Interplay of Chiral and Helical States in a Quantum Spin Hall Insulator Lateral Junction.

We study the electronic transport across an electrostatically gated lateral junction in a HgTe quantum well, a canonical 2D topological insulator, with and without an applied magnetic field. We control the carrier density inside and outside a junction region independently and hence tune the number and nature of 1D edge modes propagating in each of those regions. Outside the bulk gap, the magnetic field drives the system to the quantum Hall regime, and chiral states propagate at the edge. In this regime, we observe fractional plateaus that reflect the equilibration between 1D chiral modes across the junction. As the carrier density approaches zero in the central region and at moderate fields, we observe oscillations in the resistance that we attribute to Fabry-Perot interference in the helical states, enabled by the broken time reversal symmetry. At higher fields, those oscillations disappear, in agreement with the expected absence of helical states when band inversion is lifted.

Changes in mitochondrial stability during the progression of the Barrett's esophagus disease sequence.

BACKGROUND: Barrett's esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett's esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett's disease progression is under studied. METHODS: Using an in-vitro model representing the Barrett's esophagus disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles. RESULTS: Barrett's metaplastic cells demonstrated increased levels of ROS (p < 0.005) and increased levels of random mitochondrial mutations (p < 0.05) compared with all other stages of the Barrett's disease sequence in-vitro. Using patient in-vivo samples, Barrett's metaplasia tissue demonstrated significantly increased levels of random mitochondrial deletions (p = 0.043) compared with esophageal adenocarcinoma tissue, along with increased expression of cytoglobin (CYGB) (p < 0.05), a gene linked to oxidative stress, compared with all other points across the disease sequence. Using ex-vivo Barrett's metaplastic and matched normal patient tissue explants, higher levels of cytochrome c (p = 0.003), SMAC/Diablo (p = 0.008) and four inflammatory cytokines (all p values <0.05) were secreted from Barrett's metaplastic tissue compared with matched normal squamous epithelium. CONCLUSIONS: We have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett's disease sequence.

Precise Quantization of the Anomalous Hall Effect near Zero Magnetic Field.

We report a nearly ideal quantum anomalous Hall effect in a three-dimensional topological insulator thin film with ferromagnetic doping. Near zero applied magnetic field we measure exact quantization in the Hall resistance to within a part per 10 000 and a longitudinal resistivity under 1 Ω per square, with chiral edge transport explicitly confirmed by nonlocal measurements. Deviations from this behavior are found to be caused by thermally activated carriers, as indicated by an Arrhenius law temperature dependence. Using the deviations as a thermometer, we demonstrate an unexpected magnetocaloric effect and use it to reach near-perfect quantization by cooling the sample below the dilution refrigerator base temperature in a process approximating adiabatic demagnetization refrigeration.

Perceptions of Autonomous Shuttles for Adults With Spinal Cord Injuries.

Individuals with a spinal cord injury (SCI) have challenges using transportation. Autonomous shuttles (ASs), if accessible, may support their transportation needs. This study quantified the perceptions of AS for adults with and without SCI, before and after riding in the AS. We hypothesized that the perceptions of AS for individuals with SCI would improve, by the greatest magnitude, after riding in the AS. This mixed-method quasi-experimental design included 16 adults with SCI and 16 age-matched controls. While there were no differences between the groups, both groups reported having fewer perceived barriers to using AS after riding in the AS (p = .025). After riding in the AS, both groups stated that the AS must be available, accessible, and affordable if they are to use AS. In conclusion, adults with SCI should experience AS if they are to accept and adopt this mode of transportation.

A single-arm, open-label study of alemtuzumab in treatment-refractory patients with multiple sclerosis.

BACKGROUND: Alemtuzumab (CD52-specific humanized monoclonal antibody) was found to be an effective therapy for treatment-naive patients with relapsing-remitting multiple sclerosis. OBJECTIVE: Evaluate alemtuzumab's effects in patients with treatment-refractory relapsing-remitting multiple sclerosis. METHODS: Forty-five relapsing-remitting multiple sclerosis patients who experienced ≥2 relapses during 2 years prior to the study entry whilst receiving interferon therapy were administered 24 mg i.v. alemtuzumab/day for 5 days at baseline and 3 days 12 months later. Patients received premedication with 1 g i.v. methylprednisolone on days 1-3 at both times. RESULTS: After 2-year follow-up, the annualized relapse rate was reduced by 94% compared to pre-treatment levels, from 1.6 (2 years prior to treatment) to 0.17 for the 2 years following (P<0.0001). Moreover, 86% of patients showed stable or improved scores on the Expanded Disability Status Scale, and only 1 experienced an increase in disability lasting ≥6 months. The majority (70-88%) showed stable or improved leg, arm and cognitive function as measured by the Multiple Sclerosis Functional Composite. Serious adverse events observed in single patients were transient neutropenia and pneumonia, pulmonary emboli and deep vein thrombosis. Five patients developed clinical thyroid disorders but no opportunistic infections or cases of immune thrombocytopenic purpura were observed. CONCLUSIONS: Alemtuzumab effectively reduced relapse rates and improved clinical scores in patients with active relapsing-remitting multiple sclerosis not controlled by interferon therapy.

