Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia.

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.

Evaluation of factors affecting the association between thickening of sinus mucosa and the presence of periapical lesions using cone beam CT.

AIM: To evaluate the effect of various parameters of periapical lesion(s) on the amount and type of mucosal thickening using cone beam CT images. METHODOLOGY: CBCT scans of 1000 patients were evaluated retrospectively for the presence of apical lesions in maxillary posterior teeth associated with sinus mucosal thickening. The number of cases with pathological mucosal thickening was recorded and classified according to the amount and type of mucosal thickening. The parameters evaluated as the cause of mucosal thickening were the type and number of posterior teeth, number of root(s), diameter of the periapical lesion and distance between maxillary sinus and lesion. Descriptive statistics and multiple logistic regression was used for data analyses. Spearman's correlation coefficient was used for pair-wise comparisons. Intrarater reliability was tested by Cohen's kappa. RESULTS: Mucosal thickening associated with periapical lesions was determined in 48% of 202 cases. The most frequently detected extent of mucosal thickening was type 3 (42%), whereas flat type thickening (59%) was the most frequent type. The tooth most frequently associated with mucosal thickening was the maxillary first molar (44%). Parameters significantly affecting the extent of mucosal thickening were gender, number of roots, number of teeth with periapical lesions and diameter of periapical lesions (P < 0.05). The single parameter with an association with the type of mucosal thickening was the number of roots with an apical lesion (P < 0.05). CONCLUSION: Mucosal thickening associated with periapical lesions was observed in almost 50% of all mucosal thickening cases. Therefore, collaboration amongst endodontists and otolaryngologists is mandatory to provide successful treatment and prevent recurrence of maxillary sinusitis.

GENETIC DISORDERS OF PITUITARY DEVELOPMENT IN PATIENTS WITH SHEEHAN'S SYNDROME.

INTRODUCTION: Genetic disorders associated with the development of the pituitary gland and cranial bones may cause a genetic tendency toward Sheehan's syndrome (SS). Our aim in this study was to investigate expression disorders in the genes responsible for the development of the pituitary gland and cranial bones in patients with SS. MATERIALS AND METHODS: Forty-four patients who were previously diagnosed with SS and 43 healthy women were compared in terms of the mean expression values of genes including the prophet of PIT-1 (PROP1), HESX homeobox 1 (HESX1), POU class 1 homeobox 1 (POU1F1), LIM homeobox 3 (LHX3), LHX4, glioma-associated oncogene homolog 2 (GLI2), orthodenticle homeobox 2 (OTX2), SIX homeobox 3 (SIX3), SIX6, T-box transcription factor 19 (TBX19), transducin-like enhancer protein 1 (TLE1), TLE3, distal-less homeobox 2 (DLX2), DLX5, MSH homeobox 2 (MSX2), and paired box 3 (PAX3). RESULTS: The mean expression values of the HESX1, TLE1, TLE3, and MSX2 genes were significantly different in the SS group from the healthy control group, while the mean expression values of the remaining genes were similar. CONCLUSION: The present study concludes that abnormal expressions of HESX1, TLE1, TLE3, and MSX2 genes may cause a genetic predisposition to the development of SS.

Correlation of astrocyte elevated gene-1, basic-fibroblast growth factor, beta-catenin, Ki-67, tumor necrosis factor-alfa with prognostic parameters in ductal carcinomas and ductal intraepithelial neoplasms.

