Nitrate reduction enables safer aryldiazonium chemistry.

Aryldiazonium salts remain a staple in organic synthesis and are still prepared largely in accord with the protocol developed in the 19th century. Because of the favorable reactivity that often cannot be achieved with other aryl(pseudo)halides, diazonium chemistry continues to grow. Facile extrusion of dinitrogen contributes to the desired reactivity but is also reason for safety concerns. Explosions have occurred since the discovery of these reagents and still result in accidents. In this study, we report a diazonium chemistry paradigm shift based on nitrate reduction using thiosulfate or dihalocuprates as electron donors that avoids diazonium accumulation. Because nitrate reduction is rate-limiting, aryldiazoniums are produced as fleeting intermediates, which results in a safer and often more efficient deaminative halogenation in a single step from anilines.

Local Energy Decomposition Analysis of London Dispersion Effects: From Simple Model Dimers to Complex Biomolecular Assemblies.

ConspectusLondon dispersion (LD) forces are ubiquitous in chemistry, playing a pivotal role in a wide range of chemical processes. For example, they influence the structure of molecular crystals, the selectivity of organocatalytic transformations, and the formation of biomolecular assemblies. Harnessing these forces for chemical applications requires consistent quantification of the LD energy across a broad and diverse spectrum of chemical scenarios. Despite the great progress made in recent years in the development of experimental strategies for LD quantification, quantum chemical methods remain one of the most useful tools in the hand of chemists for the study of these weak interactions. Unfortunately, the accurate quantification of LD effects in complex systems poses many challenges for electronic structure theories. One of the problems stems from the fact that LD forces originate from long-range electronic dynamic correlation, and hence, their rigorous description requires the use of complex, highly correlated wave function-based methods. These methods typically feature a steep scaling with the system size, limiting their applicability to small model systems. Another core challenge lies in disentangling short-range from long-range dynamic correlation, which from a rigorous quantum mechanical perspective is not possible.In this Account, we describe our research endeavors in the development of broadly applicable computational methods for LD quantification in molecular chemistry as well as challenging applications of these schemes in various domains of chemical research. Our strategy lies in the use of local correlation theories to reduce the computational cost associated with complex electronic structure methods while providing at the same time a simple means of decomposition of dynamic correlation into its long-range and short-range components. In particular, the local energy decomposition (LED) scheme at the domain-based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) level has emerged as a powerful tool in our research, offering a clear-cut quantitative definition of the LD energy that remains valid across a plethora of different chemical scenarios. Typical applications of this scheme are examined, encompassing protein-ligand interactions and reactivity studies involving many fragments and complex electronic structures. In addition, our research also involves the development of novel cost-effective methodologies, which exploit the LED definition of the LD energy, for LD energy quantification that are, in principle, applicable to systems with thousands of atoms. The Hartree-Fock plus London Dispersion (HFLD) scheme, correcting the HF interaction energy using an approximate CCSD(T)-based LD energy, is a useful, parameter-free electronic structure method for the study of LD effects in systems with hundreds of molecular fragments. However, the usefulness of the LED scheme reaches beyond providing an interpretation of the calculated DLPNO-CCSD(T) or DLPNO-MP2 interaction energies. For example, the dispersion energies obtained from the LED can be fruitfully used in order to parametrize semiempirical dispersion models. We will demonstrate this in the context of an emerging semiempirical method, namely, the Natural Orbital Tied Constructed Hamiltonian (NOTCH) method. NOTCH incorporates LED-derived LD energies and shows promising accuracy at a minimum amount of empiricism. Thus, it holds substantial promise for large and complex systems.

Exploring the Accuracy Limits of PNO-Based Local Coupled-Cluster Calculations for Transition-Metal Complexes.

While the domain-based local pair natural orbital coupled-cluster method with singles, doubles, and perturbative triples (DLPNO-CCSD(T)) has proven instrumental for computing energies and properties of large and complex systems accurately, calculations on first-row transition metals with a complex electronic structure remain challenging. In this work, we identify and address the two main error sources that influence the DLPNO-CCSD(T) accuracy in this context, namely, (i) correlation effects from the 3s and 3p semicore orbitals and (ii) dynamic correlation-induced orbital relaxation (DCIOR) effects that are not described by the local MP2 guess. We present a computational strategy that allows us to completely eliminate the DLPNO error associated with semicore correlation effects, while increasing, at the same time, the efficiency of the method. As regards the DCIOR effects, we introduce a diagnostic for estimating the deviation between DLPNO-CCSD(T) and canonical CCSD(T) for systems with significant orbital relaxation.

