Gastroschisis: international epidemiology and public health perspectives

Gastroschisis offers the intriguing epidemiological situation of a pandemic, strongly associated with very low maternal age. Identifying gastroschisis, and distinguishing it from the other abdominal wall defects, is theoretically easy but difficult in practice. The baseline birth prevalence of gastroschisis before the pandemic was approximately 1 in 50,000 births and has increased since between 10- and 20-fold. In many populations worldwide, it is still increasing. Such increasing prevalence and the association with very low maternal age are well proven, but the interaction between these two findings remains unknown. Geographic gradients (decreasing prevalence from North to South) are clear in Continental Europe and suggestive in Britain and Ireland. Gastroschisis seems more frequent in Caucasians compared to African Blacks and Orientals, and in Northern compared to Southern Europeans. These observations indicate the need for investigating gene-environment interactions. Since the global human situation is marked by inequalities among as well as within countries, the medical care and public health impact of gastroschisis varies widely among regions and social strata. The postnatal benefits of prenatal diagnosis of gastroschisis include family awareness; adequate planning of delivery with alerted obstetrical, pediatric, and surgical staff; optimal risk categorization, and personalized protocol for action. The increasing prevalence of gastroschisis combined with improved medical techniques to reduce morbidity and mortality are also increasing the burden and costs of this anomaly on health systems.     

Hereditary anaemias in Portugal: epidemiology, public health significance, and control.

A countrywide prospective study aimed at establishing the prevalence of the haemoglobinopathy genes in the Portuguese population was carried out by screening 15,208 randomly selected blood samples from young males. This male based survey provided the opportunity of assessing simultaneously the prevalence of the red cell enzyme glucose-6-phosphate dehydrogenase (G6PD) deficiency, thus giving a picture of these important hereditary anaemias in Portugal. The results showed a low average frequency of beta thalassaemia (0.45%) and haemoglobin S (0.32%) carriers as well as G6PD deficiency (0.51%). However, these disorders are unevenly distributed throughout the country with a higher prevalence in some areas, mainly in the south. The relationship of this pattern of haemoglobinopathies to the known haplotypes linked to beta thalassaemia and sickle cell disease, relevant historical events, and local selective pressure was investigated. Hb D and Hb J are the commonest other structural variants. The implemented programme for control of these hereditary anaemias is described.     

Human papillomavirus vaccines

A wealth of epidemiological and molecular evidence has led to the conclusion that virtually all cases of cervical cancer and its precursor intra-epithelial lesions are a result of infection with one or other of a subset of genital human papillomaviruses (HPVs) suggesting that prevention of infection by prophylactic vaccination would be an effective anti-cancer strategy. The papillomaviruses cannot be grown in large amounts in culture in vitro, but the ability to generate HPV virus like particles (VLPs) by the synthesis and self-assembly in vitro of the major virus capsid protein L1 provides for a potentially effective sub unit vaccine. HPV L1 VLP vaccines are immunogenic and have a good safety profile. Published data from proof of principle trials and preliminary reports from large Phase III efficacy trials suggest strongly that they will protect against persistent HPV infection and cervical intra epithelial neoplasia. However, the duration of protection provided by these vaccines is not known, the antibody responses induced are probably HPV type specific and immunisation should occur pre-exposure to the virus. Second generation vaccines could include an early antigen for protection post-exposure and alternative delivery systems may be needed for the developing world.     

人乳头瘤病毒给予我们的机遇和挑战

过去的2008年是很不平常的一年.年度的诺贝尔生理/医学奖颁发给了两个病毒领域,它们是人乳头瘤病毒(HPV)和人体免疫缺陷病毒(HIV).这一举动显示出,人们已经更加深刻认识到病毒在某些疾病致病机制中的重大意义.在诺奖的历史上,虽然上世纪60～70年代有多次诺奖与病毒有关,然而与某种具体病毒直接相关的诺奖只有2次3个病毒,即1997年的朊病毒和此次2008年的HPV和HIV.     

The changing global epidemiology of Acinetobacter baumannii infections: a development with major public health implications

Acinetobacter baumannii infections have become increasingly common among critically-ill patients in intensive care units (ICUs) worldwide. A. baumannii clinical isolates are frequently resistant to most antimicrobial agents and evidence of pan-drug resistance among A. baumannii isolates (i.e., resistance to all available antimicrobial agents, including polymyxins) has been reported. These facts constitute an alarming development in the field of infectious diseases, with major public health implications. More intensive efforts are urgently required to elucidate the epidemiological and infection control issues related to these organisms and to improve the management of patients with such infections.     

