Trend of suicide by self-immolation in a 13-year timeline: was the COVID-19 pandemic a potentially important stressor?

Introduction: Self-immolation is an uncommon way of attempting and committing a suicide, with a fatality rate of 80%. The risk factors in self-immolation victims vary depending on demographic characteristics, socio-economic and cultural factors as well as religious beliefs. Whether the COVID-19 pandemic was a potentially important stressor for self-immolation is still unknown, with insufficient studies examining this issue. Therefore, in this study, we aimed to examine the trend of self-immolation in a 13-year timeline, and the potential association of COVID-19 pandemic with the increase in the incidence and severity of self-immolation injuries in Serbia in 2021. Materials and methods: The study included hospitalized patients due to intentional burns caused by self-immolation in the period from January 1, 2008 to December 31, 2021. Joinpoint regression analysis was used for the analysis of continuous linear trends of self-immolation cases with change points. Results: While a rising trend was observed in the 2008-2013 time segment, followed by a decline in the upcoming 2013-2016 time segment, a significant increase reached its maximum during COVID-19 pandemic (2021), with annual percent change of 37.1% (p = 0.001). A significant increase in the median number of cases per year was observed during 2021 compared to the previous periods (7.5 vs. 2). Frequency of patients with a psychiatric diagnosis vs. those without a psychiatric diagnosis was significantly higher during than before the COVID-19 period (66.7 vs. 36.1%, p = 0.046). Conclusion: In our study, a significant increase in the frequency of suicide attempts by self-immolation during COVID-19 pandemic was noticed. There was also an increased frequency of pre-existing psychiatric illness among patients during the pandemic period. With limited high-quality data available, the study adds to a rising body of evidence for assessment of outcomes of the pandemic on mental health and recognition of stressors for self-immolation.

The Role of Ketamine as a Component of Multimodal Analgesia in Burns: A Retrospective Observational Study.

Background: Burn wound dressing and debridement are excruciatingly painful procedures that call for appropriate analgesia-typically multimodal. Better post-procedural pain management, less opioid use, and consequently fewer side effects, which could prolong recovery and increase morbidity, are all benefits of this type of analgesia. Intravenously administered ketamine can be effective as monotherapy or in combination with opioids, especially with procedural sedation such as in burn wound dressing. Methods: This observational study investigated the effect of ketamine administered in subanesthetic doses combined with opioids during burn wound dressing. The study was conducted from October 2018 to October 2021. A total of 165 patients met the inclusion criteria. A total of 82 patients were in the ketamine group, while 83 patients were dressed without ketamine. The main outcome was the effect of ketamine on intraprocedural opioid consumption. The secondary outcome included the effect of ketamine on postprocedural pain control. Results: Patients dressed with ketamine were significantly older (p = 0.001), while the mean doses of intraoperatively administered propofol and fentanyl were significantly lower than in patients dressed without ketamine (150 vs. 220 mg, p < 0.001; and 0.075 vs. 0.150 mg, p < 0.001; respectively). Conclusions: Ketamine was an independent predictor of lower intraoperative fentanyl consumption, according to the multivariate regression analysis (p = 0.015). Contrarily, both groups of patients required postoperative tramadol treatment, while intraoperative ketamine administration had no beneficial effects on postoperative pain management.

Primary Melanoma Histopathologic Predictors of Sentinel Lymph Node Positivity: A Proposed Scoring System for Risk Assessment and Patient Selection in a Clinical Setting.

