Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process

Interactions between the multikinase inhibitor sorafenib and the BH3-mimetic obatoclax (GX15-070) were examined in human acute myeloid leukemia (AML) cells. Treatment with sorafenib/obatoclax induced pronounced apoptosis in and reduced the clonogenic growth of multiple AML lines and primary AML cells but not normal CD34(+) cells. Sorafenib triggered rapid and pronounced Mcl-1 down-regulation accompanied by enhanced binding of Bim to Bcl-2 and Bcl-xL, effects that were abolished by obatoclax coadministration. Notably, shRNA knockdown of Bim, Bak, or Bax, but not Noxa, significantly attenuated obatoclax/sorafenib lethality, whereas ectopic expression of Mcl-1 exerted a protective effect. Furthermore, exposure of leukemia cells to sorafenib and obatoclax markedly induced autophagy, reflected by rapid and pronounced LC3 processing and LC3-green fluorescent protein (GFP) punctate formation. Multiple autophagy inhibitors or VPS34 knockdown, significantly potentiated sorafenib/obatoclax lethality, indicating a cytoprotective role for autophagy in this setting. Finally, studies in a xenograft mouse model revealed that combined sorafenib/obatoclax treatment markedly reduced tumor growth and significantly prolonged survival in association with Mcl-1 down-regulation and apoptosis induction, whereas agents administered individually had only modest effects. These findings suggest that combining sorafenib with agents that inhibit Mcl-1 and Bcl-2/Bcl-xL such as obatoclax may represent a novel and potentially effective strategy in AML.     

Enhanced visible light-mediated photocatalysis,antibacterial functions and fabrication of a 3-chlorophenol sensor based on ternary Ag2O·SrO·CaO

A novel multi-metal oxide nanocomposite, Ag₂O·SrO·CaO, was synthesized by a facile co-precipitation method followed by calcinations. The synthesized nanocomposite was characterized by XRD, FESEM, EDS, TEM, FTIR spectroscopy and photoluminescence (PL) spectroscopy. The composite showed enhanced photocatalytic activity under visible light irradiation and excellent anti-bacterial performance against both Gram-positive and Gram-negative bacteria. Here, the synthesized Ag₂O·SrO·CaO nanomaterials were deposited on a glassy carbon electrode (GCE) in the form of a thin film to fabricate the desired electrochemical sensor and subjected to I–V analysis of 3-chlorophenol (3-CP) in a phosphate buffer solution (PBS). A calibration curve was plotted from the linear relation of current versus concentration and used to calculate the sensitivity (8.9684 μA μM⁻¹ cm⁻²), linear dynamic range (LDR, 0.1 nM to 0.01 mM) and lower limit of detection (DL, 97.12 ± 4.86 pM). The analytical parameters of the sensor such as response time, reproducibility and long-term stability in the detection of 3-CP were reliable. Finally, it was used to analyze real samples collected from various environmental sources and found to be acceptable.

The electrochemical detection mechanism of 3-CP in PBS buffer using the heterostructure nanocomposite Ag₂O·SrO·CaO. The proposed electrochemical reaction is supposed as C₆OH₅Cl + 11H₂O → 6CO₂ + 27H⁺ + Cl⁻ + 26e⁻.     

Circumpapillary optical coherence tomography angiography differences in perimetrically affected and unaffected hemispheres in primary open-angle glaucoma and the preperimetric fellow eye

