Development and validation of a score to assess transmural healing and response in patients with Crohn's disease.

BACKGROUND AND AIMS: As transmural healing (TH) could be the best therapeutic target in Crohn's disease (CD), we aimed to build and validate a score to assess TH and transmural response (TR), and to confirm their association with favorable CD outcomes. METHODS: DEVISE-CD project encompassed two retrospective cohorts (274 and 224 CD patients for development and validation phase, retrospectively) and one multicenter prospective validation cohort (N=46 patients). A step-by-step process was used to build the modified Clermont score (C-score). The primary endpoints were time to bowel damage progression, and steroid-free clinical remission with fecal calprotectin < 250 (CFREM) at one year for retrospective and prospective validation cohorts, respectively. RESULTS: Edema, ulcer, contrast enhancement, diffusion-weighted hyperintensity, fat wrapping, bowel thickening (>3 mm), and enlarged lymph nodes were associated to higher risk of bowel damage progression (p<0.01). Edema, diffusion-weighted hyperintensity, post-gadolinium contrast enhancement, and bowel thickening were highly coexistent (>95%) and collinear (p<0.0001). Bowel thickness had the highest sensitivity to change after treatment (SMD=0.30±1.0)(p=0.001). C-score was calculated as 0.2x(bowel thickness-3mm) + 1.5x enlarged lymph nodes + 2x ulcer. TH (C-score<0.5) (HR=0.28[0.13-0.63],p=0.002; aHR=0.15[0.04-0.53], p=0.003), TR50 (50%-decrease of C-score)(HR=0.30[0.15-0.63], p=0.001; aHR = 0.36[0.14-0.88], p=0.025) or TR25(25%-decrease of C-score)(HR=0.37[0.19-0.71], p=0.003; aHR=0.46[0.23-0.94], p=0.034) prevented bowel damage progression in development and validation cohorts, respectively. In the prospective validation cohort, achieving TH (OR=4.6[1.3-15.6], p=0.016), TR50 (OR=6.9[1.8-26.0], p=0.008) or TR25 (OR=6.0[1.6-22.3], p=0.008) after 12 weeks of anti-TNF therapy led to higher rate of CFREM at one year. CONCLUSION: C-score is a validated, reliable and easy-to-use tool to assess TH and TR in CD patients.

Targeting Breast Cancer with N-Acetyl-D-Glucosamine: Integrating Machine Learning and Cellular Assays for Promising Results.

BACKGROUND: Breast cancer is a common cancer with high mortality rates. Early diagnosis is crucial for reducing the prognosis and mortality rates. Therefore, the development of alternative treatment options is necessary. OBJECTIVE: This study aimed to investigate the inhibitory effect of N-acetyl-D-glucosamine (D-GlcNAc) on breast cancer using a machine learning method. The findings were further confirmed through assays on breast cancer cell lines. METHODS: MCF-7 and 4T1 cell lines (ATCC) were cultured in the presence and absence of varying concentrations of D-GlcNAc (0.5 mM, 1 mM, 2 mM, and 4 mM) for 72 hours. A xenograft mouse model for breast cancer was established by injecting 4T1 cells into mammary glands. D-GlcNAc (2 mM) was administered intraperitoneally to mice daily for 28 days, and histopathological effects were evaluated at pre-tumoral and post-tumoral stages. RESULTS: Treatment with 2 mM and 4 mM D-GlcNAc significantly decreased cell proliferation rates in MCF-7 and 4T1 cell lines and increased Fas expression. The number of apoptotic cells was significantly higher than untreated cell cultures (p < 0.01 - p < 0.0001). D-GlcNAc administration also considerably reduced tumour size, mitosis, and angiogenesis in the post-treatment group compared to the control breast cancer group (p < 0.01 - p < 0.0001). Additionally, molecular docking/dynamic analysis revealed a high binding affinity of D-GlcNAc to the marker protein HER2, which is involved in tumour progression and cell signalling. CONCLUSION: Our study demonstrated the positive effect of D-GlcNAc administration on breast cancer cells, leading to increased apoptosis and Fas expression in the malignant phenotype. The binding affinity of D-GlcNAc to HER2 suggests a potential mechanism of action. These findings contribute to understanding D-GlcNAc as a potential anti-tumour agent for breast cancer treatment.

