Screening mammogram utilization in women with diabetes.

OBJECTIVE: To determine whether women with diabetes undergo fewer screening mammograms than matched control subjects. RESEARCH DESIGN AND METHODS: A total of 424 women with diabetes aged 50-75 years who received their primary care from general internists at a large Midwestern multispecialty group practice were retrospectively studied for frequency of mammography from August 1997 to January 2000. Two control subjects without diabetes (n = 845) were matched to each case by age, sex, provider, and date of visit. The main outcome measure was the percentage of subjects undergoing mammography 1 year before and 30 days after an index date, defined as the most recent health care visit after August 1997 and before January 2000. RESULTS: Analysis by conditional logistic regression demonstrated that women with diabetes had significantly lower rates of mammograms than control subjects (78.1 vs. 84.9%, respectively; odds ratio 0.63, P = 0.002). After adjusting for insurance status and race, women with diabetes continued to have significantly lower rates of mammography (odds ratio 0.70, P = 0.027). CONCLUSIONS: Women with diabetes were significantly less likely to undergo screening mammography than control subjects. Considering the increasing incidence of diabetes and the equal incidence of malignancy in women with and without diabetes, it would be beneficial to improve breast cancer screening in this population.

Clinical utility of dorsal sural nerve conduction studies.

A technique of testing sensory nerve conduction of the dorsal sural nerve in the foot was used in 38 normal subjects and 70 patients with peripheral neuropathies. The normal dorsal sural sensory nerve action potential (SNAP) had a mean amplitude of 8.9 microV (range 5-15 microV), mean latency to negative peak of 4.0 ms (range 3.2-4.7 ms), and mean conduction velocity of 34.8 m/s (range 30-44 m/s). Optimal placement of the recording electrodes to obtain a maximal nerve action potential was proximal to digits 4 and 5. Cooling to below 25 degrees C prolonged the latency but did not decrease the SNAP amplitude. Among the patients with peripheral neuropathy, dorsal sural SNAP was absent in 68 (97%), whereas only 54 (77%) showed abnormalities of sural sensory conduction. The diagnostic sensitivity of sensory nerve conduction studies in peripheral neuropathies may be significantly improved by the use of this technique for evaluating the action potential of the dorsal sural nerve.

Time trends in the prevalence of atherosclerosis: a population-based autopsy study.

PURPOSE: Mortality from coronary heart disease is declining but little is known about trends in the prevalence of atherosclerosis. Autopsy rates in Olmsted County, Minnesota, are higher than the national average, offering an opportunity to address this matter. In this study, we determined the prevalence of anatomic coronary disease among autopsied Olmsted County residents and examined the generalizability of these findings. SUBJECTS AND METHODS: Reports of the 2,562 autopsies performed between 1979 and 1994 on Olmsted County residents > or =20 years of age were reviewed for the presence of coronary disease. RESULTS: Among autopsied decedents less than 60 years old at death and among coroner's cases, the prevalence of anatomic coronary disease declined with time (P for trend = 0.05); no trend was detected among older persons or noncoroner's cases. By logistic regression analysis, the crude odds ratio ([OR] per 5 years) for the association between time and anatomic coronary disease was 0.94 (95% confidence interval [CI]: 0.86 to 1.03; P = 0.18]. Age, sex, and antemortem diagnosis of heart disease were also strongly related to the presence of disease. After adjustment for sex and antemortem diagnosis of heart disease, the prevalence of anatomic coronary disease decreased more in younger people than in older people (age 40 years: OR 0.43 [95% CI: 0.24 to 0.80]; age 60 years: OR 0.62 [95% CI: 0.45 to 0.87]; age 80 years: OR 0.89 [95% CI: 0.64 to 1.23]). CONCLUSION: The prevalence of anatomic coronary disease at autopsy decreased between 1979 and 1994, particularly among younger people, supporting the notion that the burden of coronary disease has shifted toward the elderly. These results suggest that the decreased incidence of coronary artery disease has contributed to the recent decrease in coronary mortality, particularly among younger people.