Exploring the Limits of Intramolecular London Dispersion Stabilization with Bulky Dispersion Energy Donors in Alkane Solution.

We present an experimental study of a cyclooctatetraene-based molecular balance disubstituted with increasingly bulky tert-butyl (tBu), adamantyl (Ad), and diamantyl (Dia) substituents in the 1,4-/1,6-positions for which we determined the valence-bond shift equilibrium in n-hexane (hex), n-octane (oct), and n-dodecane (dod). Computations including implicit and explicit solvation support our temperature-dependent NMR equilibrium measurements indicating that the more sterically crowded 1,6-isomer is always favored, irrespective of solvent, and that the free energy is quite insensitive to substituent size.

Death receptor-dependent apoptosis and cell cycle delay induced by bioymifi in human cervical cancer cells.

In chemotherapy applied against cervical cancer, non-specific cytotoxicity and drug resistance that develops over time are trying to be overcome. Therefore, the development of effective and innovative chemotherapeutic drugs for the treatment is among the priority issues in the medical field. The anticancer activity of the Bioymifi, which can activate apoptosis by inducing DR-5 clustering and aggregation against the human cervical cancer cell line, was investigated in the current study. The cytotoxic activity of Bioymifi on the HeLa cell line was identified using XTT assay. The pathway of the cell death mechanism was analyzed through the cell cycle and Annexin V assays by the flow cytometry. DAPI staining assay was applied under fluorescence microscopy to examine the nuclear morphology. Bioymifi appeared to have a remarkable IC50 value (11.75µM) against HeLa cells. The cell cycle analysis demonstrated the increase of Bioymifi cured HeLa cells in the S phase. And also, 11.75µM of Bioymifi caused a significantly higher apoptotic effect compared to control. In addition, in vitro immunofluorescence experiments of this study represented that Bioymifi reduced Ki-67 localization in HeLa cells. Bioymifi has significantly anticancer actions in Human cervix cancer in vitro and can be combined with standard treatment.

Long-term results of micropulse laser trabeculoplasty with 577-nm yellow wavelength in patients with uncontrolled primary open-angle glaucoma and pseudoexfoliation glaucoma.

Our aim was to evaluate the long-term results of micropulse laser trabeculoplasty (MLT) with 577-nm yellow wavelength in the treatment of glaucoma. We reviewed the medical records of 51 patients (51 eyes) with uncontrolled primary open-angle glaucoma or pseudoexfoliation glaucoma who underwent 180° MLT for the first time. The success of MLT was defined as an IOP reduction of ≥ 20% and IOP < 21 mmHg after treatment. If the number of medications was increased or further laser trabeculoplasty or glaucoma surgery was required after treatment, the case was considered unsuccessful. The mean duration of patient follow-up was 18.39 ± 12.17 months (range 3-52 months). Patients included in the study used 2-4 types of antiglaucoma eye drops (mean 3.43 ± 0.7). The mean number of MLT spots was 65.54 ± 6.19, and the mean energy level was 750.98 ± 101.73 mJ. The decrease in intraocular pressure compared to baseline measurements was: 16.72 ± 11.87%, 15.07 ± 13.76%, 12.63 ± 14.29%, 16.66 ± 19.32%, and 16.75 ± 19.78% during follow-up at 3, 6, 12, 24, and 36-48 months. Successful response was achieved in 35.41%, 36.95%, 34.21%, 40%, 41.17%, and 42.85% of patients during 3, 6, 12, 18, 24, and 36-48 months of follow-ups, respectively. Of the 51 eyes studied, 12 patients (23.5%) underwent post-MLT glaucoma surgery, and 7 patients (13.7%) had cataract surgery, whose follow-up data were subsequently censored. The reduction of intraocular pressure showed a significant correlation with baseline intraocular pressure, while age and laser power showed no correlation (p > 0.05). MLT is a novel treatment option for patients with glaucoma with favorable long-term outcomes and a good safety profile.