Awareness of patients with impacted teeth about impacted teeth in Turkey: A questionnaire study.

Objective: The aim of this study is to evaluate the knowledge and awareness levels of patients who have at least one impacted tooth and who had previously applied to the dentist. Study design: This study was conducted in patients aged 15 years and older who applied to Ordu University Faculty of Dentistry for routine examination and agreed to fill out the questionnaire form. A total of 325 people participated in the survey conducted to determine the awareness of patients applying to the faculty of dentistry about their existing impacted teeth. A Pearson's chi-square test was used for hypothesis testing when expected frequencies exceeded 5. Results: It was determined that 56.9 % (185) of the participants were aware of their existing teeth, while 43.1 % (140) were not aware. When the patients were evaluated according to the institutions they had visited, it was seen that the group who were most aware of the presence of impacted tooth were those who apply to the faculty of dentistry (74.4 %). The rate of being informed by dentists in the institutions that they had previously visited was higher in patients with university or post-university graduates (p < 0.05). The most common information given by the dentists to the patients about their impacted dental problems was that the tooth should be followed up (40.4 %), while the removal of the tooth constituted 28.4 % of the information given. Conclusion: This study showed that although patients are aware of their existing impacted teeth, their level of knowledge about the risks it may pose is low. For a healthy oral care and health, patients should be adequately informed about impacted teeth.

Anti-TNF Agents Restrict Adherent-invasive Escherichia coli Replication Within Macrophages Through Modulation of Chitinase 3-like 1 in Patients with Crohn's Disease.

BACKGROUND AND AIMS: The mechanism of action of anti-tumour necrosis factor [anti-TNF] agents could implicate macrophage modulation in Crohn's disease [CD]. As CD macrophages are defective in controlling CD-associated adherent-invasive Escherichia coli [AIEC], anti-TNF agents could limit AIEC replication within macrophages. We assessed the effect of anti-TNF agents on AIEC survival within monocyte-derived macrophages [MDMs] from CD patients and attempted to identify the proteins involved. METHODS: Peripheral blood MDMs were obtained from 44 CD patients [22 with and 22 without anti-TNF agents]. MDMs were infected with reference strain AIEC-LF82. Proteomic analysis was performed before and 6 h after AIEC-LF82 infection. RESULTS: AIEC-LF82 survival was lower in MDMs from CD patients receiving anti-TNF agents compared to those who did not [-73%, p = 0.006]. After AIEC-LF82 infection, the levels of CD82 [p = 0.007], ILF3 [Interleukin enhancer-binding factor 3; p = 0.001], FLOT-1 [Flotillin-1; p = 0.007] and CHI3L1 [Chitinase 3-like 1; p = 0.035] proteins were different within CD-MDMs depending on anti-TNF exposure. FLOT-1 [ϱ = -0.44; p = 0.038] and CHI3L1 [ϱ = 0.57, p = 0.006] levels were inversely and positively correlated with AIEC survival within MDMs from CD patients with or without anti-TNF, respectively. We observed a dose-dependent decrease of AIEC-LF82 survival after adjunction of anti-TNF within MDMs, inducing an increase of FLOT-1 and decrease of CHI3L1 mRNA levels. Neutralization of intra-macrophagic CHI3L1 protein using anti-CHI3L1 antibodies reduced AIEC survival within macrophages 6 h after infection [p < 0.05]. CONCLUSION: Anti-TNF agents are able to restrict replication of pathobionts, such as AIEC, within macrophages by modulating FLOT-1 and CHI3L1 expression in CD patients.

Pharmacist's role in HIV care in France. Implication for clinical improvement of people living with HIV worldwide.

