80th Anniversary of the Publication of Endemic Syphilis in Bosnia: Survey by the School of Public Health in Zagreb.

Certain regions of Bosnia and Herzegovina were prominent European sites of endemic syphilis. In 1934 and 1935 the School of Public Health in Zagreb, later the Andrija Stampar School of Public Health, conducted two surveys on endemic syphilis in Bosnia and Herzegovina. The surveys were well-described in the monograph published in 1939 by the School, under the title Endemic Syphilis in Bosnia: Survey by the School of Public Health in Zagreb ("Endemski sifilis u Bosni anketa Skole narodnog zdravlja u Zagrebu"). This paper provides a description of the publication for the first time, presents the most important data from it, and explores its significance from the historical perspective.

Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome.

Adaptor protein (AP) complexes mediate key sorting decisions in the cell through selective incorporation of transmembrane proteins into vesicles. Little is known of the roles of AP-4, despite its loss of function leading to a severe early onset neurological disorder, AP-4 deficiency syndrome. Here we demonstrate an AP-4 epsilon subunit knockout mouse model that recapitulates characteristic neuroanatomical phenotypes of AP-4 deficiency patients. We show that ATG9A, critical for autophagosome biogenesis, is an AP-4 cargo, which is retained within the trans-Golgi network (TGN) in vivo and in culture when AP-4 function is lost. TGN retention results in depletion of axonal ATG9A, leading to defective autophagosome generation and aberrant expansions of the distal axon. The reduction in the capacity to generate axonal autophagosomes leads to defective axonal extension and de novo generation of distal axonal swellings containing accumulated ER, underlying the impaired axonal integrity in AP-4 deficiency syndrome.Abbreviations: AP: adaptor protein; AP4B1: adaptor-related protein complex AP-4, beta 1; AP4E1: adaptor-related protein complex AP-4, epsilon 1; ATG: autophagy-related; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GFAP: glial fibrillary acidic protein; GOLGA1/Golgin-97/GOLG97: golgi autoantigen, golgin subfamily a, 1; GOLGA2/GM130: golgi autoantigen, golgin subfamily a, 2; HSP: hereditary spastic paraplegia; LC3/MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule-associated protein 2; MAPK8IP1/JIP1: mitogen-acitvated protein kinase 8 interacting protein 1; NEFH/NF200: neurofilament, heavy polypeptide; RBFOX3/NeuN (RNA binding protein, fox-1 homolog [C. elegans] 3); SQSTM1/p62: sequestosome 1; TGN: trans-Golgi network; WIPI2: WD repeat domain, phosphoinositide interacting protein 2.

Miro clusters regulate ER-mitochondria contact sites and link cristae organization to the mitochondrial transport machinery.

Mitochondrial Rho (Miro) GTPases localize to the outer mitochondrial membrane and are essential machinery for the regulated trafficking of mitochondria to defined subcellular locations. However, their sub-mitochondrial localization and relationship with other critical mitochondrial complexes remains poorly understood. Here, using super-resolution fluorescence microscopy, we report that Miro proteins form nanometer-sized clusters along the mitochondrial outer membrane in association with the Mitochondrial Contact Site and Cristae Organizing System (MICOS). Using knockout mouse embryonic fibroblasts we show that Miro1 and Miro2 are required for normal mitochondrial cristae architecture and Endoplasmic Reticulum-Mitochondria Contacts Sites (ERMCS). Further, we show that Miro couples MICOS to TRAK motor protein adaptors to ensure the concerted transport of the two mitochondrial membranes and the correct distribution of cristae on the mitochondrial membrane. The Miro nanoscale organization, association with MICOS complex and regulation of ERMCS reveal new levels of control of the Miro GTPases on mitochondrial functionality.

Tentorial alignment and its relationship to cisternal dimensions of the pineal region: MRI anatomical study with surgical implications using the new clivotentorial method.

