Inflammation

Correction to: Plumbagin Prevents IL-1β-Induced Inflammatory Response in Human Osteoarthritis Chondrocytes and Prevents the Progression of Osteoarthritis in Mice The original version of this article contained mistakes, and the authors would like to correct them. The correct details are given below:

Correction to: miR-140-5p/miR-149 Affects Chondrocyte Proliferation, Apoptosis, and Autophagy by Targeting FUT1 in Osteoarthritis The original version of this article contained mistakes, and the authors would like to correct them.

Pro-inflammatory S100A9 Protein: a Double-Edged Sword in Cancer?

Carnosic Acid Inhibits CXCR3 Ligands Production in IL-27-Stimulated Human Oral Epithelial Cells Abstract Carnosic acid, which is a bioactive compound isolated from rosemary, has various pharmacological effects. However, the anti-inflammatory effect of carnosic acid on periodontitis is still unknown. The aim of this study was to investigate the effect of carnosic acid on CXC chemokine receptor 3 (CXCR3) ligands, which are involved in Th1 cells migration and accumulation, production in interleukin (IL)-27-stimulated human oral epithelial cells (TR146 cells). Carnosic acid decreased CXC chemokine ligand (CXCL)9, CXCL10, and CXCL11 production in IL-27-stimulated TR146 cells in a dose-dependent fashion. Moreover, we disclosed that carnosic acid could suppress signal transducer and activator of transcription (STAT)1, STAT3, and protein kinase B (Akt) phosphorylation in IL-27-stimulated TR146 cells. Furthermore, STAT1, STAT3, and Akt inhibitors could suppress CXCR3 ligands production in IL-27-treated TR146 cells. In summary, carnosic acid could reduce CXCR3 ligands production in human oral epithelial cell by inhibiting STAT1, STAT3, and Akt activation.

Tizoxanide Inhibits Inflammation in LPS-Activated RAW264.7 Macrophages via the Suppression of NF-κB and MAPK Activation Abstract Tizoxanide is the main active metabolite of nitazoxanide. Nitazoxanide and tizoxanide have a broad-spectrum anti-infective effect, including parasites, bacteria, and virus. In the present study, we investigated the anti-inflammatory effect of tizoxanide on lipopolysaccharide (LPS)-stimulated RAW264.7 cells and revealed underlying molecular mechanisms. The results showed that tizoxanide significantly suppressed production of NO as well as pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α in dose-dependent manner. Meanwhile, the levels of gene expression of these cytokines were inhibited significantly by tizoxanide that was discovered using RT-PCR. The increased protein levels of inducible nitric oxide synthase, heme oxygenase-1, and cyclooxygenase-2 by LPS in the cells were also reduced by tizoxanide. Moreover, we found that tizoxanide inhibited the phosphorylation of IKK-α and degradation of IκB by LPS in macrophage cells. The increased protein levels of p65 induced by LPS in the cytoplasm and nucleus were both decreased by tizoxanide, and the nuclear translocation of p65 was also restrained in cell imaging. In addition, tizoxanide considerably also inhibited LPS-activated JNK, p38, and ERK phosphorylation in RAW264.7 cells. Taken together, our results suggested that tizoxanide exerts anti-inflammatory effects, by inhibiting the production of pro-inflammatory cytokines and suppressing of the activation of the NF-κB and the MAPK signaling pathways in LPS-treated macrophage cells.

Heteroleptic Ruthenium Polypyridyl Complex Had Differential Effects on the Production of Pro-inflammatory Cytokines TNFα, IL1β, and IL6 by the Mammalian Macrophages In Vitro Abstract Modulation of the immune system has gathered more attention in the field of medicine due to the immense potential that it presents. Our immune system has important roles against cancer to infectious diseases, as well as in the development of autoimmune disorders. Therefore, being able to manipulate our immune system cells would enable us to determine the type and strength of the immune response to certain danger stimuli. Macrophages play an important role in the regulation of the immune system by producing cytokines, chemokines and by presenting antigens to other immune system cells to enable their activation; in our study, we focused on their in vitro activity in terms of pro-inflammatory cytokine production. In order to screen new immunomodulatory or immunostimulatory drug candidates, we examined the effect of ruthenium polypyridyl-based complex K30 that is used in solar cells as photosensitizer. Due to its electron transfer capacity, this material has potential to change the electron transfer reactions therefore could alter the function of the cells through metabolic changes at a cellular level. Our results suggest that K30 was differentially regulating the secretion levels of the pro-inflammatory cytokines by the LPS-activated mammalian macrophages, while it did not stimulate the macrophages by itself. K30 has an anti-inflammatory potential while lacking the immunostimulatory effect in our in vitro results and has potential to be used as anti-inflammatory drug molecule in metallic implants of the fractured bones to prevent damaging inflammatory environment and enable more efficient transplant and healing.

Shikonin Controls the Differentiation of CD4 + CD25 + Regulatory T Cells by Inhibiting AKT/mTOR Pathway Abstract CD4+CD25+ regulatory T (Treg) cells maintain the function of immune tolerance and the balance of immune cells. Defects in the number and function of Treg cells can induce the development and progression of inflammatory disease. Shikonin, the main active ingredient of Lithospermum, has anti-inflammatory and anti-tumor effects. Shikonin is also an effective drug for the treatment of psoriasis, which is a chronic inflammatory skin disease. However, the underlying mechanism is not yet clear. To evaluate the role of shikonin on the induction of Treg cells, we tested the number and function of Treg cells in vivo and in vitro. Shikonin can effectively promote the differentiation of iTreg cells by inhibiting the AKT/mTOR pathway in vitro. Moreover, in vivo, intragastrically administered shikonin effectively improved lesions in mice with imiquimod-induced psoriasis and increased the number of iTreg cells in the spleen and their secretion. Shikonin significantly increases the expression of Foxp3mRNA in skin of the psorisic mice. Therefore, we expect that shikonin can prevent the development of inflammation and treat psoriasis by regulating iTreg cells. Novel ideas for the treatment of psoriasis are also proposed.

(3R, 7R)-7-Acetoxyl-9-Oxo-de-O-Methyllasiodiplodin, a Secondary Metabolite of Penicillium Sp., Inhibits LPS-Mediated Inflammation in RAW 264.7 Macrophages through Blocking ERK/MAPKs and NF-κB Signaling Pathways Abstract Twelve polyketones were isolated from the fermentation broth of Penicillium sp., including six new compounds (supplementary material). Penicillium sp. is widely used in clinic as a highly effective and low toxic antibiotic. Among these compounds, (3R, 7R)-7-acetoxyl-9-oxo-de-O-methyllasiodiplodin named PS-2 showed significant anti-inflammatory activity. So, the anti-inflammatory mechanism of PS-2 was investigated by using lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. The results showed that PS-2 can significantly inhibit the overproduction of nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-6 (IL-6), whereas it showed no inhibition on the release of pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α). Cell-free colorimetric method demonstrated that PS-2 could obviously inhibit the enzymatic activity of cyclooxygenase-2 (COX-2). Western blot results indicated that PS-2 could significantly inhibit high expression of iNOS and COX-2 proteins. Further investigations on the anti-inflammatory mechanism showed that PS-2 could suppress the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but did not exhibit obvious inhibition on the phosphorylation of c-JunN-terminal kinase (JNK) and phosphorylated 38 (p38). In addition, PS-2 inhibited the degradation of inhibitor of kappa-B alpha (IκB-α) and translocation to nucleus of nuclear factor kappa-B (NF-κB) p65 in RAW 264.7 macrophages. These results suggested that PS-2 might be an effective intervention against inflammatory diseases.

