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1.  Levels of awakening salivary CgA in response to stress in healthy subjects 
To determine the changes in salivary chromogranin A (CgA) levels upon awakening in response to of stress by investigating the relationship between salivary CgA levels and the stress response as assessed by GHQ-28 tests.
The study cohort comprised 40 healthy male university students (age range 19–22 years). Salivary CgA levels were measured at 7:00 a.m. (awakening) and at 7:30, 8:00, and 8:30 a.m. (after awakening).
The salivary CgA level was 0.91 ± 0.20 and 0.42 ± 0.1 pmol/ml at 7:00 a.m. in students scoring low (n = 26) and high (n = 14), respectively, on the “severe depression” subscale. This difference in salivary CgA levels at 7:00 between high and low scorers was statistically significant (p < 0.05).
Our findings indicate that depression may influence secretions of salivary CgA via chronic stress-related attenuation of the sympathetic–adrenomedullary system activity.
PMCID: PMC3078297  PMID: 21431800
Chromogranin A; Stress; Awakening; Saliva; Depression
2.  Chromogranin A: Novel biomarker between periodontal disease and psychosocial stress 
The psychosocial stress has long been regarded as a significant pre-disposing factor for periodontal disease. The association between the periodontal disease and the neuroendocrine hormones has been observed. Chromogranin A (CgA) is supposed to link the activity of the neuroendocrine system to local and systemic immune functions and to be related to periodontitis.
The aim of this study was to determine the CgA levels in saliva and plasma in periodontal health and disease and to assess their potential relationship to periodontitis.
Settings and Designs:
In this case-control study, the association between periodontal disease and stress marker has been assessed.
Materials and Methods:
Sixty subjects were chosen for this study: With case group comprising of 30 subjects with chronic periodontitis and control group comprising of 30 healthy subjects. Salivary and plasma CgA levels were determined by ELISA technique. Clinical parameters included were plaque index, papillary bleeding index and clinical attachment loss and probing depth. Correlation analysis was calculated by independent sample t-test.
Significantly higher CgA levels were found in saliva and plasma of patients with chronic periodontitis compared with healthy individuals (P < 0.05). No significant difference were observed between salivary and plasma CgA levels.
The elevated level CgA in the plasma and saliva of subjects with stress induced chronic periodontitis has yielded insights into biological plausible association between the psychosocial stress and chronic periodontitis. Thus, our results suggest that CgA is a useful biomarker for evaluating at least in part the etiopathogenesis of periodontitis.
PMCID: PMC3713754  PMID: 23869129
Biomarkers; chromogranin A; chronic periodontitis; neuroendocrine hormones; plasma; psychosocial stress; saliva
3.  Comparison of the Effects of Local Cryotherapy and Passive Cross-Body Stretch on Extensibility in Subjects with Posterior Shoulder Tightness 
The objective was to compare the immediate effects of local cryotherapy (LC) and passive cross-body stretch on the extensibility of the posterior shoulder muscle in individuals with posterior shoulder tightness. Eighty-seven healthy subjects with a between-shoulder difference in internal rotation (IR) range of motion (ROM) greater than 10° were randomly divided into three groups: LC group, stretching group, and control group (n = 29 in each group). Subjects in the LC group received LC on infraspinatus and posterior deltoid muscles and subjects in the stretching group performed passive cross-body stretch. Stretch sensation was measured at the end range of passive IR and horizontal adduction (HA) using numerical rating scale, and the pressure pain threshold (PPT) at the infraspinatus and posterior deltoid muscles was measured using pressure algometry. Passive and active ROM of IR and HA of the glenohumeral joint were measured using an inclinometer. All measurements were performed at pre-intervention, post- intervention, and 10-min follow-up. Stretch sensation was significantly decreased and PPT was significantly increased in the LC and stretching groups at post-intervention, and these effects were maintained at 10-min follow-up, compared to the control group. Both the LC group and stretching group had a significantly greater increase in passive and active ROM of IR and HA, compared to the control group at post-intervention and 10-min follow-up. However, there were no significant differences in stretch sensation, PPT, or ROM of IR and HA between the LC group and stretching group. LC can be used to decrease the stretch sensation and increase PPT and ROM of IR and HA as much as a stretching exercise. LC could be an alternative method for increasing the restricted ROM of glenohumeral IR and HA for individuals with posterior shoulder tightness, especially for patients and sports players who have severe stretching discomfort.
Key PointsLocal cryotherapy (LC) decreased the uncomfortable stretch sensation, and increased the pressure pain threshold (PPT) of infraspinatus and posterior deltoid muscles in subjects with posterior shoulder tightness.Decreased stretch sensation by LC without passive stretching could improve the passive and active ROM of internal rotation and horizontal adduction in subjects with posterior shoulder tightness, similar to cross-body stretch.LC can be an alternative method to increase extensibility when individuals with posterior shoulder tightness have high stretch sensitivity and low PPT in the infraspinatus and posterior deltoid muscles.
PMCID: PMC3918572  PMID: 24570610
Cryotherapy; muscle stretching exercise; shoulder
4.  Duodenal Chromogranin A Cell Density as a Biomarker for the Diagnosis of Irritable Bowel Syndrome 
Background and Aim. Chromogranin A (CgA) is a common marker for endocrine cells. The density of duodenal CgA cells is reduced in patients with irritable bowel syndrome (IBS). Methods. The present study was undertaken to evaluate the density of duodenal CgA as a biomarker for the diagnosis of IBS. Two hundred and three patients with IBS were recruited (180 females and 23 males; mean age, 36 years; range, 18–66 years). The control group comprised 86 healthy subjects without gastrointestinal complaints (77 females and 9 males; mean age, 38 years; range, 18–67 years). Biopsy samples were taken from the duodenum during gastroscopy. Sections from these biopsy samples were immunostained for CgA using the avidin-biotin complex (ABC) method. CgA cell density was quantified by computerized image analysis. Results. The CgA cell density was lower in IBS-total and in all of the IBS subgroups than in the controls. The sensitivity and specificity for a cutoff of <200 cells/mm2 were 86% and 95%, respectively. Conclusion. The duodenal CgA cell density seems to be a good biomarker for the diagnosis of IBS. It is an inexpensive, simple, and easy-to-use method that does not require sophisticated equipment or considerable experience.
