Using the new INTRABEAM mobile intraoperative radiotherapy system during surgery for pancreatic cancer: a case report

Xiaodong Song
Zili Shao
Huihong Liang
Using the new INTRABEAM mobile intraoperative radiotherapy system during surgery for pancreatic cancer: a case report
10.1186/s13256-018-1906-6C A S E R E P O R T Open Access
Background: Pancreatic cancer is one of the most common fatal malignancies and has a poor prognosis. Surgical treatment is the most important treatment method, but there is a low rate of radical excision; moreover, the postoperative recurrence rate is high, with a local recurrence rate greater than 50%. The usefulness of intraoperative radiotherapy for pancreatic cancer has previously been examined. However, prior research was based on the traditional high-energy electron beam, which causes serious radiation toxicity. Therefore, the tumor radiation dose was limited, subsequently limiting the effect. In contrast, there is also a low-energy X-ray radiation system called INTRABEAM®. Use of INTRABEAM has been applied clinically, but the treatment effect of INTRABEAM in pancreatic cancer has not been reported. Case presentation: We present a case of a 56-year-old Chinese man with local advanced pancreatic cancer with invasion of the coeliac trunk artery and origin of the portal vein. He underwent distal pancreatectomy and splenectomy along with intraoperative radiotherapy using a portable INTRABEAM radiation system. The radiotherapy dose was 10 Gy and irradiation time was 27.4 minutes. There were no obvious postoperative complications. His abdominal pain was alleviated after surgery, and no obvious tumor recurrence has been observed in short-term follow-up. Conclusions: We believe that it is safe to apply intraoperative radiotherapy using the INTRABEAM radiation system in pancreatic cancer. This approach appears promising for further future development.

Introduction

Pancreatic cancer is the fourth leading cause of cancer-related death [1]. Surgical resection remains the mainstay therapy; however, less than 25% of patients have cancer that is resectable at the time of diagnosis [2]. Furthermore, approximately 50% of patients experience tumor recurrence after radical operation. It is believed that this high recurrence rate is associated with minimal residual disease along the border of the intact tissues that were not excised [3,4]; accordingly, intraoperative radiation therapy (IORT) has been used for patients with localized pancreatic cancer, including resectable or borderline resectable cases [5,6]. IORT has been used for decades in patients with pancreatic cancer, with the goal of pain reduction and control of locoregional tumor progression [7,8]. Formerly, IORT was performed with an electron energy source emitting a 6-20 MeV high-powered electron beam [9]: this produced promising results, but was prohibited by radiation-related complications [10]. Here, we describe a case in which we performed IORT with a low kV X-ray system called INTRABEAM® in a patient who underwent distal pancreatectomy to reduce the radiation-related complications and decrease the possibility of residual malignancy during the surgical resection. The low energy IORT system INTRABEAM provides low penetration and rapid attenuation of the radiation dose. We believed that it could eliminate the possible residual malignancies effectively and more safely than the traditional IORT.

A 56-year-old Chinese man was hospitalized 2 months after the discovery of a pancreatic mass and a 1-month history of abdominal pain. He had taken no medication before hospitalization.

A physical examination after the hospitalization did not reveal any obvious abnormalities. He had a body temperature of 36.6°C, heart rate of 99 beats per minute, blood pressure of 141/83 mmHg, respiratory rate of 20 breaths per minute, and oxygen saturation of 100%. His neurological status was normal. His family history was noncontributory. He smoked cigarettes for 20 years, but it is unknown how many cigarettes he smoked per day. He never consumed alcohol. Occupationally, he worked as an office manager.

Laboratory test results are shown in Table 1. Blood tests revealed a high level of the CA19-9 tumor marker (1525.84 U/mL). An abdominal computed tomography scan with enhancement and vascular reconstruction revealed a space-occupying lesion in the pancreatic head and neck; the findings suggested the presence of pancreatic cancer with invasion of the hepatic artery, splenic artery, mesenteric vein, and origin of the portal vein ( Fig. 1). Pathological examination of a specimen from an endoscopic ultrasound puncture biopsy revealed abnormal cells, with a morphology consistent with that of adenocarcinoma. Positron emission tomography-computed tomography revealed abnormally high fluorodeoxyglucose metabolism that was limited to the space-occupying lesion, suggesting a malignant pancreatic lesion, with atrophy of the pancreatic tail and many small nodules in the space surrounding the pancreas. He was diagnosed as having a T4N2M0 local advanced pancreatic cancer.

Six days after admission, he underwent distal pancreatectomy and splenectomy as well as intraoperative radiotherapy (described below) under general anesthesia with tracheal intubation. A subcostal incision was made to expose his abdominal cavity, and the Kocher maneuver was subsequently performed to dissect the gastrocolic ligament and duodenal lateral peritoneum, which  Fig. 1 Representative computed tomography scan images. The white circle represents the location of the tumor exposed the pancreatic tumor. The lesion was approximately 8 cm × 5 cm and had a hard texture and the tumor activity is poor (Fig. 2). Dissection and pancreatic isolation (starting from the tail and moving to the right) revealed that the tumor had invaded the superior mesenteric vein, middle colic artery, and celiac trunk artery. After isolating his spleen, the pancreatic retroperitoneum was opened, and his spleen and pancreatic tail were turned upward and isolated left to right from the posterior aspect to the superior mesenteric artery. A harmonic scalpel was used at this site to sever his pancreas, and the pancreatic duct was closed using a 4-0 Dexon suture. Local tumor remnants were observed in the posterior pancreas. The upper boundary of the remaining tumor bed reached the trunk of his abdominal cavity, the lower boundary reached his middle colic artery starting from the superior mesenteric artery, and the right boundary reached his superior mesenteric artery.

The INTRABEAM system was moved into the surgical field, and a 6-cm flatbed source applicator was selected based on the appearance of the tumor bed (Fig. 3). After applying an aseptic protective cover, the source applicator was placed close to the tumor bed, and our patient's surrounding bowel and organs were protectively insulated using two layers of surgical gauze (approximate thickness 2 cm). After all personnel had left the operating room, radiotherapy was started using the following parameters: a radiotherapy dose of 10 Gy, an irradiation time of 27.4 minutes, an acceleration voltage of 50 kV, and an acceleration current of 40 μA. A drainage tube was subsequently placed at the cut edge of his pancreas, and his abdominal cavity was closed after confirming that there was no bleeding or pancreatic leakage. The total intraoperative blood loss was 200 mL.

He passed gas on postoperative day 2, and the gastric feeding tube was subsequently removed. On postoperative day 8, < 30 mL of fluid (amylase 21 U/L) had been lost via the abdominal drainage tube, which was removed before our patient was discharged on postoperative day 9. No surgery-related complications were observed, his postoperative CA19-9 level was 924.73 U/L, and his abdominal pain completely disappeared based on the numerical rating scale for cancer pain [11]. He has been followed for 6 months after surgery, and no obvious tumor recurrence has been observed.

Discussion

Here we present a successful case of pancreatic cancer. Our patient underwent distal pancreatectomy and splenectomy along with IORT using a portable INTRABEAM radiation system. This low-energy IORT system is available to eliminate possible residual malignancies. Furthermore, it avoids the risks of severe radiotherapy-associated complications that are associated with traditional IORT.

There is a clear, increasing trend in the global incidence of pancreatic cancer, which has an extremely poor prognosis: the 5-year survival rate is < 5% [12]. Surgery is the only effective and curative treatment for pancreatic cancer, although < 25% of patients with pancreatic cancer can undergo radical surgical treatment. In addition, local recurrence develops in 50-90% of patients who undergo surgical resection, and the local recurrence rate remains high even after extensive resection. Radiotherapy is a useful palliative procedure that can provide relief from pain and other symptoms, including local pain relief in patients with unresectable tumors, which can help prolong survival and preserve quality of life. However, traditional external Fig. 2 The resected gross specimen of the pancreatic cancer and spleen Fig. 3 Intraoperative radiation therapy using the INTRABEAM radiation system radiation therapy using extracorporeal irradiation can easily lead to severe complications and suboptimal overall treatment efficacy. Thus, IORT has emerged as an effective procedure for local control of unresectable tumors or tumor remnants after resection of pancreatic cancer. Unlike external radiation therapy, IORT acts directly on the treatment site, can be delivered while sparing the surrounding organs and tissues, and can deliver a large radiation dose that provides ≥ 2 times the biological effect of separate radiation doses [13], which shortens the overall treatment time.

Current domestic and international reports indicate that the Mobetron® system is the primary tool for performing IORT in cases of pancreatic cancer [14]. This system has a high electron beam energy and radiotherapeutic effects on local tumors in relatively deep locations (> 2 cm). Previous reports [15] have described its therapeutic effects on unresectable pancreatic cancers, although a relatively deep target combined with the high electron beam energy can lead to various adverse effects, such as gastrointestinal tract bleeding, bile duct fibrosis, biliary enteric anastomosis, peripheral nerve reactions, and other pancreas-associated complications. This approach can also have important effects on posterior organs and structures (for example, the vertebrae and spinal cord), which are considered major complications of IORT for pancreatic cancer. These effects include vertebral fracture, paraplegia, intraspinal hemorrhage, autonomic dysfunction, limb paralysis, and uncoordinated movement. Therefore, patients who undergo IORT for pancreatic cancer using the Mobetron system must accept a risk of developing severe radiotherapy-associated toxicities.

In the present case, we used the INTRABEAM system for IORT because it produces softer, shallower, and lower energy X-rays (30-50 kV) than the Mobetron system [16][17][18][19]. The INTRABEAM system also provides low penetration and rapid attenuation of the radiation dose [18], which are improvements that have emerged from the evolution of minimally invasive surgery. There has been rapid clinical adoption of the INTRABEAM system in recent years, with good outcomes described in studies regarding breast-conserving surgery for breast cancer [20,21], vertebral metastasis surgery [22], and colorectal cancer surgery [23,24]; these good outcomes are attributed to the system's accuracy, minimally invasive nature, and low penetration depth. These characteristics allow the INTRABEAM system to protect important organs and tissues behind the pancreas and reduce the incidence of adverse effects that were associated with previous IORT systems. Moreover, given the low penetration depth, a relatively high radiation dose can be used at the clinical surface. For example, we used a radiation dose of approximately 10 Gy at the clinical surface; an effective irradiation intensity is achieved when the source applicator is < 5 mm from the target tissue. Thus, the INTRABEAM system is extremely practical for targeting residual tumor tissue after resection of pancreatic tumors. Previous studies have described doses of 10-30 Gy when the Mobetron system is used during IORT for pancreatic cancer [25,26], although there is no established dose when using the INTRA-BEAM system. In the present case, we selected a relatively conservative dose of 10 Gy, and our patient did not develop any radiotherapy-related side effects, although further studies are needed to optimize the radiotherapy dose in similar cases.

