Deformation of the moving magnetic skyrmion lattice in MnSi under electric current flow.

Topological defects are found ubiquitously in various kinds of matter, such as vortices in type-II superconductors, and magnetic skyrmions in chiral ferromagnets. While knowledge on the static behavior of magnetic skyrmions is accumulating steadily, their dynamics under forced flow is still a widely open issue. Here, we report the deformation of the moving magnetic skyrmion lattice in MnSi under electric current flow observed using small-angle neutron scattering. A spatially inhomogeneous rotation of the skyrmion lattice, with an inverse rotation sense for opposite sample edges, is observed for current densities greater than a threshold value j t ~ 1 MA m-2 (106 A m-2). Our result show that skyrmion lattices under current flow experience significant friction near the sample edges due to pinning, this being a critical effect that must be considered for anticipated skyrmion-based applications at the nanoscale.

Malignant transformation of early lymphoid progenitors in mice expressing an activated Blk tyrosine kinase.

The intracellular signals governing cellular proliferation and developmental progression during lymphocyte development are incompletely understood. The tyrosine kinase Blk is expressed preferentially in the B lineage, but its function in B cell development has been largely unexplored. We have generated transgenic mice expressing constitutively active Blk [Blk(Y495F)] in the B and T lymphoid compartments. Expression of Blk(Y495F) in the B lineage at levels similar to that of endogenous Blk induced B lymphoid tumors of limited clonality, whose phenotypes are characteristic of B cell progenitors at the proB/preB-I to preB-II transition. Expression of constitutively active Blk in the T lineage resulted in the appearance of clonal, thymic lymphomas composed of intermediate single positive cells. Taken together, these results indicate that specific B and T cell progenitor subsets are preferentially susceptible to transformation by Blk(Y495F) and suggest a role for Blk in the control of proliferation during B cell development.

Low molecular weight antigen arrays delete high affinity memory B cells without affecting specific T-cell help.

An ongoing, T-cell dependent, secondary antibody response to an epitope can be suppressed in vivo by low molecular weight, soluble polymers, bearing multiple copies of the same epitope. This study illustrates that such suppressive T-cell independent antigen arrays target the epitope-specific, high affinity, memory B cells for long-term functional elimination. Splenocytes from hyperimmune unsuppressed donors, when adoptively transferred into irradiated recipients will readily reconstitute a secondary anti-hapten response after antigenic challenge. No such response was observed with splenocytes transferred from hyperimmune donors suppressed with antigen arrays. The extent of suppression depended on antigen array dose and duration of exposure in the donor animals. The suppressive antigen array carryover from the donors into the recipients was negligible and insufficient to account for the observed suppression. B cells from hyperimmune mice producing high affinity anti-fluorescein antibodies, generated by multiple fluoresceinated ovalbumin (FL-OVA) injections, were helped efficiently by T cells from hyperimmune donors, which were either unsuppressed or suppressed with antigen arrays. Accordingly, help from T cells, specific for the carrier protein remains intact after such suppression. Neither lipopolysaccharide (LPS), nor additional transferred carrier-primed T cells could reverse the unresponsiveness of adoptively transferred splenocytes from suppressed animals. Flow cytometry showed that the number of hapten-specific B cells was markedly reduced after suppression. Collectively, these data show that the long term elimination of an ongoing T-cell dependent antibody response by suppressive exogenous antigen arrays is due to the functional deletion of high affinity, antigen-specific B cells, even in the presence of adequate T-cell help. The long-term nature of such functional deletion strongly suggests physical deletion of the antigen-specific B cell population.

Suppression of the antibody response to a polymorphic peptide from the platelet alloantigen integrin beta3 with low molecular weight antigen arrays.

