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Rhodopsin is a G protein-coupled receptor essential for vision and rod photoreceptor viability. Disease-associated rhodopsin mutations, such as P23H rhodopsin, cause rhodopsin protein misfolding and trigger endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR). The pathophysiologic effects of ER stress and UPR activation on photoreceptors are unclear. Here, by examining P23H rhodopsin knock-in mice, we found that the UPR inositol-requiring enzyme 1 (IRE1) signaling pathway is strongly activated in misfolded rhodopsin-expressing photoreceptors. IRE1 significantly upregulated ER-associated protein degradation (ERAD), triggering pronounced P23H rhodopsin degradation. Rhodopsin protein loss occurred as soon as photoreceptors developed, preceding photoreceptor cell death. By contrast, IRE1 activation did not affect JNK signaling or rhodopsin mRNA levels. Interestingly, pro-apoptotic signaling from the PERK UPR pathway was also not induced. Our findings reveal that an early and significant pathophysiologic effect of ER stress in photoreceptors is the highly efficient elimination of misfolded rhodopsin protein. We propose that early disruption of rhodopsin protein homeostasis in photoreceptors could contribute to retinal degeneration.

Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), an essential adaptive intracellular pathway that relieves the stress. Although the UPR is an evolutionarily conserved and beneficial pathway, its chronic activation contributes to the pathogenesis of a wide variety of human disorders. The fidelity of UPR activation must thus be tightly regulated to prevent inappropriate signaling. The nonsense-mediated RNA decay (NMD) pathway has long been known to function in RNA quality control, rapidly degrading aberrant mRNAs, and has been suggested to regulate subsets of normal mRNAs. Here, we report that the NMD pathway regulates the UPR. NMD increases the threshold for triggering the UPR in vitro and in vivo, thereby preventing UPR activation in response to normally innocuous levels of ER stress. NMD also promotes the timely termination of the UPR. We demonstrate that NMD directly targets the mRNAs encoding several UPR components, including the highly conserved UPR sensor, IRE1α, whose NMD-dependent degradation partly underpins this process. Our work not only sheds light on UPR regulation, but demonstrates the physiological relevance of NMD's ability to regulate normal mRNAs.

Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutation (SHM) and class switch recombination (CSR) in immunoglobulin genes. However, AID can also cause mutations in host genes and contribute to cancer pr

Zhi-Yong He,1,2,* Mei-Fang Li,1,2,* Jing-Hui Lin,1,2 Dong Lin,1,2 Ren-Jang Lin3 1Department of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China; 2Fujian Provincial Key Laboratory of Translation Cancer Medicine, Fuzhou 350014, Fujian Province, People’s Republic of China; 3Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA *These authors contributed equally to this work Background: Non-small-cell lung cancer (NSCLC) is a global public health problem, and brain is a common metastatic site in advanced NSCLC. Currently, whole-brain radiotherapy (WBRT) remains a major treatment for brain metastases, while EGFR-tyrosine kinase inhibitor (TKI) is the standard treatment for advanced NSCLC harboring EGFR mutations, which is also effective for brain metastases. However, whether EGFR-TKIs plus radiotherapy is superior to EGFR-TKIs alone for the treatment of advanced EGFR-mutant NSCLS with brain metastases remains controversial. This study aimed to compare the efficacy of concurrent EGFR-TKIs and WBRT vs EGFR-TKI alone in a retrospective cohort of advanced EGFR-mutant NSCLS with brain metastases.Patients and methods: The medical records of 104 treatment-naïve, advanced EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed, and there were 56 patients undergoing concurrent EGFR-TKI and WBRT, and 48 patients given EGFR-TKI alone, including 20 cases with salvage WBRT upon brain metastasis progression. The survival prognosis was compared between the two cohorts.Results: The baseline clinicopathologic factors were balanced between the two cohorts. After a median follow-up of 23 months, 35.6% of the study subjects survived. Concurrent EGFR-TKI and WBRT significantly improved the median intracranial PFS (iPFS) compared with EGFR-TKI alone (17.7 vs 11.0 months, P=0.015); however, no significant difference was seen in median overall survival between the two cohorts (28.1 vs 24.0 months, P=0.756). In addition, the median iPFS was found to significantly vary in the number of brain metastases (≤3 vs>3 metastases: 18.0 vs 12.5 months, P=0.044). Subgroup analysis showed that concurrent EGFR-TKI and WBRT improved median iPFS compared with EGFR-TKI alone in patients with more than three brain metastases (P=0.001); however, no significant difference was observed between the two regimens in patients with three or less brain metastases (P=0.526).Conclusion: Our data demonstrate that concurrent EGFR-TKI and WBRT achieves longer iPFS than EGFR-TKI alone in advanced EGFR-mutant NSCLC with brain metastases. In advanced EGFR-mutant NSCLC with three or less brain metastases, EGFR-TKI alone may be an option as a first-line therapy. Keywords: non-small-cell lung cancer, brain metastasis, epidermal growth factor receptor, tyrosine kinase inhibitor, whole-brain radiotherapy