Background and Objectives: The careful selection of adequate SLNB candidates not only aims at reducing the surgical risk while identifying SLN metastasis, but also plays a crucial role in identifying the patients eligible for adjuvant therapy. Objectives: The purpose of our study was to investigate the clinical and histologic aspects of primary melanomas that correlate with the likelihood of a positive SLNB result. Materials and Methods: A total of 101 primary melanoma patients who underwent sentinel lymph node biopsies were included in the study. General patient demographics were obtained as well as localization and melanoma-specific characteristics of primary melanoma from histologic reports in addition to data derived from SLNB melanoma histopathology reports. Results: The patients with positive SLN results had a statistically significant increased Breslow thickness (3.8 mm vs. 1.97 mm, p = 0.002), higher mitotic index rate (5/mm2 vs. 2/mm2, p = 0.009), as well as the presence of ulceration (68.4% vs. 31.6%, p = 0.007). Univariate regression analysis showed the Breslow thickness (p = 0.008), the mitotic index rate (p = 0.054), the presence of ulceration (p = 0.009), as well as the pT3-4 stage (p = 0.009) to be significant predictors of SLN positivity. The optimal cut-off values for Breslow thickness and the number of mitoses scores were determined based on ROC curve analysis. Using the Breslow thickness, mitotic index rate, presence of ulceration, and pT3-4 stage significant coefficients from the univariate regression model, a chance prediction score was developed. Conclusions: The newly developed and proposed scoring system can aid in patient selection for SLN biopsy by facilitating a more efficient risk assessment in the detection of lymph node metastases in melanoma patients.

Reconstruction of Moderately and Severely Atrophic Scalp-A Multicentric Experience in Surgical Treatment of Patients Irradiated for Tinea Capitis in Childhood and Surgical Algorithm.

Background and Objectives: Before the introduction of griseofluvin, the use of X-ray radiation was the treatment of choice for tinea capitis. More than half a century later various types of tumors have been found to be associated with childhood irradiation due to tinea capitis, most commonly cancers of the head and neck, as well as brain tumors. The often unusually aggressive and recurrent nature of these tumors necessitates the need for repeated surgeries, while the atrophic skin with an impaired vascular supply due to radiation often poses an additional challenge for defect reconstruction. We present our experience in the surgical treatment of such patients. Materials and Methods: This is a retrospective cohort study. In this study, 37 patients treated for acquired defects of the scalp with a history of irradiation therapy due to tinea capitis in childhood were included in this study, 24 male and 13 female patients. The mean age at the first appointment was 60.6 ± 7.8, with the youngest included patient being 46 and the oldest being 75 years old. Patients' characteristics, surgical treatment, and complications were analyzed and a reconstructive algorithm was developed. Results: Local flaps were used for reconstruction in 34 patients, direct sutures were used in 10 patients and 20 patients received split-thickness skin grafts for coverage of both primary and secondary defects for reconstruction of flap donor sites. One regional flap and one dermal substitute covered by an autologous skin graft were also used for reconstruction. Complications occurred in 43.2% of patients and were significantly associated with the presence of comorbidities (p = 0.001), aseptic bone necrosis (p = 0.001), as well as skin atrophy in frontal, occipital, and parietal region (p = 0.001, p = 0.042 and p = 0.001, respectively). A significant correlation between major complications and moderate skin atrophy was found only in the parietal region (p = 0.026). Conclusions: Unfortunately, many protocols developed for scalp reconstruction are not applicable in the setting of severe or diffuse scalp skin atrophy associated with high tumor recurrence rate and radiation-induced vascular impairment, such as in tinea capitis patients in Serbia. An algorithm has been developed based on the authors' experience in managing these patients.

COVID-19 and Cutaneous Squamous Cell Carcinoma-Impact of the Pandemic on Unequal Access to Healthcare.

Most skin tumors are not fatal, but if not treated in a timely manner, they can lead to significant morbidity. Due to the COVID-19 pandemic and in order to create more capacities for the treatment of COVID-19-positive patients as well as to contain the spread of the virus, the healthcare system was reorganized worldwide, leading to decreased access to preventive screening programs. The aim of this study was to evaluate the impact of the pandemic on healthcare accessibility to cutaneous squamous cell carcinoma patients in Serbia. This retrospective study was conducted at the Clinic for Burns, Plastic, and Reconstructive Surgery, University Clinical Center of Serbia in Belgrade. Patient demographics and pathohistological findings of tumors of patients living in and outside the capital in the period before, during, and after the pandemic were compared. The two groups did not show any differences regarding the largest tumor diameter prior and during the pandemic; however, this difference became extremely noticeable after the pandemic (15 mm vs. 27 mm; p < 0.001). While cSCCs are commonly slow-growing tumors, the impact of the COVID-19 pandemic is not negligible. This study found a population at a significant risk of cSCC metastasis, with additional evidence likely to emerge in the upcoming years.

