Neuropsychological tools to predict conversion from amnestic mild cognitive impairment to dementia. The TREDEM Registry.

Most of the studies about conversion from Mild cognitive impairment (MCI) to dementia have focused on amnestic MCI (aMCI) which is considered a preclinical phase of Alzheimer's disease. The aim of the present study was to identify neuropsychological tools that would best predict conversion from aMCI to dementia. Fifty-five aMCI subjects on the Treviso Dementia Registry were investigated. They underwent a neuropsychological evaluation during their first assessment and again at follow-up. Cox proportional-hazard regression models were created to measure the association between the dependent variable (dementia diagnosis or MCI status maintenance) and the neuropsychological test scores at baseline. The sample (28 women and 27 men; mean age 76.82 ± 5.88 years; education 7.62 ± 3.99 years) was observed for an average time of 2.17 ± 1.25 years. A Cox backward stepwise regression showed that the Rey Auditory Verbal Learning Test, Delayed Recall (p = .041) and Semantic Verbal Fluency tests (p = .031) appear to be useful in predicting conversion to dementia.

Epidemiology of acute cholecystitis and its treatment in Bergamo District, Northern Italy.

BACKGROUND: Acute calcolous cholecystitis (ACC) is a very common pathology in western countries. The aim of our work was to assess the epidemiology of ACC and its treatment in Bergamo, a northern Italy province, during the last seventeen years. METHODS: A restrospective analysis, covering 1997 to 2013, was performed based on the administrative register of the province Health System. Only patients admitted for ACC were selected. From 1997 to 2013 were collected 8959 cases of ACC, mean age was 61.28, 51.5% were male. RESULTS: The incidence of ACC was 48/100.000 per year; the operation rate was 66%. Overall mortality was 0.7%, mean hospitalization time was 9.7 days. The treatment of ACC in Bergamo Province seemed to be acceptable and comparable to literature results. Over the last years, laparoscopy has become the standard treatment. CONCLUSIONS: This study outlined some criticisms on the selection's methodology sourcing data from administrative registers, raising questions about truthfulness of results and usefulness for health policy issues.

Laparoscopic management of intra-abdominal infections: Systematic review of the literature.

AIM: To investigate the role of laparoscopy in diagnosis and treatment of intra abdominal infections. METHODS: A systematic review of the literature was performed including studies where intra abdominal infections were treated laparoscopically. RESULTS: Early laparoscopic approaches have become the standard surgical technique for treating acute cholecystitis. The laparoscopic appendectomy has been demonstrated to be superior to open surgery in acute appendicitis. In the event of diverticulitis, laparoscopic resections have proven to be safe and effective procedures for experienced laparoscopic surgeons and may be performed without adversely affecting morbidity and mortality rates. However laparoscopic resection has not been accepted by the medical community as the primary treatment of choice. In high-risk patients, laparoscopic approach may be used for exploration or peritoneal lavage and drainage. The successful laparoscopic repair of perforated peptic ulcers for experienced surgeons, is demonstrated to be safe and effective. Regarding small bowel perforations, comparative studies contrasting open and laparoscopic surgeries have not yet been conducted. Successful laparoscopic resections addressing iatrogenic colonic perforation have been reported despite a lack of literature-based evidence supporting such procedures. In post-operative infections, laparoscopic approaches may be useful in preventing diagnostic delay and controlling the source. CONCLUSION: Laparoscopy has a good diagnostic accuracy and enables to better identify the causative pathology; laparoscopy may be recommended for the treatment of many intra-abdominal infections.

Accuracy of plethysmographic indices as predictors of fluid responsiveness in mechanically ventilated adults: a systematic review and meta-analysis.

