Biomedical subjects

Anna Williams

Publications and source records attributed to Anna Williams.

4 recordsLinked to original sources

PubMed2005

Promoting repair in multiple sclerosis: problems and prospects.

PURPOSE OF REVIEW: Despite recent progress in treating the inflammatory component of multiple sclerosis, current therapies have no clear impact on progression of disability, which closely relates to tissue (myelin and axon) injury. Many scientists now focus their efforts on elucidating the mechanisms that lead to tissue injury, and on developing new strategies for tissue repair. We review recent breakthroughs in this field and discuss their putative applications to therapy. RECENT FINDINGS: Several hypotheses have been raised to explain the failure of remyelination, including depletion of remyelinating cells, quiescence of oligodendrocyte precursor cells and axonal inhibitory signals. Success in remyelination therapy may be achieved either by enhancing endogenous repair or by grafting exogenous remyelinating cells. Several neurotrophic factors have been shown to enhance endogenous remyelination, and many immature cells have been shown to induce efficient exogenous remyelination in animal models. Although effective remyelination probably represents the best way to prevent neurodegeneration, several alternative neuroprotective strategies are emerging. Statins, cyclins and immunophilin ligands are orally available immunomodulatory agents that may protect neurones. Other promising possibilities include the modulation of excitotoxicity, nitric oxide synthesis, or cationic channels. SUMMARY: Despite the increasing number of putative therapeutic targets, no treatment to achieve remyelination or neuroprotection has yielded positive clinical results in humans. Forging a link between basic biology and treatment of patients will require us to overcome several challenges, including assessment of efficacy of repair, improving tolerance to and delivery of neurotrophic factors, and better defining the indications for and limitations of transplantation.

Animals↗

PubMed2004

Clinicopathological and genetic study of early-onset demyelinating neuropathy.

Autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4), Dejerine-Sottas disease and congenital hypomyelinating neuropathy are variants of hereditary demyelinating neuropathy of infancy, a genetically heterogeneous group of disorders. To explore the spectrum of early-onset demyelinating neuropathies further, we studied the clinicopathological and genetic aspects of 20 patients born to unaffected parents. In 19 families out of 20, consanguinity between the parents or presence of an affected sib suggested autosomal recessive transmission. Screening of various genes known to be involved in CMT4 revealed six mutations of which five are novel. Four of these novel mutations occurred in the homozygous state and include: one in GDAP1, one in MTMR2, one in PRX and one in KIAA1985. One patient was heterozygous for a novel MTMR2 mutation and still another was homozygous for the founder mutation, R148X, in NDRG1. All patients tested negative for mutations in EGR2. Histopathological examination of nerve biopsy specimens showed a severe, chronic demyelinating neuropathy, with onion bulb formation, extensive demyelination of isolated fibres and axon loss. We did not discern a specific pattern of histopathology that could be correlated to mutations in a particular gene.

Adolescent↗

PubMed2002

Periaxin mutations cause a broad spectrum of demyelinating neuropathies.

Previous studies have demonstrated that apparent loss-of-function mutations in the periaxin gene cause autosomal recessive Dejerine-Sottas neuropathy or severe demyelinating Charcot-Marie-Tooth disease. In this report, we extend the associated phenotypes with the identification of two additional families with novel periaxin gene mutations (C715X and R82fsX96) and provide detailed neuropathology. Each patient had marked sensory involvement; two siblings with a homozygous C715X mutation had much worse sensory impairment than motor impairment. Despite early disease onset, these siblings with the C715X mutation had relatively slow disease progression and adult motor impairment typical of classic demyelinating Charcot-Marie-Tooth neuropathy. In contrast, a patient with the homozygous R82fsX96 mutation had a disease course consistent with Dejerine-Sottas neuropathy. The neuropathology of patients in both families was remarkable for demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon. Our study indicates a prominent sensory neuropathy resulting from periaxin gene mutations and suggests a role for the carboxyl terminal domain of the periaxin protein.

Adult↗

PubMed1992

Chronic epidural bupivacaine-opioid infusion in intractable cancer pain.

This study examined the efficacy and toxicity associated with chronic epidural opioid-bupivacaine infusions. In a series of 68 patients with cancer pain refractory to epidural opioids alone, analgesia was effectively regained by infusing a opioid-bupivacaine combination. Sixty-one patients (90%) were considered treatment successes, according to conventional criteria. Median length of therapy was 60-120 days, with the longest infusion lasting 277 days. Chronic bupivacaine infusion concentrations ranged from 0.1 to 0.5% with infusion rates varying from 4 to 18 ml/h. The majority of patients experienced pain relief with little or no sympathetic or sensorimotor impairment after the first 24 h at bupivacaine concentrations of 0.125-0.25% and were managed in home or chronic care settings without the need for re-hospitalization. In patients receiving higher bupivacaine concentrations, sympathetic, sensory and motor blockade were well tolerated during chronic infusion. Sensory loss was consistently observed only at bupivacaine concentrations exceeding 0.25%, and motor impairment occurred only at concentrations exceeding 0.35%. Postural hypotension was observed in 6 patients (9%) for the first 24 h only, which supports the requirement for monitoring and fluid therapy during initiation of the bupivacaine infusion. No patient experienced CNS or systemic toxicity, despite plasma total bupivacaine concentrations as high as 10.8 micrograms/ml. Serial plasma bupivacaine levels were measured in 15 patients during chronic infusion. There was considerable inter- and intra-individual variability in plasma bupivacaine concentrations and bupivacaine clearance. We conclude that epidural opioid-bupivacaine infusion is an effective and safe technique for long-term administration of analgesics in the refractory cancer patient.

Analgesia, Epidural↗