Germline mutations of the CDKN2 gene in UK melanoma families

Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin D kinase inhibitor p16, and more rarely, mutations in the gene coding for CDK4, the protein to which p16 binds, underlie susceptibility in some melanoma families. We have sequenced all exons of CDKN2 and analysed the CDK4 gene for mutations in 27 UK families showing evidence of predisposition to melanoma. Five different germline mutations in CDKN2 were found in six families. Three of the mutations (Met53Ile, Arg24Pro and 23ins24) have been reported previously. We have identified two novel CDKN2 mutations (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segregation with the disease and their likely functional effect on the CDKN2 protein. In binding assays the protein expressed from the previously described mutation, Met53Ile, did not bind to CDK4/CDK6, confirming its role as a causal mutation in the development of melanoma. Ala118Thr appeared to be functional in this assay. Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were detected in exon 2 of CDK4, suggesting that causal mutations in this gene are uncommon. The penetrance of these mutant CDKN2 genes is not yet established, nor is the risk of non-melanoma cancer to gene carriers.      

The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy

Anderson-Fabry disease (AFD) is an X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. The availability of enzyme replacement therapy (ERT) for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system--the Mainz Severity Score Index (MSSI)--to measure the severity of AFD and to monitor the clinical course of the disease in response to ERT. Thirty-nine patients (24 males and 15 females) with AFD were assessed using the MSSI immediately before and 1 year after commencing agalsidase alfa ERT. Control data were obtained from 23 patients in whom AFD was excluded. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases. The MSSI indicated that, although more men than women had symptoms classified as severe, overall, the median total severity scores were not significantly different between male and female patients. One year of ERT with agalsidase alfa led, in all patients, to a significant (p < 0.001) reduction in MSSI score (by a median of nine points). This study has shown that the MSSI score may be a useful, specific measure for objectively assessing the severity of AFD and for monitoring ERT-related treatment effects.     

Comparison of the intensity and duration of effects of inhaled bitolterol and albuterol on airway caliber and airway responsiveness to histamine

Inhaled beta-agonists can produce bronchodilatation and reduce airway hyperreactivity in patients with asthma. Using these two measures, we compared inhaled bitolterol (three puffs, 1110 micrograms), albuterol (two puffs, 180 micrograms), and placebo administered by metered-dose inhaler in a blinded, crossover study of 40 subjects with chronic asthma. On each study day, subjects underwent histamine challenges at 1 1/2 hours before, and 1/2, 2, 4, 6, and 8 hours after inhaling one of the three test-drug treatments. Both drugs produced significant bronchodilatation at 30 minutes through 4 hours and significant effects on airway reactivity at 30 minutes through 2 hours (p less than 0.05). Bitolterol also produced small but significant bronchodilator effects at 6 hours and effects on airway reactivity at 4 hours (p less than 0.05). Effects of bitolterol on airway reactivity diminished significantly more slowly than effects of albuterol in subjects with baseline provocative concentration causing a 20% fall in FEV1 greater than or equal to 1.0 mg/ml of histamine (half-life of biologic effect 1.37 versus 0.92 hours; p less than 0.05) but not in subjects with baseline provocative concentration causing a 20% fall in FEV1 less than or equal to 1.0 mg/ml (half-life of biologic effect of 1.01 versus 1.00 hours; p greater than 0.05).     

Opisthotonos following propofol: A nonepileptic perspective and treatment strategy

In this report of opisthotonos during recovery from propofol anaesthesia, we relate clinical observations with scientific considerations, and propose a strategy for treatment of this rare side effect. Following a brief operative procedure, a healthy 29-yr-old woman developed recurrent opisthotonos while recovering from anaesthesia with alfentanil, propofol, and nitrous oxide. In contrast to accumulating reports, the patient remained conscious during each episode of back extension and retrocollis. The preservation of consciousness and similarities to strychnine-induced opisthotonos suggest to us that the mechanism may have a brainstem and spinal origin. Recent investigations show that propofol potentiates the inhibitory transmitters glycine and γ-aminobutyric acid (GABA) which would enhance spinal inhibition during anaesthesia. Postanaesthetic opisthotonos, however, may be due to a propofol-induced tolerance to inhibitory transmitters. This rebound phenomenon would lead to an acute, enduring refractoriness in inhibitory pathways of the brainstem and spinal cord, resulting in increased activity of extensor motoneurons. We recommend a therapeutic strategy that restores inhibition by glycine and GABA at multiple sites; the preferred therapeutic agents would be diazepam and physostigmine. The episodes are usually short-lived, but two of the reviewed 17 patients developed recurrent retrocollis for four and 23 days following antiepileptic drug therapy. Since high doses of phenytoin and carbamazepine can result in opisthotonos, we recommend that anticonvulsants be reserved for post-anaesthetic patients with electroencephalographic evidence of seizure activity.     

Adapting a commercially available software program to improve ADR reporting

To facilitate the long-term storage, retrieval, and analysis of adverse drug reaction (ADR) data, the drug information service at the University of Texas Health Science Center at San Antonio selected a computer software program with the capability to compile sets of relational databases. Five subsets were created to form the ADR database--patient demographics, medications, American Hospital Formulary Service classifications, adverse reactions, and case reports. This computerized system allows for quick information retrieval as well as the generation of monthly ADR reports. With such information, trends in ADRs can be identified and targeted for intervention programs to improve patient care and to comply with JCAHO requirements.     

