Characteristics of HCV positive patients in an Italian urban psychiatric unit
© Raja et al; licensee BioMed Central Ltd. 2006
Received: 23 September 2005
Accepted: 01 October 2006
Published: 01 October 2006
1) to assess the prevalence of hepatitis C virus (HCV) infection in a population of acute psychiatric in-patients; 2) to find out relationships between HCV comorbidity and clinical features of psychiatric patients.
Prospective observational study in a 6-year period.
2396 cases (1492 patients) were admitted in the considered period. Forty-two patients (2.8%) were affected by HCV infection. HCV infection was more frequent in patients with less years of education, lower social class, lower last year best Global Assessment of Functioning score, more hostile or violent behavior in hospital, with a lifetime history of previous suicide attempt, and with substance-related disorders.
HCV infection in psychiatric patients constitutes a major threat to the health of psychiatric patients and is related with unfavorable social background, worse global functioning, hostile or violent behavior, substance-related disorders. It appears also to be a significant risk of suicidal behavior.
Patients with comorbid conditions probably represent majority of subjects affected by mood disorders or schizophrenia . Comorbid medical diseases may cause or worsen psychiatric disorders and have a major impact on the medical treatment of patients [2–4]. Nearly 50% of medical comorbid diseases are not diagnosed in chronic psychiatric outpatients . Also in psychiatric in-patients, medical diseases are often not diagnosed . Psychosis may impair the patient's capacity to recognize or describe emerging medical illness. Consequently, psychiatric patients often receive inadequate care . Numerous studies have demonstrated mortality rates that are at least twice as high among persons with severe mental illness, with a life expectancy ten years less than that of the general population. Some authors have attributed these poor health outcomes to clients' lack of regular medical care [7–12].
Hepatitis C is a silent disease, with symptoms developing an average of 20 years after infection. Around 85% of persons infected with hepatitis C develop lifelong chronic infection. Approximately 20% of chronically infected persons will develop cirrhosis, and approximately 3% will develop hepatocellular carcinoma . Hepatitis C is the most common chronic blood-borne infection in Italy as well as in the United States, with an estimated prevalence of 1%–2%. The prevalence of HCV infection varies by geographical region [14, 15], is higher among men than women , and may be very high in special populations. Population-based studies indicate that 40% of chronic liver disease is HCV related . People with severe mental illness appear to have a higher risk of HCV for a variety of reasons, including elevated rates of injection drug use, multiple, high-risk sexual partners, infrequent use of condoms, a tendency to trade sex for material gain, and engagement in sexual activity while using psychoactive substances . Several psychiatric disorders, including schizophrenia, depressive disorders, psychosis, bipolar disorder, anxiety disorders, were found more frequent among HCV-infected veterans compared with those who were not infected .
Klinkenberg et al  found a prevalence rate of 30% among homeless persons with co-occurring severe mental illness and substance use disorders. Serum anti-HCV antibodies were detected in 6.7% in institutionalized psychiatric patients . Psychiatric disorders were present in 60% of 206 consecutive patients with HCV infection attending a Veteran Medical Center . An American multisite study of blood-borne infections among persons with severe mental illness found a prevalence of hepatitis C of 19.6 percent, 11 times the overall population rate .
While little is known about hepatitis C outcome among the severely mentally ill, it is likely to be worse because of lack of access to and compliance with health care and further worsened by hepatic damage due to substance use. Moreover, since most psychotropic drugs are hepatically metabolized, chronic hepatitis C may complicate pharmacotherapy in this population. The high prevalence of the virus in this population also places mental health care workers at risk for infection, many of whom may be unfamiliar with universal precautions protocol . All that makes HCV infection a first rank problem in the management of psychiatric patients.
The aims of the present naturalistic study were: 1) to assess the prevalence of HCV infection in a population of acute psychiatric in-patients; 2) to find out relationships between HCV comorbidity and clinical features of psychiatric patients.