BACKGROUND: Breast cancer is the second most frequent cancer in the world. Although it is widely accepted that the etiology of breast cancer includes both genetic and environmental factors, the molecular mechanism of its development and progression remains poorly understood, and thus far, no specific signature of breast cancer gene expression has been reported to allow for patient-tailored therapy strategies. Hence, it is of great clinical value to further understand the molecular mechanisms underlying the progression of breast cancer and to identify effective early markers for the diagnosis and prognosis of the disease as well as novel therapeutic targets. MATERIALS AND METHODS: This study was conducted on a total of 90 paraffin-embedded breast tumor samples. Immunohistochemical stains for astrocyte elevated gene-1 (AEG-1), basic-fibroblast growth factor (b-FGF), beta-catenin, Ki-67, tumor necrosis factor-α (TNF-α) were performed on tissue microarray using standard procedures. Each patient age, grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) status, size, lymphovascular invasion, metastasis of lymph node (LNM), nipple and ductal hyperplasia areas were assessed. RESULTS: We observed significant relationship between the age and LNM or FGF (P = 0.018, 0.035, respectively). The relationship between histological and nuclear grade, LNM, ER, PR, HER-2 and prognostic parameters was evaluated in cases of ductal carcinomas (DC). There was a significant positive correlation between TNF-α, size, LNM (P ≤ 0.0001, 0.002, 0.005). We found that significant relationship between AEG-1 and TNF-α. There was a significant positive correlation between FGF and Ki-67 and negative correlation AEG-1. Although, FGF, TNF-α, AEG-1 staining in DC were observed higher than ductal intraepithelial neoplasms, this observation could not statistically (P ≥ 0.05). CONCLUSIONS: The present work aims to investigate the relationship between the expression of AEG-1, b-FGF, beta-catenin, Ki-67, TNF-α other prognostic parameters in DC and ductal intraepithelial neoplasm. We found a relationship between these factors.

Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia.

Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive study on PDE6C mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins. Twelve affected patients from seven independent families segregating PDE6C mutations were identified in our total patient cohort of 492 independent families. Eleven different PDE6C mutations were found including two nonsense mutations, three mutations affecting transcript splicing as shown by minigene assays, one 1 bp-insertion and five missense mutations. We also performed a detailed functional characterization of six missense mutations applying the baculovirus system to express recombinant mutant and wildtype chimeric PDE6C/PDE5 proteins in Sf9 insect cells. Purified proteins were analyzed using Western blotting, phosphodiesterase (PDE) activity measurements as well as inhibition assays by zaprinast and Pγ. Four of the six PDE6C missense mutations led to baseline PDE activities and most likely represent functional null alleles. For two mutations, p.E790K and p.Y323N, we observed reduction in PDE activity of approximately 60% and 80%, respectively. We also observed differences for Pγ inhibition. The p.E790K mutant, with an IC50 value of 2.7 nm is 20.7-fold more sensitive for Pγ inhibition, whereas the p.Y323N mutant with an IC50 of 158 nm is 3-fold less sensitive when compared with the wildtype control.

Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2.

Isolated strabismus affects 1-5% of the general population. Most forms of strabismus are multifactorial in origin; although there is probably an inherited component, the genetics of these disorders remain unclear. The congenital fibrosis syndromes (CFS) represent a subset of monogenic isolated strabismic disorders that are characterized by restrictive ophthalmoplegia, and include congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DURS). Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2), but no genes have been identified. Here, we report three mutations in ARIX (also known as PHOX2A) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription factor protein previously shown to be required for nIII/nIV development in mouse and zebrafish. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain. These findings confirm the hypothesis that CFEOM2 results from the abnormal development of nIII/nIV (ref. 7) and emphasize a critical role for ARIX in the development of these midbrain motor nuclei.

A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene.

Retinal cone photoreceptors mediate fine visual acuity, daylight vision, and color vision. Congenital hereditary conditions in which there is a lack of cone function in humans cause achromatopsia, an autosomal recessive trait, characterized by low vision, photophobia, and lack of color discrimination. Herein we report the identification of mutations in the PDE6C gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase as a cause of autosomal recessive achromatopsia. Moreover, we show that the spontaneous mouse mutant cpfl1 that features a lack of cone function and rapid degeneration of the cone photoreceptors represents a homologous mouse model for PDE6C associated achromatopsia.

Management of extensive venous thrombosis following cardiac surgery in a patient with Behcet's disease.

Behçet's disease is a multisystemic vasculitis of unknown etiology, which is characterized by recurrent urogenital ulceration, cutaneous eruptions, ocular manifestations, arthritis and vasculitis, and its diagnosis is based on clinical criteria. Herein, we report a case of a patient with Behcet's disease, who was successfully managed with anticoagulant and anti-inflammatory therapy for disseminated venous thrombosis leading to pleural effusion, Budd-Chiari syndrome and central nervous system involvement following coronary artery bypass grafting surgery.