The allelic human platelet alloantigens PIA1/PIA2 are determined by a 33 Leu-Pro substitution in the second disulfide loop of the integrin beta3 subunit of the fibrinogen receptor, alphaIIb beta3 (GPIIb-IIIa). Alloantibodies to PIA1 cause neonatal alloimmune thrombocytopenia. We studied the suppression of specific Ab production to a disulfide-looped peptide spanning the polymorphic region of integrin beta3, 24AWCSDEALPLGSPRCD39 (LPL). Mice immunized with LPL coupled to OVA (LPL-OVA) produced Abs specific for LPL. When immunized animals were injected with low m.w. dextran heavily derivitized with LPL (Dex(low)LPL(high)), levels of Ab to LPL fell immediately and remained low 1 mo later. Both high affinity and total Abs were affected. Arrays with lower peptide density or a high m.w. backbone did not induce well sustained suppression. Abs to OVA were unaffected by the arrays. Naive mice given Dex(low)LPL(high) were tolerant to subsequent immunization with LPL-OVA. In transfer experiments, irradiated recipients of spleen cells or purified 8 cells from animals suppressed with Dex(low)LPL(high) did not respond to LPL-OVA. Spleen cells from suppressed animals did not suppress the response to LPL-OVA in recipients of immune B cells. These results demonstrate that peptide arrays, by a mechanism sensitive to molecular configuration, induce tolerance to peptide immunization and suppress an ongoing, high affinity Ab response. Peptide arrays induce the elimination or irreversible anergy of specific memory B cells and do not require a non-B spleen cell population to maintain suppression.

Bone mass and subtle abnormalities in ovulatory function in healthy women.

Women with occasional anovulatory or short luteal phase menstrual cycles have been reported to lose bone mineral density (BMD) at a greatly accelerated rate compared to women without such abnormalities. To investigate this association, we performed a longitudinal study of BMD in a group of healthy premenopausal women enrolled in a comprehensive study of ovulatory function. Subjects had collected daily urine samples that were analyzed for estrone and progesterone metabolites by enzyme-linked immunoassay. The 53 participants collected urine for an average of 4.1 cycles. Computer algorithms identified 7 (13.2%) women with luteal phase abnormalities (> 1 anovulatory cycle or cycle with luteal phase length < or = 10 days) and 17 (32.1%) women with other menstrual abnormalities. Areal BMD (grams per cm2) was measured at the lumbar spine, hip, and whole body using dual energy x-ray absorptiometry; BMD was measured 2-3 times over an average observation period of 17.5 months. At baseline, women with luteal abnormalities had mean BMD similar to those of the 29 women with no abnormal cycles: lumbar spine, 1.06 vs. 1.09 g/cm2; total hip, 0.95 vs. 0.94 g/cm2; whole body, 1.15 vs. 1.11 g/cm2 (P > 0.10; adjusted for age and weight at baseline, parity, physical activity level, and calcium intake). When compared at follow-up to women with no abnormal cycles, women with luteal abnormalities tended to gain BMD at the spine and hip (P > 0.10). On whole body measurement, women with luteal abnormalities tended to lose BMD compared to women with no abnormal cycles (-1.1%/yr vs. 0%/yr; P = 0.08); however, the magnitude of loss was not unusual for women in this age range and was within the coefficient of variation for replicate measurements. Neither mean luteal phase length, percent time in luteal phase, nor average daily excretion of progesterone metabolites was associated with baseline BMD or percent annual change in BMD at any measurement site. Thus, we did not confirm a relationship between luteal abnormalities and accelerated bone loss in this population of healthy premenopausal women.

Durable elimination of high affinity, T cell-dependent antibodies by low molecular weight antigen arrays in vivo.

Ongoing Ab responses to a T cell-dependent Ag can be suppressed in hyperimmune animals by exogenous, multivalent Ag arrays. The pharmacologic basis for this suppression was studied by varying the molecular mass, ligand valence, and dose of Ag arrays, and then determining their efficacy, pharmacokinetics, and tissue distribution. Arrays ranging in molecular mass from 30 to 500 kDa caused initial clearance of specific serum Abs, but only the smaller arrays caused persistent suppression despite their relatively lower binding avidity and shorter retention in vivo. Suppression by the smaller arrays at lower doses was biphasic, implying two distinct modes of Ab elimination. High affinity IgG was eliminated preferentially, as shown by calibrated variable ligand-density ELISA. Suppressive arrays were localized discretely in the splenic germinal centers of hyperimmune animals. These results indicate that Ag array mass, ligand valence, and dose all play critical roles, and histologic compartmentalization may also be a pertinent parameter, in determining suppressive efficacy in vivo.