Necrotizing Fasciitis-Severe Complication of Bullous Pemphigoid: A Systematic Review, Risk Factors, and Treatment Challenges.

Background and objectives: Bullous pemphigoid (BP), the most common subepidermal autoimmune skin blistering disease (AIBD) has an estimated annual incidence of 2.4 to 42.8 new cases per million in different populations, designating it an orphan disease. Characterized by disruption of the skin barrier combined with therapy-induced immunosuppression, BP could pose a risk for skin and soft tissue infections (SSTI). Necrotizing fasciitis (NF) is a rare necrotizing skin and soft tissue infection, with a prevalence of 0.40 cases per 100,000 to 15.5 cases per 100,000 population, often associated with immunosuppression. Low incidences of NF and BP classify them both as rare diseases, possibly contributing to the false inability of making a significant correlation between the two. Here, we present a systematic review of the existing literature related to the ways these two diseases correlate. Materials and methods: This systematic review was conducted according to the PRISMA guidelines. The literature review was conducted using PubMed (MEDLINE), Google Scholar, and SCOPUS databases. The primary outcome was prevalence of NF in BP patients, while the secondary outcome was prevalence and mortality of SSTI in BP patients. Due to the scarcity of data, case reports were also included. Results: A total of 13 studies were included, six case reports of BP complicated by NF with six retrospective studies and one randomized multicenter trial of SSTIs in BP patients. Conclusions: Loss of skin integrity, immunosuppressive therapy, and comorbidities commonly related to BP patients are risk factors for necrotizing fasciitis. Evidence of their significant correlation is emerging, and further studies are deemed necessary for the development of BP-specific diagnostic and treatment protocols.

Impact of the COVID-19 Pandemic on Melanoma Diagnosis: Increased Breslow Thickness in Primary Melanomas-A Single Center Experience.

Early melanoma diagnosis plays a key role in ensuring best prognosis with good survival rates. The ongoing global COVID-19 pandemic has greatly impacted global and national healthcare systems, thus making it a real challenge. The aim of this study was to evaluate the impact of the pandemic on diagnostic delay in melanoma patients in Serbia. In this retrospective study, we included patients treated at the university hospital in Serbia's capitol over a period of five years and three months. We compared the prepandemic (01/JAN/17-14/MAR/20) and pandemic periods (15/MAR/20-31/MAR/22) by evaluating patient demographic data, melanoma subtype, Breslow thickness, Clark level, ulceration status, mitotic index rate and pT staging. We observed a significant reduction in the number of diagnosed patients (86.3 vs. 13.7%; p = 0.036), with melanomas having an increased median Breslow thickness (1.80 vs. 3.00; p = 0.010), a higher percentage of Clark IV-V level lesions (44.0% vs. 63.0%; p = 0.009), an increase in median mitotic index rate (2 vs. 5; p < 0.001) and a trend of increase in lesions thicker than 2 mm (37.8% vs. 53.7%; p = 0.026). We believe that this study can be a useful scenario guide for future similar events, highlighting the importance of preventive measures and timely diagnosis for the best patient outcomes.

Survival of critically ill patients with COVID-19 pneumonia-a single-center experience.