Probucol Ameliorates Complete Freund's Adjuvant-Induced Hyperalgesia by Targeting Peripheral and Spinal Cord Inflammation Abstract The effect of the lipid-lowering agent probucol in inflammatory hyperalgesia and leukocyte recruitment was evaluated in a model of subacute inflammation by Complete Freund's adjuvant (CFA). As CFA induces long-lasting nociception characterized by peripheral and spinal cord inflammation, the anti-inflammatory activity of probucol was assessed at both foci. Probucol at 0.3–3 mg/kg was administrated per oral daily starting 24 h after CFA intraplantar injection. Mechanical and thermal hyperalgesia induced by CFA were determined using an electronic anesthesiometer and hot plate apparatus, respectively. Post-treatment with probucol at 3 mg/kg inhibited CFA-induced hyperalgesia over the course of 7 days as well as paw edema. Overt pain-like behaviors, which were determined by the number of flinches and time spent licking paw immediately following CFA injection, were also reduced by probucol at 3 mg/kg administered as a pre-treatment. To investigate the mechanisms underlying the analgesic effect of probucol, neutrophil recruitment to paw was assessed by myeloperoxidase activity, cytokine production, Cox-2 expression, and NF-κB activation in both paw and spinal cord by ELISA. Iba-1, GFAP, and substance P protein expression and nuclear localization of phosphorylated NF-κB were evaluated in the spinal cord by immunofluorescence. Probucol at 3 mg/kg attenuated neutrophil recruitment, cytokine levels, and NF-κB activation as well microglia and astrocyte activation, and substance P staining in the spinal cord. Taken together, the results suggest that probucol exerts its analgesic and anti-inflammatory activity in an experimental model of persistent inflammation by targeting the NF-κB pathway in peripheral and spinal cord foci.

Silencing of STAT4 Protects Against Autoimmune Myocarditis by Regulating Th1/Th2 Immune Response via Inactivation of the NF-κB Pathway in Rats Abstract Signal transducer and activator of transcription 4 (STAT4) has been implicated in the progression of myocarditis. The aim of the current study was to investigate the role by which STAT4 influences autoimmune myocarditis in an attempt to identify a theoretical therapeutic perspective for the condition. After successful establishment of an autoimmune myocarditis rat model, the expression patterns of STAT4, NF-κB pathway–related genes, Th1 inflammatory cytokines (IFN-γ and IL-2), and Th2 inflammatory cytokines (IL-6 and IL-10) were subsequently determined. The rats with autoimmune myocarditis were treated with oe-STAT4 or sh-STAT4 lentiviral vectors to evaluate the role of STAT4 in autoimmune myocarditis, or administrated with 1 mL 10 μmol/L of BAY11-7082 (the NF-κB pathway inhibitor) via tail vein to investigate the effect of the NF-κB pathway on autoimmune myocarditis. Finally, cell apoptosis was evaluated. The serum levels of IFN-γ and IL-2, extent of IκBα and P65 phosphorylation, and the expression of STAT4 were elevated, while the serum levels of IL-6 and IL-10 as well as the expression of IκBα were reduced among the rats with autoimmune myocarditis, which was accompanied by an increase in the apoptotic cells. More importantly, the silencing of STAT4 or the inhibition of the NF-κB pathway was detected to result in a decrease in the serum levels of IFN-γ and IL-2 and an elevation of the serum levels of IL-6 and IL-10, and inhibited myocardial cell apoptosis in rats with autoimmune myocarditis. Moreover, STAT4 silencing was also observed to decrease the extent of IκBα and P65 phosphorylation while acting to elevate the expression of IκBα. Taken together, silencing of STAT4 could hinder the progression of autoimmune myocarditis by balancing the expression of Th1/Th2 inflammatory cytokines via the NF-κB pathway, which may provide a novel target for experimental autoimmune myocarditis (EAM) treatment.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Gefässchirurgie

Kompetenz in der Shuntchirurgie Zusammenfassung Kompetenz bezieht sich nicht nur auf Wissen und Fertigkeiten einer Person, sondern auch auf deren Handlungsfähigkeit im klinischen Alltag, insbesondere unter Stress. Deshalb sollten wir die Kompetenzprofile der Mitarbeiter kennen. Die shuntchirurgischen Behandlungskonzepte beruhen heute mehr auf Eminenz als auf Evidenz, weil die Zahl randomisierter Studien beschränkt ist. Es können etablierte Simulationskurse belegt werden, um Fertigkeiten in der Shuntchirurgie zu trainieren. In diesem Artikel werden am Beispiel der Shuntchirurgie „entrustable professional activities" (EPAs) formuliert. Mit diesen „anvertraubaren professionellen Tätigkeiten" können Kernkompetenzen im klinischen Alltag abgebildet werden. Diese EPAs erlauben es dem Vorgesetzten einzuschätzen, wie eigenverantwortlich eine Person arbeiten kann. Wiederholt man diese Beurteilung über die Zeit, können Veränderungen des Kompetenzprofils eines Kandidaten über eine längere Periode beobachtet werden.