The INTRABEAM system has a source applicator that comes in various shapes; this can facilitate personalized treatment based on the patient's tumor and target sites. In the present case, our surgical exploration revealed residual tumor tissue posterior to the pancreas; this residual tumor tissue invaded the retroperitoneal blood vessels, lymph nodes, and nerve plexuses. The upper boundary reached the trunk of the abdominal cavity, the lower boundary reached the middle colic artery starting from the superior mesenteric artery, and the right boundary reached the superior mesenteric artery. Because the tumor bed was relatively uniform, with no obvious compartmentalization, and had a rough surface, we selected a flatbed source applicator that was placed close to the tumor bed. The radiotherapy was performed after protecting the surrounding bowel, and our patient experienced a good postoperative course, with recovery of gastrointestinal function on postoperative day 2. Moreover, he was able to resume eating and was free from postoperative bleeding, infection, pancreatic leakage, and other complications; in addition, he had markedly relieved pancreatic cancerrelated abdominal pain. Thus, he was discharged in good general condition on postoperative day 9.

Conclusion

In summary, based on the case described here, we conclude that using the low-energy INTRABEAM system for pancreatic cancer IORT is safe and can be applied to cases of radical resection or suspicious tumor remnants. Moreover, we conclude that the flatbed source applicator was the best fit for the tumor bed of pancreatic cancer. Although our patient experienced significant pain relief, the long-term efficacy of this approach remains unclear, and large controlled studies are needed to validate our findings. There is a need for preliminary studies for using the INTRABEAM system in pancreatic cancer, including optimal radiation dose, radiation time, and source applicator choice.

s
14.6

Platelet count (per mm 3 )
273,000

Red cell count (per mm 3 )
4,700,000

Mean corpuscular volume (fl)
86

Sodium (mmol/liter)
137.6

Potassium (mmol/liter)
3.43

Chloride (mmol/liter)
91.2

Calcium (mg/dl)
2.43

Glucose (mg/dl)
82.8

Urea nitrogen (mmol/liter)
2.54

Creatinine (umol/liter)
80

Protein total (g/dl)
8.0

Albumin
4.9

Alanine aminotransferase (U/liter)
10

Aspartate aminotransferase (U/liter)
15

Bilirubin total (umol/liter)
4.7

Lactate dehydrogenase (U/liter)
188

Creatine kinase (U/liter)
118

Urine analysis
Normal

Serology for toxoplasmosis, herpes virus, CMV, EBV, rubella
Negative

CA19-9 (U/ml)
1525.84

CMV cytomegalovirus, EBV Epstein-Barr virus

AcknowledgementsNone.FundingNot applicable.Availability of data and materials All data generated or analyzed during this study are included in this published article.Authors' contributions XS wrote the manuscript and followed the patient postoperatively, ZS and HL participated in the surgery, and HL revised the manuscript. All authors read and approved the final manuscript.Ethics approval and consent to participate Not applicable.Consent for publicationWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.Competing interestsThe authors declare that they have no competing interests.
Cancer statistics. A Jemal, R Siegel, E Ward, Y Hao, J Xu, M J Thun, CA Cancer J Clin. 59Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225-49.

Cancer of the pancreas. 50 years of surgery. B Gudjonsson, Cancer. 60Gudjonsson B. Cancer of the pancreas. 50 years of surgery. Cancer. 1987;60: 2284-303.

Patterns of failure after curative resection of pancreatic carcinoma. J F Griffin, S R Smalley, W Jewell, J C Paradelo, R D Reymond, R E Hassanein, Cancer. 66Griffin JF, Smalley SR, Jewell W, Paradelo JC, Reymond RD, Hassanein RE, et al. Patterns of failure after curative resection of pancreatic carcinoma. Cancer. 1990;66:56-61.

Adjuvant radiotherapy and chemotherapy for biliary and pancreatic cancer. T A Rich, D B Evans, S A Curley, J A Ajani, Ann Oncol. 53SupplRich TA, Evans DB, Curley SA, Ajani JA. Adjuvant radiotherapy and chemotherapy for biliary and pancreatic cancer. Ann Oncol. 1994;5(Suppl 3): 75-80.

Aggressive local treatment containing intraoperative radiation therapy (IORT) for patients with isolated local recurrences of pancreatic cancer: a retrospective analysis. F Roeder, C Timke, M Uhl, G Habl, F W Hensley, M W Buechler, BMC Cancer. 12295Roeder F, Timke C, Uhl M, Habl G, Hensley FW, Buechler MW, et al. Aggressive local treatment containing intraoperative radiation therapy (IORT) for patients with isolated local recurrences of pancreatic cancer: a retrospective analysis. BMC Cancer. 2012;12:295.

Effect on local control and survival of electron beam intraoperative irradiation for resectable pancreatic adenocarcinoma. M Reni, M G Panucci, A J Ferreri, G Balzano, P Passoni, G M Cattaneo, Int J Radiat Oncol Biol Phys. 50Reni M, Panucci MG, Ferreri AJ, Balzano G, Passoni P, Cattaneo GM, et al. Effect on local control and survival of electron beam intraoperative irradiation for resectable pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2001;50:651-8.

Intraoperative irradiation for unresectable pancreatic carcinoma. W C Wood, W U Shipley, L L Gunderson, A M Cohen, G L Nardi, Cancer. 49Wood WC, Shipley WU, Gunderson LL, Cohen AM, Nardi GL. Intraoperative irradiation for unresectable pancreatic carcinoma. Cancer. 1982;49:1272-5.

Intraoperative electron beam irradiation for patients with unresectable pancreatic carcinoma. W U Shipley, W C Wood, J E Tepper, A L Warshaw, E L Orlow, S D Kaufman, Ann Surg. 200Shipley WU, Wood WC, Tepper JE, Warshaw AL, Orlow EL, Kaufman SD, et al. Intraoperative electron beam irradiation for patients with unresectable pancreatic carcinoma. Ann Surg. 1984;200:289-96.

Intraoperative radiotherapy for pancreatic cancer: 30-year experience in a single institution in Japan. K Jingu, T Tanabe, K Nemoto, H Ariga, R Umezawa, Y Ogawa, Int J Radiat Oncol Biol Phys. 83Jingu K, Tanabe T, Nemoto K, Ariga H, Umezawa R, Ogawa Y, et al. Intraoperative radiotherapy for pancreatic cancer: 30-year experience in a single institution in Japan. Int J Radiat Oncol Biol Phys. 2012;83:e507-11.

Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer. C G Willett, Del Castillo, C F Shih, H A Goldberg, S Biggs, P Clark, J W , Ann Surg. 241Willett CG, Del Castillo CF, Shih HA, Goldberg S, Biggs P, Clark JW, et al. Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer. Ann Surg. 2005;241:295-9.

ESMO Guidelines Working Group. Management of cancer pain: ESMO Clinical Practice Guidelines. C I Ripamonti, D Santini, E Maranzano, M Berti, F Roila, Ann Oncol. 237SupplRipamonti CI, Santini D, Maranzano E, Berti M, Roila F. ESMO Guidelines Working Group. Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23(Suppl 7):vii139-54.

Pancreatic cancer. M Hidalgo, N Engl J Med. 362Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605-17.

Intraoperative radiation therapy first part: rationale and techniques. F A Calvo, R M Meirino, R Orecchia, Crit Rev Oncol Hematol. 59Calvo FA, Meirino RM, Orecchia R. Intraoperative radiation therapy first part: rationale and techniques. Crit Rev Oncol Hematol. 2006;59:106-15.

Current situation and developments in intraoperative radiotherapy for pancreatic cancer. H Qu, P Zhao, Chin J Gen Surg). Zhongguo Pu Tong Wai Ke Za Zhi17Qu H, Zhao P. Current situation and developments in intraoperative radiotherapy for pancreatic cancer. Zhongguo Pu Tong Wai Ke Za Zhi (Chin J Gen Surg). 2008;17:917-9.

Intra-operative radiotherapy (IORT) in pancreatic cancer: joint analysis of the ISIORT-Europe experience. V Valentini, F Calvo, M Reni, R Krempien, F Sedlmayer, M W Buchler, Radiother Oncol. 91Valentini V, Calvo F, Reni M, Krempien R, Sedlmayer F, Buchler MW, et al. Intra-operative radiotherapy (IORT) in pancreatic cancer: joint analysis of the ISIORT-Europe experience. Radiother Oncol. 2009;91:54-9.

Quality assurance and independent dosimetry for an intraoperative x-ray device. D J Eaton, Med Phys. 39Eaton DJ. Quality assurance and independent dosimetry for an intraoperative x-ray device. Med Phys. 2012;39:6908-20.

Dosimetry measurements with an intra-operative x-ray device. D J Eaton, S Duck, Phys Med Biol. 55Eaton DJ, Duck S. Dosimetry measurements with an intra-operative x-ray device. Phys Med Biol. 2010;55:N359-69.

Radiation protection for an intraoperative X-ray device. D J Eaton, R Gonzalez, S Duck, M Keshtgar, Br J Radiol. 84Eaton DJ, Gonzalez R, Duck S, Keshtgar M. Radiation protection for an intra- operative X-ray device. Br J Radiol. 2011;84:1034-9.

Suitability of radiochromic films for dosimetry of very-low energy X-rays. M A Ebert, A H Asad, S A Siddiqui, J Appl Clin Med Phys. 102957Ebert MA, Asad AH, Siddiqui SA. Suitability of radiochromic films for dosimetry of very-low energy X-rays. J Appl Clin Med Phys. 2009;10:2957.

Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. J S Vaidya, D J Joseph, J S Tobias, M Bulsara, F Wenz, C Saunders, Lancet. 376Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet. 2010;376:91-102.

