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A significant proportion of basic proteomic research is directed towards the clinic, largely aimed at the identification of proteins as potential biomarkers of pathological conditions. Reliable protein profiling is of particular importance in the field of plasma biomarker research where selected proteins must be consistently identified and quantified in large patient cohorts. As a first step, databases of existing plasma proteomes can serve as a valuable basis for the characterization of previously identified plasma biomarker candidates. As they are a non-invasive biological samples, blood and urine are commonly used for analysis. However, the research of human plasma/serum is challenging because a large number of parameters must be satisfied in order to validate a certain molecule as a biomarker. Other samples used in clinical studies include solid tissues, a range of other body fluids and samples from genetic animals models and cell lines. A common example is the use of mass spectrometry-based proteomics as a tool to study the biological changes occurring in cancer/metastasis. Such basic scientific research aimed to discover potential biomarker candidates, is often collaborative in nature, since clinicians collaborate with the academia. Biopsies from sites affected by primary disease such as tumours, cysts or transformed organs can be obtained directly from patients. Standardized protocols and working algorithms defining sample collection, processing and storage are essential for obtaining reliable and reproducible results. They are further processed to obtain the first round of candidate molecules, specific for a pathological condition. It is of the utmost importance that the study leader facilitates mutual communication and understanding between different disciplines and provides regular feedback on study progress. The use of high throughput protein assays in the clinical setting and the advancement of proteomics-based technologies have raised expectations in the search for new protein biomarkers. However, to date, progress has been limited due to lack of an effective technological platform, poorly defined guidelines for determining groups of clinical samples, no standardized procedures for biomarker development, and quality assessment of performed studies. Successful production of diagnostic tests should be based on a clear technical and conceptual plan. The goal of the study should be to solve a clearly defined clinical question with an appropriate study design, which is a prerequisite for biomarker discovery that connects the joint work of clinical and basic research.

Presenting the work of the Department of Proteomics of the Centre for Translational and Clinical Research of the School of Medicine, University of Zagreb.

Vratobolja je jedna od najčešćih mišićnokoštanih bolesti koja rezultira značajnom boli i nesposobnosti te ima velik utjecaj na individualnoj razini, kao i na zdravstveni sustav i društvo u cjelini. Uzroci vratobolje su različiti, a etiološki prevladavaju oni mehanički povezani s degenerativnim promjenama vratne kralježnice. Svjedočimo raznim dijagnostičkim i terapijskim pristupima za ove bolesnike. Hrvatsko vertebrološko društvo Hrvatskoga liječničkog zbora predstavlja sveobuhvatni narativni pregled i smjernice za dijagnozu i liječenje bolesnika s vratoboljom, s naglaskom na najčešće uzroke. Smjernice su rezultat konsenzusa stručnjaka različitih specijalnosti, a temelje se na najboljim dokazima. Prvi dio se odnosi na dijagnostiku, a drugi, njemu komplementarni dio odnosi se na terapiju. Dijagnostički dio smjernica (1. dio) obuhvaća: klinička obilježja i evaluaciju (uključivo strukturirane upitnike), laboratorijsku dijagnostiku, slikovne metode, neurofiziološko testiranje i minimalno invazivne dijagnostičke procedure. Dio smjernica o liječenju (2. dio) uključuje: farmakološko liječenje, tjelesne medicinske vježbe, trakciju, manualnu terapiju, metode fizikalne terapije, primjenu ortoza, minimalno invazivne terapijske intervencije, kirurško liječenje, rehabilitaciju nakon kirurških zahvata i psihijatrijski pristup. Ovo su prve hrvatske smjernice za vratobolju primarno namijenjene liječničkoj profesionalnoj zajednici., Neck pain is one of the most prevalent musculoskeletal diseases which results in considerable pain and disability, and has a great impact on individual level, as well as on health-care system, and overall society. Causes of neck pain are different, and prevailing aetiology are mechanical reasons associated with degenerative changes of cervical spine. We are witnessing various diagnostic and therapeutic approaches for these patients. The Croatian Society for Vertebrology of the Croatian Medical Association is presenting a comprehensive narrative review and guidelines for the diagnosis and treatment of neck pain, focusing on the most prevalent causes. The guidelines are the result of consensus of experts of different background, based on the best available evidence. Part 1 relates to diagnosis, while the complementary Part 2 relates to treatment. For the diagnostic part (Part 1) the guidelines encompass: clinical features and evaluation (including questionnaires), laboratory tests, imaging, neurophysiology tests, and minimally invasive diagnostic procedures. The management part (Part 2) includes: pharmacology treatment, physical exercise, traction, manual therapies, physical therapy modalities, orthotics, minimally invasive therapeutic interventions, surgical treatment, rehabilitation after surgical procedures, and psychiatric approach. These are the first Croatian guidelines for neck pain intended in the first place for the physicians’ professional community.