Effect of sustained resistance training on basal metabolic rate in older women.

OBJECTIVE: To determine if basal metabolic rate (BMR) could be elevated in older women undertaking a program of progressive resistance exercise of up to 52-weeks duration. DESIGN: Randomized controlled trial with subjects assigned to either a control (CO), high-intensity (HI), or low-intensity (LO) training group for 15 weeks. BMR, body composition, energy intake and expenditure, and muscle strength were assessed at baseline and after 15 weeks. Subjects were encouraged to continue in their assigned exercise group for an additional 37 weeks, after which time they were reevaluated. SETTING: An exercise facility at a medical center. SUBJECTS: Thirty-six community-dwelling healthy women aged 65 to 79 years. INTERVENTION: Exercise groups performed three sets of 10 exercises, 3 days/week, at either 80% of one-repetition maximum (1-RM) for seven repetitions (HI) or 40% of 1-RM for 14 repetitions (LO). MEASURES: BMR by indirect calorimetry, body composition by dual energy X-ray absorptiometry, energy intake and expenditure from 4-day dietary and activity records, and dynamic muscle strength by 1-RM. RESULTS: Muscle strength increased, on average (+/- SEM), by 40 +/- 6% and 36 +/- 7% in the HI and LO groups after 15 weeks, respectively, compared with 4 +/- 1% in the nonexercising subjects (P = .0001). Fat mass decreased after 15 weeks in LO exercisers by 1.0 kg (P < .05), whereas there was a trend for fat-free mass (FFM) to increase in the HI group by 0.7 kg (P = .08). No change occurred in any group for BMR. From weeks 15 to 52, muscle strength increased a further 9 +/- 2% and 11 +/- 2% in HI and LO groups, respectively, compared with 3 +/- 1% in nonexercisers (P < .005). There was no change in BMR or any body composition parameter during this time period. CONCLUSIONS: Neither training program significantly altered BMR and both produced only minimal changes in body composition. However, both the HI and LO exercise regimens resulted in similar and substantial gains in upper and lower body muscle strength that persisted over the course of the year. This suggests that either exercise regimen may prove an effective strategy for preventing frailty and maintaining functional independence in older adults.

Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men.

Normal aging is characterized by detrimental changes in body composition, muscle strength, and somatotropic function. Reduction in muscle strength contributes to frailty and risk for fracture in the elderly. Although older adults increase muscle strength as a result of resistance exercise training, the strength gains quickly level off, with only modest increases thereafter despite continued training. To investigate whether age-related deficits in the somatotropic axis limit the degree to which muscle strength can improve with resistance training in older individuals, we conducted a double blind, placebo-controlled exercise trial. Eighteen healthy elderly men (65-82 yr) initially underwent progressive weight training for 14 weeks to invoke a trained state. Subjects were then randomized to receive either 0.02 mg/kg BW.day recombinant human GH (rhGH) or placebo, given sc, while undertaking a further 10 weeks of strength training. Sequential measurements were made of muscle strength (one repetition maximum), body composition (dual energy x-ray absorptiometry), and circulating levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3. For each exercise, strength increased for both groups (P = 0.0001) through 14 weeks of training, with little improvement thereafter. Increases in muscle strength ranged from 24-62% depending on the muscle group. Baseline plasma IGF-I concentrations were similar in both groups (mean +/- SEM, 106 +/- 9 micrograms/L), approximately half that observed in healthy young adults. In the rhGH group, IGF-I levels increased to 255 +/- 32 micrograms/L at week 15 and 218 +/- 21 micrograms/L at week 24 (P < 0.001). In the placebo group, IGF-I increased slightly to 119 +/- 6 micrograms/L at 24 weeks. IGF-binding protein-3 also increased in the rhGH group (P < 0.05). rhGH had no effect on muscle strength at any time, and no systematic difference in muscle strength was observed between groups throughout the study. Body weight did not change in either group, but lean body mass increased, and fat mass decreased (P < 0.05) in the rhGH group. Supplementation with rhGH does not augment the response to strength training in elderly men. These results suggest that deficits in GH secretion do not underlie the time-dependent leveling off of muscle strength seen with training in the elderly and provide no support for the popular view of GH as an ergogenic aid.

