Screening for early cognitive impairment in multiple sclerosis patients using the clock drawing test

The clock drawing test (CDT) is a complex task assessing integrative functions, abstract thinking and visuospatial organization. In the present study we evaluated the CDT as a possible screening instrument for early cognitive impairment in multiple sclerosis (MS) patients. In total, 107 MS patients completed the CDT as well as a battery assessing five cognitive domains. There were 73 female and 34 male participants (mean age 45.4+/-11.6 years, range 19-69). The majority (76/107) were diagnosed with a relapsing-remitting disease course. Mean expanded disability status scale (EDSS) score was 4.3+/-2.4 (range 0-8). The CDT was scored on a 1-6 point scale with "1" being a perfect score and "6" reflecting severe disorganization. Mean CDT score was 2.6+/-1.4. In 53% of patients the CDT was normal while in 11.2% dementia was apparent. The CDT score did not correlate with the total EDSS. Significant correlations were obtained with the mental functional system score of the EDSS (r = 0.78; p = 0.0001), visual learning and recall, sustained attention and concentration. Our findings demonstrate the sensitivity of the CDT to several cognitive domains. The absence of correlation with total EDSS score coupled with significant correlation with the mental functional system suggests that the CDT may be useful for screening MS patients.     

A missense mutation in CDH3, encoding P-cadherin,causes hypotrichosis with juvenile macular dystrophy

Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by early hair loss heralding severe degenerative changes of the retinal macula and culminating in blindness during the second to third decade of life. Recently, we identified a frameshift mutation in the CDH3 gene encoding P-cadherin as the proximal cause of hypotrichosis with juvenile macular dystrophy in four families. We report here another consanguineous family in which four members were diagnosed with hypotrichosis with juvenile macular dystrophy. Light and scanning electron microscopy revealed in all patients morphologic hair shaft abnormalities consistent with pili torti. Ocular fundus examination disclosed marked degeneration of the macular pigment epithelium. Electrophysiologic studies were diagnostic for severe retinal dysfunction. DNA sequence analysis of the entire coding sequence of CDH3 revealed in all affected individuals a homozygous missense mutation resulting in a single amino acid substitution at position 503 of P-cadherin sequence (R503H). The mutation completely segregated with the hypotrichosis with juvenile macular dystrophy phenotype in the family but was not detectable in 83 healthy, unrelated controls. The amino acid substitution affects a highly conserved residue and is predicted to alter a Ca2+ binding domain of P-cadherin. This is the first pathogenic missense mutation reported in CDH3 and the second mutation found to underlie hypotrichosis with juvenile macular dystrophy. Our data establish recessive mutations in CDH3 as the molecular cause of hypotrichosis with juvenile macular dystrophy and expand our understanding of the pathophysiology of this intriguing disorder.     

A novel missense mutation affecting the human hairless thyroid receptor interacting domain 2 causes congenital atrichia

Congenital atrichias represent a large and heterogeneous group of inherited hair disorders. In this report, we describe a patient affected with alopecia universalis congenita (MIM 203655). Sequence analysis revealed a G to A transition at cDNA position 3034 of the hairless hr gene present in a homozygous state in the patient and in a heterozygous state in the patient's mother, and absent in the patient's sister. The mutation is predicted to result in the substitution of an asparagine residue for an aspartate amino acid (D1012N) at a position previously shown in the rat to affect hairless binding to thyroid hormone receptor. This study presents the first evidence in humans for the functional importance of the hairless thyroid receptor interacting domain 2.     

