CD1-dependent natural killer (NK1.1(+)) T cells are required for oral and portal venous tolerance induction

BACKGROUND: Local antigen presentation via either the oral (PO) or the portal venous (PV) routes results in suppression of systemic delayed-type hypersensitivity (DTH). The responsible cell populations are not well defined. Because NK1.1(+) T cells express the Fas ligand and produce high levels of the immunosuppressive cytokine, IL-4, they may play a role in both activated T-cell apoptosis and a Th1 to Th2 immune shift, thus promoting tolerance induction. METHODS: C57BL/6 mice were tolerized to BALB/c alloantigen by PV or PO spleen cells (25 x 10(6)) on Day 0. Subcutaneous (SQ) challenge with 10 x 10(6) BALB/c cells on Day 7 was followed by footpad injection of 10 x 10(6) BALB/c cells on Day 14. Footpad swelling was measured 24 h later. A single injection of the NK1.1(+) cell-depleting antibody, PK-136, was given IP (10 mg/kg) 2 days prior to PV or PO antigen. Flow cytometry evaluated NK1.1(+) cell depletion. CD1 knockout (KO) mice, lacking NK1.1(+) T cells, were also challenged with PV and PO Balb/c in parallel experiments. RESULTS: The DTH to BALB/c antigen was markedly suppressed in C57BL/6 mice when this alloantigen was given by either PO or PV routes (P < 0.001, P < 0.001). The maintenance of an unaltered response to third-party C3H/HeJ demonstrated alloantigenic specificity. Administration of the anti-NK1.1 T cell monoclonal antibody, PK-136, resulted in complete restoration of in vivo DTH responsiveness in PO tolerance (P < 0.01), and partial restoration in PV tolerance (P < 0.05) in C57BL/6 mice. FACS confirmed virtually complete depletion of liver, splenic, Peyer's patch, and mesenteric lymph node NK1.1(+) lymphocytes. Development of both PO and PV tolerance was prevented in CD1 KO mice. CONCLUSION: NK1.1(+) T cells play an essential role in antigen-specific suppression of the DTH response mediated by both oral and portal venous tolerance.     

Latissimus dorsi pedicled flap for upper extremity soft-tissue reconstruction

The latissimus dorsi often is used as a functional muscle transfer to restore elbow and shoulder motion. Although less common, its use as a pedicled muscle flap with a split-thickness skin graft provides excellent soft-tissue coverage of large upper extremity wounds. Seven male patients ranging in age from 6-71 years were treated with a pedicled latissimus dorsi muscle flap and split-thickness skin graft for coverage of open wounds of the shoulder, arm, or elbow with exposed vital structures (mean wound size: 15x10 cm). The flap also was used as a functional muscle transfer in one patient to replace destroyed anterior and middle portions of the deltoid. Wounds resulted from trauma in three patients, infection following trauma in two, and sarcoma excision in two. All flaps healed well, and donor site morbidity was minimal. At mean 16-month follow-up (range: 3-41 months), all muscle flaps had contoured well, producing satisfactory cosmesis. Functional results were good, and all patients were satisfied with their outcome. The tendinous insertion is left intact to guard against excessive traction on the pedicle when the flap is used for soft-tissue coverage only.     

A multicenter study of the pharmacokinetics of lisinopril in pediatric patients with hypertension

The pharmacokinetic (PK) parameters of lisinopril were obtained in 46 children aged 6 months to 15 years. A lisinopril suspension (0.15 mg/kg per day) was administered to patients <6 years of age; the remaining children received lisinopril tablets, the daily dose being adjusted according to body weight, i.e., 2.5 mg if <25 kg, 5 mg if 25–45 kg, and 10 mg if >45 kg. Blood was drawn predose and on eight occasions postdose in children aged 4–15 years, and on five occasions in those aged <4 years. PK data are reported for the 46 children in terms of age groups: Group I (n = 9), aged 6–23 months; Group II (n = 8), aged 2–5 years; Group III (n = 12), aged 6–11 years; Group IV (n = 17), aged 12–15 years. The dose of lisinopril ranged from 3.07 mg/m² per day in Group I to 4.78 mg/m² per day in Group IV. C_max of lisinopril, which occurred 5–6 h postdose, varied from 22 ng/ml in Groups I and II to 44 ng/ml in Groups III and IV; AUC_{0–24 h} ranged from 301–311 ng·h/ml in Groups I and II to 550–570 ng·h/ml in Groups III and IV. No serious adverse events related to lisinopril were reported.     

A neuropsychiatric review of pediatric obsessive-compulsive disorder: etiology and efficacious treatments

Pediatric obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric condition associated with broad impairments in functioning. This paper outlines current etiological theories of OCD, providing a review of neuroanatomical, neurochemical, neuroimmunological, and cognitive–behavioral explanations. Subsequently, first-line treatment modalities are discussed (serotonin reuptake inhibitors [SRIs] and cognitive–behavioral therapy [CBT] with exposure and response prevention [E/RP]) in the context of recent pharmacological, CBT, and combined trials.     