Aberrant T cell responses to myelin antigens during clinical exacerbation in patients with multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of presumed T cell autoimmunity against self myelin. We hypothesized that if myelin-reactive T cells are associated with the disease processes, they may undergo activation and expansion during acute exacerbation. In this study, we examined the precursor frequency, epitope recognition and cytokine profile of myelin-reactive T cells in 14 relapsing/remitting MS patients during exacerbation and remission. The study revealed that T cells recognizing the immunodominant peptides of candidate myelin antigens, including myelin basic protein (MBP), proteolipid protein and myelin oligodendrocyte glycoprotein, occurred at increased precursor frequency during acute exacerbation. The T cell responses to MBP focused on the immunodominant regions (residues 83-99 and 151-170) during exacerbation and shifted toward other epitopes of MBP at the time of remission. Furthermore, there was a marked increase in the production of T(h)1 cytokines among T cell lines obtained during exacerbation compared to those obtained during remission. The study demonstrated that myelin-reactive T cells underwent selective activation and expansion during acute MS exacerbation. In contrast, myelin-reactive T cells found during remission in the same patients generally resembled those identified in healthy controls with some discrepancies. The findings suggest potential association of aberrant myelin-reactive T cell responses with acute exacerbation in MS, which may reflect transient activation of myelin-reactive T cell populations of pathogenic potential.

Th2 immune regulation induced by T cell vaccination in patients with multiple sclerosis.

T cell responses to myelin basic protein (MBP) are potentially involved in the pathogenesis of multiple sclerosis (MS). In this study, we demonstrated that subcutaneous inoculations with irradiated autologous MBP-reactive T cell clones (T cell vaccination) elicited CD8+ anti-idiotypic T cell responses and CD4+ Th2 cell responses in patients with MS. Both regulatory cell types induced by T cell vaccination contributed to the inhibition of MBP-reactive T cells while they differed in the recognition pattern and functional properties. We describe for the first time that the Th2 regulatory cells reacted with activated but not resting T cells in the context of MHC class II molecules and inhibited the proliferation of MBP-reactive T cells through the secretion of IL-4 and IL-10. The T-T cell interaction mediated by Th2 regulatory cells was independent of the antigen specificity of activated T cells. The findings have important implications for our understanding of the regulatory mechanism induced by T cell vaccination.

Interferon beta induces T-helper 2 immune deviation in MS.

OBJECTIVE: To define the in vitro effects of interferon beta la (IFN-beta1a) on myelin basic protein (MBP)-reactive T cells and to determine its regulatory mechanism on cytokine networks in patients with MS. METHODS: The proliferation and cytokine production of MBP-reactive T-cell clones were measured in thymidine uptake assays and ELISA respectively. The precursor frequency of MBP-reactive T cells was estimated in a microwell culture system. RESULTS: IFN-beta inhibited the proliferation of established MBP-reactive T-cell clones, which correlated with enhanced production of anti-inflammatory interleukin (IL)-4 and IL-10, and a decrease in tumor necrosis factor alpha (TNF-alpha) and IFN-gamma. When examined with peripheral blood mononuclear cells (PBMCs), IFN-beta was found to reduce the in vitro T-cell responses to MBP, as indicated by the significantly decreased frequency of MBP-reactive T cells. The decreased frequency of MBP-reactive T cells corresponded to an augmented production of IL-4 and IL-10. Although the level of TNF-alpha and IFN-gamma was generally unaltered or decreased, IFN-beta appeared to enhance the production of IFN-gamma in PBMCs derived from some individuals with MS. CONCLUSION: Interferon beta la (IFN-beta) suppresses myelin basic protein (MBP)-reactive T cells and induces immune deviation toward the production of T-helper 2 cytokines, which may contribute to its therapeutic benefit in MS. The study also suggests some heterogeneity in MBP-reactive T-cell responses to IFN-beta in different individuals with MS.

Impaired apoptotic deletion of myelin basic protein-reactive T cells in patients with multiple sclerosis.

