Bone morphogenic protein-2 signaling in human disc degeneration and correlation to the Pfirrmann MRI grading system

BACKGROUND CONTEXTBack and neck pain secondary to disc degeneration is a major public health burden. There is a need for therapeutic treatments to restore intervertebral disc (IVD) composition and function.PURPOSETo quantify ALK3, BMP-2, pSMAD1/5/8 and MMP-13 expression in IVD specimens collected from patients undergoing surgery for disc degeneration, to correlate ALK3, BMP-2, pSMAD1/5/8 and MMP-13 expression in IVD specimens to the 5-level Pfirrmann MRI grading system, and to compare ALK3, BMP-2, pSMAD1/5/8 and MMP-13 expression between cervical and lumbar degenerative disc specimens.STUDY DESIGNAn immunohistochemical study assessing ALK3, BMP-2, pSMAD1/5/8, and MMP-13 expression levels in human control and degenerative IVD specimens.METHODSHuman IVD specimens were collected from surgical patients who underwent discectomy and interbody fusion at our institution between 1/2015 and 8/2017. Each patient underwent MRI prior to surgery. The degree of disc degeneration was measured according to the 5-level Pfirrmann MRI grading system. Patients were categorized into either the 1) control group (Pfirrmann grades I-II) or 2) degenerative group (Pfirrmann grades III-V). Histology slides of the collected IVD specimens were prepared and immunohistochemical staining was performed to assess ALK3, BMP-2, pSMAD1/5/8, and MMP-13 expression levels in the control and degenerative specimens. Expression levels were also correlated to the Pfirrmann criteria. Lastly, the degenerative specimens were stratified according to their vertebral level and expression levels between the degenerative lumbar and cervical discs were compared.RESULTSFifty-two patients were enrolled; however, 2 control and 2 degenerative patients were excluded due to incomplete data sets. Of the remaining 48 patients, there were 12 control and 36 degenerative specimens. Degenerative specimens had increased expression levels of BMP-2 (p=.0006) and pSMAD1/5/8 (p<.0001). Pfirrmann grade 3 (p=.0365) and grade 4 (p=.0008) discs had significantly higher BMP-2 expression as compared to grade 2 discs. Pfirrmann grade 4 discs had higher pSMAD1/5/8 expression as compared to grade 2 discs (p<.0001). There were no differences in ALK3 or MMP-13 expression between the control and degenerative discs (p>.05). Stratifying the degenerative specimens according to their vertebral level showed no significant differences in expression levels between the lumbar and cervical discs (p>.05).CONCLUSIONSBMP-2 and pSMAD1/5/8 signaling activity was significantly upregulated in the human degenerative specimens, while ALK3 and MMP-13 expression were not significantly changed. The expression levels of BMP-2 and pSMAD1/5/8 correlate positively with the degree of disc degeneration measured according to the Pfirrmann MRI grading system.CLINICAL SIGNIFICANCEBMP-SMAD signaling represents a promising therapeutic target to restore IVD composition and function in the setting of disc degeneration.     

Effects of participatory workplace improvement program on stress-related biomarkers and self-reported stress among university hospital nurses: a preliminary study

Although participatory workplace improvement programs are known to provide favorable effects on high stress occupations like nursing, no studies have confirmed its effect using biomarkers. The aim of this study was to determine whether a participatory workplace improvement program would decrease stress-related symptoms as evaluated by biomarkers and self-reported stress among hospital nurses. Three actions to alleviate job stress, which were determined through focus group interviews and voting, were undertaken for two months. A total of 31 female Japanese nurses underwent measurement of inflammatory markers, autonomic nervous activity (ANA), and perceived job stress (PJS) at three-time points; before the program (T1), within a week after the completion of the program (T2), and three months after the program (T3). A series of inflammatory markers (Interferon-γ, Interleukin (IL)-6, and IL-12/23p40) decreased significantly at T2, and IL-12/23p40 and IL-15 significantly decreased at T3 compared to T1, while ANA and PJS remained unchanged. Our participatory program exerted beneficial effects in reducing inflammatory responses, but not for ANA and PJS. Further investigations with a better study design, i.e., a randomized controlled trial, and a larger sample size are warranted to determine what exerted beneficial effects on inflammatory markers and why other outcomes remained unchanged.     

Exploratory assessment of treatment‐dependent random‐effects distribution using gradient functions

In analyzing repeated measurements from randomized controlled trials with mixed‐effects models, it is important to carefully examine the conventional normality assumption regarding the random‐effects distribution and its dependence on treatment allocation in order to avoid biased estimation and correctly interpret the estimated random‐effects distribution. In this article, we propose the use of a gradient function method in modeling with the different random‐effects distributions depending on the treatment allocation. This method can be effective for considering in advance whether a proper fit requires a model that allows dependence of the random‐effects distribution on covariates, or for finding the subpopulations in the random effects.     