Specific immunotherapeutic strategy for myasthenia gravis: targeted antigen-presenting cells.

The pathogenesis of myasthenia gravis (MG) involves a T cell-dependent antibody-mediated autoimmune response directed against acetylcholine receptors (AChR). Inactivation of AChR-specific T cells should interrupt the immune response, resulting in therapeutic benefit. Since each individual's repertoire of T cells responds to a heterogeneous and unique spectrum of AChR epitopes presented in association with self-major histocompatibility complex (MHC) class II, an individualized approach is required to target all relevant AChR-specific T cells. The individual's own antigen-presenting cells (APC) can be used for this purpose, since they process and present the antigen appropriately, and express the correct MHC class II. A novel method of binding AChR to surface immunoglobulin with a heterobifunctional antibody conjugate allows us to use all B cells as APC. Conjugate-plus-AChR-treated B cells (AChR-APC) effectively targeted AChR-specific T cells, stimulating vigorous proliferative responses in a rat cell culture system. If APCs are 'fixed' with cross-linking reagents, they induce long-lasting or permanent 'anergy' of the specific T cells. We prepared AChR-APC, allowed them to process AChR in vitro, and fixed them with paraformaldehyde. Pre-culture of these fixed AChR-APC with AChR-specific T cells induced anergy: when restimulated with fresh AChR-APC, the T cells exhibited markedly reduced proliferative responses and IL-2 production, compared with responses of T cells pre-cultured with control fixed B cells. Implications for the design of antigen-specific therapeutic strategies for MG and other immune disorders will be discussed.

Inter- and intra-examiner reliability of nerve conduction measurements in normal subjects.

Nerve conduction studies are widely employed in evaluating patients with peripheral nerve disease and are often used serially to measure disease progression or to assess a therapeutic intervention. We determined the inter- and intra-examiner reliability of electrophysiological data by performing serial nerve conduction studies on 7 normal subjects. A high degree of intra-examiner reliability was present, but significant inter-examiner differences were found. Our results suggest that if nerve conduction studies are to be used longitudinally, they should optimally be performed by a single examiner to minimize the degree of variability associated with different examiners.

Conduction block in diabetic neuropathy.

Symmetric sensorimotor polyneuropathy is a common complication of diabetes. Sensory and motor evoked amplitudes and conduction velocities are reduced. Both demyelination and axon loss have been reported in pathologic studies. Conduction block (CB), a manifestation of segmental demyelination, has not been previously studied in diabetic neuropathy. We determined the prevalence of conduction block in patients with diabetes by analyzing electrodiagnostic data from 24 diabetics. Conduction block was defined as a greater than 20% drop in peak-to-peak amplitude, and a less than 15% change in negative-peak duration between proximal and distal stimulation sites. A total of 76 nerve segments were studied. The criteria for conduction block were met in only 6 segments in 6 patients. The mean decrease in peak-to-peak amplitude between stimulation sites was 28% (range 21% to 40%). We conclude that conduction block over long nerve segments is uncommon in diabetic neuropathy, and, if present, suggests that other causes for neuropathy in diabetic patients should be sought.

Mixed transcortical aphasia without anatomic isolation of the speech area.

We report two patients with mixed transcortical aphasia following left frontal lobe infarctions. Although there was no evidence of anatomic isolation of the speech area on computed tomograms or magnetic resonance imaging scans, single-photon emission computed tomography in one case demonstrated diminished blood flow over the left parietal convexity suggestive of "functional isolation" of the posterior perisylvian language zone.