Overlapping and distinct mechanisms of action of multiple sclerosis therapies.

In the last two decades MS has changed from an idiopathic condition with only symptomatic treatments to a disease with better characterized pathophysiologic underpinnings and several treatments that modify its long-term course based on specific mechanisms of action. There are now several FDA approved options for therapy at the onset of disease, and discussions have begun on choosing the best treatment in individual patients and what option to choose next in patients who are failing their current treatment. Numerous studies have begun to highlight that the underlying pathology of CNS damage may be different in subsets of patients, raising the possibility that some may respond to a treatment with a mechanism of action that is targeted to 'their' MS. Trials are ongoing of numerous new agents with different mechanisms of action and some combination therapies. A better understanding of how each therapy works may guide decisions on initiating, combining or changing therapy in a more rational way to improve patient outcomes. Further knowledge of underlying mechanisms of disease in different patients with 'the same' disease may lead to more targeted therapies, as will biomarkers that predict clinical response to therapy. Studies of the effects of various agents used in MS reveal both overlapping and distinct mechanisms of actions that may be relevant to their efficacy and side effects in individual patients. However, it is important to remember that most agents are approved based on their reduction of MRI lesions and relapse rates over a short time frame. These measures only partially correlate with long-term disability, which may be the most relevant clinical outcome for people with MS. Fixed disability requires years to become apparent, and there is a lack of large studies of biomarkers for chronic outcomes. In addition, few large studies correlate response to therapy with cognitive outcomes, which are a major cause of chronic disability. This review will attempt to summarize clinically relevant knowledge of the mechanisms of action of current FDA approved therapies for MS in the context of ongoing clinical trials of combination therapy and address rational approaches to changing therapy in a patient suspected to be 'unresponsive' to their current treatment.

Self-administration of medicine and older people.

BACKGROUND: Non-adherence to medication regimens is a significant problem in older patients, which can lead to therapeutic failure and the wastage of resources. Common causes include poor patient memory, physical difficulties, unpleasant side effects and a lack of social support. CONCLUSION: Strategies such as careful labelling, self-administration of medicine programmes, simplifying drug regimens and the use of medication compliance devices can help to promote patient adherence. Some of these interventions will work for certain patients, however the authors recommend that a multidisciplinary assessment and a regular review of each patient's ability to adhere to medication should be undertaken.

Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14.

CONTEXT: Gastroesophageal reflux (GER) has not previously been widely regarded as a hereditary disease. A few reports have suggested, however, that a genetic component may contribute to the incidence of GER, especially in its severe or chronic forms. OBJECTIVE: To identify a genetic locus that cosegregates with a severe pediatric GER phenotype in families with multiple affected members. DESIGN: A genome-wide scan of families affected by severe pediatric GER using polymorphic microsatellite markers spaced at an average of 8 centimorgans (cM), followed by haplotyping and by pairwise and multipoint linkage analyses. SETTING: General US community, with research performed in a university tertiary care hospital. SUBJECTS: Affected and unaffected family members from 5 families having multiple individuals affected by severe pediatric GER, identified through a patient support group. MAIN OUTCOME MEASURES: Determination of inheritance patterns and linkage of a genetic locus with the severe pediatric GER phenotype by logarithm-of-odds (lod) score analysis, considering a lod score of 3 or greater as evidence of linkage. RESULTS: In these families, severe pediatric GER followed an autosomal dominant hereditary pattern with high penetrance. A gene for severe pediatric GER was mapped to a 13-cM region on chromosome 13q between microsatellite markers D13S171 and D13S263. A maximum multifamily 2-point lod score of 5.58 and a maximum multifamily multipoint lod score of 7.15 were obtained for marker D13S1253 at map position 35 cM when presumptively affected persons were modeled as unknown (a maximum multipoint score of 4.88 was obtained when presumptively affected persons were modeled as unaffected). CONCLUSION: These data suggest that a gene for severe pediatric GER maps to chromosome 13q14. JAMA. 2000;284:325-334

The use of medication compliance devices by district nursing services.

This article presents a critical review of the literature relating to medication compliance devices and the findings of a survey that examined the use of such devices by district nursing services. The UKCC (1992) does not regard the loading of compliance devices by nurses as safe practice; however, compliance devices continue to be used by district nurses. The evidence base concerning the value and use of medication compliance devices is examined and significant gaps in the literature relating to the use of such devices are identified. There is an absence of studies that focus on the effect of compliance devices on adherence among older patients and the nature and frequency of drug administration errors involving these devices. The survey findings show that nurse-loaded compliance devices are used in over one-third of the sample. Further research is necessary to assess the clinical effectiveness of, and clinical risk attached to, compliance devices for older patients in the community. It is suggested that this is an issue of serious concern for primary care groups considering the principles of clinical governance.