Vinit B Mahajan,1,2 Jonathan H Lin31Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA; 2Omics Laboratory, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; 3Departments of Pathology and Ophthalmology, University of California San Diego, La Jolla, CA, USAPurpose: To describe immunohistopathological findings in autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV).Methods: An enucleated eye specimen from a patient with Stage V ADNIV was examined using standard histopathological methods and lymphocyte markers.Results: A c.731T>C CAPN5 mutation resulted in a p.Leu244Pro substitution in calpain-5. The eye showed exudative retinal detachment and neovascularization, intraocular fibrosis, and features of phthisis bulbi. Chronic inflammatory CD3-positive cell infiltrates were identified throughout the uvea, vitreous and retina, consistent with chronic uveitis.Conclusion: Mutations in CAPN5 trigger autoimmune uveitis characterized by inflammatory T-cells and severe neovascularization.Keywords: autosomal dominant neovascular inflammatory vitreoretinopathy, ADNIV, CAPN5, uveitis, CD3

Tsung-I Chen,1,2 Pu-Hsi Tsai,3 Jui-Hsing Lin,4 Ning-Yuean Lee,5 Michael TC Liang61Graduate Institute of Sport Science, National Taiwan Sport University, Taoyuan, 2Center for Physical Education, Tzu Chi University, Hualien, 3Department of Sport and Leisure, National Quemoy University, Kinmen, 4Department of Physical Education, National Pingtung University of Education, Pingtung, 5College of Living Technology, Tainan University of Technology, Tainan, Taiwan; 6Department of Kinesiology and Health Promotion, California State Polytechnic University, Pomona, CA, USABackground: To examine whether short-term, ie, five daily sessions, vigorous dynamic cycling exercise and heat exposure could achieve heat acclimation in trained athletes and the effect of heat acclimation on cutaneous blood flow in the active and nonactive limb.Methods: Fourteen male badminton and table tennis athletes (age = 19.6 ± 1.2 years) were randomized into a heat acclimation (EXP, n = 7) or nonheat acclimation (CON, n = 7) group. For 5 consecutive days, the EXP group was trained using an upright leg cycle ergometer in a hot environment (38.4°C ± 0.4°C), while the CON group trained in a thermoneutral environment (24.1°C ± 0.3°C). For both groups, the training intensity and duration increased from a work rate of 10% below ventilatory threshold (VT) and 25 minutes per session on day 1, to 10% above VT and 45 minutes per session on day 5. Subjects performed two incremental leg cycle exercise tests to exhaustion at baseline and post-training in both hot and thermoneutral conditions. Study outcome measurements include: maximum oxygen uptake (VO2max); exercise heart rate (HR); O2 pulse; exercise time to exhaustion (tmax); skin blood flow in the upper arm (SkBFa) and quadriceps (SkBFq); and mean skin (Tsk).Results: The significant heat-acclimated outcome measurements obtained during high-intensity leg cycling exercise in the high ambient environment are: (1) 56%–100% reduction in cutaneous blood flow to the active limbs during leg cycling exercise; (2) 28% drop in cutaneous blood flow in nonactive limbs at peak work rate; (3) 5%–10% reduction in heart rate (HR); (4) 10% increase in maximal O2 pulse; and (5) 6.6% increase in tmax.Conclusion: Heat acclimation can be achieved with five sessions of high-intensity cycling exercise in the heat in trained athletes, and redistribution of cutaneous blood flow in the skin and exercising muscle, and enhanced cardiovascular adaptations provide the heat-acclimated athletes with the capability to increase their endurance time in the hot environment.Keywords: VO2max, oxygen pulse, skin blood flow, cardiovascular adaptation, badminton and table tennis players, short-term heat acclimation

Vibrio vulnificus is a marine bacterium causing serious septicemia and wound infection in humans. It produces an RTX toxin that can lyse a variety of cells and is important for virulence in mice. In this study, we explored the role of RTX in pathogenesis by characterizing an RTX-deficient mutant. This mutant showed an ~2-log reduction in virulence for mice infected by various routes. Survival of the mutant at the infection site and subsequent spread into the bloodstream were impaired. In mice pretreated with cyclophosphamide to deplete the neutrophils, both the virulence and survival at the infection site of this mutant were enhanced. This mutant was further shown to be more readily cleared from the macrophage-rich mouse peritoneal cavity and phagocytosed by murine macrophages. These findings suggest that the RTX of V. vulnificus is required for bacterial survival during infection by protecting the organism from phagocytosis. [ABSTRACT FROM AUTHOR]