PMCID: PMC4083604  PMID: 25028588
5.  Chromogranin A cell density in the rectum of patients with irritable bowel syndrome 
Molecular Medicine Reports  2012;6(6):1223-1225.
In a previous study, chromogranin A (CgA) cell density in the colon of patients with irritable bowel syndrome (IBS) was found to be reduced. It has been suggested that intestinal CgA cell density may be used as a marker for the diagnosis of IBS. The rectum harbours a larger number of large intestinal endocrine cells and is more accessible for biopsies than the colon. The present study aimed at determining the CgA cell density in the rectum of IBS patients. A total of 47 patients with IBS that fulfilled the Rome Criteria III (39 females and 8 males; average age, 38 years) were included. A total of 28 patients had diarrhea (IBS-D) and 19 had constipation (IBS-C) as the predominant symptom. A total of 27 subjects that underwent colonoscopy with rectal biopsies were used as the controls. These subjects underwent colonoscopy due to gastrointestinal bleeding (the source of which was identified as haemorrhoids or angiodysplasia; 19 females and 8 males; average age, 49 years), or health worries. The rectal biopsies were immunostained for CgA and quantified by computer image analysis. The CgA density in the controls was 206.3±22.2 (mean ± SEM), in all IBS patients 190.2±14.3, in IBS-D patients 188.8±14.7 and in IBS-C patients 195.3±34.1. There was no statistically significant difference between the controls, IBS, IBS-D or IBS-C patients (P=0.5, 0.5 and 0.7, respectively). The present study showed that although the rectum comprises the same endocrine cell types as the colon, attention must be paid when drawing conclusions regarding the whole large intestine from studies carried out on the rectum. This particularly applies when endocrine cells are investigated. As CgA cell density represents the total endocrine cell content of the rectum, changes in specific endocrine cells in IBS patients cannot be excluded.
PMCID: PMC3493063  PMID: 22992886
chromogranin A; computer image analysis; immunohistochemistry; irritable bowel syndrome; rectum
6.  Subjective food hypersensitivity: assessment of enterochromaffin cell markers in blood and gut lavage fluid 
Food hypersensitivity is commonly suspected, but seldom verified. Patients with subjective food hypersensitivity suffer from both intestinal and extraintestinal health complaints. Abnormalities of the enterochromaffin cells may play a role in the pathogenesis. The aim of this study was to investigate enterochromaffin cell function in patients with subjective food hypersensitivity by measuring serum chromogranin A (CgA) and 5-hydroxytryptamine (5-HT, serotonin) in gut lavage fluid.
Sixty-nine patients with subjective food hypersensitivity were examined. Twenty-three patients with inflammatory bowel disease and 35 healthy volunteers were included as comparison groups. CgA was measured in serum by enzyme-linked immunosorbent assay. Gut lavage fluid was obtained by administering 2 L of polyethylene glycol solution intraduodenally. The first clear fluid passed per rectum was collected and 5-HT was analyzed by liquid chromatography tandem mass spectrometry.
Serum levels of CgA were significantly lower in patients with subjective food hypersensitivity than in healthy controls (P = 0.04). No differences were found in 5-HT levels in gut lavage fluid between patients with subjective food hypersensitivity and the control groups. There was no correlation between serum CgA and gut lavage 5-HT.
Decreased blood levels of CgA suggest neuroendocrine alterations in patients with subjective food hypersensitivity. However, 5-HT levels in gut lavage fluid were normal.
PMCID: PMC3160864  PMID: 21887108
food hypersensitivity; chromogranin A; serotonin; gut lavage fluid; liquid chromatography
7.  Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas 
Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors. Chromogranin A (CgA) was considered as the most practical and useful serum tumor marker in PNET patients. But peripheral blood levels of CgA are not routinely tested in Chinese patients with PNETs. This study was to assess the diagnostic value of CgA in Chinese patients with PNETs especially in patients with insulinomas.
Eighty-nine patients with PNETs including 57 insulinomas and 32 non-insulinoma PNETs as well as 86 healthy participants were enrolled in this study between September 2003 and June 2013. Serum levels of CgA were measured by ELISA method. Expression of CgA protein was detected in 26 PNET tissues including 14 insulinomas by immunohistochemical staining.
Serum levels of CgA in 89 PNET patients were significantly higher than that in healthy controls (P = 7.2 × 10−9). Serum levels of CgA in 57 patients with insulinomas (median 64.8 ng/ml, range 25–164) were slightly higher than the levels in healthy controls (median 53.4 ng/ml, range 39–94) but much lower than the levels in 32 patients with non-insulinoma PNETs (median 193 ng/ml, range 27–9021), P = 0.001. The serum CgA levels were reduced in 16 of 17 patients with insulinomas after tumor resection. ROC curve showed that CgA values at 60 ng/ml distinguished patients with insulinomas from healthy controls but its sensitivity and specificity were 66.7% and 73.3%, respectively. In contrast, CgA values at 74 ng/ml distinguished patients with non-insulinoma PNETs from healthy controls, and the sensitivity and specificity were 65.6% and 91.9%, respectively. Except for two insulinomas with negative staining of CgA, 12 insulinoma tissues showed positive staining of CgA.
CgA is a reliable serum diagnostic biomarker for PNETs but not for insulinomas.
PMCID: PMC4130880  PMID: 25099181
8.  Increase of urinary 5-hydroxyindoleacetic acid excretion but not serum chromogranin A following over-the-counter 5-hydroxytryptophan intake 
5-hydroxyindoleacetic acid (5-HIAA) excretion is commonly measured for biochemical detection of carcinoid tumours. A 77-year-old woman was referred for elevated 24 h urine 5-HIAA excretion (510 μmol/day; normal is less than 45 μmol/day) and serum chromogranin A (CgA) (72.1 U/L; normal is less than 18 U/L), both subsequently normalized after discontinuation of 5-hydroxytryptophan (5-HTP). 5-HTP, a precursor of serotonin, is not commonly listed as a substance that increases 5-HIAA levels in urine. The effect of 5-HTP on CgA has not been previously described.
