Reducing rates of Clostridium difficile infection by switching to a stand-alone NAAT with clear sampling criteria.

Background: Clostridium difficile infection is an important cause of morbidity and mortality but the optimal method of diagnosis for both patient management and infection prevention remains controversial. Methods: Our hospital made a decision to switch from the use of toxin immunoassay to a stand-alone nucleic acid test. This change was accompanied by the provision of clear sampling guidance and rejection criteria and this study aimed to assess the impact of that change. We analysed sample numbers, numbers of positive results, and the proportion of cases assessed as healthcare acquired over a 6-year period during which the testing method was changed from a toxin A/B immunoassay to a stand-alone commercial nucleic acid test after the first two years. Results: Sample numbers and numbers of cases assessed as healthcare acquired fell following the introduction of the nucleic acid test and sampling guidance, while infection rates in other hospitals in the same region remained relatively stable. Conclusions: It is our opinion that the use of a highly sensitive assay together with clear sampling guidance offers the optimal approach to patient management and best use of isolation facilities.

Palmitoylethanolamide controls reactive gliosis and exerts neuroprotective functions in a rat model of Alzheimer's disease.

Given the complex heterogeneity of pathological changes occurring in Alzheimer's disease (AD), any therapeutic effort absolutely requires a multi-targeted approach, because attempts addressing only a single event may result ineffective. Palmitoylethanolamide (PEA), a naturally occurring lipid amide between palmitic acid and ethanolamine, seems to be a compound able to fulfill the criteria of a multi-factorial therapeutic approach. Here, we describe the anti-inflammatory and neuroprotective activities of systemic administration of PEA in adult male rats given intrahippocampal injection of beta amyloid 1-42 (Aß 1-42). Moreover, to investigate the molecular mechanisms responsible for the effects induced by PEA, we co-administered PEA with the GW6471, an antagonist of peroxisome proliferator-activated receptor-α (PPAR-α). We found that Aß 1-42 infusion results in severe changes of biochemical markers related to reactive gliosis, amyloidogenesis, and tau protein hyperphosphorylation. Interestingly, PEA was able to restore the Aß 1-42-induced alterations through PPAR-α involvement. In addition, results from the Morris water maze task highlighted a mild cognitive deficit during the reversal learning phase of the behavioral study. Similarly to the biochemical data, also mnestic deficits were reduced by PEA treatment. These data disclose novel findings about the therapeutic potential of PEA, and suggest novel strategies that hopefully could have the potential not just to alleviate the symptoms but also to modify disease progression.

Are retinoids a promise for Alzheimer's disease management?

Retinoids regulate several physiological and pathological processes through the interaction with nuclear receptors. Retinoid-associated signaling which plays an essential role in neurodevelopment appears to remain active in the adult central nervous system (CNS), thus assuming a high significance in the context of neurodegeneration, and indeed retinoid analogs are thought to be promising therapeutic agents for the treatment of neurodegenerative disorders. The ability of retinoids to exert antioxidant effects, inhibit amyloid-ß (Aß) deposits and likely Aß-induced mitochondrial dysfunction, tau hyperphosphorylation, Aß-induced IL6 production and neuroinflammation, increase survival in hippocampal neurons, and reverse cognitive deficits in animal models of Alzheimer's disease (AD) is discussed. Although retinoids with their multi-target activity are revealing to be promising for management of AD which is a multifaceted biochemical phenomenon, timing as well as appropriate dosage and safety remain, however, a challenge. The end-stage lesions, namely senile plaques and neurofibrillary tangles, are, at present, considered an adaptive response to oxidative stress underlying AD, thus paradoxically late administration of retinoids could even suppress a protective mechanism by inhibiting Aß deposits.

Changing Italian nosocomial-community trends and heteroresistance in Staphylococcus aureus from bacteremia and endocarditis.

Bloodstream infections due to Staphylococcus aureus (BSI) are serious infections both in hospitals and in the community, possibly leading to infective endocarditis (IE). The use of glycopeptides has been recently challenged by various forms of low-level resistance. This study evaluated the distribution of MSSA and MRSA isolates from BSI and IE in 4 Italian hospitals, their antibiotic susceptibility--focusing on the emergence of hVISA--and genotypic relationships. Our results demonstrate that the epidemiology of MRSA is changing versus different STs possessing features between community-acquired (CA)- and hospital-acquired (HA)-MRSA groups; furthermore, different MSSA isolated from BSI and IE were found, with the same backgrounds of the Italian CA-MRSA. The hVISA phenotype was very frequent (19.5%) and occurred more frequently in isolates from IE and in both the MSSA and MRSA strains. As expected, hVISA were detected in MRSA with vancomycin minimum inhibitory concentrations (MICs) of 1-2 mg/l, frequently associated with the major SCCmec I and II nosocomial clones; this phenotype was also detected in some MSSA strains. The few cases of MR-hVISA infections evaluated in our study demonstrated that 5 out of 9 patients (55%) receiving a glycopeptide, died. Future studies are required to validate these findings in terms of clinical impact.