T cell responses to myelin basic protein (MBP) may play an important role in the pathogenesis of multiple sclerosis (MS). If MBP-reactive T cells are involved in the disease processes and undergo clonal activation and expansion, their precursor frequency would be increased in patients with MS. The frequency of MBP-reactive T cells is also influenced by regulatory mechanisms in vivo, including apoptotic deletion. In this study, we examined changes in the frequency of MBP-reactive T cells in patients with MS as a function of the apoptotic deletional mechanism in vivo, using a cell culture-based assay. A significantly increased frequency of MBP-reactive T cells was found in patients with MS relative to healthy individuals only when Fas-ligand antibody was used to block apoptosis. This result indicates that a significant proportion of MBP-reactive T cells are sensitive to apoptosis and are not deleted in vivo in patients with MS, as opposed to healthy individuals, thus suggesting a functional deficit in apoptotic deletional mechanism. Surviving Fas-sensitive MBP-reactive T cell lines represent distinct subpopulations preferentially recognizing the 111-139 region of MBP and exhibiting a Th2 cytokine profile. The findings are relevant to our understanding of regulation of MBP-reactive T cells in vivo in MS.

Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination.

Hereditary demyelinating peripheral neuropathies consist of a heterogeneous group of genetic disorders that includes hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas syndrome (DSS), and congenital hypomyelination (CH). The clinical classification of these neuropathies into discrete categories can sometimes be difficult because there can be both clinical and pathologic variation and overlap between these disorders. We have identified five novel mutations in the myelin protein zero (MPZ) gene, encoding the major structural protein (P0) of peripheral nerve myelin, in patients with either CMT1B, DSS, or CH. This finding suggests that these disorders may not be distinct pathophysiologic entities, but rather represent a spectrum of related "myelinopathies" due to an underlying defect in myelination. Furthermore, we hypothesize the differences in clinical severity seen with mutations in MPZ are related to the type of mutation and its subsequent effect on protein function (i.e., loss of function versus dominant negative).

Longitudinal studies of the duplication form of Charcot-Marie-Tooth polyneuropathy.

This study presents a longitudinal comparison of motor nerve conduction velocities (MCVs) in patients with Charcot-Marie-Tooth type 1A with proven duplication of a segment of chromosome 17p11.2p12. Results were compared for 8 CMT1A duplication patients from one family whose MCV measurements were taken 22 years apart (1967 and 1989). Measurements from a total of seven median motor and five peroneal motor MCVs were compared. Median MCVs showed a slight reduction that averaged 2.2 m/s, and peroneal MCVs showed an average decrease of 3.0 m/s. In addition, mild objective increase in limb weakness was seen in only 1 of 8 patients and subjective symptoms of gradual worsening of leg strength were noted in half the patients over the same period. In this study of a small group of CMT1A patients with proven segmental duplication of chromosome 17p11.2p12, the motor conduction velocities and clinical motor exam did not change significantly over 22 years.

Decremental motor responses to repetitive nerve stimulation in ALS.

Repetitive nerve stimulation (RNS) of the trapezius muscle at slow rates was performed on 192 patients with amyotrophic lateral sclerosis (ALS). Fifty-six patients (29%) showed classical neuromuscular decrement of 10-43% (mean 16.8%) while 44 patients (23%) had a borderline decrement of 5-9%. The trapezius was significantly more sensitive in revealing the defect than the distal hypothenar muscles. In 30 patients followed serially, the decremental response remained constant or increased with time. However, 25% of patients continued to show no decrement in spite of progression of disease. No statistical correlation was found between decrement and clinical severity, disease staging, or disease progression. The finding that at least 50% of ALS patients show some degree of decrement on RNS of the trapezius muscle suggests that functional alterations of the neuromuscular junction accompany this disease.

Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant neuropathy that can be caused by dominant point mutations in PMP22 which encodes a peripheral nerve myelin protein. Usually, CMT1A is caused by the duplication of a 1.5-megabase (Mb) region on chromosome 17p11.2-p12 containing PMP22. Deletion of a similar 1.5-Mb region is associated with hereditary neuropathy with liability to pressure palsies (HNPP), a clinically distinct neuropathy. We have identified a severely affected CMT1 patient who is a compound heterozygote for a recessive PMP22 point mutation, and a 1.5 Mb deletion in 17p11.2-p12. A son heterozygous for the PMP22 point mutation had no signs of neuropathy, while two others heterozygous for the deletion had HNPP, suggesting that point mutations in PMP22 can result in dominant and recessive alleles contributing to CMT1A.