Breast-conserving surgery for primary breast cancer: Immediate volume replacement using lateral tissue flap

We have developed a breast-conserving surgery consisting of quadrantectomy and regional lymph node dissection and immediate volume replacement using lateral tissue flap (LTF). The quadrantectomy was employed on the basis of segmental anatomy of the duct lobular system in which breast carcinoma originates. Lateral skin incision was performed from the apex of mid-axillary line to the inframammary fold, without removing the skin overlying the tumor. In the early period of breast reconstruction embraced latissmus dorsi flap (LDF) for 10 patients (reconstruction was not performed on 35 patients), but in the late period we employed LTF for 56 patients. Four of the 101 patients developed ipsilateral breast cancer during a mean follow-up period of 48 months, but none died of breast cancer. Among the 56 patients with LTF replacement no patient developed ipsilateral breast cancer. Fairly good cosmetic outcome was obtained in the patients who underwent the immediate volume replacement. Breast-conserving surgeries are reviewed, and the surgical procedure using LTF for immediate volume replacement is described.     

Risk factors for breast cancer: A case-control study of screen-detected breast cancer in Miyagi Prefecture, Japan

We examined the associations between reproductive factors and the risk of breast cancer on the basis of information from a total of 201,363 breast cancer screening program participants in Miyagi Prefecture, Japan, during 1987-1991. A case-control study method was applied on analysis. Data on 204 breast cancer cases identified and 810 screening year-, age- and screening area-matched normal controls were extracted. After adjustment for potential confounders, a trend of decreasing risk of breast cancer with increasing number of parity was observed (p for trend=0.03). Among parous women, lactation for the last child decreased the risk of breast cancer (odds ratio (OR) = 0.61, 95% confidence interval (95% CI) 0.39–0.94). These findings were consistent with those in clinical breast cancer reported previously. When cases were divided into two age groups, younger ( 49 y.o.) and older (50 y.o. ), family history of breast cancer among mother and sisters (OR=3.51, 95% CI 1.05–11.80), and lactation for the last child (OR=0.46, 95% CI 0.25–0.84) were associated with younger age breast cancer, whereas number of parity was associated with older age breast cancer (p for trend=0.03). The results by age group suggest that different mechanisms may exist in breast cancer developing at early and late onsets.     

Evaluation of a screening program on reduction of gastric cancer mortality in Japan: preliminary results from a cohort study.

BACKGROUND: Systematic population-based screening for gastric cancer is widely spread in Japan. However, the case-control study method has been the main method used to evaluate the effectiveness of the screen ing to reduce gastric cancer mortality in Japan. METHODS: This article presents a population-based cohort study. A questionnaire about lifestyles and dietary habits was distributed to 36,990 residents in a city of Japan. The response rate to the questionnaire was 92.0%. After ineligible responders had been excluded, 24,134 subjects were classified into screened and un screened groups according to their self-reports of participation in the screening the previous year. We followed them up for 40 months and linked resident death records in the city. We compared mortality from gastric cancer and all other causes between the groups by us ing the Cox proportional hazard model. RESULTS: The follow-up period was 78,156.6 person-years from September 1992 to December 1995. The multivariate relative risks for gastric cancer death of the screened group in comparison with the unscreened group were 0.72 (95% CI 0.31-1.66) among males and 1.46 (95% CI 0.43-4.90) among females. CONCLUSION: Although our data are preliminary, we were unable to demonstrate a large contribution of the present screening program to decreasing gastric cancer mortality. Further follow-up is needed to in crease the precision.     

Overtime, psychosocial working conditions, and occurrence of non- insulin dependent diabetes mellitus in Japanese men

OBJECTIVES: To ascertain the effects of overtime and psychosocial job conditions on the occurrence of non-insulin dependent diabetes mellitus (NIDDM) in Japan. DESIGN: An eight year prospective cohort study. SETTING: An electrical company in Japan. PARTICIPANTS: In 1984, a mailed questionnaire was sent to industrial workers of an electrical company in Japan. After excluding those who had a history of diabetes mellitus or other chronic diseases, 2597 male respondents were prospectively followed up for the succeeding eight years. Data from 2194 (84%) who were completely followed up were analysed. The occurrence of NIDDM during the follow up period was assessed according to the WHO criteria on the basis of an annual screening programme. MAIN RESULTS: The age adjusted incidence of NIDDM was significantly higher in those who worked overtime more than 50 hours per month than in those who worked 25 hours or less per month (p < 0.05). It was significantly higher in those who worked with new technology at baseline than in those who did not (p < 0.05). Cox's proportional hazard model indicated that those who worked overtime more than 50 hours per month had 3.7 times higher risk of NIDDM after controlling for known risk factors (p < 0.01) and those who worked with new technology had 2.4 times higher risk of NIDDM (p < 0.05). CONCLUSIONS: It is suggested that longer overtime and use of new technology are risk factors of NIDDM in Japanese men.     

Age-related stimulation by tetragastrin of gastric mucin biosynthesis in rat

The effects of tetragastrin on gastric mucin biosynthesis in middle-aged rats were compared with those in young rats. The incorporation of [3H]glucosamine and [35S]sulfate into mucin was stimulated by tetragastrin in cultured corpus mucosa from 7-week-old rats. In contrast, tetragastrin could not enhance mucin biosynthesis in stomachs from 52-week-old rats. The isosorbide dinitrate-induced stimulation of corpus mucin biosynthesis observed in middle-aged rats was essentially the same as that seen in young rats. Nitric oxide (NO) synthase activity of the corpus was significantly reduced in the middle-aged rats compared to the young rats. NO synthase-immunoreactivity was observed at surface mucous cells in the corpus mucosa of young, but not of middle-aged, rats. These results suggest that aging decreases the effect of gastrin on gastric mucin biosynthesis through the age-related loss of NO synthase function in the surface mucous cell layer of rat stomach.