Purpose:Evaluation of circumpapillary vessel density (VD) and perfusion density (PD) on optical coherence tomography angiography (OCTa) in mild-moderate glaucoma patients having unilateral visual field defects, with their fellow eyes and controls.Methods:Both eyes of 24 patients having a definitive nasal step or arcuate scotoma in one hemisphere of one eye only, and 24 controls, underwent OCTa.Results:In eyes with a superior field defect, the superior/inferior quadrant ratios, (SQ/IQ) of 3 mm scan of VD and PD were significantly higher in eyes with a superior arcuate scotoma than fellow eyes (P = 0.03,0.02) as also controls, (P = 0.004,0.001). The mean percentage loss of inferior quadrant VD between control to fellow eyes, and superior nasal step eyes were similar, 20.19%/19.57% respectively, P = 0.85, while a loss in arcuate scotoma eyes was 38.81% (P = 0.001). The percentage decrease in inferior quadrant PD in fellow eyes was 14.70%, superior nasal step 23.39%, and an arcuate scotoma 34.74% (P = 0.02). Eyes with a superior nasal step had significantly lower VD and PD absolute values in the inferior quadrant OCTa in 3 mm and 6 mm circle scan only as compared to control eyes, VD, P = 0.03,0.04/PD, P = 0.008,0.02. Fellow eyes of superior field defects had significantly lower VD and PD absolute values in the inferior quadrant in 3 mm and 6 mm circle scan as compared to control eyes, VD, P = 0.006,0.04/PD, P = 0.01,0.03. Eyes with an isolated inferior field defect in only one eye, showed a significant decrease in both VD and PD in all quadrants as compared to fellow eyes and control eyes. A significant positive correlation was found between VD and RNFL thickness in peripapillary superior unaffected quadrants in eyes with superior field defects and inferior unaffected quadrants in inferior defects (P = 0.001 and 0.01).Conclusion:There was a statistically significant increasing SQ/IQ ratio and percentage loss of vascular parameters from control to fellow eyes, those with a superior nasal step, and those with a superior arcuate scotoma. Inferior VFDs appeared to be associated with a more generalized circulatory loss. The asymmetry between hemispheres and between eyes could be used as a biomarker for early glaucomatous neuropathy.     

Visual performance of four types of diffractive multifocal intraocular lenses and a review of articles

AIM: To compare the clinical outcomes of a variety of multifocal intraocular lenses(MIOLs) in patients diagnosed with presbyopia or cataracts. METHODS: This clinical trial study included 141 patients(282 eyes) with different MIOLs implantation. The Symfony(60 eyes), the Re STOR(100 eyes), the AT LISAtri(60 eyes), and the Pan Optix(62 eyes) intraocular lenses were evaluated in this prospective interventional study. The near, intermediate, and distant visual acuities, contrast sensitivity, and defocus curve were measured as valid criteria. To statistically analyze the results, we used the Statistical Package for Social Science software, the non-parametric Wilcoxon signed-rank t, the one-way analysis of variance and the Tukey’s post-hoc test in our analysis. Moreover, we conducted a detailed literature search on the Pub Med database in English about MIOLs, in total 59 studies were included in this review article.RESULTS: The four approaches did not show any significant difference in the best-corrected distance visual acuity(P>0.05). The defocus curves at the contrast of 100% showed that trifocal IOLs had better intermediate performance than the bifocal IOL(P<0.05). There were no statistically significant differences between AT LISAtri and Pan Optix lenses for visual acuity at all distances. The eyes with Pan Optix, Symfony, and AT LISAtri IOL showed better contrast sensitivity than those Re STOR at spatial frequencies of 1, 3, and 6 cpd in photopic and mesopic conditions(P<0.001). CONCLUSION: All four groups of the multifocal lenses were satisfying in terms of distance and near vision. Also, the group of trifocal lenses led to satisfactory outcomes in intermediate vision, without degradation in quality of vision.     

Transrectal Ultrasound Guided Hydrodistension – A New Surgical Way in Transgender Surgery