Clinical, cytogenetic, and molecular evidence for an infant with Smith-Magenis syndrome born from a mother having a mosaic 17p11.2p12 deletion.

We describe an infant with del(17) (p11.2p12) whose deleted chromosome was inherited from a mosaic mother. The child had manifestations consistent with Smith-Magenis syndrome. The mother appeared to be of normal intelligence and she had minimal findings of Smith-Magenis syndrome. Separation of chromosome 17 homologues in somatic cell hybrids and molecular studies confirmed the cytogenetic diagnoses and the fact that the mother was mosaic. Furthermore, molecular analysis demonstrated novel breakpoints in this family, with the deletion extending into and completely encompassing the markers duplicated in Charcot-Marie-Tooth (CMT) disease. Although this Smith-Magenis syndrome patient is completely deleted for the CMT region, her electrophysiological findings are different from those found in CMT. This is the only reported case of Smith-Magenis syndrome with transmission from a partially affected mosaic mother. Transmission of interstitial deletions from mosaic parents may be more common than thought; therefore, parental chromosomes should be examined when interstitial deletions are identified.

Diagnosis of acute cerebral infarction: comparison of CT and MR imaging.

The appearance of acute cerebral infarction was evaluated on MR images and CT scans obtained in 31 patients within 24 hr of the ictus; follow-up examinations were performed 7-10 days later in 20 of these patients and were correlated with the initial studies. Acute infarcts were visible more frequently on MR images than on CT scans (82% vs 58%). Proton density- and T2-weighted scans usually demonstrated regions of hyperintensity corresponding to acute infarcts, but proton density-weighted scans often showed better definition of the lesion in terms of regional anatomy. Follow-up MR images and CT scans identified approximately 88% of subacute strokes, 54% of which were better defined and/or larger than on the initial examination. In 20% of lesions, "hemorrhagic" characteristics were seen on at least one examination. CT and MR imaging were comparable in delineating acute hemorrhage, but MR detected more cases with evidence of hemorrhage on follow-up examinations. MR appears to be more sensitive than CT in the imaging of acute stroke.

DNA duplication associated with Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-tooth disease type 1A (CMT1A) was localized by genetic mapping to a 3 cM interval on human chromosome 17p. DNA markers within this interval revealed a duplication that is completely linked and associated with CMT1A. The duplication was demonstrated in affected individuals by the presence of three alleles at a highly polymorphic locus, by dosage differences at RFLP alleles, and by two-color fluorescence in situ hybridization. Pulsed-field gel electrophoresis of genomic DNA from patients of different ethnic origins showed a novel SacII fragment of 500 kb associated with CMT1A. A severely affected CMT1A offspring from a mating between two affected individuals was demonstrated to have this duplication present on each chromosome 17. We have demonstrated that failure to recognize the molecular duplication can lead to misinterpretation of marker genotypes for affected individuals, identification of false recombinants, and incorrect localization of the disease locus.

Motor neuron destruction in guinea pigs immunized with bovine spinal cord ventral horn homogenate: experimental autoimmune gray matter disease.

Guinea pigs immunized with bovine spinal cord ventral horn homogenate develop muscle weakness with electromyographic and morphologic evidence of denervation. Pathological examination demonstrates a loss of motoneurons and scattered inflammatory foci primarily localized to the spinal cord. Immunohistochemical techniques document the presence of immunoglobulin G at the motor end plate and around the external membrane and within the cytoplasm of motoneurons. This syndrome of experimental autoimmune gray matter disease (EAGMD) differs from experimental autoimmune motor neuron disease induced by inoculation with purified motoneurons and also differs from experimental autoimmune encephalomyelitis. The existence of two different forms of immune-mediated motoneuron destruction suggests that a number of cytoplasmic and membrane antigens may give rise to an immunologically based attack on the motor system.

Experimental autoimmune motoneuron disease.

