The Impact of Phenotype of Inflammatory Bowel Diseases, Inflammation Activity and Therapy on Mucosal Mature Cd83+ Dendritic Cell.

Background: Crohn's disease (CD) and ulcerative colitis (UC) are well-defined phenotypes of chronic inflammatory bowel diseases (IBDs). A mechanism of inflammation in these diseases is partially controlled by the intestinal dendritic cell (DC). In this study, we observed a mature CD83+ DC in colonic bioptic samples, and its correlation with disease phenotype and activity. Methods: The study included 219 subjects: 100 with UC, 44 with CD and 75 healthy subjects. Colonic biopsy specimens were incubated with the primary antibody Anti-CD83. Intraepithelial CD83+ DCs were counted per 100 enterocytes. The presence of CD83+ DC was analysed according to the type of IBD, histopathologic inflammation activity and treatment outcome. Results: The presence of mature CD83+ DCs (0, ≥1) differed according to disease types of IBD (p = 0.001), histologic inflammation activity (p = 0.049) and applied therapy (p = 0.001). The odds for CD83+ DC presence were 5.2 times higher in the CD group than in the control/UC group. The odds for CD83+ DC presence were 2.6 times higher in subjects without inflammation or chronic inflammation than with acute inflammation. They were also 3.7 times higher in subjects without therapy. The cut-off value 0.5 CD83+ DC (Rock analysis area = 0.699; SE 0.046; p < 0.001; 95% CI: 0.609-0.788) had been assessed as a differentiation marker between UC and CD. Conclusion: Presence of CD83+ DC could be used as a possible parameter in distinction between UC and CD, as well as a predictor of inflammation activity and treatment outcome.

Elevated Tumor Cell-Intrinsic STING Expression in Advanced Laryngeal Cancer.

Laryngeal cancer is the second most common malignancy of the head and neck, worldwide. Immunotherapy targeting checkpoint inhibitors has been approved for the treatment of patients with recurrent or metastatic laryngeal cancer but has a relatively low response rate and outcomes that leave many patients underserved. Targeting the cGAS-STING signaling pathway can potentially improve the activation of immune effector cells, although its role in the development and progression of laryngeal cancer has not yet been investigated in depth. Fifty-nine tumor samples from patients with pathologically confirmed squamous cell carcinoma of the larynx, stage I-IV non-metastatic disease, who were treated at the University Hospital of Split, were immunohistochemically stained for the expression of STING, cGAS, CD8, CD68, and CD163. Elevated tumor cell-intrinsic STING expression was positively associated with stage IV (p = 0.0031), pT3, and pT4 laryngeal cancers (p = 0.0336) as well as with higher histological grades (G2 and G3) (p = 0.0204) and lymph node-positive tumors (p = 0.0371). After adjusting for age, sex, location, and cGAS expression, elevated STING expression was significantly associated with stage IV cancer in a multiple logistic regression model (ß = 1.849, SE = ±0.8643, p = 0.0324). Elevated STING expression represents a potentially favorable predictive biomarker for new therapeutic approaches involving STING agonists combined with immunotherapy and DNA-damaging agents (radiotherapy, cisplatin, and PARP inhibitors) in laryngeal cancer.

Treatment of Inflammatory Dentigerous Cyst Using a Surgical T Drain in a Child.

Dentigerous cysts are rarely reported in young children. They are usually asymptomatic and only identified when becoming significantly large. Treatment by enucleation may damage structures like the inferior alveolar nerve, maxillary sinus, or permanent teeth, thus reducing the child's quality of life. Therefore, conservative surgical treatment such as decompression is indicated. This case report describes the treatment and subsequent complete regression of an inflammatory dentigerous cyst based on the decompression method using a customized surgical tube in a 10-year-old girl. The innervation was preserved, and permanent teeth erupted.

Obstructive Giant Inflammatory Polyposis as a First Manifestation of Crohn's Disease: A Case Report.

Colonic inflammatory polyps (pseudopolyps) are common feature of inflammatory bowel diseases. They usually do not grow excessively, rarely reaching more than 15 mm in size, at which point they are termed giant inflammatory polyps. Clinical presentation of these polyps can vary greatly, ranging from being completely asymptomatic, usually detected incidentally, to abdominal cramps, rectal bleeding or intestinal obstruction. More importantly, giant inflammatory polyps can be easily mistaken for colonic malignancy, although without having malignant potential themselves. These polyps rarely regress with successful medical treatment of inflammatory bowel diseases and often require surgical treatment. We present an unusual case of giant inflammatory polyps which was the first presentation of inflammatory bowel disease. It was initially mistaken for colonic malignancy with intestinal obstruction, which led to surgical treatment.