T suppressor cell growth factor and anti-CD3 antibodies stimulate reciprocal subsets of T lymphocytes.

Because of the central role of IL-2 in clonal expansion of T cells, we have postulated that lymphocyte subpopulations with opposing regulatory functions might be independently regulated by differential requirements for expression of cell-surface IL-2-R. Purified CD4+ and CD8+ cells proliferated in an IL-2-dependent manner to crosslinked anti-T cell receptor antibodies (anti-CD3-Seph). Similarly, both CD4+ and CD8+ cells became IL-2 responsive after incubation in T suppressor cell growth factor (TsGF), a newly described approximately 8,000 Mr product of activated CD4+ cells. In support of our hypothesis, however, we observed that subpopulations of CD4+ and CD8+ cells, possessing distinct cell-surface antigens, showed differential responses to these stimuli. Those cells of suppressor-inducer or suppressor-effector phenotype failed to proliferate when cultured in anti-CD3-Seph plus IL-2, but did proliferate in an IL-2-dependent manner to TsGF. Furthermore, the suppressor-effector population was unresponsive to TsGF plus IL-2 when cocultured in anti-CD3-Seph, suggesting that functionally induced Ts may be refractory to growth stimuli. Conversely, cells with helper-inducer or cytolytic phenotype proliferated when incubated in anti-CD3-Seph and IL-2, while remaining essentially unresponsive to TsGF and IL-2. The results could not be explained by differences in the level of CD3 expression by the T cell subsets. Thus, cells within the helper and suppressor lineages appear to have distinct and reciprocal patterns for the induction of IL-2 responsiveness.

Part-per-million quantization and current-induced breakdown of the quantum anomalous Hall effect.

In the quantum anomalous Hall effect, quantized Hall resistance and vanishing longitudinal resistivity are predicted to result from the presence of dissipationless, chiral edge states and an insulating two-dimensional bulk, without requiring an external magnetic field. Here, we explore the potential of this effect in magnetic topological insulator thin films for metrological applications. Using a cryogenic current comparator system, we measure quantization of the Hall resistance to within one part per million and, at lower current bias, longitudinal resistivity under 10 mΩ at zero magnetic field. Increasing the current density past a critical value leads to a breakdown of the quantized, low-dissipation state, which we attribute to electron heating in bulk current flow. We further investigate the prebreakdown regime by measuring transport dependence on temperature, current, and geometry, and find evidence for bulk dissipation, including thermal activation and possible variable-range hopping.

Proliferative signals for suppressor T cells. Helper cells stimulated with pokeweed mitogen in vitro produce a suppressor cell growth factor.

To define molecular signals elaborated by inducer populations supporting growth or differentiation of T8+ cells, we collected supernatants of pokeweed mitogen (PWM)-stimulated cultures depleted of T8+ cells. When added to purified T8+ cells, these supernatants caused significant proliferation. PWM plus interleukin 2 (IL-2) in amounts equivalent to those in the supernatant could not reconstitute the response caused by the supernatant. T8+ cells activated by supernatants obtained from PWM-pulsed T4+ cells suppressed fresh PWM cultures. Although exhibiting little proliferation, T8+ cells cultured for 6 d in PWM plus IL-2 still suppressed a fresh PWM response. The supernatants therefore contain an additional T suppressor cell growth factor (TsGF). Elaboration of TsGF required radiosensitive T4+Leu8+ cells. Molecular weight determination by high performance liquid chromatography gave a single peak of TsGF activity at approximately 8,000. Finally, whereas TsGF in the absence of IL-2 could not support the proliferation of T suppressor cells, it did cause T8+ cells to become strongly IL-2 receptor-positive.

Quantitative analysis of buprenorphine and norbuprenorphine in urine using liquid chromatography tandem mass spectrometry.