To determine whether, and to what extent, oral 5-HTP increases urine 5-HIAA excretion and serum CgA levels in healthy volunteers.
A randomized, prospective, double-blind, placebo-controlled crossover study, with a four-day washout period, was performed in a general community setting. Eight healthy subjects aged 22 to 58 years were recruited by advertising. Bedtime ingestion of 5-HTP 100 mg/day was compared with placebo ingestion for 10 days. Twenty-four hour urine excretion of 5-HIAA and serum CgA were the main outcome measures.
Median (range) urinary 5-HIAA excretion was 204 μmol/day (22 μmol/day to 459 μmol/day) during 5-HTP intake, compared with 18 μmol/day (12 μmol/day to 36 μmol/day) during placebo intake (P=0.017). 5-HTP did not affect clinical symptoms or serum CgA levels.
Oral 5-HTP increases urinary 5-HIAA excretion with considerable interindividual variation. In a small number of subjects, oral 5-HTP did not affect serum CgA levels. Therefore, increased 5-HIAA levels with normal CgA levels may suggest 5-HTP ingestion. The use of over-the-counter 5-HTP should be excluded as the cause of increased urinary 5-HIAA levels before initiating diagnostic tests to search for a carcinoid tumour. 5-HTP should be added to popular references as a substance that may cause increased 5-HIAA excretion.
PMCID: PMC2659120  PMID: 18209781
5-hydroxytryptophan; 5-hydroxyindoleacetic acid; Carcinoid; Chromogranin A
9.  Effect of snack eating on sensitive salivary stress markers cortisol and chromogranin A 
To investigate the effect of snack eating on salivary cortisol and chromogranin A (CgA).
From 14∶00 to 18∶00, starting two hours after consumption of a midday meal, saliva samples were collected every 30 minutes from 15 healthy males, 7 of whom (snack group) ate a snack immediately after the sampling at 15∶00. Salivary cortisol and CgA levels were determined by ELISA. Samples were controlled according to salivary flow rates.
For the snack group, after snack consumption, salivary cortisol increased to exceed significance (p<0.05) at 15∶30 and rose even higher at 16∶00. In the control group, there was no such change. There was no significant change in salivary CgA in either the snack group or the control groups during the sampling period.
These findings suggest that no food should be consumed for at least 90 mins before saliva sampling for cortisol determination and that salivary CgA is probably not affected by snack eating.
PMCID: PMC2723385  PMID: 21432335
cortisol; chromogranin A (CgA); stress marker; human saliva; snack eating
10.  Serum chromogranin-A in hepatocellular carcinoma: Diagnostic utility and limits 
AIM: The utility of serum alpha-fetoprotein (α-FP) for the detection of hepatocellular carcinoma (HCC) is questionable. High serum levels of chromogranin-A (CgA) have recently been reported in HCC. Impaired hepatic, renal, and heart functions influence circulating CgA. The aim of this study was to assess sensitivity and specificity of serum CgA as a marker of HCC in patients with liver cirrhosis (LC).
METHODS: Serum CgA levels were measured by RIA in 339 patients of which 54 HCC, 132 LC, 45 chronic hepatitis (CH), 27 chronic heart failure (CHF), 36 chronic renal failure (CRF), 45 chronic inflammatory bowel disease (IBD) as disease controls and in 75 healthy controls. Patients with liver disease or IBD and concomitant renal and/or heart failure were excluded. Pearson correlation, non-parametric combination test and confidence interval analysis were used for statistical analysis.
RESULTS: Serum CgA above normal values (100 ng/mL) were found in 83% of HCC patients, in 48% of LC patients, in 20% of CH patients, in 33% of IBD patients, in 92% of CRF patients, in 100% of CHF patients, and in none of the healthy controls. The mean CgA values in HCC (769±1 046), in LC (249±369), in CH (87±94), in CRF (1390±1401), in CHF (577±539), in IBD (146±287) were significantly higher than those in healthy controls (48±18). HCC patients had higher CgA values (P<0.01) than LC, CH, and IBD patients but did not differ from those with CRF or CHF. The 95% CI for the mean (250-1289 ng/mL) in HCC patients was selected as a CgA range and the lower value of such range was assumed as cut-off. Sensitivity and specificity of CgA, calculated in relation to the cut-off in patients with cirrhosis and HCC, were respectively 61% (CI 48-73%) and 82% (CI 75-88%). Serum α-FP values were >200 ng/mL in 21% of the HCC patients and in none of the LC patients. No significant correlation was found between α-FP and CgA in patients with HCC and in patients with cirrhosis.
CONCLUSION: When HCC is suspected and α-FP is normal or <200 ng/mL, CgA serum values represent a complementary diagnostic tool, unless kidney or heart failure is present.
PMCID: PMC4305722  PMID: 15800991
Chromogranin-A; Hepatocellular carcinoma; Liver cirrhosis; Chronic hepatitis; Diagnosis
11.  Development and Validation of a Multidimensional Prognostic Index for One-Year Mortality from Comprehensive Geriatric Assessment in Hospitalized Older Patients 
Rejuvenation research  2008;11(1):151-161.
