SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia.

Mutations in the SPG3A gene encoding the novel GTPase atlastin have recently been implicated in causing autosomal dominant hereditary spastic paraplegia (ADHSP) in six unrelated families. The phenotype of affected individuals in all cases has been of an early onset uncomplicated form of the disease. One particular missense mutation, R239C, in exon 7 of SPG3A has been identified in three of these families. We performed mutation screening by direct sequencing of all 14 exons and flanking sequences of the SPG3A gene in affected individuals from 12 unrelated English families, all with an early onset uncomplicated ADHSP in whom spastin mutations had previously been excluded. The R239C mutation was found to co-segregate with the disease in one English ADHSP family confirming a widespread prevalence for this commonly occurring mutation. No additional SPG3A mutations were identified in the remaining 11 families suggesting that even within this specific sub-set of early onset uncomplicated ADHSP patients atlastin mutations are relatively rare.

A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia.

The authors performed a clinical and genetic study of a large consanguineous English family with uncomplicated autosomal recessive hereditary spastic paraplegia (ARHSP). Linkage to the previously described SPG5A locus was established with maximum multipoint lod score of 4.84. The locus was refined to a 23.6 cM interval between markers D8S1833 and D8S285. No evidence of oxidative phosphorylation defects was found in muscle biopsies from two affected individuals.

Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene.

Hereditary spastic paraplegia (HSP) is a heterogeneous condition characterised in its pure form by progressive lower limb spasticity. Mutations in SPG4 (encoding spastin) may be responsible for up to 40% of autosomal dominant (AD) cases. A cohort of 41 mostly pure HSP patients from Britain and Austria, 30 of whom displayed AD inheritance, was screened for mutations in SPG4 by single strand conformation polymorphism (SSCP) analysis followed by sequencing of samples with mobility shifts. We identified eight SPG4 mutations in pure AD HSP patients, seven of which were novel: one missense mutation within the AAA cassette (1633G>T), two splice site mutations (1130-1G>T, 1853+2T>A) and four frameshift mutations (190_208dup19, 1259_1260delGT, 1702_1705delGAAG, 1845delG). A novel duplication in intron 11 (1538+42_45dupTATA) was also detected. We report the HUGO-approved nomenclature of these mutations as well. Furthermore, we detected a silent change (1004G>A; P293P), previously reported as a mutation, which was also present in controls. The frequency of SPG4 mutations detected in pure AD HSP was 33.3%, suggesting that screening of such patients for SPG4 mutations is worthwhile. Most patients will have unique mutations. Screening of SPG4 in apparently isolated cases of HSP may be of less value.

Intrinsic spinal cord lesions complicating epidural anaesthesia and analgesia: report of three cases.

Serious neurological complications related to epidural anaesthesia and analgesia are only rarely reported. We describe the clinical and radiological features of three patients who sustained intrinsic spinal cord lesions after attempted epidural catheterisation. In each case there was an early onset of motor and sensory impairment after the procedure and MRI demonstrated similar, extensive, paracentral, high signal intensity lesions within the cord on T2 weighted images. Possible mechanisms to explain these MRI appearances are discussed. It is proposed that the most likely cause of these lesions was direct trauma to the spinal cord during the procedure and subsequent injection of fluid into the spinal cord producing localised hydromyelia. The prognosis in each case was for a gradual recovery of motor function but spinothalamic sensory impairment and severe spontaneous pain over the affected area persisted.

Relative bioavailability of danazol in dogs from liquid-filled hard gelatin capsules.

Danazol was dissolved in non-aqueous mixtures containing either polyethylene glycol 400 or polysorbate 80, and filled into hard gelatin capsules at 50 mg concentrations. The bioavailability of these formulations was compared with commercial danazol capsules in a two-way crossover study using young female beagle dogs. Both formulations showed greater oral bioavailability when compared with either the 100 or 200 mg commercial brand of danazol. The bioavailability of the polyethylene glycol 400 and polysorbate 80 formulations was enhanced 3.7 and 15.8 times, respectively, when compared at the 100 mg dose level.

Mortality and morbidity of prostatectomy. How far does preselection and pre-operative care influence the result?

Mortality and morbidity rates of prostatectomy have been progressively reduced over the past years, but with increasing ageing of the population, a limit is reached when medical complicating factors ensue, beyond which operative intervention carries an unacceptable risk. Results of surgery have little meaning if patients who are not fit or too old are excluded and not shown. It is with the above objectives in view that a prospective study is reported where all patients who presented or were admitted with prostatic symptoms over 1 year were recorded. There were 246 patients. Age, presentation and ASA (American Society of Anesthesiologists) status, post-operative problems and stay were noted. Joint assessment with a senior anaesthetist was performed in all higher-risk patients. 132 patients were operated on, 91% by transurethral resection of the prostate. 66% were ASA 2 and 3. Age itself bore no relation to length of post-operative stay but ASA status did. There was no mortality. However, 12 (9%) ASA 4 cases were excluded from surgery. It is concluded that with careful assessment, patients who are old and medically compromised can undergo prostatectomy safely, but one has to identify accurately those unsuitable for surgery and offer alternative treatment.

Epidural fentanyl and monoamine oxidase inhibitors.

The successful use of continuous epidural fentanyl infusion to control postoperative pain in a patient treated with monoamine oxidase inhibitors is described. The use of epidural opioids may be a safe technique for the management of such patients.

Plasma concentrations and relative bioavailability of naftidrofuryl from different salt forms.

The relative bioavailability of the vasodilator naftidrofuryl from formulations containing its oxalate or citrate salt has been estimated using a specific HPLC assay, and a less specific fluorimetric assay, to measure plasma drug concentrations. The conclusions of the study were the same irrespective of the assay employed. The relative rate, but not the extent, of bioavailability of naftidrofuryl from the citrate salt (peak 1096 ng ml-1 at 0.76 h) was marginally greater (p = 0.003) than that from the oxalate salt (peak 922 ng ml-1 at 0.94 h). The degree of intersubject variability was similar after administration of either salt form. The mean half-life of naftidrofuryl was 1.8 h and its mean residence time was 2.5 h.

A double-blind comparison of nefopam and placebo used as a premedication in children.

Forty-two children received either nefopam or a matched placebo as oral premedication in a double-blind trial. Nefopam performed no better than placebo as a premedication and as postoperative analgesic. Its use is not recommended in paediatric anaesthesia because of a significantly high incidence of vomiting on awakening.

Occurrence of an abnormal lipoprotein in patients with liver disease.

An abnormal lipoprotein, containing a high proportion of unesterified cholesterol and phospholipid, has previously been described as occurring in the serum of patients with obstructive jaundice, and has been called lipoprotein X. Using an immunoelectrophoretic method for the detection of lipoprotein X in serum, the sera of 97 patients with liver disease have been screened and the associated biochemical features measured.Lipoprotein X was found in 45% of cases of liver disease with cholestatic features, and was not detected in cases of liver disease without cholestasis. The incidence of lipoprotein X in different causes of cholestatis varied, and while it was commonest in cases of extrahepatic obstruction of recent onset, occurring in 75% of cases, it was also found in primary biliary cirrhosis in 48% of cases, and in cholestatic hepatitis, less commonly.The cause of the appearance of lipoprotein X is unknown, but analysis of associated biochemical features suggested a relationship to physical biliary obstruction rather than a derangement of liver cell function.