Multiple sclerosis: long-term outcomes in ethnic minorities. Analysis of a UK population-based registry.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is most frequent in Caucasian populations. However, studies of MS in other ethnic groups may offer unique insights into genetic and environmental influences on the disease, and data on long-term outcomes in these patients is limited. In this work clinical features and time to disability milestones were investigated in ethnic minority (EM) patients with MS in a UK population and comparisons were made to a Caucasian cohort from the same region. METHODS: In all, 1949 MS patients (1866 Caucasian, 83 EM) were identified from a regional disease registry. Cox proportional hazards regression was used to analyse the time to Expanded Disability Status Scale (EDSS) 3.0, 4.0 and 6.0. RESULTS: Ethnic minority patients were younger at disease onset (28.6 years vs. 32.8 years, P = 0.001), and primary progressive MS was less common (EM 4.8%, Caucasian 11.6%, P = 0.03). After correction for clinical variables, ethnicity was associated with time to EDSS 3.0 [EM: hazard ratio (HR) 1.75, P < 0.0001] and 4.0 (HR 1.46, P = 0.03), but not 6.0 (HR 1.5, P = 0.05). CONCLUSIONS: Ethnic minority patients reach early levels of fixed disability more rapidly than Caucasian patients, but this effect diminishes at later stages of the disease. This has implications for clinical management of these patients.

Specific timely appointments for triage reduced waiting lists in an outpatient physiotherapy service.

OBJECTIVES: Waiting lists with triage systems are commonly used in outpatient physiotherapy but may not be effective. Could an alternative model of access and triage reduce waiting times over a sustained period with no additional resources? DESIGN: Observational study comparing retrospective data for 11 months prior to the introduction of a new model of access compared with data for the equivalent 11 months afterwards. PARTICIPANTS: Patients referred to a physiotherapy outpatient department at an outer metropolitan hospital before (n=721) and after (n=707) the introduction of the new model. INTERVENTION: A model of access and triage known as 'specific timely appointments for triage' (STAT), in which appointment slots are preserved in advance specifically for new patients based on calculation of average demand. OUTCOME MEASURES: Time from referral to first assessment, number of appointments per patient, occasions of non-attendance and total length of stay in the service. RESULTS: Median time from referral to first appointment was 18 days [interquartile range (IQR) 11 to 33 days] in the pre-intervention group, compared with 14 days (IQR 9 to 21 days) in the post-intervention group (P<0.01). The number of physiotherapy appointments also reduced (IQR 2 to 6 vs IQR 1 to 4; P<0.01). There were no changes in non-attendance rates or total time in the service. CONCLUSION: Waiting time for outpatient physiotherapy was 22% lower in the year following the introduction of the STAT model. While acknowledging the limitations of a pre- and post-measurement design, this model may have potential for reducing waiting times for outpatient physiotherapy without additional resources.

Alemtuzumab for multiple sclerosis: Long term follow-up in a multi-centre cohort.

BACKGROUND: Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear understanding of its application and durability of effect in clinical practice has yet to evolve. OBJECTIVES: To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab. METHODS: Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review. RESULTS: One hundred patients were identified with a mean follow-up of 6.1 years (range 1-13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty-seven patients developed secondary autoimmunity. CONCLUSION: Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime.

Site-specific clinical disease onset in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis is a chronic inflammatory disorder of the central nervous system characterized by acute episodes of neurological dysfunction thought to reflect focal areas of demyelination occurring in clinically eloquent areas. These symptomatic relapses are generally considered to be random clinical events occurring without discernible pattern. The hypothesis that relapses may follow a predetermined sequence and may provide insights into underlying pathological processes was investigated. METHODS: Employing prospective clinical database data from 1482 patients who had experienced one or more consecutive relapses were analysed. Using regression analysis, site and symptom of index event were compared with those of first relapse. RESULTS: It is demonstrated that following disease ignition subsequent relapses may not be random events but dependent on characteristics of the index event. All anatomical sites were more likely to be affected in the first relapse if that site had been involved in the index event with a similar association observed when comparing by symptoms. CONCLUSION: These findings have importance in understanding the evolution of the disease and predicting individual disease progression and may aid with patient counselling and management.