In France, antiretroviral (ARV) treatment can be dispensed by hospital and/or community pharmacies. Since January 2016, an online patient medication file can be used to optimize dispensing, but medication interviews have not yet been incorporated into this system. To understand both people living with HIV (PLHIV) and their pharmacists' habits and expectations of patient medication file and interviews, two consecutive national surveys were organized. The first one, carried out in October 2016 in care centers, was an anonymous questionnaire for PLHIV. The second one was an online survey for community and hospital pharmacies conducted in February 2017. A total of 1137 PLHIV (68% men, of mean age 50.2 ± 11.5 years, CD4 count 671 ± 354, 90% with undetectable HIV viral load (VL) and 64.2% reporting comorbidities) and 246 pharmacies responded. While the existence of the online medication file is known by 58% of PLHIV, only 40% of pharmacists declare it to be systematically offered. It was offered to 120/694 (17%) PLHIV and 96 (80%) accepted it. Currently, 78 (7%) PLHIV feel well taken care of because they are offered medication interviews, 343/1078 (32%) would like to take advantage of this program, mainly those with a shorter ARV duration (OR ARV duration 0.97 [0.95-0.99]), a VL less often undetectable (OR undetectable VL 0.55 [0.31-0.98]), and those who feel anxious more often (OR anxious 2.38 [1.48-3.84]). These results suggest that better implementation of medication files and interviews will strengthen current clinical pathways.

Clinical, virological and immunological features of HIV-positive children internationally adopted in France from 2005-2015.

OBJECTIVE(S): To describe the clinical, virological and immune characteristics of internationally adopted children on arrival in France and after 6-months follow-up. DESIGN: Multicenter retrospective study. METHODS: 30 centers from 24 cities were asked to include, after informed consent, HIV+ children living in France and internationally adopted between 1st Jan 2005 and 1st Jan 2015. Sociodemographic, medical and biological variables collected during the first medical evaluation in France and 6 months later were analyzed. RESULTS: 41 HIV+ adoptees were included (female: 56%; median age: 3.91 years) in 14 centers. Adoptees tend to represent an increasing part of newly diagnosed HIV positive children over the years. The majority came from East-Asia. At arrival, one child was diagnosed with lymphobronchial tuberculosis and three with latent chronic hepatitis B, cleared HBV infection and chronic active hepatitis C, respectively. The mean CD4% was 32.8 ± 9% (range: 13-49%). The 34 children (83%) have been initiated on treatment from their countries of origin. Of these, 25 (74%) had an undetectable viral load (VL) on arrival. Resistance to ART was detected in five. At 6 months, 36 adoptees received ART, and the VL was undetectable in 29 children (71%), with one acquired resistance to NRTI & NNRTI. CONCLUSIONS: An increasing number of HIV-infected children have been internationally adopted in France since 2005. Most of the children have been initiated on treatment from their countries of origin, had good immunity, with few opportunistic infections, and infrequently detectable VL. Low level of mutation conferring resistance was detected.

Pentraxin 3 concentrations of the mothers with preterm premature rupture of membranes and their neonates, and early neonatal outcome.

BACKGROUND: Pentraxin 3 (PTX3) is an acute phase reactant which has been used to detect intra-amniotic infections (IAI) in pregnancy, but the prognostic value of PTX3 concentrations on neonates has not been studied. We aimed to investigate the relationship between maternal PTX3-neonatal PTX3 concentrations and early neonatal outcome. METHODS: The mothers diagnosed with preterm prelabor rupture of membranes (PPROM) (n = 28) and their preterm infants (n = 28) were included in the study. PTX3 concentrations were studied in plasma in the maternal peripheral blood and umbilical/peripheral vein in the neonates. The relationship between the mPTX3-nPTX3 concentrations and neonatal outcome were investigated using non-parametric tests and binary logistic regression analysis. RESULTS: The mean mPTX3 concentration was 10.35 ± 7.82 µg/L. Ten (35.7%) of all mothers were within the normal range and 18 (64.3%) in high percentile (≥ 97.5 percentile). There was no relation between mPTX3 concentrations and clinical or histologic chorioamnionitis, latency of PPROM, and early neonatal outcome. Mean nPTX3 concentrations was 9.18 ± 7.83 µg/L and high nPTX3 concentrations were detected in five (17.8%) neonates. nPTX3 concentrations were inversely correlated with gestational age and correlated with rate of intraventricular hemorrhage (IVH) and mortality. Neonates with high nPTX3 concentrations also have lowered APGAR scores, increased rate of respiratory distress syndrome, clinical sepsis, IVH, necrotizing enterocolitis and prolonged NICU stay. CONCLUSION: High PTX3 concentrations of the newborns are associated with some worsened early neonatal outcome including lower gestational age at delivery, increased rate of IVH and mortality. Maternal PTX3 concentrations are not an adequate marker in defining clinical or histologic chorioamnionitis and early neonatal outcome.

