Propofol phosphate,a water-soluble propofol prodrug: in vivo evaluation

After a single IV injection of the water-soluble propofol prodrug propofol phosphate (PP) in mice, rats, rabbits, and pigs, propofol was produced rapidly (1-15 min), inducing dose-dependent sedative effects. In mice, the hypnotic dose (HD(50)), lethal dose (LD(50)), and safety index (defined as a ratio: LD(50)/HD(50)) were 165.4 mg/kg, 600.6 mg/kg, and 3.6, respectively. Propofol was produced with half-lives of 5.3 +/- 0.6 min in rats, 2.1 +/- 0.6 min in rabbits, and 4.4 +/- 2.4 min in pigs. The maximal concentration was dose and species dependent. The elimination half-life was 24 +/- 12 min in rats, 21 +/- 16 min in rabbits, and 225 +/- 56 min in pigs. Propofol generated from PP produced pharmacological effects similar to those described in the literature. We found a correlation between PP dose and duration of sedation with propofol concentrations larger than 1.0 microg/mL, which produced somnolence and sedation in rats and pigs. Adequate sedation and, at large enough doses, anesthetic-level sedation were produced after the administration of PP. Overall, PP, the water-soluble prodrug of propofol, seems to be a viable development candidate for sedative and anesthetic applications. IMPLICATIONS: Propofol phosphate, a water-soluble prodrug of the widely used IV anesthetic propofol, was developed and evaluated in mice, rats, rabbits, and pigs after IV injection. The results of the study clearly demonstrate the feasibility of the prodrug approach to achieve sedative and anesthetic levels of propofol in laboratory animals; this warrants further evaluation in humans.     

Analysis of valve motion after the reimplantation type of valve-sparing procedure (David I) with a new aortic root conduit

BACKGROUND: The reimplantation type of valve-sparing procedure does not allow proper reconstruction of the sinuses of Valsalva. We assessed the valve motion after a reimplantation type (David I) of valve-sparing procedure using a new Dacron conduit that incorporates sinuses of Valsalva. METHODS: Nine consecutive patients undergoing an aortic valve-sparing procedure using the new conduit were studied using two-dimensional transesophageal echocardiography shortly (2 +/- 1 months) after operation to determine root distensibility, expressed as percent change in radius and as pressure strain of the elastic modulus. Next, monodimensional view was used to assess valve motion in its various phases (rapid valve opening velocity, slow closing leaflet displacement, rapid valve closing velocity, maximal leaflet displacement, and leaflet displacement before valve closure). Seven healthy individuals served as control subjects. RESULTS: Root distensibility was reduced at the level of the annulus and sinotubular junction but was similar to control subjects at the level of the sinuses (percent change in radius, 4.1% +/- 0.8% versus 4.5% +/- 1.2%; pressure strain of the elastic modulus, 1,286 +/- 674 g/cm2 versus 1,195 +/- 628 g/cm2). Rapid valve opening (69 +/- 34.4 cm/s versus 51 +/- 11.9 cm/s) and closing (47.6 +/- 16 cm/s versus 36.4 +/- 9 cm/s) velocity as well as slow closing leaflet displacement (24% +/- 4.7% versus 22.1% +/- 7.9%), maximal leaflet displacement (20.1 +/- 4 mm versus 22.7 +/- 1.9 mm), and leaflet displacement before valve closure (15.2 +/- 3 mm versus 17.6 +/- 0.8 mm) were similar to control subjects. CONCLUSIONS: The new aortic root conduit used in a reimplantation type of valve-sparing procedure allows the anatomic reconstruction of the aortic root with leaflet motion similar to that of normal subjects.     

Spontaneous esophageal perforation presenting as meningitis

This report describes a unique case of spontaneous esophageal perforation (Boerhaave's syndrome) presenting as meningitis. After a delay in diagnosis (16 days), the patient was successfully treated with debridement, primary closure, and drainage. Although rare, central nervous system infections have been reported in association with esophageal perforation caused by instrumentation, trauma, and malignancy. We report this case of spontaneous esophageal perforation giving rise to meningitis.     

Pulmonary valve lipoma presenting as syncope

We report a case of a pulmonary valve lipoma presenting as syncope in a 28-year-old woman. Surgical excision of the mass was performed in urgency and the patient was discharged uneventfully.     