PURPOSE: To systematically review the accuracy of the variation in pulse oxymetry plethysmographic waveform amplitude (∆POP) and the Pleth Variability Index (PVI) as predictors of fluid responsiveness in mechanically ventilated adults. METHODS: MEDLINE, Scopus and the Cochrane Database of Systematic Reviews were screened for clinical studies in which the accuracy of ∆POP/PVI in predicting the hemodynamic response to a subsequent fluid bolus had been investigated. Random-effects meta-analysis was used to summarize the results. Data were stratified according to the amount of fluid bolus (large vs. small) and to the study index (∆POP vs. PVI). RESULTS: Ten studies in 233 patients were included in this meta-analysis. All patients were in normal sinus rhythm. The pooled area under the receiver operating characteristic curve (AUC) for identification of fluid responders was 0.85 [95 % confidence interval (CI) 0.79-0.92]. Pooled sensitivity and specificity were 0.80 (95 % CI 0.74-0.85) and 0.76 (0.68-0.82), respectively. No heterogeneity was found within studies with the same amount of fluid bolus, nor between studies on ∆POP and those on PVI. The AUC was significantly larger in studies with a large bolus amount than in those with a small bolus [0.92 (95 % CI 0.87-0.96) vs. 0.70 (0.62-0.79); p < 0.0001]. Sensitivity and specificity were also higher in studies with a large bolus [0.84 (95 % CI 0.77-0.90) vs. 0.72 (0.60-0.82) (small bolus), p = 0.08 and 0.86 (95 % CI 0.75-0.93) vs. 0.68 (0.56-0.77) (small bolus), p = 0.02], respectively. CONCLUSIONS: Based on our meta-analysis, we conclude that ∆POP and PVI are equally effective for predicting fluid responsiveness in ventilated adult patients in sinus rhythm. Prediction is more accurate when a large fluid bolus is administered.

Human neurotrophin receptor p75NTR defines differentiation-oriented skeletal muscle precursor cells: implications for muscle regeneration.

Satellite cells are resident stem cells of adult skeletal muscle that have roles in tissue repair. Although several efforts have led to the functional characterization of distinct myogenic populations in animal models, the translation of these findings to humans has been limited. Here, we analyzed the expression and function of the neurotrophin receptor p75NTR in human skeletal muscle precursor cells. We combined histological investigations of muscle biopsies with molecular and cellular analyses of primary muscle precursor cells. p75NTR is expressed by most satellite cells in vivo and is a marker for regenerating fibers in inflamed and dystrophic muscle. p75NTR mRNA and protein are also detectable in primary myoblasts, and these levels increase transiently when cell differentiation is triggered. Transcriptome analyses of p75NTR high versus p75NTR low muscle cells showed that p75NTR is the prototype marker for a precursor cell population that has a broad transcriptional repertoire associated with muscle development and maturation. Several in vitro experiments, including receptor blockade and gene silencing in myoblasts, proved that p75NTR specifically regulates myogenesis and dystrophin expression. Taken together, the results indicate that p75NTR is a novel marker of human differentiation-prone muscle precursor cells that is involved in myogenesis in vivo and in vitro.

Hypofractionated stereotactic radiotherapy for oligometastases in the brain: a single-institution experience.

The treatment of brain metastases is changing. Many different radiotherapy options are now available and under clinical evaluation. As part of this effort, we retrospectively evaluated the efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) in patients with up to three brain metastases. Sixty-five patients with 81 lesions were treated with hypofractionated radiotherapy. Median dose was 24 Gy in three fractions. Median follow-up was 24.6 months. Actuarial tumour control was 75 and 45% at 9 months and 24 months after treatment, respectively. Median survival time was 7.5 months, and 32% of the patients died from brain tumour progression. Actuarial overall survival was 75% at 3 months and 25% at 12 months. Recursive partitioning analysis class was the only significant prognostic factor. Neoadjuvant whole-brain radiotherapy (in 29 patients) had no impact on survival or local control. Neurological status improved in 42 patients (65%). Adverse events were rare and usually mild. This experience suggests HSRT should be considered as an alternative approach in the treatment of one to three metastatic lesions in selected patients.

Language abilities and gestural communication in a girl with bilateral perisylvian syndrome: a clinical and rehabilitative follow-up.

We present the neuropsychological and linguistic follow-up of a girl with bilateral perisylvian polymicrogyria during 4 years of gestural and verbal speech therapy. Some researchers have suggested that children with bilateral perisylvian polymicrogyria mentally fail to reach the syntactic phase and do not acquire a productive morphology. This patient achieved a mean length of utterance in signs/gestures of 3.4, a syntactic phase of completion of the nuclear sentence and the use of morphological modifications. We discuss the link between gesture and language and formulate hypotheses on the role of gestural input on the reorganization of compensatory synaptic circuits.

