Exploring Unorthodox Dimensions for Two-Electron Atoms.

Melding quantum and classical mechanics is an abiding quest of physical chemists who strive for heuristic insights and useful tools. We present a surprisingly simple and accurate treatment of ground-state two-electron atoms. It makes use of only the dimensional dependence of a hydrogen atom, together with the exactly known first-order perturbation value of the electron-electron interaction, both quintessentially quantum, and the D → ∞ limit, entirely classical. The result is an analytic formula for D-dimensional two-electron atoms with Z ≥ 2. For D = 3 helium, it gives accuracy better than 2 millihartrees, which is better than current density functional theory. A kindred explicit formula for correlation energy exploits interpolation between D → ∞ and D = 1 or 2; when added to the Hartree-Fock energy, it improves accuracy for D = 3 helium to better than 0.1 millihartrees.

Types of female partners reported by black men who have sex with men and women (MSMW) and associations with intercourse frequency, unprotected sex and HIV and STI prevalence.

We used baseline data from a study of Black MSM/MSMW in 6 US cities to examine the association of female partnership types with disease prevalence and sexual behaviors among the 555 MSMW participants. MSMW reported more than three times as many total and unprotected sex acts with each primary as they did with each non-primary female partner. We compared MSMW whose recent female partners were: (1) all primary ("PF only", n = 156), (2) both primary and non-primary ("PF & NPF", n = 186), and (3) all non-primary ("NPF only", n = 213). HIV/STI prevalence did not differ significantly across groups but sexual behaviors did. The PF only group had the fewest male partners and was the most likely to have only primary male partners; the PF & NPF group was the most likely to have transgender partners. PF & NPF men reported the most sex acts (total and unprotected) with females; NPF only men reported the fewest. Implications for HIV risk and prevention are discussed.

A study of perceived racial discrimination in Black men who have sex with men (MSM) and its association with healthcare utilization and HIV testing.

In HPTN 061, a study of Black men who have sex with men (MSM), we evaluated the association of healthcare-specific racial discrimination with healthcare utilization and HIV testing among 1167 HIV-negative participants. Median age was 38 years, 41 % were uninsured, and 38 % had an annual household income <$10,000. Overall, 19 % reported healthcare-specific racial discrimination directed toward family, friend, or self; 61 % saw a healthcare provider in the previous 6 months and 81 % HIV tested within the past year. Healthcare-specific racial discrimination was positively associated with seeing a provider [adjusted odds ratio (AOR) = 1.4 (1.0, 2.0)] and HIV testing [AOR = 1.6 (1.1, 2.4)] suggesting that barriers other than racial discrimination may be driving health disparities related to access to medical care and HIV testing among Black MSM. These results contrast with previous studies, possibly due to measurement or cohort differences, strategies to overcome discrimination, or because of greater exposure to healthcare.

Microarray analysis reveals abnormal chromosomal complements in over 70% of 14 normally developing human embryos.

STUDY QUESTION: What are the aneuploidy rates and incidence of mosaicism in good-quality human preimplantation embryos. SUMMARY ANSWER: High-level mosaicism and structural aberrations are not restricted to arrested or poorly developing embryos but are also common in good-quality IVF embryos. WHAT IS KNOWN ALREADY: Humans, compared with other mammals, have a poor fertility rate, and even IVF treatments have a relatively low success rate. It is known that human gametes and early preimplantation embryos carry chromosomal abnormalities that are thought to lower their developmental potential. STUDY DESIGN, SIZE AND DURATION: The embryos studied came from nine young (age <35 years old) IVF patients and were part of a cohort of embryos that all resulted in healthy births. These 14 embryos inseminated by ICSI and cryopreserved on Day 2 of development were thawed, cultured overnight and allowed to succumb by being left at room temperature for 24 h. Following removal of the zona pellucida, blastomeres were disaggregated and collected. PARTICIPANTS/MATERIALS, SETTING AND METHODS: There were 91 single blastomeres collected and amplified by multiple displacement amplification. Array-comparative genomic hybridization was performed on the amplified DNA. Array-data were normalized and aneuploidy was detected by the circular binary segmentation method. MAIN RESULTS AND THE ROLE OF CHANCE: The good-quality embryos exhibited high rates of aneuploidy, 10 of 14 (71.4%) of the embryos being mosaic. While none of the embryos had the same aneuploidy pattern in all cells, 4 of 14 (28.6%) were uniformly diploid. Of the 70 analysed blastomeres, 55.7% were diploid and 44.3% had chromosomal abnormalities, while 29% of the abnormal cells carried structural aberrations. WIDER IMPLICATIONS OF THE FINDINGS: Finding such a high rate of aneuploidy and mosaicism in excellent quality embryos from cycles with a high implantation rate warrants further research on the origin and significance of chromosomal abnormalities in human preimplantation embryos. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Instituut voor de aanmoediging van innovatie door Wetenschap en Technologie in Vlaanderen (IWT-Vlaanderen). A.M. is a PhD student at the IWT-Vlaanderen. C.S. is a postdoctoral fellow at the FWO Vlaanderen. There are no competing interests.