GLP-1 agonist liraglutide improves ouabain-induced mania and depressive state via GSK-3ß pathway.

Bipolar disorder (BD) is a severe mental illness characterized by aberrant mood changes between hypomania and mania or mixed states and depression. Metabolic changes also accompany disease progression and cause significant morbidity. Symptomatic treatment options are available, but asymptomatic patients and poor drug responders are significant problems. Based on the most common pharmacological agent that is used in the treatment, lithium and its main mechanisms of action, oxidative stress, and glycogen synthase kinase-3ß (GSK-3ß) signaling are extensively investigated. However, knowledge about the effects of compounds that positively affect oxidative stress and GSK-3ß signaling, such as glucagon-like peptide-1 (GLP-1) mimetics, liraglutide, is still missing. Therefore, in this study, we aimed to investigate the effects of liraglutide on the ouabain-induced bipolar disease model in rats. After intracerebroventricular single dose ouabain administration, animals were treated with 100, 200, and 400 µg/kg liraglutide (s.c.) and valproic acid (200 mg/kg, i.p.) for 10 d. The locomotion and depressive states of animals were assessed by an open field, forced swimming test, and sucrose preference tests. Serum total antioxidant (TAS) and oxidant states (TOS) and glutathione, malonyl dialdehyde (MDA) levels in the brain tissue were determined. GSK-3ß phosphorylation was evaluated by western blotting. Our results demonstrated that liraglutide attenuated ouabain-induced hyperlocomotion and depressive state. Additionally, liraglutide prevented oxidative stress after ouabain administration. Decreased GSK-3ß phosphorylation due to the ouabain insult was alleviated by liraglutide treatment. These findings indicate that the manic and depressive-like behaviors are ameliorated by liraglutide, which exerted antioxidant action, possibly improving GSK-3ß phosphorylation.

Open-Shell Variant of the London Dispersion-Corrected Hartree-Fock Method (HFLD) for the Quantification and Analysis of Noncovalent Interaction Energies.

The London dispersion (LD)-corrected Hartree-Fock (HF) method (HFLD) is an ab initio approach for the quantification and analysis of noncovalent interactions (NCIs) in large systems that is based on the domain-based local pair natural orbital coupled-cluster (DLPNO-CC) theory. In the original HFLD paper, we discussed the implementation, accuracy, and efficiency of its closed-shell variant. Herein, an extension of this method to open-shell molecular systems is presented. Its accuracy is tested on challenging benchmark sets for NCIs, using CCSD(T) energies at the estimated complete basis set limit as reference. The HFLD scheme was found to be as accurate as the best-performing dispersion-corrected exchange-correlation functionals, while being nonempirical and equally efficient. In addition, it can be combined with the well-established local energy decomposition (LED) for the analysis of NCIs, thus yielding additional physical insights.

Effects of acupuncture on pain and levels of IL-17 and IL-23 in the treatment of non-thermal endovenous ablation: A randomized clinical trial.

OBJECTIVES: Acupuncture is one of the oldest therapeutic interventions in the world for the treatment of pain, musculoskeletal diseases, and inflammation. This study aimed to investigate the effect of acupuncture on pain and IL-17 and IL-23 levels in the treatment of endovenous ablation. METHODS: The study was a randomized controlled trial. Patients were divided into group C (Control, n = 35) and group A (Acupuncture, n = 35). Group A patients were treated with acupuncture 24 h preoperatively. Follow-up checkups were conducted intraoperatively, postoperatively, and on the third day. RESULTS: There was no difference between men; there was a difference between women. Visual analog scale score was lower in group A at the intraoperative third and fifth minutes (0.00 vs. 1 and 0.00 vs. 0.5). Analgesic consumption was lower in group A at the end of third day (p = 0.024). Postoperative IL-17 levels were higher than preoperative levels in group A (23.58 vs. 19.33). Postoperative IL-23 levels were lower than preoperative levels in group A (13.66 vs. 29.51). Group C showed increased postoperative IL-23 levels (28.81 vs. 33.51). Preoperative IL-17 and postoperative IL-23 levels were lower in group A than in group C (19.33 vs. 27.69 and 13.66 vs. 33.51). Although no difference was observed between group A and group C in preoperative saphenous vein diameter, postoperative saphenous vein diameter was smaller in group A (p = 0.008). Saphenous vein diameter was smaller on day 3 in group A than in group C (p = 0.043). CONCLUSION: Acupuncture is effective on acute pain and level of IL-23 in the treatment of endovenous ablation using cyanoacrylate.