Posterior fossa abnormalities in hereditary spastic paraparesis with spastin mutations.

BACKGROUND: Hereditary spastic paraparesis (HPS) linked to mutations in the spastin gene (SPG4) is considered to be a pure form of spastic hereditary paraparesis. However, in this disease also other signs of central nervous system involvement are frequently found. METHODS: Clinical, genetical and neuroradiological investigations were carried out in a large family with autosomal dominant spastic paraparesis and in a sporadic case with spastic paraparesis. RESULTS: Additional clinical and molecular data are provided, studying other members of the same pedigree, as already described, with a five-base deletion in exon 9 of the SPG4 gene (1215-1219delTATAA) whose members show MRI anomalies that fall within the Dandy-Walker continuum. Furthermore, an unrelated female patient with hypoplasia of the cerebellar vermis is indicated, carrying a de novo previously reported mutation of the SPG4 gene (c.1741C>T p.R581X). CONCLUSIONS: Spastin may play an important role in the development of the central nervous system and in particular in the development of the structures of posterior fossa.

Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study.

BACKGROUND: Congenital muscular dystrophies (CMD) with reduced glycosylation of alpha-dystroglycan (alpha-DG) are a heterogeneous group of conditions associated with mutations in six genes encoding proven or putative glycosyltransferases. OBJECTIVES: The aim of the study was to establish the prevalence of mutations in the six genes in the Italian population and the spectrum of clinical and brain MRI findings. METHODS: As part of a multicentric study involving all the tertiary neuromuscular centers in Italy, FKRP, POMT1, POMT2, POMGnT1, fukutin, and LARGE were screened in 81 patients with CMD and alpha-DG reduction on muscle biopsy (n = 76) or with a phenotype suggestive of alpha-dystroglycanopathy but in whom a muscle biopsy was not available for alpha-DG immunostaining (n = 5). RESULTS: Homozygous and compound heterozygous mutations were detected in a total of 43/81 patients (53%), and included seven novel variants. Mutations in POMT1 were the most prevalent in our cohort (21%), followed by POMT2 (11%), POMGnT1 (10%), and FKRP (9%). One patient carried two heterozygous mutations in fukutin and one case harbored a new homozygous variant in LARGE. No clear-cut genotype-phenotype correlation could be observed with each gene, resulting in a wide spectrum of clinical phenotypes. The more severe phenotypes, however, appeared to be consistently associated with mutations predicted to result in a severe disruption of the respective genes. CONCLUSIONS: Our data broaden the clinical spectrum associated with mutations in glycosyltransferases and provide data on their prevalence in the Italian population.

POMT1 and POMT2 mutations in CMD patients: a multicentric Italian study.

Mutations in POMT1 and POMT2 genes were originally identified in Walker-Warburg syndrome (WWS) and subsequently reported in patients with milder phenotypes characterised by mental retardation with or without brain abnormalities and without ocular malformations. As part of a multicentric Italian study we screened the POMT1 and POMT2 genes in 61 congenital muscular dystrophy (CMD) patients with alpha-dystroglycan reduction on muscle biopsy and/or clinical and radiological findings suggestive of the known forms of CMD with alpha-dystroglycan deficiency. The aim of the study was to establish how frequently mutations in POMT1 and POMT2 occur in CMD patients in the Italian population and to evaluate the spectrum of associated phenotypes. Thirteen patients showed mutations in POMT1 and five harboured mutations in POMT2, accounting for a total of 20 different mutations, eight of which were novel (two in POMT1 and six in POMT2). Normal brain MRI associated with mental retardation and microcephaly was the most frequent finding in patients with mutations in POMT1 (six out of 13), but was also found in a patient with POMT2 mutations. Predominant cerebellar hypoplasia was also frequent both in patients with POMT1 (three out of 13) and POMT2 (three out of 5) mutations. A MEB phenotype with frontal cortical dysplasia and pons abnormalities was found in two patients with POMT1 and in one with POMT2 mutations, while a WWS phenotype was only found in a case with mutations in POMT1. Mutations causing frameshifts and stop codons were responsible for the more severe phenotypes. Our results provide further evidence that, as previously reported for FKRP, the array of mutations in POMT1 and POMT2 is ample and the spectrum of associated phenotypes is wider than initially thought.

Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression.

BACKGROUND AND PURPOSE: Pharmacological inhibition of beta-amyloid (Abeta) induced reactive gliosis may represent a novel rationale to develop drugs able to blunt neuronal damage and slow the course of Alzheimer's disease (AD). Cannabidiol (CBD), the main non-psychotropic natural cannabinoid, exerts in vitro a combination of neuroprotective effects in different models of Abeta neurotoxicity. The present study, performed in a mouse model of AD-related neuroinflammation, was aimed at confirming in vivo the previously reported antiinflammatory properties of CBD. EXPERIMENTAL APPROACH: Mice were inoculated with human Abeta (1-42) peptide into the right dorsal hippocampus, and treated daily with vehicle or CBD (2.5 or 10 mg kg(-1), i.p.) for 7 days. mRNA for glial fibrillary acidic protein (GFAP) was assessed by in situ hybridization. Protein expression of GFAP, inducible nitric oxide synthase (iNOS) and IL-1beta was determined by immunofluorescence analysis. In addition, ELISA assay of IL-1beta level and the measurement of NO were performed in dissected and homogenized ipsilateral hippocampi, derived from vehicle and Abeta inoculated mice, in the absence or presence of CBD. KEY RESULTS: In contrast to vehicle, CBD dose-dependently and significantly inhibited GFAP mRNA and protein expression in Abeta injected animals. Moreover, under the same experimental conditions, CBD impaired iNOS and IL-1beta protein expression, and the related NO and IL-1beta release. CONCLUSION AND IMPLICATIONS: The results of the present study confirm in vivo anti-inflammatory actions of CBD, emphasizing the importance of this compound as a novel promising pharmacological tool capable of attenuating Abeta evoked neuroinflammatory responses.

Fourteen-day infusion of ifosfamide in the management of advanced breast cancer refractory to protracted continuous infusion of 5-fluorouracil.

AIMS AND BACKGROUND: Ifosfamide is an active drug in advanced breast cancer. Short-term continuous infusion schedules have been evaluated with encouraging results. The aim of the study was to evaluate in patients with advanced breast cancer a 14-day infusion schedule previously tested at our center in soft tissue sarcomas. METHODS: From July 1998 to February 2000, 26 consecutive patients with heavily pretreated breast cancer, progressing during protracted continuous infusion of fluorouracil, were treated with ifosfamide at the dose of 800 mg/m2/day for 14 consecutive days by means of an elastomeric pump via an in-dwelling Groshong catheter. The median age of the patients was 52 years (range, 32-67) and median PS was 1 (range, 1-3). All patients were pretreated with anthracyclines or taxanes; the median number of chemotherapy lines in the metastatic phase was 2 (range, 1-4). Predominant metastatic sites wen soft tissues in 5 patients, lung in 6, liver in 7 and serosal cavities in 3. RESULTS: Twenty-four patients were assessable for response Two complete responses and 2 partial remissions were noted for an overall 16.6% response rate. The duration of response was 3+, 5, 8 and 10 months, respectively. Stabilization or mi nor response was observed in 2 more patients. The main tox ic effect was myelosuppression (grade 1-2 in 15 patients grade 3-4 in 4). Other toxicities included nausea in 14 patients (grade 3 in 2) and grade 1-2 vomiting in 2 patients. Hair lost or alopecia was universal. CONCLUSIONS: The regimen yielded some clinically useful re sponses with acceptable toxicity. Its evaluation in less ad vanced cases appears to be warranted.

Combination chemotherapy with navelbine and continuous infusion of 5-fluorouracil in metastatic, chemotherapy refractory breast cancer.