OBJECTIVES: Tentorial alignment and dimensions of posterior fossa cisterns are measurements whose variability can decrease surgical freedom if not taken into account when choosing the approach to the pineal region. The aim is to provide quantitative anatomical information regarding these dimensions, and to discuss their relevance in two most commonly used approaches to this region: the occipital transtentorial and supracerebellar-infratentorial approach. PATIENTS AND METHODS: A retrospective study of midsagittal T1-weighted MRI images of 410 randomly selected healthy subjects was performed. The clivus-tentorium (C-T) angle was measured to assess tentorial alignment. The following distances were used as craniocaudal cisternal measurements: quadrigeminal cistern = superior colliculi - inferior part of the splenium of corpus callosum (SC-ISCC), and superior cerebellar cistern = vermis - inferior part of the splenium of corpus callosum (VER-ISCC). RESULTS: Median C-T angle value was 19 ±â€¯7°, the quadrigeminal cistern height 6.7 ±â€¯1.6 cm, and the superior cerebellar cistern height 10.4 ±â€¯2.6 cm. The C-T angle was negatively correlated with the SC-ISCC distance (r = -0.271; p <  0.001) and the VER-ISCC distance (r = -0.052, p >  0.001). The SC-ISCC distance was positively correlated with the VER-ISCC distance (r = 0.282; p < 0.001). CONCLUSION: Our new method of measuring tentorial alignment provides a simple and effective aid in preoperative planning. For the first time, we present data on craniocaudal dimensions of posterior fossa cisterns, their relationship with tentorial alignment, and discuss their relevance in SCIT and OT approaches.

Miro proteins coordinate microtubule- and actin-dependent mitochondrial transport and distribution.

In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho-GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating Miro1/2 double-knockout mouse embryos and single- and double-knockout embryonic fibroblasts, we demonstrate the essential and non-redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double-knockout cells. In contrast, we show that TRAK2-mediated retrograde mitochondrial transport is Miro1-dependent. Interestingly, we find that Miro is critical for recruiting and stabilising the mitochondrial myosin Myo19 on the mitochondria for coupling mitochondria to the actin cytoskeleton. Moreover, Miro depletion during PINK1/Parkin-dependent mitophagy can also drive a loss of mitochondrial Myo19 upon mitochondrial damage. Finally, aberrant positioning of mitochondria in Miro1/2 double-knockout cells leads to disruption of correct mitochondrial segregation during mitosis. Thus, Miro proteins can fine-tune actin- and tubulin-dependent mitochondrial motility and positioning, to regulate key cellular functions such as cell proliferation.

Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy.

Impairment of the autophagy-lysosome pathway is implicated with the changes in α-synuclein and mitochondrial dysfunction observed in Parkinson's disease (PD). Damaged mitochondria accumulate PINK1, which then recruits parkin, resulting in ubiquitination of mitochondrial proteins. These can then be bound by the autophagic proteins p62/SQSTM1 and LC3, resulting in degradation of mitochondria by mitophagy. Mutations in PINK1 and parkin genes are a cause of familial PD. We found a significant increase in the expression of p62/SQSTM1 mRNA and protein following mitophagy induction in human neuroblastoma SH-SY5Y cells. p62 protein not only accumulated on mitochondria, but was also greatly increased in the cytosol. Increased p62/SQSMT1 expression was prevented in PINK1 knock-down cells, suggesting increased p62 expression was a consequence of mitophagy induction. The transcription factors Nrf2 and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1. We report that both Nrf2 and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf2 or TFEB knockdown. TFEB translocation also increased expression of itself and lysosomal proteins such as glucocerebrosidase and cathepsin D following mitophagy induction. We also report that cells with increased TFEB protein have significantly higher PGC-1α mRNA levels, a regulator of mitochondrial biogenesis, resulting in increased mitochondrial content. Our data suggests that TFEB is activated following mitophagy to maintain autophagy-lysosome pathway and mitochondrial biogenesis. Therefore, strategies to increase TFEB may improve both the clearance of α-synuclein and mitochondrial dysfunction in PD. Damaged mitochondria are degraded by the autophagy-lysosome pathway and is termed mitophagy. Following mitophagy induction, the transcription factors Nrf2 and TFEB translocate to the nucleus, inducing the transcription of genes encoding for autophagic proteins such as p62, as well as lysosomal and mitochondrial proteins. We propose that these events maintain autophagic flux, replenish lysosomes and replace mitochondria.

DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites.

The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development.

Recipe from the past for the future: public health intervention represent a process for century.