DNA Methylome Changes of Muscle- and Neuronal-Related Processes Precede Bladder Cancer Invasiveness.

Bladder cancer (BC) is the ninth leading cause of cancer death with one of the highest recurrence rates among all cancers. One of the main risks for BC development is exposure to nitrosamines present in tobacco smoke or in other products. Aberrant epigenetic (DNA methylation) changes accompanied by deregulated gene expression are an important element of cancer pathogenesis. Therefore, we aimed to determine DNA methylation signatures and their impacts on gene expression in mice treated with N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), a carcinogen similar to compounds found in tobacco smoke. Following BBN administration mice developed non-invasive or invasive bladder cancers. Surprisingly, muscle- and neuronal-related pathways emerged as the most affected in those tumors. Hypo- and hypermethylation changes were present within non-invasive BC, across CpGs mapping to the genes involved in muscle- and neuronal-related pathways, however, methylation differences were not sufficient to affect the expression of the majority of associated genes. Conversely, invasive tumors displayed hypermethylation changes that were linked with alterations in gene expression profiles. Together, these findings indicate that bladder cancer progression could be revealed through methylation profiling at the pre-invasive cancer stage that could assist monitoring of cancer patients and guide novel therapeutic approaches.

Activation of cGAS-STING Pathway Is Associated with MSI-H Stage IV Colorectal Cancer.

Colorectal cancer is the second most common cause of cancer-related mortality in adults. Understanding colorectal tumorigenesis at both the cellular and molecular levels is crucial for developing effective treatment options. Forty-one biopsy samples from patients with metastatic CRC (mCRC) were collected at Split University Hospital in Croatia. A total of 41 patients (21 with microsatellite unstable tumours and 20 with microsatellite stable tumours) were randomly included in the study. Immunolabelling of cGAS and STING in metastatic CRC was performed and further complemented by histological classification, tumour grade, and KRAS, NRAS, and BRAF mutational status of mCRC. In bivariate analysis, elevated expression of cGAS and STING was positively associated with MSI-H colon cancer (Fisher's exact test, both p = 0.0203). Combined expression analysis of cGAS and STING showed a significantly higher percentage of patients with mCRC MSI-H with a fully or partially activated cGAS-STING signalling pathway (chi-square test, p = 0.0050). After adjusting for age, sex, and STING expression, increased cGAS expression remained significantly associated with MSI-H colon cancer in a multiple logistic regression model (ß = 1.588, SE = ±0.799, p = 0.047). The cGAS-STING signalling axis represents a compelling new target for optimization of immune checkpoint inhibitor therapeutic approaches in patients with MSI-H stage IV CRC.

BBN-driven urinary bladder cancer mouse model.

Around 3% of new cancer diagnoses and 2% of all cancer deaths every year are caused by urinary bladder cancer (BC). This indicates a great need for intensive studying of BC by using different approaches including indispensable mice models. The most common preclinical mouse model of bladder carcinogenesis relies on the use of a nitrosamine compound, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) which causes high-grade, invasive tumors in the urinary bladder. BBN-induced bladder cancer in mice recapitulates the histology and manifests genetic alterations similar to human muscle-invasive bladder cancer. Here we present a detailed protocol for the induction of BC in mice which is based on the administration of 0.05%-0.1% BBN in drinking water. Six-to-eight-week-old mice are treated orally with BBN for 12weeks and tumors are expected 8weeks after the termination of BBN regimen. Histopathologic examination of the lesions should be routinely assessed after hematoxylin and eosin staining by an experienced pathologist and it can vary from urothelial dysplasia to invasive bladder cancer with glandular and squamous divergent differentiation, the incidence of which might depend on the mouse strain, gender, BBN concentration and the timeline of the protocol. Utilizing half of the urinary bladder tissue for the isolation and analysis of RNA, DNA and proteins provides a comprehensive insight into the biology of BC and reduces the number of mice per study. Finally, the successful use of the BC model can facilitate fundamental biomedical discoveries leading to novel diagnostic and therapeutic approaches with clinical benefits.