Perianastomosen-Hämodynamik bei arteriovenösen Fisteln

Nicht belegter oder erwartbarer Benefit durch neues Device in der Shuntchirurgie

Experimentelle Untersuchung zur Effektivität und Sicherheit der kathetergestützten Thrombektomie Zusammenfassung Hintergrund Die kathetergestützte Thrombektomie ist ein Standardverfahren zur Rekanalisation von thrombotisch bedingten arteriellen Gefäßverschlüssen. Jedoch existieren kaum experimentelle und wenige klinische Daten zur Effektivität und Sicherheit der heute verfügbaren Systeme und Verfahren. Fragestellung Wie verhalten sich die unterschiedlichen Verfahren zur kathetergestützten Thrombektomie im Hinblick auf die Effektivität der jeweiligen Methode, der Gefahr von Gefäßendothelschäden durch die Thrombektomie und das Auftreten von Embolien zueinander? Material und Methoden In dieser In-vitro-Studie wurde die Thrombektomie von 3 unterschiedlichen Thrombusentitäten (grau/rot/weiß) mit 4 unterschiedlichen Katheterverfahren (Aspirationsthrombektomie, Fogarty-Katheter, lasergestützte Thrombektomie + Aspiration, Stent-Retriever + Aspiration) hinsichtlich ihrer Effektivität und sicheren Anwendung im physiologischen Flussmodell und am porcinen Gefäßphantom der A. femoralis superficialis (AFS) untersucht und miteinander verglichen. Ergebnisse Es konnte eine akzeptable First-Pass-Rekanalisation sowohl bei der klassischen Embolektomie nach Fogarty als auch bei der Anwendung des Stent-Retrievers nachgewiesen werden. Die laserassistierte Rekanalisation + Aspiration zeigte ebenfalls passable Ergebnisse, wohingegen die alleinige Aspirationsthrombektomie des „grauen" sog. Mischthrombus sich als nicht effektiv herausstellte. Die beiden effektivsten Verfahren waren die Thrombektomie mit dem Fogarty-Katheter und dem Stent-Retriever, jedoch verbunden mit der höchsten Embolierate für alle 3 Thrombusentitäten (37,5–60 %). Die histologische Auswertung zeigte lediglich für den Einsatz des Fogarty-Katheters signifikante Gefäßschäden nach Thrombektomie. Schlussfolgerungen Während die Aspiration lediglich zur Thrombektomie weißer Abscheidungsthromben erfolgreich eingesetzt werden konnte, verzeichnete die Thrombektomie mit dem Fogarty-Katheter eine hohe Erfolgsrate in der First-Pass-Rekanalisation unabhängig von der Thrombusentität jedoch auf Kosten ausgeprägter Endothelschäden. Passable Ergebnisse konnten ebenfalls für die laserassistierte Rekanalisation und den Einsatz des Stent-Retrievers erzielt werden, bei letzterem jedoch verbunden mit einer hohen Embolisationsrate. Zukünftig könnte auf der Basis der hier dargestellten Experimente eine differenzierte und zielgerichtete Anwendung von kathetergestützten Verfahren zur Thrombektomie in der klinischen Praxis erfolgen.

Akute Oberbauchschmerzen durch seltenen Auslöser

Rauchstopp und Risikoreduktion Zusammenfassung Rauchen ist der wichtigste Risikofaktor der peripheren arteriellen Verschlusskrankheit (PAVK). Der Rauchstopp ist und bleibt der Goldstandard in der Empfehlung zur Sekundärprävention. Die E‑Zigarette/Tabakerhitzer werden für die Raucher empfohlen, denen der Rauchstopp nicht gelingt oder die das nicht wünschen. In dieser Gruppe der Raucher, die für Rauchstoppstrategien nicht zugänglich ist, kann laut dem Positionspaper der Dachgesellschaft Sucht bei fortgesetztem Rauchen durch die Umstellung eine mehr als 90 % Reduktion der Schadstoffexposition erreicht werden. Den Ärzten, die in Deutschland Gefäßpatienten behandeln, fehlt es allerdings an grundlegenden Kenntnissen zur Vielfalt der angebotenen E‑Zigaretten/Tabakerhitzer, ihrer Anwendung und ihrer Emissionen. Daher ist eine offene und fachliche Diskussion unter Kardiologen, Angiologen und Gefäßchirurgen zum Thema Rauchstopp und Risikoreduktion notwendig.

Mitteilungen der DGG

Die Arteria iliaca interna – das unterschätzte Gefäß?

Vaskuläre Ursachen der erektilen Dysfunktion Zusammenfassung Hintergrund Die erektile Dysfunktion (ED) als eine Form der vaskulären Störung des Penis hat mit anderen kardiovaskulären Erkrankungen in der Arteriosklerose eine gemeinsame Ursache. Fragestellung Gibt es einen Zusammenhang zwischen einer ED und anderen kardiovaskulären Risiken beim Mann? Lässt sich ein möglicher Zusammenhang im Falle der ED prädiktiv nutzen? Material und Methode Auswertung und Diskussion aktueller Grundlagenarbeiten und Übersichtsartikel zum Thema. Ergebnisse Diabetes mellitus, metabolisches Syndrom, kardiovaskuläre Erkrankungen und erektile Dysfunktion (ED) sind teils einander bedingende und verstärkende Gesundheitsrisiken bei Männern, wobei die ED und kardiale Ereignisse in der Arteriosklerose eine gemeinsame Ursache finden. Die Arterien des Penis sind jedoch sehr viel feiner als z. B. die Koronararterien des Herzens, weshalb sich Veränderungen am Penis meist sehr viel früher zeigen. Schlussfolgerungen Eine durch vaskuläre Risikofaktoren induzierte ED lässt sich mithilfe des penilen Doppler-Ultraschalls nichtinvasiv darstellen. Eine risikoadaptierte Behandlung des betreffenden Patienten mit Blick auf sein kardiovaskuläres Risikoprofil wird dadurch möglich. Somit ist die ED als prädiktiv für kardiovaskuläre Risiken mit etwa 3 bis 5 Jahren Vorlauf anzusehen.

Gefäßspezifische Radiologie

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Pediatrics

Sialoblastoma of the submandibular gland: a distinct entity? Abstract Sialoblastoma is a rare congenital malignant tumor of the salivary glands. A case of a submandibular sialoblastoma in a 1.5-year-old child is presented. A comparative analysis on 79 pediatric cases reported in the literature suggests a less aggressive behavior for submandibular sialoblastoma in comparison with other sites. Classically, diagnosis is confirmed by open biopsy, but fine-needle aspiration may offer an alternative with reduced morbidity. Expression of AFP and high levels of Ki-67 have been associated with poor prognosis. Whilst early surgical resection with negative margins is widely accepted as first-line treatment, there is no consensus on therapy of recurrence and follow-up. MRI and sonography represent valid tools for the follow-up, which is usually restricted to 3–5 years. Conclusion: Submandibular sialoblastomas may have a different biological profile in comparison with parotid tumors with the absence of metastasis and much lower rate of recurrence. Comprehensive diagnostics should include additional options such as fine-needle aspiration and markers to assess cell proliferation and AFP. Literature suggests that surgery alone is sufficient for the treatment of tumors with low malignancy. Follow-up should be tailored according to the tumor site and might be limited to 3–5 years. What is Known: • Sialoblastoma is a rare congenital malignant tumor with an unpredictable clinical outcome. What is New: • Sialoblastoma of submandibular origin seems to have a less aggressive behavior in comparison with other sites. • Fine-needle aspiration and markers to assess proliferation index (i.e., suggestive of potential more aggressive course/malignancy) should be strongly considered in the diagnostic work-up. • Radical surgery as first-line therapy and a 3–5-year follow-up are acceptable for tumors with a low malignancy.

Somatic symptom disorder should be suspected in children with alleged chronic Lyme disease Abstract We report a case series of seven children admitted to a tertiary level pediatric ward for long-lasting physical symptoms with a previous diagnosis of chronic Lyme disease. In these children, medical history and clinical features were strongly suggestive of a psychopathological disorder, mainly a somatic symptom disorder. What is Known: • There is an increasing number of diagnoses of chronic Lyme disease both in North America and in Europe. Adults receive this diagnosis to explain chronic physical complaints often with negative history and serology. What is New: • Somatic symptom disorder should be suspected in children and adolescents with non-specific symptoms diagnosed with chronic Lyme disease.

