Citations

Abstract Interleukin (IL)-10 is elevated in cancer and is thought to contribute to immune tolerance and tumor growth. Defying these expectations, the adoptive transfer of IL-10–expressing T cells to mice with polyposis attenuates microbial-induced inflammation and suppresses polyposis. To gain better insights into how IL-10 impacts polyposis, we genetically ablated IL-10 in T cells in APCΔ468 mice and compared the effects of treatment with broad-spectrum antibiotics. We found that T cells and regulatory T cells (Treg) were a major cellular source of IL-10 in both the healthy and polyp-bearing colon. Notably, T cell–specific ablation of IL-10 produced pathologies that were identical to mice with a systemic deficiency in IL-10, in both cases increasing the numbers and growth of colon polyps. Eosinophils were found to densely infiltrate colon polyps, which were enriched similarly for microbiota associated previously with colon cancer. In mice receiving broad-spectrum antibiotics, we observed reductions in microbiota, inflammation, and polyposis. Together, our findings establish that colon polyposis is driven by high densities of microbes that accumulate within polyps and trigger local inflammatory responses. Inflammation, local microbe densities, and polyp growth are suppressed by IL-10 derived specifically from T cells and Tregs. Cancer Res; 73(19); 5905–13. ©2013 AACR.

We previously reported that activation of muscarinic acetylcholine receptors (mAChR) of M3 subtype causes hydrolysis of phosphoinositides and inhibits voltage-gated Ca2+ channel activity in small cell lung carcinoma (SCLC) cells. We now report that mAChR activation causes exponentially growing SCLC cells to arrest in S and G2/M phases of the cell cycle, concomitant with a decrease in DNA synthesis. Cell cycle progression and DNA synthesis resume when mAChR are down-regulated. In serum-starved SCLC cells, mAChR activation inhibits DNA synthesis induced by serum, bombesin, insulin, or insulin-like growth factor-I. The finding that DNA synthesis is inhibited even when mAChR are activated after exposure of cells to growth factors indicates that decreased signal transduction by growth factor receptors is not the mechanism of mAChR-mediated growth inhibition. Our data suggest that mAChR activation disrupts a common event that is induced by different growth factors and is fundamental for cell cycle progression.

IntroductionMuscle sympathetic nerve activity (MSNA) is an independent prognostic marker in patients with heart failure (HF). Therefore, its relevance to the treatment of HF patients is unquestionable.ObjectivesIn this study, we investigated the effects of cardiac resynchronization therapy (CRT) on MSNA response at rest and during exercise in patients with advanced HF.MethodsWe assessed 11 HF patients (51 ± 3.4 years; New York Heart Association class III–IV; left ventricular ejection fraction 27.8 ± 2.2%; optimal medical therapy) submitted to CRT. Evaluations were made prior to and 3 months after CRT. MSNA was performed at rest and during moderate static exercise (handgrip). Peak oxygen consumption (VO2) was evaluated by means of cardiopulmonary exercise test. HF patients with advanced NYHA class without CRT and healthy individuals were also studied.ResultsCRT reduced MSNA at rest (48.9 ± 11.1 bursts/min vs 33.7 ± 15.3 bursts/min, P < 0.05) and during handgrip exercise (MSNA 62.3 ± 13.1 bursts/min vs 46.9 ± 14.3 bursts/min, P < 0.05). Among HF patients submitted to CRT, the peak VO2 increased (12.9 ± 2.8 mL/kg/min vs 16.5 ± 3.9 mL/kg/min, P < 0.05) and an inverse correlation between peak VO2 and resting MSNA (r = –0.74, P = 0.01) was observed.ConclusionsIn patients with advanced HF and severe systolic dysfunction: (1) a significant reduction of MSNA (at rest and during handgrip) occurred after CRT, and this behavior was significantly superior to HF patients receiving only medical therapy; (2) MSNA reduction after CRT had an inverse correlation with O2 consumption outcomes.