Vitamin A Rich Diet Diminishes Early Urothelial Carcinogenesis by Altering Retinoic Acid Signaling.

Urinary bladder cancer is one of the leading malignancies worldwide, with the highest recurrence rates. A diet rich in vitamin A has proven to lower the risk of cancer, yet the molecular mechanisms underlying this effect are unknown. We found that vitamin A decreased urothelial atypia and apoptosis during early bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Vitamin A did not alter urothelial cell desquamation, differentiation, or proliferation rate. Genes like Wnt5a, involved in retinoic acid signaling, and transcription factors Pparg, Ppara, Rxra, and Hoxa5 were downregulated, while Sox9 and Stra6 were upregulated in early urothelial carcinogenesis. When a vitamin A rich diet was provided during BBN treatment, none of these genes was up- or downregulated; only Lrat and Neurod1 were upregulated. The lecithin retinol acyltransferase (LRAT) enzyme that produces all-trans retinyl esters was translocated from the cytoplasm to the nuclei in urothelial cells as a consequence of BBN treatment regardless of vitamin A rich diet. A vitamin A-rich diet altered retinoic acid signaling, decreased atypia and apoptosis of urothelial cells, and consequently diminished early urothelial carcinogenesis.

Targeting Stat3 signaling impairs the progression of bladder cancer in a mouse model.

Bladder cancer is the fourth most commonly diagnosed malignancy in men worldwide and has one of the highest recurrence rates of all cancers. This cancer type is unique because chronic inflammation caused by Schistosoma haematobium can cause bladder cancer, while inflammation induced by Bacillus Calmette Guerin is the therapeutic cornerstone for this cancer type. Activation of proinflammatory IL-6/Stat3 axis promotes the development of different cancers by acting on cancer cells as well as by modulating cancer microenvironment. Using a genetic and pharmacological approach in a mouse model, we demonstrated the importance of IL-6 and Stat3 signaling in bladder cancer. Our findings show that pharmacological inhibition of Stat3 with WP1066 effectively delays progression and invasiveness of bladder cancer in N-butyl-N-(4-hydroxybutyl) nitrosamine-induced mouse model. Moreover, either IL-6 blockade or Stat3 inhibition sensitized bladder cancer to anti-PD-L1 immune therapy. Taken together, our study demonstrates an important role of IL-6/Stat3 signaling in bladder cancer and creates a rationale for testing the therapeutic potential of Stat3 inhibitors in human MIBC both alone or in combination with anti-PD-L1 and anti-IL-6 therapy.

Difference in Presence and Number of CD83+ Dendritic Cells in Patients with Ulcerative Colitis and Crohn's Disease.

Different pathophysiological models provide insight into the important role of CD83+ dendritic cells (DCs) in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). There were 154 subjects included in this study: 60 with UC, 19 with CD and 75 in the control group. Colonic biopsy was performed in all subjects. Specimens were incubated with a primary anti-CD83 antibody. Intraepithelial DCs per 100 enterocytes were counted. The results were analysed according to demographic data, type of IBD and histological inflammation pattern. The odds ratio for CD83+ DCs=0 in the UC group was 3.4 times higher than that in the control group (OR = 3.4; 95% CI: 1.63-7.14; p = 0.001), and the odds ratio for CD83+ DCs ≥1 in the CD group was 5.3 times higher than that in the UC group (OR = 5.3; 95% CI: 1.4-20.2; p = 0.014). The odds ratio for CD83+ DCs=0 in the acute inflammation group was 2.7 times higher than that in the group without inflammation (OR = 2.7; 95% CI: 1.2-5.9; p = 0.011). In the group of patients with CD and acute inflammation (n = 11), there was only one subject without CD83+ DCs (p = 0,024). These results suggest an association of CD83+ DCs with the type of IBD and the histological inflammation pattern.

Microbiota Alters Urinary Bladder Weight and Gene Expression.

We studied the effect of microbiota on the transcriptome and weight of the urinary bladder by comparing germ-free (GF) and specific pathogen-free (SPF) housed mice. In total, 97 genes were differently expressed (fold change > ±2; false discovery rate (FDR) p-value < 0.01) between the groups, including genes regulating circadian rhythm (Per1, Per2 and Per3), extracellular matrix (Spo1, Spon2), and neuromuscular synaptic transmission (Slc18a3, Slc5a7, Chrnb4, Chrna3, Snap25). The highest increase in expression was observed for immunoglobulin genes (Igkv1-122, Igkv4-68) of unknown function, but surprisingly the absence of microbiota did not change the expression of the genes responsible for recognizing microbes and their products. We found that urinary bladder weight was approximately 25% lighter in GF mice (p = 0.09 for males, p = 0.005 for females) and in mice treated with broad spectrum of antibiotics (p = 0.0002). In conclusion, our data indicate that microbiota is an important determinant of urinary bladder physiology controlling its gene expression and size.

