Current status and challenges of drug development for hormonal treatment of endometriosis: a systematic review of randomized control trials.

OBJECTIVE: The aim of this systematic review is to summarize the data obtained from randomized controlled trials looking at new pharmacologic treatments for endometriosis published over the last decade with a focus on hormonal therapeutic options for endometriosis-associated pelvic pain (EAPP), excluding studies focusing on fertility. METHODS: We identified relevant original studies in the English language through a search of the MEDLINE, Scopus, and EMBASE (2012 to present) databases using the appropriate MeSH terms and applying the article type filter 'randomized controlled trials'. A total of 219 records were found during the electronic search. After a detailed evaluation and review of the manuscripts, 11 primary articles met the inclusion criteria. A systematic review of the data was conducted. RESULTS: This review included several emerging drug therapies for EAPP. Randomized control trials showed promising results with several oral gonadotropin-releasing hormone antagonists (elagolix, relugolix, ASP1707, linzagolix). However, studies of other hormonal agents such as aromatase inhibitors and selective progesterone receptor modulators have not yielded significant or new advantages. Selective estrogen receptor modulators have not been represented in randomized control trials and have failed to demonstrate clinical efficacy. CONCLUSION: Although numerous novel agents are being investigated for the treatment of endometriosis, there is still no significant progress in the development of curative rather than suppressive drugs. Therefore, further efforts are needed to develop an effective and hopefully curative treatment for this chronic, costly, and overwhelming disease.

POOR POSTNATAL WEIGHT GAIN AS A PREDICTOR OF RETINOPATHY OF PREMATURITY.

The purpose of this study was to re-evaluate cut-off values used in screening for retinopathy of prematurity (ROP) in Croatia and to propose postnatal weight gain as an additional criterion, based on the Colorado Retinopathy of Prematurity prediction model. Medical records of 267 premature infants from the Zagreb University Hospital Centre that underwent ROP screening between January 2009 and December 2010 were reviewed retrospectively. Collected data included gestational age, birth weight, sex, weekly weight measurements and fundus examination records. Results showed the cut-off values of gestational age (GA) and birth weight (BW) used in Croatia to be appropriate and postnatal weight gain in the first 28 days could be used as an additional criterion on screening in the following way: net weight gain in the first 28 days of ≤932 g for prediction of any form of ROP and of ≤660 g for prediction of severe ROP should be added to the existing criteria of GA (≤32 weeks) and/or BW (≤1500 g). Infants with a non-physiological postnatal weight gain are exception. This is the first Croatian study to propose postnatal weight gain as an additional criterion on ROP screening and requires further validation on a larger sample of Croatian infants.

[Expectations after ban on asbestos]. / Ocekivanja vezana uz bolesti izazvane azbestom nakon zabrane upotrebe azbesta.

This article brings a brief review of asbestos exposure and asbestos-related diseases in Croatia in view of the asbestos ban. The first cases of asbestosis were diagnosed in workers from an asbestos-cement factory in 1961. Between 1990 and 2007, 403 cases of asbestosis had been registered as occupational disease: 300 with parenchymal fibrosis and the rest with parenchymal and pleural changes, or pleural plaques. As a rule, asbestos-related changes were diagnosed at an early stage thanks to regular checkups of the exposed workers. Pleural plaques, considered to be the consequence of asbestos exposure, were also occasionally found in subjects who lived in areas with asbestos processing plants, but were not occupationally exposed. Early epidemiological studies on respiratory and gastrointestinal tract tumours in areas with an asbestos processing plant (1994) and an asbestos-cement plant (1995, 1996) focused on the occurrence of malignant tumours in persons exposed to asbestos at work or in the environment. More recently, the focus has shifted to the malignant pleural mesotelioma (MPM). An epidemiological study published in 2002 showed that the MPM incidence was significantly higher in the coastal area than in the rest of the country. About two thirds of patients with the tumour were occupationally exposed to asbestos. This uneven distribution of the tumour incidence is obviously related to shipbuilding and other industrial sources of asbestos exposure located in the coastal Croatia. Sources of environmental exposure to asbestos also have to be taken into account. The second part of this article ventures into the issues ahead of us, after asbestos has been banned in the country. The long latency period of cancers, and particularly of asbestos-related mesothelioma, implies that the incidence of this tumour will not drop over the next few decades. In Croatia, the average annual rate of MPM between 1991 and 2006 was 40, and ranged between 20 in 1991 to 61 in 1999. In 2006 it was 58. Age-standardised incidence of this tumour between 1991 and 1997 was 0.74 per 100,000 (1.34 per 100,000 for men and 0.27 per 100,000 for women). Sadly, the diagnosis of mesothelioma is seldom timely, and treatment is usually unsuccessful.