Dietary curcumin inhibits atherosclerosis by affecting the expression of genes involved in leukocyte adhesion and transendothelial migration.

SCOPE: The aim of the study was to examine the atheroprotective effect of dietary curcumin in a mouse model of atherosclerosis and to identify its cellular and molecular targets at the vascular level. METHODS AND RESULTS: ApoE(-/-) mice were fed with curcumin at 0.2% (wt/wt) in diet for 4 months. This supplementation reduced the extent of atherosclerotic lesion by 26% and induced changes in expression of genes implicated in cell adhesion and transendothelial migration or cytoskeleton organization, as revealed by a transcriptomic analysis in the aorta. Expression profile of these genes suggests reduction in both leukocyte adhesion and transendothelial migration. In agreement with this hypothesis, we observed a reduction (-37%) in macrophage infiltration in the plaque, as measured by immunohistochemistry, and, in vitro, a lower adhesion of monocytes to TNF-α-stimulated endothelial cells (-32%) after exposure to a nutritionally achievable concentration of curcumin. These changes in gene expression could be related to the observed increased expression of IκB protein and decrease of TNF-α-induced NF-κB/DNA binding and NF-κB-transcriptional activity upon exposure to curcumin. CONCLUSION: Our findings pointed out that the antiatherogenic effect of curcumin could be linked to its effect on gene networks and cell functions related to leukocyte adhesion and transendothelial migration via NF-κB-dependent pathways.

Body weight, length and head circumference at birth in a cohort of Turkish newborns.

OBJECTIVE: Intrauterine growth references are primarily useful indicators in the assessment of the general health status of newborn infants. Although Lubchenco's references are still used in many neonatal care units, we believe that there is a need for up-to-date intrauterine growth references specific for different populations. To develop gestational age-and gender-specific national references for birth weight, birth length and head circumference. METHODS: Data were collected from neonatal records of perinatology services of eleven hospitals from January to December 2009. The anthropometry of a total of 4750 singleton live births born between 28 and 41 weeks of gestation were recorded. Means and standard deviations were calculated, and percentiles for each gender and gestational week were produced using the LMS program. The results were compared with US infants and also with local data. RESULTS: Gestational age- and gender-specific 3rd, 5th, 10th, 15th, 25th, 50th, 75th, 85th, 90th, 95th and 97th percentile values were produced. Comparison of the 10th, 50th and 90th percentile values showed that the boys were heavier and longer than the girls. Head circumference values were also higher in the boys. Proportions of small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) infants in the sample were 10.1%, 79.1% and 10.8%, respectively. CONCLUSION: These gender- and gestational age-specific references will be of use in clinical practice and also for research purposes until more comprehensive, reliable and accessible national data pertaining to the intrauterine growth of Turkish infants are produced.

Multiple intraoral teratoma in a newborn infant: epignathus.

Teratomas originating from the oral cavity are named as epignathus. It is a rare type of teratoma. An 11-day old male newborn was diagnosed with cleft palate and intraoral masses. The mass on the right side was protruding from the mouth. Another one on the left side was extending from the nasopharynx to the oropharynx. The diagnosis of mature teratoma was made based on the histopathological study of surgically excised masses. We desired to report on this case since multiple localized epignatus in a newborn with cleft palate has not been described yet in the literature.

Post-operative subcutaneous fat necrosis in a newborn: a case report.

Subcutaneous fat necrosis of the newborn (ScFN) is an uncommon condition of neonates and infants. The disorder is caused by generalized and local tissue hypoperfusion. The ScFN tends to improve spontaneously with or without some severe complications such as hypercalcemia. The ScFN may occur as iatrogenic after hypothermic surgical interventions. We present iatrogenic ScFN in a newborn with uncomplicated hypercalcemia due to cold exposure on operating table during at an umbilical cord hernia operation. To our knowledge, this is the first report of a patient in whom ScFN occurred during a commonly performed and relatively short-term "nonhypothermic" operation.

A novel mutation in the MC2R gene causing familial glucocorticoid deficiency type 1.