BACKGROUND: The protracted continuous infusion (PCI) of 5-fluorouracil (5-FU) has proven in several studies an active and well tolerated treatment for advanced, pretreated breast cancer. Navelbine has also activity in this setting. PATIENTS AND METHODS: Heavily pretreated patients with metastatic breast carcinoma were eligible for the study. Treatment consisted of 5-FU 250 mg/m2 given as a PCI by an elastomeric pump and navelbine 20 mg/m2 on days 1 and 8, every four weeks. Eighty-three patients (median age 54 years; range 32-82 years) entered the study. The median number of metastatic tumour sites was 2, with visceral involvement in 56 patients. Apart from five patients with contraindications, all patients had been pretreated with anthracyclines. Thirty-one patients had received taxanes and seventy-four bolus 5-FU. RESULTS: A median of 5 cycles (range 1-14) per patient was administered. The median duration of 5-FU infusion was 17 weeks (range, 4-90). In the 80 evaluable patients (3 not yet evaluable) 12 complete remissions and 24 partial remissions occurred (response rate, 45%). Median duration of response was 9 months. Toxicity was mild. Median survival was 20 months. CONCLUSIONS: PCI-5-FU combined with navelbine offers a reasonable chance of tumour regression with modest side effects in patients with heavily pretreated breast cancer.

Does a peculiar EEG pattern exist also for FRAXE mental retardation?

OBJECTIVE: FRAXE mental retardation, a recently identified rare genetic condition, is due to a mutation of the FMR2 gene, located at Xq28 region. The phenotype is non-specific and characterized by developmental delay, speech, reading and writing problems, poor adaptive skills, anxiety, aggressiveness, obsessive-compulsive disturbance, and hyperactivity. The objective of this study was to describe the characteristic EEG pattern found in one patient with FRAXE mental retardation. METHODS: EEG (with photic stimulation and hand/foot tapping) and median nerve somatosensory evoked potentials were recorded in a 8-year-old male patient with FRAXE mental retardation (diagnosis confirmed by molecular genetic analysis) and speech disturbances. RESULTS: The patient never presented seizures; however, sleep enhanced multifocal spikes were found in the EEG. Moreover, tactile stimulation of hands and feet, as well as intermittent photic stimulation, provoked the appearance of spikes. Somatosensory evoked potentials from the median nerves showed a 'giant' component at around 60 ms. CONCLUSIONS: Considering the rarity of both FRAXE mental retardation and tactile evoked spikes, their association in the same subject might be considered as not casual. If confirmed by future studies, these neurophysiological findings might be considered as a marker for FRAXE mental retardation.

Clinical correlates of brain morphometric features of subjects with low-functioning autistic disorder.

Numerous neuropathologic and imaging studies have reported different structural abnormalities in the brains of autistic subjects. However, whether or not the degree of brain abnormality is correlated with the severity of developmental impairment in autistic disorder is still unknown. The midsagittal area of the cerebrum, corpus callosum, midbrain, cerebellar vermis, and vermal lobules VI and VII was measured by means of magnetic resonance imaging in 22 boys with low-functioning autistic disorder and in 11 age-matched normal controls. Morphometric measures were statistically compared between groups and correlated with age and scores on the Psychoeducational Profile-Revised and the Childhood Autism Rating Scale. A significant negative correlation was found between midsagittal area of the cerebrum and age in patients with autistic disorder, and a positive correlation was found between the midsagittal area of the midbrain and some subscales of the Psychoeducational Profile-Revised.

Sleep in subjects with autistic disorder: a neurophysiological and psychological study.

Polysomnography (EOG, EEG, EMG) was carried out in 17 male children and adolescents with autistic disorder, in seven patients with mental retardation and fragile X syndrome, and in five age- and sex-matched normal male subjects. Density of rapid eye movements was not significantly different in the three groups of subjects; however, some sleep parameters such as time in bed, sleep period time, and total sleep time were significantly lower in subjects with autistic disorder than in normal controls; moreover, patients with autistic disorder showed values of sleep period time, first REM latency and percent (%) sleep stage 1 lower than those of patients with fragile X syndrome with mental retardation. Density of muscle twitches was significantly higher in patients with autistic disorder than in normal controls. In contrast only minor differences were observed between patients with autistic disorder and those with fragile X syndrome with mental retardation. Furthermore, some psychoeducational profile-revised items such as perception and eye-hand coordination, showed significant correlation with some sleep parameters (time in bed, sleep latency, stage shifts, first REM latency and wakefulness after sleep onset). Childhood Autism Rating Scale (CARS) scores to visual response and non-verbal communication showed significant correlation with some tonic sleep parameters, such as sleep period time, wakefulness after sleep onset, and total sleep time. Relating to people and activity level items were found to be significantly correlated with rapid eye movement density. Our results suggest the existence of a sleep pattern in autistic patients different from that observed in subjects with mental retardation and from that of normal controls. In addition, these findings indicate that sleep parameters in these patients are correlated with some psychological indices generally used for the diagnosis of autistic disorder; for this reason, polysomnographies might be useful in the comprehension of the neurophysiological mechanisms underlying this condition.

