-up was obtained in 62 of 77 patients (80.9%) for an average of 38.1 months (range, 2 to 132 months). There were a total of 13 deaths, and 8 were disease-related (LCNEC, 4 deaths; SCC, 2 deaths; LSNEC, 1 death; and AC tumor, 1 death. The mean disease-free intervals for patients with these neoplasms were the following: TC tumor, 41.3 months; AC tumor, 20 months; LCNEC, 20.4 months; LSNEC, 25 months; and SCC, 48 months. The overall 3-year survival rate was 45.2% (28 of 62 patients). CONCLUSION: This report will emphasize the classification, surgical management, and treatment considerations of pulmonary neuroendocrine neoplasms. Despite the poor overall prognosis in high-grade neuroendocrine tumors of the lung, surgery remains a viable adjunct in the early stages of this disease.

Amphicrine carcinoma of the uterine cervix.

A case of amphicrine carcinoma of the uterine cervix is described in a 27-year-old woman whose initial cervical biopsy specimen showed small cell undifferentiated neuroendocrine carcinoma. Despite an initial complete clinical response to VP-16 and carboplatin, residual tumor was noted in the cervical cone biopsy specimen and she was treated with external-beam irradiation and cesium implants. The neoplasm subsequently metastasized and required additional VP-16 and carboplatin for control. The pathologic features and biologic behavior of this unusual type of neuroendocrine neoplasm are described in this case report.

Cervical carcinoma in pregnancy.

Forty-one cases of invasive carcinoma of the cervix associated with pregnancy that were treated at the Walter Reed Army Medical Center from January 1961 through April 1979 were reviewed. Postpartum patients were included in the study if the diagnosis of cancer was made within 6 months of delivery. Three cases of clinical stage IA disease treated by Wertheim-Taussig hysterectomy had a 5-year survival rate of 100%. There were 22 cases of stage IB disease with a 5-year actuarial survival rate of 90%. Four patients with stage IB were treated by radiotherapy, 17 by Wertheim-Taussig hysterectomy, and 1 by a combination of pelvic irradiation, cesium application, and simple extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy for a barrel-shaped cervix. Twelve cases of stage II disease treated by radiotherapy had a 5-year actuarial survival rate of 24%. There were no survivors in 2 cases of stages III and IV disease. The 5-year actuarial survival rate of patients with stage I carcinoma of the cervix associated with pregnancy is not statistically different from that of nonpregnant patients, regardless of the method of treatment.

The significance of moderate and severe inflammation on class I Papanicolaou smear.

The significance of a cytologic diagnosis of moderate and severe inflammation with a normal (class I) Papanicolaou smear has not been addressed. A retrospective review of 596 consecutive cervical smears performed over 13 months revealed 85 women who had a class I cytologic smear with moderate to severe inflammation. Seventy-eight patients had colposcopic examinations and were considered for this study. Fifty-nine (75.6%) had cervical punch biopsies and/or endocervical biopsies. Of the 78, 19 (24.4%) had cervical condylomata and nine (11.5%) had cervical intraepithelial neoplasia. We conclude that class I cytologic smears with moderate to severe inflammation may be associated with findings of condylomata and cervical dysplasia.

Classification of endometrial cells on cervical cytology.

One hundred eighty-eight women who had endometrial cells on cervical cytologic specimens during the secretory phase or in the postmenopausal period were studied retrospectively. Each had undergone hysterectomy or endometrial biopsy within 12 months of the original smear. The endometrial cells were classified as typical, atypical, or suspicious for carcinoma. Among premenopausal subjects, three of 57 with typical cells had endometrial hyperplasia, one of two with atypical cells had endometrial polyps, and both with cells suspicious for carcinoma had endometrial carcinoma. In the postmenopausal group, ten (13.5%) of 74 with typical endometrial cells had either hyperplasia or carcinoma, and five (22.7%) of 22 with atypical cells and 24 77.4%) of 31 patients with suspicious cells had either hyperplasia or carcinoma. The present findings and a review of the pertinent literature demonstrate that the classification system used is helpful in predicting the risk for endometrial disease in patients with endometrial cells seen on cervical cytologic smears during the secretory phase or in the postmenopausal period.

Pregnancy following conservative surgery and adjunctive chemotherapy for stage III immature teratoma of the ovary.

A 24-year-old woman with stage III grade 3 immature teratoma of the ovary was treated with a unilateral salpingo-oophorectomy and nine courses of vincristine, actinomycin D, and cyclophosphamide combination chemotherapy. She had a negative second-look exploration; 30 months after initial surgery she became pregnant, and subsequently delivered a normal child at term. This is the first report of a successful pregnancy following conservative surgery and chemotherapy for advanced-stage immature teratoma.