Flint corn silage management: influence of maturity stage, inoculation with Lentilactobacillus buchneri, and storage time on fermentation pattern, aerobic stability, and nutritional characteristics.

Introduction: High quality corn silage depends on factors such as corn type, stage of crop development at harvest time, fermentation time, in addition to use or not of inoculants. This study aimed to investigate the impact of maturity stage, bacterial inoculation, and storage time on fermentation, aerobic stability, and nutritional characteristics of flint corn silage and their implications for corn silage management. Methods: A flint corn hybrid was harvested very early, early, and medium (at 250, 300 and 350 g dry matter (DM)/kg as fed, respectively) and ensiled in mini-silos without (control) or with Lentilactobacillus buchneri CNCM I-4323 at 1 × 105 cfu/g for 120, 240 and 360 d to investigate how these factors interact with each other. Results and discussion: There was only a small increase (7 g/kg starch; p = 0.003) in starch digestibility (starch-D) in the silages stored for 360 d when compared to that stored for 240 d, but with no difference for 120 d. Despite the reduced starch-D (526 vs. 694 g/kg starch; p < 0.001), silages produced from medium harvest had higher (p < 0.001) starch content (317 vs. 137 g/kg DM) and higher amount of digestible starch (169 vs. 98.5 g/kg DM; p < 0.001) compared to very early harvest. The 2-way interactions (inoculation × storage time and maturity × storage time) showed that inoculation of corn silage with L. buchneri increased (p < 0.001) the aerobic stability, and that more mature crop silage had higher aerobic stability (140 h; p = 0.036) than the others (118 and 48.5 h for those silages from very early and early harvest). Conclusion: The storage for a longer time (>120 d) with the goal of increasing silage digestibility did not occur. Harvesting whole-crop flint corn with 300 to 350 g/kg DM is desirable to have higher DM yield and starch accumulation. Inoculation with L. buchneri is recommended to preserve the silage against aerobic deterioration. This study has shown the importance of harvesting flint corn at the right time, and the need for inoculation with L. buchneri to ensure greater yield, starch accumulation, and silage preservation, if 120 days of storage are not exceeded.

ESHRE PGD consortium best practice guidelines for fluorescence in situ hybridization-based PGD.

In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. The subsequent years have seen the introduction of new technologies as well as evolution of current techniques. Additionally, in light of recent advice from ESHRE on how practice guidelines should be written and formulated, the Consortium believed it was timely to revise and update the PGD guidelines. Rather than one document that covers all of PGD, the new guidelines are separated into four new documents that apply to different aspects of a PGD programme, i.e. organization of a PGD centre, fluorescence in situ hybridization (FISH)-based testing, amplification-based testing and polar body and embryo biopsy for PGD/preimplantation genetic screening (PGS). Here, we have updated the sections that pertain to FISH-based PGD. PGS has become a highly controversial technique. Opinions of laboratory specialists and clinicians interested in PGD and PGS have been taken into account here. Whereas some believe that PGS does not have a place in clinical medicine, others disagree; therefore, PGS has been included. This document should assist everyone interested in PGD/PGS in developing the best laboratory and clinical practice possible. Topics covered in this guideline include inclusion/exclusion criteria for FISH-based PGD testing, referrals and genetic counselling, preclinical validation of tests, FISH-based testing methods, spreading of cells for analysis, set-up of local IVF centre and transport PGD centres, quality control/ quality assurance and diagnostic confirmation of untransferred embryos.