BackgroundCreating the neovaginal canal in transwomen is one of the most delicate steps of Genital Gender Affirming Surgery (GGAS). Injury to the rectum is a rare but serious complication that can lead to further surgery and even creation of a colostomy.AimImplementation of a novel hydrospacing technique (HST) based on transrectal ultrasound (TRUS)-guided hydrodistension.MethodsBetween June 2018 and June 2020 54 transwomen received GGAS with HST. Immediately before GGAS transperineal hydrodistension was performed using a TSK-Supra-Needle (20 Gauge, 120 mm length), that was placed under direct TRUS-guided visual control between Denonvilliers’ fascia and the anterior rectal wall. 40 – 60 ml normal saline were administered perineally to separate Denonvilliers’ fascia from the anterior rectal wall to create a dissection of at least 20 mm. For better intraoperative visualization the hydrodissected space was also dyed using 2ml of methylenblue while retracting the needle. A retrospectively analysed, clinically and demographically comparable series of 84 transwomen who underwent GGAS between June 2016 and June 2018 served as control group. All 138 surgeries were performed by the same experienced surgeon.OutcomesThe effect of the novel hydrospacing technique on neovaginal dimensions and operating time.ResultsPatients in both groups did not differ in baseline patient characteristics such as age and body mass index (HST 35 vs 38 years in control group, P = .44 and body mass index 26 vs 25 kg/m², P = .73). Vaginal depth and width were significantly larger in the HST subgroup as compared to controls (14.4 cm vs 13.5 cm, P = .01 and 4.2 cm vs 3.8 cm, P < .001). No statistically significant difference occurred in intraoperative rectal injury (n = 0 in HST group, n = 2 in control group, P = .26). Median total OR-time was comparable for GGAS including HST before vaginoplasty to standard technique (211 minutes for HST vs 218 minutes; P = 0.19).Clinical implicationsThe proposed additional surgical step during GGAS is minimally invasive and safe, simplifies GGAS and potentially helps to avoid complications such as rectal injury.Strength & LimitationsSingle-surgeon series, limited follow-up time and no prospective randomization.ConclusionHST is a safe and feasible procedure, which facilitates a safe preparation of the neovaginal canal during male to female GGAS.Panic A, Rahmani N, Kaspar C, et al. Transrectal Ultrasound Guided Hydrodistension – A New Surgical Way in Transgender Surgery. J Sex Med 2021;18:1135–1141.     

Diabetic emergencies including hypoglycemia during Ramadan

Majority of physicians are of the opinion that Ramadan fasting is acceptable for well-balanced type 2 patients conscious of their disease and compliant with their diet and drug intake. Fasting during Ramadan for patients with diabetes carries a risk of an assortment of complications. Islamic rules allow patients not to fast. However, if patient with diabetes wish to fast, it is necessary to advice them to undertake regular monitoring of blood glucose levels several times a day, to reduce the risk of hypoglycemia during day time fasting or hyperglycemia during the night. Patient with type 1 diabetes who fast during Ramadan may be better managed with fast-acting insulin. They should have basic knowledge of carbohydrate metabolism, the standard principles of diabetes care, and pharmacology of various antidiabetic drugs. This Consensus Statement describes the management of the various diabetic emergencies that may occur during Ramadan.     

Laparoscopic donor nephrectomy: an increasingly common cause for testicular pain and swelling

INTRODUCTION

Laparoscopic donor nephrectomy (LDN) is now a well established method for kidney procurement from living donors. In our centre, LDN is currently offered only to donors suitable for a left nephrectomy. The aim of this study was to investigate the incidence of testicular pain and swelling following LDN.

METHODS

A total of 25 left-sided LDN male patients were assessed in a prospective structured interview together with a control cohort of 25 male patients who had undergone left-sided open donor nephrectomy (ODN).

RESULTS

Data were collected on testicular pain, swelling, numbness, urinary symptoms and sexual dysfunction from all 50 patients (100% response rate). Of the 25 LDN patients, 11 (44%) experienced ipsilateral testicular pain and/or swelling. In most instances, pain was of immediate onset, mild to moderate in severity, lasted for a few days to several weeks and was associated with testicular swelling (10 of 11 cases). However, testicular pain and/or swelling were not apparent in ODN patients, with only 2 of 25 (8%) experiencing mild testicular pain, 1 of whom also had swelling.

CONCLUSIONS

Testicular pain and swelling following LDN is a common problem. It is underreported in the literature and should be included in the differential diagnoses of testicular pain and swelling. Further investigation is required to confirm our findings.     

Risk factors in IVIG-resistant Kawasaki disease and correlation with Japanese scoring systems — a study from Eastern India

Clinical Rheumatology - To assess the risk factors of intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) and to evaluate the performance of the three Japanese risk-scoring systems,...