Psychiatric diagnoses of the 1492 patients
N° of cases (%)
Bipolar disorder mania
Bipolar disorder depression
Bipolar disorder mixed
Dysthymic disorder or depression NOS
Psychotic disorder NOS
Alcohol or Substance related disorder
behavioral misconduct related with Mental retardation
behavioral misconduct related with Dementia
Delirium, Mood or Psychotic disorder due to general medical condition
Continuous variables in patients with and without hcv infection
No HCV infection
38.6 (± 11.3)
42.1 (± 14.6)
Hospitalization length (days)
13.6 (± 12.0)
11.1 (± 12.7)
9.2 (± 2.8)
10.8 (± 4.0)
12.1 (± 3.4)
14.4 (± 4.3)
21.6 (± 4.9)
23.6 (± 7.6)
Last year best GAF score
42.9 (± 15.1)
50.5 (± 15.1)
Age at the onset of the disorder
23.4 (± 13.4)
29.1 (± 13.5)
BPRS total score
61.0 (± 14.9)
58.7 (± 13.3)
2.1 (± 2.8)
1.2 (± 1.9)
5.8 (± 0.6)
5.7 (± 0.6)
We collected all the data as part of our clinical routine. Consensus was not asked to the patients for the use of the anonymous epidemiological data. As the main purpose of the study was descriptive in nature, we did not specify hypotheses related to the study objectives in advance.
Categorical variables in patients with and without hcv infection
No HCV infection
25 (59.5%)/17 (40.5%)
628 (43.3%)/822 (56.7%)
Previous suicide attempt (Y/N)
14 (33.3%)/12 (28.6%)
213 (14.7%)/627 (43.2%)
Any alcohol or substance use disorder
Alcohol use disorder
Cannabis use disorder
Cocaine use disorder
Opioid use disorder
Confidential interval 95%
Previous suicide attempt
1.24 – 6,61
2,31 – 12,22
Scolarity (High school)
0,23 – 1,39
Scolarity (University years)
0,08 – 1,57
Morrison scale (1–7)
0,50 – 2,84
Morrison scale (8–9)
0,49 – 12,82
The strengths of the study were its large sample size and the high number of socio-demographic and clinical variables assessed in most patients. Despite these strengths, we must acknowledge several significant limitations. First, as in all non-epidemiological studies, the sample may not be representative. Hospital-based samples are not representative of the spectrum of the disorder found in the general population or in outpatient samples. Second, history of previous suicide attempts was not available in nearly 40% of the patients. However, we have no reason to suspect that these patients were different from those whose history of previous suicide attempts was assessed. Actually, we were not able to assess the history of previous suicide attempts only in patients who were early transferred to other PICUs for overcrowding of our PICU or for administrative reasons, i.e. not for clinical reasons. In the emergency psychiatric setting, complete neuropsychiatric assessment of all patients is almost impossible to achieve. The percentage of patients whose history of previous suicide attempts was not assessed was similar in the HCV (16/42; 38.1%) and the non-HCV group (42.0%) [χ2 = 0.123; fd = 1;p = .726]. Third, because so many comparisons were made, significance might be reached by chance in some cases. A cautious interpretation of the marginally significant findings is suggested.
The high rate of HCV infection found in the present study arises concern, especially considering the almost unavoidable chronic course of the infection and its serious consequences. However, the rate is much lower in comparison with the results of previous studies on psychiatric population.
The lower prevalence of HCV infection in our study in comparison with previous studies is probably due to two factors. First, in the emergency psychiatric setting, the HCV prevalence is likely to be lower in comparison with that observed in chronic psychiatric patients. Among a population of Spanish acute psychiatric in-patients, the prevalence of HCV seropositivity was 5.1% , a result similar to that observed in the present study. Second, the number of patients with a primary diagnosis of substance-related disorder was relatively low in our sample (52/1492, 3.5%). In Italy, patients with a primary diagnosis of substance-related disorder are treated in specific departments, and not in mental health departments. They are seldom admitted to PICUs. As a consequence, almost only patients with a secondary diagnosis of substance-related disorder entered our study. Consistently with previous studies, we noted a higher frequency of HCV infection in men. However, the difference in gender prevalence failed to reach the statistical significance. In the United States, the rates of hepatitis C infection differ by gender: 2.5% for men compared with 1.2% for women . Among persons with severe mental illness, hepatitis C rates are higher and also differ by gender: 19.6% for men and 9.8% for women .