Loss of primary cilia upregulates renal hypertrophic signaling and promotes cystogenesis

Primary cilia dysfunction alters renal tubular cell proliferation and differentiation and associates with accelerated cyst formation in polycystic kidney disease. However, the mechanism leading from primary ciliary dysfunction to renal cyst formation is unknown. We hypothesize that primary cilia prevent renal cyst formation by suppressing pathologic tubular cell hypertrophy and proliferation. Unilateral nephrectomy initiates tubular cell hypertrophy and proliferation in the contralateral kidney and provides a tool to examine primary cilia regulation of renal hypertrophy. Conditional knockout of the primary cilia ift88 gene leads to delayed, adult-onset renal cystic disease, which provides a window of opportunity to conduct unilateral nephrectomy and examine downstream kinetics of renal hypertrophy and cyst formation. In wild-type animals, unilateral nephrectomy activated the mTOR pathway and produced appropriate structural and functional hypertrophy without renal cyst formation. However, in ift88 conditional knockout animals, unilateral nephrectomy triggered increased renal hypertrophy and accelerated renal cyst formation, leading to renal dysfunction. mTOR signaling also increased compared with wild-type animals, suggesting a mechanistic cascade starting with primary ciliary dysfunction, leading to excessive mTOR signaling and renal hypertrophic signaling and culminating in cyst formation. These data suggest that events initiating hypertrophic signaling, such as structural or functional loss of renal mass, may accelerate progression of adult polycystic kidney disease toward end-stage renal disease.     

Mid-term survivorship results for a rotating-platform knee prosthesis

Interest in mobile-bearing knee prostheses is increasing in the US market. We studied results at 2 to 5 years with a mobile-bearing system that includes a cobalt-chrome tibial tray and femoral component with a polyethylene cruciate-retaining tibial component insert that allows rotation around a central axis and can be used with cruciate-retaining or posterior-stabilized femoral components. The inserts used in this study were cruciate retaining and did not include the posterior-stabilized design. The goal of this study was to demonstrate the function and safety of this prosthesis along with the lack of spinout, which is a major concern in the mobile-bearing knee. Four hundred thirty-five knees constituted the study cohort and underwent survivorship analysis and complication reporting. Routine clinic evaluations included pre- and postoperative radiographs and Knee Society knee and function scores at 6 and 12 weeks and every 2 years. The most recent follow-up data within 2 to 5 years was included for the study along with survey data. Flexion at most recent follow-up averaged 125°. Knee Society score at most recent visit averaged 88 of 100. Knee Society function score averaged 83 of 100. Radiographic results were available for 226 knees, with 97.3% assessed as normal and 6 with these issues: patella stress fracture (3), aseptic tibial loosening (1), patellar osteolysis (1), and patella aseptic loosening (1). In comparison with the fixed-bearing knee equivalent, this mobile-bearing knee demonstrated at least equivalent results in terms of survivorship, function, and patient satisfaction in the short- and mid-term.     

Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial

Background

Neurogenic detrusor overactivity (NDO) frequently results in urinary incontinence (UI) which impairs quality of life (QOL) and puts the upper urinary tract at risk.

Objective

To assess the effects of onabotulinumtoxinA (BOTOX^®, Allergan, Inc.) on UI, urodynamic variables, and QOL in incontinent patients with NDO.

Design, setting, and participants

This multicentre, randomised, double-blind, placebo-controlled study enrolled patients with multiple sclerosis (MS; n = 154) or spinal cord injury (SCI; n = 121) with UI due to NDO (≥14 UI episodes per week).

Intervention

Patients received 30 intradetrusor injections of onabotulinumtoxinA 200 U (n = 92), 300 U (n = 91), or placebo (n = 92), avoiding the trigone.

Measurements

Primary end point was change from baseline in UI episodes per week (week 6). Secondary end points included urodynamics (maximum cystometric capacity [MCC], maximum detrusor pressure during first involuntary detrusor contraction [P_detmaxIDC]), and Incontinence Quality of Life (I-QOL) total score. Adverse events (AEs) were assessed.

Results and limitations

At baseline, mean UI episodes per week (33.5) were similar across groups. At week 6, onabotulinumtoxinA 200 U and 300 U significantly reduced UI episodes per week (−21.8 and −19.4, respectively) compared with placebo (−13.2; p < 0.01); onabotulinumtoxinA benefit was observed by the first posttreatment study visit at week 2. Improvements in MCC, P_detmaxIDC, and I-QOL at week 6 were significantly greater with both onabotulinumtoxinA doses than with placebo (p < 0.001). Benefits were observed in both the MS and SCI populations. The median time to patient request for retreatment was the same for both onabotulinumtoxinA doses (42.1 wk) and greater than placebo (13.1 wk; p < 0.001). Most frequent AEs were localised urologic events (urinary tract infections and urinary retention, which were dose related in patients not using clean intermittent catheterisation [CIC] at baseline). Significant increases in postvoid residual were observed in patients not using CIC prior to treatment, and 12%, 30%, and 42% of patients in the placebo, 200-U, and 300-U groups, respectively, initiated CIC posttreatment.