Neck pain is one of the most prevalent musculoskeletal diseases which results in considerable pain and disability, and has a great impact on individual level, as well as on health-care system, and overall society. Causes of neck pain are different, and prevailing aetiology are mechanical reasons associated with degenerative changes of cervical spine. We are witnessing various diagnostic and therapeutic approaches for these patients. The Croatian Society for Vertebrology of the Croatian Medical Association is presenting a comprehensive narrative review and guidelines for the diagnosis and treatment of neck pain, focusing on the most prevalent causes. The guidelines are the result of consensus of experts of different background, based on the best available evidence. This part (Part 1) relates to diagnosis, while the complementary part (Part 2) relates to treatment. For the diagnostic part (Part 1) the guidelines encompass: clinical features and evaluation (including questionnaires), laboratory tests, imaging, neurophysiology tests, and minimally invasive diagnostic procedures. The management part (Part 2) includes: pharmacology treatment, physical exercise, traction, manual therapies, physical therapy modalities, orthotics, minimally invasive therapeutic interventions, surgical treatment, rehabilitation after surgical procedures, and psychiatric approach. These are the first Croatian guidelines for neck pain intended in the first place for the physicians’ professional community., Vratobolja je jedna od najčešćih mišićnokoštanih bolesti koja rezultira značajnom boli i nesposobnosti te ima velik utjecaj na individualnoj razini, kao i na zdravstveni sustav i društvo u cjelini. Uzroci vratobolje su različiti, a etiološki prevladavaju oni mehanički povezani s degenerativnim promjenama vratne kralješnice. Svjedočimo raznim dijagnostičkim i terapijskim pristupima za ove bolesnike. Hrvatsko vertebrološko društvo Hrvatskoga liječničkog zbora predstavlja sveobuhvatni narativni pregled i smjernice za dijagnozu i liječenje bolesnika s vratoboljom, s naglaskom na najčešće uzroke. Smjernice su rezultat konsenzusa stručnjaka različitih specijalnosti, a temelje se na najboljim dokazima. Ovaj prvi dio odnosi se na dijagnostiku, a drugi njemu komplementarni dio odnosi se na terapiju. Dijagnostički dio smjernica (1. dio) obuhvaća: klinička obilježja i evaluaciju (uključivo strukturirane upitnike), laboratorijsku dijagnostiku, slikovne metode, neurofiziološko testiranje i minimalno invazivne dijagnostičke postupke. Dio smjernica o liječenju (2. dio) uključuje: farmakološko liječenje, tjelesne medicinske vježbe, trakciju, manualnu terapiju, metode fizikalne terapije, primjenu ortoza, minimalno invazivne terapijske intervencije, kirurško liječenje, rehabilitaciju nakon kirurških zahvata i psihijatrijski pristup. Ovo su prve hrvatske smjernice za vratobolju primarno namijenjene liječničkoj profesionalnoj zajednici.

Aim To assess the potential of the soluble transforming growth factor β receptor type III (sTGFβrIII), a key regulator in TGFβ signaling, as a biomarker for diagnosis and stratification of patients with acute pancreatitis (AP). Methods In this small prospective pilot study, patients’ (N=22) plasma samples were obtained at three time points: the first and fourth day of hospitalization and the day of hospital discharge. Healthy controls’ plasma (N=25) was obtained at a single time point. Concentration of sTGFβrIII in plasma was determined by ELISA. Data were analyzed by fitting linear or linear mixed models. Results Plasma sTGFβrIII levels at presentation (day 1) were similar in AP patients and healthy participants, irrespectively of the disease severity. sTGFβrIII levels in patients were constant during hospital stay. Conclusion These observations do not support further evaluation of plasma sTGFβrIII levels in this setting, but do not exclude a potential biological role of TGFβ and membrane-bound TGFβrIII in AP pathophysiology