Familial glucocorticoid deficiency (FGD) or hereditary unresponsiveness to adrenocorticotropin (ACTH) is an autosomal recessive disorder characterized by isolated glucocorticoid deficiency associated with normal mineralocorticoid secretion. Mutations in genes encoding either ACTH receptor or melanocortin 2 receptor accessory protein are responsible for the disease in about 50% of cases, named FGD type 1 and type 2, respectively. Patients may present with hyperpigmentation, recurrent infections, failure to thrive, hypoglycemic seizures, and coma in infancy or early childhood. Here we report the case of a 17-day-old newborn diagnosed with FGD type 1 who presented with hyperbilirubinemia and hyperpigmentation, a sign which was erroneously assumed to be due to prolonged phototherapy by the referring physician. Hormone analysis showed low cortisol and high ACTH levels with normal serum electrolytes and renin-aldosterone axis. Genetic analysis revealed a novel homozygous melanocortin 2 receptor mutation p.Leu225Arg in the patient. The healthy parents were heterozygous for the mutation.

Intrahepatic and adrenal hemorrhage as a rare cause of neonatal anemia.

Vaginal delivery of the macrosomic fetus may result in hemorrhage of intra-abdominal organs. Mostly affected organs are the liver and adrenal glands. Hemorrhage of liver is usually occurs as a subcapsular hemorrhage and it is clinically presented an abdominal mass without symptoms of anemia. But intraparenchymal hemorrhage of liver is very rare and there is no sign of abdominal mass. However, in contrast to subcapsular hemorrhage, symptoms of anemia are rapidly developed in newborns. A macrosomic newborn by vaginal delivery at term. Within 6 h after delivery, the patient showed pallor without tachycardia and hypotension. In laboratory studies, hemoglobin level failed from 14 g/dL to 10 g/dL within 6 h. Physical examination revealed no signs of abdominal mass. Intraparenchymal hemorrhage in the sixth segment of liver and right adrenal hemorrhage were detected on the ultrasonographic scan. Hepatic function tests were normal in the whole follow-up period, and hemorrhage resolved within two weeks. Following months after discharge, adrenal hemorrhage also resolved without any complication. Hepatic hemorrhages, causing hemorrhagic anemia in neonates, usually occur in subcapsular form. Intraparenchymal hepatic hemorrhage should especially be considered in those newborns, which are rapidly developed symptoms of anemia without any abdominal mass.

Aortic intima-media thickness in nicotine-exposed rat pups during gestation and lactation period.

There have been several studies confirming an association between maternal smoking during pregnancy and low birth weight. The detrimental effect of nicotine exposure beginning in fetal life continues during lactation, in infancy and in the early childhood period. In our previous studies, we found increased aortic intima-media thickness (aIMT) as a preatherosclerotic lesion in neonates with intrauterine growth restriction and in infants of smoking mothers. We aimed to evaluate histopathologically the effect of nicotine exposure during pregnancy and lactation period on fetal growth and aIMT at postnatal 45 days of age (end of the mid-adolescent period) in rat pups living in the same conditions. Gravid rats were assigned into three groups. In nicotine A, pregnant rats received 6 mg/kg/day nicotine intraperitoneally during pregnancy from 1 to 21 days of gestation and lactation (until postnatal day 21). Nicotine B received 3 mg/kg/day nicotine for the same period. Control pregnant rats received only saline intraperitoneally. Abdominal aIMT was studied histopathologically at postnatal 45 days of age. Nicotine exposure resulted in decreased birth weight and pregnancy weight gain. The mean aIMT values of the rat pups exposed to nicotine in both nicotine A and B groups were higher than those of the control group (103.78 ± 21.33 µm, 99.11 ± 30.12 µm, and 62.56 ± 7.18 µm, respectively). In conclusion, the detrimental effect on birth weight of nicotine exposure that began in fetal life is dose dependent. Nicotine exposure during intrauterine life and the lactation period causes increased aIMT in rat pups.