Microembolic air load during contrast-transcranial Doppler: a trigger for migraine with aura?

BACKGROUND: There is a well-known association between migraine with aura (MA) and right-to-left shunt (RILES) because of patent foramen ovale (PFO). The occurrence of MA attacks after microbubble (MB) injection during contrast-enhanced transcranial Doppler (ce-TCD) has been recently described. OBJECTIVES: The aim of this study was to analyze the prevalence of RILES in a consecutive cohort of MA patients and to characterize the occurrence of MA attacks after diagnostic ce-TCD. METHODS: A total of 159 consecutive MA patients underwent ce-TCD with air-mixed saline to disclose RILES. RILES was characterized in terms of MB amount (small-moderate or large) and occurrence at rest and/or during Valsalva maneuver (permanent or latent). RESULTS: RILES was revealed in 79/159 patients (∼ 50%). Permanent RILES were detected in 56/79 (71%) and latent RILES in 23/79 (29%) MA patients. The occurrence of a typical MA attack was overall observed in 12/159 patients (7.5%; 95% CI: 4-12.8%), but arose only in RILES-positive ones, immediately after ce-TCD (12/79; 15.2%; P< .001). All 12 patients had permanent RILES (12/56; 21.4%; P= .015) and MA attack was mostly observed in large RILES-positive patients, even without statistical significance (P= .118). CONCLUSIONS: Microembolic air load could act as a trigger of MA attack. According to recent studies and to the clinical characteristics observed in our patients, microembolization because of MB injection might provoke a decrease in cerebral oxygen saturation, thus triggering cortical spreading depression and, thereafter, MA attack. Larger and prospective studies will be necessary to confirm our data and observe a wider correlation.

Temporal lobe epilepsy: neuropathological and clinical correlations in 243 surgically treated patients.

The present study included analysis of data from 243 patients surgically treated for Temporal Lobe Epilepsy (TLE). Resection was confined to the temporal lobe, with at least two years of follow-up, and specimens sufficiently preserved to allow a precise evaluation of both lateral neocortex and hippocampus. The frequency of different types of lesion and hippocampal sclerosis (HS), isolated or associated with neocortical lesions, risk factors and surgical outcomes in relation to neuropathological findings were evaluated. We found tumours in 33% of patients, malformations of cortical development (MCD) in 45%, isolated HS in 14%, no lesion in 5% and less common lesions in 3%. HS was present in 8% of tumour cases and 70% of MCD. Statistical analysis of antecedents was significantly associated only with febrile seizures (FS). In MCD patients with no history of FS, a strong association between HS and duration of epilepsy was revealed. A Class I outcome was identified in 87% of cases with tumours and 79% in cases with MCD. In 93 patients the antiepileptic drug therapy was withdrawn. Our findings show that MCD, which is significantly associated with HS, is the most common lesion in TLE and support the concept that an optimal outcome is obtained when mesial and neocortical structures are removed. FS are particularly relevant in patients with focal cortical dysplasia and HS.

Transcranial Doppler and transesophageal echocardiography: comparison of both techniques and prospective clinical relevance of transcranial Doppler in patent foramen ovale detection.

