Epigenomic and transcriptomic landscaping unraveled candidate repositioned therapeutics for non-functioning pituitary neuroendocrine tumors.

PURPOSE: Non-functioning pituitary neuroendocrine tumors are challengingly diagnosed tumors in the clinic. Transsphenoidal surgery remains the first-line treatment. Despite the development of state-of-the-art techniques, no drug therapy is currently approved for the treatment. There are also no randomized controlled trials comparing therapeutic strategies or drug therapy for the management after surgery. Therefore, novel therapeutic interventions for the therapeutically challenging NF-PitNETs are urgently needed. METHODS: We integrated epigenome and transcriptome data (both coding and non-coding) that elucidate disease-specific signatures, in addition to biological and pharmacological data, to utilize rational pathway and drug prioritization in NF-PitNETs. We constructed an epigenome- and transcriptome-based PPI network and proposed hub genes. The signature-based drug repositioning based on the integration of multi-omics data was performed. RESULTS: The construction of a disease-specific network based on three different biological levels revealed DCC, DLG5, ETS2, FOXO1, HBP1, HMGA2, PCGF3, PSME4, RBPMS, RREB1, SMAD1, SOCS1, SOX2, YAP1, ZFHX3 as hub proteins. Signature-based drug repositioning using hub proteins yielded repositioned drug candidates that were confirmed in silico via molecular docking. As a result of molecular docking simulations, palbociclib, linifanib, trametinib, eplerenone, niguldipine, and zuclopenthixol showed higher binding affinities with hub genes compared to their inhibitors and were proposed as potential repositioned therapeutics for the management of NF-PitNETs. CONCLUSION: The proposed systems' biomedicine-oriented multi-omics data integration for drug repurposing to provide promising results for the construction of effective clinical therapeutics. To the best of our knowledge, this is the first study reporting epigenome- and transcriptome-based drug repositioning for NF-PitNETs using in silico confirmations.

[Variation in the assessment of facial aesthetics of women during the past 150 years]. / Variatie in beoordeling van aangezichtsesthetiek van vrouwen gedurende de afgelopen 150 jaar.

Variation in the assessment of facial aesthetics through time was investigated with the help of measurements of actresses from 1875 to 2020 most widely considered to be beautiful. Measurements were carried out on reasonably standardised profile and frontal photographs. During the length of the period studied, the following trends in changing attitudes to facial beauty were recognised: a steady increase in the redness and prominence of lips, a decrease in eye height and an increase in eye width, and with it, a decrease in the height/width ratio or the eyes. In addition, the chin-neck angle and the nasolabial angle became sharper. This trend was especially evident after 1950. Both the group of actresses from 1875 to 1900 and a group of British female students from 2005 showed a relatively flatter lip profile, a more prominent chin and a larger nasolabial angle. After 2000 a mild preference developed for somewhat more redness of the upper and lower lips both frontally and from the side, somewhat more prominent lips, sharper nasolabial and chin-neck angles and a narrower eye height.

[Transient pink tooth discoloration during orthodontic treatment]. / Voorbijgaande roze coronale verkleuring van een gebitselement tijdens orthodontische behandeling.

A healthy adult male patient presented himself, 11 days after a fixed orthodontic appliance was placed, with a sudden pink discoloration of the dental crown of tooth 21. The emergency dentist on call diagnosed the discoloration as non-painful peri-apical periodontitis, partly on the basis of a radiograph, and recommended endodontic treatment of tooth 21. Prior to endodontic treatment, the patient was first seen by the orthodontist who had initiated treatment. Tooth 21 was investigated and reacted normally to percussion and palpation but did not react to the cold test. The patient was referred to an endodontist who made the likely diagnosis: 'Transient apical breakdown'. No endodontic treatment was carried out and the orthodontic treatment was not interrupted. Six weeks after the discoloration appeared, visible recovery was evident.

[Possibilities and limitations of treatment with clear aligners. An orientation]. / Mogelijkheden en beperkingen van orthodontische behandeling met clear aligners. Een verkenning.