Predictors of cognitive level and depression severity are different in patients with left and right hemispheric stroke within the first year of illness

Causes of cognitive impairment after stroke are not yet clear because a large number of sociodemographic and clinical variables complicate the understanding of the phenomenon. We aim to evaluate sociodemographic and clinical predictors of cognitive level and depression in subjects with different lesion laterality. We assessed 153 right (n = 87) and left (n = 66) unilateral first-ever stroke patients within the first year of illness with the Structured Clinical Interview for DSM-IV-Patient Edition, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, the State Trait Anger Expression Inventory, the Barthel Index, and the Mini Mental State Examination (MMSE). Sociodemographic variables were also measured. Sixty-two (41 %) patients suffered from Major Depression (MDD), and 26 (17 %) suffered from Minor Depression (MIND). An univariate analysis of variance showed that MMSE scores were different throughout the groups of left and right stroke patients with MDD, MIND and without depression. Left stroke patients with MDD were more cognitively impaired than all the other groups. This result was valid after controlling for the effect of lesion location on cognitive level difference between the groups. A series of stepwise multiple regression analyses indicated that depression severity was a predictor of cognitive level and vice-versa in left hemispheric stroke patients only. Moreover, educational level in right hemispheric stroke patients and state-anger and number of regions affected in left hemispheric stroke patients were other predictors of cognitive level. The study confirms the hypothesis that predictors of cognitive level and depression severity are different in subjects with different laterality of lesion and that MDD is associated with cognitive impairment in left stroke patients. Received: 4 February 2002, Received in revised form: 14 May 2002, Accepted: 22 May 2002 Correspondence to Gianfranco Spaletta, MD     

Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia

We studied nine Italian families with a pure form of autosomal dominant spastic paraplegia (ADHSP) to assess the frequency of mutations in the SPG4 gene. We observed marked intrafamilial variability in both age-at-onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70. Four of nine probands harboured SPG4 mutations, We identified three new SPG4 mutations, all predicting a loss-of-function with apparently important consequences for spastin function. RT-PCR studies predict loss-of-function as a possible mechanism leading to spastin-related HSP. The current study expands the spectrum of allelic variants in SPG4, confirming their pathological significance in pure AD-HSP and suggesting implications for the presumed function of spastin. Received: 15 December 2000, Received in revised form: 29 May 2001, Accepted: 18 June 2001     

A novel mutation in the SURF1 gene in a child with Leigh disease,peripheral neuropathy,and cytochrome-c oxidase deficiency

We report a 16-month-old boy with psychomotor regression, muscle hypotonia, peripheral neuropathy, and lactic acidosis. Brain magnetic resonance imaging showed a bilateral abnormal signal in the substantia nigra and in the subthalamic nucleus, suggestive of Leigh disease. Histochemical analysis of skeletal muscle showed decreased cytochrome-c oxidase activity. Biochemical analysis of respiratory chain enzymes in muscle homogenate and in cultured fibroblasts showed isolated cytochrome-c oxidase deficiency. Western blot analysis in fibroblasts showed the absence of Surf1 protein. Genetic analysis of the SURF1 gene revealed that the patient was compound heterozygous for a previously reported mutation at the splice-junction site of intron 3 (240 + 1G > T), and for a novel 4-bp deletion in exon 6 (531_534delAAAT). Our data further enlarge the spectrum of mutations in SURF1 gene in patients with Leigh disease and cytochrome-c oxidase deficiency, contributing to better characterization of the clinical and neuroradiologic features of this group of patients for genotype-phenotype correlations.     

The ketogenic diet in children, adolescents and young adults with refractory epilepsy: an Italian multicentric experience

PURPOSE: This collaborative study by three Italian groups of child neuropsychiatrists was carried on to evaluate the efficacy and safety of the classic 4:1 ketogenic diet as add-on treatment in refractory partial or generalized epilepsy in children, adolescents and young adults. METHODS: We performed a prospective add-on study in 56 refractory epilepsy young patients (age 1-23 years, mean 10.4 years), all with both symptomatic and cryptogenic, generalized or partial epilepsies. Child neuropsychiatrists worked with nutritional team for sample selection and patients management. The ketogenic diet was added to the baseline antiepileptic drugs and the efficacy was rated according to seizure type and frequency. During treatment, seizure frequency, side effects, urine and blood ketone levels and other parameters were systematically evaluated. RESULTS: Patients have been treated for 1-18 months (mean 5 months). A >50% reduction in seizure frequency was gained in 37.5 and 26.8% of patients after 3 and 6 months, respectively, at 12 months, this number fell by 8.9%. No significant relationship between diet efficacy and seizure or epilepsy type, age at diet onset, sex and etiology of epilepsy was noted. Nevertheless, it seems noteworthy that 64% of our patients with neuronal migration disorders improved on this diet. Adverse effects occurred, mainly in the first weeks of treatment, in 32 patients (57.1%), but were generally mild and transient. In seven patients (12.5%) it was possible to withdraw one to two AED after 3-4 months on ketogenic diet. CONCLUSION: This initial experience with the ketogenic diet was effective in difficult-to-treat patients with partial and generalized epilepsies, though its efficacy dropped significantly by 9-12 months.