Neurohypophysial hormones and renal function in fish and mammals.

The two major basic neurohypophysial peptides, arginine vasopressin (AVP) of mammals and arginine vasotocin (AVT) of all non-mammalian vertebrates, share common structure and major roles in regulating renal function. In this review the complexity of AVP actions within the mammalian kidney is discussed and comparisons are made with the emerging picture of AVT's renal effects in fish. It has become apparent that the antidiuretic action of the neurohypophysial hormones is an ancient phylogenetic phenomenon, although this is based upon reduced glomerular filtration in fish by comparison with predominant tubular effects in mammals. Nonetheless, there appears to be retention of AVP effects upon the functional heterogeneity of nephron populations in mammals. Preliminary evidence for the possible existence of V(2)-type (tubular) neurohypophysial hormone receptors in fish, implies possible AVT actions which parallel those in mammals on tubular ion transport. Further insight from recent mammalian tubule microperfusion studies suggests that in teleost fish both apical (tubular lumen) and basolateral (blood borne) AVT have the potential to modulate renal function, though this remains to be examined.

Pheromone interactions and ionic communication in gametes of aquatic fungusAllomyces macrogynus.

The flagellate male and female gametes of the aquatic fungusAllomyces macrogynus are each attracted to a sexual pheromone produced by the opposite gamete type. The sperm attractant, sirenin, causes chemotaxis to female gametes. Examination of sperm chemotaxis shows that the pheromone influences the frequency of directional changes and the duration of a chemotactic run. Physiological experiments using tertiary amine local anesthetics or calcium chelators such as EGTA demonstrate that sirenin stimulates the influx of calcium ions (Ca(2+)) into the sperm cytoplasm. Radiological experiments with(45)CaCl2 have demonstrated this calcium flux directly. Structurally, sirenin is an oxygenated sesquiterpene that consists of a cyclopropyl ring attached onto an isohexenyl side chain. The pheromone displays a threshold concentration for attraction at 10 pM in chemotaxis bioassays. Structure-activity relationships with racemic sirenin and sirenin analogs indicate that biological activity requires a terminal hydroxymethyl group on the side chain. In addition, a hydrophobic group must be present at the other end of the sirenin molecule. Besides sirenin, the sperm cells ofA. macrogynus produce a female attractant, parisin. While the molecular nature of this attractant is not completely resolved, some general features of the molecule suggest it may be similar structurally to sirenin.

Effects of Analogs of the Fungal Sexual Pheromone Sirenin on Male Gamete Motility in Allomyces macrogynus.

The ability of various structural analogs of the sexual pheromone sirenin to attract male gametes of the aquatic fungus Allomyces macrogynus was determined. Previous studies had shown that several structural analogs and stereoisomers of natural l-sirenin were devoid of activity at physiological concentrations. We now report the discovery of a structural analog that exhibits biological activity indistinguishable from the natural pheromone. The bioassay system used to determine chemotaxis was calibrated using synthetic, racemic sirenin, which exhibited a threshold concentration for gamete attraction at an applied concentration of 10 picomolar. The new synthetic monohydroxy analog of sirenin also had a threshold concentration of 10 picomolar. In the process of developing a new total synthesis of sirenin, a variety of other analogs were prepared and tested. All of these analogs exhibited threshold concentrations at 1 micromolar or higher, although attraction at these higher concentrations still varied according to their structural resemblance to sirenin. Thus, the results of these studies demonstrate that the hydroxymethyl group attached to the six-membered ring of sirenin is not essential for biological activity at physiological concentrations. The studies with other analogs demonstrate that biological activity at any concentration involves a balance between hydrophilic hydroxyl groups and hydrophobic hydrocarbon groups in the structure.