ESHRE PGD consortium best practice guidelines for organization of a PGD centre for PGD/preimplantation genetic screening.

In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. Subsequent years have seen the introduction of new technologies as well as the evolution of current techniques. Additionally, in light of recent advice from ESHRE on how practice guidelines should be written/formulated, the Consortium believed it was timely to update the PGD guidelines. Rather than one document that covers all of PGD, the new guidelines are separated into four documents, including one relating to organization of the PGD centre and three relating to the methods used: DNA amplification, fluorescence in situ hybridization and biopsy/embryology. Here, we have updated the sections on organization of the PGD centre. One area that has continued to expand is Transport PGD, in which patients are treated at one IVF centre, whereas their gametes/embryos are tested elsewhere, at an independent PGD centre. Transport PGD/preimplantation genetic screening (PGS) has a unique set of challenges with respect to the nature of the sample and the rapid turn-around time required. PGS is currently controversial. Opinions of laboratory specialists and clinicians interested in PGD and PGS have been taken into account here. Current evidence suggests that PGS at cleavage stages is ineffective, but whether PGS at the blastocyst stage or on polar bodies might show improved delivery rates is still unclear. Thus, in this revision, PGS has been included. This document should assist everyone interested in PGD/PGS in developing the best laboratory and clinical practice possible.

Spectral signatures of inter-system crossing mediated by energetically distant doorway levels: examples from the acetylene S1 state.

We review recent research on the acetylene S(1) state that illustrates how mechanistic rather than phenomenological information about intersystem crossing (ISC) may be obtained directly from frequency-domain spectra. The focus is on the dynamically rich "doorway-mediated" ISC domain that lies between isolated spectroscopic spin-orbit perturbations and statistical-limit interactions between one singlet "bright state" and a quasi-continuum of triplet "dark states". New and improved experimental and data processing techniques permit the statistical-model curtain to be drawn back to reveal mechanistically explicit pathways via one or more identifiable, hence, manipulatable, doorway states, between a user-selected bright state and the undifferentiated bath of dark states.

Comments to regional problems of analgesic risk perception.

OBJECTIVES: The aim of our study was to analyse analgesic risk perception and then to compare analgesic drug choice among general practitioners. METHOD: The structured questionnaire was used and completed during continuous medical education lectures. Series of targeted open or close questions and visual analog scale (VAS) to determine drug risk perception were used. Slovak general practitioners attending continuous medical education lectures during 2004-2005 were invited to participate in the study. Group 1 consisted of respodents from Bratislava (capital city of Slovakia, n = 245) and group 2 consisted of general practitioners from 3 other cities (middle and eastern Slovakia, n = 325). Data were compared to reported adverse drug reactions. RESULTS: Quarter of doctors 25.3% (n = 62), (25.2% (n = 82) respectively), considered non-steroidal anti-inflammatory drugs to be the safest group of analgesics. Gastrointestinal damage in general was perceived as most common adverse drug reaction. 72.41% (75.94% respectively) of respondents considered analgesics as exactly or probably danger. Perceived drug risk labeled on VAS was 4.23 (SD 1.52), (3.22 (SD 2.19) respectively) (p < 0.05). Total number of reported adverse drug reactions in years 1998-2002 was 3249, 412 were related to analgesic use. Specific organotoxic adverse drug reactions (nephrotoxicity, etc.) were reported rarely. CONCLUSION: The actual perception of analgesic risk in Slovakia seems to be generally inadequate. We found only a low support of spontaneous adverse drug reactions reporting to the national monitoring system (Tab. 1, Fig. 2, Ref. 11).

The causes of misdiagnosis and adverse outcomes in PGD.

The European Society of Human Reproduction and Embryology PGD Consortium has collected data on PGD cycles and deliveries since 1997. From 15,158 cycles, 24 misdiagnoses and adverse outcomes have been reported; 12/2538 cycles after polymerase chain reaction and 12/12,620 cycles after fluorescence in situ hybridization. The causes of misdiagnosis include confusion of embryo and cell number, transfer of the wrong embryo, maternal or paternal contamination, allele dropout, use of incorrect and inappropriate probes or primers, probe or primer failure and chromosomal mosaicism. Unprotected sex has been mentioned as a cause of adverse outcome not related to technical and human errors. The majority of these causes can be prevented by using robust diagnostic methods within laboratories working to appropriate quality standards. However, diagnosis from a single cell remains a technically challenging procedure, and the risk of misdiagnosis cannot be eliminated.

