Evaluation of the effects of duloxetine treatment on anterior segment parameters by optical coherence tomography.

PURPOSE: To evaluate the effects of Duloxetine on anterior segment parameters and intraocular pressure (IOP) in open angle eyes. METHODS: 38 eyes of 38 patients with fibromyalgia who had open or wide open angles according to the Shaffer classification. Anterior segment optic coherence tomography was performed before and after (month 3) Duloxetine treatment. IOP, central corneal thickness (CCT), corneal endothelial cell density (CECD) and anterior chamber depth (ACD) were also recorded and evaluated. RESULTS: No statistically significant difference was determined in IOP, CCT and CECD (p > 0.05). However, a statistically significant decrease was determined in both the temporal and nasal anterior chamber angle, angle opening distance, nasal trabecular-iris space area and ACD values between the baseline and month 3 (p < 0.001). DISCUSSION: We think that the short term use of Duloxetine does not lead to clinically significant changes despite their statistically significant effects on the anterior chamber parameters.

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML.

Transcription factors (TFs) play critical roles in hematopoiesis, and their aberrant expression can lead to various types of leukemia. The t(8;21) leukemogenic fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia and can enhance hematopoietic stem cell renewal while blocking differentiation. A key question in understanding AE-mediated leukemia is what determines the choice of AE to activate self-renewal genes or repress differentiation genes. Toward the resolution of this problem, we earlier showed that AE resides in the stable AETFC complex and that its components colocalize on up- or down-regulated target genes and are essential for leukemogenesis. In the current study, using biochemical and genomic approaches, we show that AE-containing complexes are heterogeneous, and that assembly of the larger AETFC (containing AE, CBFß, HEB, E2A, LYL1, LMO2, and LDB1) requires LYL1. Furthermore, we provide strong evidence that the LYL1-containing AETFC preferentially binds to active enhancers and promotes AE-dependent gene activation. Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.

DOT1L complex regulates transcriptional initiation in human erythroleukemic cells.

DOT1L, the only H3K79 methyltransferase in human cells and a homolog of the yeast Dot1, normally forms a complex with AF10, AF17, and ENL or AF9, is dysregulated in most cases of mixed-lineage leukemia (MLLr), and has been believed to regulate transcriptional elongation on the basis of its colocalization with RNA polymerase II (Pol II), the sharing of subunits (AF9 and ENL) between the DOT1L and super elongation complexes, and the distribution of H3K79 methylation on both promoters and transcribed regions of active genes. Here we show that DOT1L depletion in erythroleukemic cells reduces its global occupancy without affecting the traveling ratio or the elongation rate (assessed by 4sUDRB-seq) of Pol II, suggesting that DOT1L does not play a major role in elongation in these cells. In contrast, analyses of transcription initiation factor binding reveal that DOT1L and ENL depletions each result in reduced TATA binding protein (TBP) occupancies on thousands of genes. More importantly, DOT1L and ENL depletions concomitantly reduce TBP and Pol II occupancies on a significant fraction of direct (DOT1L-bound) target genes, indicating a role for the DOT1L complex in transcription initiation. Mechanistically, proteomic and biochemical studies suggest that the DOT1L complex may regulate transcriptional initiation by facilitating the recruitment or stabilization of transcription factor IID, likely in a monoubiquitinated H2B (H2Bub1)-enhanced manner. Additional studies show that DOT1L enhances H2Bub1 levels by limiting recruitment of the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex. These results advance our understanding of roles of the DOT1L complex in transcriptional regulation and have important implications for MLLr leukemias.

Amniotic fluid levels of selected trace elements and heavy metals in pregnancies complicated with neural tube defects.