Treatment of AKR-2B mouse fibroblasts with serum growth factors or inhibitors of protein synthesis, such as cycloheximide, results in a stimulation of cytoskeletal beta-actin transcription but has no effect on transcription of muscle-specific isotypes, such as the vascular smooth muscle (VSM) alpha-actin gene. Deletion mapping and site-specific mutagenesis studies demonstrated that a single "CArG" element of the general form CC(A/T)6GG was necessary and possibly sufficient to impart serum and cycloheximide-inducibility to the beta-actin promoter. Although the VSM alpha-actin promoter exhibits at least three similar sequence elements, it remained refractory to serum and cycloheximide induction. However, deletion of a 33 base pair sequence between -191 and -224 relative to the transcription start site resulted in the transcriptional activation of this muscle-specific promoter in rapidly growing or serum-stimulated fibroblasts. Although the activity of this truncated promoter was potentiated by cycloheximide in a manner indistinguishable from that of the beta-actin promoter, this was dependent on a more complex array of interacting elements. These included at least one CArG box and a putative upstream activating element closely associated with the -191 to -224 inhibitory sequences. These results demonstrate that the expression of a muscle-specific actin gene in fibroblasts is suppressed by a cis-acting negative control element and that in the absence of this element, the promoter is responsive to growth factor-induced signal transduction pathways.

Objective: To present the unique case of a collegiate wrestler with C7 neurologic symptoms due to T1–T2 disc herniation. Background: A 23-year-old male collegiate wrestler injured his neck in a wrestling tournament match and experienced pain, weakness, and numbness in his left upper extremity. He completed that match and 1 additional match that day with mild symptoms. Evaluation by a certified athletic trainer 6 days postinjury showed radiculopathy in the C7 distribution of his left upper extremity. He was evaluated further by the team physician, a primary care physician, and a neurosurgeon. Differential Diagnosis: Cervical spine injury, stinger/burner, peripheral nerve injury, spinal cord injury, thoracic outlet syndrome, brachial plexus radiculopathy. Treatment: The patient initially underwent nonoperative management with ice, heat, massage, electrical stimulation, shortwave diathermy, and nonsteroidal anti-inflammatory drugs without symptom resolution. Cervical spine radiographs were negative for bony pathologic conditions. Magnetic resonance imaging showed evidence of T1–T2 disc herniation. The patient underwent surgery to resolve the symptoms and enable him to participate for the remainder of the wrestling season. Uniqueness: Whereas brachial plexus radiculopathy commonly is seen in collision sports, a postfixed brachial plexus in which the T2 nerve root has substantial contribution to the innervation of the upper extremity is a rare anatomic variation with which many health care providers are unfamiliar. Conclusions: The injury sustained by the wrestler appeared to be C7 radiculopathy due to a brachial plexus traction injury. However, it ultimately was diagnosed as radiculopathy due to a T1–T2 thoracic intervertebral disc herniation causing impingement of a postfixed brachial plexus and required surgical intervention. Athletic trainers and physicians need to be aware of the anatomic variations of the brachial plexus when evaluating and caring for patients with suspected brachial plexus radiculopathies.

AbstractMicrosporidia are opportunistic pathogens that usually cause a limited disease in the gastrointestinal tract. Occasionally, they can cause disseminated disease. In solid organ transplant recipients, disseminated disease has been reported only rarely. We describe a 68‐year‐old woman who presented with fever, cough, and acute kidney injury 6 months after kidney transplantation. Dissemination was confirmed by identification of microsporidial spores in urine and bronchoalveolar lavage fluid. Polymerase chain reaction analysis identified the species as Encephalitozoon cuniculi.

ABSTRACTVan der Woude syndrome is the most common form of syndromic orofacial clefting, accounting for 1–2% of all patients with cleft lip and/or cleft palate. Van der Woude and popliteal pterygium syndromes are caused by mutations in IRF6, but phenotypic variability within and among families with either syndrome suggests that other genetic factors contribute to the phenotypes. The aim of this study was to identify common variants acting as genetic modifiers of IRF6 as well as genotype–phenotype correlations based on mutation type and location. We identified an association between mutations in the DNA‐binding domain of IRF6 and limb defects (including pterygia). Although we did not detect formally significant associations with the genes tested, borderline associations suggest several genes that could modify the VWS phenotype, including FOXE1, TGFB3, and TFAP2A. Some of these genes are hypothesized to be part of the IRF6 gene regulatory network and may suggest additional genes for future study when larger sample sizes are also available. We also show that families with the Van de Woude phenotype but in whom no mutations have been identified have a lower frequency of cleft lip, suggesting there may be locus and/or mutation class differences in Van de Woude syndrome. © 2013 Wiley Periodicals, Inc.