Low-kilovoltage, single-dose intraoperative radiation therapy for breast cancer: results and impact on a multidisciplinary breast cancer program. S R Grobmyer, J L Lightsey, C M Bryant, C Shaw, A Yeung, N Bhandare, J Am Coll Surg. 216Grobmyer SR, Lightsey JL, Bryant CM, Shaw C, Yeung A, Bhandare N, et al. Low-kilovoltage, single-dose intraoperative radiation therapy for breast cancer: results and impact on a multidisciplinary breast cancer program. J Am Coll Surg. 2013;216:617-23.

Kypho-IORT--a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases. F Wenz, F Schneider, C Neumaier, U Kraus-Tiefenbacher, T Reis, R Schmidt, Radiat Oncol. 511Wenz F, Schneider F, Neumaier C, Kraus-Tiefenbacher U, Reis T, Schmidt R, et al. Kypho-IORT--a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases. Radiat Oncol. 2010;5:11.

Unresectable colorectal cancer can be cured with multimodality therapy. K L Mathis, H Nelson, J H Pemberton, M G Haddock, L L Gunderson, Ann Surg. 248Mathis KL, Nelson H, Pemberton JH, Haddock MG, Gunderson LL. Unresectable colorectal cancer can be cured with multimodality therapy. Ann Surg. 2008;248:592-8.

Intra-operative radiotherapy of rectal cancer: results of the French multi-institutional randomized study. J B Dubois, E Bussieres, P Richaud, P Rouanet, Y Becouarn, S Mathoulin-Pélissier, Radiother Oncol. 98Dubois JB, Bussieres E, Richaud P, Rouanet P, Becouarn Y, Mathoulin-Pélissier S, et al. Intra-operative radiotherapy of rectal cancer: results of the French multi-institutional randomized study. Radiother Oncol. 2011;98:298-303.

Intraoperative radiotherapy for resected pancreatic cancer: a multiinstitutional retrospective analysis of 210 patients. K Ogawa, K Karasawa, Y Ito, Y Ogawa, K Jingu, H Onishi, Int J Radiat Oncol Biol Phys. 77Ogawa K, Karasawa K, Ito Y, Ogawa Y, Jingu K, Onishi H, et al. Intraoperative radiotherapy for resected pancreatic cancer: a multi- institutional retrospective analysis of 210 patients. Int J Radiat Oncol Biol Phys. 2010;77:734-42.

Intraoperative radiotherapy in pancreatic cancer: a systematic review. A Ruano-Ravina, O R Almazan, F Guedea, Radiother Oncol. 87Ruano-Ravina A, Almazan OR, Guedea F. Intraoperative radiotherapy in pancreatic cancer: a systematic review. Radiother Oncol. 2008;87:318-25.


Pupillometry in Chinese Female Patients with Depression: A Pilot Study
2014

Jikun Wang
School of Psychology and Cognitive Science
Key Laboratory of Brain Functional Genomics, MOE & STCSM
East China Normal University
200062ShanghaiChina

Department of Psychosomatic Medicine
Shanghai East Hospital
Tongji University School of Medicine
200092ShanghaiChina

Yaodong Fan
Department of Neurosurgery
The Third Affiliated Hospital of Kunming Medical College
650032KunmingChina

Xudong Zhao
Department of Psychosomatic Medicine
Shanghai East Hospital
Tongji University School of Medicine
200092ShanghaiChina

Nanhui Chen firstname.lastname@example.com.
Kunming Institute of Zoology
Chinese Academy of Sciences
650223KunmingChina

International Journal of Environmental Research and Public Health

Pupillometry in Chinese Female Patients with Depression: A Pilot Study

Int. J. Environ. Res. Public Health
11201410.3390/ijerph110202236Received: 26 November 2013; in revised form: 27 January 2014 / Accepted: 28 January 2014 /* Authors to whom correspondence should be addressed; E-Mails:depressionpupillary light reflexpupillometryChinese females
The pupillary responses to light in patients with depression and normal controls were evaluated among Chinese females. Four parameters related to the pupil were assessed using a video-based pupillometer. The results showed that there were significant differences in the pupil area in the darkness and the pupil area at the peak of constriction between depressed patients and normal controls.

Introduction

Depression is a common mental disorder featuring as the most prominent symptom a low mood. Significant deficits in neurocognitive function such as poor attention and impaired memory processing due to dysfunction of the central cholinergic system, also accompany depression [1,2]. Pupillometry has been applied as an easy non-invasive method to assess the central cholinergic system OPEN ACCESS function [3]. The pupillary constriction and the re-dilation process are governed by the action of the Edinger-Westphal nucleus (EW) and the Locus Coeruleus (LC) through their projections to the ciliary ganglion and the ciliospinal center of Budge-Waller, respectively [3]. Acetylcholine (ACH) is the primary neurotransmitter that mediates the pupillary light reflex. In addition, the EW nucleus is cholinergic in nature [4]. Therefore, the pupillary light reflex has been investigated in disorders with significant cholinergic impairment, such as Parkinson's disease [4], Alzheimer's disease [5], depression [6], and generalized anxiety disorder [7].

The evidence concerning pupillary light response in depressed patients is complex. For example, Sokolski and DeMet [8] hypothesized that muscarinic receptor sensitivity could increase during depression, and their data suggested that depression possesses both peripheral and central muscarinic hypersensitivity [9,10]. This hypersensitive pupil reaction may be trait-dependent and regulated by M3 muscarinic receptors through a pathway that involves G-protein-mediated activation of phosphatidylinositol.

Sokolski and DeMet also proposed that increased cholinergic sensitivity in depressed patients results in pupillary constriction [11]. In addition, they [12] further reported that younger depressed patients exhibited larger pupil areas than age-matched normal controls, which could reflect an increased demand on the noradrenergic system. The maximal pupillary dilation in depressed patients has been shown to decrease with aging [12], which may result from the loss of cortical noradrenergic neurons. Fountoulakis et al. [6] reported that there was a marginally significant decrease in the latency to constriction in patients with depression. Siegle et al. [13] used pupillary analysis as an index to assess the effect of cognitive therapy on depression for several reasons: (1) pupillary responses reflect cognitive and emotional processing; and (2) the pupillary reaction reflects relevant brain mechanisms of limbic activity and cognitive control [14]. Research by Fountoulakis et al. [6] suggested that cholinergic and other neurotransmitters may play a significant role in development and the modulation of emotion.

Although several studies have applied pupillometry analysis in depressed patients of European origin, there is a dearth of such analysis for depressed patients in the Chinese population. In addition, pupillary analysis technology has improved substantially and our knowledge of depression has advanced over time too, making it necessary to re-evaluate the pupillary light reflex in depressed patients. Furthermore, there is a need for pupillary analysis in depressed patients in other ethnic groups because depressive symptoms may vary among patients with different genetic background. Thus, the aim of the present study was to evaluate the pupillary light reflex in depressed patients and normal controls in China, especially for female Chinese individuals aged 21 to 39.

Methods

Participants

Patients with first-episode depression were recruited from the outpatient clinic of the Psychiatry Department at the Affiliated East Hospital of Tongji University in Shanghai, China. Normal controls were recruited by community advertisements. Patients were interviewed with the Structured Clinical Interview for DSM-IV (SCID) [15]. The patient group consisted of 15 depressed female patients with a mean age of 31.1 years (SD = 3.5, range = 23-38), and diagnosed with major depressive disorder based on DSM-IV criteria [16].The control group consisted of 15 female controls with a mean age of 31.9 years (SD = 4.7, range = 22-38). The normal controls were free of medications for at least two weeks prior to the pupillary light reflex tests. The study was approved by the IRB of Tongji University School of Medicine, and written consent was obtained from each participant after the study was explained in detail.

Pupillary Analysis

Pupillary dilation was assessed during each participant's first visit to the hospital. The pupil dilation from the left eye was assessed in the morning from 8:00 a.m. to 11:00 a.m. in a moderately lit room. A manual monocular pupillometer (Kunming Yilikete Co., Kunming, China) was used to video-record the pupillary light reflex [the resolution was 320 × 240 pixels, and the frame rate was 15 frames-persecond using the gray-level technique (8 bit)]. Before testing, the participant was asked to close her eyes and took a rest for 10 min. During the testing, the participants held the pupillometer which had eye covers to protect the eyes from light. While holding the pupillometer, the participant was asked to open her eyes for 2 min to adapt to the darkness. The participant was then asked to look straight ahead, and a red light was shone on the participant's right eye inducing the shrinkage of both pupils. The red light was used to stimulate the alertness of depressed patients [17,18]. A uniform wavelength infrared light was focused on the left eye using the pupillometer. The indirect light reflex video of the left pupil was recorded by a camera in the pupillometer for further analysis. A computer software calculated the area of the pupil for each frame of the video to yield a pupil area curve for the pupillary light reflex.

The pupil recognition algorithm was based on a circular Hough transformation [19]. The video data were analyzed by Matlab software (MathWorks, Natick, MA, USA), and the Matlab code was customized by our laboratory. Blinks were eliminated by local regression, and the data were further smoothed using the median filter.

Three trials were performed for each participant, and each trial consisted of three stages: the first stage was 1 s before dark adaptation ended, the second stage was when the light in the pupillometer was turned on for 2 s and the third stage was when the light was turned off. The participant was asked to hold the pupillometer for at least 30 s until the pupil re-dilation to its maximum size was measured.

Data Analysis

Independent t tests were used to compare the data between the depressed patients and the normal controls. Four pupillary parameters were calculated, including the pupil area in the darkness (in mm 2 ), the pupil area at the peak of constriction (in mm 2 ), the latency time for constriction (in s) and the duration of pupillary constriction (in s). The parameters of pupillary light reflex included the pupil area in darkness (which means the pupil area when they are in darkness), pupil area in largest constriction (which means the pupil area when constricting the most), latency for constriction (which means the time spent from the beginning of light to the constriction of pupils), and the duration of constriction (which means the time spent from the beginning of pupillary constriction to the largest constriction of the pupil).

Results

The results showed that the pupil area in the darkness and the pupil area at the peak of constriction were larger in depressed patients compared with normal controls and there were significant differences in the pupil area in darkness and the pupil area at the peak of constriction between the depressed patients and the controls (Table 1). There was no significant difference, however, in the latency time to constriction or the duration of constriction between the two groups.

