Aberrant spatiotemporal activation profiles associated with math difficulties in children: a magnetic source imaging study

The study investigates the relative degree and timing of cortical activation in parietal, temporal, and frontal regions during simple arithmetic tasks in children who experience math difficulties. Real-time brain activity was measured with magnetoencephalography during simple addition and numerosity judgments in students with math difficulties and average or above average reading skills (MD group, N = 14), students with below average scores on both math and basic reading tests (MD/RD group, N = 16) and students with above average scores on standardized math tests (control group, N = 25). Children with MD showed increased degree of neurophysiological activity in inferior and superior parietal regions in the right hemisphere compared to both controls and MD/RD students. Left hemisphere inferior parietal regions did not show the expected task-related changes and showed activity at a significant temporal delay. MD students also showed increased early engagement of prefrontal cortices. Taken together, these findings may indicate increased reliance on a network of right hemisphere parietal (and possibly frontal areas as well) for simple math calculations in students who experience math difficulties but perform within normal range in reading.     

Role of endothelin-1 in tamoxifen resistance: Mechanism for a new possible treatment strategy in breast cancer

Breast cancer is the prevalent cancer worldwide. Excessive exposure to endogenous estrogen across a woman's lifespan contributes to and may be a causal factor in breast cancer. Tamoxifen is a mixed estrogen agonist and antagonist, which is used in treatment and prevention of breast cancer as an estrogen antagonist. Many patients experience resistance to tamoxifen for which many mechanisms have been suggested. Endothelin-1 acts as a mitogen for human breast fibroblasts and it affects tumor cell proliferation, invasion, angiogenesis, neovascularization, mitogenesis, and apoptosis inhibition. Previous studies have shown that estradiol is effective in inhibiting endothelin synthesis in breast tissue and cardiovascular system. Tamoxifen as an estrogen receptor (ER) agonist in cardiovascular system has a cardioprotective effect and decreases endothelin level as a vasoconstrictor in cardiovascular system. But in breast tissue tamoxifen acts as an ER antagonist. According to the role of endothelin in breast cancer and inhibitory effect of estrogen on endothelin, we hypothesized that tamoxifen causes increasing in endothelin level or endothelin receptors probably by inhibitory effect on ER in breast tissue, leading to tamoxifen resistance. Therefore a combination of tamoxifen with endothelin antagonist seems to be a reasonable therapeutic strategy.     

Estrogen receptor–β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor–β (ERβ) in BPH and PCa. ERβ agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFα knock-out mice fail to respond to ERβ agonist, demonstrating the requirement for TNFα signaling. In human tissues, ERβ agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133⁺ enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERβ causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERβ agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERβ agonist for treatment of PCa and/or BPH with or without androgen withdrawal.     

Androgen receptor gene and sex-specific Alzheimer's disease

Women are at a 2-fold risk of developing late-onset Alzheimer's disease (AD) (onset at 65 years of age or older) compared with men. During perimenopausal years, women undergo hormonal changes that are accompanied by metabolic, cardiovascular, and inflammatory changes. These all together have been suggested as risk factors for late-onset AD. However, not all perimenopausal women develop AD; we hypothesize that certain genetic factors might underlie the increased susceptibility for developing AD in postmenopausal women. We investigated the Androgen Receptor gene (AR) in a clinical cohort of male and female AD patients and normal control subjects by sequencing all coding exons and evaluating the length and distribution of the CAG repeat in exon 1. We could not establish a correlation between the repeat length, sex, and the disease status, nor did we identify possible pathogenic variants. AR is located on the X chromosome; to assess its role in AD, X-inactivation patterns will need to be studied to directly correlate the actual expressed repeat length to a possible sex-specific phenotypic effect.     