Eyelid myoclonia with absences in three subjects with mental retardation.

Eyelid myoclonia with absences is a rare epileptic syndrome, characterized by eyelid myoclonia, absences, and photosensitivity. On the basis of its clinical and EEG features, this syndrome has been classified as a specific new entity among the idiopathic generalized epilepsies. We report three subjects, aged 4, 16, and 31 years, respectively, with eyelid myoclonia, and absences, mental retardation and other abnormalities of the central nervous system. Our findings suggest that, at least in some cases, eyelid myoclonia and absences can represent a peculiar phenomenon of symptomatic epilepsies.

Familial cortical tremor, epilepsy, and mental retardation: a distinct clinical entity?

OBJECTIVE: To describe a European family with cortical tremor, epilepsy, and mental retardation, the pedigree of which indicates an autosomal dominant inheritance of the disease. DESIGN: Clinical, laboratory, neurophysiological, and neuroimaging data were studied. SETTING: Institute for research on mental retardation. PATIENTS: Two siblings (aged 25 and 28 years) and their 49-year-old mother had postural and action tremor, seizures, and mental retardation. Only tremor was present in the maternal grandmother (aged 68 years). The electroencephalogram showed diffuse spike-and-wave complexes and/or posterior spikes, and a photoparoxysmal response in the 4 subjects. The typical electrophysiologic features of cortical reflex myoclonus, such as giant somatosensory evoked potentials, enhancement of the C-reflex, and jerk-locked premyoclonus spikes, were found in all patients. CONCLUSION: This syndrome may represent a specific form of familial cortical tremor with a benign form of epilepsy and a new genetic model of cortical hyperexcitability inherited with an autosomal dominant mechanism.

[Does the preoperative administration of ketorolac improve postoperative analgesia]. / La somministrazione preoperatoria di ketorolac migliora l'analgesia postoperatoria?

AIM OF THE STUDY: 1) To verify the usefulness of ketorolac administration (30 mg i.v.) before a surgical operation in terms of postoperative analgesia improvement; 2) To evaluate the impact of preoperative ketorolac administration on perioperative renal function and on intraoperative water balance; 3) to evaluate the presence of adverse effect due to preoperative NSAID use. DESIGN: Prospective randomized trial. SETTING: University surgical department. PATIENTS AND METHODS: Forty adult patients undergoing major abdominal surgery, randomized in 2 groups: in group 1 ketorolac (30 mg i.v.) was administered immediately after the induction and, for postoperative analgesia, ketorolac (30 mg i.v.) was administered beginning at the time of skin closure; in group 2 no ketorolac was administered before the operation and postoperative treatment was the same. Buprenorphine (0.3 mg i.m.) was administered in case of unsatisfactory analgesia. Fluids infused and diuresis were measured intraoperatively. One, 6 and 24 hours after the end of operation pain was evaluated using pain intensity score and VAS. The day after the operation serum creatinine and urea were measured. RESULTS: No statistically significant differences were found between groups regarding fluids infused, intraoperative diuresis, postoperative pain, adverse effects and number of bleeding episodes. More than 50% of patients, in either groups, required opioids administration. CONCLUSIONS: Ketorolac (30 mg i.v.) administration before a major abdominal operation does not improve postoperative analgesia nor determines significant alterations in renal function or increase in the frequency of abnormal bleedings. Opiate administration is necessary in more than 50% of the patients to achieve adequate analgesia.

A new family with periventricular nodular heterotopia and peculiar dysmorphic features. A probable X-linked dominant trait.

OBJECTIVE: To describe 3 sisters with brain periventricular heterotopia and peculiar dysmorphic features as a probable X-linked dominant trait. DESIGN: Clinical, laboratory, neurophysiological, and brain imaging data were studied. SETTING: Research institute for mental retardation. PATIENTS: The 3 sisters had mental retardation, drug-resistant epilepsy, gray matter heterotopia, and peculiar malformations (low nasal bridge, upslanting palpebral fissures, palpebral edema, attached hypoplastic earlobes, thickened calvaria, rectal fibrovascular polyps, urinary tract anomalies, and increased foot length). The patients were 35, 30, and 25 years old and belonged to a sibship of 6, born of nonconsanguineous healthy parents. CONCLUSION: The 3 patients constitute a well-defined clinical entity not previously described of a probable X-linked dominant nature.