Nonionic triblock copolymers facilitate delivery of exogenous proteins into the MHC class I and class II processing pathways.

Nonionic triblock copolymers are relatively nontoxic adjuvants that induce high-titer, long-lasting antibody responses. We have previously shown that these adjuvants also induce cell-mediated immunity including lymphokine production by CD4(+) T cells and cytolytic responses by CD8(+) T cells. These copolymers are thought to modulate hydrophobic adhesive interactions between antigens (Ag) and lymphoid cells. We sought to test the hypothesis that copolymers facilitate uptake of exogenous Ag by antigen-presenting cells (APC) using an in vitro model system. Our data show that nonionic triblock copolymers enhanced presentation of soluble ovalbumin (OVA) to the major histocompatibility complex (MHC) class II-restricted CD4(+) T cells and MHC class I-restricted CD8(+) T cells, respectively. Presentation of OVA via the class I pathway was enhanced by copolymers in both phagocytic and nonphagocytic APC. However, copolymers did not enhance binding of peptides to the MHC molecules on APC, presentation of endogenously synthesized Ag, or presentation of exogenous Ag delivered by electroporation. These results provide additional evidence that these nonionic triblock copolymers can serve as powerful adjuvants for augmenting both humoral and cell-mediated immunity to protein Ag.

Oxygen consumption, heart rate, and rating of perceived exertion in young adult women during backward walking at different speeds.

Backward walking has gained popularity as an adjunct to treatment for patients undergoing rehabilitation for patellofemoral pain syndrome and anterior cruciate ligament injuries. Researchers have suggested that backward walking decreases the compressive forces at the patellofemoral joint while also preventing overstretching of the anterior cruciate ligament. Prior to this study, precise prescription of backward walking speeds for women was not possible. The purpose of this study was to determine the relationship between heart rate, oxygen consumption, and backward walking speeds. Twenty-five healthy, adult female volunteers participated in this study. Subjects were tested at speeds of 0.96, 1.20, 1.43, 1.67, and 1.91 m/sec. Subjects also performed a graded exercise stress test. Analysis revealed curvilinear relationships between oxygen consumption and speed as well as between heart rate and speed. With these results, clinicians may now prescribe specific speeds of backward walking for women to elicit a desired cardiopulmonary response.

Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children.

We determined four carnitine constituents (total and free carnitine and short- and long-chain fatty acid carnitine esters) in serum from 471 patients treated for convulsions with phenobarbital, valproic acid, phenytoin, and/or carbamazepine. The 471 patients were in eight treatment groups; four were treated with monotherapy and four with polytherapy. The means of all four carnitine constituents were significantly reduced in all treatment groups (except for free carnitine in four groups). Total carnitine was reduced by 23% to 48%, free carnitine by 9% to 45%, short-chain fatty acid carnitine by 46% to 64%, and long-chain fatty acid carnitine by 6% to 29%. Patient frequency of reduction for total carnitine was 20% of all patients (10% for free carnitine), 23% of patients receiving valproate (9% for free carnitine), 36% of those receiving phenobarbital (21% for free carnitine), 12% of those receiving phenytoin (8% for free carnitine), and 8% of those receiving carbamazepine (1% for free carnitine). Only for phenobarbital was there an inverse correlation between the serum concentration of the drug and that of carnitine concentration. One patient receiving carbamazepine had a 59% reduction in the total and a 65% reduction in the free carnitine concentration and a fivefold increase in long-chain fatty acid carnitine, values similar to those seen in neonatal lethal carnitine palmitoyl transferase II deficiency. It remains to be determined whether a reduction in serum carnitine values in patients receiving anticonvulsant therapy is of clinical consequence, whether the reduction is present in some patients before the start of therapy, when and by what mechanism carnitine levels may become reduced during therapy, and whether the reduction exists in the solid tissues of these patients.

Comparison of total serum lipids measured by two methods.