Ten-year trend in prevalence and outcome of Down syndrome with congenital heart disease in a middle-income country Abstract Limited data are available on the survival of patients with Down syndrome and congenital heart disease (CHD) from middle-income countries. This retrospective cohort study was performed to determine the trends in the prevalence and survival of such patients born from January 2006 to December 2015 in Malaysia. Among 754 patients with Down syndrome, 414 (55%) had CHD, and no significant trend was observed during the 10 years. Of these 414 patients, 30% had lesions that closed spontaneously, 35% underwent surgery/intervention, 9% died before surgery/intervention, and 10% were treated with comfort care. The overall mortality rate was 23%, the median age at death was 7.6 months, and no significant changes occurred over time. The early and late post-surgery/intervention mortality rates were 0.7% and 9.0%, respectively. Most deaths were of non-cardiac causes. The overall 1-, 5-, and 10-year survival rates were 85.5%, 74.6%, and 72.9%, respectively. Patients with severe lesions, persistent pulmonary hypertension of the newborn, atrioventricular septal defect, and pulmonary hypertension had low survival at 1 year of age. Conclusion: The prevalence of CHD in patients with Down syndrome is similar between Malaysia and high-income countries. The lower survival rate is attributed to limited expertise and resources which limit timely surgery. What is Known: • The survival of patients with Down syndrome with congenital heart disease (CHD) has improved in high-income countries. However, little is known about the survival of patients with Down syndrome with CHD from middle-income countries. • In the Caucasian population, atrioventricular septal defect is the most common type of CHD associated with Down syndrome. What is New: • In middle-income countries, the prevalence of CHD is the same as in high-income countries, but with a lower survival rate. • In the Asian population, ventricular septal defect is the most common type of CHD in patients with Down syndrome.

Genotype and phenotype analysis of a cohort of patients with congenital hyperinsulinism based on DOPA-PET CT scanning Abstract Congenital hyperinsulinism (CHI) is a clinically, genetically, and morphologically heterogeneous disorder. 18F DOPA-PET CT scanning greatly improves its clinical outcome. Here, we presented the first Chinese 18F DOPA-PET CT scanning–based CHI cohort highlighting the variable ethic clinical phenotypes and genotypes. Fifty CHI patients were recruited. Median age at presentation was 2 days. Median fasting time was 2 h. Mean insulin level was 25.6 μIU/ml. Fifty-two percent of patients were diazoxide-unresponsive with significantly shorter fasting tolerance time and higher serum insulin level compared with the responsive patients. Seventy-four percent of patients experienced at least one adverse drug reaction. Tremendously increased focal lesions (32%) were detected and 75% of them were cured through surgery. Thirty-one nucleotide sequence changes were identified in 48% patients. Four novel variants (Q608X, Q1347X, Q289X, F1489S) in ABCC8 gene and 2 novel variants (G132A, V138E) in KCNJ11 gene were detected. Of the variants, 87.1% harbored in ABCC and KCNJ11 genes. T1042Qfs*75 in ABCC8 gene was the most common mutation. Conclusion: Highly increased portion of focal lesion was presented in Chinese CHI patients compared with that of the previous reports. Intolerance to diazoxide was much more evident in Chinese or East Asian than other populations. Certain hotspot mutations harbored in Chinese CHI patients. What is Known: • 18F DOPA-PET CT scanning can provide informative guidance for surgical procedure when medical therapy is not well responded in CHI patients. What is New: • Intolerance to diazoxide is much more evident in Chinese and East Asian CHI patients compared with the other ethnic populations. • Novel mutations were detected in ABCC8 and KCNJ11 gene. Hotspot mutations such as T1042Qfs*75, I1511K, E501K, G111R in ABCC8 gene, and R34H in KCNJ11 gene are predominantly responsible for Chinese CHI patients.

A new simple formula built on the American Academy of Pediatrics criteria for the screening of hypertension in overweight/obese children Abstract We evaluated the performance of a new simple formula (NSF) for the screening of hypertension by American Academy of Pediatrics Guidelines 2017 (AAPG2017) in children with overweight/obesity (OW/OB). The performance of the NSF and the modified blood pressure to height ratio (MBPHR3) thresholds against AAPG2017 was evaluated; both methods were also compared to assess the association with concentric left ventricular hypertrophy (cLVH). The study included 3259 OW/OB children (5–13 years). Two centers served as learning sample (LS) (n = 1428), four centers served as validation sample (VS) (n = 1831), and the echocardiographic evaluation was available in 409 children in VS. The NSF was [1.5 × systolic blood pressure (mmHg) + diastolic blood pressure (mmHg)] − [(26 × height (m)] − age (years). A cut-off of the NSF ≥ 193 mmHg showed sensitivity, specificity, positive, and negative predictive values of 0.92, 0.93, 0.83, and 0.97, respectively, versus the standard procedure. Against AAPG2017, the NSF showed higher specificity and positive predictive values than the MBPHR3 thresholds. Among hypertensive children defined by AAPG2017, NSF, or MBPHR3, the odds ratio (95%CI) for cLVH was respectively 1.73 (1.06–2.83), 1.69 (1.05–2.75), and 1.18 (0.75–1.85). Conclusions: The NSF shows a very high performance for the screening of OW/OB children at risk of hypertension and cLVH. What is Known: • The American Academy of Pediatrics released updated guidelines (AAPG 2017) to classify hypertension (HTN) in children. • The process needs categorization of height percentiles and comparison of blood pressure versus gender and age-adjusted values. What is New: • A user-friendly formula built on the AAPG 2017 was validated for the categorization of HTN in children with overweight/obesity. • The formula showed high performance in identifying children with HTN versus the standard procedure (sensitivity 0.92, specificity 0.93) and similar ability in identifying hypertensive children with concentric left ventricular hypertrophy versus the standard procedure (40% and 39% respectively).

Benefits of medical clowning in the treatment of young children with autism spectrum disorder Abstract We investigated the contribution of group therapy delivered by a medical clown to young children diagnosed with autism spectrum disorder (ASD). So far, scientific publications regarding medical clowning focus on general health advantages. The current study is the first controlled research examining the use of medical clowning in the therapy for children with ASD. Twenty-four children aged 2–6 years old with ASD enrolled in our special education intensive program were examined before and after group sessions with clown intervention (CI) and other intervention (OI). We tested stereotypic behaviors, verbal expression, play reciprocity, and social smiles. Data was collected during 12 weeks of intervention, and the trajectory of change was evaluated in addition to the pre-/post-intervention. Conclusion: improvement over time in all measures: Significant increase in word production, play reciprocity, and amount of social smiles during CI as compared with OI. We also found a reduction in frequency of stereotypic behaviors during and following CI as compared with before CI. These preliminary results indicate that medical clowning may be beneficial for young children with ASD, since it promotes communication and social reciprocity in a fun and lively interventional setting. What is Known: • Many therapies are used and proven as efficacious interventions for children with ASD. • So far, medical clowning was not tested as an intervention or therapy for ASD. What is New: • Medical clowning sessions with children with ASD elicited enhanced communication during the interventions as compared with other interventions. • Medical clowning sessions contributed to a decrease in frequency of stereotypic movements over time, in children with ASD.

RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit—successes and challenges Abstract Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant's phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%. Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed. What is Known: • Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation. What is New: • This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES). • In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.

Influence of chronic diseases on the olfactory function in children Abstract The association between smell impairment and chronic diseases has been reported in some studies in adults. Such information is not available for chronic diseases in children. The aim of this study was to examine olfactory function of children with chronic diseases such as diabetes mellitus type 1, hypothyroidism, and bronchial asthma in combination with allergic rhinitis in comparison to healthy controls. The data were obtained from n = 205 participants (104 boys, 101 girls) between the age of 6 and 17 years. Seventy-eight of the participants were healthy controls, n = 43 had diabetes mellitus type 1, n = 50 suffer from allergic rhinitis or bronchial asthma, and 34 presented a reduced function of their thyroid in medical history. All participants underwent olfactory testing including olfactory threshold using "Sniffin' Sticks" and odor identification using the "U-Sniff" test. In addition, a depression inventory and cognitive testing using the Ravens Progressive Matrices was performed. No significant difference in olfactory function was observed for any of the chronic diseases in children in comparison to healthy controls. Further analysis showed a trend in significance for a subpopulation of children with bronchial asthma and comorbidities performed worse on the olfactory threshold test compared to patients with bronchial asthma without comorbidities. Pediatric patients suffering from chronic diseases scored higher on the depression inventory compared to healthy controls. Conclusion: In conclusion, this study demonstrates that the influence of chronic diseases (bronchial asthma, diabetes mellitus type 1 and hypothyroidism) on olfactory function in childhood, if any, seems to be insignificant. This is partly in contrast to adult patients. Further research should be conducted in a subgroup of patients with bronchial asthma, allergic rhinitis, and atopic dermatitis or other comorbidities to better understand the association of allergic diathesis and olfactory function and the putative pathogenesis of olfactory dysfunction. What is known: • The association between smell impairment and chronic diseases has been reported in some studies in adults. • Such information is not available for chronic diseases in children. What is new: • The influence of chronic diseases (bronchial asthma, diabetes mellitus type 1, and hypothyroidism) on olfactory function in childhood, if any, seems to be insignificant. • In patients with bronchial asthma and allergic rhinitis, only a subgroup of patients with additional comorbidity (atopic dermatitis) showed a tendency to a reduced sense of smell.

Diaphragm electromyography results at different high flow nasal cannula flow rates Abstract Heated, humidified, high-flow nasal cannula (HHHFNC) is increasingly being used, but there is a paucity of evidence as to the optimum flow rates in prematurely born infants. We have determined the impact of three flow rates on the work of breathing (WOB) assessed by transcutaneous diaphragm electromyography (EMG) amplitude in infants with respiratory distress or bronchopulmonary dysplasia (BPD). Flow rates of 4, 6 and 8 L/min were delivered in random order. The mean amplitude of the EMG trace and mean area under the EMG curve (AEMGC) were calculated and the occurrence of bradycardias and desaturations recorded. Eighteen infants were studied with a median gestational age of 27.8 (range 23.9–33.5) weeks and postnatal age of 54 (range 3–122) days. The median flow rate prior to the study was 5 (range 3–8) L/min and the fraction of inspired oxygen (FiO2) was 0.29 (range 0.21–0.50). There were no significant differences between the mean amplitude of the diaphragm EMG and the AEGMC and the number of bradycardias or desaturations between the three flow rates. Conclusions: In infants with respiratory distress or BPD, there was no advantage of using high (8 L/min) compared with lower flow rates (4 or 6 L/min) during support by HHHFNC. What is known: • Humidified high flow nasal cannulae (HHHFNC) is increasingly being used as a non-invasive form of respiratory support for prematurely born infants. • There is a paucity of evidence regarding the optimum flow rate with 1 to 8 L/min being used. What is new: • We have assessed the work of breathing using the amplitude of the electromyogram of the diaphragm at three HHHFNC flow rates in infants with respiratory distress or BPD. • No significant differences were found in the EMG amplitude results or the numbers of bradycardias or desaturations at 4, 6 and 8 L/min.

The role of sleep-related cognitive functions in the spectrum of benign epilepsy with centro-temporal spikes Abstract Heterogeneous cognitive deficits have been described in the spectrum of benign epilepsy with centro-temporal spikes, which strongly correlate with the intensity of interictal epileptiform discharges and its spreading, in particular during sleep, mostly within the perisylvian cognitive network. The aim of this review is to discuss current findings regarding the connection between sleep alterations and cognitive function in the spectrum of benign epilepsy with centro-temporal spikes. A longer sleep onset latency is the only evident sleep macrostructure alteration reported in the spectrum of benign epilepsy with centro-temporal spikes. On a microstructural level, a higher spike count of descending compared to ascending slopes of sleep cycles, an impairment of slow wave downscaling, and amplitude and slope of slow waves were found in the spectrum of benign epilepsy with centro-temporal spikes. Moreover, children with benign epilepsy with centro-temporal spikes had a reduced non-rapid eye movement sleep instability, in terms of cyclic alternating pattern, similar to that found in children with attention-deficit hyperactivity disorders and in children with obstructive sleep apnea and centro-temporal spike during sleep. Children with benign epilepsy with centro-temporal spikes have a known comorbidity with attention-deficit hyperactivity disorders and obstructive sleep apnea. Conclusion: Considering the common sleep microstructure alterations, the presence of attention deficit and hyperactivity and/or sleep apnea may be a considered warning sign in the case of benign epilepsy with centro-temporal spikes. What is Known: • Sleep related-cognitive deficits have been described in the spectrum of benign epilepsy with centro-temporal spikes. The degree of sleep alterations may predict the neurocognitive outcome, and help clinicians to choose the right treatment. What is New: • Considering the common sleep microstructure alterations, attention deficit and sleep apnea, may be a considered warning signs.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Clinical Pharmacology

The misleading use of the term pragmatic in pre-licensing medicine trials

Promising effects of moderate-dose corticosteroid therapy in the blanking period for prevention of atrial fibrillation (AF) recurrences in patients undergoing AF ablation

Effects of guggulsterones-containing thermogenic complex on elvitegravir plasma concentrations: a case report

Medication and medical diagnosis as risk factors for falls in older hospitalized patients Abstract Objective To examine the impact of medication and medical conditions on the fall risk in older hospitalized patients. Design Matched case-control study. Setting Large regional hospital in a mid-sized German city. Subjects Four hundred eighty-one inpatients aged ≥ 65 years who fell during hospitalization ("cases") and a control group of 481 controls, matched for age, gender, and hospital department. Methods Diagnosis, medication, vital parameters, and injuries were compared between cases and controls. Univariate and multivariable odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated. Main results Several drugs were significantly associated with falls in multivariate analyses: long-acting benzodiazepines (adjusted OR = 3.49; 95%-CI = 1.16–10.52), serotonin-noradrenalin reuptake inhibitors (SNRI) (2.57; 1.23–5.12), Z-drugs (2.29; 1.38–3.59), low-potency neuroleptics (1.87; 1.08–3.23), ACE inhibitors/sartans (1.42; 1.07–1.89). Digoxin (0.32; 0.11–0.99) and aldosterone receptor antagonists (0.54; 0.33–0.88) were negatively associated with falls. No significant association in multivariate analyses was found for short- and intermediate-acting benzodiazepines, mirtazapine, and opioids. Hyponatremia (1.52; 1.15–2.03) and leukocytosis (1.39; 1.05–1.87) in blood examination on admission showed significant association with falls. As secondary diagnoses, Parkinson syndrome (2.38; 1.27–4.46) and delirium (3.74; 2.26–6.21) were strongly associated with falls. The use of more than one psychoactive drug was a separate risk factor for falls (p < 0.0001). Conclusion Several drugs including SNRI, neuroleptics, and Z-drugs showed a significant association with inpatient falls. The frequently prescribed tetracyclic antidepressant mirtazapine did not appear to increase the risk of falls. Psychoactive polypharmacy should be avoided.