Our objective was to construct and validate a Multidimensional Prognostic Index (MPI) for 1-year mortality from a Comprehensive Geriatric Assessment (CGA) routinely carried out in elderly patients in a geriatric acute ward. The CGA included clinical, cognitive, functional, nutritional, and social parameters and was carried out using six standardized scales and information on medications and social support network, for a total of 63 items in eight domains. A MPI was developed from CGA data by aggregating the total scores of the eight domains and expressing it as a score from 0 to 1. Three grades of MPI were identified: low risk, 0.0–0.33; moderate risk, 0.34–0.66; and severe risk, 0.67–1.0. Using the proportional hazard models, we studied the predictive value of the MPI for all causes of mortality over a 12-month follow-up period. MPI was then validated in a different cohort of consecutively hospitalized patients. The development cohort included 838 and the validation cohort 857 elderly hospitalized patients. Of the patients in the two cohorts, 53.3 and 54.9% were classified in the low-risk group, respectively (MPI mean value, 0.18 ± 0.09 and 0.18 ± 0.09); 31.2 and 30.6% in the moderate-risk group (0.48 ± 0.09 and 0.49 ± 0.09); 15.4 and 14.2% in the severe-risk group (0.77 ± 0.08 and 0.75 ± 0.07). In both cohorts, higher MPI scores were significantly associated with older age (p = 0.0001), female sex (p = 0.0001), lower educational level (p = 0.0001), and higher mortality (p = 0.0001). In both cohorts, a close agreement was found between the estimated mortality and the observed mortality after both 6 months and 1 year of follow-up. The discrimination of the MPI was also good, with a ROC area of 0.751 (95%CI, 0.70–0.80) at 6 months and 0.751 (95%CI, 0.71–0.80) at 1 year of follow-up. We conclude that this MPI, calculated from information collected in a standardized CGA, accurately stratifies hospitalized elderly patients into groups at varying risk of mortality.
PMCID: PMC2668166  PMID: 18173367
12.  An explanatory randomised placebo controlled trial of levothyroxine supplementation for babies born <28 weeks’ gestation: results of the TIPIT trial 
Trials  2013;14:211.
Babies born before 28 weeks’ gestation have lower plasma thyroid hormone concentrations than more mature infants. This may contribute to their risk of poor developmental outcome. Previous studies have suggested that thyroxine supplementation for extremely preterm neonates may be beneficial. The aim of this study was to investigate the effect of administration of supplemental thyroxine to very premature babies on brain size and somatic growth at 36 weeks’ corrected gestational age (CGA).
In this explanatory multicentre double blind randomised placebo controlled trial, 153 infants born below 28 weeks’ gestation were randomised to levothyroxine (LT4) supplementation or placebo until 32 weeks’ CGA. The primary outcome was brain size assessed by the width of the subarachnoid space measured by cranial ultrasound at 36 weeks’ CGA. Lower leg length was measured by knemometry.
Babies in the LT4-supplemented and placebo groups had similar baseline characteristics. There were no significant differences between infants given LT4 (n=78) or placebo (n=75) for width of the subarachnoid space, head circumference at 36 weeks’ CGA, body weight at 36 weeks’ CGA or mortality. Infants who received LT4 had significantly shorter leg lengths at 36 weeks’ CGA although adjusted analysis for baseline length did not find a statistical difference. There was a significant correlation between low FT4 and wider subarachnoid space. No unexpected serious adverse events were noted and incidence of adverse events did not differ between the two groups.
This is the only randomised controlled trial of thyroxine supplementation targeting extremely premature infants. Supplementing all babies below 28 weeks’ gestation with LT4 had no apparent effect on brain size. These results do not support routine supplementation with LT4 for all babies born below 28 weeks’ gestation.
Trial registration
Current Controlled Trials ISRCTN89493983
EUDRACT number: 2005-003-09939
PMCID: PMC3711854  PMID: 23841945
Thyroxine supplementation; RCT; Extreme preterm; Brain; Growth
13.  The effectiveness of the Uchida-Kraepelin test for psychological stress: an analysis of plasma and salivary stress substances 
The hypothalamic-pituitary-adrenocortical (HPA) axis and sympathetic adrenomedullary (SAM) system are the major stress-response pathways. Plasma adrenocorticotropic hormone (ACTH) represents HPA axis activity, while plasma catecholamines are used as markers of the SAM system. Salivary alpha amylase (AA), chromogranin A (CgA), and immunoglobulin A (IgA) are candidate markers of stress activation, although their role has not been established. The Uchida-Kraepelin (U-K) test is a questionnaire that requires intense concentration and effort, and has been used as a tool to induce mental stress. However, it is not clear whether or not the test is effective as a psychological/mental stressor.
In this study, normal young women took the U-K test and serial measurements of plasma ACTH and catecholamines (dopamine, noradrenaline, and adrenaline) (n = 10), as well as salivary AA, CgA, and IgA (n = 16) before, during and after the test.
We found no changes in any of these parameters at any time point during or after the U-K test.
Our findings indicate that the U-K test is not a suitable for measuring the psychological/mental stress of young women because the plasma data showed that it did not affect the HPA axis and SAM system. The U-K test should be employed carefully as a psychological/mental stressor due to insufficient scientific evidence of its effectiveness. In addition, salivary AA, CgA, and IgA should not simply be compared with previous reports, because the mechanism of secretion and normal range of each salivary parameter remain unknown. Salivary AA, CgA, and IgA may not be suitable candidate markers of psychological/mental stress.
PMCID: PMC2679058  PMID: 19341484
14.  Stretching Before and After Exercise: Effect on Muscle Soreness and Injury Risk 
Journal of Athletic Training  2005;40(3):218-220.
Reference: Herbert RD, Gabriel M. Effects of stretching before and after exercise on muscle soreness and risk of injury: systematic review. BMJ. 2002;325:468.
Clinical Question: Among physically active individuals, does stretching before and after exercise affect muscle soreness and risk of injury?
Data Sources: Studies were identified by searching MEDLINE (1966–February 2000), EMBASE (1988–February 2000), CINAHL (1982–1999), SPORT Discus (1949–1999), and PEDro (to February 2000). I searched the reference lists of identified studies manually until no further studies were identified. The search terms stretch, exercise, warm-up, and cool down were used in all databases except MEDLINE. In MEDLINE, an optimized OVID search strategy was used. This strategy included the terms searched in the other databases as well as terms such as flexibility, athletic injuries, sports, soreness, and muscle.
Study Selection: The search was limited to English-language articles obtained from the electronic searches and the subsequent manual searches. This review included randomized or quasirandomized investigations that studied the effects of any stretching technique, before or after exercise, on delayed-onset muscle soreness, risk of injury, or athletic performance. Studies were included only if stretching occurred immediately before or after exercising.
