The BTLA and PD-1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells.

BACKGROUND: B- and T-lymphocyte attenuator (BTLA) and programmed cell death-1 (PD-1) inhibit γδ T cell homeostasis and activation. This study aimed to determine whether BTLA and PD-1 signaling pathways were convergent or independent in human peripheral blood γδ T cells. Herein we demonstrate that the signalings of BTLA and PD-1 regulated proliferation and cytotoxicity of human γδ T cells, respectively. METHODS: Human peripheral blood γδ T cells were cultured with inactivated Jurkat cells in the presence of interleukin-2 and zoledronate (Zol) for 14 days. Flow cytometry was performed to evaluate the phenotypes and functions of γδ T cells. RESULTS: The proliferation of the γδ T cells was increased when PBMCs were cocultured with inactivated herpes virus entry mediator (HVEM)low Jurkat cells. The cytotoxicity of the expanded γδ T cells was not affected by coculture with inactivated HVEMlow Jurkat cells and was further increased in the presence of anti-PD-L1 mAb. These results suggest that the inactivation of the BTLA signaling pathway during expansion could help produce more γδ T cells without compromising γδ T cell function. The inhibition of BTLA or PD-1 signaling repressed phosphorylation of the src homology region 2-containing protein tyrosine phosphatase 2 and increased the phosphorylation of protein kinase B in γδ T cells. However, there were no synergistic or additive effects by a combination of BTLA and PD-1 blockade. CONCLUSION: These results suggest that BTLA signaling is crucial in regulating γδ T cell proliferation and function and that the BTLA and PD-1 signaling pathways act independently on the proliferation and cytotoxicity of human peripheral γδ T cells.

Does education modify motor compensation in Parkinson's disease?

BACKGROUND: In Alzheimer's disease, higher educational attainment is associated with fewer cognitive deficits despite similar pathological lesions. In animal models of Parkinson's disease (PD), enhanced levels of cognitive and physical stimulation can reduce motor deficits due to dopaminergic neuronal loss. Therefore, in this study, we tested whether higher educational attainment has a beneficial influence on PD motor symptoms. METHODS: We included data from 182 patients with de novo PD without dementia, who underwent dopamine transporter (DAT) scans for an initial diagnostic work-up. Patients were divided into 2 groups according to their educational attainment; high education (HE-PD; ≥12years of education) and low education (LE-PD; <12years of education). RESULTS: The HE-PD group exhibited significantly higher mini-mental state exam scores, fewer motor deficits, and lower DAT binding to the posterior putamen than the LE-PD group, despite a similar duration of PD symptoms. A general linear model revealed that this difference in motor deficits remained statistically significant after controlling for potential confounding factors (p=0.032). CONCLUSION: These results suggest that higher educational attainment can lead to reduced motor deficits in PD despite greater reductions in dopamine levels.

Is normosmic Parkinson disease a unique clinical phenotype?

OBJECTIVE: Olfactory dysfunction is present in the majority of patients with early-stage Parkinson disease (PD) and can precede the onset of motor symptoms by many years. We performed this study to evaluate whether normosmic patients with PD had different clinical features compared to hyposmic patients. METHODS: We analyzed the data of 208 de novo patients with PD (mean age, 65.4 ± 9.7 years; range, 38-85 years; 104 men) who underwent both olfactory function tests and dopamine transporter (DAT) scans. RESULTS: Normosmic patients were significantly younger and had fewer motor deficits than hyposmic patients with PD. Striatal subregional DAT activities were comparable between the 2 groups, but intersubregional gradients were significantly higher in normosmic than hyposmic PD. A general linear model showed that normosmic patients with PD showed significantly fewer motor deficits after controlling the patient's age, sex, symptom duration, and DAT activity in the posterior putamen (p = 0.016). Levodopa-equivalent dose at approximately 2.5 years follow-up tended to be lower in normosmic than in hyposmic PD (p = 0.055). CONCLUSIONS: These results suggest that normosmic PD is a unique clinical phenotype with a more benign course, compared to hyposmic PD. Either less pathologic involvement in the olfactory system or a greater potential for olfactory neurogenesis in normosmic PD may contribute to this benign process compared to hyposmic PD.

Is Dominant-Side Onset Associated With a Better Motor Compensation in Parkinson's Disease?

INTRODUCTION: Unilateral onset and persistent asymmetry of motor signs are unique features of PD. The dominant hemisphere may have more efficient motor networks with greater neural reserve to cope with pathological changes. Therefore, this study compared dominant-side onset and non-dominant-side onset PD to evaluate whether dominant-side onset patients have greater neural reserve and fewer motor deficits despite similar pathological changes. METHODS: We included the data of 157 consecutive, de novo PD patients with documented right-handedness who underwent dopamine transporter PET scans for an initial diagnostic workup. Among them, 118 patients with significant asymmetric motor deficits were selected for the analyses. RESULTS: Dominant-side patients (i.e., the majority of motor deficits on the right side) showed significantly fewer motor deficits (i.e., the part III score of the UPDRS) than non-dominant-side patients (18.0 ± 8.1 and 22.9 ± 10.1, respectively; P = 0.005). Other variables, including symptom duration and striatal dopaminergic activities, were similar between the two groups. A general linear model showed that this difference in motor deficits remained statistically significant after controlling for patient age, sex, symptom duration, and striatal dopaminergic activity in the posterior putamen (P = 0.013). CONCLUSION: These results suggest that dominant-side patients have greater neural reserve, allowing them to better cope with PD-related pathological changes (i.e., fewer motor deficits despite similar dopamine reduction) compared to non-dominant-side patients.