INTRODUCTION: The aim of the study was to determine the survival probability of critically ill patients with COVID-19 infection who needed mechanical ventilation and to determine the efficacy of Tocilizumab use. METHODOLOGY: The study was designed as a retrospective analysis of consecutive patients older than 18 years, treated in an intensive care unit. The criteria for admission to the intensive care unit was severe respiratory failure requiring mechanical ventilation. All patients received corticosteroid therapy (methylprednisolone 1-2 mg/kg). Tocilizumab was used at a dose of 8 mg/kg in patients with a severe form of the disease (onset, or developed ARDS), followed by cytokine storm (IL-6 ≥ 40 ng/L and CRP ≥ 50 mg/L). RESULTS: 88 patients were included in the study. Intrahospital mortality was 48.86%. No statistically significant difference was observed between patients with and without tocilizumab therapy. In the group of patients in whom this therapy was applied, the values of intrahospital survival were 45.7%, while in the group without this therapy the probability of intrahospital survival was only 0.93%. The probability of survival in the group with noninvasive mechanical ventilation (NIV) was 94.7%, while in the group with invasive mechanical ventilation (IMV) 0.78%. The duration of symptoms before hospitalization (RR-1.088 CI 1.025-1.155, p < 0.05), as well as the duration of IMV (RR-0.906 CI 0.841-0.976, p < 0.05), were shown to be an independent predictor of poor outcome. CONCLUSIONS: The mortality of patients with the most severe form of respiratory failure caused by COVID-19 infection remains high. Independent predictors of poor outcomes were needed for invasive mechanical ventilation and the duration of symptoms before hospitalization or late initiation of appropriate therapy.

A targeted antisense therapeutic approach for Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by premature death from myocardial infarction or stroke. It is caused by de novo single-nucleotide mutations in the LMNA gene that activate a cryptic splice donor site, resulting in the production of a toxic form of lamin A, which is termed progerin. Here we present a potential genetic therapeutic strategy that utilizes antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block pathogenic splicing of mutant transcripts. Of several candidates, PPMO SRP-2001 provided the most significant decrease in progerin transcripts in patient fibroblasts. Intravenous delivery of SRP-2001 to a transgenic mouse model of HGPS produced significant reduction of progerin transcripts in the aorta, a particularly critical target tissue in HGPS. Long-term continuous treatment with SRP-2001 yielded a 61.6% increase in lifespan and rescue of vascular smooth muscle cell loss in large arteries. These results provide a rationale for proceeding to human trials.

Monitoring Oxidative Status in Winemaking by Untargeted Linear Sweep Voltammetry.

An electrochemical portable device based on linear sweep voltammetry was evaluated for studying the redox behavior of polyphenolic compounds in industrial scale winemaking to infer the effects of selected early processing steps on the vinification trials of Pinot gris, Chardonnay, Vermentino and Sangiovese grapes. For each sample, the redox behavior showed a distinctive voltammetric signal pattern related to the processing step during winemaking, therefore being useful as a potential fingerprint for wine identification and to provide insights about the phenolic content. For instance, there was a high correlation (R2 = 0.72) between the total phenolic compounds (PhenOx) and the easily oxidizable compounds (EasyOx), the latter representing approx. 30% on average of the total phenolics. Furthermore, the maceration of red grapes was concluded after 29 days based on information driven by the phenolics pattern. As expected, during alcoholic fermentation, white wines showed a lower content of phenolic compounds than those found in red wines, with an average ratio PhenOx/EasyOx of about 4.7, 5.0 and 3.6 for Chardonnay, Pinot gris and Vermentino, respectively. The portable tool with miniaturized disposable electrodes showed interesting analytical features that can be exploited for on-site and real-time quality control for monitoring change in phenolic composition during wine processing and storage, and for tailoring winemaking practices to enhance the color stability of products.

The Oxygen Consumption Kinetics of Commercial Oenological Tannins in Model Wine Solution and Chianti Red Wine.

