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.

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.

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.

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.

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.

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.

Evidence for neurotoxicity associated with amoxicillin in juvenile rats.

Amoxicillin (AMX) is one of the most commonly prescribed antibiotics for children, and childhood is the period to have the highest risk for toxicity cases including drug-induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, confusion, convulsions, and behavioral changes) have been reported related to AMX treatment. In the present study, we aimed to determine the neurotoxic effects of AMX administration at clinically relevant doses in female juvenile rats. AMX was administered in single oral daily doses of 25 and 50 mg/kg for 14 days. According to our results, while AMX administration caused a significant increase in the immobility time of animals, swimming time of these animals significantly decreased. AMX administration significantly reduced the onset of pentylenetetrazole-induced convulsions. The serotonin levels of brain tissues in the AMX-administered groups were decreased significantly, which is thought to be related to depression. The glutamate levels in brain tissues increased significantly in AMX-administered groups, which is thought to be related to convulsion. Otherwise, superoxide dismutase and catalase activities were significantly decreased in brain tissues of AMX-administered groups. In conclusion, AMX administration triggered depression and shortened the time of the appearance of first seizure in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of AMX-induced neurotoxicity.

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.

Bio-engineered synovial membrane to prevent tendon adhesions in rabbit flexor tendon model.

During tendon injuries, the tendon sheath is also damaged. This study aims to test effectiveness of engineered tendon synovial cell biomembrane on prevention of adhesions. Forty New Zealand Rabbits enrolled into four study groups. Engineered synovial sheath was produced by culturing cell suspension on fabricated collagen matrix membrane. Study groups were: tendon repair (group A), tendon repair zone covered with plane matrix (Group B), synovial suspension injection into the zone of repair over matrix (Group C), and biomembrane application (Group D). Biomechanical evaluations of tendon excursion, metacarpophalangeal and proximal interphalangeal joints range of motion, H&E and Alcian Blue with neutral red staining, and adhesion formation graded for histological assessments were studied. Ten non-operated extremities used as control. Tendon excursions and range of motions were significantly higher and close to control group for Group D, p < 0.05. Adhesion formation was not different among Groups C, D, and Control, p > 0.005. Hyaluronic acid synthesis was demonstrated at groups C and D at the zone of injury. Application of synovial cells into the tendon repair zone either by cell suspension or within a biomembrane significantly decreases the adhesion formation. Barrier effect of collagen matrix and restoration of hyaluronic acid synthesis can explain the possible mechanism of action.

Examination of the effects of thiamine and thiamine pyrophosphate on Doxorubicin-induced experimental cardiotoxicity.

BACKGROUND AND PURPOSE: To investigate the effect of thiamine and thiamine pyrophosphate on doxorubicin-induced cardiotoxicity biochemically and histopathologically and to examine whether doxorubicin cardiotoxicity is related to the conversion of thiamine into thiamine pyrophosphate and inhibition of thiamine pyrophosphokinase (TPK) enzyme. EXPERIMENTAL APPROACH: A total of 48 Albino Wistar male rats were used. Rats were divided into groups as thiamine + doxorubicin (TIA + DOX), thiamine pyrophosphate + doxorubicin (TPP + DOX), DOX, and healthy (HEA) groups. One hour after the administration of thiamine and TPP in 25 mg/kg doses, 5 mg/kg doxorubicin were injected to all groups except HEA group during 7 days. Then, the samples were collected for biochemical (glutathione [GSH], malondialdehyde [MDA], DNA damage, creatine kinase (CK), CK-MB, and troponine I [TP-I]), molecular (TPK), and histopathological examinations. KEY RESULTS: Oxidant parameters (MDA and DNA damage) decreased and antioxidant parameter (GSH) increased in TPP + DOX group. In addition, levels of CK, CK-MB, and TP-I were low in the TPP + DOX group and high in the TIA + DOX and DOX groups. Cardiac tissue was protected in TPP + DOX group, and no protective effect was observed in TIA + DOX and DOX groups. Messenger RNA expression of TPK was decreased in DOX and TIA + DOX groups. CONCLUSION AND IMPLICATIONS: The cardiotoxic effect of doxorubicin originated from the inhibition of TPK enzyme resulting in insufficient production of thiamine pyrophosphate.

The prevention of ischemia/reperfusion induced oxidative damage by venous blood in rabbit kidneys monitored with biochemical, histopatological and immunohistochemical analysis.