Half-dose ticagrelor versus high-dose clopidogrel in reducing platelet reactivity in acute coronary syndrome patients with high on-clopidogrel platelet reactivity (divide study) Abstract Purpose High on-treatment platelet reactivity (HTPR) after clopidogrel administration in patients with acute coronary syndrome (ACS) has been associated with an increased risk of adverse events. Our previous studies reported that half-dose ticagrelor provides a similar inhibitory effect on adenosine diphosphate (ADP)–induced platelet aggregation as standard-dose ticagrelor, but half-dose of ticagrelor has not been studied in Chinese ACS patients with HTPR. This study aimed to compare the antiplatelet action of half-dose ticagrelor with high-dose clopidogrel in ACS patients with HTPR. Methods In this single-center randomized controlled trial, 80 (of 418 screened, 19.13%) ACS patients with HTPR while on clopidogrel were randomized to either half-dose ticagrelor (90 mg LD, then 45 mg twice daily) or high-dose clopidogrel (150 mg once daily). Platelet function was assessed by thromboelastography (TEG) and light transmission aggregometry (LTA), and adverse events were monitored throughout the study for 30 days. Results The ADP-induced platelet inhibition rate (IR) as measured by TEG was significantly higher for half-dose ticagrelor compared with high-dose clopidogrel (70.40% [61.10%–91.70%] vs. 44.25% [34.67%–79.07%], p = 0.001). The repeated HTPR rate was dramatically higher for high-dose clopidogrel compared with half-dose ticagrelor (6 of 32, 18.75% vs. 1 of 35, 2.85%; p = 0.04). No patients in either treatment group exhibited a major bleeding event or other adverse events. Conclusions In ACS patients with HTPR, half-dose ticagrelor is more effective than high-dose clopidogrel in reducing platelet reactivity (NCT03062462).

Pharmacokinetics of venlafaxine in treatment responders and non-responders: a retrospective analysis of a large naturalistic database Abstract Purpose To assess in a large naturalistic sample, whether clinical response to a treatment with venlafaxine is associated with different patterns of plasma concentrations of active moiety, AM (sum of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN)). Methods Applying a regression model, plasma concentrations and plasma concentrations corrected-by-dosage (C/D) for AM were included as independent variable with Clinical Global Impressions-Improvement (CGI-I) scale ratings as dependent variable. Moreover, AM, VEN, and ODVEN were compared between treatment responders and non-responders, defining response as much or very much improved on the CGI-I scale based on the non-parametric Mann-Whitney U (M-W-U) test with a significance level of 0.05. Results No correlations were found between AM and C/D AM plasma concentrations and CGI-I ratings (regression coefficient 0.0, CI 0.000, 0.001, p = 0.492 for AM and 0.047, CI − 0.065, 0.159, p = 0.408 for C/D AM). Venlafaxine daily dosage did not differ between responders and non-responders (217.7 ± 76.9 vs. 222.0 ± 72.7 mg/day, p = 0.45 for M-W-U). Responders displayed lower ODVEN (p = 0.033) and AM (p = 0.031) plasma concentrations than non-responders (p = 0.033 and 0.031, respectively for M-W-U). No other differences were detected. Using a cut-off level of 400 ng/mL for AM concentrations, a higher percentage of responders was reported in the group of patients with AM < 400 ng/mL (13.04%) compared to patients with AM > 400 ng/mL (8%) (p = 0.038). Conclusions Higher ODVEN and AM concentrations in non-responders than in responders indicate that treatment escalation above upper thresholds of therapeutic reference ranges of venlafaxine is not promising. Hence, the therapeutic reference range for venlafaxine can help in improving outcomes in a measurement-based care model that takes advantage of therapeutic drug monitoring.

The effect of ketoconazole on praziquantel pharmacokinetics and the role of CYP3A4 in the formation of X-OH-praziquantel and not 4-OH-praziquantel Abstract Aim The study sought to determine the effect of ketoconazole (KTZ) on the pharmacokinetics of praziquantel (PZQ) and on the formation of its major hydroxylated metabolites, cis- and trans-4-OH-PZQ, and X-OH-PZQ in healthy subjects. Methods Two treatments were evaluated by single-dose PK studies; the reference treatment was a 20 mg/kg dose of praziquantel given alone. The test treatment was a 20 mg/kg dose of praziquantel given in combination with 200 mg of ketoconazole. The study had a balanced and randomised cross-over design. Serial blood samples were collected between 0 and 12 h after each drug administration. PZQ, and cis- and trans-4-OH-PZQ and X-OH-PZQ concentrations in plasma were determined by LC-MS. A non-compartmental approach was used for pharmacokinetic analysis. Data were analysed using ANOVA and assessment of the 90% confidence interval of the geometric means of the log-transformed PK parameters obtained for each treatment. Results The pharmacokinetics of PZQ following the two treatments, PZQ alone and PZQ + KTZ, were not equivalent based on the assessment of the 90% CI of the geometric mean ratios of the AUC and Cmax (α = 0.05). The geometric mean ratios of the AUC and Cmax were found to be 176.8% and 227% respectively. The 90% CI of the AUC and Cmax were found to be 129.8%–239.8% and 151.4%–341.4% respectively. The AUC of PZQ was increased by 75% with KTZ co-administration (3516 vs 6172 ng h/ml) (p < 0.01). Meanwhile, the mean AUC of trans-4-OH-PZQ increased by 67% (61,749 ng h/ml vs 103,105 ng h/ml) (p < 0.01). X-OH-PZQ levels were reduced by about 57% (semi-quantified as 7311 ng h/ml vs 3109 ng h/ml by using trans-4-OH as standards) (p < 0.01) with KTZ co-administration. Conclusions The relative bioavailability of praziquantel was increased by concomitant KTZ administration. KTZ preferentially inhibited the formation of X-OH-PZQ rather than 4-OH-PZQ, confirming in vitro data which implicates CYP3A4 in the formation of X-OH-PZQ rather than 4-OH-PZQ. The 4-hydroxylation of PZQ was shown to be the major metabolic pathway of PZQ, as evidenced by larger quantities of 4-OH-PZQ produced, thus explaining the modest albeit significant effect of ketoconazole on PZQ pharmacokinetics.

Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement Abstract Purpose Establishment of causality between drug exposure and adverse drug reactions (ADR) is challenging even for serious ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Several causality assessment tools (CAT) exist, but the reliability and validity of such tools is variable. The objective of this study was to compare the reliability and validity of existing ADR CATs on SJS/TEN cases. Methods Seven investigators completed three CAT (ALDEN, Naranjo, Liverpool) for 10 SJS/TEN cases. Each CAT categorized the causality of 30 potential drugs as definite/very probable, probable, possible, or doubtful/unlikely. An additional reviewer provided expert opinion by designating the implicated drug(s) for each case. A Kappa score was generated to compare CAT responses both by method (reliability of all 7 reviewers, by CATs) and by reviewer (reliability of the 3 CAT, by reviewer). A c statistic was calculated to assess validity. Results Inter-rater reliability by CAT was poor to fair: ALDEN 0.22, Naranjo 0.11, and Liverpool 0.12. Reliability was highest when causality classification was definite/very probable (0.16–0.41). Similarly, intra-rater reliability by reviewer was poor. When comparing the validity of the overall CAT to expert reviewer, area under the curve was highest for ALDEN (c statistic 0.65) as compared to Liverpool (0.55) or Naranjo (0.54). Conclusion Available CAT have poor reliability and validity for drug-induced SJS/TEN. Due to the importance of determining ADR causality for research, industry, and regulatory purposes, development of an enhanced tool that can incorporate data from immunological testing and pharmacogenetic results may strengthen CAT usefulness and applicability for drug-induced SJS/TEN.

Safety aspects of antiepileptic drugs—a population-based study of adverse effects relative to changes in utilisation Abstract Purpose Antiepileptic drugs (AEDs) are increasingly used, and knowledge about adverse effects is scarce based on clinical studies. The purpose of the present study was to characterise adverse effects reports of AEDs in Norway relative to changes in utilisation in various indications from population-based data to elucidate important safety aspects of use of AEDs. Methods Aggregated data of adverse effects reported for AEDs in Norway from the EudraVigilance-database (2004–2013) in addition to indication-specific use of AEDs during 2004–2015 from the Norwegian Prescription Database were used. Results The use of AEDs increased twofold the last decade due to use in psychiatry and neuropathic pain: lamotrigine, pregabalin, gabapentin, valproate, and carbamazepine. There were 1593 adverse effects reported (403 Individual Case Safety Reports, 2/3 women), 0–95 years (mean 46). Most adverse effects were reported for pregabalin (593), carbamazepine (265), lamotrigine (206), gabapentin (144), and valproate (119), where pregabalin had by far the highest reports in relation to the number of users. The most frequently reported adverse drug effects included rash, dizziness, cross-sensitivity reactions, and pyrexia. Overall, nervous system disorders constitute the largest organ class with the majority of the reports. Reporting of fatal outcomes is mandatory, and sudden unexplained death in epilepsy (SUDEP) was reported in 34 occasions. Conclusions This study demonstrates that most adverse effects reported concerned AEDs increasingly used in non-epilepsy indications: neuropathic pain (pregabalin, gabapentin, carbamazepine) and psychiatry (lamotrigine, valproate, carbamazepine). Pregabalin had the highest prevalence of adverse effects reported in relation to number of users. This elucidates an important part of pharmacovigilance for improved safety and considerations in clinical practice.

The effect of L-carnitine on inflammatory mediators: a systematic review and meta-analysis of randomized clinical trials Abstract Aim and background Reducing inflammation by nutritional supplements may help to reduce the risk of many chronic diseases. Our aim in this meta-analysis was to determine the effect of L-carnitine on inflammatory mediators including C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Methods Our systematic search to find relevant randomized clinical trials (RCTs) was performed up to October 2018 using ISI Web of Science, Google Scholar, PubMed/Medline, and SCOPUS. In this meta-analysis, the weighted mean differences (WMD) with standard errors (SE) were used to pool the data. WMD was calculated by subtracting change-from-baseline mean values in the control group from change-from-baseline mean values in the intervention group in each study. To identify heterogeneity among studies, the I2 statistic was employed. The protocol was registered with PROSPERO (No. CRD42019116695). Results Thirteen articles were included in our systematic review and meta-analysis. The results of the meta-analysis indicated that L-carnitine supplementation was significantly associated with lower levels of CRP in comparison to controls (WMD = −1.23 mg/L; 95% CI: −1.73, −0.72 mg/dL; P < 0.0001). Also, a slight but statistically significant decrease was observed in IL-6 and TNF-α levels (WMD = −0.85 pg/dL; 95% CI: −1.38, −0.32 pg/dL; P = 0.002 and WMD = −0.37 pg/dL; 95% CI: −0.68, −0.06 pg/dL; P = 0.018, respectively). Conclusion Our results indicate that L-carnitine reduced inflammatory mediators, especially in studies with a duration of more than 12 weeks. Further studies with different doses and intervention durations and separately in men and women are necessary.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Fetal Medicine

Cystic Lesion in the Fetal Scalp: A Systematic Approach Abstract During an anomaly scan, cystic lesion in the scalp may be encountered while examining the fetal head. Some of these originate from the scalp tissue and can be dealt with postnatally by simple excision. Others may be more than just scalp cysts and have an intracranial communication. The objective of this communication is to illustrate a few cystic lesions in the fetal scalp and suggest a systematic approach in arriving at a diagnosis.

Role of TUI in First Trimester Evaluation of Palate Abstract The purpose of the study is to report on the application of tomographic ultrasound imaging (TUI) in prenatal sonographic study of fetal palate in 11–14 week scan. TUI is a technology that allows the examiner to obtain a volume data set that allows the display of numerous 2D slices from a given volume on any of the three orthogonal planes. It allows automatic slicing of the volume datasets displaying multiple parallel images. The fetal palate was examined with TUI in thirteen abnormal volumes and in ninety-four normal volumes. The appearance of maxillary line in sagittal sections and the base of the retronasal triangle in coronal sections serve as key landmarks in evaluating palatine clefts. The intact palatal line in sagittal sections was observed in all the ninety-four normal volumes. The midline anatomy of the palate has been described in the study emphasising that the vomer can mimic palate in midsagittal section in secondary palatine clefts. The parasagittal sections truly reflects the presence or absence of the palate without the confounding factor of the vomer bone which was demonstrated in the abnormal volumes with TUI. The potential advantage of TUI in evaluating palate is that it allows the display of both midsagittal and parasagittal sections simultaneously. The different types of cleft have a constant reproducible pattern in TUI imaging which can be used to diagnose palatine clefts including isolated cleft of palate. Prospective studies are needed to confirm these promising results.