The presence of anomalous extraocular bands in Duane retraction syndrome.

PURPOSE: To determine the prevalence of anomalous extraocular bands in patients who underwent surgery for Duane syndrome and to compare the clinical findings in patients with and without bands. METHODS: Thirty-one patients with Duane syndrome who had their first surgery on rectus muscles to correct the primary deviation and abnormal head posture were included in this retrospective study. Patients were divided into two groups depending on the identification of anomalous extraocular bands intraoperatively. Baseline clinical characteristics were compared between the groups. RESULTS: A total of 31 patients were included. Anomalous bands were found in 6 of 19 (32%) patients with esotropic Duane syndrome and 9 of 12 (75%) with exotropic Duane syndrome (P = 0.02). In esotropic Duane syndrome, the bands were localized under the medial rectus muscle in 5 patients and under the lateral rectus muscle in 1 patient. All of the bands in patients with exotropic Duane syndrome were under the lateral rectus muscle. The amount of preoperative primary deviation, globe retraction, and up- or downshoot were similar between groups. All of the bands had distinct tight insertion on the sclera, requiring a sharp dissection for disinsertion. In 7 cases, the anomalous band was a translucent structure that could be identified under the surgical microscope as scleral indentation during forced duction testing. Histological examination of 6 cases revealed only fibrous tissue in 4 and accompanying striated muscle tissue in 2 patients. CONCLUSIONS: The present study highlights the incidence of anomalous bands in Duane syndrome. Repeating forced duction testing after disinsertion of the affected muscle and excision of the anomalous band is helpful for intraoperative identification of these structures.

The protective effect of lycopene against oxidative kidney damage associated with combined use of isoniazid and rifampicin in rats.

It is known that the combined use of antibiotics, such as isoniazid and rifampicin, in the treatment of tuberculosis causes oxidative kidney damage. The aim of this study was to biochemically and histopathologically investigate the effect of lycopene on oxidative kidney damage due to the administration of isoniazid and rifampicin in albino Wistar male rats. Lycopene at a dose of 5 mg/kg was orally administered to lycopene+isoniazid+rifampicin (LIR) rats, and normal sunflower oil (0.5 mL) was orally administered to isoniazid+rifampicin (IR) and healthy control (HG) rats as vehicle by gavage. One hour after the administration of lycopene and vehicle, 50 mg/kg isoniazid and rifampicin were given orally to the LIR and IR groups. This procedure was performed once a day for 28 days. Rats were sacrificed by a high dose of anesthesia at the end of this period, and oxidant-antioxidant parameters were measured in the removed kidney tissues. Creatinine and blood urea nitrogen (BUN) levels were measured in blood samples, and kidney tissues were also evaluated histopathologically. The combined administration of isoniazid and rifampicin changed the oxidant-antioxidant balance in favor of oxidants, and it increased blood urea nitrogen and creatinine levels, which are indicators of kidney function. Co-administration of isoniazid and rifampicin also caused oxidative kidney damage. Lycopene biochemically and histopathologically decreased oxidative kidney damage induced by isoniazid and rifampicin administration. These results suggested that lycopene may be beneficial in the treatment of nephrotoxicity due to isoniazid and rifampicin administration.

Acquired Comitant Esotropia in Children and Young Adults: Clinical Characteristics, Surgical Outcomes, and Association With Presumed Intensive Near Work With Digital Displays.