Our results are consistent with the study of Dinwiddie et al.  who found that patients positive for hepatitis C virus were more likely to be male, slightly less well educated, and to have a psychoactive substance use disorder diagnosis but no other psychiatric diagnosis. Differently from our study but in accordance with the study of Osher et al , they also found that HCV patients were slightly older than the comparison group. However, Osher et al  hypothesized that age might not be a risk factor in and of itself but may reflect a complicated cohort effect involving the Vietnam War era. HCV is transmitted primarily through direct percutaneous exposure to blood. Blood transfusion accounted for a substantial proportion of HCV infections before 1990, when routine test began, but now accounts for only a small percentage . Although the main route of transmission is via contaminated blood, in up to 50% of the cases no recognizable transmission factor/route can be identified . While, it is not possible to ascertain the causes of such a high rate, it is tempting to hypothesize that promiscuous and unsafe sexual behavior associated with severe psychiatric illness may be implied as significant risk factor. However, the role of sexual behavior as a risk factor for HCV transmission is still unclear. In a multisite study of blood-borne infections among persons with severe mental illness, the rate of hepatitis C was higher for men at each of the five sites of the study ranging from 7.9% to 35.5%, compared with 4.9% to 16.9% for women . In the same study, sexual risks did not appear to play a major role in hepatitis C transmission since women had significantly more lifetime unprotected sex risks, including vaginal sex, anal sex, sex in exchange for drugs, and sex in exchange for money or gifts. The rate of sexual transmission of hepatitis C virus was found low also in the studies of Tor et al  and Fiscus et al . On the other hand, the results of other studies support a more prominent role of sexual transmission of hepatitis C [32–37].
In accordance with previous studies, we found HCV infection related with the diagnoses of any substance-related disorder, alcohol-related disorder, cannabis-related disorder, cocaine-related disorder, opioid-related disorder. The logistic regression confirmed the independent association between any substance-related disorder and HCV infection with a large effect size. While it is easy to attribute the higher prevalence of HCV infection among patients with a opioid-related disorder to their frequent habit of using non sterile needles, it is less clear why the HCV infection is also more prevalent among patients who use only oral or inhalant drugs. HCV prevalence as high as 46% has been found in populations with alcoholic liver disease, even when subject with intravenous drug use and with history of blood transfusion were excluded . Also among alcoholics without liver disease the hepatitis C rate (4.8%) is higher than that in the general population  and even tobacco use has been found correlated with the susceptibility to HCV infection . Risky behavior or unknown biological factors associated with substance-related disorder may account for the higher risk of HCV infection in these patients.
Unexpectedly, we found a higher rate of HCV infection among patients with a history of suicide attempt. The logistic regression confirmed the independent association between history of previous suicide attempt and HCV infection. This is the original and major result of the present study which has never been reported before, although depressive symptoms are very frequent during both the acute and chronic stages of hepatitis C , and suicidal behavior has been repeatedly reported in patients affected by HCV infection . The result is not easy to explain. Two hypotheses are offered. First, specific treatment of HCV infection, inducing or worsening a depressive state, might have precipitated suicidal behavior. Several reports described suicides or suicide attempts in the course of interferon treatment [43–49]. However, as already noted, no patient had been treated with interferon. Second, HCV infection may be associated with severer forms of psychiatric disorders which carry a higher risk of suicide. The last hypothesis was supported by the findings of worse global functioning in the last year and more hostile or violent behavior during the hospitalization in patients with HCV infection.
= Hepatitis C Virus
= Psychiatric Intensive Care Unit
not otherwise specified
= Brief Psychiatric Rating Scale
= Global Assessment of Functioning
= Clinical Global Impression.