Cooled (4°C) lidocaine during office cystoscopy improves patient satisfaction and comfort: A prospective,randomized, double-blind,controlled study

IntroductionOffice-based flexible cystoscopy is often associated with considerable discomfort in male patients. We devised this study to prospectively evaluate the efficacy of cooling intraurethral lidocaine jelly to 4°C prior to use in office-based cystoscopy in an effort to reduce male patient discomfort.MethodsA total of 600 male patients scheduled for office diagnostic cystoscopy were enrolled and randomized into three groups for a prospectively controlled, double-blind study. Each group received one of the three methods of intraurethral lubrication: plain room temperature lubricant (control) (CON), room temperature lidocaine (LI), or lidocaine at 4°C (LI4°C). Perceived pain was recorded on a Likert visual analog scale (VAS) of 1–10 where 0=no pain and 10=excruciating pain. Kruskal-Wallis test assessed the efficacy of cooling lidocaine compared to room temperature lidocaine and control. Subjective pain reporting was corroborated with instantaneous objective pulse rate recording eliminating perception bias.ResultsThere was no significant difference in cystoscopy duration between all groups. Mean pain scores (mean ± standard deviation) were 4.05±0.91, 2.74±1.01, and 1.8±0.84, respectively, for groups CON, LI, and LI4°C (p=0.02). There was a 32.34% reduction in the mean pain score of LI and a further reduction of 34.3% was achieved in LI4°C when compared to CON. Body mass index (BMI) and prostate weight had a significant positive correlation with pain score, whereas no such correlation was found with age.ConclusionsCooling lidocaine to 4°C provides additional analgesic benefit in men undergoing office cystoscopy and increases compliance.     

Impact of maintenance immunosuppressive regimens – balance between graft protective suppression of immune functions and a near physiological immune response

The Symphony study showed superior 1‐year kidney graft outcome in patients on immunosuppression with tacrolimus/mycophenolate mofetil (Tacr/MMF). To analyze whether differences in clinical outcome between maintenance regimens may be explained by their impact on clinically relevant immune parameters, we assessed CD4 helper activity, immunoglobulin‐secreting cell (ISC) formation, neopterin, sCD30, and intracellular cytokine production in a prospective study in 77 renal transplant recipients treated with cyclosporine A/azathioprine (CsA/Aza), CsA/MMF, Tacr/Aza or Tacr/MMF at 2 years post‐transplant. Tacr‐ compared with CsA‐based immunosuppression was independently associated with increased IL‐2 (P < 0.0001, CD4 cells; P = 0.014, CD8 cells) and CD4 cell IL‐4 responses (P = 0.046; stepwise logistic regression) resulting in physiological responses in Tacr/Aza patients as compared with 25 healthy controls. MMF versus Aza treatment was proven to be an independent variable associated with suppression of CD4 cell IL‐10 responses (P = 0.008), B‐cell IL‐6R expression (P < 0.0001) and ISC formation [P = 0.020, staphylococcus cowan strain I (SAC I); P = 0.021, pokeweed mitogen (PWM)]. Our data suggest that Tacr/MMF had the most effective impact on graft protective Th2 responses (enhanced CD4 cell IL‐4 by Tacr, decreased CD4 cell IL‐10 responses by MMF) and suppression of B‐cell functions (MMF), whereas Tacr/Aza was associated with physiological IL‐2 and IL‐4 and stronger humoral responses which may reduce the risk of infectious disease complications. (ClinicalTrials.gov number: NCT00150891).     

Does autoantigen administration inhibit recurrence of type 1 diabetes in transplanted islets?

Type 1 diabetes is a chronic disease with a subclinical prodromal period resulting from autoimmune destruction of pancreatic beta-cells. At the time of clinical symptoms of diabetes, the majority of islets have irreversibly been destroyed. Thus, the only cure for type 1 diabetes is pancreas (or islet) transplantation. To reach this goal, both allograft rejection and recurrent autoimmunity must be overcome. These have partly been achieved at the cost of lifelong immunosuppression, however, the risk to benefit ratio for immunosuppressive drugs to insulin usage remains obscure. To eliminate the need for immunosuppression, several tolerance induction protocols have been developed which particularly target alloimmune responses, whereas no tolerance induction protocol that particularly prevents the recurrence of autoimmunity has been suggested. It is hypothesized that autoantigen-based interventions may inhibit the recurrence of type 1 diabetes in transplanted pancreas (or islets) through the induction of specific tolerance to beta-cell autoantigens.