Antenatal Presentation of TMEM5 Gene-Associated Congenital Muscular Dystrophy Expanding the Phenotypic and Genotypic Spectrum Abstract We describe a clinicoautopsy phenotype of an occipital skull defect, ventriculomegaly, agenesis of corpus callosum and Dandy Walker Malformation (DWM) with a novel single base insertion in the TMEM5 gene, known to cause Walker Warburg syndrome. The clinical features of DWM extends the phenotype, while the pathogenic variant observed expands the mutational spectrum of the syndrome. This case highlights the importance of detailed postnatal phenotyping after a pregnancy is discontinued for an antenatallly detected malformation. Fetal samples must also be preserved for genetic tests to allow an etiological diagnosis in these situations. It is important for the fetal medicine specialists to remember to test for single gene disorders, after a normal chromosomal microarray especially in case of recurrence of a disease in a family.

Two Dimensional Visualization of Optic Chiasma in Fetus Abstract The purpose of this study is to investigate methods to visualize and measure the fetal optic chiasma (OC) using transabdominal and/or transvaginal two-dimensional (2D) ultrasound in the coronal plane. The role of analyzing optic chiasma cannot be down scaled in prognosticating septo-optic dysplasia (SOD) and agenesis of septum pellucidum. This is a retrospective study of 117 random cases referred for various indications. The gestational age of the fetuses included in the study was between 19 and 37 weeks. The OC was visualized and measured in the 2D coronal plane with color Doppler by transabdominal and/or transvaginal routes. There were 97 normal low risk cases and 19 abnormal cases in the study. We conclude that it is possible to locate and measure OC width by transabdominal and transvaginal scans from 19 week onwards. It is possible to get equally good views by both, transabdominal and transvaginal routes.

Echogenic Kidneys as an Antenatal Clue to the Metabolic Etiology: A Case Report Abstract Antenatally diagnosed echogenic kidneys have several underlying etiologies such as aneuploidies, monogenic isolated or syndromic polycystic kidney disease, infections and rarely with inborn error of metabolism. Even a careful evaluation for additional abnormalities may not be able to provide a specific diagnosis. However with next generation sequencing, the diagnostic odyssey can be ended successfully. We report one such case of carnitine palmitoyltransferase II deficiency (CPT2) deficiency that manifested as isolated echogenic kidneys with early neonatal demise where successful early prenatal diagnosis was possible in the subsequent pregnancy.

First Trimester Diagnosis of Sirenomelia: A Case Report Abstract Sirenomelia or the mermaid syndrome is a rare and lethal congenital anomaly. It is characterized by fusion of lower extremities. It is associated with bilateral renal agenesis, anomalies of rectum, sacrum, cardiovascular system and abdominal wall. Pathognomic finding is a single umbilical artery, the 'persistent vitelline artery' which distinguishes sirenomelia from caudal regression syndrome. Sirenomelia has strong association with maternal diabetes mellitus. We report a case of sirenomelia diagnosed in first trimester. Early diagnosis was possible as protocol-based anatomic evaluation was performed. Diagnosis of sirenomelia is easier in first trimester as severe oligohydramnios in later gestation hampers the fetal evaluation.

Role of Autopsy in Diagnosis and Genetic Counselling of Congenital Malformations: a Prospective Analytical Study Abstract The study aimed to determine the role of autopsy in refining the antenatal diagnosis of fetal anomalies and its effect on genetic counseling. The objectives of the study were to correlate the findings of antenatal ultrasound with that of perinatal autopsy, to determine the contribution of autopsy in refining the antenatal diagnosis and whether it altered the genetic counseling. This was a prospective, non-interventional analytical study conducted in the Department of Obstetrics and Gynaecology, JIPMER with the approval of Institutional Ethics Committee. Fourty-six fetuses which were stillborn/aborted or expired in newborn period due to congenital malformations were included. The findings of antenatal ultrasound were correlated with postnatal autopsy findings. The genetic counselling based on antenatal findings were compared with that based on postnatal findings and any change in the counselling given were noted and analysed. More than 70% of anomalies among the 46 fetuses included in the study were detected by the mid trimester anomaly scan. Male predominance was seen in this study (24 male fetuses). A definitive diagnosis or documentation of anomalies by autopsy was possible in all 46 fetuses (100%). Single system anomalies were noted in 24 (52.17%) fetuses and multisystem involvement was observed in 19 (41.3%) fetuses. Among fetuses with multiple malformation syndrome, 15.8% of fetuses had probable single gene etiology, 26.3% were probably sporadic and 57.9% were unclassified. Autopsy was valuable in prenatal genetic counseling by confirming the USG findings with (5) or without additional information (30) in 35/46 (76.1%) cases and by changing the diagnosis in 11/46 (23.9%) cases. Autopsy led to refinement of the recurrence risk in 23.9% of cases (increased in 19.6% and decreased in 4.3%). From the present study, we conclude that the results demonstrate a good correlation between prenatal diagnosis by USG and post mortem diagnosis by autopsy. Prenatal ultrasound and postnatal autopsy are complementary and supplement each other. The value of autopsy in reconfirming the ultrasound finding and providing additional information is irrefutable. Though autopsy may not provide exact diagnosis or establish definitive etiology, it is an invaluable tool for genetic counseling in fetal anomalies.

Placento-Cranial Adhesion: A New Syndromic Association Abstract Cases of placento-cranial adhesion are rare and most of them are incompatible with life. A few case reports in the literature have included such cases under the overarching rubric of amniotic band syndrome. We present autopsy findings of four cases with gestation period ranging from 16 to 21 weeks. All of them displayed placenta-cranial adhesion, low weight for gestation, absence of flat bones of skull, anencephaly, dysmorphic facial features, short umbilical cord and limb/digit amputation with oligohydrambios. Three out of four showed nasal groove. We propose that there are grounds for syndromic association of the features mentioned above. Furthermore, it is important that whenever such cases are identified termination of pregnancy should be considered. The article also underscores the importance of fetal autopsies.

Looking Back at Fetal Medicine in India in 2018, and Looking Forward to 2019

Evaluating the Utility of Next Generation Sequencing Technology in the Diagnosis and Prevention of Genetic Disorders in India, the Early Experiences Abstract To describe the utilization of Next Generation Sequencing technologies for genetic counseling and prenatal diagnosis. Ten families requested prenatal testing in view of previously affected offspring with genetically heterogeneous/hitherto undiagnosed disorders. Next generation sequencing was offered as a first tier investigation (1) in the probands who had not been diagnosed by baseline investigations, and (2) in cases where preliminary examination/testing suggested a genetically heterogeneous disorder, while the precise diagnosis was not available. The subsequently identified molecular basis enabled prenatal testing. The disorders included primary microcephaly, epidermolysis bullosa, inborn error of metabolism, infantile hypotonia, neuro-regression and sensorineural hearing loss. Five out of ten couples approached us during an ongoing pregnancy with two in the second trimester of gestation. Demise of the proband resulted in incomplete investigations in three cases. In seven cases, the disorder suspected was genetically heterogeneous and hence next generation testing was carried out while in the remaining three it was performed to ascertain the underlying gene involved. Fetal analysis detected recurrences in two cases, and the couples concerned decided to discontinue the pregnancies. Next generation sequencing proved a useful tool in select situations to overcome some of the challenges hindering a precise diagnosis in genetically heterogenous disorders.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com