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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.  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
5.  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
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.  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
8.  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
9.  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
10.  Screening older cancer patients for a Comprehensive Geriatric Assessment: A comparison of three instruments 
Journal of geriatric oncology  2011;2(2):121-129.
The Vulnerable Elders Survey (VES-13) has been validated for screening older cancer patients for a Comprehensive Geriatric Assessment (CGA). To identify a widely acceptable approach that encourages oncologists to screen older cancer patients for a CGA, we examined the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) and Karnofsky Index of Performance Status (KPS) scales’ ability to identify abnormalities on a CGA and compared the performance of the two instruments with the VES-13.
We enrolled 117 participants, ≥65 years with stage I–IV cancer into this cross-sectional study. Our primary outcome variable was ≥two abnormalities on the CGA, (Yes or No). We employed receiver operating characteristic curve analysis to compare the discriminatory abilities of the three instruments to identify ≥two abnormalities on the CGA.
Of the 117 participants, 43% had ≥two abnormalities on the CGA. The VES-13 was predictive of ≥two abnormalities on the CGA, area under the curve (AUC)=0.85 [(95% CI: 0.78–0.92); sensitivity=88%, specificity=69%, at cut-off ≥3]. The ECOG-PS and KPS showed similar discriminatory powers, AUC=0.88 [(95% CI: 0.83–0.94); sensitivity=94%, specificity=55%, at cut-off ≥1]; and AUC=0.90 [(95% CI: 0.84–0.96); sensitivity=78%, specificity=91%, at cut-off ≤80%], respectively.
The ECOG-PS and KPS were equivalent to the VES-13 in identifying older cancer patients with at least two abnormalities on the CGA. Given that oncologists are already conversant with the KPS and ECOG-PS, these two instruments offer medical oncologists a widely acceptable approach for screening older patients for a CGA.
PMCID: PMC3173499  PMID: 21927633
Older; Cancer; Comprehensive Geriatric Assessment; Screening; VES-13; KPS; ECOG-PS
11.  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
12.  Clinical Usefulness of Plasma Chromogranin A in Pancreatic Neuroendocrine Neoplasm 
Journal of Korean Medical Science  2013;28(5):750-754.
Chromogranin A (CgA) is widely used as an immunohistochemical marker of neuroendocrine neoplasms and has been measurable in plasma of patients. We assessed the clinical role of plasma CgA in diagnosing pancreatic neuroendocrine neoplasm (PNEN). CgA was checked in 44 patients with pancreatic mass who underwent surgical resection from 2009 through 2011. The cutoff value for diagnosing PNEN and the relationships between CgA and clinicopathologic variables were analyzed. Twenty-six patients were PNENs and 18 patients were other pancreatic disorders. ROC analysis showed a cutoff of 60.7 ng/mL with 77% sensitivity and 56% specificity, and the area under the curve (AUC) was 0.679. Among PNEN group, the sensitivity and specificity of diagnosing metastasis were 100% and 90% respectively when CgA cutoff was 156.5 ng/mL. The AUC was 0.958. High Ki-67 index (160.8 vs 62.1 ng/mL, P = 0.001) and mitotic count (173.5 vs 74.6 ng/mL, P = 0.044) were significantly correlated with plasma CgA, but the tumor size was not. In conclusion, CgA has a little value in diagnosing PNEN. However, the high level of CgA (more than 156.5 ng/mL) can predict the metastasis. Also, plasma CgA level correlates with Ki-67 index and mitotic count which represents prognosis of PNENs.
PMCID: PMC3653089  PMID: 23678268
Pancreatic Neuroendocrine Neoplasm; Chromogranin A; Diagnosis; Pancreatic Neoplasms
13.  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
14.  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
15.  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
16.  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
17.  Usefulness of the Comprehensive Geriatric Assessment in Older Patients with Upper Gastrointestinal Bleeding: A Two-Year Follow-Up Study 
The potential usefulness of standardized comprehensive geriatric assessment (CGA) in evaluating treatment and follow-up of older patients with upper gastrointestinal bleeding is unknown.