One property of oenological tannins, oxygen reactivity, is commonly exploited in winemaking. The reactivity is mediated by the presence of catalysts (i.e., transition metals and sulfur dioxide) and protects wine against oxidation. This work compares the oxygen consumption rate (OCR) of four commercial oenological tannins (two procyanidins from grape skin and seed, an ellagitannin from oak wood and a gallotannin from gallnut) in a model wine solution and Chianti red wine. All samples were subjected to consecutive cycles of air saturation at 20 °C to increase the total level of oxygen provided. After each cycle, the oxygen level was measured by means of a non-invasive luminescent sensor glued to a transparent surface (sensor dots) until there was no further change in substrate reactivity. The OCR followed first-order kinetics, regardless of the tannin. As expected, the ellagitannin showed the fastest OCR, followed by the two from grape seeds and skins and finally the gallotannin. The total O2 consumption in the red wine was almost double that of the model solution, due to the oxidation of wine substrates. The measurement of OCR is helpful for setting up an advanced winemaking protocol that makes use of tannins to reduce the use of sulfur dioxide.

N-Benzyl Derivatives of Long-Chained 4-Amino-7-chloro-quionolines as Inhibitors of Pyocyanin Production in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a leading cause of nosocomial infections that are becoming increasingly difficult to treat due to the occurrence of antibiotic resistant strains. Since P. aeruginosa virulence is controlled through quorum sensing, small molecule treatments inhibiting quorum sensing signaling pathways provide a promising therapeutic option. Consequently, we synthesized a series of N-octaneamino-4-aminoquinoline derivatives to optimize this chemotype's antivirulence activity against P. aeruginosa via inhibition of pyocyanin production. The most potent derivative, which possesses a benzofuran substituent, provided effective inhibition of pyocyanin production (IC50 = 12 µM), biofilm formation (BFIC50 = 50 µM), and motility. Experimentally, the compound's activity is achieved through competitive inhibition of PqsR, and structure-activity data were rationalized using molecular docking studies.

Giant dermatofibrosarcoma protuberans vulvae: rare clinical presentation and literature review.

Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing fibro-cutaneous tumor of low to intermediate grade malignancy. It is characterized by local dermal and subcutaneous infiltration, but also with destructive infiltration of the surrounding tissues (muscle, fascia, and bone). The size of the tumor varies from small nodular to large neglected masses. Males and females are equally affected. The tumor is most often localized in the trunk and the proximal extremities. At a molecular level, more than 90% of all DFSP arise from the translocation of chromosomes 17 and 22. Clinically, it usually occurs in the form of flesh-colored or slightly yellow-brown skin tumor, irregular borders or multinodular appearance. The definitive diagnosis of DFSP is made by biopsy in combination with histological morphology and immunohistochemistry. The standard treatment for DFSP is surgical resection. Radiation treatment is an option for primary inoperable tumors and prior multiple recurrences. There is no consensus about chemotherapy regimens. Imatinib - a tyrosine kinase inhibitor - is approved in Europe for the treatment of inoperable primary tumors, locally inoperable recurrent disease, and metastatic DFSP. The recommended dose is 400-600 mg/daily. DFSP of the vulva is extremely rare, with less than 60 cases reported in the literature. Tumor behavior of DFSP of the vulva does not differ from other DFSP localizations. Spontaneous regressions are common while distant metastases are rare. Multidisciplinary approach requiring wide resection, margin assessment and reconstruction is the therapy of choice.

Enpp1 inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling.

The differentiated phenotype of articular chondrocytes of synovial joints needs to be maintained throughout life. Disruption of the articular cartilage, frequently associated with chondrocyte hypertrophy and calcification, is a central feature in osteoarthritis (OA). However, the molecular mechanisms whereby phenotypes of articular chondrocytes are maintained and pathological calcification is inhibited remain poorly understood. Recently, the ecto-enzyme Enpp1, a suppressor of pathological calcification, was reported to be decreased in joint cartilage with OA in both human and mouse, and Enpp1 deficiency causes joint calcification. Here, we found that hedgehog (Hh) signaling activation contributes to ectopic joint calcification in the Enpp1-/- mice. In the Enpp1-/- joints, Hh signaling was upregulated. Further activation of Hh signaling by removing the patched 1 gene in the Enpp1-/- mice enhanced ectopic joint calcification, whereas removing Gli2 partially rescued the ectopic calcification phenotype. In addition, reduction of Gαs in the Enpp1-/- mice enhanced joint calcification, suggesting that Enpp1 inhibits Hh signaling and chondrocyte hypertrophy by activating Gαs-PKA signaling. Our findings provide new insights into the mechanisms underlying Enpp1 regulation of joint integrity.