[Causes of climatic changes and their consequences on human health]. / Uzroci klimatskih promjena i njihove posljedice za zdravlje covjeka.

Environmental disasters are common phenomena caused by human factors. Disaster episodes may be the result of climatic changes such as global warming, which can lead to floods or drought. Greenhouse gases, and especially the ozone, represent a special problem. Atmospheric pollutions are the result of fire, storm dusts, winds, acid rain, etc. Underwater earthquakes very often end in tsunami with waves of up to 30 meters. Disasters described in the territory of Croatia include atmospheric pollutions, fires, floods, and droughts. All disasters affect the health of the population, particularly of the elderly. This most often includes the cardiovascular and respiratory systems, allergic reactions, and carcinogenic effects, resulting in increased mortality.

The role of polio-vaccine in pleural mesothelioma--an epidemiological observation.

From the Croatian Cancer Registry (period 1991-1997) 194 malignant pleural mesothelioma patients were collected. According to participation in polio vaccination mass campaign in 1961 that covered the entire Croatian population aged 3 months to 20 years, mesothelioma patients were divided in vaccinated (N=58), and non-vaccinated (N=136) subjects. Significantly higher percentage of those with a history of occupational exposure to asbestos was found in vaccinated (79%) compared to non-vaccinated group (63%). This is the opposite to what would be expected if potential SV40 contamination of polio vaccine used had a causative role in the development of the tumour. On the other hand, shorter latency period reflected by very high percentage of 45-year-old or younger mesothelioma patients in vaccinated group (15 out of 58), with all of them having a history of occupational asbestos exposure, raises a question for a possible enhancing effect of the vaccine used to asbestos exposure, if it was contaminated with SV40.

Mycotoxic and aristolochic acid theories of the development of endemic nephropathy.

Despite many efforts of scientists and epidemiologists, the aetiology of endemic nephropathy (EN) is still unknown. This disease occurs in the rural population of geographically limited areas of Bulgaria, Bosnia and Herzegovina, Croatia, Romania, and Serbia, and a number of theories have been proposed about its aetiology. The mycotoxin theory has prevailed until now, based on the studies of nephrotoxic mycotoxin ochratoxin A (OTA) that revealed higher frequency of OTA-positive food and blood samples in endemic than in non-endemic areas.However, a new aristolochic acid (AA) theory of EN origin has been proposed recently, due to the histological similarities in kidney lesions between patients suffering from EN and patients suffering from Chinese herbs nephropathy caused by AA. Until now it has not been unequivocally proved that the inhabitants of EN areas are exposed to higher concentration of AA than in other regions and the exposure pathways are rather uncertain. This paper presents most important studies supporting both theories, indicating also the inconsistencies of each.

[Present cardiovascular morbidity and mortality in Croatia]. / Kardiovaskularni morbiditet i mortalitet--dosadasnje spoznaje.

Individual clinical and/or epidemiological studies on the prevalence of cardiovascular diseases in Croatia are described. The studies based on regional approach and distribution are specially analyzed, with a note that there have been only few such studies from the highland parts of Croatia. An overview of several studies dealing with the influence of region, air pollution, and specific mortality due to cardiovascular diseases is also presented. An overview of available literature sources from international tertiary databases and National University Library is provided.

[Women and medical skill--historic view]. / Zene i medicinsko umijece--povijesni ogled.

By the Banal edict of 28 June 1903, while the country was part of the Austrian-Hungarian monarchy, women physicians in Croatia were granted permission to carry out medical practice. In the memory of that occasion a historical overview of the women's role in medical science and practice is presented. The evidence of women's medical skills dates back to 2500 BC in Ancient Egypt. The 11th and 12th centuries saw first women gain access to medical schools in Europe. Women doctors practiced mainly gynaecology, obstetrics, cosmetics, skin and eye diseases. It took another seven centuries for them to be treated as men's equals as far as medical training and permission to work were concerned. In the 18th and 19th centuries the number of female physicians greatly increased in Europe, USA, and Canada. In Croatia the first woman medical doctor was Milica Sviglin Cavov, who graduated from the Medical School in Zürich in 1893, but was not allowed to work in the home country. The first woman to practice medicine in Croatia was Karola Maier Milobar in 1906. The first woman to have graduated from the Medical School in Zagreb, capital of Croatia, following its opening in 1917, was Kornelija Sertic The paper concludes with a view of the present-day role of women in medical practice, education and science.

Evidence against a role for SV40 in human mesothelioma.