ESHRE PGD consortium data collection VII: cycles from January to December 2004 with pregnancy follow-up to October 2005.

The seventh report of the ESHRE PGD Consortium is presented documenting cycles collected for the calendar year 2004 and follow-up of the pregnancies and babies born subsequent to these cycles up to October 2005. Since the beginning of the data collections, there has been a steady increase in the number of cycles, pregnancies and babies reported. For data collection VII, 45 centres have participated, reporting on 3358 cycles to oocyte retrieval (OR), 679 pregnancies and 528 babies born. Five hundred and fifty nine OR were reported for chromosomal abnormalities, 113 OR for sexing for X-linked diseases, 520 OR for monogenic diseases, 2087 OR for PGS, and 79 OR for social sexing. Data VII is compared with the cumulative data for data collections I-VI.

Potassium channels in hippocampal neurones are absent in a transgenic but not in a chemical model of Alzheimer's disease.

We have investigated using single channel patch-clamp methods potassium channel prevalence in hippocampal neurones from two animal models of AD. Experiments have been carried out on transgenic mice (Tg2576) carrying the Swedish mutation (K670N/M671L) and rats receiving ventricular infusions of okadaic acid. In cell-attached patches from hippocampal neurones from the Tg2576 and control littermate mice there were three principal unitary conductance - 22 pS, 111 pS and 178 pS. The two channels of intermediate and large conductance were voltage-dependent, highly active in cell-attached patches, activity decreasing markedly on hyperpolarisation. The large conductance channel was sensitive to TEA, iberiotoxin, was activated in excised inside-out patches by Ca 2+(i) and is the type I maxi-K+ channel. Significantly, there was a reduction in the prevalence of a TEA-sensitive 113 pS channel in neurones from TG2576 mice with a corresponding increase in prevalence of the maxi-K+ channel. There was no difference in the characteristics of maxi-K+ between patches in neurones from the transgenic and littermate controls. In the rat model single channel analysis was performed on hippocampal neurons from three groups of animals i.e. non-operated, and these receiving an infusion of vehicle or vehicle with okadaic acid. Three principal unitary conductances of around 18 pS, 118 pS and 185 pS were also observed in cell-attached recordings from these three groups. The intermediate and high conductance channels were blocked by TEA or 4-AP or 140 mM RbCl. There were no statistically significant differences in the channel prevalence or channel density between the control and test groups.

Structural heterogeneity of the axonemes of respiratory cilia and sperm flagella in normal men.

The ultrastructure of normal human cilia and flagella was examined and quantitatively assessed to determine the normal variations in the structure of the axoneme. Ciliated respiratory epithelial cells and spermatozoa from 10 normal, nonsmoking male volunteers who had normal semen parameters were fixed for electron microscopy. Tannic acid and MgSO4 were included during fixation to enhance, in particular, axonemal components. In 75 axonemal cross sections per sample, the number of outer doublet and central singlet microtubules, outer and inner dynein arms, and radial spokes were recorded. Statistical analysis of the results showed a marked reduction, from the expected value of nine, in the numbers of inner dynein arms (mean +/- SE, cilia, 5.31 +/- 0.13; sperm, 5.38 +/- 0.16) and radial spokes (cilia, 4.95 +/- 0.22; sperm, 5.80 +/- 0.19). The ideal axoneme with all its structural components was seen in only 0.13% of cilia and 0.80% of sperm tails. Significantly more doublet microtubules (P less than 0.05) and less central microtubules (P less than 0.01) and radial spokes (P less than 0.01) were seen in cilia than in sperm tail axonemes. Between subjects there was little variation in the mean number of a structure seen per axoneme. However, within each sample, the variation was considerably higher, particularly for the inner and outer dynein arms and radial spokes. The doublet microtubules had significantly greater standard deviations in the sperm tails compared with the cilia (P less than 0.01), and furthermore, a significantly greater number of sperm tails compared with cilia showed the incorrect number of doublet microtubules (P less than 0.02). In one semen sample, with normal semen analysis, 20% of the sperm tails showed incorrect numbers of doublet microtubules, ranging from 12 + 2 to 5 + 2 compared with only 1.3% in cilia from this subject. This study has demonstrated that the ideal axoneme is rarely seen even in normal samples, probably because of the technical difficulties in resolution and visualization, and stresses the need for thorough documentation of axonemal ultrastructure. This work provides a normal data base for comparison with patients who have chronic respiratory disease and suspected infertility.