In the poor Bosnia, in the early 20(th) century endemic syphilis was widespread. Combating this disease entailed the necessity of etiology research, diagnosis and clinical nature of the disease, as well as the insight into the epidemiological image of this unresolved health problem. Thanks to the visionary, the enthusiasm and persistence of the expert team of doctors from that time in Croatia, School of Public Health and the Rockefeller Foundation as financial support, conditions were created to conduct population monitoring and research called "survey". The team of experts from Croatia and Bosnia led by Dr. Ante Vuletic began this important public health intervention in Central Bosnia underneath the mountain Vlasic 1934. In villages of mountain Vlasic people were living in very difficult social and unsanitary conditions. "Interviewers" worked in makeshift clinics in the rural schools Opare, Rankovici, Vitovlje Mehorica, Turbe, Bila and Gornji Vakuf. A hundred years later, a team of university professors from the School of Public Health "Andrija Stampar" led by Professor Silvije Viletic followed the footsteps of century "survey" on Vlasic in the summer of 2014. They determined that with the integrated approach to population monitoring and testing endemic syphilis in Bosnia was successfully suppressed.

The changing pattern of cardiovascular risk factors: the CroHort study.

Croatia has a long tradition of non-communicable disease prevention, but also obstacles to the implementation of preventive programs related to the general attenuation of public health and primary health care sector. The aim of this study was to determine trends in behavioral and biomedical risk factors and evaluate primary non-communicable disease and cardiovascular prevention. Physical inactivity was a leading risk factor with increasing trend and prevalence of 33.9% and 38.9% in men and women in 2008. In 2008, obesity was present in 26.1% and 34.1%, and hypertension in 65.8% and 59.7% of men and women. During the follow-up only smoking and alcohol consumption in men decreased significantly, while alcohol consumption and obesity in women, and hypertension in both sexes significantly increased. In the present situation, with the existing trends and environment it will not be possible to stop negative trends. Revitalization of public health activities and primary health care is essential.

Five-year cumulative incidence of obesity in adults in Croatia: the CroHort study.

The objective of this paper was to evaluate the 5-year incidence of obesity on a sample of 3229 adults and investigate the potential effect of several sociodemographic and lifestyle habits on weight change and obesity incidence in these individuals. The average annual rate of increase in the prevalence of obese adults between 2003 and 2008 was 10.60% for men and 11.08% for women. Analysis showed that development of obesity in 5-year period in women in Croatia is significantly positively associated with frequent consumption of "hidden" fats of animal origin and significantly negative with each higher education level. No significant predictor of obesity has been found in men. Obesity remains a serious health problem for the Croatian population; the alarming rates of excess body weight continue to increase. Preventive measures should urgently be undertaken.

Prevalence and five-year cumulative incidence of abdominal obesity in Croatian women of childbearing age: the CroHort study.

Generalised obesity is increasing in prevalence globally, however trends in abdominal obesity are less well known. In 2003, 1,999 women of childbearing age participated in the Croatian Adult Health Survey, of whom 598 (29.9%) participated in the second cycle in 2008. For 2008, the prevalence of abdominal obesity using the International Diabetes Federation (IDF) criterion (waist circumference > or = 80 cm) was estimated at 70.3% (95% CI 61.8% to 75.7%), whereas the prevalence of abdominal obesity using the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP III) criterion (waist circumference > or = 88 cm) was estimated at 48.6% (42.6% to 54.7%). The preceding five-year cumulative incidence was 54.3% (44.5% to 64.2%) and 35.2% (28.0% to 42.4%) using the IDF and NCEP ATP III criteria, respectively. The burden of abdominal obesity is high and rapidly increasing in Croatian women of childbearing age, the key population subgroup for obesity control.

Obesity--new threat to Croatian longevity.

The aim of this study was to examine the association of weight gain and life expectancy at birth in Croatia. Mean body mass index was based on the data from the Croatian Adult Health Survey 2003. Birth rate and mortality data needed for life expectancy calculation were supplied by the Central Bureau of Statistics. The results suggest that the increase in mean body mass index value (1.31 kg m(-2) for women and 1.41 kg m(-2) for men) will shorten life expectancy at birth for one year. Obesity, if unchecked, might have a negative effect on life expectancy in Croatia. Despite widespread knowledge about how to reduce the severity of the problem, observed trends in obesity in Croatia continue to worsen. These trends threaten to diminish the health and life expectancy of current and future generations.