The aim of this research was to evaluate the efficiency and effectiveness of an orthodontic treatment with clear-aligner systems, specifically with Invisalign®. In addition to a review of the literature, 4 orthodontists and 9 patients treated with fixed orthodontic therapy and Invisalign® were interviewed. The literature showed that it is difficult to correct an extrusion, rotation or overjet with clear aligners. Often 'refinement' (additional intervention during treatment) is necessary to achieve the best possible end result. The patients interviewed experienced few limitations in their daily lives caused by the clear aligners and hardly any pain. Treatment duration was comparable to that with fixed appliances; it depended on the experience of the orthodontist, the complexity of the case and cooperation of the patient. The cost of an Invisalign® treatment is higher than that of fixed-appliance therapy. Additionally, making a plan for clear-aligner treatment often takes more time for the orthodontist than planning treatment for fixed-appliance therapy.

A RARE CAUSE OF PITUITARY APOPLEXY: CABERGOLINE THERAPY.

Pituitary apoplexy (PA) is a life-threatening clinical syndrome. Dopamine receptor agonists are the drugs of choice in the treatment of prolactinomas. The use of cabergoline is reported to cause an increased risk of PA, particularly in macroprolactinomas of cystic nature. In this report, we present a patient with a cystic macroprolactinoma who developed PA on the 16th week of cabergoline treatment.

MUSCULAR HYPERTROPHY AS ATYPICAL INITIAL PRESENTATION OF HYPOTHYROIDISM.

Hypothyroidism is a common endocrine disease with characteristic symptoms and signs such as fatigue, weight gain, intolerance of cold, constipation, depression, mental slowdown and muscle cramps. Myopathic changes are observed in 30-80% of patients with hypothyroidism, but muscular hypertrophy with muscle stiffness has been reported in less than 10% of patients. Hoffmann's syndrome is a specific form of the hypothyroid-associated myopathy, rarely seen. Symptoms of this syndrome include proximal muscle weakness, hypertrophies in extremities, stiffness, muscle cramps, spontaneous muscle pain; and are associated with increased muscle enzymes. These findings can be seen at any time during hypothyroidism. Hofmann's syndrome has a very good prognosis. Its response to hormone replacement therapy is very good. Therefore, in patients with myopathy-like symptoms, considering in the differential diagnosis that the myopathy may be a reflection of hypothyroidism will facilitate the diagnosis and treatment. In this case, we aimed to present together Hashimoto thyroiditis and muscular hypertrophy, which is an atypical presentation of hypothyroidism and rarely seen in the literature, namely Hoffmann's syndrome.

Neurofibromatosis type 1 and malignancy in childhood.

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary neurocutaneous syndrome characterized by multi-system involvement and an increased incidence of both benign and malignant tumors. In this study, we evaluated the clinical presentation and prognosis of NF1 and malignancy. Between 1975 and 2013, 26 (5%) of the 473 patients with NF1 at our center developed non-neurofibroma neoplasms. The patient files of 26 subjects with tumors, other than optic glioma, were analyzed retrospectively to evaluate clinical features and treatment results. The age at diagnosis of NF1 ranged from 3 months to 16 years (median 5.5 years). The age range at tumor diagnosis was 1.5-33 years (median 8 years) in these 26 patients. The tumor histological subtypes included the following: 12 soft-tissue tumors (6 malignant peripheral nerve sheath tumors (MPNST), 5 rhabdomyosarcomas (RMS) and 1 malignant fibrous histiocytoma), 11 brain tumors (6 low-grade gliomas, 3 high-grade gliomas, and 2 medulloblastoma), 2 neuroblastomas and 1 non-Hodgkin's lymphoma. Twelve of 26 patients were alive at the time of the study. Although benign brain tumors with NF1 are more common, high-grade brain tumors also occur. Thus, careful and regular follow-up is crucial for early detection of malignancy in NF1 patients.

The evaluation of Nesfatin-1 levels in patients with OSAS associated with metabolic syndrome.