SV40 has been implicated in the etiology of 40% to 60% of human mesotheliomas. These studies could have important medical implications concerning possible sources of human infection and potential therapies if human tumors are induced by this agent. We did PCR-based analysis to detect SV40 large T antigen DNA in human mesotheliomas. None of 69 tumors in which a single copy gene was readily amplified contained detectable SV40 large T antigen sequences. Under these conditions, it was possible to detect one copy of integrated SV40 DNA per cell in a mixture containing a 5,000-fold excess of normal cells using formalin-fixed preparations. Kidney, a known reservoir of SV40 in monkeys, from some of these individuals were also negative for SV40 large T antigen sequences. A subset of mesotheliomas was analyzed for SV40 large T antigen expression by immunostaining with a highly specific SV40 antibody. These tumors as well as several human mesothelioma cell lines previously reported to contain SV40 large T antigen were negative for detection of the virally encoded oncoprotein. Moreover, mesothelioma cell lines with wild-type p53 showed normal p53 function in response to genotoxic stress, findings inconsistent with p53 inactivation by the putative presence of SV40 large T antigen. Taken together, these findings strongly argue against a role of SV40 by any known transformation mechanism in the etiology of the majority of human malignant mesotheliomas.

Incidence of malignant pleural mesothelioma in coastal and continental Croatia: epidemiological study.

AIM: To evaluate the actual incidence of malignant pleural mesothelioma in Croatia, geographical distribution of the disease, and relevance of occupation and some other characteristics of diseased subjects. METHOD: Data on the incidence of pleural mesothelioma over a seven-year period (1991-1997) were collected from the Croatian Cancer Registry. In each case, the tumor diagnosis was histologically verified. Registration of the patients was based on their place of residence. Also, in 2001, a short questionnaire was sent to patients' families to gather additional information on patients' occupation (exposure to asbestos), smoking habits, and length of residence in the registered place. In many cases some of the answers had to be clarified by telephone or through a personal contact. Data obtained from 20 counties (administrative units) of Croatia were grouped into two larger areas: coastal and continental. The data for the city of Zagreb were presented separately. RESULTS: During the 1991-1997 period, the Registry recorded a total of 248 malignant pleural mesotheliomas (197 in men and 51 in women). The poll gathered additional data for 194 patients (78.2%): 153 (77.7%) men and 41 (80.4%) women. Eight in a million people on average were diagnosed with malignant pleural mesothelioma per year. Age standardized incidence rates (per 100,000) by residence showed an uneven geographical distribution for men: 2.66 in coastal area, 0.69 in continental area, and 0.75 in the city of Zagreb. Goodness-of-fit test for observed rates vs expected for Croatia were chi-square=145, df=2, p<0.001; post-hoc tests: coastal vs continental area chi-square=12.3, df=1, p=0.001; and coastal area vs city of Zagreb chi-square=4.4, df=1, p=0.035. In women with mesothelioma, these rates were 0.38, 0.24, and 0.18, respectively, and the differences were not statistically significant. CONCLUSION: Assuming that the information obtained by the poll on the occupation of diseased subjects was a true characterization of all recorded cases of pleural mesothelioma, more than two-thirds of subjects with the studied tumor had an occupational exposure to asbestos. Uneven distribution of the tumor, with higher rate in men in the coastal area, may be related to shipbuilding and other industrial sources of asbestos exposure in that part of the country.

[Work capacity--approach and evaluation criteria]. / Radna sposobnost--pristup i kriteriji u ocjeni.

In occupations involving specific risk factors, the employer is required by law to have his candidates/employees physically examined in the course of pre-placement/work, as a measure of health and safety protection. Upon examination, the occupational health physician issues to the employer a statement of the candidate's/employee's suitability for work. Mandatory pre-placement and periodic medical examinations are also required for workers who may affect the health and safety of the public such as workers in public transportation or food processing. This paper looks into the implementation of regulations and actual practice in performing relevant medical examinations. One of the issues described is the determination of a worker's temporary disability. Practicing physician determines a disability and rates the physical impairment. She or he has to translate clinical information into a decision about whether a patient is able to work. This decision is the basis for healthcare compensation and benefits and requires knowledge not only of the illness or injury and the patient, but also of the job tasks and exposure. From the medical standpoint, it may be difficult to determine when a period of temporary disability has ended or if a degree of impairment has remained, and when the temporary partial or total disability has become permanent. The paper discusses the assessment of total or partial permanent disabilities based on the new Pension Insurance Act (1998) and the differences from earlier criteria, summarising the implementation of new regulations for years 2000 and 2001.