The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice.

BACKGROUND: Bladder cancer (BC) is the most common malignant disease of the urinary tract. Recurrent high grade non muscle invasive BC carries a serious risk for progression and subsequent metastases. The most common preclinical mouse model for bladder cancer relies on administration of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to mice. BBN-induced tumors in mice recapitulate the histology of human BC and were characterized with an overexpression of markers typical for basal-like cancer subtype in addition to a high mutational burden with frequent mutations in Trp53, similar to human muscle invasive BC. METHODS: Bladder cancer was induced in C57BL/6J male mice by administering the BBN in the drinking water. A thorough histopathological analysis of bladder specimen during and post BBN treatment was performed at 2, 4, 16, 20 and 25 weeks. RNA sequencing and qPCR was performed to assess the levels of expression of immunologically relevant genes at 2 weeks and 20 weeks during and post BBN treatment. RESULTS: We characterized the dynamics of the inflammatory response in the BBN-induced BC in mice. The treatment with BBN had gradually induced a robust inflammation in the first 2 weeks of administration, however, the inflammatory response was progressively silenced in the following weeks of the treatment, until the progression of the primary carcinoma. Tumors at 20 weeks were characterized with a marked upregulation of IL18 when compared to premalignant inflammatory response at 2 weeks. In accordance with this, we observed an increase in expression of IFNγ-responsive genes coupled to a pronounced lymphocytic infiltrate during the early stages of malignant transformation in bladder. Similar to human basal-like BC, BBN-induced murine tumors displayed an upregulated expression of immunoinhibitory molecules such as CTLA-4, PD-L1, and IDO1 which can lead to cytotoxic resistance and tumor escape. CONCLUSIONS: Despite the recent advances in bladder cancer therapy which include the use of checkpoint inhibitors, the treatment options for patients with locally advanced and metastatic BC remain limited. BBN-induced BC in mice displays an immunological profile which shares similarities with human MIBC thus representing an optimal model for preclinical studies on immunomodulation in management of BC.

Apoptosis as a Prognostic Factor in Colorectal Carcinoma: Comparison of TUNEL Method and Immunohistochemical Expression of Caspase-3.

The development of colorectal cancer is known to be characterized by a sequence of events during which normal colonic epithelium gradually transforms to carcinoma, the adenoma-carcinoma sequence. Apoptosis plays an important role in the development and maintenance of tissue homeostasis. Currently, there is no agreement in the literature about the prognosis of apoptosis in colorectal cancer. The number of studies examining the expression of caspases in colorectal cancer is very limited, and they have not examined any correlation between expression and patient survival. This study included histologic samples from 179 patients diagnosed with colon cancer. We used the TdT-mediated X-dUTP nick end labeling method and caspase-3 labeling to identify the degree of apoptosis. Our results show that lower apoptotic index measured by TdT-mediated X-dUTP nick end labeling method and lower immnuhistochemical expression of caspase-3 is associated with shorter disease-free survival and overall survival. However, only apoptotic index is proven to be an independent survival indicator. The results of our study are consistent with the proposed models of carcinogenesis of colorectal cancer that emphasize resistance to apoptosis as a decisive factor in the progression of the disease and resistance to treatment.

Expression of Mitochondrial Respiratory Chain Complexes in the Vaginal Wall in Postmenopausal Women with Pelvic Organ Prolapse.

BACKGROUND/AIMS: Pelvic organ prolapse (POP) is a common disease affecting adult women. It is a result of the vaginal wall disorder as well as damage of the supportive structures contributing to the integrity of the pelvic floor. Mitochondrial disorders may have an important role in the vaginal wall degeneration leading to POP. The goal of this research is to examine if POP is associated with an altered expression of mitochondrial respiratory chain complexes. METHODS: Samples of vaginal tissue were collected from 16 postmenopausal women: 10 had POP and 6 had other forms of benign gynecological disease. Using western blot, samples were analyzed to assess the expression of mitochondrial proteins including citrate synthase (CS), individual complexes of the mitochondrial respiratory chain and alpha smooth muscle actin (SMA). RESULTS: A significantly reduced expression of SMA and complex II in vaginal tissue of women with POP was found, compared to the control group (p < 0.05), with a tendency for a reduced expression of CS (p = 0.06) and other complexes in the POP group. CONCLUSIONS: Our results indicate that there is a decreased quantity of the smooth muscle and a decreased expression of mitochondrial markers in the vaginal wall of women with prolapse suggesting their possible role in the pathogenesis of POP.