Data Extraction: Data extraction and assessment of study quality were well described. The principal outcome measures were measurements of muscle soreness and indices of injury risk. Results from the soreness studies were pooled by converting the numeric scores to percentages of the maximum possible score. These data were then reported as millimeters on a 100-mm visual analogue scale. Results of comparable studies were pooled using a fixed-effects model meta-analysis. Survival analysis using a Cox regression model was calculated on the time-to-event (injury) data.
Main Results: The total number of articles identified using the search criteria was not provided; however, 5 studies on stretching and muscle soreness met inclusion and exclusion criteria. All of the studies meeting the criteria employed static stretching. One group reported the findings from 2 experiments, resulting in 6 studies meeting the inclusion and exclusion criteria. For the risk of injury, 2 studies, both investigating lower extremity injury risk in army recruits undergoing 12 weeks of basic training, met inclusion and exclusion criteria. On the basis of the PEDro scale, the methodologic quality of the studies included in the review was moderate (range, 2–7 of 10), with a mean of 4.1. For the studies on muscle soreness, 3 groups evaluated postexercise stretching, whereas 2 evaluated preexercise stretching. The participant characteristics from the 5 studies were noted to be reasonably homogeneous. Subjects in all studies were healthy young adults between the ages of 18 and 40 years (inclusive). For all studies but one, total stretching time per session ranged from 300 to 600 seconds. The exception was one study in which total stretching time was 80 seconds. Data from 77 subjects were pooled for the meta-analysis of muscle soreness outcomes at 24, 48, and 72 hours after exercising. At 24 hours postexercise, the pooled mean effect of stretching after exercise was −0.9 mm (on a 100-mm scale; negative values favor stretching), with a 95% confidence interval (CI) of −4.4 to 2.6 mm. At 48 hours, the pooled mean effect was 0.3 mm (95% CI = −4.0 to 4.5 mm), whereas at 72 hours, the pooled mean effect was −1.6 mm (95% CI = −5.9 to 2.6 mm). In each of these analyses, the results were not statistically significant in favor of either stretching or not stretching. For the studies on risk of lower extremity injury, the authors provided time-to-event (injury) data from 2630 subjects (65 military trainee platoons). These data were then combined and resulted in the allocation of 1284 subjects to stretching groups and 1346 subjects to control groups. The survival analysis identified a pooled estimate of the all-injuries hazard ratio of 0.95 (ie, a 5% decrease in injury risk; 95% CI = 0.78 to 1.16), which was not statistically significant.
Conclusions: The data on stretching and muscle soreness indicate that, on average, individuals will observe a reduction in soreness of less than 2 mm on a 100-mm scale during the 72 hours after exercise. With respect to risk of injury, the combined risk reduction of 5% indicates that the stretching protocols used in these studies do not meaningfully reduce lower extremity injury risk of army recruits undergoing military training.
PMCID: PMC1250267  PMID: 16284645
15.  Chromogranin A cells in the stomachs of patients with sporadic irritable bowel syndrome 
Molecular Medicine Reports  2014;10(4):1753-1757.
Several abnormalities have been demonstrated in the intestines of patients with irritable bowel syndrome (IBS); however, the endocrine cells in the stomachs of these patients have not been investigated. The aim of the present study was to determine whether there are any abnormalities in the endocrine cells of the stomachs of patients with IBS using chromogranin A (CgA) as a common marker for endocrine cells. A total of 76 patients were included, of which 26 presented with diarrhoea as the predominant symptom (IBS-D), 21 exhibited diarrhoea and constipation (IBS-M), and 29 experienced constipation as the predominant symptom (IBS-C). In addition, 59 healthy volunteers were recruited as controls. The patients and the controls underwent gastroscopy, and biopsy samples were obtained from the antrum and corpus of the stomach. The biopsy samples were immunostained and the CgA-positive cell density and the intensity of the CgA immunoreactivity were determined. The CgA-positive cell densities in the antra of patients with IBS-M were significantly reduced relative to the controls (P<0.01), while the densities were significantly increased in the antra and corpora of the IBS-C patients (P<0.01 and P<0.001 respectively). The intensities of CgA immunoreactivity did not differ significantly between the IBS patients and the controls. The abnormalities in the densities of endocrine cells were not associated with concomitant changes in the intensities of immunoreactivity; this may indicate unchanged synthesis and/or release of the hormones. In conclusion, the difference in the density of endocrine cells among the IBS subtypes may reflect a role of these cells in the differential symptomologies of these subtypes.
PMCID: PMC4148368  PMID: 25109259
computer image analysis; endocrine cells; immunohistochemistry; immunoreactivity intensity
16.  Systematic comprehensive geriatric assessment in elderly patients on chronic dialysis: a cross-sectional comparative and feasibility study 
BMC Nephrology  2012;13:30.
Elderly dialysis patients are prone to disabilities and functional decline. This aggravates their last period of life. It would be valuable to be able to preserve daily function and quality of life. Identification of domains requiring additional attention is not common practice in standard care. Therefore, we performed a systematic Comprehensive Geriatric Assessment (CGA) to assess physical and psychosocial function and tested its feasibility in daily practice. The CGA is used more frequently in the assessment of elderly cancer patients, and we therefore compared the outcomes to this group.
A cross-sectional, multicenter study, between June 1st and September 31st, 2009, in four Dutch outpatient dialysis units. Fifty patients aged 65 years or above who received dialysis because of end-stage renal disease (ESRD) were randomly included. We assessed the CGA during a systematic interview with patients and their caregivers. The cancer patients had had a similar CGA in an earlier study. We compared prevalences between groups.
In the dialysis population (68.0% 75 years or above, 76.6% on haemodialysis) caregivers often observed behavioral changes, such as deviant eating habits (34.0%) and irritability (27.7%). In 84.4%, caregivers felt overburdened by the situation of their family member. Somatic and psychosocial conditions were frequently found (polypharmacy (94.6%), depression (24.5%)) and prevalence of most geriatric conditions was comparable to those in elderly cancer patients.