To evaluate the usefulness of the CGA as a 2-year mortality multidimensional prognostic index (MPI) in older patients hospitalized for upper gastrointestinal bleeding.
Materials and Methods
Patients aged ≥65 years consecutively hospitalized for acute upper gastrointestinal bleeding were included. Diagnosis of bleeding was based on clinical and endoscopic features. All patients underwent a CGA that included six standardized scales, i.e., Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Short Portable Mental Status Questionnaire (SPMSQ), Mini Nutritional Assessment (MNA), Exton-Smith Score (ESS) and Comorbity Index Rating Scale (CIRS), as well as information on medication history and cohabitation, for a total of 63 items. A MPI was calculated from the integrated total scores and expressed as MPI 1 = low risk, MPI 2 = moderate risk, and MPI 3 = severe risk. The predictive value of the MPI for mortality over a 24-month follow-up was calculated.
36 elderly patients (M 16/F 20, mean age 82.8 ± 7.9 years, range 70–101 years) were included in the study. A significant difference in mean age was observed between males and females (M 80.1 ± 4.8 vs. F 84.9 ± 9.3 years; p < 0.05). The causes of upper gastrointestinal bleeding were duodenal ulcer in 38.8%, gastric ulcer in 22.2%, and erosive gastritis in 16.6% of the patients, while 16.6% had gastrointestinal bleeding from unknown origin. The overall 2-year mortality rate was 30.5%. 18 patients (50%) were classified as having a low-risk MPI (mean value 0.18 ± 0.09), 12 (33.3%) as having a moderate-risk MPI (mean value 0.48 ± 0.08) and 6 (16.6%) as having a severe-risk MPI (mean value 0.83 ± 0.06). Higher MPI grades were significantly associated with higher mortality (grade 1 = 12.5%, grade 2 = 41.6%, grade 3 = 83.3%; p = 0.001). Adjusting for age and sex, the prognostic efficacy of MPI for mortality was confirmed and highly significant (odds ratio 10.47, 95% CI 2.04–53.6).
CGA is a useful tool for calculating a MPI that significantly predicts the risk of 2-year mortality in older patients with upper gastrointestinal bleeding.
PMCID: PMC2645635  PMID: 17468547
Comprehensive geriatric assessment; Multidimensional prognostic index; Upper gastrointestinal bleeding; diagnosis
18.  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
19.  Prenatal smoking exposure and psychiatric symptoms in adolescence 
Explore associations between smoking in pregnancy and psychiatric symptoms in the adolescent offspring.
A prospective population based follow-up of 84 adolescents at 14 years of age, of whom 32 of the mothers reported smoking during pregnancy.
Main outcome measures
The Achenbach System of Empirically Based Assessment (ASEBA), ADHD-Rating Scale IV, Autism Spectrum Screening Questionnaire (ASSQ), Children's Global Assessment Scale (CGAS), estimated IQ based on four subscales of WISC-III.
Adolescents who were born by smokers had significantly more rule-breaking and aggressive behaviour, externalizing and total problems on the ASEBA than adolescents of non-smokers (p < 0.01), when reported by mothers, fathers and teachers. ADHD symptoms were reported more frequently (p < 0.05), and mothers also reported more internalizing symptoms (p < 0.05) and social problems (p < 0.001). The ASSQ sum score was higher (p < 0.001), and overall function as measured by the CGAS was lower (p < 0.01) for the smoking-exposed group. Associations were still present after controlling for possible confounding factors.
Adolescents exposed to prenatal smoking had higher scores for both externalizing and internalizing psychiatric symptoms, which could not be explained by a broad range of possible psychosocial confounders. Thus, smoking in pregnancy may be a marker for increased risk of psychiatric symptoms in the offspring.
PMCID: PMC2049061  PMID: 17407460
Adolescent; Mental health; Pregnancy; Tobacco smoke
20.  Elevated Peripheral Blood Plasma Concentrations of Tie-2 and Angiopoietin 2 in Patients with Neuroendocrine Tumors 
Gastro-entero-pancreatic/neuroendocrine (NET) tumors are highly vascularized neoplasms. However, our knowledge concerning circulating levels of the angiogenic factors in NET patients still remains insufficient.