Cancer during pregnancy - clinical characteristics, treatment outcomes and prognosis for mothers and infants.

OBJECTIVE: To assess which obstetrical characteristics and treatment improved outcomes and prognosis of pregnant women with malignancy. METHODS: A prospective study, undertaken between 2005 and 2014, involving 35 pregnant women who were diagnosed with malignant tumors during pregnancy. Patients were followed-up for 1 year after delivery. The pregnancy course and outcome and parameters that could influence the condition of mother and fetus were evaluated. RESULTS: Most malignancies were hematological, diagnosed in the second trimester and treated with combined therapy (surgery/adjuvant) after pregnancy. Most fetuses were in good state throughout pregnancy, but were delivered by caesarean section (CS) before term. Adjuvant therapy during pregnancy mostly caused transitory deterioration of fetal conditions. The majority of both mothers and infants were in a good state 12 months postpartum, although numerous mothers were still ill and on therapy. Surviving pregnancy and preventing tumors progression during pregnancy were the best predictors of mothers' future condition (P=0.022). High birthweight and term delivery were the most important factors for good outcome of the infants (P=0.001). CONCLUSIONS: If the tumor is not progressing, pregnancy should be continued as long as possible to obtain adequate birthweight of the infant. Second trimester surgery is safe, while other therapies should preferably be applied after delivery.

Hippo signaling interactions with Wnt/ß-catenin and Notch signaling repress liver tumorigenesis.

Malignant tumors develop through multiple steps of initiation and progression, and tumor initiation is of singular importance in tumor prevention, diagnosis, and treatment. However, the molecular mechanism whereby a signaling network of interacting pathways restrains proliferation in normal cells and prevents tumor initiation is still poorly understood. Here, we have reported that the Hippo, Wnt/ß-catenin, and Notch pathways form an interacting network to maintain liver size and suppress hepatocellular carcinoma (HCC). Ablation of the mammalian Hippo kinases Mst1 and Mst2 in liver led to rapid HCC formation and activated Yes-associated protein/WW domain containing transcription regulator 1 (YAP/TAZ), STAT3, Wnt/ß-catenin, and Notch signaling. Previous work has shown that abnormal activation of these downstream pathways can lead to HCC. Rigorous genetic experiments revealed that Notch signaling forms a positive feedback loop with the Hippo signaling effector YAP/TAZ to promote severe hepatomegaly and rapid HCC initiation and progression. Surprisingly, we found that Wnt/ß-catenin signaling activation suppressed HCC formation by inhibiting the positive feedback loop between YAP/TAZ and Notch signaling. Furthermore, we found that STAT3 in hepatocytes is dispensable for HCC formation when mammalian sterile 20-like kinase 1 and 2 (Mst1 and Mst2) were removed. The molecular network we have identified provides insights into HCC molecular classifications and therapeutic developments for the treatment of liver tumors caused by distinct genetic mutations.

Versatility of Radial Forearm Free Flap for Intraoral Reconstruction.