Introduction and objective. Complications of portal hypertension begin to develop at hepatic vein pressure gradient (HVPG) ≥10 mm Hg (considered as clinically significant portal hypertension, CSPH), hence early identification of patients with CSPH is of high importance. HVPG is an invasive procedure, with limited availability, thus noninvasive tests represent an attractive diagnostic alternative. In this study, we aimed to identify the potential new serum biomarkers for CSPH in patients with compensated advanced chronic liver disease (cACLD) by serum proteomic profiling. Methods. The presence of CSPH in patients with cACLD and no history of liver decompensation was assessed by HVPG measurement. Serum samples were pooled based on HVPG result into groups without (HVPG 2x higher concentrations in the CSPH group were fibulin-1, mannose-binding protein C, macrophage colony-stimulating factor 1 receptor, plexin domain-containing protein 2, and phosphatidylcholine-sterol acyltransferase. Conclusion. We identified candidate serum biomarkers for early recognition of CSPH in patients with cACLD. These proteins are likely involved in the pathophysiology of portal hypertension development and might represent potential therapeutic targets, which warrants further investigation.

Skolioza predstavlja učestalu deformaciju kralješnice koju karakterizira patološka lateralna zakrivljenost kralješnice povezana s različitim stupnjem hiperlordoze i poremećajem rotacije s Cobb-ovim kutom zakrivljenosti većim od 10 stupnjeva. Patogeneza i etiologija skolioze je multifaktorijalna te uključuje brojne dokazane okolišne (konzumiranje alkohola, nedostatak vitamina kod KS) i genetske (jednonukleotidni polimorfizam) faktore, no unatoč tome točni molekularni i stanični mehanizmi razvoja bolesti i dalje su nepoznati.

Bone Morphogenetic Proteins (BMPs) are growth and differentiation factors within the TGFβ superfam- ily of proteins. They induce ectopic and orthotopic endochondral bone formation and are involved in the regulation of cell proliferation, differentiation, apoptosis and mesenchymal-epithelial interactions in critical morphogenetic processes of tissues beyond bone. BMP2 and BMP7 osteogenic devices have been approved for enhancing healing in patients with long bone defects and anterior spinal fusion proce- dures. However, due to a high price and various serious adverse events including heterotopic ossifica- tion, retrograde ejaculation and pain their clinical use have been limited. In this review we discuss the BMP discovery, biology and their use in clinical studies with particular reference to the newly developed BMP6 based autologous bone graft substitute (ABGS). A novel ABGS consisting of an autologous bone coagulum (ABC) carrier with dispersed BMP6 to initiate the differentiation of mesenchymal cells into endochondral bone. The ABC met the conditions for an optimal delivery system for BMP6 due to han- dling simplicity, without an immunogenic and inflammatory response at the implantation site. Addition of allograft or synthetic ceramics to ABGS demonstrated in animal models significantly increased volume and better microarchitecture of the newly formed bone. The first clinical study was conducted in patients with distal radial fractures (Phase I study) and the second in patients undergoing high tibial osteotomy (Phase I/II study) and no serious adverse events have been observed. Finally, in the ongoing OSTEO- proSPINE study ABGS enforced with allograft bone is evaluated in patients with chronic back pain due to degenerative disc diseases. The novel ABGS bone mimetic is a major breakthrough and contribution to bone biology and regenerative medicine of skeletal repair., Koštani morfogenetski proteini (BMP) čine grupu čimbenika rasta i diferencijacije unutar TGFβ nado- bitelji. Oni induciraju stvaranje ektopične i ortotopične endohondralne kosti te su uključeni u regulaciju stanične proliferacije, diferencijacije, apoptoze i mezenhimalno-epitelne interakcije u važnim tkivnim morfogenetskim procesima izvan koštanog sustava. Koštane naprave koje sadrže BMP2 i BMP7 pro- tein odobrene su za poboljšanje koštanog cijeljenja kod pacijenata s defektima dugih cjevastih kostiju i kod prednje spinalne fuzije kralježnice. Međutim, zbog visoke cijene i mnogobrojnih nuspojava koje su uključivale pojavu heterotopičnih osifikacija, retrogradnu ejakulaciju i bol, njihova je klinička prim- jena ograničena. U ovom smo preglednom radu raspravili otkriće BMP molekula, njihovu biologiju i primjenu u kliničkim studijama s posebnim osvrtom na nedavno otkrivenu novu autolognu koštanu napravu (ABGS) koja sadrži BMP6. Novi ABGS sastoji se od nosača autolognog koaguluma (ABC) s otopljenim BMP6 koji je ključan za pokretanje diferencijacije mezenhimalnih stanica u smjeru stvaranja endohondralne kosti. ABC je ispunio sve potrebne uvjete za formulaciju optimalnog nosača za BMP6 isključivo zbog jednostavnosti priprave i primjene te odsustva imunogenog i upalnog odgovora na mjestu implantacije. Uz dodatak alografta ili sintetičke keramike što je potvrđeno na životinjskim modelima došlo je do značajnog povećanja volumena te poboljšanja mikroarhitekture novonastale kosti. Prvo kliničko ispitivanje provedeno je na pacijentima s distalnim prijelomima radijusa (faza I studije), a drugo na pacijentima koji su podvrgnuti visokoj osteotomiji tibije (faza I/II studije) bez uočenih ozbiljnih nuspojava. Trenutno je u tijeku studija OSTEOproSPINE u kojoj se testira učinkovitost ABGS u kom- binaciji s koštanim alograftom u bolesnika s kroničnim bolovima u leđima uzrokovanim degenerativnim promjenama intervertebralnog diska. Nova ABGS koštana naprava značajna je prekretnica i napredak u području koštane biologije te regenerativne medicine koštanog sustava.