Addressing the System-Size Dependence of the Local Approximation Error in Coupled-Cluster Calculations.

Over the last two decades, the local approximation has been successfully used to extend the range of applicability of the "gold standard" singles and doubles coupled-cluster method with perturbative triples CCSD(T) to systems with hundreds of atoms. The local approximation error grows in absolute value with the increasing system size, i.e., by increasing the number of electron pairs in the system. In this study, we demonstrate that the recently introduced two-point extrapolation scheme for approaching the complete pair natural orbital (PNOs) space limit in domain-based pair natural orbital CCSD(T) calculations drastically reduces the dependence of the error on the system size, thus opening up unprecedented opportunities for the calculation of benchmark quality relative energies for large systems.

Unveiling the complex pattern of intermolecular interactions responsible for the stability of the DNA duplex.

Herein, we provide new insights into the intermolecular interactions responsible for the intrinsic stability of the duplex structure of a large portion of human B-DNA by using advanced quantum mechanical methods. Our results indicate that (i) the effect of non-neighboring bases on the inter-strand interaction is negligibly small, (ii) London dispersion effects are essential for the stability of the duplex structure, (iii) the largest contribution to the stability of the duplex structure is the Watson-Crick base pairing - consistent with previous computational investigations, (iv) the effect of stacking between adjacent bases is relatively small but still essential for the duplex structure stability and (v) there are no cooperativity effects between intra-strand stacking and inter-strand base pairing interactions. These results are consistent with atomic force microscope measurements and provide the first theoretical validation of nearest neighbor approaches for predicting thermodynamic data of arbitrary DNA sequences.

Effects of Propofol versus Sevoflurane on Postoperative Pain and Neuroendocrine Stress Response in Oocyte Pickup Patients.

Background: Pain aggravates the autonomic response to stress and raises neuroendocrine stress hormone levels. We compared the effects of propofol and sevoflurane on postoperative pain and neuroendocrine stress hormones. A prospective, randomized, and controlled trial was conducted with 60 patients. Methods: We randomly allocated patients to groups P (remifentanil/propofol, n = 30) and S (remifentanil/sevoflurane, n = 30). Preoperative blood samples were taken to measure serum adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), glucagon, cortisol, aldosterone, and prostaglandin E2 (PGE2) levels. Intraoperatively and postoperatively, clinical parameters were monitored at different time points. The hormone levels were again measured in the follicular fluid and blood postoperatively. Result: Demographic data were similar. The preoperative serum aldosterone levels were significantly higher in group P (p=0.001). Preoperative and postoperative serum ACTH, glucagon, cortisol, and PGE2 levels were significantly different in group P (p=0.009, p=0.004, p=0.029, and p=0.002); serum ACTH, glucagon, and PGE2 levels increased while serum cortisol levels decreased postoperatively. In group S, serum CRH and aldosterone levels, both increased in the postoperative period compared to the preoperative (p=0.001, p=0.006). Postoperatively, glucagon and PGE2 levels were both higher in group P than group S (p=0.019, p=0.015). In postoperative follicular fluid, glucagon and PGE2 levels were higher in group P, while cortisol levels were higher in group S (p=0.001, p=0.007, and p=0.001). Conclusion: The effects of anesthetic agents were different. In group P, in the preoperative and postoperative evaluation, ACTH, glucagon, and PGE2 increased postoperatively, while cortisol decreased. In group S, aldosterone and CRH increased postoperatively. Glucagon and PG E2 were higher in group P than S, postoperatively.

Effectiveness and Safety of Coadministration of Intravitreal Dexamethasone Implant and Silicone Oil Endotamponade for Proliferative Diabetic Retinopathy with Tractional Diabetic Macular Edema.