INTRODUCTION: The radial forearm free flap has an important role in reconstruction of the oncologic defects in the region of head and neck. OBJECTIVE: The aim was to present and evaluate clinical experience and results in the radial forearm free transfer for intraoral reconstructions after resections due to malignancies. METHODS: This article illustrates the versatility and reliability of forearm single donor site in 21 patients with a variety of intraoral oncologic defects who underwent immediate (19 patients, 90.5%) or delayed (2 patients, 9.5%) reconstruction using free flaps from the radial forearm. Fascio-cutaneous flaps were used in patients with floor of the mouth (6 cases), buccal mucosa (5 cases), lip (1 case) and a retromolar triangle (2 cases) defects, or after hemiglossectomy (7 cases). In addition, the palmaris longus tendon was included with the flap in 2 patients that required oral sphincter reconstruction. RESULTS: An overall success rate was 90.5%. Flap failures were detected in two (9.5%) patients, in one patient due to late ischemic necrosis, which appeared one week after the surgery, and in another patient due to venous congestion, which could not be salvaged after immediate re-exploration. Two patients required re-exploration due to vein thrombosis.The donor site healed uneventfully in all patients, except one, who had partial loss of skin graft. CONCLUSION: The radial forearm free flap is, due to multiple advantages, an acceptable method for reconstructions after resection of intraoral malignancies.

Neonatal outcome in pregnant patients with antiphospholipid syndrome.

AIMS: The study aim was to evaluate pregnancy outcomes in patients with antiphospholipid syndrome (APS) and to determine which clinical parameters present risk factors for adverse pregnancy outcomes in these patients. METHODS: The study included 55 patients with APS treated at the Clinic for Ob/Gyn, Clinical Center of Serbia, from 2006 to 2012. The control group consisted of 55 healthy pregnant women. Data regarding previous pregnancies and conception method were registered. Immunological and laboratory tests were performed. Pregnancy outcomes, including miscarriage, intrauterine fetal death, hypertensive disorders, diabetes mellitus, phlebothrombosis, fetal growth restriction, premature delivery, delivery method, perinatal asphyxia, respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis were followed. RESULTS: The premature delivery rate in APS patients was 31.8%, and pregnancy loss was 18.2%. Significantly more patients with APS had thrombocytopenia, pregnancy losses, intrauterine growth restriction, and perinatal asphyxia compared with the control group. More miscarriages, preterm delivery, lower birth weight, preeclampsia, and IgM anticardiolipin antibody levels significantly correlated with adverse pregnancy outcomes. Although rare, respiratory distress syndrome can also worsen neonatal health status. According to ROC analysis, previous miscarriages correctly explained 66.3% of adverse pregnancy outcome cases. We generated four equations of adverse pregnancy outcome risk factors. CONCLUSIONS: The most important prognostic factor for pregnancy outcome in APS patients is the number of previous miscarriages. Using appropriate current therapeutic protocol can enable live birth of a healthy newborn in most cases.

Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification.

Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gαs restricts bone formation to the skeleton by inhibiting Hedgehog signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia, a human disease caused by null mutations in GNAS, which encodes Gαs, Hedgehog signaling is upregulated in ectopic osteoblasts and progenitor cells. In animal models, we show that genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification, whereas inhibition of this signaling pathway by genetic or pharmacological means strongly reduces the severity of this condition. As our previous work has shown that GNAS gain-of-function mutations upregulate WNT-ß-catenin signaling in osteoblast progenitor cells, resulting in their defective differentiation and fibrous dysplasia, we identify Gαs as a key regulator of proper osteoblast differentiation through its maintenance of a balance between the Wnt-ß-catenin and Hedgehog pathways. Also, given the results here of the pharmacological studies in our mouse model, we propose that Hedgehog inhibitors currently used in the clinic for other conditions, such as cancer, may possibly be repurposed for treating heterotopic ossification and other diseases caused by GNAS inactivation.

Madelung disease: a rare case associated with gynaecomastia and scrotal involvement.

Madelung disease is rare, and characterised by accumulation of fatty non-encapsulated tissue in the head, neck, shoulders, and upper extremities. The aetiology is not completely known, but the association with alcohol intake is clear. We present a neglected case that was associated with bilateral asymmetrical gynaecomastia. To the best of our knowledge, this is a pattern of involvement not previously reported. The treatment of choice is lipectomy for severe cases and liposuction for less extensive accumulations of fat.