The anatomy of the frontal sinus is highly variable and its variations affect the occurrence/course of pathological processes. We investigated its size and relationship to the orbit, searching for patterns that would allow it to be classified anatomically. Cone beam computed tomography was applied to 91 skulls (age range 21- 86 years) to determine sinus height, width, length, and length of contact with the orbit in the coronal and sagittal planes. In addition, orbital roof pneumatization in the coronal plane was categorized as: none ; only medial part pneumatized ; the medial and a portion of the central part pneumatized ; roof predominantly pneumatized. Sinus dimensions varied widely (mm): height 6.2-50.0 ; width 3.7-54.0 ; length 2.4-45.0 ; frontal orbital contact 4.0-41.6 ; sagittal orbital contact 0.0-41.2. Pneumatization of the orbital roof (coronal plane) mostly affected the medial and a portion of the central part (50%), or the roof was predominantly pneumatized (32%). Three "types" of sinus (cluster analysis) were distinguished by the extent of pneumatization of the orbital roof in the coronal plane: "small", pneumatization absent or only of the medial part ; "medium-sized", pneumatization of the medial and a portion of the central part ; "large", roof predominantly pneumatized. All dimensions were significantly different among the types (P < 0.001). Sinus type was fairly predictive of the extent of contact with the orbit in the sagittal plane (not routinely assessed clinically). The data confirm the variability of frontal sinus anatomy and suggest a simple and straightforward classification with potential clinical relevance. Clin. Anat. 31:576-582, 2018

Sažetak. Prevalencija stenoze spinalnog kanala slabinske regije u stalnom je porastu zbog starenja pučanstva. Naime, unatoč etiološkoj raznovrsnosti, ona najčešće nastaje kao posljedica degenerativnih promjena na kralježnici. Nema općeprihvaćene klasifikacije stenoze spinalnog kanala slabinske regije. Za postavljanje dijagnoze potrebno je povezati nalaze iz anamneze, kliničkog statusa i slikovnih metoda zajedno s elektrofiziološkim nalazima. Liječenje bolesnika sa stenozom spinalnog kanala slabinske regije može biti konzervativno (farmakološko i nefarmakološko) i kirurško, s tim da se u potonjem u posljednje vrijeme preferiraju minimalno invazivne tehnike. U ovom radu dajemo sveobuhvatni suvremeni pogled na stenozu spinalnog kanala slabinske regije., Summary. Lumbar spinal stenosis (LSS) is becoming an increasingly prevalent condition due to trends of aging population. That is because, although etiologically heterogenous, it is most often the consequence of degenerative changes of the spine. There is no generally accepted classification of LSS. To make the diagnosis of LSS it is crucial to interrelate history, clinical examination and imaging alongside with neurophysiological findings. The treatment of patients with LSS may be conservative (pharmacological and non-pharmacological) and surgical, and in this respect in the latter minimally invasive techniques are preferred lately. In this paper we comprehensively present a state-of-the-art view on LSS.