Purpose: To investigate the efficacy and safety of coadministered intravitreal dexamethasone (IVD) implant and silicone oil endotamponade during pars plana vitrectomy (PPV) for the treatment of proliferative diabetic retinopathy (PDR) with tractional diabetic macular edema (DME). Methods: In this prospective, controlled, and randomized clinical study, the eyes with PDR and vitreomacular traction syndrome that underwent PPV with silicone oil endotamponade were divided into 2 groups. Group 1 was defined as the control group, and no other procedures were performed. IVD was implanted to the eyes in Group 2. In both groups, panretinal photocoagulation was completed to the missed areas during PPV. All cases followed for 6 months, postoperatively. Retinal findings were followed with optical coherence tomography and fluorescein fundus angiography. Results: A total of 52 eyes of 52 patients were included in the study. Twenty-six eyes of 23 patients were included in both groups. The improvement in best corrected visual acuity was statistically significantly higher in Group 2 (P > 0.05). In the postoperative period, the DME development rate and intravitreal ranibizumab (IVR) injection requirement were significantly higher in Group 1 (P > 0.05). There was no statistically significant difference in the proliferative vitroretinopathy development rate between the groups (P < 0.05). Conclusion: Coadministration of IVD implant and silicone oil endotamponade to the eyes with PDR during vitrectomy seems to be safe and effective application and may decrease the rate of DME and the requirement of IVR injection.

Design, synthesis, and anticancer activity of novel 4-thiazolidinone-phenylaminopyrimidine hybrids.

4-Thiazolidinones and phenylaminopyrimidines are known as anticancer agents. Imatinib is the pioneer phenylaminopyrimidine derivative kinase inhibitor, which is used for the treatment of chronic myeloid leukemia. With a hybrid approach, a novel series of 5-benzylidene-2-arylimino-4-thiazolidinone derivatives containing phenylaminopyrimidine core were designed, synthesized, and tested for their anticancer activity on K562 (chronic myeloid leukemia), PC3 (prostat cancer), and SHSY-5Y (neuroblastoma) cells. Since superior anticancer activity was observed on K562 cells, further biological studies of selected compounds (8, 15, and 34) were performed on K562 cells. For the synthesis of designed compounds, thiourea compounds were converted to 2-imino-1,3-thiazolidin-4-ones with α-chloroacetic acid in the presence of sodium acetate. 5-Benzylidene-2-imino-1,3-thiazolidin-4-one derivatives were obtained by Knoevenagel condensation of 2-imino-1,3-thiazolidin-4-ones with related aldehydes. Compounds 8, 15, and 34 were evaluated for cell viability, apoptosis studies, cell cycle experiments, and DNA damage assays. IC50 values of compounds 8, 15, and 34 were found as 5.26 ± 1.03, 3.52 ± 0.91, and 8.16 ± 1.27 µM, respectively, in K562 cells. Preferably, these compounds showed less toxicity towards L929 cells compared to imatinib. Furthermore, compounds 8 and 15 significantly induced early and late apoptosis in a time-dependent manner. Compounds 15 and 34 induced cell cycle arrest at G0/G1 phase and compound 8 caused cell cycle arrest at G2/M phase. Based on DNA damage assay, compounds 8 and 15 were found to be more genotoxic than imatinib towards K562 cells. To put more molecular insight, possible Abl inhibition mechanisms of most active compounds were predicted by molecular docking studies. In conclusion, a novel series of 5-benzylidene-2-arylimino-4-thiazolidinone derivatives and their promising anticancer activities were reported herein.

The effect of probiotics on intestinal motility in an experimental short bowel model.

PURPOSE: To investigate the effect of probiotics on spontaneous contractions of smooth muscle isolated from jejunum and ileum of rat model. METHODS: Four rat groups were created (n=8, in each) including control (Group 1), control+probiotic (Group 2), short bowel (Group 3), and short bowel+probiotic (Group 4). Groups 1 and 2 underwent sham operation, Groups 3 and 4 underwent massive bowel resection. Bifidobacterium Lactis was administered in Groups 2 and 4 daily (P.O.) for three weeks. On postoperative week 3, rats were sacrificed, and jejunum and ileum smooth muscle were isolated for organ bath. Muscle contraction changes were analyzed before and after addition of antagonists. RESULTS: Short bowel group exhibited increased amplitude and frequency of spontaneous contractions. The addition of probiotics significantly decreased enhanced amplitude and frequency of bowel contraction in short bowel group and returned to control values. L-NNA increased amplitude and frequency of contractions in all groups. While indomethacin and nimesulide increased the amplitude in all groups, the frequency was only increased in jejunum. Hexamethonium and tetrodotoxin did not change the contraction characteristics in all groups. CONCLUSION: We suggest that early use of probiotics may significantly regulate bowel motility, and accordingly improve absorption of nutrients in short bowel syndrome.