Human papillomavirus and cervical cancer

Of the many types of human papillomavirus (HPV), more than 30 infect the genital tract. The association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Although HPV is essential to the transformation of cervical epithelial cells, it is not sufficient, and a variety of cofactors and molecular events influence whether cervical cancer will develop. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Identification of precancerous lesions has been primarily by cytologic screening of cervical cells. Cellular abnormalities, however, may be missed or may not be sufficiently distinct, and a portion of patients with borderline or mildly dyskaryotic cytomorphology will have higher-grade disease identified by subsequent colposcopy and biopsy. Sensitive and specific molecular techniques that detect HPV DNA and distinguish high-risk HPV types from low-risk HPV types have been introduced as an adjunct to cytology. Earlier detection of high-risk HPV types may improve triage, treatment, and follow-up in infected patients. Currently, the clearest role for HPV DNA testing is to improve diagnostic accuracy and limit unnecessary colposcopy in patients with borderline or mildly abnormal cytologic test results.     

Human papillomavirus and anal neoplasia

Anal cancer is a rare disease in the general population, but the incidence of anal cancer is higher in certain at-risk groups, such as men who have sex with men (MSM), and immunosuppressed individuals, including those with HIV infection. Among HIV-positive MSM, the incidence of anal cancer may be as high as 10 times greater than current rates of cervical cancer in the general population of women. Anal cancer is associated with human papillomavirus (HPV) infection and may be preceded by high-grade anal intraepithelial neoplasia (HGAIN). HGAIN and anal HPV infection are both highly prevalent in groups at risk for anal cancer. Current issues include determining the effect of antiretroviral therapy on the natural history of HGAIN and the incidence of anal cancer, optimizing diagnostic and therapeutic approaches to HGAIN, and determining the potential for prophylactic HPV vaccines to prevent anal HPV infection and anal cancer in at-risk groups.     

The epidemiology of human papillomavirus infection and cervical cancer

Cervical cancer has been recognized as a rare outcome of a common Sexually Transmitted Infection (STI). The etiologic association is restricted to a limited number of viral types of the family of the Human Papillomaviruses (HPVs). The association is causal in nature and under optimal testing systems, HPV DNA can be identified in all specimens of invasive cervical cancer. As a consequence, it has been claimed that HPV infection is a necessary cause of cervical cancer. The evidence is consistent worldwide and implies both the Squamous Cell Carcinomas (SCC), the adenocarcinomas and the vast majority (i.e. > 95%) of the immediate precursors, namely High Grade Squamous Intraepithelial Lesions (HSIL)/Cervical Intraepithelial Neoplasia 3 (CIN3)/Carcinoma in situ. Co-factors that modify the risk among HPV DNA positive women include the use of oral contraceptives (OC) for five or more years, smoking, high parity (five or more full term pregnancies) and previous exposure to other sexually transmitted diseases such as Chlamydia Trachomatis (CT) and Herpes Simplex Virus type 2 (HSV-2). Women exposed to the Human Immunodeficiency Virus (HIV) are at high risk for HPV infection, HPV DNA persistency and progression of HPV lesions to cervical cancer.     

Human papillomavirus and cancer: the epidemiological evidence.

OBJECTIVE: Summary of the studies carried out by the IARC on HPV and cervical cancer is presented. RESULTS: the first one was the international prevalence survey of HPV types in invasive cervical cancer (ICC) conducted in up to 22 countries. Overall, 99.7% of 1000 cases with histologically confirmed ICC were also shown to be HPV DNA positive using the GP5+/GP6+ or E7 primers, indicating that HPV is a necessary cause of cervical cancer. The most prevalent HPV types were HPV 16 (53%), HPV 18 (15%), HPV 45 (9%), HPV 31 (6%) and HPV 33 (3%). HPV 16 was the most common type in all geographical regions, followed by HPV 18 that was particularly, common in South-East Asia. The second set of studies included case-control studies carried out in 13 countries. They included about 2000 cases and 2000 controls. Positivity, for any HPV DNA yielded a pooled odds ratio (OR) of 70. The association was equally strong for both squamous cell (OR=74) and adenocarcinoma (OR=50) and for HPV 16 and 18 as well as for the less common HPV types. Our results indicate that in addition to HPV 16 and 18, HPV 31, 33, 35, 45, 51, 52, 58 and 59 now can be considered as carcinogenic. The third group of studies is aimed to determine the HPV DNA prevalence in random, age-stratified (by 5 years, 15-19 to 65+) subsamples (1100 women) of the general population. Two age-peaks (<25 and >59 years), have been found in some countries (Costa-Rica, Mexico, Colombia) but not in all (Argentina). Whether the second peak is due to viral reactivation, variations in screening or represents a birth-cohort effect remains to be determined. The distribution of the most prevalent HPV types in the general population (HPV 16, 18, 45, 31, 58, 33, 35) resembles that for cervical cancer cases. CONCLUSIONS: our studies provide the most solid epidemiological evidence, to conclude that HPV is not only the central cause of cervical cancer worldwide but also a necessary cause.     