Safety of nateglinide as used in general practice in England: results of a prescription-event monitoring study.

Nateglinide (Starlix((R))) is licensed for the treatment of Type 2 diabetes in patients inadequately controlled with metformin. The study objective was to monitor the safety and use of nateglinide prescribed by primary care physicians (GPs) in England, using the observational cohort technique, Prescription-Event Monitoring. Exposure data were derived from dispensed nateglinide prescriptions issued October 2001-June 2004; demographic and outcome data, from questionnaires sent to patients' GPs at least 6 months after patients' first prescription. Incidence densities (IDs; number of first reports of an event/1,000 patient-months exposure) were calculated for month 1 (ID(1)), months 2-6 (ID(2-6)); rate differences [ID(1)-ID(2-6) (+99% CI)] were examined. Cohort comprised 4,557 patients, median age 60 (IQR 51, 68 years); 2,439 (53.5%) male; 3,463 (76.0%) received nateglinide in combination with metformin. GPs reported 1,625 reasons for stopping in 1,474 (32.3%) patients and 80 events as adverse drug reactions in 66 (1.5%) patients. Events associated with starting treatment included nausea/vomiting [ID(1)-ID(2-6) 9.6 (99% CI 5.3, 13.9)], malaise/lassitude [ID(1)-ID(2-6) 6.03 (99% CI 2.2, 9.9)]. No serious hypersensitivity reactions were reported. Two pregnancies (< 0.1%) and 73 deaths (1.6%) were reported. Nateglinide appeared to be generally well tolerated when used in combination with metformin for the treatment of Type 2 diabetes.

Safety profile of repaglinide as used in general practice in England: results of a prescription-event monitoring study.

Repaglinide is a prandial glucose regulator indicated for management of type 2 diabetes. This post-marketing study used the observational cohort technique of prescription-event monitoring (PEM) to monitor safety of repaglinide prescribed in primary care in England. Patients were identified from dispensed prescriptions issued by general practitioners (GPs) between December 1998 and January 2001. Demographic and clinical event data were collected from questionnaires posted to GPs at least six months after the date of first prescription for each patient. The cohort consisted of 5731 patients [median age 60 (IQR 51-68), 49.9% male]. Event incidence densities (IDs) [no. 1st reports/1000 patient-months of exposure] were calculated for all events reported. The most frequently recorded clinical events in the first month were diarrhoea (ID(1) 10.3), malaise/lassitude (ID(1) 8.1) and nausea/vomiting (ID(1) 7.9). The most frequently reported reason for stopping was 'not effective' (647), with the most common clinical reasons being diarrhoea (60), malaise/lassitude (55) and intolerance (54). One hundred and thirteen adverse drug reactions (ADRs) were reported, with the most frequently specified being diarrhoea (10), abdominal pain (10) and nausea/vomiting (9). We concluded that repaglinide is generally well tolerated when used in general practice in England and did not identify any serious unrecognised adverse events.

Observational cohort study to monitor the use and safety of carvedilol in the treatment of heart failure in clinical practice in England--1st interim report.