- Jeste DV, Gladsjo JA, Lindamer LA, Lacro JP: Medical comorbidity in schizophrenia. Schizophr Bull. 1996, 22: 413-430.View ArticlePubMedGoogle Scholar
- Hewer W, Rossler W: Mortality of patients with functional psychiatric illnesses during inpatient treatment. Fortschr Neurol Psychiatr. 1997, 65: 171-181.View ArticlePubMedGoogle Scholar
- Zubenko GS, Marino LJ, Sweet RA, Rifai AH, Mulsant BH, Pasternak RE: Medical comorbidity in elderly psychiatric inpatients. Biol Psychiatry. 1997, 41: 724-736. 10.1016/S0006-3223(96)00337-X.View ArticlePubMedGoogle Scholar
- Reeves RR, Torres RA: Exacerbation of psychosis by misinterpretation of physical symptoms. South Med J. 2003, 96: 702-704. 10.1097/01.SMJ.0000078686.34109.11.View ArticlePubMedGoogle Scholar
- Farmer S: Medical problems of chronic psychiatric patients in a community support program. Hosp Comm Psychiatry. 1987, 38: 745-749.Google Scholar
- Woo BK, Daly JW, Allen EC, Jeste DV, Sewell DD: Unrecognized medical disorders in older psychiatric inpatients in a senior behavioral health unit in a university hospital. J Geriatr Psychiatry Neurol. 2003, 16: 121-125. 10.1177/0891988703016002011.View ArticlePubMedGoogle Scholar
- Black DW: Iowa record-linkage study: death rates in psychiatric patients. J Affect Disord. 1998, 50: 277-282. 10.1016/S0165-0327(98)00019-6.View ArticlePubMedGoogle Scholar
- Dembling B: Mental disorder as a contributing cause of death in the U.S. in 1992. Psychiatr Serv. 1997, 48: 45-View ArticlePubMedGoogle Scholar
- Dembling BP, Chen DT, Vachon L: Life expectancy and causes of death in a population treated for serious mental illness. Psychiatr Serv. 1999, 50: 1036-1042.View ArticlePubMedGoogle Scholar
- Felker B, Yazel JJ, Short D: Mortality and medical comorbidity among psychiatric patients: a review. Psychiatr Serv. 1996, 47: 1356-1363.View ArticlePubMedGoogle Scholar
- Harris EC, Barrablough B: Excess mortality of mental disorder. Br J Psychiatry. 1998, 173: 11-53.View ArticlePubMedGoogle Scholar
- Stroup TS, Gilmore JH, Jarskog LF: Management of medical illnesses in persons with schizophrenia. Psychiatr Ann. 2000, 30: 35-40.View ArticleGoogle Scholar
- Rosenberg SD, Swanson JW, Wolford GL, Osher FC, Swartz MS, Essock SM, Butterfield MI, Marsh BJ, Five-Site Health and Risk Study Research Committee: The five-site health and risk study of blood-borne infections among persons with severe mental illness. Psychiatr Serv. 2003, 54: 827-835. 10.1176/appi.ps.54.6.827.View ArticlePubMedGoogle Scholar
- Desenclos JC: Epidemiology of hepatitis C. Rev Prat. 2000, 50: 1066-1070.PubMedGoogle Scholar
- Memon MI, Memon MA: Hepatitis C: an epidemiological review. J Viral Hepat. 2002, 9: 84-100. 10.1046/j.1365-2893.2002.00329.x.View ArticlePubMedGoogle Scholar
- Balogun MA, Ramsay ME, Hesketh LM, Andrews N, Osborne KP, Gay NJ, Morgan-Cap P: The prevalence of hepatitis C in England and Wales. J Infect. 2002, 45: 219-226. 10.1053/jinf.2002.1059.View ArticlePubMedGoogle Scholar
- Williams I: Epidemiology of hepatitis C in the United States. Am J Med. 1999, 107 (6B): 2S-9S. 10.1016/S0002-9343(99)00373-3.View ArticlePubMedGoogle Scholar
- Davidson S, Judd F, Folley D, Hocking B, Thompson S, Hyland B: Risk factors for HIV/AIDS and hepatitis C among the chronic mentally ill. Aust N Z J Psychiatry. 2001, 35: 203-209. 10.1046/j.1440-1614.2001.00867.x.View ArticlePubMedGoogle Scholar
- El-Serag HB, Kunik M, Richardson P, Rabeneck L: Psychiatric disorders among veterans with hepatitis C infection. Gastroenterology. 2002, 123: 476-482. 10.1053/gast.2002.34750.View ArticlePubMedGoogle Scholar