The aims of this study were to determine the levels of trace elements and heavy metals, namely aluminum (Al), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), molybdenum (Mo), cadmium (Cd), tin (Sn), antimony (Sb), mercury (Hg), and lead (Pb), in the amniotic fluid of pregnant women, and to investigate their relationship with neural tube defects (NTDs). The study included 36 pregnant women whose fetuses were complicated with NTDs (study group) and 39 pregnant women with unaffected healthy fetuses (control group), who were matched for body mass index and gestational weeks. The amniotic fluid levels of trace elements and heavy metals were measured using inductively coupled plasma-mass spectrometry and compared between the two groups. Significantly lower mean levels of Zn and Mo and significantly higher levels of Al, Sn, Sb, and Hg in the study group than in the healthy control group were observed, which implied that these elements are possibly correlated with risk factors for the occurrence of NTDs. In contrast, there were no significant differences in the levels of Cr, Mn, Co, Ni, Cu, As, Cd, and Pb between the groups (P ≥ .05).

Measuring and regulating oxygen levels in microphysiological systems: design, material, and sensor considerations.

As microfabrication techniques and tissue engineering methods improve, microphysiological systems (MPS) are being engineered that recapitulate complex physiological and pathophysiological states to supplement and challenge traditional animal models. Although MPS provide unique microenvironments that transcend common 2D cell culture, without proper regulation of oxygen content, MPS often fail to provide the biomimetic environment necessary to activate and investigate fundamental pathways of cellular metabolism and sub-cellular level. Oxygen exists in the human body in various concentrations and partial pressures; moreover, it fluctuates dramatically depending on fasting, exercise, and sleep patterns. Regulating oxygen content inside MPS necessitates a sensitive biological sensor to quantify oxygen content in real-time. Measuring oxygen in a microdevice is a non-trivial requirement for studies focused on understanding how oxygen impacts cellular processes, including angiogenesis and tumorigenesis. Quantifying oxygen inside a microdevice can be achieved via an array of technologies, with each method having benefits and limitations in terms of sensitivity, limits of detection, and invasiveness that must be considered and optimized. This article will review oxygen physiology in organ systems and offer comparisons of organ-specific MPS that do and do not consider oxygen microenvironments. Materials used in microphysiological models will also be analyzed in terms of their ability to control oxygen. Finally, oxygen sensor technologies are critically compared and evaluated for use in MPS.

Ganciclovir ophthalmic gel treatment shortens the recovery time and prevents complications in the adenoviral eye infection.

The purpose of this study was to determine the effectiveness of ganciclovir ophthalmic gel (GOG) in the treatment of adenoviral eye infection (AEI) by looking at the effect of the drug on shortening recovery time, preventing transmission, reducing sequelae, and on complications such as corneal infiltrates and conjunctival pseudomembranes. 200 patients' examination records were evaluated retrospectively. Patients who were within the first 3 days of AEI were divided into two groups: Group 1 with 100 patients who used artificial tears as treatment, and Group 2 with 100 patients who used GOG plus artificial tears (GAT). All patients underwent an eye examination by the same ophthalmologist on the 1st, 5th, 10th, and 15th day after treatment. Using the examination records, variables were compared using SPSS 22.0. There was a statistically significant difference between Groups 1 and 2. Group 2 showed better and faster response to treatment. There was less transmission to the contralateral eye and environment, and less formation of corneal subepithelial infiltrate and conjunctival pseudomembrane in Group 2. Only three patients in Group 2 had corneal involvement. A comparison of each group pre-treatment and during treatment revealed improved signs and symptoms in Group 2 (p < 0.005). The study showed a trend toward more rapid improvement, less corneal and conjunctival involvement, and less transmission to the contralateral eye and environment in the GAT group. These results need to be confirmed by additional studies.

Postoperative analgesic efficacy of fascia iliaca block versus periarticular injection for total knee arthroplasty.