AIMS: This is an interim report of a prospective observational cohort study to monitor the safety and tolerability of carvedilol in clinical practice when prescribed for heart failure in England. The utilization of carvedilol, management of adverse events in the community and the symptomatic progression of heart failure were examined. It is a non-interventional, observational cohort surveillance study using questionnaires sent to the patients' general practitioners. METHODS: The general practitioners (GPs) of the patients identified by the Prescription Pricing Authority were sent an eligibility questionnaire if the patient had been newly prescribed carvedilol between September 1999 and July 2001. Further questionnaires requesting baseline clinical information about eligible patients (carvedilol indicated for cardiac failure) and subsequent event data were sent to consenting GPs at 12 months. The questionnaires also requested specific information about initiation and supervision of treatment, including severity of heart failure and treatment withdrawal. The data were analyzed by using descriptive statistics. In addition, the incidence densities (ID) of each event (per 1000 person-months of treatment) were calculated, ranked and the difference between the ID of each event in the first (ID1) and subsequent 5 months of exposure (ID2) was tested by constructing 99% confidence intervals (CI). Selected events of clinical interest would be followed-up for further information to enable causal association with carvedilol to be assessed. RESULTS: In this interim report we have data on a cohort of 847 eligible patients for whom we have received information from the first follow-up questionnaire. The treatment of carvedilol was initiated in a majority of cases by hospital specialists (87%, n = 735), however, for most of them, further supervision of treatment was done under shared care between GPs and hospitals (70%, n = 595). More than 90% of the patients were started on carvedilol in the recommended dose range for the management of cardiac failure. Amongst the patients where NYHA grade of cardiac failure was expressed, the majority of patients treated with carvedilol had NYHA II (37%, n = 281) and III (40%, n = 297) symptoms at the start of carvedilol treatment. On treatment with carvedilol, improvement in NYHA status was reported for 43% (n = 364) of this cohort, whilst less than 2.5% (n = 20) of the patients deteriorated. The events reported with the highest ID1 were malaise/lassitude (14.6), dizziness (12.2), cardiac failure (9.7), dyspnea (9.7) and hypotension (8.5). The most common events reported as reasons for stopping carvedilol were "drug not effective", "dyspnea", "dizziness" and "lassitude". No events were identified as new signals (according to the ID1-ID2 statistic) of adverse events associated with carvedilol. There have been no events identified in this cohort that have required specific follow-up at the time of writing this paper. CONCLUSIONS: In summary, the interim results show that there is effective cooperation between hospital specialists and GPs in the use of carvedilol in the management of patients with heart failure. It also shows that carvedilol was well-tolerated and that patients with mild and moderate heart failure benefit symptomatically when treated with carvedilol in routine clinical practice.

Salmeterol: a study by prescription-event monitoring in a UK cohort of 15,407 patients.

OBJECTIVE: To examine the safety of the long-acting beta2-agonist, salmeterol, in general medical practice in the U.K. DESIGN: In Prescription-Event Monitoring (PEM) the exposure data are derived from prescriptions confidentially provided by the Prescription Pricing Authority. Outcome data are obtained by questionnaires (green forms) on which prescribing medical practitioners recorded event (safety) data. Additional information is obtained from the patients' lifetime clinical records, from follow-up of all pregnancies, and from death certificates. SETTING: PEM provides an observational cohort study in which there is no interference with the medical decision on which drug is prescribed for individual patients. SUBJECTS: A total of 15,407 patients were given salmeterol and observed for a minimum of 1 year. RESULTS: Headache, tremor, and palpitations were associated with the use of salmeterol. No unexpected major adverse events were noted, although in this study there was a total of 1022 deaths. Of these, 73 were due to asthma, but only 39 of these patients were taking salmeterol in the last month of life. All of these deaths appear on careful examination of the clinical records to have been due to natural causes, although in a minority (four, 10%) of the group of 39 subjects, a temporal relationship between death and the use of salmeterol makes it difficult to exclude a possible association. The study suggests that advanced age and severity of disease were the most likely factors contributing to asthma mortality in the population studied. CONCLUSION: Headache, tremor, and palpitations occur as adverse effects of salmeterol and lead to withdrawal of the drug in some subjects. No unexpected adverse reaction has been noted and paradoxical bronchospasm was reported in only three subjects. The study has produced no evidence that salmeterol contributed to death in any of the patients examined.

Loss of the thalamic nuclei for "head direction" impairs performance on spatial memory tasks in rats.

This study sought to characterize the effects of removing the nuclei of primary importance in relaying the thalamic head direction signal to the hippocampal formation (the anterior dorsal [AD] and lateral dorsal [LD] nuclei) on the performance of a variety of spatial and nonspatial tasks. The results indicate that combined excitotoxic lesions of the AD and LD nuclei produce marked deficits on a variety of spatial tasks. These tasks included T-maze alternation and the ability to locate a hidden platform set at a fixed distance and fixed direction from a beacon in a Morris water maze. Although object recognition appeared unaffected, marked impairments were found in the ability to detect when an object was placed in a novel position (object-in-place memory).

Troglitazone and liver function abnormalities: lessons from a prescription event monitoring study and spontaneous reporting.