An animal model of disease of the lower motoneurons has been developed by inoculating guinea pigs with bovine motoneurons. Four of 9 immunized female animals and 4 of 5 immunized male animals developed symptoms of neuromuscular degeneration marked by weakness, evidence of denervation by electromyographic and morphological criteria, and a loss of motoneurons within the spinal cord. No inflammatory foci were noted within parenchyma or meninges of the central nervous system. The immunized guinea pigs developed high serum titers of IgG class antibodies to motoneurons. Immunohistochemical studies demonstrated the presence of IgG within spinal cord motoneurons and at the end-plates of immunized animals. This experimental autoimmune motoneuron disease may provide important insights into the cause and pathogenesis of amyotrophic lateral sclerosis, a human motoneuron disease.

Cerebral infarction: diagnosis and assessment of prognosis by using 123IMP-SPECT and CT.

A multicenter prospective study was performed in 49 patients with 77 regions of cerebral infarction. Each patient was evaluated in the acute (0-5 days) and subacute (6-17 days) phases by (1) clinical neurologic examination, (2) CT scans, and (3) N-isopropyl-p-123I-iodoamphetamine (123IMP) single-photon emission CT (SPECT) scans. The abilities of the scans to (1) detect a lesion and (2) predict the clinical outcome were assessed. For lesion detection, 123IMP-SPECT was superior to CT in the first 2 days, but the scans were equally effective 3-5 days after onset. In the subacute phase, IV contrast-enhanced CT was superior to 123IMP-SPECT and unenhanced CT. The clinical outcome was only mildly correlated with the results of the acute and subacute 123IMP-SPECT and the acute CT scans. Reduction in lesion size on the subacute scans did not correlate with clinical improvement. We conclude that the parameters measured by CT and 123IMP-SPECT in patients with acute cerebral infarction cannot reliably be used to predict clinical outcome. 124I contamination of 123IMP and the use of low-energy collimators may have decreased lesion detectability.

Elevated frequencies of 6-thioguanine-resistant lymphocytes in multiple sclerosis patients treated with cyclophosphamide: a prospective study.

An autoradiographic assay for 6-thioguanine-resistant (TGr) lymphocytes was used to determine the frequency of in vivo derived variant T lymphocytes in peripheral blood from multiple sclerosis (MS) patients treated with monthly intravenous infusions of 750 mg/m2 of cyclophosphamide (CP). To analyze the time-course of response to CP, the MS patients were studied prospectively. Samples were obtained from the patients before the beginning of CP therapy, 4-5 times during the course of treatment, and, finally, 2 or 3 months after the completion of therapy. 2 weeks after the first CP infusion, the variant frequencies (Vfs) of the MS patients were significantly increased (p less than 0.05) above their pre-treatment values, but by 4 weeks following the first CP infusion the Vfs had fallen to normal or near-normal levels. After subsequent treatments, the frequencies of variant TGr cells were again higher than pre-treatment Vfs. However, within 7-13 weeks after the cessation of CP therapy, the Vfs of all subjects had returned to normal levels. The transient nature of the response indicates rapid in vivo selection against CP-induced TGr mutant cells. The mean pre-treatment Vf of the 4 MS patients who were cigarette smokers was 6.56 X 10(-6) which was significantly greater (p less than 0.05) than the mean Vf (1.52 X 10(-6) of the 4 MS patients who were non-smokers. The mean Vf from 8 assays of healthy non-smokers was 1.92 X 10(-6).

Controlled pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis.

Monthly intravenous cyclophosphamide treatment was compared with placebo treatment for one year in a controlled trial of 14 patients with relapsing/remitting multiple sclerosis. Eight patients received placebo and six patients received cyclophosphamide. The cyclophosphamide group showed a definite trend to have less frequent and less prolonged episodes than the placebo group. When each group served as their own controls, the cyclophosphamide group had a significant decrease in episodes while the placebo group did not. When the placebo group was then given cyclophosphamide, they also had a significant decrease in episodes. When all patients who were receiving cyclophosphamide were combined for analysis, the decrease in episodes was even more evident. Complications were minimal. These results suggest that monthly intravenous doses of cyclophosphamide may influence the frequency and duration of episodes of relapsing/remitting multiple sclerosis.