Social conditioning of health behaviors among adults in Croatia: the CroHort study.

The aim of this study was to examine the social conditioning of health behaviors of adults in Croatia, based on the data from Croatian Adult Health Survey 2003. This cross-sectional study on a representative random sample of 9070 Croatian adults showed that obesity was significantly and socially conditioned in women, whereas for men the indication of social conditioning has not reached a statistically significant level. Health behaviors were socially conditioned in both sexes. Men's living habits were more irregular than those of women. Compared with women, men consumed more cured meat products, consumed alcohol excessivelly and smoked cigarettes more often, whereas they ate less fruits and vegetables. Health promotion strategies based on the behavioral correlates of overweight and obesity are needed to prevent excess weight gain in the Croatian population. While for men a unique educational model is applicable, women require more specialized programs, adapted to their social background.

Behavioral pattern of overweight and obese school children.

The aim of this study was to determine socio economic, health status, nutritional and behavioral differences in obese, overweight and normal weight children attending first grade elementary school. In overweight group there is 13.8% of boys and 12.6% of girls, in obese group 8.3% of boys and 6.9% of girls. In factor analysis 12 factors was excluded with cumulative loading of 60% variability. Discriminant analysis was performed with 12 factors as predictive variables and discriminant variables were three BMI groups: normal weight, overweight and obese. Function 1 discriminate well normal weight group from overweight and obese group. Overweight and obese groups is described with lower number of children in the family and lower order of birth, higher education of parents, they eat less vegetables and fruits, spend more time playing computer games, have less physical activity, drink more alcohol with their meals, exactly opposite to normal weight group.

[Visceral obesity]. / Visceralna debljina.

Some studies indicate that visceral obesity may be a better predictor of morbidity and mortality related to cardiovascular diseases and type 2 diabetes than general obesity measured by the body mass index. A causal relationship seems to exist between the accumulation of visceral fat and occurence of cardiovascular diseases and type 2 diabetes. Assessment of cardiometabolic risk comprises information on intra-abdominal obesity, as well as traditional risk factors. Visceral fat acts as a large endocrine gland, excreting cytokines and adipokines which leads to insulin resistance and proinflammatory state, whereas subcutaneous fat may act as a protective metabolic sink. Of anthropometric measures, waist circumference seems to best correlate with visceral fat.

Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance.

Notch signaling is implicated in the pathogenesis of multiple myeloma expressing high level of active Notch proteins NOTCH1 and JAGGED1 in tumor plasma cells. We investigated expression of NOTCH1 and JAGGED1 in bone marrow trephine biopsies of 80 newly diagnosed multiple myeloma and 20 monoclonal gammopathy of undetermined significance patients using immunohistochemical methods. The number of positive tumor cells was counted per 1000 tumor cells and the intensity of staining was assessed semi quantitatively. Multiple myelomas expressed NOTCH1 in 92.31% (72/78) and JAGGED1 in 92.21% (71/77) cases. NOTCH1 staining was strong in the majority of cases (59.7%), whereas JAGGED1 was predominately weak (67.6% of cases). In contrast, both markers were negative in all monoclonal gammopathy of undetermined significance cases. However, upon progression of disease from monoclonal gammopathy of undetermined significance to multiple myeloma (seen in 4 patients), analysis of the subsequent bone marrow biopsy showed weak expression of both markers in tumorous plasma cells. Immunohistochemistry results were compared with the pattern of bone marrow infiltration, plasma cell differentiation, and the presence of t(11;14)(q13,q32), t(14;16)(q32;q23),and t(4;14)(p16.3;q23) and overall survival in multiple myeloma patients. A significant correlation was found between strong NOTCH1 staining in multiple myeloma plasma cells and the diffuse type of bone marrow infiltration (P = .002) and an immature morphologic type of plasma cells (P = .043). After a median follow-up of 20.3 months, in multiple myeloma patients no difference in overall survival between NOTCH1 (P = .484) and JAGGED1 (P = .822) positive and negative cases were found. In conclusion, our results indicate importance of NOTCH1 and JAGGED1 expression in plasma cell neoplasia and a possible diagnostic value of their immunohistochemical evaluation of bone marrow infiltrates for multiple myeloma.