OBJECTIVES: To investigate whether there were any cases of liver function abnormalities possibly associated with troglitazone use in general practice in England. DESIGN: A prescription-event monitoring (PEM) study was undertaken between October 1997 and December 1997. SETTING: Data from prescriptions were obtained electronically for the troglitazone cohort in the immediate postmarketing period. STUDY PARTICIPANTS: Event data were obtained for a total of 1344 patients. RESULTS: Troglitazone was effective in 394 (75%) of the 529 patients for whom an opinion was given. The most frequent reasons for stopping treatment related to drug tolerability were malaise/lassitude (16 reports), abnormal liver function tests (II reports) and nausea/vomiting (9 reports). The major cause of stopping troglitazone was because the drug was withdrawn from the market (1101 reports). 30 patients with liver dysfunction were identified from the cohort. In 9 of these patients there were alternative explanations for the liver dysfunction and hence these patients were not followed up further. 21 patients were followed up, for whom 19 questionnaires were returned. In 5 patients their liver dysfunction was assessed as possibly related to troglitazone, in 6 patients the liver dysfunction was unlikely to be attributed to troglitazone, while in 7 patients it was difficult to assess the causality because of limited information and confounding factors. The remaining patient was not included as this individual did not fit the inclusion criteria of the study. CONCLUSION: Although the cohort is small (the drug was available for only 3 months in the UK), 5 patients with abnormal liver function, considered possibly related to troglitazone were detected in this PEM study. It is possible for PEM to contribute to the elucidation of safety signals in the UK.

Profiles of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolone antibacterials: experience from large cohorts from the Drug Safety Research Unit Prescription-Event Monitoring database.

OBJECTIVE: To investigate how frequently serious dysrhythmic cardiovascular, and hepatotoxic events are reported during routine clinical use of fluoroquinolones (quinolones) in general practice. DESIGN: Cohorts prescribed quinolones (cohort sizes: ciprofloxacin 11 477; enoxacin 2790; ofloxacin 11 033 and norfloxacin 11 110; mean age in each cohort of 48.6 to 57.0 years) were selected from the Drug Safety Research Unit's Prescription-Event Monitoring (PEM) database. The monitoring periods were November 1988 to January 1989 for ciprofloxacin; April 1989 to January 1991 for enoxacin; May 1991 to December 1991 for ofloxacin and October 1990 to October 1991 for norfloxacin. Data collected over the total PEM surveillance period on selected gastrointestinal events were extracted and reviewed to identify possible hepatic events, together with selected cardiovascular events associated with dysrhythmias. For each quinolone, times to onset of the event and patient-months of observation (denominator values) were calculated. The analysis was based on two observation periods: rate of event during the first 7 days following dispensing of a prescription for each drug (W(1)), and rate of event during the second to sixth week inclusive (W(2)). RESULTS: Scrutiny of original green forms revealed no evidence of drug-induced hepatic dysfunction within 42 days of drug administration for any of the quinolones monitored. No evidence was found of drug-induced dysrhythmic events associated with enoxacin within 42 days of drug administration. Of the other quinolones, 'atrial fibrillation' was reported most often within 42 days following ciprofloxacin administration, with no change in event rate over that time, crude relative risk (CRR)[W(1)/W(2)] 1.0 [95% confidence interval (CI) 0.02 to 8.92]. Other less serious events associated with dysrhythmia were reported with varying incidence within 42 days of quinolone administration. The crude rate of palpitation did not change significantly over that time for ciprofloxacin, ofloxacin and norfloxacin: CRR 0.83 (95% CI 0.02 to 6.86), 2.00 (95% CI 0.19 to 12.20) and 4.99 (95% CI 0.06 to 391.94), respectively. Syncope and tachycardia were also reported for ofloxacin [CRR 9.99 (95% CI 0.52 to 589.49 for both events)] and ciprofloxacin [1.0 (95% CI 0.02, 8.92)] and 2.50 (95% CI 0.04, 47.96) for syncope and tachycardia, respectively]. CONCLUSION: It cannot be ruled out that some rare hepatic and dysrhythmic events associated with quinolones may be drug related. The primary purpose of PEM is signal generation. Compared with the other quinolones, ciprofloxacin was associated with the highest number of reports of dysrhythmic cardiovascular events occurring within 42 days of administration. This requires further investigation by other types of epidemiological study.