To accurately assess vitamin E status, the ratio of serum vitamin E to total serum lipids is required. We compared two methods of measuring total serum lipids: (a) the calculated sum of measured cholesterol, triglycerides, and phospholipids, and (b) the colorimetric method. Over the entire range of total lipid concentrations (151-1,728 mg/dl), there was an excellent correlation between methods (r = 0.930; p less than 0.001). No significant differences between measurements by these methods were found over the entire range and between 0 and 1,000 mg/dl; however, between 1,000 and 1,728 mg/dl, the measured total lipid concentration was higher (p = 0.023) than the added total lipid measurements. Despite this discrepancy, the methods appear comparable for clinical use in assessing vitamin E/total lipid status; the measured total lipids would be the preferred method because of the low cost and ease of performance of the test.

Simultaneous measurement of 25-hydroxy, 24,25-dihydroxy-, and 1,25-dihydroxyvitamin D without use of HPLC.

A procedure is described for measuring the concentration of three major vitamin D metabolites: 25(OH)D, 24,25(OH)2D and 1,25(OH)2D, in 0.5 ml serum. The analytes are extracted using C18, and separated using aminopropyl solid phase extraction cartridges. 25(OH)D is separated completely; less than or equal to 10% overlap is observed between the 24,25(OH)2D and the 1,25(OH)2D fractions, and this overlap did not interfere in subsequent competitive radioligand assay. Coefficient of variation (SEM/mean x 100%) is intra-assay (n = 10) 5.8, 3.1, 5.2%, and inter-assay (n = 5) 10.1, 8.7 and 6.4%, respectively. Recoveries of the three analytes added to a single specimen are 103, 95 and 111%, respectively. One technician can extract and fractionate up to 24 specimens in one day, ready for HPLC or direct estimation.

Correlation of cerebral perfusion pressure and Glasgow Coma Scale to outcome.

Cerebral Perfusion Pressures (CPP) and Glasgow Coma Scale (GCS) scores were monitored to guide the management of severely head-injured patients. These measures were correlated to outcome (Glasgow Outcome Scale-GOS) in 136 consecutive patients at least 1 year after injury. The GOS showed highly significant positive correlations to either CPP or GCS assessments (p less than 0.001). Two parameters that are correlated with subsequent death in most patients include 1) highest (h) GCS = 3 or 4 (Day 1: 31 of 32 patients died, and Day 2: 19 of 19 patients died), and 2) CPP less than or equal to 60 mm Hg more than 33% of the hourly measures during Day 2 (36% of all subsequent deaths; 11% overlap with the highest Glasgow Coma Scale). The Day 2 measures identifying two groups that have a greater than 75% incidence of "good outcome" or GOS = 4 or 5 include 1) hGCS greater than or equal to 6 (N = 45) and 2) the average (a) CPP greater than or equal to 90 mm Hg (N = 26). Of the 45 patients with a GOS = 4 or 5 who had both CPP and GCS recorded on the third day, 44 were identified by these "good outcome" parameters.

Correction of vitamin E deficiency in children with chronic cholestasis. II. Effect on gastrointestinal and hepatic function.

Although secondary vitamin E deficiency causes a reversible neurologic disorder in children with chronic cholestasis, the effect of this deficiency state on other organ systems is unknown. We studied the effects of vitamin E therapy on selected gastrointestinal and hepatic functions in five children with chronic cholestasis and well-documented biochemical and neurologic evidence of vitamin E deficiency. After 2 to 3 years of oral or parenteral vitamin E therapy, there was no improvement in fecal fat losses, severity of vitamin E malabsorption (as measured by an oral vitamin E tolerance test) or total serum fatty acid concentrations. Serial analyses of liver function blood tests demonstrated a marked decline in fasting serum cholylglycine concentrations during 18 to 31 months of vitamin E therapy, while other liver function tests showed no consistent changes. We conclude that vitamin E deficiency does not appear to alter intestinal absorption of fat or vitamin E; however, vitamin E deficiency may further impair already compromised hepatic function during pathologic conditions such as cholestasis.

Phosphoenolpyruvate carboxykinase activity in human liver.