Conclusions

OnabotulinumtoxinA significantly reduced UI and improved urodynamics and QOL in MS and SCI patients with NDO. Both doses were well tolerated with no clinically relevant differences in efficacy or duration of effect between the two doses (http://www.clinicaltrials.gov; NCT00461292).     

Features Associated with Successful Recruitment of Diverse Patients onto Cancer Clinical Trials: Report from the American College of Surgeons Oncology Group

Background

The clinical trials mechanism of standardized treatment and follow-up for cancer patients with similar stages and patterns of disease is the most powerful approach available for evaluating the efficacy of novel therapies, and clinical trial participation should protect against delivery of care variations associated with racial/ethnic identity and/or socioeconomic status. Unfortunately, disparities in clinical trial accrual persist, with African Americans (AA) and Hispanic/Latino Americans (HA) underrepresented in most studies.

Study Design

We evaluated the accrual patterns for 10 clinical trials conducted by the American College of Surgeons Oncology Group (ACOSOG) 1999–2009, and analyzed results by race/ethnicity as well as by study design.

Results

Eight of 10 protocols were successful in recruiting AA and/or HA participants; three of four randomized trials were successful. Features that were present among all of the successfully recruiting protocols were: (1) studies designed to recruit patients with regional or advanced-stage disease (2 of 2 protocols); and (2) studies that involved some investigational systemic therapy (3 of 3 protocols).

Discussion

AA and HA cancer patients can be successfully accrued onto randomized clinical trials, but study design affects recruitment patterns. Increased socioeconomic disadvantages observed within minority-ethnicity communities results in barriers to screening and more advanced cancer stage distribution. Improving cancer early detection is critical in the effort to eliminate outcome disparities but existing differences in disease burden results in diminished eligibility for early-stage cancer clinical trials among minority-ethnicity patients.     

Elevated levels of HER-2/neu and androgen receptor in clinically localized prostate cancer identifies metastatic potential

BACKGROUND: In this study, we investigated the expression of HER-2/neu and AR in clinically organ-confined prostate cancer to determine whether alterations in these signaling pathways contribute to the development of metastatic disease. METHODS: HER-2/neu and AR immunoreactivity were evaluated in archived prostatic tissues obtained from 53 men with clinically organ-confined disease who underwent radical prostatectomy. Associations between AR and HER-2/neu immunostaining and disease outcome were determined. RESULTS: Seventy percent (37/53) of tumors exhibited high levels of HER-2/neu immunostaining and 68% (36/53) of tumors had elevated AR levels. Patients with high levels of both HER-2/neu and AR had the highest rate of PSA failure (56%, 15/27) compared with no PSA failures amongst seven patients with low levels of both HER-2/neu and AR (log rank statistic 7.69, P = 0.021). Concurrent high levels of HER-2/neu and AR expression were significantly associated with high pathological stage (P = 0.027) and development of metastatic disease (P = 0.022). CONCLUSIONS: These findings support the notion that both the HER-2/neu and AR signaling pathways may contribute to development of metastatic disease. The subset of prostate tumors with increased HER-2/neu and AR levels may benefit from treatment strategies that target both signaling pathways.     

An evaluation of semen characteristics in men 45 years of age or older after daily dosing with tadalafil 20mg: results of a multicenter, randomized, double-blind, placebo-controlled, 9-month study

OBJECTIVES: Assess the effects on spermatogenesis of daily tadalafil 20mg over three spermatogenesis cycles in men >or= 45 yr. METHODS: In this double-blind, placebo-controlled, noninferiority study, healthy men (or with mild erectile dysfunction) were randomized to receive tadalafil 20mg (n=125) or placebo (n=128) for 9 mo followed by a 6-mo, treatment-free period. Semen and serum samples were provided at baseline and every 10-12 wk. The primary outcome was the proportion of subjects with >or= 50% reduction in sperm concentration at end point. Secondary outcomes included sperm concentration, number per ejaculate, motility and morphology; serum concentrations of testosterone, luteinizing and follicle-stimulating hormones; and tolerability. RESULTS: Of 253 men enrolled, 191 (75%) completed treatment phase: 2 of 96 (2.1%, placebo) and 12 of 95 (12.6%, tadalafil) subjects had >or= 50% reduction in sperm concentration. Tadalafil was noninferior to placebo because the upper 95% confidence interval for the difference in proportions of tadalafil and placebo subjects with a >or= 50% reduction in sperm concentration was 17.5%, significantly less than the prespecified noninferiority margin of 20% (p=0.015). Ninety-four percent (179 of 191) of men completed the 6-mo, treatment-free period: Baseline sperm concentration levels were restored in 8 of 12 (tadalafil) and 1 of 2 (placebo) men. There were no significant differences between groups in secondary end points. Common treatment-emergent adverse events were headache, back pain, dyspepsia, gastroesophageal reflux disease, and myalgia. Twelve (9.6%) tadalafil and seven (5.5%) placebo subjects discontinued because of adverse events. CONCLUSIONS: This study demonstrated no deleterious effects of 9 mo of daily tadalafil 20mg on spermatogenesis or hormones related to testicular function in men >or= 45 yr.