Discussion

The present study used a modern optical method to assess the pupil responses to light in first-episode depressed patients. To the best of our knowledge, this is the first study to compare pupil dilation in response to light between depressed patients and normal controls in the Chinese population. The pupil area in the darkness before light stimulation was greater in the depressed patients than in the normal controls. This finding is consistent with a previous study in which younger patients with depression exhibited a larger pupil area than age-matched normal controls [12]. This finding could reflect an increased demand for the noradrenergic system, and in support of this, another study has suggested that depression is associated with lower levels of noradrenaline (NOR) [2].

A previous study has shown that the largest amplitude of pupil constriction may be a measure of ACH activity because NOR activity is already offset [6]. Our results show that the pupil area at the peak of constriction was greater in the depressed patients compared with the normal controls, supporting the hypothesis that ACH activity decreases in depression; however, Fountoulakis et al. [6] did not find any significant difference in ACH activity in depressed patients compared with controls.

Changes in pupil during constriction reflect cholinergic effects [20]. The latency to constriction is a marker of the balance between ACH and NOR, since the constriction of the pupil begins when ACH activity plus NOR blockade by ACH, overcome NOR activity [6]. Our results showed that the latency to constriction was significantly longer in depressed patients than in normal controls. Fountoulakis et al. [6] explored the pupillary responses to light and found a significant difference in the latency to constriction between depressed patients and normal controls suggesting that the activity of both ACH and NOR is decreased in depression. Interestingly, the reduction in NOR activity was greater than that in ACH activity. It is noteworthy that the present results focused on dynamic pupillary response rather than static pupil size control, suggesting the existence of lower level of NOR and ACH hypoactivity in depressed patients.

Other studies have also investigated the pupillary response in depressed patients. For example, Sokolski and DeMet showed that depressed patients exhibited increased cholinergic sensitivity resulting in pupillary constriction [8,11]. Interestingly, one study did not find a significant difference in pupillary light reflex between depressed patients and normal controls [9]. In addition, another study demonstrated that the maximum velocity and the maximum acceleration of re-dilation of the pupils were decreased in depressed patients [21], supporting the monoamine hypothesis of depression and suggesting that norepinephrine is the major neurotransmitter related to the re-dilation of the pupil.

There are a number of hypotheses on the development of depression. For example, the adrenergic-cholinergic balance hypothesis proposed that depression involves a hypercholinergic state [22], based on studies showing that depressed patients exhibited heightened cholinergic reactions to pilocarpine eyedrops [8]. In contrast, patients with more severe mania have been shown to exhibit decreased cholinergic tone [12]. Taken together, these studies suggest that mood is associated with the degree of cholinergic tone, and cholinergic dysfunction may be manifested in the peripheral and the central nervous systems. Anticholinergic drugs have been demonstrated to be a potential treatment for depression; however, the effects of the treatment have yielded conflicting results [23,24]. Hence, cholinergic hypersensitivity has been considered as a personality trait that predisposes individuals to depression-like sensitivity to stress rather than depression itself [25]. In summary, cholinergic deficits may explain the cognitive symptoms of depression (e.g., poor attention and concentration and impaired memory and information processing) rather than the affective symptoms [2].

The monoamine hypothesis of depression proposed that depression is associated with lower levels of brain monoamines, such as serotonin, NOR and dopamine [2], and mounting evidence has supported this hypothesis. For example, the mechanisms of action of many classes of antidepressant drugs involve elevating monoamine levels [26].

The understanding of depression has markedly increased over time. Today, major depressive disorder is thought to be a multifactorial syndrome that consists of disruptions in mood, cognition and other processes including sleep, appetite and libido [27]. Because depression is a complex mental disorder, it is unlikely that the neuronal system alone can fully explain the nature of depression [2]. For example, the loss of pleasure may result from dopaminergic and noradrenergic impairments [28], and the cognitive symptoms associated with depression could be explained by cholinergic dysfunction [2]. Interestingly, previous studies have shown that subjects with depression exhibit a variety of symptoms, and the influence of multiple neurotransmitters on the pathogenesis of depression may explain why previous studies on pupil analysis in depression have reported contradictory results. Further studies are needed to replicate the results that the pupil area in the darkness and the pupil area at the peak of constriction were larger in the depressed patients compared with the normal controls and to discriminate the depressed patients with different symptoms (e.g., delineate between patients with and without cognitive symptoms).

The present results showed that the pupil area in the darkness and the pupil area at the peak of constriction were greater in the depressed patients than the normal controls, suggesting that pupil analysis could be an easy noninvasive method to discriminate depressed patients from normal controls.

Other studies have also proposed that pupillary responses may provide a simple noninvasive method to evaluate cholinergic sensitivity in patients with affective disorders [29].

There are several limitations intrinsically associated with the present study. First, larger patient groupa including male patients are necessary to further substantiate the results. Secondly, it is necessary for further studies to include more pupillary variables. Thirdly, since 2 min is too short for dark-adaptation resulting in pupil size alteration during the test, a longer adaptation time is needed in future studies to optimize the test paradigm. Although it appears that we uncovered an alteration of pupil size in depressed patients, mechanistic studies on possible causes of this effect are needed. Topical blocking agents such as dapiprazole could be applied to determine whether or not this is an enhancement of the peripheral adrenergic pathway. Finally, the pupillary light reflex could not be simplified into simply cholinergic and adrenergic components since the light reflex starts with a complicated process of phototransduction in the retina, proceeding to the pretectal area where an unknown neurotransmitter activates an interneuron that projects to the EW nucleus. This nucleus is under inhibitory control and in turn alters the size of the pupil and the extent of the light reflex. Thus, further studies are necessary to investigate the involvement of cholinergic or noradrenergic system in this process. In summary, pupillometry could be an easy noninvasive method that exhibits a broad range of clinical implications. In addition, pupillometry may be useful for the investigation of early cholinergic impairment, such as the cognitive symptoms observed in depression.

Conclusions

The findings suggest that the pupil analysis could be an easy noninvasive method to discriminate depressed patients from normal controls, and pupillary responses may provide a simple noninvasive method to evaluate cholinergic sensitivity in patients with affective disorders.

Table 1 .
1Mean and standard deviation of pupillary variables in depressed patients and normal controls. Values reflect the results of t-test between these two diagnostic groups. * p < 0.05, ** p < 0.01.Items
Depressed Patients (n = 15) Normal Controls (n = 15)
p
Mean
SD
Mean
SD
Age
31.1
3.5
31.9
4.7
0.474
Pupil area in darkness
32.38
5.40
26.00
5.12
0.002 **
Pupil area in largest constriction
20.77
5.79
16.86
3.84
0.039 *
Latency for constriction
0.29
0.06
0.27
0.04
0.213
Duration of constriction
2.11
0.16
2.03
0.22
0.287

p-
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Author ContributionsJikun Wang and Nanhui Chen designed the study. Jikun Wang, Yaodong Fan, Xudong Zhao and Nanhui Chen collected the samples and analyzed the data. Jikun Wang, Yaodong Fan, Xudong Zhao and Nanhui Chen written and revised the manuscript.Conflicts of InterestThe authors declare no conflict of interest.
Neurocognitive mechanisms in depression: Implications for treatment. L Clark, S R Chamberlain, B J Sahakian, Annu. Rev. Neurosci. 32Clark, L.; Chamberlain, S.R.; Sahakian, B.J. Neurocognitive mechanisms in depression: Implications for treatment. Annu. Rev. Neurosci. 2009, 32, 57-74.

The cholinergic system and depression. G Dagyte, ; Den, J A Boer, A Trentani, Behav. Brain Res. 221Dagyte, G.; Den Boer, J.A.; Trentani, A. The cholinergic system and depression. Behav. Brain Res. 2011, 221, 574-582.

Cholinergic deficiency in Alzheimer's and Parkinson's disease: Evaluation with pupillometry. D F Fotiou, V Stergiou, D Tsiptsios, C Lithari, M Nakou, A Karlovasitou, Int. J. Psychophysiol. 73Fotiou, D.F.; Stergiou, V.; Tsiptsios, D.; Lithari, C.; Nakou, M.; Karlovasitou, A. Cholinergic deficiency in Alzheimer's and Parkinson's disease: Evaluation with pupillometry. Int. J. Psychophysiol. 2009, 73, 143-149.

Tropicamide effects on pupil size and pupillary light reflexes in Alzheimer's and Parkinson's disease. E Granholm, S Morris, D Galasko, C Shults, E Rogers, B Vukov, Int. J. Psychophysiol. 47Granholm, E.; Morris, S.; Galasko, D.; Shults, C.; Rogers, E.; Vukov, B. Tropicamide effects on pupil size and pupillary light reflexes in Alzheimer's and Parkinson's disease. Int. J. Psychophysiol. 2003, 47, 95-115.

Changes in pupil reaction to light in Alzheimer's disease patients: A preliminary report. F Fotiou, K N Fountoulakis, M Tsolaki, A Goulas, A Palikaras, Int. J. Psychophysiol. 37Fotiou, F.; Fountoulakis, K.N.; Tsolaki, M.; Goulas, A.; Palikaras, A. Changes in pupil reaction to light in Alzheimer's disease patients: A preliminary report. Int. J. Psychophysiol. 2000, 37, 111-120.

Changes in pupil reaction to light melanchonic patients. K Fountoulakis, F Fotiou, A Iacovides, J Tsiptsios, A Goulas, M Tsolaki, C Ierodiakonou, Int. J. Psychophysiol. 31Fountoulakis, K.; Fotiou, F.; Iacovides ,A.; Tsiptsios, J.; Goulas, A.; Tsolaki, M.; Ierodiakonou, C. Changes in pupil reaction to light melanchonic patients. Int. J. Psychophysiol. 1999, 31, 121-128.

Attenuation of the pupillary light reflex in anxious patients. A Bakes, C M Bradshaw, E Szabadi, Brit. J. Clin. Pharmacol. 30Bakes, A.; Bradshaw, C.M.; Szabadi, E. Attenuation of the pupillary light reflex in anxious patients. Brit. J. Clin. Pharmacol. 1990, 30, 377-381.

Increased pupillary sensitivity to pilocarpine in depression. K N Sokolski, E Demet, Prog. Neuro-Psychopharmacol Biol. Psychiatry. 20Sokolski, K.N.; DeMet, E.M. Increased pupillary sensitivity to pilocarpine in depression. Prog. Neuro-Psychopharmacol Biol. Psychiatry 1996, 20, 253-262.