- Klinkenberg WD, Caslyn RJ, Morse GA, Yonker RD, McCudden S, Ketema F, Constantine NT: Prevalence of human immunodeficiency virus, hepatitis B, and hepatitis C among homeless persons with co-occurring severe mental illness and substance use disorders. Compr Psychiatry. 2003, 44: 293-302. 10.1016/S0010-440X(03)00094-4.View ArticlePubMedGoogle Scholar
- Cividini A, Pistorio A, Regazzetti A, Cerino A, Tinelli C, Mancuso A, Ribola M, Galli ML, Agnusdei A, Leone M, Silini E, Mondelli MU: Hepatitis C virus infection among institutionalised psychiatric patients: a regression analysis of indicators of risk. J Hepatol. 1997, 27: 455-463. 10.1016/S0168-8278(97)80348-0.View ArticlePubMedGoogle Scholar
- Nguyen HA, Miller AI, Dieperink E, Willenbring ML, Tetrick LL, Durfee JM, Ewing SL, Ho SB: Spectrum of disease in U.S. veteran patients with hepatitis C. Am J Gastroenterology. 2002, 97: 1813-1820. 10.1111/j.1572-0241.2002.05800.x.View ArticleGoogle Scholar
- Rosenberg SD, Goodman LA, Osher FC, Swartz MS, Essock SM, Butterfield MI, Constantine NT, Wolford GL, Salyers MP: Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness. Am J Public Health. 2001, 91: 31-37.PubMed CentralView ArticlePubMedGoogle Scholar
- Dinwiddie SH, Shicker L, Newman T: Prevalence of hepatitis C among psychiatric patients in the public sector. Am J Psychiatry. 2003, 160: 172-174. 10.1176/appi.ajp.160.1.172.View ArticlePubMedGoogle Scholar
- Morrison EF: A hierarchy of aggressive and violent behaviors among psychiatric inpatients. Hosp Commun Psychiatry. 1992, 43: 505-506.Google Scholar
- Fernandez-Egea E, Gomez Gil E, Corbella Santoma B, Salamero Baro M, Blanch Andreu J, Vades Miyar M: Serological testing and prevalence of human immunodeficiency, hepatitis B and C viruses infections among acute psychiatric inpatients. Med Clin (Barc). 2002, 119: 690-692.View ArticleGoogle Scholar
- Alter MJ, Kruszon-Moran D, Nainan OV, Mc Quillan GM, Gao F, Moyer LA, Kaslow RA, Margolis HS: The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Eng J Med. 1999, 341: 556-562. 10.1056/NEJM199908193410802.View ArticleGoogle Scholar
- Osher FC, Goldberg RW, McNary SW, Swartz MS, Essock SM, Butterfield MI, Rosenberg SD, the Five-Site Health and Risk Study Research Committee: Substance abuse and the transmission of hepatitis C among persons with severe mental illness. Psychiatr Serv. 2003, 54: 842-847. 10.1176/appi.ps.54.6.842.View ArticlePubMedGoogle Scholar
- Butterfield MI, Bosworth HB, Meador KG, Stechuchak KM, Essock SM, Osher FC, Goodman LA, Swanson JW, Bastian LA, Horner RD, Five-Site Health and Risk Study Research Committee: Gender differences in hepatitis C infection and risks among persons with severe mental illness. Psychiatr Serv. 2003, 54: 848-853. 10.1176/appi.ps.54.6.848.View ArticlePubMedGoogle Scholar
- Tor J, Llibre JM, Carbonell M, Muga R, Ribera A, Soriano V, Clotet B, Sabria M, Foz M: Sexual transmission of hepatitis C virus and its relation with hepatitis B virus and HIV. Br Med J. 1990, 301: 1130-1133.View ArticleGoogle Scholar
- Fiscus SA, Kelly WF, Battigelli DA, Weber DJ, Schoenbach VJ, Landis SE, Wilber JC, Van der Host CM: Hepatitis C virus seroprevalence in clients of sexually transmitted disease clinics in North Carolina. Sex Transm Dis. 1994, 21: 155-160.View ArticlePubMedGoogle Scholar
- Cilla G, Perez-Trallero E, Iturriza M, Arrizabalaga J, Iribarren JA: Possibility of heterosexual transmission of hepatitis C virus. Eur J Microbiol Infect Dis. 1991, 10: 533-534. 10.1007/BF01963948.View ArticleGoogle Scholar