Cost comparison of sevoflurane with isoflurane anesthesia in arthroscopic menisectomy surgery

PURPOSE: To determine the "real world" cost of sevoflurane compared with isoflurane in balanced general anesthesia for daycare arthroscopic menisectomy, we prospectively investigated perioperative drug requirement and expense as well as recovery time. METHODS: Following intravenous induction, 40 consenting adult patients randomly received either sevoflurane- or isoflurane-based anesthesia with a standardized gas inflow rate of 3 l x min. Recovery was assessed in the postanesthetic recovery room (PARR) in a double-blind manner at 15 min intervals using the Aldrete scoring system until patients met discharge criteria. RESULTS: Patient demographics, anesthetic duration, volatile potency and adjunct drug requirements were similar in the two groups. Total perioperative drug cost per patient was CAN$38.10+/-10.13 (mean +/- SD) for the sevoflurane group and $23.87+/-6.59 for the isoflurane group (P<0.01). Although the nonvolatile drug cost was comparable between the two groups, the volatile drug cost per patient was $19.40+/-8.80 for sevoflurane and $4.50+/-1.90 for isoflurane (P<0.01). This four-fold sevoflurane-to-isoflurane cost difference was the product of two ratios, both based on the volume of liquid anesthetic: the ratio of consumption, 2.1; and the ratio of institutional price, 2.1. Intraoperative hemodynamic response, time until discharge from the PARR and incidences of postoperative nausea and vomiting did not significantly differ between the two groups. CONCLUSIONS: When used to maintain equipotent balanced general anesthesia for daycare arthroscopic menisectomy, volatile consumption and cost were greater for sevoflurane compared with isoflurane. Nonvolatile perioperative drug cost and recovery times were similar, however, in the two groups.     

Age and stimulus dependency of visually evoked cerebral blood flow responses

BACKGROUND AND PURPOSE: During visual stimulation, the increased metabolic demand is coupled with an increase of cerebral blood flow velocity (pCBFV) in the posterior cerebral artery (PCA). Investigation of the visually evoked flow responses (VEFR, expressed as percentage of increase from baseline pCBFV values) was suggested for different conditions of vasoneuronal disorders in the absence of any systematic investigation in healthy subjects. METHODS: We investigated VEFRs from both PCAs to various increasingly complex paradigms (diffuse light, alternating checkerboard patterns, and a color video movie stimulation; 5, 10, 20, and 30-second intervals) in 60 healthy volunteers (mean age, 41.5+/-14.9 years; range, 24 to 80 years; 28 male, 32 female) at different recording sites (P1 versus P2 segments of PCAs). RESULTS: With increasing complexity of stimulation, the VEFRs increased significantly (24.3+/-10.3%, 28.5+/-13.5%, and 43.4+/-10.7%, respectively). Twenty-second stimulation intervals yielded maximal responses (41.5+/-13.2%) compared with 5-, 10-, and 30-second intervals (22.6+/-14.1%, P=0.001; 34.4+/-11.7%, P=0.0042; and 35.5+/-9.9%, P=0.0032, respectively). Significantly higher responses were gained from P2 segments than from P1 segments (42.7+/-7.2% versus 28.2+/-7.1%). Although VEFRs tended to decrease in amplitude with age (mean, 41. 7+/-10.5% [20 to 40 years], 35+/-9.2% [40 to 60 years], and 33.9+/-8.6% [60 to 80 years]); without significant sex-related differences, only the percentage decrement of the pulsatility indices during stimulation were significant (mean, 24+/-10.7% [20 to 40 years], 20+/-7.3% [40 to 60 years], and 13+/-11.2% [60 to 80 years]). CONCLUSIONS: For optimal stimulus conditions for maximum VEFRs, a colored video stimulation of 20-second intervals should be used to combine responses not only from the primary visual projection fields (V1 and V2) but also from temporal lobe areas (V3 through V5) often supplied by the PCA.     

Functional hallux rigidus in the rheumatoid foot

Hallux rigidus results from arthritic involvement of the first metatarsophalangeal joint. The authors have observed loss of motion at this joint in patients with rheumatoid arthritis in the absence of hallux valgus or joint destruction. A hyperextension deformity of the interphalangeal joint has also been observed, with a painful callus beneath it. The first metatarsophalangeal joint appears normal on roentgenograms, and passive motion of the joint is normal when it is examined clinically. The loss of first metatarsophalangeal motion is functional, and stems from muscle spasm of the great toe intrinsic muscles in an effort to relieve pressure on the lesser metatarsal heads. The interphalangeal hyperextension may develop secondary to "functional hallux rigidus."     

Neisseria gonorrhoeae screening in pregnancy

All patients undergoing prenatal care at the U.S Naval Hospital in Yokosuka, Japan, have a gonorrhea culture performed at their intake visit. The objective of this study was to determine the prevalence of Neisseria gonorrhoeae in this military population and to propose an effective antenatal screening strategy based on the data. A retrospective 10-month review of patient data was performed. In addition, the guidelines for antenatal N. gonorrhoeae screening by the American College of Obstetricians and Gynecologists, the Centers for Disease Control and Prevention, the U.S. Department of Health and Human Services, and the World Health Organization were reviewed. During the study period, none of the screened patients (N = 518) had a gonococcal infection. The screening program at this facility will be modified based on the low-risk nature of the pregnant population. Specifically, high-risk patients will be screened selectively in the third trimester.