Immunoglobulin treatment in refractory Myasthenia gravis

Failure to induce and maintain remission in severe exacerbations of myasthenia gravis (MG), despite optimal care, is a common problem. We evaluated the efficacy and safety of high-dose intravenous immunoglobulin (IVIg) therapy in an open-label study of 10 patients with severe generalized myasthenia and an acute deterioration unresponsive to conventional therapy including high-dose corticosteroids, cyclosporine, and azathioprine. Intravenous Ig at a loading dose of 400 mg/kg was administered daily for 5 consecutive days, with maintenance IVIg treatment at a dose of 400 mg/kg, once every 6 weeks. Significant improvement occurred in all patients, beginning at 6 +/- 2 days of treatment as measured by the Osserman scale, fatigue variables, muscle strength, and respiratory function tests. No side effects were observed during induction of remission. Further IVIg treatments were highly efficacious in maintaining the remission. The severity of the disease decreased by 2.5 +/- 0.8 grades of the Osserman scale over a period of 1 year (P <0.001), in parallel with reduction of immunosuppressive therapy as well as a decrease in acetylcholine receptor antibody titers (P < 0.01). Intravenous Ig therapy seems to be highly potent for inducing rapid improvement in refractory myasthenia during acute deterioration as well as for maintaining remission.     

What price for general surgery?

BACKGROUND: This study aims to determine the cost-benefit analysis of adding a full emergency general surgery (EGS) arm to a trauma/critical care (TCC) service with limited EGS activity in a Level I trauma center. METHODS: Data on the composition, activity, and billings of a TCC were collected and compared before (January 1, 2002-June 30, 2003) and after (July 1, 2003-December 31, 2003) it assumed the care of all unassigned EGS patients. These included patient volume and demographics, service, procedures, on-call/service activity, and professional billings and collections. Data are means +/- SD or percentages. Intergroup comparisons were performed by using t test or chi2 as appropriate; significance was assumed for values of p < 0.05. RESULTS: Deploying an EGS arm increased coverage weeks (+52 weeks) and necessitated additional staffing (pre-EGS, n = 5; post-EGS, n = 6). Trauma operative volume remained constant (8.2 vs. 10.3 per month), EGS and elective case load increased (28.7 vs. 60 per month; p < 0.01), and the EGS case/consult ratio decreased from 0.81 to 0.64 (p < 0.01). This expanded activity was associated with reduced on-call nonclinical hours, from 3.2 +/- 0.9 to 1.1 +/- 0.8 (p < 0.01), and increased outpatient visits (68.6 vs. 91.1 per month; p < 0.01) and off-service time used for elective operations (22.3 vs. 76%; p < 0.01). Billings significantly increased in each arm compared with the pre-EGS study period (operating room, +44.8; intensive care unit, +12.5; outpatient, +48.7%; p < 0.01). CONCLUSION: Integrating a full EGS into a TCC service encumbers increased nontrauma unscheduled clinical activity in the operating room, clinic, and floors, which resulted in enhanced billings. These beneficial effects were accrued at the expense of individual time and investment in recruiting additional faculty.     

Cervical muscles weakness in chronic whiplash patients

BACKGROUND: Isometric cervical strength has been used for assessing the severity of cervical spine pathologies. However there is a conspicuous dearth of information relating to cervical strength data in patients suffering from chronic whiplash. Therefore the objective of this study was to compare absolute and ratio-based isometric cervical strength scores in chronic whiplash patients with reported corresponding scores in healthy subjects. METHODS: Isometric cervical strength was measured in the directions of flexion, extension, right and left lateral flexion in 97 patients, 51 women and 46 men, using a wall-mounted dynamometer. FINDINGS: Compared to published values of normal subjects, whiplash patients suffered sharp reductions of about 90% in both genders and in all directions. The consistency of the isometric cervical strength scores as indicated by the mean coefficient of variation was relatively low, 17% and 20% in men and women respectively. The flexion/extension strength ratio ranged 0.8--0.9, slightly higher than the reported range for normal subjects. This ratio was highly correlated (r=0.91, P=0.01) with the mean coefficient of variation in a subgroup of 9 patients. INTERPRETATION: In the absence of an obvious reason such as sever atrophy or grossly dysfunctional neurological control the indicated weakness of the cervical muscles may be associated with learned pain avoidance behavior which is typical among this group of patients.     