PURPOSE: The association of obstructive sleep apnea syndrome (OSAS) and metabolic syndrome (MS) has been demonstrated in studies and in recent years; the effect of OSAS on insulin resistance independent of the level of obesity is being investigated. Nesfatin-1 is a newly defined 82 amino acid protein with a precursor molecule of NUCB2 (nucleobindin 2). Nesfatin-1 is not only essential in regulation of food ingestion but also important in regulation of some brain functions, autonomic regulation, stress, mental state, and paradoxical sleep. We aimed to evaluate the relationship between OSAS and MS and the MS dependent or independent effect of Nesfatin-1 on this relationship. METHODS: Patients admitted with clinical signs of OSAS are included. Patients are divided into three groups based on Apnea-Hypopnea Index (AHI) on Polysomnography (PSG) as mild, moderate, and severe OSAS. A total of 59 patients were included the control patients. Several OSAS parameters and laboratory findings which are and are not MS dependent are compared. Nesfatin-1 levels are evaluated in all OSAS patients with and without MS. RESULTS: There were significantly more males in all groups (p = 0.007). There was no significant difference between groups in terms of Nesfatin-1 levels. Nesfatin-1 levels were significantly lower in MS group compared to non-MS group (p = 0.021). CONCLUSION: Nesfatin-1 which is known to play a role in the pathophysiology of insulin resistance can be a beneficial target in developing new therapeutic targets for treatment of patients with obesity without any toxic effects in the future.

Pregnancy outcomes and prognostic factors in patients with intrahepatic cholestasis of pregnancy.

The aim of this study was to describe maternal and fetal characteristics associated with intrahepatic cholestasis of pregnancy (ICP) and to determine clinical and biochemical predictors of fetal complications. A total of 89 singleton pregnancies with ICP were analysed, retrospectively. All data concerning laboratory results, symptom onset time, treatment response, delivery time and infant information were recorded in the study protocol. The mean gestational age at diagnosis was 32.6 ± 3.4 weeks; mean time of delivery was 36.8 ± 1.9 weeks. Binary logistic regression revealed that gestational age at diagnosis was predictive of preterm delivery (OR = 2.3, 95% CI: 1.5-3.3, p = 0.001). The incidence of respiratory distress syndrome (RDS), fetal growth restriction, fetal distress and preterm delivery were significantly higher in patients who were diagnosed before 30 weeks than after 34 weeks' gestation (p < 0.01). Gestational age at diagnosis is an important independent factor predicting adverse perinatal outcomes in patients with ICP.

The place of D-dimer and L-lactate levels in the early diagnosis of acute mesenteric ischemia.

INTRODUCTION: Acute mesenteric ischemia (AMI) is an abdominal-vascular emergency which is rare and has high mortality rates (60-80 %) due to late diagnosis (1-3). Although it is known that extravascular reasons like intestinal intussusception, volvulus, strangulated hernias and obstructions can cause intestinal gangrene, these are rarely the cause of AMI (1). MATERIALS AND METHODS: In this study, we used male Wistar-Albino rats weighing 250-300 grams obtained from Pamukkale University Experimental Research Laboratory. Animals were exposed to light-dark cycles for 12 hours and had free access to food and water. They were kept in cages for 7 days to stabilise their intestinal flora. In animals of group I, nothing was made other than taking 0.5 ml blood intracardially. In other animals, abdomen was reached with midline laparotomy and superior mesenteric artery (SMA) was located. In group II (operative control group), SMA was isolated and manipulated but was not ligated. In Group III (intestinal ischemia group), SMAwas isolated and ligated with 3/0 silk tie distally to the aorta. After this process, intestinal ischemia was achieved which was confirmed by paleness and pulselessness of intestines, caecum and right colon. Later on, abdomen was closed with double 3/0 polyglactin sutures. At postoperative 1st, 4th and 6th hours 0.5 ml blood was taken intracardially from the animals in groups II and III in order to quantify D-dimer and L-lactate levels. LABORATORY TESTS: D-dimer: Blood samples which were put into tubes containing sodium citrate, were seperated from plasma with centrifugation at 4000 rpm for 7 minutes.L-lactate: Blood L-lactate levels were determined from blood taken into capillary tubes with the help of immobilised enzyme electrode technology using YSI 1500 Sport portative lactate analyzer (Yellow Springs Instruments Inc., Ohio-USA). HISTOPATHOLOGIC VERIFICATION: Two cm long intestinal samples were taken from animals in which SMA was ligated in order to achieve mesenteric ischemia and these samples were fixed in 10 % formol. DISCUSSION: As a result, in rats with SMA occlusion serum D-dimer levels were not increased significantly when compared either in the group or with the basal values of the control group and values in operative control group. Therefore, it is concluded that D-dimer is not a useful marker for early diagnosis of AMI. On the other hand, it is revealed that blood L-lactate levels began to increase significantly following 4th hour of mesenteric ischemia and it is shown that this increase continued at the 6th hour. In addition, considering the utmost importance of the early diagnosis in patients with the clinical suspicion of AMI, L-lactate seems to be a suitable marker to use in emergency departments because it is achieved with a portable device that gives fast and accurate results. Nevertheless, our results are need to be supported by clinical studies with larger patient series (Tab. 2, Fig. 11, Ref. 39).