Lateral thermal damage of mesoappendix and appendiceal base during laparoscopic appendectomy in children: comparison of the harmonic scalpel (Ultracision), bipolar coagulation (LigaSure), and thermal fusion technology (MiSeal).

BACKGROUND: The aim of this study was to compare lateral thermal damage of mesoappendix and appendiceal base using three different instruments for sealing and cutting of mesoappendix. MATERIALS AND METHODS: A total number of 99 patients (54 males and 45 females) who underwent laparoscopic appendectomy because of suspected appendicitis between December 2013 and May 2015 were enrolled in the study. The patients were divided in three groups based on instrument used for sealing of mesoappendix: group 1 (Ultracision; n = 36), group 2 (LigaSure; n = 32), and group 3 (MiSeal; n = 31). Lateral thermal damage, intraoperative and postoperative complications, duration of surgery, hospital stay, and economic value were compared within groups. RESULTS: The median age of patients was 14 y (range 3-17). A histopathologic analysis revealed a positive diagnosis of appendicitis in 84 patients (85%). The median lateral thermal damage on appendiceal base using Ultracision, LigaSure, and MiSeal was 0.10 mm, 0.16 mm, and 0.10 mm respectively, and on mesoappendix, 0.08 mm, 0.13 mm, and 0.08 mm, respectively. Significantly higher thermal damage was found on mesoappendix (P = 0.015) and appendiceal base (P = 0.012) in patients treated with LigaSure than in patients from other groups. There were no statistical differences among the groups regarding intraoperative and postoperative complications (P = 0.098). No significant difference in thermal damage between appendicitis and nonappendicitis group was found (P = 0.266). CONCLUSIONS: Using of Ultracision, LigaSure, and MiSeal for sealing of mesoappendix in laparoscopic appendectomy in children is safe and useful. LigaSure produces significantly greater lateral thermal damage compared with other instruments.

Immunohistochemical expression of hypoxia-inducible factor-1α in stromal cells of vaginal tissue in post-menopausal women with pelvic organ prolapse.

Background & objectives: Pelvic organ prolapse (POP) is a common medical condition that affects adult women of different ages. The support of a normal pelvic floor is the result of complex interactions between ligaments, muscles, connective tissue and vaginal walls. Hypoxia and oxidative stress can reduce protein synthesis in the pelvic muscles that may contribute to muscular atrophy. Hypoxia-inducible factor-1α (HIF-1α) is a transcriptional activator which, expressed in response to hypoxia, activates a number of genes involved in cellular response to hypoxia. However, a potential role of hypoxia and oxidative stress in pathogenesis of POP is not known. This study was aimed to compare the level of HIF-1α immunohistochemical expression in the vaginal stromal cells of postmenopausal women with and without POP. Methods: Samples of the vaginal tissue from 120 menopausal women were obtained during surgery, and immunohistochemical expression of HIF-1α was assessed. There were 60 women with POP while 60 women in the control group were without prolapse but with benign gynaecological diseases. Results: In post-menopausal women with prolapse, significant differences were observed in the number of HIF-1α-positive stromal cells in the vaginal tissue compared to the control group. There was a significant increase in the number of HIF-1α in the stromal cells of the vaginal tissue in women with prolapse. Interpretation & conclusions: Difference in expression of HIF-1α in stromal cells of the vaginal tissue in the post-menopausal women with and without POP suggests that prolonged hypoxia probably has an important role in the aetiopathogenesis of POP.

Protective effect of urapidil on testicular torsion-detorsion injury in rats.