Geriatric conditions were highly prevalent among elderly dialysis patients and prevalences were comparable in both populations. The CGA proved feasible for recognition of these conditions and of overburdened caregivers. This could prevent further functional decline and preserve quality of life.
PMCID: PMC3413513  PMID: 22646084
17.  Increased gastric chromogranin A cell density following changes to diets of patients with irritable bowel syndrome 
Molecular Medicine Reports  2014;10(5):2322-2326.
The gut endocrine cells control and regulate several functions of the gastrointestinal tract. They have been reported to be abnormal in irritable bowel syndrome (IBS), with alterations occurring in several functions regulated by these cells. Furthermore, it has been established that gut endocrine cells interact with the gut lumen contents, particularly the nutrients. The present study was undertaken to establish whether the positive outcome of dietary guidance observed in patients suffering from IBS is associated with a change in gastric endocrine cells. A total of 46 patients with IBS participated in the present study, of which 14 completed all aspects. These patients included nine females and five males with a mean age of 34 years (range, 20–45 years). In the healthy control group, nine females and five males, with a mean age of 54 years (range 26–70 years) were selected. The patients and controls underwent gastroscopy with biopsy samples taken from the corpus and antrum of the stomach. Each patient attended three sessions that lasted ~45 min each, and received individual guidance on their dietary management. The patients followed the diet prescribed for a minimum of three months, then further samples were taken using a method similar to that used for the initial biopsies. The biopsy samples were immunostained using the avidin-biotin complex method for chromogranin A (CgA) and quantified by computerized image analysis. The patients with IBS presented a low density of CgA compared with the controls. The density of CgA increased in these patients following dietary guidance and changes in food intake. The present observations emphasized the interaction between food intake and gut endocrine cells. The current study also suggests that the positive effects of dietary guidance may be attributed to changes in gut endocrine cell density.
PMCID: PMC4214334  PMID: 25174455
diet; computerized image analysis; chromogranin A; guts endocrine cells; immunohistochemistry
18.  Decreased plasma Chromogranin A361-372 (Catestatin) but not Chromogranin A17-38 (Vasostatin) in female dogs with bacterial uterine infection (pyometra) 
Pyometra often induces systemic inflammatory response syndrome (SIRS) and early diagnosis is crucial for survival. Chromogranin A (CgA) is a neuroendocrine secretory protein that is co-released with catecholamines from the adrenal medulla and sympathetic nerve endings. A prognostic value of CgA has been found in humans that are critically ill or that have SIRS associated with infection. CgA has not yet been studied in dogs with bacterial infection. The aim of the study was to investigate CgA, measured by Chromogranin A361-372 (Catestatin; Cst) and Chromogranin A17-38 (Vasostatin; VS) in healthy dogs and in dogs with pyometra.
Fifty dogs with pyometra, sampled prior to surgery and 64 healthy female dogs were included. In 19 pyometra cases, blood samples were also collected postoperatively. Concentrations of Cst and VS were measured in heparinised plasma and Cst also measured in EDTA plasma, by in-house radioimmunoassays. Student’s t-test and Wilcoxon two-sample test was used to test for differences between dog groups. Pre- and postoperative samples in dogs with pyometra were analysed by paired t-test. Pearson correlation was used to investigate associations of laboratory variables and hospitalization. P < 0.05 was considered significant.
Concentrations of Cst were decreased in pyometra dogs (mean ± SE, 1.01 ± 0.05 nmol/L) compared to healthy dogs (mean ± SE, 1.70 ± 0.03 nmol/L) (p ≤ 0.0001). VS concentrations did not differ significantly between dogs with pyometra (0.40 ± 0.04 nmol/L) and healthy dogs (0.42 ± 0.03 nmol/L). Mean ± SE pre- and postoperative concentration of Cst (1.0 ± 0.04 nmol/L and 0.9 ± 0.2 nmol/L) and VS (0.36 ± 0.04 nmol/L and 0.36 ± 0.04 nmol/L) in dogs with pyometra did not differ significantly. Neither Cst nor VS concentrations were associated with duration of hospitalization and were not significantly different in the four dogs with pyometra that had prolonged (≥3 d) postoperative hospitalization.
Concentrations of Cst, but not VS, were decreased in pyometra. Cst and VS concentrations before and after ovariohysterectomy did not differ significantly and were not associated with duration of hospitalization. Further studies are warranted to evaluate a possible diagnostic or prognostic value for Cst and VS.
Electronic supplementary material
The online version of this article (doi:10.1186/s12917-015-0328-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4318355  PMID: 25636335
Pyometra; Chromogranin A; Catestatin; Vasostatin; C-reactive protein; Biomarker; Dog; Uterine infection
19.  Comprehensive geriatric assessment for older adults admitted to hospital 
Comprehensive geriatric assessment (CGA) is a multidimensional, interdisciplinary diagnostic process to determine the medical, psychological and functional capabilities of a frail elderly person in order to develop a co-ordinated and integrated plan for treatment and long-term follow up.
We sought to evaluate the effectiveness of CGA in hospital for older adults admitted as an emergency.
Search methods
We searched the Cochrane Effective Practice and Organisation of Care (EPOC) Group Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), the Database of Abstracts of Reviews of Effects (DARE), MEDLINE, EMBASE, CINAHL and AARP Ageline, and handsearched high-yield journals.
Selection criteria
We searched for randomised controlled trials comparing CGA (whether by mobile teams or in designated wards) to usual care.
Data collection and analysis
Two review authors initially assessed eligibility and trial quality and extracted published data.
Main results
Twenty-two trials evaluating 10,315 participants in six countries were identified. Patients in receipt of CGA were more likely to be alive and in their own homes at up to six months (OR 1.25, 95% CI 1.11 to 1.42, P = 0.0002) and at the end of scheduled follow up (median 12 months) (OR 1.16, 95% CI 1.05 to 1.28, P = 0.003) when compared to general medical care. In addition, patients were less likely to be institutionalised (OR 0.79, 95% CI 0.69 to 0.88, P < 0.0001). They were less likely to suffer death or deterioration (OR 0.76, 95% CI 0.64 to 0.90, P = 0.001), and were more likely to experience improved cognition in the CGA group (OR 1.11, 95% CI 0.20 to 2.01, P = 0.02). Subgroup interaction in the primary outcomes suggests that the effects of CGA are primarily the result of CGA wards.