- Salvaggio A, Conti M, Albano A, Pianetti A, Muggiasca ML, Re M, Selvaggio L: Sexual transmission of hepatitis C virus and HIV-1 infection in intravenous drug users. Eur J Epidemiology. 1993, 9: 279-284. 10.1007/BF00146264.View ArticleGoogle Scholar
- Sladden TJ, Hickey AR, Dunn TM, Beard Jr: Hepatitis C transmission on the north coast of New South Wales: explaining the unexplained. Med J Australia. 1997, 166: 290-293.PubMedGoogle Scholar
- Centers for Disease Control and Prevention: Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Morbidity and Mortality Weekly Report. 1998, 47 (RR-19): 1-39.Google Scholar
- Hershow RC, Kalish LA, Sha B, Till M, Cohen M: Hepatitis C virus infection in Chicago women with or at risk for HIV infection. Sex Transm Dis. 1998, 25: 527-532.View ArticlePubMedGoogle Scholar
- Ward H, Pallecaros A, Green A, Day S: Health issues associated with increasing use of "crack" cocaine among female sex workers in London. Sex Transm Infect. 2000, 76: 292-293. 10.1136/sti.76.4.292.PubMed CentralView ArticlePubMedGoogle Scholar
- Marsano LS, Pena LR: The interaction of alcoholic liver disease and hepatitis C. Hepatogastroenterology. 1998, 45: 331-339.PubMedGoogle Scholar
- Corrao G, Carle F, Lepore AR, Zepponi E, Galatola G, Di Orio F: Interaction between alcohol consumption and positivity for antibodies to hepatitis C virus on the risk of liver cirrhosis: a case-controlled study. Eur J Epidemiol. 1992, 9: 634-639. 10.1007/BF00145376.View ArticleGoogle Scholar
- Stuyt EB: Hepatitis C in patients with co-occurring mental disorders and substance use disorders: is tobacco use a possible risk factor?. Am J Addiction. 2004, 13: 46-52. 10.1080/10550490490265316.View ArticleGoogle Scholar
- Dieperink E, Willenbring M, Ho SB: Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry. 2000, 157: 867-876. 10.1176/appi.ajp.157.6.867.View ArticlePubMedGoogle Scholar
- Rodger AJ, Roberts S, Lanigan A, Bowden S, Brown T, Crofts N: Assessment of long term outcomes of community-acquired hepatitis C infection in a cohort with sera stored from 1971 to 1975. Hepatology. 2000, 32: 582-587. 10.1053/jhep.2000.9714.View ArticlePubMedGoogle Scholar
- Janssen HL, Brouwer JT, van der Mast RC, Schalm SW: Suicide associated with alfa-interferon therapy for chronic hepatitis. J Hepatol. 1994, 21: 241-243. 10.1016/S0168-8278(05)80402-7.View ArticlePubMedGoogle Scholar
- Bourat L, Larrey D, Michel H: Attempted suicide during treatment of chronic viral hepatitis C with interferon. Apropos of 2 cases. Gastroenterol Clin Biol. 1995, 19: 1063-PubMedGoogle Scholar
- Rifflet H, Vuillemin E, Oberti F, Duverger P, Laine P, Garre JB, Cales P: Suicidal impulses in patients with chronic viral hepatitis C during or after therapy with interferon alpha. Gastroenterol Clin Biol. 1998, 22: 353-357.PubMedGoogle Scholar
- Fukunishi K, Tanaka H, Maruyama J, Takahashi H, Kitagishi H, Ueshima T, Maruyama K, Sakata I: Burns in a suicide attempt related to psychiatric side effects of interferon. Burns. 1998, 24: 581-583. 10.1016/S0305-4179(98)00073-4.View ArticlePubMedGoogle Scholar
- Pardelli R, Vivaldi I, Maccanti O, Sani S, Menicagli V: Attempted suicide during interferon therapy: a case report and literature review. Infez Med. 1998, 6: 221-224.PubMedGoogle Scholar
- Windemuth D, Bacharach-Buhles M, Hoffman K, Altmeyer P: Depression and suicidal intentions as a side effect of high dosage of interferon-alpha therapy: two cases. Hautarzt. 1999, 50: 266-269. 10.1007/s001050050899.View ArticlePubMedGoogle Scholar
- Kovacs A, Szomor A, Abraham I, Nagy F, Losonczy H: Orv Hetil. 2002, 143: 2183-2187.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.