The influence of major depression and its treatment on heart rate variability and pupillary light reflex parameters. K.-J Bar, W Greiner, T Jochum, M Friedrich, G Wagner, H Sauer, J. Affect. Disord. 82Bar, K.-J.; Greiner, W.; Jochum, T.; Friedrich, M.; Wagner, G.; Sauer, H. The influence of major depression and its treatment on heart rate variability and pupillary light reflex parameters. J. Affect. Disord. 2004, 82, 245-252.

Changes in the pupil reflex arc in depressive patients. K N Fountoulakis, M Siamouli, G Kaprinis, F Fotiou, J. Affect. Disord. 87Fountoulakis, K.N.; Siamouli, M.; Kaprinis, G.; Fotiou, F. Changes in the pupil reflex arc in depressive patients. J. Affect. Disord. 2005, 87, 341-342.

Pupillary cholinergic sensitivity to pilocarpine increases in manic lithium responders. K N Sokolski, E M Demet, Biol. Psychiatry. 45Sokolski, K.N.; DeMet, E.M. Pupillary cholinergic sensitivity to pilocarpine increases in manic lithium responders. Biol. Psychiatry 1999, 45, 1580-1584.

Cholinergic sensitivity predicts severity of mania. K N Sokolski, E M Demet, Psychiatry Res. 95Sokolski, K.N.; DeMet, E.M. Cholinergic sensitivity predicts severity of mania. Psychiatry Res. 2000, 95, 195-200.

Remission prognosis for cognitive therapy for recurrent depression using the pupil: Utility and neural correlates. G J Siegle, S R Steinhauer, E S Frideman, W S Thompson, M E Thase, Biol. Psychiatry. 69Siegle, G.J.; Steinhauer, S.R.; Frideman, E.S.; Thompson, W.S.; Thase, M.E. Remission prognosis for cognitive therapy for recurrent depression using the pupil: Utility and neural correlates. Biol. Psychiatry 2011, 69, 726-733.

Do the seconds turn into hours? Relationships between sustained pupil dilation in response to emotional information and self-reported rumination. G J Siegle, S R Steinhauer, C S Carter, W Ramel, M E Thase, Cognit. Ther. Res. 27Siegle, G.J.; Steinhauer, S.R.; Carter, C.S.; Ramel, W.; Thase, M.E. Do the seconds turn into hours? Relationships between sustained pupil dilation in response to emotional information and self-reported rumination. Cognit. Ther. Res. 2003, 27, 365-382.

The structured clinical interview for DSM-III-R (SCID) I: History, rationale, and description. R L Spitzer, J B Williams, M Gibbon, M B First, Arch. Gen. Psychiatry. 49Spitzer, R.L.; Williams, J.B.; Gibbon, M.; First, M.B. The structured clinical interview for DSM-III-R (SCID) I: History, rationale, and description. Arch. Gen. Psychiatry 1992, 49, 624-629.

. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR;

Characteristics of the pupillary light reflex in the alert Rhesus Monkey. R J Clarke, H Zhang, P D Gamlin, J. Neurophysiol. 89Clarke, R.J.; Zhang, H.; Gamlin, P.D. Characteristics of the pupillary light reflex in the alert Rhesus Monkey. J. Neurophysiol. 2003, 89, 3179-3189.

Studying the effect of iris mechanics on the pupillary light reflex using brimonidine-induced anisocoria. Y Chen, R H Kardon, Investig. Ophthalmol. Vis. Sci. 54Chen, Y.; Kardon, R.H. Studying the effect of iris mechanics on the pupillary light reflex using brimonidine-induced anisocoria. Investig. Ophthalmol. Vis. Sci. 2013, 54, 2951-2958.

. Circular Hough Transform, Circular Hough Transform. Avaliable online: http://www.cvmt.dk/education/teaching/e07/ MED3/IP/Simon_Pedersen_CircularHoughTransform.pdf (accessed on 7 February 2014).

Pupillary responses and attentional allocation problems on the backward masking task in schizophrenia. E Granholm, S P Verney, Int. J. Psychophysiol. 52Granholm, E.; Verney, S.P. Pupillary responses and attentional allocation problems on the backward masking task in schizophrenia. Int. J. Psychophysiol. 2004, 52, 37-51.

Pupillometry in depressed patients. M Nakou, D Fotiou, A Fotiou, D Tsiptsios, I Kalliolia, C Brozou, V Stergiou, E Giza, E Theodoridou, C Giantselidis, 10.1186/1744-859X-5-S1-S324Ann. Gen. Psychiatry. 5Nakou, M.; Fotiou, D.; Fotiou, A.; Tsiptsios, D.; Kalliolia, I.; Brozou, C.; Stergiou, V.; Giza, E.; Theodoridou, E.; Giantselidis, C. Pupillometry in depressed patients. Ann. Gen. Psychiatry 2006, 5, doi:10.1186/1744-859X-5-S1-S324.

Cholinergic dysfunction in depression. D S Janowsky, D H Overstreet, Pharmacol. Toxicol. 66Janowsky, D.S.; Overstreet, D.H. Cholinergic dysfunction in depression. Pharmacol. Toxicol. 1990, 66, 100-111.

Nicotinic acetylcholine receptors as targets for antidepressants. R D Shytle, A A Silver, R J Lukas, M B Newman, D V Sheehan, P R Sanberg, Mol. Psychiatry. 7Shytle, R.D.; Silver, A.A.; Lukas, R.J.; Newman, M.B.; Sheehan, D.V.; Sanberg, P.R. Nicotinic acetylcholine receptors as targets for antidepressants. Mol. Psychiatry 2002, 7, 525-535.

The antidepressant effects of anticholinergic drugs. R H Howland, J. Psychosoc. Nurs. Ment. Health Serv. 47Howland, R.H. The antidepressant effects of anticholinergic drugs. J. Psychosoc. Nurs. Ment. Health Serv. 2009, 47, 17-20.

Cholinergic neurotransmission seems not to be involved in depression but possibly in personality. J Fritze, M Lanczik, E Sofic, M Struck, P Riederer, J. Psychiatr. Neurosci. 20Fritze, J.; Lanczik, M.; Sofic, E.; Struck, M.; Riederer, P. Cholinergic neurotransmission seems not to be involved in depression but possibly in personality. J. Psychiatr. Neurosci. 1995, 20, 39-48.

Research and treatment approaches to depression. M L Wong, J Licinio, Nature Rev. Neurosci. 2Wong, M.L.; Licinio, J. Research and treatment approaches to depression. Nature Rev. Neurosci. 2001, 2, 343-351.

. E J Nestler, M Barrot, R J Dileone, A J Eisch, S J Gold, L M Monteggia, Neurobiology of depression. Neuron. 34Nestler, E.J.; Barrot, M.; DiLeone, R.J.; Eisch, A.J.; Gold, S.J.; Monteggia, L.M. Neurobiology of depression. Neuron 2002, 34, 13-25.

The other face of depression, reduced positive affect: The role of catecholamines in causation and cure. D Nutt, K Demyttenaere, Z Janka, T Aarre, M Bourin, P L Canonico, S Stahl, J. Psychopharmacol. 21Nutt, D.; Demyttenaere, K.; Janka, Z.; Aarre, T.; Bourin, M.; Canonico, P.L.; Stahl, S. The other face of depression, reduced positive affect: The role of catecholamines in causation and cure. J. Psychopharmacol. 2007, 21, 461-471.

Decreases in dilated pupil size in depressed patients with age may reflect adrenergic changes. K N Sokolski, B D Nguyen, E M Demet, Psychiatry Res. 94Sokolski, K.N.; Nguyen, B.D.; DeMet, E.M. Decreases in dilated pupil size in depressed patients with age may reflect adrenergic changes. Psychiatry Res. 2000, 94, 267-272.


BMC Public Health Can the concept of Health Promoting Schools help to improve students' health knowledge and practices to combat the challenge of communicable diseases: Case study in Hong Kong?

Albert Lee firstname.lastname@example.com
Centre for Health Education and Health Promotion
The Chinese University of Hong Kong
Hong KongChina

Department of Community and Family Medicine
The Chinese University of Hong Kong
Hong KongChina

Martin Cs Wong
Department of Community and Family Medicine
The Chinese University of Hong Kong
Hong KongChina

Vera Mw Keung
Centre for Health Education and Health Promotion
The Chinese University of Hong Kong
Hong KongChina

Hilda Sk Yuen
Centre for Health Education and Health Promotion
The Chinese University of Hong Kong
Hong KongChina

Frances Cheng email@example.com
Centre for Health Education and Health Promotion
The Chinese University of Hong Kong
Hong KongChina

Jennifer Sy Mok email@example.com
Centre for Health Education and Health Promotion
The Chinese University of Hong Kong
Hong KongChina

BMC Public Health Can the concept of Health Promoting Schools help to improve students' health knowledge and practices to combat the challenge of communicable diseases: Case study in Hong Kong?
10.1186/1471-2458-8-42BioMed Central Page 1 of 8 (page number not for citation purposes) Research article * Corresponding author
Background:The growing epidemics of emerging infectious diseases has raised the importance of a setting approach and include the Health Promoting School (HPS) framework to promote better health and hygiene. Built on the concept of 'the' HPS framework, the Hong Kong Healthy Schools Award scheme includes "Personal Health Skills" as one of its key aspects to improve student hygiene knowledge and practices. This study examines the differences in student perceptions, knowledge and health behaviours between those schools that have adopted the HPS framework and those that have not adopted.Methods:A cross-sectional study using multi-stage random sampling was conducted among schools with awards (HSA) and those schools not involved in the award scheme nor adopting the concept of HPS (non-HPS). For HSA group, 5 primary schools and 7 secondary schools entered the study with 510 students and 789 students sampled respectively. For the 'Non-HPS' group, 8 primary schools and 7 secondary schools entered the study with 676 students and 725 students sampled respectively. A self-administered questionnaire was used as the measuring instrument.Results: Students in the HSA category were found to be better with statistical significance in personal hygiene practice, knowledge on health and hygiene, as well as access to health information. HSA schools were reported to have better school health policy, higher degrees of community participation, and better hygienic environment.Conclusion: Students in schools that had adopted the HPS framework had a more positive health behaviour profile than those in non-HPS schools. Although a causal relationship is yet to be established, the HPS appears to be a viable approach for addressing communicable diseases.