Treacher Collins syndrome with multiple congenital heart defects after paroxetine exposure: case report.

Treacher Collins syndrome is an autosomal dominant disorder of craniofacial development with an incidence of I in 40,000 to in 70,000 live births. It is characterized by abnormalities of the pinnae which are frequently associated with atresia of the external auditory canals and anomalies of the middle ear ossicles. Rarely congenital heart defects can be present. Prenatal paroxetine exposure may enhance the risks of major malformation, particularly cardiac defects. This article reports a newborn, whose mother used paroxetine during pregnancy, presenting with multiple congenital heart defects associated to typical physical characteristics of Treacher Collins syndrome.

Crisponi syndrome: a new mutation in CRLF1 gene associated with moderate outcome.

SUMMARY: Crisponi syndrome (CS) is a rare, autosomal recessive disorder, characterized by hyperthermia, extensive muscular contractions in the face after even minimal stimuli or crying, hypertonia, opisthotonus, camptodactyly, and typical facial features. Recently, it has been demonstrated that CRLF1 (cytokine receptor-like factor 1) gene mutation is associated with CS. Here we report a case of CS with a new mutation in the CRLF1 gene associated with moderate clinical phenotype.

Papillorenal syndrome with de novo reciprocal translocation t(2;15) (q31; q26).

Renal hypoplasia is a congenital anomaly, the etiology of which is not yet fully known. Genetic studies have shown that certain genes, in utero environmental factors and molecular mechanisms have a role in the identification ofnephron formation and kidney size. The coexistence of bilateral renal hypoplasia and optic disc coloboma is observed in papillorenal syndrome, which caused by the mutation of the PAX2 gene. In the case presented in this article, bilateral renal hypoplasia and optic disc coloboma have been detected to coexist. The analysis of the PAX2 gene, which was carried out with an eye to the papillorenal syndrome, did not reveal any mutations. However, de novo t(2;15) (q31; q26) (reciprocal translocation) was detected in chromosome analysis. As far as we know, there are not any publications focusing on the clinical importance of this type of translocation. In cases with renal hypoplasia and optic disc coloboma, the possibility of a de novo translocation between chromosomes 2 and 15 should be considered.

A novel mutation of laminin ß-2 gene in Pierson syndrome manifested with nephrotic syndrome in the early neonatal period.

Pierson syndrome is a rare autosomal recessive disorder which is mainly characterized by congenital nephrotic syndrome (CNS), diffuse mesangial sclerosis (DMS) and distinct ocular abnormalities, including microcoria. Most affected children exhibit early onset of chronic renal failure, neurodevelopmental deficits, and blindness. It is caused by a homozygous or compound heterozygous mutation in the gene encoding laminin beta2 (LAMB2) on chromosome 3p21. In this article, we report on a patient with CNS, bilateral megalocornea and microcoria. The patient had developed renal failure at very early postnatal period and died of septic shock. A novel homozygous donor splice mutation (IVS4 + 2T > C) in LAMB2 gene was identified in the patient.

A statistical experimental design approach for mineralization and detoxification of diethyl phthalate by H2O2/UV-C process.

In the present study, a three-factor central composite design (CCD) was implemented to evaluate the major factors (treatment time, initial H2O2 dose and initial diethyl phthalate (DEP) concentration) influencing the H2O2/UV-C treatment of aqueous DEP solution. Significant regression models for total organic carbon (TOC) removal and residual H2O2 concentration were derived using analysis of variance (ANOVA), which were found to be adequate to perform the process variables optimization. According to the applied ANOVA, treatment time (positive effect) and initial H2O2 dose (negative effect after an optimum value) were found to be significant on the H2O2/UV-C process performance. TOC removal efficiencies were enhanced with increasing initial H2O2 dose up to an optimum value, and further increases in H2O2 dose resulted in a decrease in TOC removals due to the hydroxyl radical scavenging effect. When initial H2O2 dose increased from 10 to 30 mM, the TOC removal efficiency improved from 41 to 100% for DEPo of 100 mg/L for treatment time of 50 min. Further increase in initial H2O2 dose to 50 mM decreased the TOC removal efficiency down to 38%. The results of toxicity assessments with Vibrio fischeri on aqueous DEP solutions subjected to H2O2/UV-C treatment revealed complete detoxification at the optimum conditions.