PURPOSE: To describe the clinical characteristics and surgical outcomes of acquired comitant esotropia with symptomatic diplopia. METHODS: The clinical features and surgical outcomes of 27 patients with diplopia due to acquired comitant esotropia were retrospectively reviewed. Exclusion criteria were a history of prematurity, cerebral palsy, head trauma, or febrile illness before the onset of acquired comitant esotropia, incomitant strabismus, accommodative spasm, and divergence paralysis. Neurological evaluation and neuroimaging was normal in all patients. RESULTS: Mean age at onset of esotropia and diplopia was 17.8 ± 10.3 years (range: 6 to 44 years). Eighteen patients had simple myopia (range: -0.25 to -7.75 diopters [D]), 5 patients had hypermetropia (range: 0.50 to 1.50 D), and 4 patients had emmetropia. The angle of deviation prior to surgery was 35.6 ± 10.3 prism diopters (PD) for far and 38.0 ± 10.5 PD for near fixation. Twenty-three patients (85%) were prism responders. A history of excessive near work (≥ 4 hours a day) with digital displays was present in 21 (78%) patients. Diplopia resolved and some level of stereovision was achieved in all patients postoperatively. Three patients had recurrence of esotropia in long-term follow-up. CONCLUSIONS: The differentiation of a serious pathology from a straightforward optically or medically treatable condition in patients with a subacute or chronic history of diplopia is challenging for the clinician. The recognition of acquired comitant esotropia due to presumed intensive near activities with digital display may avoid time-consuming and costly laboratory investigations. Most of the patients in this series were prism responders and surgery for the prism-adapted angle was successful in restoring binocular vision. [J Pediatr Ophthalmol Strabismus. 2020;57(4):251-256.].

Superior or inferior rectus transposition in esotropic Duane syndrome: a longitudinal analysis.

PURPOSE: To evaluate the results of superior rectus transposition (SRT) or inferior rectus transposition (IRT) in esotropic Duane syndrome. METHODS: The medical records of patients with esotropic Duane syndrome who underwent ciliary vessel-sparing SRT or IRT by a single surgeon in private practice were included. Pre- and postoperative head posture, primary position deviation, fundus torsion, collapse in pattern, and improvement in ductions were analyzed between groups. RESULTS: A total of 21 patients were included: 7 had a V-pattern esotropia and/or larger abduction deficiency in downgaze compared to upgaze and underwent IRT; 14 underwent SRT of which 6 had A pattern and/or larger abduction deficiency in upgaze compared to downgaze. Orthotropia within 10Δ of esotropia was achieved in 10 patients (71.4%) with SRT and 4 patients (57.1%) with IRT. Pattern was reduced and abduction improved in all patients. The improvement in abduction was slightly better in elevation after SRT compared with IRT (1.7 ± 1 vs 1.4 ± 0.7; P = 0.4) and in depression after IRT compared to SRT (2 ± 1.2 vs 1.1 ± 0.7; P = 0.05). CONCLUSIONS: Both SRT and IRT procedures effectively correct the head posture and primary position deviation in esotropic Duane patients. SRT can be advantageous in patients with an A pattern or more limitation of abduction in elevation; IRT, in patients with a V pattern or more limitation of abduction in depression.

Botulinum toxin-A injection in esotropic Duane syndrome patients up to 2 years of age.

PURPOSE: To evaluate the role of botulinum toxin-A (BTX) injection as the primary treatment for patients with esotropic Duane retraction syndrome ≤2 years of age. METHODS: The medical records of patients with esotropic Duane syndrome who underwent unilateral or bilateral BTX injection to the medial rectus muscle at or before 2 years of age were reviewed retrospectively. The following data were extracted from the record: laterality, age at the time of injection, primary position deviation, duction deficit, anomalous head posture, globe retraction before and after injection, further surgeries, and complications. Success was defined as permanent resolution of esotropia and head turn in primary position at final follow-up. RESULTS: A total of 15 patients (14 unilateral, 1 bilateral) were included. Before BTX injection the mean primary esotropia at near with full cycloplegic refraction was 29.3Δ ± 14.4Δ; the mean head turn, 23° ± 11°. Mean duration of follow-up was 37 ± 29 months (range, 7-96 months). Orthotropia and resolution of head turn was achieved in 7 patients (46.7%). In subgroup analysis, success rate gradually decreased from 100% in patients ≤7 months of age to 33.3% in patients 8-12 months of age, and 20% in patients >12 months of age. Seven patients (46.7%) required surgery (medial rectus recession and/or superior rectus transposition) because of residual head turn and esodeviation following BTX. CONCLUSIONS: In this patient cohort, orthotropia in primary position and correction of head turn were achieved with a single BTX injection in about half of the patients ≤2 years of age and all patients ≤7 months of age. BTX injection early in infancy can obviate the need for surgery in esotropic Duane syndrome.

QSAR of genotoxic active benzazoles.