Extrapolation to the Limit of a Complete Pair Natural Orbital Space in Local Coupled-Cluster Calculations.

The domain-based local pair natural orbital (PNO) coupled-cluster DLPNO-CCSD(T) method allows one to perform single point energy calculations for systems with hundreds of atoms while retaining essentially the accuracy of its canonical counterpart, with errors that are typically smaller than 1 kcal/mol for relative energies. Crucial to the accuracy and efficiency of the method is a proper definition of the virtual space in which the coupled-cluster equations are solved, which is spanned by a highly compact set of pair natural orbitals (PNOs) that are specific for each electron pair. The dimension of the PNO space is controlled by the TCutPNO threshold: only PNOs with an occupation number greater than TCutPNO are included in the correlation space of a given electron pair, whilst the remaining PNOs are discarded. To keep the error of the method small, a conservative TCutPNO value is used in standard DLPNO-CCSD(T) calculations. This often leads to unnecessarily large PNO spaces, which limits the efficiency of the method. Herein, we introduce a new computational strategy to approach the complete PNO space limit (for a given basis set) that consists in extrapolating the results obtained with different TCutPNO values. The method is validated on the GMTKN55 set using canonical CCSD(T) data as the reference. Our results demonstrate that a simple two-point extrapolation scheme can be used to significantly increase the efficiency and accuracy of DLPNO-CCSD(T) calculations, thus extending the range of applicability of the technique.

The Impact of Everolimus and Radiation Therapy on Pulmonary Fibrosis.

Background and objectives: Everolimus (EVE) is a mammalian target of the rapamycin (mTOR) inhibitor that is widely used in cancer patients. Pulmonary toxicity, usually manifesting as interstitial pneumonitis, is a serious adverse effect of this drug. Radiation therapy, which is often administered in conjunction with chemotherapy for synergistic effects, also causes pulmonary fibrosis. In view of pulmonary damage development in these two forms of cancer treatment, we have examined the effect of EVE administration individually, in combination with radiation given in varying sequences, and its relation to the extent of pulmonary damage. Materials and Methods: We performed an experimental study in albino rats, which were randomized into five groups: (1) control group, (2) EVE alone, (3) EVE 22 h after radiation, (4) EVE 2 h after irradiation, and (5) only radiation. Sixteen weeks after thoracic irradiation, rat lung tissue samples were examined under light microscopy, and the extent of pulmonary damage was estimated. After this, we calculated median fibrosis scores in each group. Results: The highest fibrosis score was noted in Group 4. Among the five groups, the control group had a significantly lower median fibrosis score compared to the others. When the median fibrosis score of the group that received concurrent EVE with radiation therapy (RT) (Group 4) was compared with that of the control group, the difference was statistically significant (p = 0.0022). However, no significant differences were achieved among the study groups that received EVE only or RT only, whether concurrently or sequentially (p > 0.05). Conclusion: EVE is an effective treatment option for the management of several malignancies and is often combined with other therapies, such as radiation, for a more efficient response. However, an increased risk of pulmonary fibrosis should also be anticipated when these two modalities are combined, as they both can cause pulmonary damage, especially when administered concurrently.

The Effects of Tofacitinib-Mediated Janus Kinase/Signal Transducers and Activators of the Transcription Signal Pathway Inhibition on Collagen Biosynthesis in Hepatic and Skin Fibroblast Cell Culture.