Authors’ conclusions
Comprehensive geriatric assessment increases a patient’s likelihood of being alive and in their own home at up to 12 months.
PMCID: PMC4164377  PMID: 21735403
*Frail Elderly; *Hospitalization; *Outcome and Process Assessment (Health Care); Comprehensive Health Care [*methods]; Emergencies; Geriatric Assessment [*methods]; Independent Living; Mortality; Aged; Humans
20.  Catecholamine-secreting carotid body paraganglioma: successful preoperative control of hypertension and clinical symptoms using high-dose long-acting octreotide 
A 48-year-old hypertensive and diabetic patient presented with a 10-year history of progressive right facial pain, tinnitus, hearing loss, sweating, and palpitations. Investigations revealed a 5.6 cm vascular tumor at the carotid bifurcation. Her blood pressure (BP) was 170/110, on lisinopril 20 mg od and amlodipine 10 mg od and 100 U of insulin daily. A catecholamine-secreting carotid body paraganglioma (CSCBP) was suspected; the diagnosis was confirmed biochemically by determining plasma norepinephrine (NE) level, 89 000 pmol/l, and chromogranin A (CgA) level, 279 μg/l. Meta-iodobenzylguanidine and octreotide scanning confirmed a single tumor in the neck. A week after giving the patient a trial of octreotide 100 μg 8 h, the NE level dropped progressively from 50 000 to 25 000 pmol/l and CgA from 279 to 25 μg/l. Treatment was therefore continued with labetalol 200 mg twice daily (bid) and long-acting octreotide-LA initially using 40 mg/month and later increasing to 80 mg/month. On this dose and with a reduced labetalol intake of 100 mg bid, BP was maintained at 130/70 and her symptoms resolved completely. CgA levels returned to normal in the first week and these were maintained throughout the 3 month treatment period. During tumor resection, there were minimal BP fluctuations during the 10 h procedure. We conclude that short-term high-dose octreotide-LA might prove valuable in the preoperative management of catecholamine-secreting tumors. To the best of our knowledge, this is the first report on the successful use of octreotide in a CSCBP.
Learning points
The value of octreotide scanning in the localization of extra-adrenal pheochromocytoma.Control of catecholamine secretion using high-dose octreotide.This is a report of a rare cause of secondary diabetes and hypertension.
PMCID: PMC4120363  PMID: 25136449
21.  Effect of laughter on salivary flow rates and levels of chromogranin A in young adults and elderly people 
Salivary chromogranin A (CgA) levels and salivary flow rates were measured to evaluate the stress relief effect of laughter on the young and the elderly.
Thirty healthy volunteers (15 aged 20–25 years; 15 aged 62–83 years) performed a serial arithmetic task for 15 min and then watched a comedy video for 30 min. On a different day, as a control, they watched a non-humorous video after performing a task similar to the first one. Saliva samples were collected immediately before and after the arithmetic task, 30 min after completing the task (immediately after watching the film), and 30 min after watching the film (60 min after completing mental task). Salivary CgA levels were determined by enzyme-linked immunosorbent assay.
In the elderly group, salivary flow rates, which had declined by the end of the arithmetic task, were statistically significantly higher after watching the comedy video. In the young group, salivary CgA levels, which had increased by the end of the task, had statistically significantly declined after watching the comedy video. No such post-task changes were apparent in control results; in the young group, there was a statistically significant interprotocol difference in salivary CgA levels.
These findings suggest that laughter may relieve stress, particularly in the young people.
PMCID: PMC3493625  PMID: 22481535
Chromogranin A; Laughter; Salivary flow rates; Stress; The elderly
22.  Risk factors for rectal lymphogranuloma venereum in gay men: results of a multicentre case-control study in the UK 
Sexually Transmitted Infections  2014;90(4):262-268.
To identify risk factors for rectal lymphogranuloma venereum (rLGV) in men who have sex with men (MSM).
A case-control study at 6 UK hospitals compared MSM with rLGV (cases) with rLGV-negative controls: MSM without potential rLGV symptoms (CGa) and separately, MSM with such symptoms (CGs).
Between 2008 and 2010, there were 90 rLGV cases, 74 CGa and 69 CGs recruited. Lifestyles and sexual behaviours in the previous 3 months were reported using internet-based computer-assisted self-interviews. Logistic regression was used to investigate factors associated with rLGV.
Cases were significantly more likely to be HIV-positive (89%) compared with CGa (46%) and CGs (64%). Independent behavioural risks for rLGV were: unprotected receptive anal intercourse (adjusted OR (AOR)10.7, 95% CI 3.5 to 32.8), fisting another (AOR=6.7, CI 1.8 to 25.3), sex under the influence of gamma-hydroxybutyrate (AOR=3.1, CI 1.3 to 7.4) and anonymous sexual contacts (AOR=2.7, CI 1.2 to 6.3), compared with CGa; unprotected insertive anal intercourse (AOR=4.7, CI 2.0 to 10.9) and rectal douching (AOR=2.9 CI 1.3 to 6.6), compared with CGs. An incubation period from exposure to symptoms of 30 days was indicated.
Unprotected receptive anal intercourse is a key risk factor for rectal LGV with the likelihood that rectal-to-rectal transmission is facilitated where insertive anal sex also occurs. The association between HIV and rLGV appears linked to HIV-positive men seeking unprotected sex with others with the same HIV status, sexual and drug interests. Such men should be targeted for frequent STI screening and interventions to minimise associated risks.
PMCID: PMC4033107  PMID: 24493859
Chlamydia Trachomatis; Lymphogranuloma Venereum; Gay Men; Sexual Behaviour; HIV
23.  A new human chromogranin 'A' immunoradiometric assay for the diagnosis of neuroendocrine tumours 
British Journal of Cancer  2001;84(5):636-642.