BACKGROUND: Patent foramen ovale (PFO) has been investigated in several conditions apart from cryptogenic ischemic stroke. Contrast transesophageal echocardiography (cTEE) is the gold standard for the diagnosis, although it has some known limitations. Contrast transcranial Doppler (cTCD) allows a semiquantitative estimation of right-to-left shunt (RLS) volume. The aims of our study were to confirm the diagnostic accuracy of cTCD in PFO diagnosis and to compare the abilities of cTCD and cTEE to detect a RLS and PFO, respectively, under normal breathing. The latter could represent an important feature for its clinical significance. METHODS: A total of 100 consecutive patients (59 women and 41 men, age 46 +/- 12 years) were evaluated after stabilized ischemic stroke/transient ischemic attack, migraine, and lacunae, and before neurosurgery in sitting position. All patients undertook cTEE and cTCD, at rest and under Valsalva maneuver (VM). cTEE under VM was the reference standard. A categorization of patients and a semiquantitative cTCD classification were proposed. RESULTS: In all, 63 of 100 patients had PFO diagnosed by cTEE. A general concordance of up to 90% between both techniques was found. cTCD sensitivity and specificity were 96.8% and 78.4%, respectively. In 17 of 100 patients with cTEE-proven PFO under VM, cTCD and cTEE detected RLS at rest in 75% (95% confidence interval [CI] 62%-85%) and 48% (95% CI 35%-61%) of cases, respectively (P < .001). cTEE disclosed RLS at rest in about 71% (95% CI 9%-42%) of cTCDs showing a "shower-curtain" pattern and only in about 22% (95% CI 52%-85%) of those cTCDs without that pattern. CONCLUSIONS: In diagnosing PFO, cTCD has a good accuracy compared with cTEE. To detect a RLS at rest, cTCD appears to be more sensitive than cTEE. The latter resulted positive under normal breathing, mostly in cases of significant RLS at cTCD. Our results point out the impact of cTCD in the evaluation of RLS volume, thus aiding, in association with the anatomic details by cTEE, in the prevention of the occurrence or recurrence of paradoxical embolism in individuals with and without cerebrovascular diseases. The combination of cTEE and cTCD could be considered the real gold standard for PFO in the near future.

A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis.

beta-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673-->valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced beta-amyloid (Abeta) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Abeta aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.

Cisplatinum and BCNU chemotherapy in primary glioblastoma patients.

BACKGROUND: The prognosis of patients with glioblastoma is very poor with a mean survival of 10-12 months. Currently available treatment options are multimodal, which include surgery, radiotherapy, and chemotherapy. However, these have been shown to improve survival only marginally in glioblastoma multiforme (GBM) patients. Methylated methylguanine methyltransferase (MGMT) promoter is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. METHODS: A retrospective analysis on 160 adult patients (> or =16 years) treated for histologically confirmed GBM between 2003 and 2005 at our Institution was performed. All patients were treated with conventional fractionated radiotherapy and a combined chemotherapy treatment with Cisplatin (CDDP) (100 mg/sqm on day 1) and carmustine (BCNU) (160 mg/sqm on day 2); the treatment was repeated every 6 weeks for five cycles. Toxicity, progression free survival and overall survival were assessed. RESULTS: The median number of chemotherapy cycles delivered to each patient was 5 (range 3-6), with no patients discontinuing treatment because of refusal or toxicity. Dose reduction was required in 16 patients (10%), and all patients completed radiotherapy, whereas 5 patients discontinued chemotherapy before completing all planned cycles for disease progression. The primary toxicities were: neutropenia (grade 3-4: 23%), thrombocytopenia (grade 3-4: 18.5%), and nausea and vomiting (13%). Median progression-free survival times and 1-year progression free survival were 7.6 months (95% CI 6.6-8.5) and 17.3%, respectively. OS was 15.6 months (95% CI 14.1-17.1). CONCLUSIONS: Our results for PFS and overall survival are comparable with those obtained with temozolomide, but the toxicity occurring in our series was more frequent and persistent. The toxicity, and mainly the modalities of administration associated with cisplatin and BCNU combination, argues against future use in the treatment of patients with GBM.

BDNF and its receptors in human myasthenic thymus: implications for cell fate in thymic pathology.

Here we show that in myasthenic thymus several cell types, including thymic epithelial cells (TEC) and immune cells, were the source and the target of the neurotrophic factor brain-derived growth factor (BDNF). Interestingly, many actively proliferating medullary thymocytes expressed the receptor TrkB in vivo in involuted thymus, while this population was lost in hyperplastic or neoplastic thymuses. Furthermore, in hyperplastic thymuses the robust coordinated expression of BDNF in the germinal centers together with the receptor p75NTR on all proliferating B cells strongly suggests that this factor regulates germinal center reaction. Finally, all TEC dying of apoptosis expressed BDNF receptors, indicating that this neurotrophin is involved in TEC turnover. In thymomas both BDNF production and receptor expression in TEC were strongly hindered. This may represent an attempt of tumour escape from cell death.

Treatment of recurrent glioblastoma: can local delivery of mitoxantrone improve survival?