The aim of this study was to measure plasma concentrations of VEGF, angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), soluble Tie-2, endostatin, osteopontin (OPN) and chromogranin A (CgA) in 36 NET patients and 16 controls.
Only the plasma concentrations of Tie-2 and CgA were higher in NET patients as compared to controls. These levels were within the reference range in controls; however one control demonstrated slightly elevated Tie-2 and 4 elevated CgA. Similarly, in the subgroup of patients with carcinoid syndrome, only Tie-2 and CgA concentrations were higher than those in patients with non-functioning NETs. In turn, in the subgroup of metastatic patients, only Ang-2 levels were higher than in those with localized disease. A positive correlation was found between Ang-2 and Tie-2 levels in metastatic patients and between Ang-1 and Tie-2 in localized NETs.
The plasma concentration of Tie-2 is proposed as an additional marker for NET patients and seems to be similarly effective as the currently used CgA level. Moreover, higher plasma levels of Ang-2 together with the positive correlation between Ang-2 and Tie-2 levels in metastatic subjects, implies that cases with a Tie-2 level above the upper limits, together with higher level of Ang-2 seem to be highly predictive of metastases.
PMCID: PMC3291970  PMID: 22408401
angiogenic factors; NET patients; Ang-1; Ang-2; Tie-2
21.  A Process-Oriented Breastfeeding Training Program for Healthcare Professionals to Promote Breastfeeding: An Intervention Study 
Breastfeeding Medicine  2012;7(2):85-92.
The aim of the study was to evaluate the effects of process-oriented training in supportive breastfeeding counseling for midwives and postnatal nurses on the time lapse between the initial breastfeeding session, introduction of breastmilk substitutes and solids, and the duration of breastfeeding.
Materials and Methods
Ten municipalities in Sweden were randomized to either the intervention or control groups. The intervention included a process-oriented training program for midwives and postnatal nurses in the intervention municipalities. Primiparas (n=540) living in either an intervention or control municipality were asked to participate in a longitudinal study to evaluate the care given. Data collection for control group A (CGA) (n=162) started before the intervention was initiated. Data for control group B (CGB) (n=172) were collected simultaneously with the intervention group (IG) (n=206). The mothers responded to questionnaires at 3 days, 3 months, and 9 months postpartum.
As a result of the process-oriented training program for midwives and postnatal nurses, the IG mothers had a significantly longer duration of exclusive breastfeeding, even if the initial breastfeeding session did not occur within 2 hours after birth, than the corresponding group of CGA mothers (p=0.01). Fewer infants in the IG received breastmilk substitutes (in the first week of life) without medical reasons compared with the control groups (p=0.01). The IG infants were significantly older (3.8 months) when breastmilk substitutes were introduced (after discharge from the hospital) compared with the infants in the control groups (CGA, 2.3 months, p=0.01; CGB, 2.5 months, p=0.03).
A process-oriented training program for midwives and postnatal nurses was associated with a reduced number of infants being given breastmilk substitutes during the 1st week without medical reasons and delayed the introduction of breastmilk substitutes after discharge from the hospital.
PMCID: PMC3317786  PMID: 22168946
22.  Chromogranins can be measured in samples from cats and dogs 
BMC Research Notes  2014;7:336.
Methods for objective evaluation of stress in animals are important, but clinically difficult. An alternative method to study the sympathetic activity may be to investigate Chromogranin A (CGA), Chromogranin B (CGB) and Secretogranin II (SG2). The aim of this study was to investigate the cross-reactivity of CGA, CGB and SG2 between man, cat and dog and to explore possibilities to measure these proteins in samples from cats and dogs.
Adrenal gland extracts from feline and canine species were measured by region-specific radioimmunoassays in different dilution steps to explore possible inter species cross reactivity. High cross reactivity was found for cats in the CGA17-38, CGA324-337, CGA361-372, CGB and SG2 assays. High cross reactivity was found for dogs in the CGA17-38, CGA361-372, CGB and SN assays. The method measuring the intact CGA was not useful for measurements in cats and dogs.