OBJECTIVES: This study aims to investigate the effects of Janus kinase/signal transducers and activators of the transcription (JAK/STAT) pathway inhibition on collagen biosynthesis in fibroblast cell culture by tofacitinib. MATERIALS AND METHODS: BJ-CRL-1474® (skin) and BRL3A® (hepatic) fibroblast cell cultures were proliferated in a suitable medium. Tofacitinib was administered to fibroblast cells proliferating in 96-well flasks at concentrations of 25, 50, 100, 200, 400, and 800 nM. Tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-3 (MMP-3), transforming growth factor beta 1 (TGF-ß1), and hydroxyproline levels were measured using the enzyme-linked immunosorbent assay method. RESULTS: Tofacitinib showed cytotoxic effect on skin and liver cell culture. The cytotoxic effect of tofacitinib started at 100 nM (p<0.05). The highest effect was obtained at 800 nM. The time-dependent cytotoxic effect of tofacitinib was significantly higher at all concentrations after 72 hours than at 24 and 48 hours (p<0.05). The level of TGF-ß1 was significantly lower even at a tofacitinib concentration of 25 nM (p<0.05). There were significant decreases in MMP-3, TIMP-1, and hydroxyproline levels after tofacitinib administration (p<0.05). CONCLUSION: Tofacitinib inhibited fibroblast cell proliferation in a concentration-dependent manner in a fibroblast cell culture. However, further extensive animal and human studies are necessary to determine the clinical significance of this effect.

Can subthreshold micropulse yellow laser treatment change the anti-vascular endothelial growth factor algorithm in diabetic macular edema? A randomized clinical trial.

Purpose: To compare the efficacy of subthreshold micropulse yellow laser (SMYL) and intravitreal aflibercept injection (IAI) combination therapy with IAI monotherapy in the treatment of diabetic macular edema (DME) and to evaluate the number of injections and SMYL sessions required. Methods: This prospective study compared a group of 28 patients treated with a combination of SMYL and IAI with a group of 28 patients treated only with IAI. All patients initially received 3 monthly IAIs, and the monotherapy group was given additional injections as needed. The combination therapy patients additionally received SMYL after the loading phase. The primary outcome measures were the change in the best-corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline to month 12; the secondary outcomes were the mean number of required injections and SMYL sessions. Results: In the monotherapy group, the BCVA improved from 0.38 ± 0.10 to 0.20 ± 0.10 logMAR; in the combination group, BCVA improved from 0.40 ± 0.09 to 0.17 ± 0.06 logMAR at the end of the 12th month. The CMT was reduced from 451.28 ± 44.85 to 328.8 ± 49.69 µm in the monotherapy group and from 466.07 ± 71.79 to 312.0 ± 39.29 µm in the combination group. Improvement of the mean BCVA and reduction of the mean CMT were similar in each group. The combination group required significantly fewer injections (3.21 ± 0.41 vs 5.39 ± 1.54; P < 0.001). By month 12, 75% of patients in the monotherapy group had required additional IAIs when compared with 16% in the combination group (P < 0.001). Conclusion: SMYL combination therapy demonstrated significant visual improvements in patients with DME. In the combination group, the retreatment rate and number of required injections were significantly lower compared with the IAI monotherapy group.

The effect of probiotics on ıntestinal motility in an experimental short bowel model

Abstract Purpose To investigate the effect of probiotics on spontaneous contractions of smooth muscle isolated from jejunum and ileum of rat model. Methods Four rat groups were created (n=8, in each) including control (Group 1), control+probiotic (Group 2), short bowel (Group 3), and short bowel+probiotic (Group 4). Groups 1 and 2 underwent sham operation, Groups 3 and 4 underwent massive bowel resection. Bifidobacterium Lactis was administered in Groups 2 and 4 daily (P.O.) for three weeks. On postoperative week 3, rats were sacrificed, and jejunum and ileum smooth muscle were isolated for organ bath. Muscle contraction changes were analyzed before and after addition of antagonists. Results Short bowel group exhibited increased amplitude and frequency of spontaneous contractions. The addition of probiotics significantly decreased enhanced amplitude and frequency of bowel contraction in short bowel group and returned to control values. L-NNA increased amplitude and frequency of contractions in all groups. While indomethacin and nimesulide increased the amplitude in all groups, the frequency was only increased in jejunum. Hexamethonium and tetrodotoxin did not change the contraction characteristics in all groups. Conclusion We suggest that early use of probiotics may significantly regulate bowel motility, and accordingly improve absorption of nutrients in short bowel syndrome.