Background

Health behaviours are strongly determined by the differ-ent social, economic and environmental circumstances of individuals and populations. Improvement of health lit-eracy can help individuals to tackle the determinants of health better as it builds up the personal, cognitive and social skills which determine the ability of individuals to gain access to, understand and use of information to promote and maintain good health [1]. Schools are essential in helping students to achieve health literacy [2]. The concept of the health promoting school (HPS) has been advocated as an effective approach to promote health in schools [3,4]. It embodies a holistic, whole school approach in which a broad health education curriculum is supported by the environment and ethos of the school and shifts health into a more dynamic and political domain to address the determinants of heath [2,5]. Healthy Schools Award schemes are very popularamong the European countries as structured frameworks acting as systems for monitoring and recognition of achievements [6]. Moon has shown positive award-related changes in terms of children's health behaviours, and that the awarded schools have more health promoting culture and organization [7].

The outbreak of Severe Acute Respiratory Syndrome (SARS) has highlighted the importance of maintaining a healthy and hygienic environment as one of the effective public health measures to combat infectious diseases, but the major challenge is that some of the most important public health measures are to be taken outside the health sector [8]. Schools have become an important setting to build up the skills and capacity for students, parents and the wider community to combat the challenges of outbreak of communicable diseases [9]. Rosen et al has demonstrated that a hygiene program can produce a sustained increase in hand washing rates among toilet-trained preschool children [10]. Hand washing has been shown to be an effective means to prevent spread of infection [11]. These findings illuminate the potential of schools as promising venues for promoting hygiene and health in prevention of infectious diseases.

The Centre for Health Education and Health Promotion, The Chinese University of Hong Kong (CHEP) launched the first territory-wide "Healthy Schools Award Scheme" (HSA) in 2001 [12]. It was modeled on the World Health Organization (WHO) Regional Office of the Western Pacific Health Promoting School (HPS) framework covering six key areas (health policy, physical and social environments, community relationships, personal health skills and health services) designed to assist schools in addressing particular health issues strategically [13][14][15][16]. The scheme has developed a set of indicators and guidelines to meet the local needs. Each key area has a number of components with targets for the schools to achieve [13][14][15]. The participating schools attended training programme on development planning at the start of the project helping them to appreciate the breadth of the scheme and consolidate their thoughts for appropriate action. The HSA project team met with the co-ordinating group of the school to identify and prioritize four to five areas of potential action. The project team visited the school at least once per term to offer advice and support and obtained detailed information on each of the activities for evaluation. The amount of support given varied from area to area according to the needs of the schools and the summary of health promoting activities have been described in the special issues [17][18][19].

The process of selection of indicators for the scheme and also the accreditation process have incorporated advice and validation by a number of local and international experts in the field [15,20]. A practical manual with detailed guidelines was developed for participating schools [13,14]. "Personal health skills" is one key component, where basic knowledge and skills in hygienic measures and prevention of communicable diseases are incorporated in a variety of school activities like classroom teaching, interactive learning initiatives, community-wide health promoting campaigns, and teaching staffs are equipped with relevant training and resources [9,[13][14][15]20].

While process evaluations showed that health promoting activities had been successfully implemented in schools, the evaluation of the effectiveness of HPS reported a wide range of outcomes [21][22][23]. This survey explores the differences in student perceptions, knowledge and health behaviours between schools that have adopted the HPS framework and those non-HPS. The Education Authority in Hong Kong recommended using the concept of HPS to improve school health and hygiene [24,25] with the hypothesis that children in HPS schools more likely to perceive that their school is a healthier place. The result would have significant impact on the future planning, implementation and substantiation of HPS in different parts of the World as the problem of emerging infectious diseases becomes a global issue.

Method

Subjects and sampling

A cross-sectional study was conducted in two categories of schools, namely HSA and non-HPS by multi-stage random sampling.

At the time of the study there were 24 primary and 17 secondary schools that had obtained awards for HPS. For comparison between the two categories of schools, assuming the odds ratio of 2 with the non-HPS school having prevalence of 30% of parents participated in school cleaning activities, a sample size of 240 were needed for each group (N = {1.28 × [P 1 × (1-P 1 ) + P 2 × (1-P 2 )] -2 + 1.96 × [2 P 0 (1-P 0 )] -2 } 2 /(P 2 -P 1 ) 2 P1 = proportion of control, P 2 = P 1 × OR/1 + P 1 (OR-1); P 0 = P 1 + P 2 /2) [26]. Random sampling method was used to target at least 500 students from primary and secondary schools in HSA category (double the required numbers) and 750 non-HPS category (triple the required numbers) from primary and secondary schools. Schools were randomly selected from each category respectively and letters of invitation were sent out in lots of tens to the selected schools until the targeted numbers of students had been reached.

The first stage consisted of random selection by category and the selected schools were invited by letters. In the second stage, we stratified the participating schools by grades, with samples from Primary 4 (P4) to Primary 6 (P6) (aged around [10][11][12] and Secondary 1 (S1) to Secondary 3 (S3) (aged around [13][14][15]. The third stage was a systematic random sampling, where one class of students was randomly selected from each grade to participate in the survey.

Measures

The questionnaire testing health-related knowledge and hygienic practice was devised by the research team in CHEP based on evaluation tools used by Hong Kong HSA [12,15,20] and the content was further validated by two medical doctors with postgraduate degrees in Public Health. Health-related knowledge was reported as a score for each student, and other outcome measures adopt an ordinal scale (e.g. "very clean", "clean", "not quite", "not clean"), which was then grouped into binary variables (e.g. "very clean" and "clean" as a group vs. those not) for statistical analysis. The complete set of questionnaire had been pilot tested in a primary school for face-validity and reliability with good results. The items are well understood. The 2-week test-retest reliability has shown all the items with kappa statistic 0.7 or higher.

The following aspects were examined in the survey: For the HSA group, 510 students and 789 students were sampled from 5 primary schools and 7 secondary schools respectively. For the 'Non-HPS' group, 676 students and 725 students were sampled from 8 primary schools and 7 secondary schools respectively. The response rate from students of the participating schools was nearly 100% for all the schools (except those absent from schools). Letters were sent out to students and parents to obtain consent for participation on voluntarily basis. The questionnaires were collected without identifiers to ensure confidentiality. It took about 30 minutes to complete the questionnaire. No refusal was noted from parents and students. The study has been approved by Survey and Behaviour Research Ethics Committee of the Chinese University of Hong Kong

Data analysis

Proportions of students with particular behaviours and perception of school environment were tabulated. Chi square statistics was used to analyse the difference in proportions between HSA and non-HPS. For knowledge, scores were calculated for each category and t test statistics was used to analyse the difference.

Results

Demographic Profiles

The sample consisted of approximately equal gender distribution (see Table 1). The majority of students (around 79%) were born in Hong Kong, with a minority born in Mainland (21%) or other countries. The mean age of the participants from secondary schools was 14.46 (S.D. ±

Personal hygienic practices and skills at school, home and public areas

Handwashing practices In terms of hand washing habits after toileting, only small difference was detected as this is something that has been enmeshed into the children's everyday life especially since the SARS epidemic.

There was a significant difference between HSA schools and non-HPS schools in teachers reminding students to wash their hand before meals ( Table 2). Also higher proportion of secondary school students washed hands with their own initiatives before meals although the reverse was observed amongst primary students (Table 2) Tooth Brushing and Bathing Table 2 shows that in primary schools, higher proportion of students from HSA schools (28.2%) always brushed their teeth after meal than the non-HPS category (19.7%) with statistical significance (p = 0.001) ( Table 2).

The majority of students had a bath everyday but HSA primary school students reported a significantly higher proportion than non-HPS schools (99.6% vs. 98.1%, p = 0.02; table 2).

Correct self care with fever

Higher proportion of students from HSA schools in both primary and secondary schools (80.9% vs 75.2% and 64.0% vs 58.0% respectively) coped correctly when they had fever with statistical significance (p = 0.02; Table 2).

School health policy

There was no significant difference amongst primary school children encouraged to wear face mask or staying away from school if they had symptoms of Upper Respiratory Tract Infection (URTI). However difference was observed in mask wearing between the HSA and non-HPS secondary schools (86.8% vs 80.4%) and in staying away from schools if students had URTI symptoms (93.6% vs 90.1%) with statistical significance (p = 0.001 and p = 0.01 respectively, Table 3).

The Hygiene Charter, launched in 2003 as a community initiative supported by various business and industry sectors to pledge their long-term commitment to fight against the challenges posed by SARS and create a healthy and hygienic environment for Hong Kong [23]. Its website is of high reference value for schools. In secondary schools, higher proportion of students from the HSA group reported that teachers had mentioned the Hygiene Charter website (28% vs 15.3%; p < 0.001) ( Table 3).

Community participation by schools

In secondary schools, higher proportion of students from the HSA group (23.6% vs 19.2%) felt that their schools joined community cleaning with statistical significance (p = 0.04) ( Table 4). The organization of activities to promote health and hygiene was also reported by higher proportion of students from the HSA than the non-HPS  (Table 4).

School physical environment

Primary school students in the HSA group had higher proportion choosing ''very clean'' or ''clean'' for playground hygiene (72.2%) as compared to 61.6% in the non-HPS group (p < 0.001; Table 4). For classroom 73.6% of students from HSA schools chose ''very clean'' or ''clean'' compared with 68.5% in non-HPS schools (p = 0.058) (   with cleaning with statistical significance. More HSA primary school students reported having prefects for environmental protection (63.1% vs. 59.7%), and similarly in secondary schools (49.4% vs. 23.7%) with statistical significance (p < 0.001) ( Table 4).

Literacy on health and hygiene

In most areas of health-related knowledge, it was found that the majority of students in both groups have ever acquired related knowledge. There was no significant difference amongst the secondary school students between the HSA and non-HPS groups in the overall scores for both categories (12.40 vs. 12.41; p = 0.95). However in primary schools, the difference in overall scores between the two groups was found to be statistically significant (12.13 vs 11.58; p < 0.001) ( Table 5).