Region-specific assays measuring defined parts of CGA, CGB and SG2 can be used for measurements in samples from cats and dogs. These results are promising and will allow for further studies of these proteins as possible clinical biomarkers in cats and dogs.
PMCID: PMC4055239  PMID: 24899097
Chromogranin; Secretogranin; Canine; Feline; Human; Radioimmunoassay
23.  Hypothesis-Driven Candidate Gene Association Studies: Practical Design and Analytical Considerations 
American Journal of Epidemiology  2009;170(8):986-993.
Candidate gene association studies (CGAS) are a useful epidemiologic approach to drawing inferences about relations between genes and disease, especially when experimental data support the involvement of specific biochemical pathways. The value of CGAS is apparent when allele frequencies are low, effect sizes are small, or the study population is limited or unique. CGAS is also valuable for validating previous reports of genetic associations with disease in different populations. Despite the many advantages, the information generated from CGAS is sometimes compromised because of either inefficient study design or suboptimal analytical approaches. Here the authors discuss issues related to the study design and statistical analyses of CGAS that can help to optimize their usefulness and information content. These issues include judicious hypothesis-driven selection of biochemical pathways, genes, and single nucleotide polymorphisms, as well as appropriate quality control and analytical procedures for measuring main effects and for evaluating environmental exposure modifications and interactions. A study design algorithm using the example of DNA repair genes and cancer is presented for purposes of illustration.
PMCID: PMC2765367  PMID: 19762372
cancer; data analysis; DNA repair; genetic epidemiology; genome-wide association study; haplotypes; polymorphism, single nucleotide; research design
24.  Effect of stretching duration on active and passive range of motion in the lower extremity 
OBJECTIVES: To investigate the effect of different durations of stretching (five or 15 seconds) on active and passive range of motion (ROM) in the lower extremity during a five week flexibility training programme. METHOD: Twenty four university sport club members (19 men, five women), with a mean (SD) age of 20.5 (1.35) years, were randomly assigned to one of three groups (two treatment and one control). The two treatment groups participated in a static active stretching programme three times a week for a five week period, holding each stretch for a duration of either five or 15 seconds. The total amount of time spent in a stretched position was controlled. The five second group performed each stretch nine times and the 15 second group three times resulting in a total stretching time of 45 seconds for both groups for each exercise. The control group did not stretch. Active and passive ROM were determined during left hip flexion, left knee flexion, and left knee extension before and after the training programme using an inclinometer. RESULTS: Two factor within subject analysis of variance indicated no significant difference in ROM before and after the training programme for the control group. However, significant improvements in active and passive ROM (p < 0.05) were shown in both treatment groups after the five week training programme. Two factor analysis of variance with repeated measures and post hoc analysis showed significant differences between the treatment groups and the control group for the improvements observed in active (p < 0.05) and passive (p < 0.05) ROM. The five and 15 second treatment groups did not differ from one another when ROM was assessed passively, but significant differences were apparent for active ROM, with the 15 second group showing significantly greater improvements (p < 0.05) than the five second group. CONCLUSION: These findings suggest that holding stretches for 15 seconds, as opposed to five seconds, may result in greater improvements in active ROM. However, sustaining a stretch may not significantly affect the improvements gained in passive ROM. 

PMCID: PMC1756178  PMID: 10450481
25.  Bracing and Taping Techniques and Patellofemoral Pain Syndrome 
Journal of Athletic Training  2012;47(3):358-359.
D'hondt NE, Struijs PA, Kerkhoffs GM, et al. Orthotic devices for treating patellofemoral pain syndrome. Cochrane Database Syst Rev. 2002;(2):CD002267.
Clinical Question:
Is there an effective bracing or taping technique for treating patellofemoral pain?