Lumbar spinal stenosis (LSS) is becoming an increasingly prevalent condition due to trends of aging population. That is because, although etiologically heterogenous, it is most often the consequence of degenerative changes of the spine. There is no generally accepted classification of LSS. To make the diagnosis of LSS it is crucial to interrelate history, clinical examination and imaging alongside with neurophysiological findings. The treatment of patients with LSS may be conservative (pharmacological and non-pharmacological) and surgical, and in this respect in the latter minimally invasive techniques are preferred lately. In this paper we comprehensively present a state-of-the-art view on LSS.

Background. Dimensions and shape of maxilla and mandible are highly influenced by the presence of teeth and force produced by masticatory muscles. As a consequence both dimensions and shape might change with aging. Aim. Our goal was to compare the extent of these changes between maxilla and mandible. Material and Methods. We examined 169 maxillae and 42 mandibles (age range 20–80 years) using digital caliper. There were 14 measures on maxilla and 11 measures on mandible. Measures were labeled as vertical, horizontal or sagittal in order to study growth in three dimensions. Bones were divided into three groups based on presence of teeth and alveolar process: group 1 — completely preserved teeth and alveolar process ; group 2 — partialy preserved teeth or alveolar process ; group 3 — all teeth lost and alveolar process completely resorbed. Results and Discussion. In both maxilla and mandible only vertical measures showed significant change with aging. On the maxilla all vertical measures in group 3 decreased when compared to group 1. Decrease ranged from 8% to 17%. Group 2 didn’t show significant changes when compared to group 1. On the other hand on mandible only those vertical measures containg alveolar process component decreased. Decrease was significant in both group 2 (ranging from 4.5 and 20%) and group 3 (ranging from 22.5 and 59%). Conclusions. Teeth loss causes vertical dimensions regression on both maxilla and mandible, whereas change of masticatory muscles function with aging plays minor role. The impact of teeth loss is more profound on mandible than on maxilla.

Background. Postnatal development of upper jaw is complicated process highly influenced by teeth eruption and sinus development. Aim. The aim of our study was to elucidate dynamics of this process and investigatechanges in dimensions of different parts of upper jaw. Material and Methods. In our study we used 255 maxillae (age range: birth-30y) from skull collection of Institute of Anatomy. We measured longitudinal (A1=maximal bone length ; A2=orbital surface length ; A3=palatine process length), transversal (B1=maximal bone width ; B2=palatine process width) and vertical (C1=maximal bone height ; C2=orbital margin-alveolar edge ; C3=infraorbital foramen-alveolar edge ; C4=anterior nasal spine- alveolar edge) dimensions using caliper. For each dimension growth index (adult dimension/dimension at birth) was calculated. 102 THE 10th INTERNATIONAL SYMPOSIUM ON CLINICAL AND APPLIED ANATOMY Morphology. 2018 Results and Discussion. All measured dimensions increased linearly till the end of puberty but they didn’t increase at the same rate. Growth rates for all dimensions were similar in the first year of life but after that period growth rates of vertical dimensions became much higher compared to those of longitudinal and transversal dimensions. The highest growth index was observed for vertical dimensions (C3=3.37 ; C2=3.19 ; C4=2.6 ; C1=2.57)while for the other dimensions growth index was moderate (between 1.79 and 1.97). Conclusions. During postnatal development of upper jaw there is biggest increase in vertical dimensions while longitudinal and transversal dimensions increase at almost the same rate. The increase in vertical dimensions growth rate after the first year of life correlates with the teeth eruption and maxillary sinus pneumatization. Understandingnormal development of maxilla is important in maxillofacial surgery and diagnosis of upper jaw malformations.

Type III transforming growth factor beta receptor (TGFbrIII) modulates TGFbeta superfamily signaling. Its tutor tissue expression is downregulated in human breast cancer. We assumed that its soluble form (sTGFbrIII) could be detectable in plasma with potential use in diagnostics/follow-up of breast cancer patients. For this purpose, we aimed to develop an indirect ELISA for its quantification and test its utility in a cohort of women with breast cancer. Our data suggest a high potential of plasma sTGFbrIII as a vowel diagnostic and prognostic biomarker in breast cancer.