Buprenorphine is an opioid analgesic drug that is used as an alternative to methadone to treat heroin addiction. Established methods for the analysis of buprenorphine and its metabolites in urine such as gas chromatography-mass spectrometry (GC-MS) involve complicated sample extraction procedures. The aim of the present study was to develop a sensitive yet straightforward method for the simultaneous analysis of buprenorphine and norbuprenorphine in urine using liquid chromatography-MS-MS. The method comprised an enzymatic hydrolysis using Patella vulgata b-glucuronidase, followed by centrifugation and direct analysis of the supernatant. The limits of detection and quantitation were < 1 microg/L for buprenorphine and < 1 and 4 microg/L, respectively, for norbuprenorphine. Assay coefficients of variation (CVs) were < 15%, with the exception of concentrations close to the limit of quantitation, where CVs were below 20%. In direct comparison with an established GC-MS protocol, the method showed minimal negative bias (8.7% for buprenorphine and 1.8% for norbuprenorphine) and was less susceptible to sample carryover. The extent of conjugation in unhydrolyzed urine was investigated and found to be highly variable, with proportions of unconjugated buprenorphine and norbuprenorphine of 6.4% [range 0% to 67%; standard deviation (SD) 9.7%] and 34% (range 0% to 100%; SD 23.8%), respectively.

Transcutaneous electrical stimulation and acupuncture: comparison of treatment for low-back pain.

Twelve patients suffering chronic low-back pain were treated with both acupuncture and transcutaneous electrical stimulation. The order of treatments was balanced, and changes in the intensity and quality of pain were measured with the McGill Pain Questionnaire. The results, based on a measure of overall pain intensity, show that pain relief greater than 33% was produced in 75% of the patients by acupuncture and in 66% by electrical stimulation. The mean duration of pain relief was 40 h after acupuncture and 23 h after electrical stimulation. Although the mean scores are larger for acupuncture than for transcutaneous stimulation, statistical analyses of the data failed to reveal significant differences between the two treatments on any of the measures. Both methods, therefore, appear to be equally effective, and probably have the same underlying mechanism of action. Consideration of the advantages and disadvantages of the two methods suggests that that transcutaneous electrical stimulation is potentially the more practical, since it can be administered under supervision by paramedical personnel.

Human suppressor T cells: induction, differentiation, and regulatory functions.

T-cell-mediated suppression of human immune responses involves a complex interaction between distinct lymphocyte subsets with suppressor-inducer and suppressor-effector functions. Recent studies with subset-specific monoclonal antibodies have defined a characteristic phenotype of suppressor-inducer cells (CD4+ Leu8+ 2H4+ 4B4-) that can be distinguished from that of helper cells for antibody synthesis (CD4+ Leu8- 2H4- 4B4+). Similarly, suppressor-effector cells (CD8+CD11+Tp44-) can typically be defined as a subset separable from cytotoxic T cells (CD8+CD11-Tp44+). Both antigen-specific and nonspecific interactions are important in suppressor T-cell activation and function. Soluble signals required for differentiation of CD8+ suppressor cells include an indomethacin-sensitive monocyte product and interferon gamma. In contrast, proliferation of the CD8+ suppressor cell subset depends on stimulation first by a product of CD4+Leu8+ cells, T suppressor cell growth factor, and second by interleukin 2. Although the molecular basis of antigen-specific interactions between CD4+ and CD8+ cells in suppressor cell generation has not been defined, it may involve both conventional, presumably MHC-restricted, interactions between antigen and antigen receptors, as well as anti-idiotypic interactions of suppressor-effectors with determinants on suppressor-inducer receptors. Progress in elucidating requirements for activation, growth, and differentiation of suppressor cells should facilitate long-term culture of such cells and lead to clearer understanding of mechanisms of suppressor-cell mediated immunoregulation.

Extraosseous primary and recurrent giant cell tumors: transforming growth factor-beta1 and -beta2 expression may explain metaplastic bone formation.

Giant cell tumor (GCT) of bone is a locally aggressive neoplasm with a high incidence of recurrence, usually at the site of previous osseous involvement. Primary and recurrent intraosseous lesions typically are lytic and do not show evidence of tumor-associated osteogenesis. Rarely, GCT recurs or is primary within soft tissue, and not infrequently, these extraosseous lesions show metaplastic bone formation that is visible radiographically. The authors report two recurrent and one primary case of extraosseous GCT, all of which exhibited significant deposits of metaplastic bone localized to the periphery of the lesions. In situ hybridization showed messenger RNA (mRNA) for transforming growth factor beta1 (TGF-beta1) and transforming growth factor beta2 (TGF-beta2) in neoplastic stromal cells and osteoclast-like giant cells within the recurrent and primary extraosseous tumors as well as in active osteoblasts on the surfaces of recently formed spicules of metaplastic bone. In situ hybridization also revealed mRNA for TGF-beta1 and TGF-beta2 in primary intraosseous tumors from these cases and from four cases in which neither extraosseous recurrence nor osseous metaplasia was identified. In the microenvironment of the extraosseous soft tissue, production of these osteoinductive growth factors by GCT may have a paracrine effect on mesenchymal progenitor cells, thereby stimulating the osteoblastic differentiation and metaplastic bone formation associated with these lesions.

The relationship between the human sperm hypoosmotic swelling test, routine semen analysis, and the human sperm zona-free hamster ovum penetration assay.