Cellular response in humans following vaccination with gripax influenza virus

Cellular response of peripheral blood lymphocytes to influenza antigens was measured in a group of young nurse-student volunteers (17–24 years old), following vaccination with a formol-inactivated trivalent influenza vaccine (Gripax). Cord blood lymphocytes (controls) did not react with any of the antigens. This excluded the possibility of any nonspecific mitogenicity of viral antigens. Viability of the cells was indicated by their responsiveness to phytohemagglutinin (PHA). Prior to immunization antigenic recognition to circulating strains (A/England (H₃N₂) and B/Hong Kong) was found in about 44% of the vaccinees; recognition of the recent strain A/USSR (H₁N₁) was found in only 10.5%. Following vaccination, approximately 80% of the subjects exhibited cellular response to all three vaccine strains. This includes the negative subjects, who showed an approximate 70% rate of conversion. There was no correlation between the antibody state and cellular response prior to and following vaccination as gathered from matched data of each participant.     

Cognitive patterns and progression in multiple sclerosis: construction and validation of percentile curves

BACKGROUND AND OBJECTIVES: Rate and pattern of progression of cognitive decline in multiple sclerosis (MS) has not been clearly identified. The present study aimed to identify correlations between cognitive tests and disease duration, construct longitudinal cognitive curves, and assess pattern of change over time. METHODS: The Neuropsychological Screening Battery for Multiple Sclerosis was administered in 150 consecutive MS patients, and tests that correlated with disease duration were identified. Percentile curves were constructed and the pattern of cognitive decline over time explored. The cognitive curves were validated in an additional group of 83 patients with MS. RESULTS: Three of four measures of the spatial recall test (SPART 7/24), and the paced auditory serial addition task for two seconds (PASAT 2'), correlated with disease duration. These tests were used to construct cross-sectional curves identifying the pattern of cognitive decline over time in the MS population. On the basis of this cross-sectional analysis, the earliest cognitive decline occurred in the SPART 7/24 trials 1-5 between one and three years from onset, followed by decline in the SPART delayed recall between three and seven years, and then by decline in the PASAT 2' after seven years from onset. CONCLUSIONS: Verbal fluency and verbal memory appear to be affected earliest in MS. The pattern of cognitive decline is further characterised by a decrease in visuospatial learning, followed by delayed recall, and then by attention and information processing speed. Cognitive percentile curves can be used to evaluate the pattern of progression and identify patients at increased risk.     

T-cell vaccination in multiple sclerosis

T cells that are autoreactive against myelin antigens play a pivotal role in the pathogenesis of multiple sclerosis (MS). The concept of T cell vaccination (TCV) has been developed to generate an immune response against these autoreactive pathogenic T cells. Immunologic data accumulated so far demonstrates depletion of T cells reactive against immunodominant myelin peptides after immunization in the animal model of experimental autoimmune encephalomyelitis, as well as in vaccinated MS patients. Clinical trials have confirmed the safety and efficacy of TCV in a small number of immunized MS patients. TCV resulted in reduced relapse rates and slowed the progression of neurological disability and MRI brain lesion load. Recently, there have been several double-blind, placebo-controlled studies initiated to evaluate the role of TCV in MS. Specifically, it is important to examine the effect of early TCV, given after the first episode suggestive of the disease, in order to prevent the process of epitope spreading.     

Relationship between low back pain in post-menopausal women and mineral content of lumbar vertebrae

Until recently, chronic low back pain in post-menopausal women was commonly attributed to osteoporosis. This opinion has since been challenged on many counts, but controversy persists. The objective of this study was to examine this relationship. In 67 post-menopausal women, the mineral content of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry and the age-normalized bone mineral index (ANBMI), the Z-score, was determined. Mean ANBMI in 40 subjects who complained of chronic low back pain (Group 1) was compared with mean ANBMI in the 27 who did not (Group 2). Pain intensity and related disability were quantified using standard questionnaires. Their respective correlations with ANBMI index and age at onset of menopause were examined. Correlation coefficients and significance of group differences were examined by appropriate statistical methods. The results showed that the mean ANBMI in Group 1 subjects was 96.5 +/- 16.9%, in Group 2 subjects it was 88.6 +/- 10.0%. Neither pain intensity nor disability was correlated with ANBMI. A weak but significant positive correlation was noted between body mass index and intensity of low back pain (r = 0.37; P < 0.05). The occurrence and severity of chronic low back pain in post-menopausal women, and the disability thereof, appear to be unrelated to the mineral content of lumbar vertebrae.