The comparison of fetal behavior in high risk and normal pregnancies assessed by four dimensional ultrasound.

OBJECTIVE: We compared fetal behavior (FB) in high risk and normal pregnancies using four dimensional ultrasound (4DUS). METHODS: For assessment of FB in high risk and normal pregnancies, we used a scoring system of Kurjak's antenatal neurological test (KANET). The newborns were assessed by a postnatal neurological test, Amiel-Tison neurological assessment at term (ATNAT). The scores of KANET in high risk (N=116) and in normal pregnancies (N=110) were compared. After delivery, the results of KANET from both groups were compared with ATNAT test. RESULTS: There was a statistically significant difference between group of high risk and normal pregnancies, for 8 out of 10 parameters in KANET: isolated anteflection of the head, eye blinking, facial expressions, mouth movements, isolated hand movement, hand to face movement, fist and finger movements, general movements. There was no difference for cranial sutures and isolated leg movements. Comparison of KANET and ATNAT showed statistically significant, moderate correlation between the two tests, which means that the neuropediatric exam (ATNAT) confirmed the prenatal 4DUS finding (KANET). CONCLUSION: The difference of FB between the high risk and normal pregnancies was evident. These preliminary results are promising but further studies have to be done before the test could be recommended for wider clinical practice.

Prognostic value of computed tomography morphologic characteristics in stage I non-small-cell lung cancer.

BACKGROUND: In this study, we describe the prognostic value of NSCLC morphologic characteristics obtainable by computed tomography (CT) in the preoperative staging. Starting with the initial hypothesis that CT morphologic characteristics of NSCLC have a prognostic value, we conducted a retrospective study that included 194 patients. PATIENTS AND METHODS: All patients underwent surgery because of stage IA or IB non-small-cell lung carcinoma (NSCLC). Surgical procedures were performed in our clinic over the period of 9 years and 8 months starting in June 1996 and ending in February 2006. Preoperative CT scans and clinical data available for each patient were analyzed retrospectively. RESULTS: Over the study period, 93 patients died. The mean survival time was 78.6 months (95% confidence interval was 72.63-84.57 months). After a 2-year follow-up, 85.57% of patients were alive, but this decreased to 63.9% living patients after 5 years. Morphologic tumor characteristics were obtained by analyzing CT images available for each patient. These CT morphologic characteristics were divided into 5 categories: size, tumor edges, structure, and periphery of the tumor, as well as its relation to visceral pleura. We correlated each of these characteristics to the survival of patients. CONCLUSION: We conclude that, within stage I NSCLC, patient survival and disease prognosis vary significantly depending on such morphologic characteristics. This fact is one of the weakest points of the current tumor-node-metastasis (TNM) classification. Along with already-established tumor prognostic attributes such as size and TNM grade, we identified CT morphologic characteristics as powerful additional prognostic factors for NSCLC.

Regional pattern of cardiovascular risk burden in Croatia.

The objective of this study was to investigate regional gradient of a synthetic cardiovascular burden (CVRB) in Croatia. Analysis was based on a multistage stratified sample representative of general adult population in six regions of Croatia (Croatian Adult Health Survey). Synthetic CVRB was defined by incidents (heart attack, stroke), blood pressure, overweight/obesity (BMI, waist circumference), and risky behaviours (smoking, physical inactivity, high alcohol consumption, inadequate nutrition). Total CVRB in Croatia was 44.7% for men and 50.3% for women. Combining both high and moderate CVRB, men were found to be under more risk than women (72.8% vs. 61.7%, respectively). The result showed an east-north-west gradient in continental Croatia, with high CVRB in Eastern (40.2%) and Central region (44.3%), City of Zagreb (45.7%) and Northern region (53.1%). Mountainous region had the lowest prevalence of respondents with high CVRB (39.2%). Coastal region with the prevalence of 46.3% of high CVRB was nearly the same as the City of Zagreb. The results suggest the presence of substantial regional differences in the cardiovascular risk burden.