STUDY OBJECTIVE: This study evaluated the postoperative analgesic efficacies of fascia iliaca block and periarticular drug injection techniques after TKA (total knee arthroplasty) surgeries. DESIGN: Prospective, randomized clinical trial. SETTING: University Teaching and Research Center. PATIENTS: Seventy-one American Society of Anesthesiologists (ASA) I-III patients between 48 and 70 years of age who underwent total knee arthroplasty were randomized. INTERVENTIONS: Tenoxicam (20 mg) was administered intramuscularly to both groups of patients 30 minutes before surgery. Patients were randomized into two groups to receive fascia iliaca block before the induction of anesthesia (Group FI) or periarticular drug injection during the surgery (Group PI). All surgeries were performed under general anesthesia using standard techniques. Postoperative analgesia was provided with patient-controlled intravenous morphine. MEASUREMENTS: Total morphine consumption was the primary outcome measure and was recorded postoperatively at 1, 2, 6, 12 and 24 hours. Pain levels at rest and on movement (knee flexion) were evaluated using the Visual Analogue Scale (VAS) and recorded at the same time points. Patients' demographics, rescue analgesic demands, side effects, hemodynamics, and satisfaction scores were also recorded. MAIN RESULTS: The groups had similar VAS scores both at rest and on movement (P>.05). However, the amount of cumulative morphine and use at each follow-up period was higher in Group PI (P<.0001). The groups did not differ significantly in rescue analgesic use or side effects, such as nausea/vomiting, hemodynamic variables, and patient satisfaction scores (P>.05). CONCLUSIONS: Fascia iliaca block may be used as an alternative method to periarticular injection, and it effectively reduces the amount of morphine used to relieve post-TKA pain.

Stakeholder perspectives on European priorities for comprehensive liver cancer control: a conjoint analysis.

BACKGROUND: As liver cancer incidence and mortality remain high in many parts of Europe, a more comprehensive response is required to reduce the burden. Expert stakeholders should be involved in the design of responses because they have important insights about potentially effective responses and will be affected by policy changes. We aimed to prioritize liver cancer control strategies based on European liver cancer stakeholders' views of which strategies would have the greatest impact in a comprehensive liver cancer control plan. METHODS: One hundred liver cancer clinical, policy and advocacy stakeholders from France, Germany, Italy, Spain and Turkey were surveyed. Respondents completed 12 conjoint choice tasks in which they chose which of two subsets of 11 strategies would have the greatest impact in their country. RESULTS: All strategies were considered likely to have a positive impact (P < 0.01). The highest priority strategy was monitoring of at-risk populations, followed by centres of excellence, clinical education, multidisciplinary management, national guidelines, measuring social burden, public awareness, risk assessment and referral, research infrastructure and access to treatments. CONCLUSIONS: Canvassing stakeholder views through a conjoint analysis survey provided a robust quantitative prioritization that can complement traditional qualitative consultation processes. The prioritized strategies provide a logical starting point for decision makers considering developing national plans or collaborative efforts to achieve comprehensive liver cancer control in Europe.

Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database.

OBJECTIVE: Limited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to provide a rationale for their management. METHODS: Analysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas. RESULTS: Adrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10 mm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40 mm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC. CONCLUSIONS: Adrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone-renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour.

Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'etude des Tumeurs Endocrines.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed. OBJECTIVE: The aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1. DESIGN: Data regarding a study of 734 cases of MEN1 from the multicenter 'Groupe d'étude des Tumeurs Endocrines' were analyzed. RESULTS: There were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (P=0.06, P=0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P<0.001, P<0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (P=0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%). CONCLUSION: The phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia.

Opioids for cancer pain: availability, accessibility, and regulatory barriers in Turkey and Pallia-Turk Project.

Palliative care is an emerging topic in Turkey within recent years. Currently, there are only few number of palliative care services across the country and majority of the centers are pain control units. Morphine consumption rate per capita is low, accessibility and availability of morphine products are also limited. One of the main headings of Turkish Cancer Control Programme 2009-2015 is palliative care and a serial palliative care unit implementation with continuous training programmes is planned to be finalized until 2015. This article reviews the current palliative care situation in Turkey, opioid availability in Turkey and also briefly summarizes Pallia-Turk Project which is unique with respect to many different aspects for implementation, and can be a good model for many other countries that still did not have such an implemented palliative care program.

Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d'Etude des Tumeurs Endocrines.