PURPOSE: The aim of this study was to investigate the effect of urapidil and low-molecular weight heparin (LMWH) on testicular torsion-detorsion injury in rats. METHODS: Thirty-two male Sprague-Dawley rats were used. In the torsion-detorsion (T/D) group, the left testis was twisted at 720° for 3 h. After 3 h of reperfusion, the testis was removed. Urapidil or LMWH was administered intraperitoneally 30 min before detorsion in the treatment groups. RESULTS: Unilateral testicular torsion-detorsion caused significant increases in the malondialdehyde level and apoptosis and significant decreases in the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in ipsilateral testes (p < 0.001). The rats treated with urapidil had a significant decrease in the malondialdehyde level and apoptosis and significant increases in the SOD and GPx activities in ipsilateral testes compared to the T/D group (p < 0.001). Animals treated with LMWH showed non-significant reductions in malondialdehyde levels and apoptosis compared to the T/D group. In addition, no significant difference in the SOD activities (p = 0.52) between the groups was found. The increase in the GPx activities was significant in the LMWH group compared to the T/D group (p < 0.001). CONCLUSION: The administration of urapidil before detorsion prevents ischemia/reperfusion cellular damage in testicular tissue. LMWH was not found to have a beneficial effect on testicular T/D injury in rats.

Unusual cause of acute abdomen in a child--torsion of greater omentum: report of two cases.

INTRODUCTION: Torsion of the omentum is twisting along its long axis and a rare cause of acute abdomen. Depending on associated conditions, it is classified as primary and secondary. It may mimic different pathologies presenting as acute abdomen, most common of them being acute appendicitis. Current choice for management of omental torsion is laparoscopic surgery. CASE PRESENTATION: We present two cases of omental torsion of two boys who presented with abdominal pain, nausea and vomiting and underwent emergency laparoscopy. CONCLUSION: Omental torsion is very rare, and its diagnosis is usually made only after surgery. At laparoscopy, omental torsion is suspected when the appendix is normal and the symptoms and findings of torsion are present. Laparoscopy is a safe and effective approach for the diagnosis and management of omental torsion, with the advantages of reduced postoperative pain and hospital stay.

Beneficial effect of nifedipine on testicular torsion-detorsion injury in rats.

OBJECTIVE: To investigate the effect of nifedipine on testicular torsion-detorsion injury. MATERIALS AND METHODS: Twenty-four adult male Sprague-Dawley rats were randomly divided into 3 groups, each containing 8 rats. Rats in the control group underwent a sham operation of the left testis. In the torsion-detorsion (T/D) group, the left testis was twisted at 720° for 3 hours. After 3 hours of reperfusion, at the end of the experiment, the testes were removed. Rats in the treatment group received the same surgical procedure as the T/D group, but nifedipine was administered intraperitoneally (100 µg/kg) 30 minutes before the time of detorsion. RESULTS: Unilateral testicular torsion-detorsion caused a significant increase in the malondialdehyde level and apoptosis and caused significant decreases in superoxide dismutase and glutathione peroxidase activities in ipsilateral testes. The rats treated with nifedipine had a significant decrease in malondialdehyde level and apoptosis and had significant increases in superoxide dismutase and glutathione peroxidase activities in ipsilateral testes compared with those of the T/D group. CONCLUSION: These results suggest that biochemical and histological torsion-detorsion injury occurs in the ipsilateral testes after a 3-hour torsion and 3-hour detorsion and that administration of nifedipine before detorsion prevents ischemia/reperfusion cellular damage in the testicular tissue.

Which theory for the origin of syphilis is true?

INTRODUCTION: There are four theories about the origin of syphilis, of which the mostly represented one is the Columbian theory. This theory suggests that syphilis was brought into Europe in 1493 ad by the ship from Caribbean islands. AIM: The aim of this study is to test all theories on a sample of 403 skeletons: 135 from prehistory, 134 from antique, and 134 from medieval period and new age from the Dalmatia (Croatia). METHODS: All skeletons were examined using standard anthropological methods. Paleopathological analysis was performed on each skeleton as well as additional radiographic method on one isolated skeleton. MAIN OUTCOME MEASURES: Paleopathological changes on skeletal remains connected with treponematosis. RESULTS: Paleopathological analysis revealed one skeleton from the antique period (second to 6th century A.D.) that exhibited skeletal markers similar to those described in one clinical case in which congenital syphilis was confirmed by a Wasserman reaction. Skeletal remains of this person were examined macroscopically and radiographically, and the differential diagnostics eliminated other considered pathologies as well as trauma. CONCLUSIONS: The finding of skeletal markers of syphilis on a skeleton from the antique supports the theory of pre-Columbian syphilis origin.