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Impairment of pulmonary function is a major prognostic indicator in amyotrophic lateral sclerosis (ALS). Forced vital capacity (FVC) and maximal voluntary ventilation (MVV) decline linearly and are commonly used to assess disease progression. The aim of this study was to evaluate the usefulness of testing respiratory muscle strength in ALS with a novel test, sniff nasal pressure (Pn(sn)), in parallel with more classic tests such as maximal inspiratory pressure (PI(max)) and maximal expiratory pressure (PE(max)). Sixteen patients with ALS were examined monthly over a period of 18 +/- 10 months. At the time of inclusion in the study, values were normal for FVC (107% of predicted value) and MVV (87% of predicted value) but abnormally low for Pn(sn) (67% of predicted value), PI(max) (69% of predicted value), and PE(max) (54% of predicted value). Late in the course of ALS, all patients could perform Pn(sn) whereas 6 could not perform PI(max) and 7 could not perform PE(max). The rate of deterioration was most often linear and similar for FVC (-4.1% of predicted value per month), MVV (-4.3% of predicted value per month), and Pn(sn) (-4.2% of predicted value per month). We conclude that Pn(sn) was the single respiratory test combining linear decline, sensitivity in mild disease, and feasibility in advanced disease. Being easy to perform and inexpensive, Pn(sn) appears well suited to assess the decline of respiratory muscle strength in ALS.

Purpose: To determine the spectrum of clinical presentations of patients with chronic progressive external ophthalmoplegia (CPEO)., Methods: Retrospective study of 13 cases with CPEO., Results: Eight patients presented an isolated CPEO, three patients had an associated retinopathy (Kearns-Sayre syndrome), one case suffered from retinopathy, deafness, diabetes mellitus and dysphagia, and one patient had an associated dysphagia. Mitochondrial DNA deletions were found in two cases., Conclusions: Our cases illustrate the wide spectrum of mitochondrial ocular myopathies. As patients present mostly with ptosis and ophthalmoplegia, ophthalmologists should be aware of these rare conditions.

Neuronal growth factors hold promise for providing therapeutic benefits in various neurological disorders. As a means of ensuring adequate central nervous system delivery of growth factors and minimizing significant adverse side effects associated with systemic delivery methods, we have developed an ex vivo gene therapy approach for protein delivery using encapsulated genetically modified xenogeneic cells. Ciliary neurotrophic factor (CNTF) has been shown in various rodent models to reduce the motor neuron cell death similar to that seen in amyotrophic lateral sclerosis (ALS). The initial trials focusing on the systemic administration of CNTF for ALS have been discontinued as a result of major side effects, thus preventing determination of the potential efficacy of the molecule. In order to deliver CNTF directly to the nervous system, we conducted a phase I study in which six ALS patients were implanted with polymer capsules containing genetically engineered baby hamster kidney cells releasing approximately 0.5 microgram of human CNTF per day in vitro. The CNTF-releasing implants were surgically placed within the lumbar intrathecal space. Nanogram levels of CNTF were measured within the patients' cerebrospinal fluid (CSF) for at least 17 weeks post-transplantation, whereas it was undetectable before implantation. Intrathecal delivery of CNTF was not associated with the limiting side effects observed with systemic delivery. These results demonstrate that neurotrophic factors can be continuously delivered within the CSF of humans by an ex vivo gene therapy approach, opening new avenues for the treatment of neurological diseases.

The gene therapy approach presented in this protocol employs a polymer encapsulated, xenogenic, transfected cell line to release human ciliary neurotrophic factor (hCNTF) for the treatment of Amyotrophic Lateral Sclerosis (ALS). A tethered device, containing around 10(6) genetically modified cells surrounded by a semipermeable membrane, is implanted intrathecally; it provides for slow continuous release of hCNTF at a rate of 0.25 to 1.0 micrograms/24 hours. The semipermeable membrane prevents immunologic rejection of the cells and interposes a physical, virally impermeable barrier between cells and host. Moreover, the device and the cells it contains may be retrieved in the event of side effects. A vector containing the human CNTF gene was transfected into a line of baby hamster kidney cells (BHK) with calcium phosphate using a dihydrofolate reductase-based selection vector with a SV40 promoter and contains a HSV-tk killer gene. hCNTF is a potent neurotrophic factor which may have utility for the treatment of ALS. Systemic delivery of hCNTF in humans has been frustrated by peripheral side effects, the molecule's short half life, and its inability to cross the blood-brain barrier. The gene therapy approach described in this protocol is expected to mitigate such difficulties by local intrathecal delivery of a known quantity of continuously-synthesized hCNTF from a retrievable implant.

A 39 year-old patient suffered bilateral painless visual loss while consuming abusively alcohol and cigarettes. Family history was remarkable for a similar episode in the patient's brother 21 years ago, while drinking and smoking heavily. A diagnosis of toxic optic neuropathy was made in another institution, but due to the positive family history, mitochondrial DNA was studied for a point mutations associated with Leber's hereditary optic neuropathy. A homoplasmic mutation at nucleotide 11778 was found. The patient's brother could not be studied. This case emphasizes the probable deleterious effects of epigenetic factors such as alcohol and cigarette smoke in patients harbouring mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy and the need for mitochondrial DNA studies in atypical cases of optic neuropathy.

The complete nucleotide sequence of human papillomavirus type 41 (HPV-41) has been determined. HPV-41 was originally isolated from a facial wart, but its DNA has subsequently been detected in some skin carcinomas and premalignant keratoses (Grimmel et al., Int. J. Cancer, 1988, 41, 5-9; de Villiers, Grimmel and Neumann, unpublished results). The analysis of the cloned HPV-41 nucleic acid reveals that its genome organisation is characteristic as for other papillomavirus types. Yet, the analysis indicates at the same time that this virus is most distantly related to all other types of human-pathogenic papillomaviruses sequenced thus far and appears to identify HPV-41 as the first member of a new subgroup of HPV. The overall nucleotide homology to other sequenced HPV types is below 50%. The closest other HPV type is represented by HPV-18, sharing 49% identical nucleotides. The typical E2 binding sequence ACCN6GGT, found in all papillomaviruses analyzed to date, does not occur in the URR of the HPV-41 genome. Modified E2 binding sequences, as described for BPV 1 (Li et al., Genes Dev. 1989, 3, 510-526), are located in the domain proximal to the E6 ORF. These are ACCN6GTT, AACN6GGT and the two perfect palindromic sequences AACGAATTCGTT.