The purpose of this study was to investigate the biochemical, histopathological and immunohistochemical effects of venous blood on ischemia/reperfusion-induced oxidative DNA damage and mutation in rabbit kidneys in comparison to melatonin treatment, which has a known protective effect against ischemia/reperfusion (IR) injury. The rabbits were divided into five groups: renal ischemia (RI), renal ischemia-reperfusion (RIR), renal ischemia-venous blood-reperfusion (RIVR), melatonin + renal ischemia-reperfusion (MRIR), and the healthy sham control group (HG). Melatonin (2.5 mg/kg delivered intraperitoneally) was administered one hour prior to ischemia. In the RIVR group, 1 ml of venous blood was administered 5 minutes before the reperfusion. The xanthine oxidase activity in the kidney tissue was determined as 53.50 ± 1.72, 31.00 ± 6.39, 45.66 ± 9.20, 28.66 ± 6.05 and 14.33 ± 1.28 U/g protein; the MDA levels were 6.32 ± 0.02, 19.50 ± 1.33, 7.00 ± 0.96, 7.50 ± 0.76 and 4.75 ± 0.34 mmol/g protein; and the GSH levels were 4.50 ± 1.08, 2.76 ± 0.13, 5.48 ± 0.22, 4.93 ± 0.55 and 6.98 ± 0.33 nmol/g protein in the RI, RIR, RIVR, MRIR and HG groups, respectively. Blood, blood urea nitrogen (BUN) and creatinine levels were classified as high only in the RIR group. The MRIR and RIVR groups, in which oxidative stress was best suppressed, had much milder histopathological and immunohistochemical findings compared to the RIR group. This study has revealed that it is useful to initiate reperfusion of the ischemic tissue with venous blood.

Horizontal muscle transposition or oblique muscle weakening for the correction of V pattern?

PURPOSE: To report and to analyze the efficacy of horizontal rectus muscle transposition and inferior oblique muscle weakening in terms of pattern correction for patients with V pattern. METHODS: The review of the medical files identified 55 patients who had esotropia (ET) or exotropia (XT) with V pattern. The primary outcome measure was the amount of V pattern collapse (Δ). RESULTS: Of the 55 patients (mean age 22.1 ± 9.5 years), 27 (49.1%) were males and 28 (50.9%) were females. The type of deviations was XT in 30 patients (54.5%) and ET in 25 patients (45.5%). Inferior oblique muscle weakening was performed in 43 (78.2%) patients, whereas horizontal muscle transposition was carried out in 12 (21.8%) patients in addition to recession-resection procedures. The amount of pattern was significantly reduced in both groups (P=0.01 for the horizontal offset group and P<0.01 for the oblique muscle weakening group). CONCLUSION: Oblique muscle weakening surgery and horizontal muscle offset are effective in the correction of V pattern when the amount of pattern is under 30Δ.

Predictors and outcomes of minor cerebrovascular events after cardiac surgery: a multivariable analysis of 1346 patients.

AIM: There are no extensive data exist regarding the epidemiology and prognosis of minor cerebrovascular events (MCVE) in adults after cardiac surgery. The aim of this study was to determine perioperative predictors of MCVE and impact on postoperative outcomes after cardiac surgery. METHODS: The database of 1346 adult patients between June 2004-May 2011 were retrospectively analyzed to determine risk factors for postoperative MCVE and prognostic impact in our instution. MCVE was defined as ''a new focal neurologic deficit which appears in the postoperative period''. Data were collected on patient characteristics, intraoperative variables and outcomes, postoperative course, and discharge status by univariate analyses. Then multivariate logistic regression with forward elimination determined six important denominators of the 24 factors examined on univariate analysis for MCVE. RESULTS: Twenty-six patients suffered a postoperative minor stroke (2%) at a median of 24 hours postoperatively. Head computed tomography was performed in 19 patients (73%) of whom ischemic stroke were identified in 4 (21.05%) patients and pituitary macroadenoma was diagnosed in one patient treated with surgery. Patients who experienced MCVE had no operative mortality and were discharged without any neurological deficit. Multivariable logistic regression analysis identified six risk factors for MCVE: unstable angina pectoris, hyperlipidemia, cerebrovascular accident within two years, EF<50, intra-aortic balloon counterpulsation and higher Euroscore values. CONCLUSION: Unstable angina pectoris, hyperlipidemia, cerebrovascular accident within last two years, EF<50, intra-aortic balon counterpulsation and higher Euroscore values in adults after cardiac surgery are independent predictors of minor stroke as compared with similar predictors of major stroke.