Previously synthesized 2,5-disubstituted benzoxazole and benzimidazole derivatives, were tested for their genotoxic activity in the Bacillus subtilis rec- assay. The results revealed that 5-methyl-2-(p-aminobenzyl)benzoxazole exhibited the highest genotoxic response, which was comparable to 4-nitroquinoline 1-oxide (4-NQO), the reference agent of classical positive mutagen. Among the other tested compounds, four showed a genotoxic activity. A QSAR study revealed that structural parameters IY(C(2)H(4)) and IY(CH(2)O), indicating the bridge elements between the phenyl moiety and the fused ring system at position 2 and the quantum chemical parameter (DeltaE ), showing the difference between HOMO and LUMO energies, were found significant for enhancing the genotoxic activity in these compounds. In addition, the substituent effects on positions R and R(1) were found important for the activity as well as holding a substituent possessing a maximum length with a minimum width property on position R(1) like alkyl groups. On the other hand, substituting position R with an electron donating group instead of electron withdrawing group increased the genotoxic activity.

Synthesis, antimicrobial activity and QSARs of new benzoxazine-3-ones.

New ethyl 3,4-dihydro-3-oxo-4,6,7-trisubstituted-2H-1,4-benzoxazine-2-acetate derivatives were synthesized and their structures were elucidated by IR, (1)H NMR and mass spectral data. Antimicrobial activity of the compounds was investigated by using the method of twofold serial dilution technique against different Gram-positive, Gram-negative bacteria and some Candida species in comparison to standard drugs. Microbiological results indicated that the synthesized compounds possessed a broad spectrum of activity having MIC values of 6.25-100 micro g/ml against the tested microorganisms. The QSAR analysis of a set of these compounds tested for growth inhibitory activity against Candida krusei was performed by using the computer-assisted multiple regression procedure. The activity contributions for substituent effects of these compounds were determined from the correlation equation for predictions of the lead optimization.

3D-QSAR study on heterocyclic topoisomerase II inhibitors using CoMSIA.

Selective topoisomerase II (Topo II) inhibitors have interested to a great extent for the design of new antitumoral compounds in recent years. Comparative molecular similarity indices analysis (CoMSIA) was performed on a series of previously synthesized benzoxazole, benzimidazole, and oxazolo(4,5-b)pyridine derivatives as eukaryotic Topo II inhibitors. A training set of 16 heterocyclic compounds was used to establish the CoMSIA model. They were constructed and geometrically optimized using SYBYL v7.0. The predictive ability of the model was assessed using a test set of 7 compounds. The best model has demonstrated a good fit having r2 value of 0.968 and cross-validated coefficient q2 value as 0.562 including steric and hydrophobic fields. The hydrophobic interactions showed a dominant role for increasing Topo II inhibitor activity and hydrophilic substituent was found more important than hydrophobic one on the 5 or 6 position of benzazole moiety. The model obtained from the present study can be useful for the modification and/or evaluation of the development of new Topo II inhibitors as potential antitumor compounds.

Anesthetic management for cesarean delivery in a woman with Gilles de la Tourette's syndrome.

Gilles de la Tourette's syndrome is a chronic neuropsychiatric disorder with an early childhood onset featuring mainly motor and vocal tics. We present the anesthetic management for cesarean delivery of a 21-year-old pregnant woman with Tourette's syndrome. She had shrugging of the shoulders and sudden, jerky, repetitive, irregular movements of the hands. General anesthesia was given for cesarean delivery. A live male infant weighing 3130 g was delivered. Her perioperative course was uneventful. No complication was observed. The patient and baby were discharged on the 4th postoperative day. It was decided to prescribe haloperidol 5 mg per day after lactation. Anesthesiologists should remember that there are special considerations when managing anesthesia in patients with Tourette's syndrome. The motor tics may lead to technical difficulty in performing regional anesthesia and surgery. Therefore general anesthesia may be appropriate in order to prevent agitation or involuntary movements. If patient movement and agitation can be controlled by sedation, regional block may be attempted. Drugs such as metoclopramide, ondansetron, midazolam and opioids may be used safely for anesthesia in Tourette's syndrome.