Data Sources:
The authors searched the Cochrane Musculoskeletal Injuries Group specialized register (December 2001), the Cochrane Controlled Trials Register (2000, issue 2), MEDLINE (January 1966 to March 2000), EMBASE (January 1988 to March 2000), CINAHL (January 1982 to March 2000), and PEDro (up to March 2000) without language limitations. They also contacted relevant orthotic companies and searched the included reference lists of the retrieved articles. The search terms for MEDLINE were anterior knee pain, arthralgia, knee joint, patella, and patellofemoral pain. The search terms for EMBASE were brace, chondropathy, dynamic splint, knee, orthosis, orthotics, patella, patella chondromalacia, patellofemoral joint, randomized control trial, and strap. The search terms for CINAHL were anterior knee pain, brace, orthot, orthos, randomi, strap, tape, patell, and patellofemoral. In PEDro, the subsequent composite of search terms was therapy: manipulation, massage, mobilization, orthoses, splinting, stretching, strength training, taping; subdiscipline: musculoskeletal, orthopaedics, sports; method: clinical trial; problem: muscle weakness, pain, reduced joint compliance; body part: foot or ankle, lower leg or knee.
Study Selection:
All randomized and quasi-randomized trials comparing the effectiveness of knee or foot orthotics for treatment of patellofemoral pain syndrome were included. Any trials that described the use of orthotic devices in conjunction with operative treatment were excluded from this review. Using these inclusion criteria, 2 reviewers independently assessed the potentially eligible studies and resolved any disagreements through conversation and negotiation by a third reviewer. Although the authors mentioned that the review's purpose was to assess knee and foot orthoses, none of the included studies assessed foot orthoses. Therefore, all trials that examined foot orthotics were excluded.
Data Extraction:
Using a preset extraction form, 2 reviewers independently entered data into a review manager software program (RevMan 2000; The Cochrane Collaboration, Oxford, United Kingdom). This program was produced by the Cochrane Collaboration to support systematic reviews. Any further information needed regarding methods and data was requested from the authors. Because of heterogeneity of the study population, interventions, and follow-up periods, statistical pooling was not conducted. In place of statistical pooling, the strength of scientific evidence was graded based on a scale of A through D, with A being the strongest evidence-based research and D being the weakest evidence-based research.
Main Results:
The search strategy identified 15 trials, of which only 5 trials met all the inclusion criteria and had enough data to be considered for pooling. The 5 trials involved 362 participants who were assessed for pain, functional improvement, isokinetic muscular strength, motivation, subjective success, worst pain, usual pain, subjective clinical pain, and patellofemoral congruence angle. Of the 5 studies included in the review, only the following statistically significant differences were found. The Protonics orthosis significantly decreased pain and improved function based on the Kujala score versus no treatment. A home exercise program with McConnell taping and biofeedback decreased pain and improved function based on the Functional Index Questionnaire versus home exercise and monitored therapy. In addition, the Protonics orthosis versus no treatment resulted in a patellofemoral congruence angle change; McConnell taping versus Couman bandage improved satisfaction with applied therapy and isokinetic muscle strength at 300°/s of knee flexion. No other findings included in the review studies were statistically significant. The included studies were inadequate in their methodologic quality and incomplete in their research-based evidence, which was obtained by their investigators.
According to the systematic review by D'hondt et al, the strength of retrieved research-based evidence of effectiveness of orthotic devices in the treatment of patellofemoral pain syndrome was graded C. This grade was appropriate because all trials had low-quality methodologic evidence to support or reject the effectiveness of orthotics and taping techniques in reducing pain. Although very little scientific evidence is available regarding the use of orthotics and taping techniques, D'hondt et al identified trends in orthotics and taping techniques that should be considered in clinical practice. A comprehensive exercise and stretching program with tape application was more effective in decreasing worst pain and usual pain and increasing functional improvement. This finding indicates that patellofemoral pain syndrome is best treated by using more than 1 intervention. In addition, no difference was apparent in pain outcomes between McConnell taping technique and Couman bandage: neither technique resolved pain. The Protonics orthosis actively affected patellar tracking by reducing internal rotation of the femur and compression on the lateral aspect of the patella. As a result, the Protonics orthosis reduced pain compared with no treatment. In contrast, the Couman bandage is used only to guide the patellar tracking pattern and massage the structures around the patella during motion. Yet a home exercise program with the addition of a stretching program and McConnell taping decreased pain and increased function, which may suggest that a combination of treatment approaches is needed to effectively treat the condition, as found in previous studies.
PMCID: PMC3392166  PMID: 22892417
knee orthotics; knee pain; rehabilitation

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