In this study, the records of 276 adult patients with recurrent glioblastoma (GBM) treated at recurrence at our institution between 2004 and 2006 were reviewed for progression-free survival (PFS), overall survival (OS), and toxicity. At recurrence, all patients underwent systemic treatment with temozolomide (200 mg/sqm on days 1-5 every 28 days) until tumor progression. Patients, whose tumor was judged resectable without risk of adjunctive neurological deficit, underwent a second surgery with or without positioning of a Rickam/Ommaya reservoir. The reservoir was used for locoregional chemotherapy with mitoxantrone. Two hundred seventy-six rGBL patients (pts) were divided into three subgroups: A 161 pts treated only with temozolomide, B 50 pts re-operated-on +temozolomide, and C 65 pts re-operated on + temozolomide + locoregional CHT. For group A, the 6 month PFS and 6 month survival (ST) were 39.3 and 43%, respectively, with a median survival time (mST) of 5 months (range 4-6) and 25% of pts alive at 9 months. For group B, the 6 month PFS and 6 month survivors were 64 and 74.1%, respectively, with a mST of 8 months (range 6-10) and 25% of pts alive at 12 months. For group C, the 6 month PFS and 6 month survivors were 70.7 and 87.7%, respectively, with a mST of 11 months (range 9-13) and 25% of pts alive at 18 months (A vs. B vs. C, log-rank P < 0.001) (B vs. C, P = 0.041) (A vs. B P = 0.009). Cox proportional hazard model was used to obtain Hazard Ratio (HR) for type of treatment corrected by age and time (in months) between diagnosis and first recurrence: second tumor debulking was statistically effective for survival, reducing by 36% the risk of death (HR = 0.64; 0.46-0.89), but the most significant favorable prognostic factor for survival was the local delivery of mitoxantrone which reduced the risk of death to 50% (HR = 0.50; 0.38-0.68).

Salvage chemotherapy with procarbazine and fotemustine combination in the treatment of temozolomide treated recurrent glioblastoma patients.

The purpose of this study was to evaluate safety and efficacy of Procarbazine (PCB) and fotemustine (FTM) combination in the treatment of pre-temozolomide treated, recurrent GBM patients. The primary end-point was progression free survival at 6 months (PFS-6). Secondary end-points were overall survival, response rates (CR + PR) and toxicity. About 54 patients (41 men and 13 women) aged 26-68 years (median age, 53.5 years) with recurrent GBM were treated. PCB was administered as an oral dosage of 450 mg on days 1-2 and a total dose of 300 mg on day 3. FTM was administered on day 3, 3 h after the last PCB intake at a dose of 110 mg/mq/BSA. The treatment was repeated every 5 weeks. Treatment was continued for a maximum of six cycles or until disease progression. After two cycles of chemotherapy: 6 patients (11.2%) experienced a neuroradiographic partial response (PR), 29 patients (53.7%) had stable disease (SD), and 19 patients (35.1%) had progressive disease (PD). For the whole group of patients, the median PFS was 19.3 weeks (95% CI, 14.1-24.4 weeks), and PFS-6 was 26.7% (95% CI, 10.6-42.8%). Overall MST from the beginning of PCB + FTM chemotherapy was 28.7 weeks (95% CI, 24.8-32.7 weeks). At 6 and 12 months, 64.4% (95% CI, 51.5-77.3%) and 23.6% (95% CI, 10.1-37.1%) of patients were alive. The median survival time calculated from the first diagnosis was 20.8 months (95% CI, 16.7-24.8). We concluded that the PCB + FTM combination as done in the current trial for patients with recurrent GBM after treatment with TMZ showed some benefit with regards to increased survival and that a Phase III trial is warranted.

Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma.

