The Role of Interleukin-6 in Castleman Disease.

Since its discovery, improvements in treating Castleman disease and its variants have centered on interleukin-6 (IL-6). IL-6 was discovered from T-cell factors (BCDF or BSF-2), which induced B-cell maturation. Most symptoms of the plasma cell variant of Castleman disease are linked to the hyperfunction of IL-6, constitutively produced in the affected lymph nodes (1989), suggesting IL-6 is key in the pathogenesis of multicentric Castleman disease (MCD). The results of several studies have shown that most MCD symptoms and abnormal laboratory results are improved by anti-IL-6 MCD treatments, such as tocilizumab, a humanized anti-IL-6 receptor antibody, and siltuximab, an anti-IL-6 antibody.

The effects of resistance training of swallowing muscles on dysphagia in older people: A cluster, randomized, controlled trial.

OBJECTIVE: This study examined the effects of resistance training of swallowing muscles in community-dwelling older individuals with dysphagia. METHODS: A cluster randomized controlled trial was performed in day-service and day-care facilities. The participants were older (≥65 y) community-dwelling individuals with dysphagia. The intervention group performed a tongue resistance exercise and a head flexion exercise against manual resistance. Both groups received a brochure on dysphagia rehabilitation. The primary endpoint was an improvement in dysphagia assessed by the Eating Assessment Tool (EAT-10) score. Tongue pressure was the secondary endpoint. RESULTS: Participants included 47 men and 57 women, with a mean age ± standard deviation of 80 ± 7 y. At baseline, the median EAT-10 score was 7 (interquartile range, 5-12). A total of 91 patients, 43 in the intervention group (8 clusters) versus 48 in the control group (11 clusters), were assessed postintervention. The percentage of participants with EAT-10 scores <3 was not statistically significantly different between the two groups (intervention group, 23% versus control group, 19%, P = 0.598). Postintervention median EAT-10 scores were 6 (interquartile range, 3-10) in each group (P = 0.665) and mean tongue pressure was 23.9 ± 10.0 versus 25.9 ± 10.9 kPa (P = 0.376). The intervention did not significantly affect the EAT-10 score or tongue pressure in a mixed effects random intercept model. The Mini Nutritional Assessment Short Form score correlated significantly with the postintervention EAT-10 score. CONCLUSIONS: Resistance training of swallowing muscles did not improve dysphagia in this study. Better nutritional status correlated independently with improved swallowing function.

Substrate specificity of TOR complex 2 is determined by a ubiquitin-fold domain of the Sin1 subunit.

The target of rapamycin (TOR) protein kinase forms multi-subunit TOR complex 1 (TORC1) and TOR complex 2 (TORC2), which exhibit distinct substrate specificities. Sin1 is one of the TORC2-specific subunit essential for phosphorylation and activation of certain AGC-family kinases. Here, we show that Sin1 is dispensable for the catalytic activity of TORC2, but its conserved region in the middle (Sin1CRIM) forms a discrete domain that specifically binds the TORC2 substrate kinases. Sin1CRIM fused to a different TORC2 subunit can recruit the TORC2 substrate Gad8 for phosphorylation even in the sin1 null mutant of fission yeast. The solution structure of Sin1CRIM shows a ubiquitin-like fold with a characteristic acidic loop, which is essential for interaction with the TORC2 substrates. The specific substrate-recognition function is conserved in human Sin1CRIM, which may represent a potential target for novel anticancer drugs that prevent activation of the mTORC2 substrates such as AKT.

Validity and reliability of the Patient Centred Assessment Method for patient complexity and relationship with hospital length of stay: a prospective cohort study.

OBJECTIVES: Several instruments for evaluating patient complexity have been developed from a biopsychosocial perspective. Although relationships between the results obtained by these instruments and the length of stay in hospital have been examined, many instruments are complicated and not easy to use. The Patient Centred Assessment Method (PCAM) is a candidate for practical use. This study aimed to test the validity and reliability of the PCAM and examine the correlations between length of hospital stay and PCAM scores in a regional secondary care hospital in Japan. DESIGN: Prospective cohort study. PARTICIPANTS AND SETTING: Two hundred and one patients admitted to Ouji Coop Hospital between July 2014 and September 2014. MAIN PREDICTOR: PCAM total score in initial phase of hospital admission. MAIN OUTCOME: Length of stay in hospital. RESULTS: Among 201 patients (Female/Male=98/103) with mean (SD) age of 77.4±11.9 years, the mean PCAM score was 25±7.3 and mean (SD) length of stay in hospital (LOS) 34.1±40.9 days. Using exploratory factor analysis to examine construct validity, PCAM evidently has a two-factor structure, comprising medicine-oriented and patient-oriented complexity. The Spearman rank correlation coefficient for evaluating criterion-based validity between PCAM and INTERMED was 0.90. For reliability, Cronbach's alpha was 0.85. According to negative binomial regression analyses, PCAM scores are a statistically significant predictor (p<0.001) of LOS after adjusting for age, gender, Mini Nutritional Assessment Short-Form, Charlson Comorbidity Index, serum sodium concentration, total number of medications and whether public assistance was required. In another model, each factor in PCAM was independently correlated with length of stay in hospital after adjustment (medicine-oriented complexity: p=0.001, patient-oriented complexity: p=0.014). CONCLUSION: PCAM is a reliable and valid measurement of patient complexity and PCAM scores have a significant correlation with hospital length of stay.

Rab-family GTPase regulates TOR complex 2 signaling in fission yeast.

BACKGROUND: From yeast to human, TOR (target of rapamycin) kinase plays pivotal roles in coupling extracellular stimuli to cell growth and metabolism. TOR kinase functions in two distinct protein complexes, TOR complex 1 (TORC1) and 2 (TORC2), which phosphorylate and activate different AGC-family protein kinases. TORC1 is controlled by the small GTPase Rheb, but little is known about TORC2 regulators. RESULTS: We have identified the Ryh1 GTPase, a human Rab6 ortholog, as an activator of TORC2 signaling in the fission yeast Schizosaccharomyces pombe. Mutational inactivation of Ryh1 or its guanine nucleotide exchange factor compromises the TORC2-dependent phosphorylation of the AGC-family Gad8 kinase. In addition, the effector domain of Ryh1 is important for its physical interaction with TORC2 and for stimulation of TORC2 signaling. Thus, GTP-bound Ryh1 is likely to be the active form stimulatory to TORC2-Gad8 signaling. Consistently, expression of the GTP-locked mutant Ryh1 is sufficient to promote interaction between TORC2 and Gad8 and to induce Gad8 hyperphosphorylation. The loss of functional Ryh1, TORC2, or Gad8 brings about similar vacuolar fragmentation and stress sensitivity, further corroborating their involvement in a common cellular process. Human Rab6 can substitute Ryh1 in S. pombe, and therefore Rab6 may be a potential activator of TORC2 in mammals. CONCLUSIONS: In its GTP-bound form, Ryh1, an evolutionarily conserved Rab GTPase, activates TORC2 signaling to the AGC kinase Gad8. The Ryh1 GTPase and the TORC2-Gad8 pathway are required for vacuolar integrity and cellular stress resistance in S. pombe.