Does in vitro fertilization affect the hearing levels of women?

OBJECTIVE: This study aimed to determine whether there is a relationship between changes in blood estrogen levels and hearing threshold levels in women undergoing in vitro fertilization (IVF). PATIENTS AND METHODS: Sixty patients with normal otoscopic examination findings and scheduled for IVF treatment were included in the study. All patients underwent pure tone audiometry, tympanogram tests, and otoacoustic emission measurements (TEOAE) during IVF treatment, and estrogen levels were measured simultaneously. The patients were divided into three groups based on estrogen levels during IVF. The patients' audiological test results at the beginning and end of treatment (the 12th day) were compared between the groups. RESULTS: There was an increase in hearing levels on the 12th day of treatment compared to the beginning of treatment in all the study groups. This increase was significant between Group 1 and Group 2 and between Group 1 and Group 3 (p<0.05). The best hearing in audiometry was determined in the patients in Group 2. While a significant increase was observed in TEOAE (otoacoustic emission) measurements in Groups 1 and 2, a significant decrease was determined in Group 3 (p<0.05). Middle ear pressure and compliance measurements on the tympanogram tests were significantly lower in Group 3 compared to Groups 1 and 2 (p<0.05). CONCLUSIONS: During IVF treatment, as the estrogen level increases, it causes an increase in the level of hearing, but this increase does not continue after specific doses.

Serum pNF-H levels in the first six hours after experimental mild traumatic brain injury in rats.

OBJECTIVE: Mild traumatic brain injury (mTBI) cases with a normal CT scanning account for the vast majority of all TBI patients. The aim of this study was to investigate the course of serum Phosphorylated Neurofilament Heavy Chain (pNF-H) levels in the first six hours after trauma in rats in experimental mTBI. MATERIALS AND METHODS: In this experimental animal study, 32 female Sprague-Dawley rats were enrolled equally (n=8) into 3 experimental groups and 1 control group. In experimental groups, animals were exposed to a mTBI with a free fall of 50-gram metal disc from a height of 80 cm. We compared serum pNF-H levels at the 2nd, 4th, and 6th hours after traumatic brain injury in the experimental groups with the control group. RESULTS: Serum pNF-H levels at the 2nd and 4th hours after traumatic brain injury were statistically significantly higher than the control group. Serum pNF-H levels gradually decreased at the 4th and 6th hours compared to the 2nd hour and decreased to a similar level to the control group at the 6th hour after injury. CONCLUSIONS: A high serum pNF-H value, could be used in the diagnosis and management of mTBI patients.

Acromion types and morphometric evaluation of painful shoulders.

BACKGROUND: Due to its many variations, the scapula is among the most frequently examined bones. Especially the acromion can be of different shapes and sizes. Measurements of the morphometric structures in the shoulder joint make it easier to explain the cause of the various shoulder problems. The objective of this study is putting emphasis on the importance of acromion types, os acromiale presence and acromial morphometric measurements in the aetiology and diagnosis of shoulder pain. MATERIALS AND METHODS: A retrospective study, based on 100 patients of both genders who presented with the complaints of shoulder pain and underwent magnetic resonance imaging, was conducted. Within this scope, types of acromion, slope of acromion, length of acromion, length of coracoid process, the distance between acromion and coracoid process, lateral acromial angle (LAA), critical shoulder angle (CSA), acromial index (AI) and acromiohumeral distance were measured. The data were analysed considering the gender and acromion types and the presence of os acromiale is investigated. RESULTS: The most common acromion was type II (curved) (frequency rate 62%) while the rate of type I (flat) and type III (hooked) acromions were 21% and 17%, respectively. The length of acromion and coracoid process were found to be significantly longer in males, while no significant difference between genders in terms of the distance between acromion and coracoid process were observed. Furthermore, while negative correlation between LAA and AI as well as LAA and CSA were observed; positive correlation between AI and CSA was found. In addition, there was negative correlation between slope of acromion and acromiohumeral distance. Besides, acromiohumeral distance was significantly higher in males. Regarding the presence of os acromiale, it was observed in 3 women out of 59 and 2 men out of 41, which indicated no significant difference between genders. CONCLUSIONS: It is evaluated that the morphometric measurement is of importance in contributing clinically in distinguishing the problems that may occur according to gender and acromion types.