Reliable data on large cohorts of patients with glioblastoma are needed because such studies differ importantly from trials that have a strong bias toward the recruitment of younger patients with a higher performance status. We analyzed the outcome of 676 patients with histologically confirmed newly diagnosed glioblastoma who were treated consecutively at a single institution over a 7-year period (1997-2003) with follow-up to April 30, 2006. Survival probabilities were 57% at 1 year, 16% at 2 years, and 7% at 3 years. Progression-free survival was 15% at 1 year. Prolongation of survival was significantly associated with surgery in patients with a good performance status, whatever the patient's age, with an adjusted hazard ratio of 0.55 (p < 0.001) or a 45% relative decrease in the risk of death. Radiotherapy and chemotherapy improved survival, with adjusted hazard ratios of 0.61 (p = 0.001) and 0.89 (p = 0.04), respectively, regardless of age, performance status, or residual tumor volume. Recurrence occurred in 99% of patients throughout the follow-up. Reoperation was performed in one-fourth of these patients but was not effective, whether performed within 9 months (hazard ratio, 0.86; p = 0.256) or after 9 months (hazard ratio, 0.98; p = 0.860) of initial surgery, whereas second-line chemotherapy with procarbazine, lomustine, and vincristine (PCV) or with temozolomide improved survival (hazard ratio, 0.77; p = 0.008). Surgery followed by radiotherapy and chemotherapy should be considered in all patients with glioblastoma, and these treatments should not be withheld because of increasing age alone. The benefit of second surgery at recurrence is uncertain, and new trials are needed to assess its effectiveness. Chemotherapy with PCV or temozolomide seems to be a reasonable option at tumor recurrence.

Sedation of neurologically impaired children undergoing MRI: a sequential approach.

BACKGROUND: The purpose of this retrospective study was to determine the efficacy of a sequential approach meant to rescue failed chloral hydrate sedation and to obtain a low rate of adverse events along with predictable timings in neurologically impaired children undergoing magnetic resonance imaging. METHODS: We retrospectively evaluated 1104 chloral hydrate sedations performed between 2002 and 2004 on 862 children weighing <26 kg. If the desired sedation score (3 on the Skeie Scale) was not reached within 30 min after oral administration of chloral hydrate, sedation was considered as potentially failed, and supplementation with sevoflurane, i.m. or i.v. ketamine, and i.v. pentobarbital and midazolam was started. RESULTS: Twenty-seven sessions failed because of excessive movement. Mean induction time was significantly higher for patients who received supplementation (52.2 min vs 39.1 min), while no differences in recovery and total sedation times were found. Supplementation significantly increased the incidence of respiratory obstruction (4.6% vs 2.4%), although the incidence of other adverse events was unaffected. CONCLUSIONS: Administering up to 1.5 g of chloral hydrate without supplementation was associated with a failure rate of approximately 20%, but the proposed sequential approach enabled us to rescue the majority of failed sedations while maintaining an acceptably low incidence of adverse events.

[Asthma: current therapeutic approach]. / Asma bronchiale: iter terapeutico.

Asthma is a chronic reversible respiratory disease characterized by inflammation and bronchial smooth muscle contraction. The therapeutic approach must improve the acute symptoms, avoid disease exacerbations and prevent the pulmonary functional decay.

Generating signals of drug-adverse effects from prescription databases and application to the risk of arrhythmia associated with antibacterials.

BACKGROUND: Although it is well known that a variety of antibacterials may incidentally cause malignant arrhythmia, the list of drugs causing arrhythmia and the impact of these adverse effects are still uncertain. We investigated on this topic by using a large prescription database with different observational designs. METHODS: Prescription data on all incident users of several antibacterial and antiarrhythmic drugs over the period July 1997 through December 1999 were retrieved from the Drug Prescription Database (DPD) of the Italian Province of Varese. The association between the use of antibacterial and antiarrhythmic drugs was investigated by applying prescription sequence symmetry, cohort and nested case-control designs. RESULTS: Lower proarrhythmic effects were on an average obtained from prescription sequence symmetry approach with respect to both cohort and nested case-control. Evidence of association between exposure to drugs (erythromycin and ciprofloxacin) and the risk of arrhythmia was consistently found by the three approaches. No other signals were generated from the prescription sequence symmetry analysis. Two drugs (clarithromycin and levofloxacin) showed patterns compatible with an arrhythmic effect according to both cohort and nested case-control designs. CONCLUSIONS: Prescription databases are useful tools to explore drug safety through both conventional and emerging observational designs. In spite of its appealing features, prescription sequence symmetry design shows lower sensitivity with respect to conventional designs. Evidence about the association between the use of certain macrolides and fluoroquinolones and the onset of arrhythmia is confirmed by this study.