The activity of phosphoenolpyruvate carboxykinase (EC 4.1.1.32) (PEPCK), a rate-limiting gluconeogenic enzyme, was found decreased by others in genetically determined disorders and in Sudden Infant Death Syndrome (SIDS). To understand these findings, we made a systematic study of normal human hepatic PEPCK activities in specimens obtained under various conditions from patients not suspected of having SIDS. PEPCK was assayed by the method of Ballard and Hanson [J. Biol. Chem., 244 (1969) 5625] and activity reported as units (1 mumol/min) per gram protein. Intra-assay precision was 4.1% (n = 1094); inter-assay precision using the same homogenate was 10.4% (n = 51); and inter-assay precision using different homogenates of the same tissue specimen was 16.3% (n = 17). The assay was linear with time and enzyme concentration for at least 60 min up to 1.3 mU/assay and for at least 5 min up to 20 mU/assay. Biopsy specimens had significantly (P = 0.015) higher PEPCK activity, 12.60 +/- 3.01 U/g (range 3.5-10.4, n = 9) compared to specimens obtained at autopsy, 3.20 +/- 0.45 U/g (range 0-8.6, n = 33). Specific activity was not significantly correlated with the patient's age, fresh vs. frozen tissue, postmortem intervals up to 68 h, or length of storage at -70 degrees C up to 21 years. One patient had activity at autopsy (tissue obtained less than 2 h postmortem) 26% less than was observed in his biopsy specimen. Autopsy samples separated by differential centrifugation into mitochondrial and cytosolic fractions and checked with marker enzymes ornithine transcarbamylase (mitochondrial) and arginase (cytosolic) had considerable cross-contamination between the two fractions in fresh and frozen specimens.

An hepatic metabolic profile in sudden infant death (SIDS).

Levels of 18 enzymes and metabolites were measured in liver obtained at autopsy from 41 infants, 28 of whom were found unexpectedly dead at home. Four infants had meningitis, 11 had pathologic findings not clearly sufficient to explain death (SUD), and 13 were considered totally unexplained pathologically (SIDS). The possible contributions of postmortem interval, age and diet to the results are reviewed. No characteristic metabolic profile was recognized amongst SUD and SIDS groups. It is speculated that the amount of glycogen found in liver may provide insight into premortal events and reflect the rapidity of the death mechanism. Five individuals (20%) were suspected of having major metabolic abnormality including glycogenosis (1), urea cycle defect (1), and possibly abnormal levels of carnitine palmityl transferase (3).

Accurate intracranial pressure monitoring: technical note.

Intracranial pressure (ICP) monitoring may be misleading or inaccurate in patients who have sustained cerebral death or who have had cerebrospinal fluid drainage (e.g., due to skull fracture or craniotomy). ICP recording in these patients requires particular attention to the monitoring technique to avoid misleading values that may result in inappropriate therapy. We review methods for obtaining accurate ICP readings from fluid-interface systems using either a ventricular catheter or a subarachnoid screw. We suggest attention to the following: (a) elevation of the pressure in the external tubing and connections to ensure that there are no microleaks , (b) injection of a small volume of saline intracranially, and (c) awareness of what constitutes a true ICP reading.

Cholesterol ester storage disease and mesenteric lipodystrophy.

Cholesterol ester storage disease is a rare, inherited metabolic disorder of lipid associated with acid cholesteryl ester hydrolase deficiency. Thus far, 15 cases have been reported in the world literature. Reported here is the autopsy study of the oldest patient with this disease. The lipid storage occurred in the forms of birefringent needle-shaped crystals limited to hepatocytes and non-birefringent autofluorescent granules accumulated within the foam cells of the hepatic portal triads, duodenum, and ovaries. The cholesterol content of the liver was 16 times normal, primarily caused by increased cholesterol ester. Only trace cholesteryl ester hydrolase activity was demonstrated in the liver. An additional unique finding in our case was the presence of mesenteric lipodystrophy. Whether these two rare disorders observed in our patient represent unrelated conditions or have an etiologic association remains unknown.

Effect of mannitol on increased intracranial pressure.

We studied 61 patients with a closed head injury and increased intracranial pressure (ICP). The ICP was monitored continuously, concomitant with the administration of 20% mannitol. If the ICP remained higher than 25 mm Hg for 10 minutes or more, the patient was included in the study. Analysis of monitoring records delineated four variables that were related to the response of ICP to mannitol: (a) the level of ICP 1 hour before mannitol was administered, (b) the level of ICP when mannitol was administered, (c) the amount of mannitol that was administered immediately before the resulting changes in ICP were measured, and (d) the cumulative amount of mannitol given over the 6 hours before the most recent mannitol dosage was administered. The level of the ICP measurements and the cumulative amount of preceding doses of mannitol influenced the response of ICP to mannitol more than did the size of the dose of mannitol. These findings imply that: (a) the initial administration of more mannitol than is absolutely needed may lead to larger doses being required to control ICP and (b) for that reason, mannitol given on a gram/kilogram, an hourly, or a serum osmolarity basis to control increased ICP has negative long term effects because more mannitol may be required to decrease ICP when an excessive amount of it has been given previously.