BACKGROUND: In hereditary medullary thyroid carcinoma (HMTC), prophylactic surgery is the only curative option, which should be properly defined both in time and extent. OBJECTIVES: To identify and characterize prognostic factors associated with disease-free survival (DFS) in children from HMTC families. DESIGN: We conducted a retrospective analysis of a multi-center cohort of 170 patients below age 21 at surgery. Demographic, clinical, genetic, biological data [basal and pentagastrine-stimulated calcitonin (CT and CT/Pg, respectively)], and tumor node metastasis (TNM) status were collected. DFS was assessed based on basal CT levels. Kaplan-Meier curves, Cox regression, and logistic regression models were used to determine factors associated with DFS and TNM staging. RESULTS: No patients with a preoperative basal CT <31 ng/ml had persistent or recurrent disease. Medullary thyroid carcinoma defined by a diameter ≥10 mm [hazard ratio (HR): 6.0; 95% confidence interval (95% CI): 1.8-19.8] and N1 status (HR: 20.8; 95% CI: 3.9-109.8) were independently associated with DFS. Class D genotype [odds ratio (OR): 48.5, 95% CI: 10.6-225.1], preoperative basal CT >30 ng/liter (OR: 43.4, 95% CI: 5.2-359.8), and age >10 (OR: 5.5, 95% CI: 1.4-21.8) were associated with medullary thyroid carcinoma ≥10 mm. No patient with a preoperative basal CT <31 ng/ml had a N1 status. Class D genotype (OR: 48.6, 95% CI: 8.6-274.1), and age >10 (OR: 4.6, 95% CI: 1.1-19.0) were associated with N1 status. CONCLUSION: In HMTC patients, DFS is best predicted by TNM staging and preoperative basal CT level below 30 pg/ml. Basal CT, class D genotype, and age constitute key determinants to decide preoperatively timely surgery.

Nuclear deadenylation/polyadenylation factors regulate 3' processing in response to DNA damage.

We previously showed that mRNA 3' end cleavage reaction in cell extracts is strongly but transiently inhibited under DNA-damaging conditions. The cleavage stimulation factor-50 (CstF-50) has a role in this response, providing a link between transcription-coupled RNA processing and DNA repair. In this study, we show that CstF-50 interacts with nuclear poly(A)-specific ribonuclease (PARN) using in vitro and in extracts of UV-exposed cells. The CstF-50/PARN complex formation has a role in the inhibition of 3' cleavage and activation of deadenylation upon DNA damage. Extending these results, we found that the tumour suppressor BARD1, which is involved in the UV-induced inhibition of 3' cleavage, strongly activates deadenylation by PARN in the presence of CstF-50, and that CstF-50/BARD1 can revert the cap-binding protein-80 (CBP80)-mediated inhibition of PARN activity. We also provide evidence that PARN along with the CstF/BARD1 complex participates in the regulation of endogenous transcripts under DNA-damaging conditions. We speculate that the interplay between polyadenylation, deadenylation and tumour-suppressor factors might prevent the expression of prematurely terminated messengers, contributing to control of gene expression under different cellular conditions.

Knee joint synovial cyst following total knee arthroplasty with bone allograft.

Allograft has been shown to be highly successful for managing large osseous defects in total knee arthroplasty. We report a 68-year-old woman in whom a bone allograft had been used during total knee arthroplasty owing to a massive segmental medial tibia plateau defect 4 years earlier. Eighteen months after surgery, a 10x10 cm knee synovial cyst was detected by computed tomography scanning on the anteromedial side of the tibial plateau, and an en-bloc surgical excision was performed. At 36-month follow-up, a 16x12 cm cyst was found. Excision was again performed with removal of the allograft and application of an autologous iliac graft. After allograft removal, clinically and radiologically satisfactory results were achieved at the final follow-up.

Protective effects of melatonin against formaldehyde-induced oxidative damage and apoptosis in rat testes: an immunohistochemical and biochemical study.

This study investigated the protective effects of melatonin against formaldehyde-induced oxidative damage and apoptosis in rat testes. A total of 21 male Wistar rats were divided into three groups. Group I was used as a control, Group II was injected every other day with formaldehyde for 1 month, whereas Group III was injected every other day with formaldehyde and melatonin for 1 month. At the end of the experimental period animals were sacrificed and the testes removed and dissected from the surrounding tissues for immunohistochemical evaluation. In addition, the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) were determined. The levels of SOD and GSH-Px decreased significantly, whereas the level of MDA significantly increased in animals treated with formaldehyde compared with the controls. Apoptosis of spermatogenetic and Leydig cells of testicular tissues was observed. In contrast, rats with melatonin SOD and GSH-Px enzyme activity increased whereas MDA levels decreased with formaldehyde exposure along with apoptosis. In view of the present findings, it is suggested that melatonin treatment may prevent formaldehyde-induced oxidative damage and apoptosis in rat testes.