Higher proportion of primary school students in HSA group had chosen "very much" or "quite a lot" in getting health information from student health ambassadors (32.8% vs 17.7%; p < 0.001), media (46.5% vs. 43.2%; p = 0.002), and pamphlets (52.3% vs 46.2% p = 0.04) with statistical significance (Table 5). For secondary schools, it was also found that higher proportion of students in HSA group had chosen "very much" or "quite a lot" in getting health information from student ambassadors (19.0% vs 10.5%; p < 0.001) and pamphlets (36.5% vs 27.3% p < 0.001) with statistical significance (Table 5).

Discussion

On the whole, students from the HSA group showed positive outcomes in most aspects of health and hygiene particularly the hygiene practice of students and actions taken by schools. It is not unexpected as HPS embodies a holistic, whole school approach to personal and community health promotion [27]. The Hong Kong Healthy Schools Award scheme builds on the concept of HPS which helps to create a supportive environment for healthy development in schools, home and the community [6]. Studies have shown that students from schools which had comprehensively embraced the HPS concept as indicated by attaining the 'Healthy School Award', were better, in terms of health and educational outcomes, than students from schools that did not reach the standard of the award [28,29].

St Leger and Nutbeam [30] stated that HPS contributes to four school related outcomes. They are: (a) lifelong learning; (b) competencies and behaviors; (c) specific cognate knowledge and skills; and (d) self attributes. Therefore HSA schools would confer a great impact on school health and hygiene, in addition to students' health habits, as was demonstrated in the present study.

Positive changes were observed in certain aspects of school health and hygiene particularly in getting relevant health information from various reliable sources amongst secondary students in the HSA group. Previous studies have indicated the potential for a settings approach to school health, like the Hong Kong HSA scheme (HKHSA), to provide a promising strategic framework allowing health literacy outcome to be achieved [2,31]. This group of schools also established actions to promote better health and hygiene as the schools participated in community cleaning activities and the parents also supported the schools in cleaning activities. This study reveals that these HSA schools have also organized more health promotion activities. This moves to a more collaborative communitybased approach for students to learn, as opposed to a teacher-dominated school hierarchy [2], is one of the strategies to achieve critical health literacy [1].

School-based implementation of HPS was shown to be associated with significant greater levels of positive personal health habits. Although this study is cross-sectional and no cause and effect can be established, it would still highlight how HKHSA might exert its influence individually as well as the school level. Although some of the significant findings of this study is marginal, HPS has only been implemented over a short duration in Hong Kong. HPS programme has been shown to be effective if the intervention is intensive over a long duration [32]. Recent evidence suggests that the way the school is lead and managed, students' experiences in participating and taking responsibility for shaping policies, practices and procedures, teachers-students relationship and school engagement with its local community including parents actually builds many protective factors for health and minimises risk taking behaviour [32][33][34][35]. Many of these gains have occurred without a specific health 'intervention'. It appears that a whole school approach to build and maintain a caring school social environment might be the most effective way in achieving good health outcomes.

However putting the HPS in practice takes considerable amount of time and efforts and effective implementation requires commitment and support of various schools' stakeholders. The success of HPS depends heavily on teachers' training like Health Education diploma programmes, which could introduce the concepts to the teachers so they can start making improvements on some fundamental areas of school health and hygiene [36,37]. With time and more teachers being exposed to the concept, teachers would then gradually develop their schools to become HPS. The primary school students in HSA group have shown to have better knowledge scores. Although the difference in knowledge scores between two groups is not statistically significant in secondary schools, it is well known fact that there are other factors in adolescents leading to behaviour and practice change apart from knowledge and belief.

There are some limitations of this study. Schools with more health conscious students or their families might be more willing to adopt HPS. The study design might not be able to control for that history which would have some threat to internal validity. It is a cross sectional survey so it might not capture the longer-term impact of HPS on health behaviours of students due to the different components of HSA interventions. The differences observed might or might not be due to the effect of intervention and future longitudinal studies are needed to ascertain the causal effect fostered by HSA. Furthermore, some outcomes were reported by students only and may involve recall in the past few months, and the effect of multiple comparisons should be taken into account when interpreting statistical significance. In addition, we assumed that randomized sampling minimized the heterogeneity of different clusters and demographic characteristics among schools, which have not been controlled for. This study did not comprehensively assess all the outcomes of HPS as there are different types of outcomes which require different methods of data collection. [14] A descriptive design was adopted instead of randomised control study design because one cannot randomly select schools from all schools in Hong Kong as intervention group since schools need to comply with the standards of HPS to make it an effective programme.

Conclusion

The study has demonstrated that schools involved in HPS activities through the HSA scheme in Hong Kong had more favorable hygiene practice of students, school environment and atmosphere in health and hygienic practice. Although all schools in Hong Kong have health elements in the curriculum, the primary objective of HPS is to modify the behaviours of school students rather than information giving, so more positive changes are observed in those schools that participated and met the standards in the HSA scheme. These findings highlight the potential of HPS in equipping schools to handle public health crisis such as SARS [9]. Therefore it is highly recommended that schools would further enhance the practice of HPS to empower their students, staffs and parents to enhance preparedness of possible future epidemics of communicable diseases. [38].

-FC, HY and VK were responsible for conception and design, analysis and interpretation of data, and gave the final approval -JM was responsible for conception and design, revising the manuscript and gave the final approval

•
Students' knowledge on health and hygiene • Personal health habits Data collection Data collection was done between May and June of 2005.

Table 1 :
1Grade and Gender of the respondents by school category HSA: awarded schools in the HSA Scheme Non-HPS schools are those not in the HSA scheme and whose teachers did not attend any training in HPS or diplomas 1.33) and 14.51 (S.D. ± 1.25) year-old in HSA and non-HPS schools respectively. The mean age of the participants from primary schools was 11.15 (S.D. ± 0.95) and 11.54 (S.D. ± 1.56) year-old in HSA and non-HPS schools respectively.Primary schools
HSA (n = 510)
Non-HPS (n = 676)

P.4
165(32.4%)
228 (33.7%)
P.5
168(32.9%)
217 (32.1%)
P.6
177(34.7%)
231 (34.2%)
Boy
242(47.6%)
359 (53.3%)
Girl
266(52.4%)
315 (46.7%)

Secondary schools
HSA (n = 789)
Non-HPS (n = 725)

S.1
260(33.0%)
217 (29.9%)
S.2
273(34.6%)
260 (35.9%)
S.3
256(32.4%)
248 (34.2%)
Boy
367(46.9%)
308 (42.6%)
Girl
415(53.1%)
415 (57.4%)

(Note: A minority of the students missed filling in their demographic
data)

Table 2 :
2Personal hygienic practices and skills at school, home and public areasHSA
Non-HPS
P value

Table 4 )
4. Secondary school students in HSA group had
higher proportion choosing ''very clean'' or ''clean'' for
stairs (68.7% vs 63.3% p = 0.03) and tuck shop (60.2% vs
53.3% p = 0.01) (Table 4).

More HSA primary (75.0% vs. 64.4%; p < 0.001) and sec-
ondary (52.5% vs. 34.2%, p < 0.001) students perceived
their schools having assigned prefects to monitor or help

Table 4 :
4Community Participation and Physical EnvironmentHSA
Non-HPS
p value

Table 3 :
3Students' perception of school health policyHSA
Non-HPS
p value

Table 5 :
5Literacy on health and hygieneHSA
Non-HPS
p value

(page number not for citation purposes)
Competing interestsThe author(s) declare that they have no competing interests.Authors' contributionsContributions by different authors are as followings-:-AL and MW were responsible for conception and design, analysis and interpretation of data, drafting and revising the manuscript and gave the final approvalPre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/8/42/prepub
Health literacy as a public health goal: a challenge for contemporary health education and communication strategies into the 21 st century. D Nutbeam, Health Promotion International. 153Nutbeam D: Health literacy as a public health goal: a challenge for contemporary health education and communication strategies into the 21 st century. Health Promotion International 2000, 15(3):259-267.

St Leger L: Schools, health literacy and public: possibilities and challenges. Health Promotion International. 162St Leger L: Schools, health literacy and public: possibilities and challenges. Health Promotion International 2001, 16(2):197-205.

The health promoting school: organisation and policy development in Welsh secondary schools. D Nutbeam, Health Education. 46Nutbeam D: The health promoting school: organisation and policy development in Welsh secondary schools. Health Edu- cation 1987, 46:109-115.

Health promoting schools: healthy eating policies in schools -an evaluation of the effects on pupils' knowledge, attitudes and behaviour. I Young, Health Education Journal. 521Young I: Health promoting schools: healthy eating policies in schools -an evaluation of the effects on pupils' knowledge, attitudes and behaviour. Health Education Journal 1993, 52:1.

The health promoting school in Europe: Conceptualising and evaluating the change. C Parsons, D Stears, C Thomas, Health Education Journal. 55Parsons C, Stears D, Thomas C: The health promoting school in Europe: Conceptualising and evaluating the change. Health Education Journal 1996, 55:311-321.

Developing the "health-promoting school" -a national survey of healthy school awards. E Rogers, A V Moon, M A Mullee, V M Speller, P J Roderick, Public Health. 112Rogers E, Moon AV, Mullee MA, Speller VM, Roderick PJ: Develop- ing the "health-promoting school" -a national survey of healthy school awards. Public Health 1998, 112:37-40.

Helping schools to become health-promoting environments -an evaluation of the Wessex Healthy Schools Award. A M Moon, M A Mullee, L Rogers, R L Thompson, V Speller, P Roderick, Health Promotion International. 14Moon AM, Mullee MA, Rogers L, Thompson RL, Speller V, Roderick P: Helping schools to become health-promoting environ- ments -an evaluation of the Wessex Healthy Schools Award. Health Promotion International 1999, 14:111-122.

Severe Acute Respiratory Syndrome: Challenge for Public Health Practice in Hong Kong. A Lee, Asm Abdullah, Journal of Epidemiology and Community Health. 57Lee A, Abdullah ASM: Severe Acute Respiratory Syndrome: Challenge for Public Health Practice in Hong Kong. Journal of Epidemiology and Community Health 2003, 57:655-658.

Healthy Schools Support Group, How would schools step up public health measure to control spread of SARS. A Lee, F Cheng, H Yuen, M Ho, Journal of Epidemiology and Community Health. 57Lee A, Cheng F, Yuen H, Ho M: Healthy Schools Support Group, How would schools step up public health measure to control spread of SARS? Journal of Epidemiology and Community Health 2003, 57:945-949.