The functional integrity of sperm membranes of 270 semen samples collected from fertile men and the male partners in couples with infertile marriages was assessed by the hypoosmotic swelling test and the results correlated with routine semen analysis and the human sperm zona-free hamster ovum penetration assay. Semen samples with abnormal semen parameters had lower values of percentage of swollen sperm after hypoosmotic treatment in comparison with those with normal semen parameters. A weak positive correlation was observed between sperm swelling and sperm morphologic features (r = 0.32, P less than 0.05) and between sperm swelling and sperm motility (r = 0.22, P less than 0.05). Insignificant correlation was observed between sperm swelling and in vitro sperm fertilizing capacity, as assessed by the zona-free hamster ovum penetration assay. The results indicate that the sperm swelling test and the zona-free hamster ovum penetration assay are evaluating different functional qualities of sperm that are apparently not associated with each other.

Failure of withdrawal bleeding during combined oral contraceptive therapy: "amenorrhoea on the pill".

Serum follicle stimulating hormone, luteinising hormone and oestradiol-17beta concentrations have been measured in 21 patients with failure of withdrawal bleeding during combined oral contraceptive therapy and 21 matched controls with a normal bleeding pattern. Gonadotrophin and oestradiol-17beta concentrations were effectively suppressed in all patients during the phase of contraceptive ingestion. During the week between courses of treatment, there was a significant rise in the gonadotrophin (p less than 0.02) and oestradiol (p less than 0.05) concentrations in the patients but not in the controls. It is suggested that patients with failure of withdrawal bleeding during combined oral contraceptive therapy may have higher total oestrogen levels during the treatment-free week because of a less persistent suppression of hypothalamic-pituitary-ovarian function.

The Tullio phenomenon and perilymph fistula.

Establishing the diagnosis of perilymph fistula remains a dilemma. At this time, identification of an active perilymph fistula can be confirmed only by surgery. On the basis of clinical history and audiovestibular testing, 54 patients underwent middle ear exploration for possible perilymph fistula at the Colorado Ear Clinic between July 1980 and June 1986. This group represents approximately 1% of all surgical procedures performed during that period. Seven patients (12%) were found to have the Tullio phenomenon preoperatively. Six of these were found to have active, free-flowing fistulas at the time of exploration. The presence of a Tullio phenomenon may be helpful in preoperative assessment of a patient with suspected perilymph fistula.

Tolerability and safety of novel half milliliter formulation of glatiramer acetate for subcutaneous injection: an open-label, multicenter, randomized comparative study.

Daily glatiramer acetate (GA) 20 mg/1.0 mL is a first-line treatment for relapsing-remitting multiple sclerosis (RRMS). To reduce the occurrence of injection pain and local injection site reactions (LISRs), a reduced volume formulation of GA was developed. This study compared pain and LISRs after injecting the marketed and the novel formulations. RRMS patients currently injecting GA participated in this multicenter, randomized, crossover comparative study. All patients administered once-daily subcutaneous injections of GA 20 mg/1.0 mL (marketed formulation) or GA 20 mg/0.5 mL (reduced volume formulation) for 14 days. Patients were crossed-over to the alternate treatment for an additional 14 days. Using a Visual Analog Scale (VAS), patients recorded in daily diaries the severity of injection pain immediately and 5 min post-injection, and the presence and severity of LISRs (swelling, redness, itching, lump) within 5 min and 24 h post-injection. VAS pain scores were ranked significantly lower immediately and 5 min after GA 20 mg/0.5 mL injections (p < 0.0001). Although LISRs were rare for both preparations, the severity of reactions ranked significantly lower and fewer symptoms occurred within 5 min and 24 h of using the reduced volume formulation (p < 0.0001). GA injected subcutaneously in a reduced volume formulation is a more tolerable option.

S-phase-specific expression of the Mad3 gene in proliferating and differentiating cells.

The Myc/Max/Mad transcription factor network plays a central role in the control of cellular proliferation, differentiation and apoptosis. In order to elucidate the biological function of Mad3, we have analysed the precise temporal patterns of Mad3 mRNA expression during the cell cycle and differentiation in cultured cells. We show that Mad3 is induced at the G1/S transition in proliferating cells; expression persists throughout S-phase, and then declines as cells pass through G2 and mitosis. The expression pattern of Mad3 is coincident with that of Cdc2 throughout the cell cycle. In contrast, the expression of Mad3 during differentiation of cultured mouse erythroleukemia cells shows two transient peaks of induction. The first of these occurs at the onset of differentiation, and does not correlate with the S-phase of the cell cycle, whereas the second is coincident with the S-phase burst that precedes the terminal stages of differentiation. Our results therefore suggest that Mad3 serves a cell-cycle-related function in both proliferating and differentiating cells, and that it may also have a distinct role at various stages of differentiation.