The correlation of correction magnitude and tibial slope changes following open wedge high tibial osteotomy.

We investigated whether there is a correlation between coronal plane correction magnitude and tibial slope in patients treated with medial open wedge high tibial osteotomy (OWHTO) and also measured changes in patellar height. Thirty-four knees treated with for varus deformities were retrospectively reviewed and the follow-up period of the patients was averaged 24.1 months. Preoperative and postoperative measurements of the Hospital for Special Surgery (HSS) score, Insall-Salvati index, posterior tibial slope angle, mechanical axis deviation, proximal medial tibial angle (PMTA) was used to determine. All patients had a significant increase in their HSS score postoperatively (P < 0.0001). There was no significant correlation between the differences in patellar heights (P = 0.368). The mechanical axis deviation was altered by a mean of 25.5 +/- 10.9 mm and the difference was statistically significant (P < 0.05). The mean posterior tibial slope angle on preoperative radiographs was 9.0 +/- 5.1 degrees ; on postoperative radiographs it was 11.7 +/- 5.7 degrees and the difference was statistically significant (P < 0.007). Seventeen knees (50%) demonstrated postoperative posterior tibial slope angle increases; 7 knees (21%) had a decrease in this angle, while 10 knees (29%) showed no change. Statistical analyses revealed that the mechanical axis deviation was not correlated with change in tibial slope (P = 0.837). Although we could not find a correlation between tibial slope change and the amount of coronal correction, 50% of our patients demonstrated increased tibial slope.

The 3' processing factor CstF functions in the DNA repair response.

Following DNA damage, mRNA levels decrease, reflecting a coordinated interaction of the DNA repair, transcription and RNA processing machineries. In this study, we provide evidence that transcription and polyadenylation of mRNA precursors are both affected in vivo by UV treatment. We next show that the polyadenylation factor CstF, plays a direct role in the DNA damage response. Cells with reduced levels of CstF display decreased viability following UV treatment, reduced ability to ubiquitinate RNA polymerase II (RNAP II), and defects in repair of DNA damage. Furthermore, we show that CstF, RNAP II and BARD1 are all found at sites of repaired DNA. Our results indicate that CstF plays an active role in the response to DNA damage, providing a link between transcription-coupled RNA processing and DNA repair.

Hamartoma of the breast.

Breast hamartoma is a rare benign tumour that leads to unilateral breast enlargement without a palpable localized mass lesion. Histologically, a hamartoma consists of varying amounts of adipose, gland, fibre and smooth muscle tissue. The characteristic mammographic appearance of hamartoma of breast has distinct mammographic features with circumscription and fat and soft-tissue density surrounded by a thin radiopaque capsule or pseudocapsule. Ultrasonographic findings include a well-defined mass lesion consisting of echogenic and sonolucent areas. We present histopathological and radiological findings of a 42-year-old female patient with breast hamartoma who has no complaint.

[A Multiple endocrine neoplasia type-1 observatory in a French-speaking area. A tool from the Endocrine Tumor study Group (GTE)]. / Observatoire francophone des néoplasies endocriniennes multiples de type 1. Un outil du Groupe d'étude des Tumeurs Endocrines (GTE).

Wermer's syndrome or Multiple Endocrine Neoplasia Type-1 (MEN1) is an autosomal dominant inherited disease, related to mutations in MEN1, an approximately 10-kb gene encoding menin, localized on chromosome 11q13. The Endocrine Tumor Group (GTE) has set up a MEN1 observatory of 1001 regularly followed MEN1 cases. This observatory aims at registering and evaluating MEN1 cases in a large cohort. Any new study on a particular unexplored aspect of the disease may be proposed by a physician to the GTE. This article describes the way to diagnose a new MEN1 case and to register it. Procedures for participating in a new study are presented. Some original results are quoted.