Human papillomavirus testing methods

Testing for human papillomavirus (HPV) relies exclusively on techniques of molecular biology using nucleic acid probes. Tests for HPV using nucleic acid probes have been commercially available since the late 1980s, but early tests were cumbersome, involving the use of nucleic acid probes labeled with radioactive phosphorus (32P). These early HPV tests did not achieve widespread use because they did not detect all oncogenic HPV genotypes. The current commercial HPV detection kit, Digene's Hybrid Capture 2 kit, detects virtually all high-risk oncogenic HPV types, as well as most low-risk nononcogenic HPV genotypes. The Hybrid Capture 2 test format is a proprietary nucleic acid hybridization signal amplification system owned by Digene Corporation. Virtually all test formats for DNA sequence analysis are amenable to applications intended to detect and perhaps quantify the various HPV genotypes. These methods can involve direct hybridization with complementary DNA probes, such as Southern blotting or in situ hybridization, signal amplification, such as the Hybrid Capture 2 method or target nucleic acid amplification, most notably the polymerase chain reaction (PCR). Polymerase chain reaction has been used for HPV detection, genotyping, and viral load determination. General or consensus primer-mediated PCR assays have enabled screening for a broad spectrum of HPV types in clinical specimens using a single PCR reaction. Following amplification using consensus primers, individual HPV genotypes are identified using a variety of methods. Using consensus primers in a test format known as real-time quantitative PCR (RQ-PCR), it is possible to generate viral load (concentration) data from reaction curves generated by monitoring PCR reaction kinetics in real time.     

Human papillomavirus reporting: minimizing patient and laboratory risk

Risk management efforts in the cytology laboratory must address the gap between what can be achieved with medical history's most effective cancer screening test, the Papanicolaou (Pap) test, and even higher entrenched public expectations. Data from the Atypical Squamous Cells of Undetermined Significance (ASCUS)/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) now provide level I clinical evidence from a large, randomized, controlled, multicenter clinical trial that reflex human papillomavirus (HPV) DNA testing of ASCUS cases is generally the preferred method for initial assessment of the most prevalent category of abnormal Pap interpretation. The proposed combination of HPV DNA testing with cytologic Pap testing, the DNA Pap test, further shows the potential to nearly eliminate false-negative screening results, based on sensitivity and negative predictive values reported in available studies. Human papillomavirus DNA testing also appears to represent a significant enhancement for detection of endocervical adenocarcinomas, which are difficult to detect and prevent. Human papillomavirus DNA testing, when used in conjunction with cervical cytology, can significantly reduce risk to both the patient and the laboratory.     

Human papillomavirus: current status and issues of vaccination

An association between human papillomavirus (HPV) infection and the development of cervical cancer was initially suggested over 30 years ago, and today there is clear evidence that certain subtypes of HPV are the causative agents of such malignancies. Papillomaviruses make up a vast family that comprises hundreds of different viruses. These viruses infect epithelia in humans and animals and cause benign hyperproliferative lesions, commonly called warts or papillomas, which can occasionally progress to squamous cell cancer. HPV infections are considered the most common among sexually transmitted diseases. One of the most prevalent cancer types induced by HPV (mostly types 16 and 18) is cervical cancer. Vaccination is the most effective means of preventing this infectious disease. These prophylactic vaccines, based on virus-like particles (VLPs), are extremely effective in providing protection from infection in almost 100 % of cases. VLP vaccines of HPV are subunit vaccines consisting only of the major viral capsid protein of HPV. There are two types of vaccine available: bivalent vaccine (against HPV-16/18) and quadrivalent vaccine (against HPV-6/11/16/18). Second-generation prophylactic HPV vaccines, currently in clinical trials, may hold several merits over the current bivalent and quadrivalent vaccines, such as protection against additional oncogenic HPV types, less dependence on cold-chain storage and distribution, and non-invasive methods of delivery.     

Human papillomavirus infections and oral tumors

In the past 20 years, there has been an increasing interest in human papillomaviruses (HPV) because of their potential role in the pathogenesis of malignant tumors. In 1983, we published the first evidence that HPV might be involved in oral squamous cell carcinomas. The identification of morphological similarities between oral and cervical mucosa lead us to this original proposal. In a recent meta-analysis, HPV was indeed confirmed as an independent risk factor for oral carcinoma. To date, totally more than 100 types of HPV have been identified. As in anogenital cancers, HPV type 16 is the most prevalent type in oral carcinomas. The benign oral lesions, associated with HPV infection, include squamous cell papilloma, condyloma acuminatum, verrucca vulgaris and focal epithelial hyperplasia (FEH). Papillomas and condylomas are mostly caused by HPV type 6 or 11, while oral verrucas are associated with the skin types 2 or 4. A family history of FEH has been suggested. The FEH lesions are caused by HPV types 13 and 32, only detected in oral epithelium. In immunocompromised patients, benign HPV-induced lesions are characterized by atypical morphology and the simultaneous detection of multiple HPV types. Oral benign HPV lesions are mostly asymptomatic, and may persist or regress spontaneously.