Can a handwashing intervention make a difference? Results from a randomized controlled trial in Jerusalem preschools. L Rosen, O Manor, D Engelhard, D Brody, B Rosen, H Peleg, M Meir, D Zucker, Preventive Medicine. 421Rosen L, Manor O, Engelhard D, Brody D, Rosen B, Peleg H, Meir M, Zucker D: Can a handwashing intervention make a differ- ence? Results from a randomized controlled trial in Jerusa- lem preschools. Preventive Medicine 2006, 42(1):27-32.

A causal link between handwashing and risk of infection? Examination of the evidence. E A Larson, Infect Control Hosp Epidemiol. 9Larson EA: A causal link between handwashing and risk of infection? Examination of the evidence. Infect Control Hosp Epi- demiol 1988, 9:28-36.

Helping schools to promote healthy educational environments as new initiatives for school based management: the Hong Kong Healthy Schools Award Scheme. A Lee, 1Lee A: Helping schools to promote healthy educational envi- ronments as new initiatives for school based management: the Hong Kong Healthy Schools Award Scheme. Promotion and Education 2002, S1:29-32.

Development of indicators and guidelines for the Hong Kong Healthy Schools Award Scheme. A Lee, M Ho, Tcy Leung, Journal of Primary Care and Health Promotion. 11Lee A, Ho M, Leung TCY, et al.: Development of indicators and guidelines for the Hong Kong Healthy Schools Award Scheme. Journal of Primary Care and Health Promotion 2004, 1(1):4-9.

Editor: Hong Kong Healthy Schools Award Scheme: Practical Guide to the Health Promoting School. Full manual and Abridged version (74 pages) Centre for Health Education and Health Promotion. Lee ASchool of Public HealthThe Chinese University of Hong KongLee A, Editor: Hong Kong Healthy Schools Award Scheme: Practical Guide to the Health Promoting School. Full manual and Abridged version (74 pages) Centre for Health Education and Health Promotion, School of Public Health, The Chinese University of Hong Kong; 2003.

Evaluating health promoting schools in Hong Kong: the development of a framework. A Lee, Ffk Cheng, St Leger, L , Health Promotion International. 202Lee A, Cheng FFK, St Leger L: Evaluating health promoting schools in Hong Kong: the development of a framework. Health Promotion International 2005, 20(2):177-186.

WHO Regional Office for the Western Pacific: Health-Promoting Schools Series 5: Regional guidelines. Development of health-promoting schools -A framework for action 1996. WHO Regional Office for the Western Pacific: Health-Promoting Schools Series 5: Regional guidelines. Development of health-promoting schools -A framework for action 1996. WHO/WPRO

Centre for Health Education and Health Promotion: The Hong Kong Healthy Schools Award Scheme Special Issue 2005 Hong Kong: Centre for Health Education and Health Promotion, The Chinese University of Hong Kong. 988-98341-9-7Centre for Health Education and Health Promotion: The Hong Kong Healthy Schools Award Scheme Special Issue 2005 Hong Kong: Centre for Health Education and Health Promotion, The Chinese University of Hong Kong; 2005. ISBN 988-98341-9-7

Centre for Health Education and Health Promotion: The Hong Kong Healthy Schools Award Scheme Special Issue 2004 Hong Kong: Centre for Health Education and Health Promotion, The Chinese University of Hong Kong. Centre for Health Education and Health Promotion: The Hong Kong Healthy Schools Award Scheme Special Issue 2004 Hong Kong: Centre for Health Education and Health Promotion, The Chinese University of Hong Kong; 2004. ISBN: 962-86985-0-8

Centre for Health Education and Health Promotion: The Hong Kong Healthy Schools Award Scheme Special Issue 2003 Hong Kong: Centre for Health Education and Health Promotion, The Chinese University of Hong Kong. Centre for Health Education and Health Promotion: The Hong Kong Healthy Schools Award Scheme Special Issue 2003 Hong Kong: Centre for Health Education and Health Promotion, The Chinese University of Hong Kong; 2003.

Evaluating health promotion in schools: a case study of design, implementation and results from the Hong Kong Healthy Schools Award Scheme. Promotion & Education. A Lee, L St Leger, A Moon, 7Lee A, St Leger L, Moon A: Evaluating health promotion in schools: a case study of design, implementation and results from the Hong Kong Healthy Schools Award Scheme. Promo- tion & Education 2005, 7(3-4):123-130.

Student participation: a democratic education perspective -experience from the health-promoting schools in Macedonia. V Simovska, Health Education Research. 192Simovska V: Student participation: a democratic education perspective -experience from the health-promoting schools in Macedonia. Health Education Research 2004, 19(2):198-207.

Evaluations of health-promoting schools: a review of nine studies. W Mukoma, A J Flisher, Health Promotion International. 193Mukoma W, Flisher AJ: Evaluations of health-promoting schools: a review of nine studies. Health Promotion International 2004, 19(3):357-368.

Database of Abstracts of Reviews of Effectiveness: Health Promoting schools and health promotion in schools: two systematic reviews (Structured abstract) Centre for Review and Dissemination. Database of Abstracts of Reviews of Effectiveness: Health Promoting schools and health promotion in schools: two systematic reviews (Structured abstract) Centre for Review and Dissemination; 2006.

Hong Kong, Sar Government, Team Clean Report of Hong Kong Special Administrative Government. Hong Kong SAR Government: Team Clean Report of Hong Kong Special Administrative Government 2003.

Hygiene Charter: Laying down the spirit of Healthy City. Gallery Paper. A Lee, K M Chan, Journal of Epidemiology and Community Health. 5930Lee A, Chan KM: Hygiene Charter: Laying down the spirit of Healthy City. Gallery Paper. Journal of Epidemiology and Commu- nity Health 2005, 59:30.

. B R Kirkwood, Essentials of Medical Statistics Blackwell Scientific Publications. Kirkwood BR: Essentials of Medical Statistics Blackwell Scientific Publi- cations, Oxford; 1998.

The health promoting school in Europe: Conceptualising and evaluating the change. C Parsons, D Stears, C Thomas, Health Education Journal. 55Parsons C, Stears D, Thomas C: The health promoting school in Europe: Conceptualising and evaluating the change. Health Education Journal 1996, 55:311-321.

Does a healthy school award scheme make a difference? The evaluation of the Wessex Healthy Schools Award. A Moon, United KingdomDepartment of Public Health Medicine, University of SouthamptonPhD ThesisMoon A: Does a healthy school award scheme make a difference? The evaluation of the Wessex Healthy Schools Award, unpublished PhD Thesis, Department of Public Health Medicine, University of Southampton, United Kingdom 1999.

L: Can Health Promoting Schools contribute to the better health and well being of young people: Hong Kong experience. A Lee, F Cheng, Y Fung, St Leger, Journal of Epidemiology and Community Health. 60Lee A, Cheng F, Fung Y, St Leger L: Can Health Promoting Schools contribute to the better health and well being of young people: Hong Kong experience? Journal of Epidemiology and Community Health 2006, 60:530-536.

A model for mapping linkages between health and education agencies to improve school health. L St Leger, D Nutbeam, Journal of School Health. 70St Leger L, Nutbeam D: A model for mapping linkages between health and education agencies to improve school health. Jour- nal of School Health 2000, 70:45-50.

Health promoting schools and health promotion in schools: two systematic reviews. D Lister-Sharp, S Chapman, S Stewart-Brown, A Sowden, Health Technology Assessment. 3Lister-Sharp D, Chapman S, Stewart-Brown S, Sowden A: Health promoting schools and health promotion in schools: two sys- tematic reviews. Health Technology Assessment 1999, 3:1-207.

What is the evidence on school health promotion in improving school health or preventing disease and specifically what is the effectiveness of the health promoting schools approach? Copenhagen: World Health Organization. S Stewart-Brown, Stewart-Brown S: What is the evidence on school health promotion in improving school health or preventing disease and specifically what is the effectiveness of the health promoting schools approach? Copenhagen: World Health Organization; 2006.

Promoting social inclusion in schools: A group-randomized trial on student health risk behaviour and wellbeing. G Patton, L Bond, J Carlin, L Thomas, H Butler, S Glover, R Catalano, G Bowes, American Journal of Public Health. 969Patton G, Bond L, Carlin J, Thomas L, Butler H, Glover S, Catalano R, Bowes G: Promoting social inclusion in schools: A group-ran- domized trial on student health risk behaviour and well- being. American Journal of Public Health 2000, 96:9.

Improving the odds: The untapped power of schools to improve the health of teens Center for Adolescent Health and Development. R Blum, C Mcneely, P Rinehart, University of MinnesotaBlum R, McNeely C, Rinehart P: Improving the odds: The untapped power of schools to improve the health of teens Center for Adolescent Health and Development, University of Minnesota; 2002.

Global Perspective on Health Promotion Effectiveness. L St Leger, L J Kobe, A Lee, D Mccall, I ; Young, D Mcqueen, C Jones, SpringerNew York, USASchool Health: -AchievementsSt Leger L, Kobe LJ, Lee A, McCall D, Young I: School Health: -Achieve- ments, Challenges and Priorities Edited by: McQueen D, Jones C. Global Perspective on Health Promotion Effectiveness. Springer, New York, USA; 2007.

Implementation of comprehensive school health education in elementary schools: focus on teacher concerns. A Hausman, S B Ruzek, Journal of School Health. 653Hausman A, Ruzek SB: Implementation of comprehensive school health education in elementary schools: focus on teacher concerns. Journal of School Health 1995, 65(3):81-86.

A comprehensive "Healthy Schools Programme" to promote school health: The Hong Kong experience in joining the efforts of Health and Education Sectors. A Lee, S H Lee, K K Tsang, C Y To, Journal of Epidemiology and Community Health. 57Lee A, Lee SH, Tsang KK, To CY: A comprehensive "Healthy Schools Programme" to promote school health: The Hong Kong experience in joining the efforts of Health and Educa- tion Sectors. Journal of Epidemiology and Community Health 2003, 57:174-177.

Will SARS epidemics recur. A Lee, Journal of Epidemiology and Community Health. 57770Lee A: Will SARS epidemics recur? Journal of Epidemiology and Community Health 2003, 57:770.