We investigated whether plasma chromogranin A (CgA), measured by a new immunoradiometric assay, may be a sensitive and specific marker of phaeochromocytoma and of other neuroendocrine tumours. This study involved 121 patients of whom 20 with phaeochromocytoma, 28 with other neuroendocrine tumours (19 gastroenteropancreatic tumors, 3 medullary thyroid and 6 small cell lung carcinomas), 25 with solid nonfunctioning adrenocortical tumours and 48 with essential hypertension. In addition, 130 normal subjects were taken as controls. Plasma catecholamines were measured by using high-performance liquid chromatography, and CgA by a two-site sandwich immunoradiometric assay involving monoclonal antibodies raised against the unprocessed central domain (145–245) of human CgA. Plasma CgA in controls (49.0 ± 3.1 ng ml–1, mean ± SE) and in essential hypertensives (50.8 ± 3.5 ng ml–1) was lower (P< 0.0001) than in adrenocortical tumours (91.8 ± 13.2 ng ml–1), in phaeochromocytomas (254 ± 49 ng ml–1) and in patients with other neuroendocrine tumours (469 ± 84 ng ml–1). Plasma CgA and catecholamines identified 13 and 18 out of 20 phaeochromocytomas with sensitivity of 65% and 90%, respectively. Combined measurement of both markers improved sensitivity up to 100%. In the other neuroendocrine tumours, CgA was abnormal in 23/28 cases (sensitivity 82%) and in 6 it was the only circulating marker of disease. In gastroenteropancreatic tumours, CgA measurement identified all cases (sensitivity 100%). Specificity of CgA in patients with essential hypertension was 98%. In conclusion, CgA determination showed high sensitivity in identifying gastroenteropancreatic tumours and, in association with catecholamines, in detecting patients with phaeochromocytoma. CgA sometimes appeared to be the only circulating marker of disease. Since the specificity of CgA proved to be excellent, this assay may be useful for diagnosis both of functioning and non-functioning neuroendocrine tumours. © 2001 Cancer Research Campaign
PMCID: PMC2363780  PMID: 11237384
chromogranin A; phaeochromocytoma; neuroendocrine tumours
Shoulder dysfunction and injury are common in throwing athletes. Loss of internal rotation has been correlated to shoulder pathologies. The purpose of this study was to assess the effects of a stretching protocol on passive internal rotation. The purpose of this study was assess the effects of a stretching protocol on passive internal rotation motion in the throwing shoulders of collegiate baseball players.
Study Design:
Pre-Post, intervention, using a within subjects comparison of a convenience sample.
Glenohumeral internal rotation and external rotation of the throwing and non-throwing shoulders of NCAA Division I baseball players were measured using a universal goniometer. Determinations were made as to the degree of Glenohumeral Internal Rotation Deficit (GIRD) in the throwing shoulder. A daily (5 days per week), 12-week posterior capsule stretching program was administered. Post-stretching internal rotation and external rotation measures were again obtained. The coaches and athletic trainers of the included team monitored the players for shoulder injuries and innings of training/competition lost due to shoulder injuries during the 12 week intervention.
A significant increase in range of motion was found for dominant arm internal rotation (IR) and total range of motion (TOT) following the stretching program. No statistically significant improvement in range of motion was found for external rotation (ER), non-throwing arm internal rotation (NDIR), non-throwing arm external rotation (NDER), and non-throwing arm total motion (NDTOT).
Implementation of a posterior capsule stretching program may be helpful to facilitate increased passive internal rotation range of motion at the glenohumeral joint. Further research should be performed using a control group not receiving the stretching program in order to more completely establish the impact of stretching on measures of passive glenohumeral range of motion.
Level of Evidence:
PMCID: PMC3414068  PMID: 22893856
GIRD; glenohumeral internal rotation; stretching
25.  Clinical Significance of Treatment Effects with Aripiprazole versus Placebo in a Study of Manic or Mixed Episodes Associated with Pediatric Bipolar I Disorder 
Published studies in adult and pediatric bipolar disorder have used different definitions of treatment response. This analysis aimed to compare different definitions of response in a large sample of children and adolescents.
Anexploratory analysis of a 4-week, multicenter, placebo-controlled study assessed patients (n=296; ages, 10–17 years) with an acute manic/mixed episode associated with bipolar I disorder who were randomized to aripiprazole (10 or 30 mg/day) or placebo. The primary efficacy endpoint was mean change from baseline to week 4 in Young Mania Rating Scale (YMRS) total score. Additional assessments included: Clinical Global Impressions–Bipolar Disorder (CGI-BP) Overall and Mania scales, Child Global Assessment Scale (CGAS), and parent and subject General Behavior Inventory. Response was compared across seven operational definitions. Cohen's κ and Spearman's correlation tested relationships between various response definitions or changes in outcome measures and clinically meaningful improvement (defined as a CGI-BP Overall Improvement score of 1 or 2).
Response rates varied depending upon the operational definition, but were highest for 95% reliable change (statistical method used to determine individual change from previous assessment) and ≥33% reduction in YMRS total score. Response rate definitions with the highest validity in terms of predicting clinically meaningful improvement were: ≥50% reduction on YMRS (κ=0.64), a composite definition of response (YMRS <12.5, Children's Depression Rating Scale-Revised (CDRS-R) ≤40, and CGAS ≥51; κ=0.59), and 95% reliable change on the CGAS or 33% reduction on YMRS (κ=0.56). Parent ratings of symptoms were generally better at detecting symptom improvement than were subject ratings (κ=∼0.4–0.5 vs. ∼0.2 when compared with CGI-BP Overall Improvement score).
Clinically meaningful definitions of response in acute treatment of a manic/mixed episode in pediatric subjects include a 50% change in YMRS and a composite measure of response. Parent-reported measures of symptom improvement appear reliable for assessing symptom change.
PMCID: PMC3696952  PMID: 23480324

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