Presacral neurectomy for chronic pelvic pain.

Over an eight-year period, 50 presacral neurectomies were performed at Madigan Army Medical Center for chronic pelvic pain failing response to medical management. Each hospital record was reviewed and 45 patients answered a questionnaire grading the severity of their pain from 0 to 10 for dysmenorrhea, dyspareunia, and other pelvic pain before and after surgery. The results showed success rates of 73% in relieving dysmenorrhea, 77% in relieving dyspareunia, and 63% in relieving other pelvic pains. The addition of a bilateral uterosacral ligament resection to the presacral neurectomy did not increase the success rate. There was an 18% lateral pelvic pain recurrence rate, and no recurrence of dysmenorrhea. Complications occurred in 4%.

A comparative pilot study of enalapril, a new converting enzyme inhibitor, and hydrochlorothiazide in essential hypertension.

Eight patients with essential hypertension completed a double-blind, randomly allocated crossover comparison of either 5 or 10 mg enalapril maleate, 50 mg hydrochlorothiazide, or their combination administered once daily during sequential two-week periods. Blood pressure, pulse rate, plasma renin activity, angiotensin-converting enzyme activity, plasma aldosterone concentration, and urinary electrolytes were monitored for 24 hours after placebo and on days 1 and 14 of each treatment period. After two weeks of each treatment, only the combination of enalapril and hydrochlorothiazide significantly lowered the mean seated diastolic blood pressure (SDBP). Likewise, SDBP control (less than or equal to 90 mm Hg) was achieved only after combination therapy; six of the eight patients were controlled by the combination for up to 24 hours. The initial SDBP response to combination therapy differed with the sequence of drug addition; however, by day 14 the responses were comparable, regardless of whether hydrochlorothiazide or enalapril was first given. Mean converting enzyme activity was suppressed by enalapril in all patients, though it did not always correlate with changes in SDBP or plasma aldosterone. Mean plasma renin activity increased, but the increase was significant only on the combination. There were no serious adverse effects.

Comparative antihypertensive effects of enalapril maleate and hydrochlorothiazide, alone and in combination.

Enalapril maleate is an investigational oral prodrug whose hydrolyzed diacid metabolite is a potent angiotensin-converting enzyme inhibitor. Fourteen patients with mild to moderate hypertension were evaluated after receiving placebo, and two weeks of treatment with each of the following: enalapril maleate (20 mg b.i.d.), hydrochlorothiazide (25 mg b.i.d.), and the two in combination. In comparison to placebo, the magnitudes of the blood pressure reduction after enalapril and hydrochlorothiazide alone were comparable. The reduction in blood pressure following enalapril was evident throughout the 12-hour dosing interval. The combination of enalapril and hydrochlorothiazide resulted in a marked further reduction in blood pressure that was greater than that predicted from the responses to the individual drugs (P less than 0.05). Biochemical parameters confirmed inhibition of angiotensin-converting enzyme during enalapril treatment; serum angiotensin-converting enzyme activity proved an excellent monitor of compliance. Enalapril was generally well tolerated. Adverse effects included symptomatic hypotension in three patients when enalapril was first added to hydrochlorothiazide and hyperesthesia of the oral mucosa without a loss of taste in one patient on enalapril. Enalapril maleate alone and especially in combination with hydrochlorothiazide appears to be an effective, well-tolerated converting enzyme inhibitor with at least a 12-hour duration of action.

Tracheal resections: lessons learned.

Tracheal resection and primary anastomosis can be performed for the management of congenital, traumatic, iatrogenic, and neoplastic etiologies of tracheal stenosis. During a 19-year period, we performed 45 tracheal resections on 38 patients with low operative mortality (7.9%) and morbidity. One patients had congenital tracheal stenosis (group 1); 4 patients had stenosis resulting from traumatic lesions (group 2); 18 patients had stenosis caused by tracheostomy or endotracheal tubes (group 3); and 15 patients had stenosis caused by a variety of neoplastic lesions (nine primary and six secondary) (group 4). Preoperative evaluation and surgical and anesthesia management are described. Eight tracheal stents were used (three Neville prostheses and five Montgomery T tubes). Disastrous results occurred with the Neville prosthesis, but acceptable results were obtained when the Montgomery T tube was used. There were several "lessons learned" during the evolution of this series. Chest roentgenograms are not useful. Tracheal tomography and computed tomography are extremely informative in evaluation of iatrogenic and neoplastic lesions. Proper mobilization allows primary anastomosis after almost all resections. Excellent results were obtained with iatrogenic lesions. Increased mortality and morbidity occur in patients undergoing resection for neoplastic lesions; however, 5-year survival is good, and results are gratifying.