Thyroid hypoplasia as a cause of congenital hypothyroidism in monozygotic twins concordant for Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RSTS), a genetic disorder characterized by growth retardation, mental deficiency, dysmorphic face, broad thumbs and large toes, generally affects monozygotic twins concordantly. Thyroid hypoplasia (TH) is a common cause of congenital hypothyroidism (CH) and often accompanies dysmorphic syndromes. A pair of female twins were admitted to our neonatology unit 16 hours after delivery. They were born at 35 weeks of gestation. Both twins had an unusual dysmorphic facial appearance with microcephaly, as well as broad short thumbs and large toes. Based on the presence of characteristic dysmorphic features, the twins were diagnosed as RSTS. Thyroid function tests in the first twin revealed the following results: free thyroxine (T4) 8.4 pg/mL, thyrotropin (TSH) 4.62 mIU/L, thyroglobulin (TG) 213.24 ng/mL and a normal level of urinary iodine excretion (UIE). Thyroid function test results in the second twin in the second week were: free T4 5.9 pg/mL, TSH 9.02 mIU/L, TG 204.87 ng/mL, and normal UIE levels. Thyroid volumes were 0.36 mL and 0.31 mL in the first and second twin, respectively. TH was confirmed by technetium 99 m pertechnetate thyroid scans in both infants. Thyroid function tests normalized with L-thyroxine replacement therapy (10 µg/kg/day) around the end of the 3(rd) week of life. The infants were discharged planning their follow-up by both endocrinology and cardiology units. The rarity of cases of twins with RSTS (concordant) co-existing with CH led us to present this report.

Dandy-Walker malformation: a rare association with hypoparathyroidism.

Dandy-Walker malformation is characterized by cystic dilatation of the fourth ventricle and an enlarged posterior cranial fossa with upward displacement of the tentorium, lateral sinuses, and torcular, with agenesis or hypoplasia of the cerebellar vermis. Dandy-Walker malformation occurs in approximately the 4th week of gestation and is associated with various abnormalities involving the cardiac, skeletal, genitourinary, and gastrointestinal systems. The parathyroid gland also forms in the 3rd and 4th gestational weeks. Reported here is the case of a male infant with Dandy-Walker malformation with ventricular and atrial septal defect, unilateral renal agenesis, and hypoparathyroidism. To our knowledge, this rare association with neural crest events during the development of Dandy-Walker malformation has not been reported previously.

Neonatal episodic hypoglycemia: a finding of valproic acid withdrawal.

The treatment of epilepsy during pregnancy is a worldwide problem. Drugs need to be used to control seizures in the mothers. In utero, exposure to valproic acid (VPA) and phenytoin (PH) may cause congenital malformations and also withdrawal symptoms such as irritability, jitteriness and symptoms of hypoglycemia. We present here a newborn with episodic hypoglycemia due to in utero exposure to VPA and PH. The mother was diagnosed as having complex partial epilepsy and was treated with PH (200 mg/day) and VPA (600 mg/day). The offspring developed jitteriness on the second day of life. The infant was hypoglycemic (32 mg/dl). These findings were accepted as withdrawal symptoms, since serum levels of VPA and PH were 37.8 µg/ml (50-100 µg/ml) and 6.37 µg/dl (10-20 µg/ml), respectively. Measurement of blood glucose is important and should be carefully monitored in infants exposed to antiepileptics in utero.

Neonatal sludge: a finding of congenital hypothyroidism.

Congenital hypothyroidism is one of the most urgent diseases of the neonate. When diagnosed and treated at an early stage, its most important complication, mental retardation, is preventable. The signs of congenital hypothyroidism are nonspecific in neonates. Only 5% of the cases have characteristic clinical findings. One of the most important and earliest signs is prolonged jaundice during the neonatal period. We report herein a case of congenital hypothyroidism, who presented with icterus accompanied with sludge formation into the gallbladder, which disappeared after treatment with L-thyroxine.

Iodine overload and severe hypothyroidism in two neonates.

Iodine overload frequently leads to transient hyperthyrotropinemia or hypothyroidism, and rarely to hyperthyroidism in neonates. Iodine exposure can be prenatal, perinatal or postnatal. Herein we report two newborn infants who developed severe hypothyroidism due to iodine overload. The overloading was caused by excessive use of an iodinated antiseptic for umbilical care in the first case, and as a result of maternal exposure and through breast milk with a high iodine level in the second case. Presenting the two cases, we wanted to draw attention to these preventable causes of hypothyroidism in infants.