Diaphragm breathing movement measurement using ultrasound and radiographic imaging: a concurrent validity.

Recent ultrasound imaging evidence asserts that the diaphragm is an important multifunctional muscle to control breathing as well as stabilize the core and posture in humans. However, the validity and accuracy of ultrasound for the measurement of dynamic diaphragm movements during breathing and functional core activities have not been determined. The specific aim of this study was to validate the accuracy of ultrasound imaging measurements of diaphragm movements by concurrently comparing these measurements to the gold standard of radiographic imaging measurements. A total of 14 asymptomatic adults (9 males, 5 females; mean age =28.4 ± 3.0 years) were recruited to participate in the study. Ultrasound and radiographic images were used concurrently to determine diaphragm movement (inspiration, expiration, and excursion) during tidal breathing. Pearson correlation analysis showed strong correlations, ranging from r=0.78 to r=0.83, between ultrasound and radiographic imaging measurements of the diaphragm during inhalation, exhalation, and excursion. These findings suggest that ultrasound imaging measurement is useful to accurately evaluate diaphragm movements during tidal breathing. Clinically, ultrasound imaging measurements can be used to diagnose and treat diaphragm movement impairments in individuals with neuromuscular disorders including spinal cord injuries, stroke, and multiple sclerosis.

Clinical implication of subgrouping in valgus femoral neck fractures: comparison of 31-B1.1 with 31-B1.2 fractures using the OTA/AO classification.

OBJECTIVES: This study aimed to identify the clinical implications of valgus-impacted femoral neck fractures and compare fractures with >15-degree angle of impaction (31-B1.1) against fractures with <15-degree angle of impaction (31-B1.2). DESIGN: Retrospective study. PATIENTS/PARTICIPANTS: We enrolled 78 patients with 31-B1 femoral neck fractures who were treated by screw osteosynthesis. MAIN OUTCOME MEASUREMENTS: We evaluated the clinical and radiographic outcomes. RESULTS: Thirty-six patients sustained 31-B1.1 fractures, and 42 patients sustained 31-B1.2 fractures. The average follow-up period was 15 months, and bony union occurred in all cases. The mean femur neck shortening was 8.88 mm for B1.1 and 3.70 mm for B1.2 fractures (P < 0.001). The mean sliding distance of the screw was 3.36 mm for B1.1 fractures and 1.38 mm for B1.2 fractures (P < 0.001). The mean Harris hip score was 82.0 for B1.1 and 88.8 for B1.2 fractures (P = 0.029). Avascular necrosis (AVN) of the femoral head occurred in 4 patients with B1.1 fractures, and none with B1.2 fractures (P = 0.041). Eighteen of the 78 patients required a second operation, and 15 of them were included in 31-B1.1 fracture (P = 0.003). Three patients underwent arthroplasty due to AVN, and 15 patients required hardware removal due to pain after bony union. CONCLUSIONS: More femoral neck shortening and less functional recovery should be expected in valgus-impacted femoral neck fracture patients based on the severity of the initial deformity. Even though we obtained bony union in all of the cases, the risk of AVN and second operation after bony union was higher with greater initial deformity. LEVEL OF EVIDENCE: Therapeutic level III.

A phase II study of irinotecan plus cisplatin for patients with advanced stage IIIB or IV NSCLC previously treated with nonplatinum-based chemotherapy.

BACKGROUND: Irinotecan (1) and cisplatin (P) are active chemotherapy agents with clinical synergy in non-small-cell lung cancer (NSCLC). We evaluated the efficacy of IP regimen as a salvage treatment of patients with NSCLC that progressed after nonplatinum-containing regimen(s). METHODS: Eligibility required histologically confirmed NSCLC, bidimensionally measurable disease, ECOG PS 0-2, and progressive disease after nonplatinum-based chemotherapy. Treatment consisted of I (65 mg/m2) and P (30 mg/m2) i.v. on Days 1 and 8 of a 21-day cycle, for a maximum of 6 cycles. An informed consent was obtained from all patients. RESULTS: Between August 2002 and May 2004, 32 patients with median age of 56 years (range, 42-74) were enrolled. Twenty-four (75%) patients were men, and 28 (88%) had ECOG PS 0 or 1. Twenty-five patients had adenocarcinoma and 6 had squamous-cell carcinoma. All patients were evaluated for response and toxicity, and the response rate was 40.6%. After a median follow-up of 18.5 months, the median survival time was found to be 9.3 months, with a 1-year survival rate of 43.8%. Toxicities were moderate and manageable, with 47% G3 and 9% G4 neutropenia, 19% G3 diarrhea, and 22% G3 asthenia. There was no G4 nonhematologic toxicity. CONCLUSIONS: The irinotecan and cisplatin combination is an active and well-tolerated regimen for the patients with advanced NSCLC that progressed after nonplatinum-containing regimen(s).