Patients with chronic non-specific low back pain (LBP) walk with more synchronous (in-phase) horizontal pelvis and thorax rotations than controls. Low thorax-pelvis relative phase in these patients appears to result from in-phase motion of the thorax with the legs, which was hypothesized to affect arm swing. In the present study, gait kinematics were compared between LBP patients with lumbar disc herniation and healthy controls during treadmill walking at different speeds and with different step lengths. Movements of legs, arms, and trunk were recorded. The patients walked with larger pelvis rotations than healthy controls, and with lower relative phase between pelvis and thorax horizontal rotations, specifically when taking large steps. They did so by rotating the thorax more in-phase with the pendular movements of the legs, thereby limiting the amplitudes of spine rotation. In the patients, arm swing was out-of phase with the leg, as in controls. Consequently, the phase relationship between thorax rotations and arm swing was altered in the patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: . This study examined test-retest agreement and measurement errors for the Rivermead Mobility Index (RMI) and the Mobility subscale of the Stroke Rehabilitation Assessment of Movement (M-STREAM) in patients with chronic stroke and mild to moderate disability. The authors aimed to determine the level of agreement between test and retest as well as the extent to which a mobility score varies on test-retest measurements. METHODS: . Both mobility measures were tested on 50 chronic stroke patients twice, 7 days apart. Intraclass correlation coefficient (ICC(2,1)), a relative reliability index, was used to examine the level of agreement between test and retest. Absolute reliability indices, including the standard error of measurement and the smallest real differences, were used to determine the extent to which the mobility scores varied due to chance variation in measurement. RESULTS: Test-retest agreements were excellent for both mobility measures. The standard errors of measurement of the RMI and the M-STREAM, representing the smallest change threshold that indicates a real improvement (beyond measurement error) for a group of individuals, were 0.8 and 1.5, respectively. The smallest real differences of the RMI and the M-STREAM, exhibiting the smallest change threshold that indicates a real improvement for a single individual, were 2.2 and 4.2, respectively. CONCLUSION: . The RMI and the M-STREAM have high agreement between the test-retest measurements with acceptable measurement errors due to variation in measurement. The 2 measures can be used by clinicians and researchers to assess the mobility performance and monitor changes over time in stroke patients. [ABSTRACT FROM AUTHOR]

The comparative effect of famotidine or cimetidine on theophylline disposition was determined in healthy volunteers. Cimetidine, but not famotidine, caused a reduction in the rate of elimination of theophylline. The mean total body clearance of theophylline was reduced from 57.6 ml min-1 before cimetidine to 39.5 ml min-1 during cimetidine; and the half-life was prolonged from 8.7 h before cimetidine to 12 h during cimetidine. The volume of distribution and renal excretion of theophylline were not affected by either famotidine or cimetidine. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess the diagnosis accuracy rate of neck ultrasonography (US) characteristics in thyroid cancer. Materials and Methods: A retrospective study of patients who underwent thyroid surgery for palpable thyroid nodules at the department of Otolaryngology Head and Neck surgery, Kaohsiung Medical University Hospital, Taiwan. Results: Between January 1993 and December 2006, 378 patients with palpable thyroid nodules underwent thyroid total lobectomy or total thyroidectomy. Preoperation evaluations included neck US, ultrasound-guided fine-needle aspiration cytology (USGFNA) and technetium-99m scintigraphy. Postoperative histopathology revealed 297 are benign and 81 are malignant. Comparing preoperative surveys with postoperative histopathology, the outcome analyses included the sensitivity, specificity, accuracy rate, positive predictive value and negative predictive value. The sensitivity of US, USGFNA, and technetium-99m scintigraphy were, respectively, 51.9%, 75.0%, and 73.8%; the specificity were, respectively, 93.9%, 94.6%, and 25.3%; the accuracy rate were, respectively, 86.8%, 90.8%, and 35.0%; positive predictive value were, respectively, 63.6%, 76.9%, and 19.8%; negative predictive value were, respectively, 90.5%, 94.1%, and 79.5%. Conclusions: The neck US is a useful method in the evaluation of thyroid nodules, and the US characteristics can be used to distinguish the risk of malignant thyroid nodules. We recommend neck US in all patients with thyroid nodules, and if any malignant characteristics were noted, USGFNA can be arranged. [ABSTRACT FROM AUTHOR]

The effect of a high potency antacid and food on the bioavailability of famotidine was studied in 17 healthy volunteers in an open randomized three-way cross-over trial. After an overnight fast, famotidine was administered to each subject as follows: 40 mg famotidine orally alone; 40 mg orally with antacid; and 40 mg orally with a standard breakfast. Coadministration of the antacid caused a small but significant reduction in the maximum plasma concentration (Cmax) of famotidine from 81.1 +/- 54.2 to 60.8 +/- 21.6 ng ml-1 (P less than 0.05) and a small decrease in the area under plasma concentration-time curve [AUC] from 443.3 +/- 249.2 to 355.0 +/- 125.1 ng ml-1 h (P greater than 0.05). However, there was only a minimal effect of food on these parameters; the Cmax and [AUC] were 81.6 +/- 29.6 ng ml-1 and 434.8 +/- 145.9 ng ml- 1 h, respectively. [ABSTRACT FROM AUTHOR]