Campath-1H, an anti-CD52 monoclonal antibody, was used as induction therapy (40 mg i.v. total dose) in 29 primary human renal transplants, and the patients were maintained on rapamycin monotherapy (levels 8-15 ng/mL) post-transplant. Campath-1H profoundly depletes lymphocytes long-term and more transiently depletes B cells and monocytes. All patients are alive and well at 3-29 months of follow up. One graft was lost because of rejection. There have been no systemic infections and no malignancies. Eight of 29 patients have experienced rejection, which was successfully treated in seven of eight patients. Five of these patients had pathological evidence of a humoral component of their rejection. Seven of the 29 patients were converted to standard triple therapy on account of rejection. Rapamycin was generally well tolerated in that there were no significant wound-healing problems; two lymphoceles required surgical drainage; and most patients were treated with a lipid-lowering agent. Flow crossmatch testing post-transplant revealed evidence of alloantibody in two patients tested with previous combined cellular and humoral rejection. Biopsies have shown no chronic allograft nephropathy to date. In view of the relatively high incidence of early humoral rejection, we plan to modify the immunosuppressive regimen in subsequent pilot studies. This clinical trial provides insight into the use of Campath-1H induction in combination with rapamycin maintenance monotherapy.

Ten weeks of brisk treadmill walking improved 6MWT distance, cardiorespiratory function, and patient-reported quality of life in female patients with group 1 PH.

Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)-18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination.

The relationship between muscle deoxygenation and activation was examined in three different muscles of the quadriceps during cycling ramp exercise. Seven young male adults (24 ± 3 yr; mean ± SD) pedaled at 60 rpm to exhaustion, with a work rate (WR) increase of 20 W/min. Pulmonary oxygen uptake was measured breath-by-breath, while muscle deoxygenation (HHb) and activity were measured by time-resolved near-infrared spectroscopy (NIRS) and surface electromyography (EMG), respectively, at the vastus lateralis (VL), rectus femoris (RF), and vastus medialis (VM). Muscle deoxygenation was corrected for adipose tissue thickness and normalized to the amplitude of the HHb response, while EMG signals were integrated (iEMG) and normalized to the maximum iEMG determined from maximal voluntary contractions. Muscle deoxygenation and activation were then plotted as a percentage of maximal work rate (%WR(max)). The HHb response for all three muscle groups was fitted by a sigmoid function, which was determined as the best fitting model. The c/d parameter for the sigmoid fit (representing the %WR(max) at 50% of the total amplitude of the HHb response) was similar between VL (47 ± 12% WR(max)) and VM (43 ± 11% WR(max)), yet greater (P < 0.05) for RF (65 ± 13% WR(max)), demonstrating a "right shift" of the HHb response compared with VL and VM. The iEMG also showed that muscle activation of the RF muscle was lower (P < 0.05) compared with VL and VM throughout the majority of the ramp exercise, which may explain the different HHb response in RF. Therefore, these data suggest that the sigmoid function can be used to model the HHb response in different muscles of the quadriceps; however, simultaneous measures of muscle activation are also needed for the HHb response to be properly interpreted during cycle ramp exercise.

Summary Objective To investigate the effectiveness of an exercise intervention for decreasing fatigue severity and increasing physical activity in individuals with pulmonary arterial hypertension (PAH). A small, phase 2 randomized clinical trial of the effect of aerobic exercise training on fatigue severity and physical activity in patients with idiopathic or PAH associated with other conditions was conducted. Methods Twenty-four patients with PAH (24 female; age: 54.4 ± 10.4 years; BMI: 30.8 ± 7.2 kg/m2) participated in the study. A convenience sample was recruited in which 9% (28 of 303) of screened patients were enrolled. The project was carried out in a clinical pulmonary rehabilitation clinic during existing pulmonary rehabilitation program sessions. Patients with PH were randomized into a 10-week program that consisted of patient education only or patient education plus an aerobic exercise-training regimen. Both groups received 20 lectures, two per week over the 10-weeks, on topics related to PAH and its management. The aerobic exercise training consisted of 24–30 sessions of treadmill walking for 30–45 min per session at an intensity of 70–80% of heart rate reserve, three days per week over the 10 weeks. Results After 10-weeks of intervention, patients receiving aerobic exercise training plus education reported routinely engaging in higher levels of physical activity (p < 0.05) and a decrease in fatigue severity (p = 0.03). Patients in the education only group did not report changes in fatigue severity or participation in physical activity. Conclusions The 10-week aerobic exercise training intervention resulted in increased physical activity and decreased fatigue in individuals with PAH.

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A major mechanism for generating tolerance in developing T cells is the intrathymic clonal deletion of T cells that have receptors for those self antigens that are presented on hematopoietic cells. The mechanisms of tolerance induction to antigens not expressed in the thymus remain unclear. Tolerance to self antigens can be generated extrathymically through the induction of clonal nonresponsiveness in T cells with self-reactive receptors. A second mechanism of extrathymic tolerance was identified: clonal elimination of mature T cells with self-reactive receptors that had previously displayed functional reactivity.