Dimeric Proanthocyanidins on the Stability of Dentin and Adhesive Biointerfaces.

A dentin biomodification strategy with selective proanthocyanidin (PAC)-enriched extracts reinforces dentin and dentin-resin interfaces. Enrichment of the extracts according to the degree of polymerization allows exploration of bioactive principles of PACs and structure-activity relationships. This study investigated the sustained dentin matrix biomodification and dentin-resin bioadhesion of 2 fractions consisting exclusively of B-type PAC dimers with or without a single galloyl motif (specifically, DIMERG and DIMERNG) and their precursor material, enriched grape seed extract (e-GSE; Vitis vinifera). The biomodification potential was determined by long-term evaluation of the apparent modulus of elasticity and collagen solubility (hydroxyproline release). Chemical characterization of the dentin matrix was performed by attenuated total reflectance-Fourier-transform infrared spectroscopy. The bioadhesive properties were assessed by a microtensile bond strength test at different time points, and macro-hybrid layers were produced to verify the degree of conversion of the adhesive resin. Fractions consisting of DIMERG, DIMERNG, and their precursor, e-GSE, increased the modulus of elasticity at all time points and reduced collagen degradation. Specimens treated with DIMERNG remained stable throughout 12 mo of storage, whereas a significant drop in the modulus of elasticity was observed for the DIMERG and e-GSE groups at 6 mo. The fractions and precursor did not affect the degree of resin conversion at the hybrid layer. Changes in infrared resonances corresponding to collagen cross-links in the dentin matrix occurred for all treatments. Higher bond strength was observed for dentin treated with e-GSE as compared with DIMERG and DIMERNG; all biointerfaces remained stable after 12 mo. Nongalloylated PACs mediate stable dentin biomodification, which includes protective activity against collagen degradation and reinforcement of the anchoring dentin matrix. Collectively, PACs with a higher degree of oligomerization offer a robust bioadhesion between the hydrophilic dentin matrix and the hydrophobic adhesive.

Effectiveness of HERO 642 versus Hedström files for removing gutta-percha fillings in curved root canals: an ex vivo study.

AIM: To compare the effectiveness of gutta-percha removal and the maintenance of canal anatomy when using the HERO 642 system or Hedström files (H-files) in mandibular molar teeth. METHODOLOGY: The root canals of 40 mandibular molar teeth were instrumented using H-files and filled with gutta-percha and sealer. After 1 year in storage, the roots were sectioned horizontally to provide apical, middle and coronal root thirds. Sections were photographed, and an individual muffle was produced for each tooth. Teeth were randomly divided into four groups (n = 10) and the gutta-percha removed using either the HERO 642 system or H-files, with or without solvent. Digital images of the root canals were then re-taken. Root thirds were inspected for lateral perforations, and the percentage of the residual canal filling was determined on postoperative images. Transportation and centring ratio were calculated using preoperative and postoperative images of the cross-sections of root thirds. RESULTS: H-files groups were associated with less filling material than the HERO 642 system (H-files-HERO 642 P = 0.056, H-files-HERO 642+solvent P = 0.041, H-files + solvent-HERO 642 P = 0.018, H-files + solvent-HERO 642 + solvent P = 0.016). The percentage of residual filling material was similar in the apical thirds, and the contribution of solvent to canal debridement was not statistically significant (P > 0.05). Perforation occurred mesiobuccally in 48% of specimens in the apical sections of mesial roots. There were no significant differences for centring ratio, transportation and perforation rate between groups. CONCLUSIONS: H-files left less gutta-percha overall; however, there was no difference in the apical third. The effect of solvent was not remarkable. Both instrument systems created a large number of perforations.