Effects of Photobiomodulation With Two Wavelengths of 630 and 810 nm on Diabetic Neuropathy.

Introduction: Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes patients. Among different therapeutic approaches for treating DPN, low-level laser therapy (LLLT) or photobiomodulation (PBM) is a new promising non-invasive technique. This study aims to evaluate the effect of visible and infra-red LLLT on DPN. Methods: Sixty DPN patients enrolled in a randomized-controlled study. The patients were randomly divided into the same population of control and laser groups. The patients in the laser group received LLLT with two wavelengths of 630 and 819 nm and conventional therapy, and those in the control group received conventional therapy alone. Irradiation of the patients lasted 15 minutes per session, and it was performed over the surface of each foot three times a week for 12 sessions. The patients were evaluated at baseline and at the end of the study with the Michigan Neuropathy Screening Instrument (MNSI) and microfilament test. Results: Patients' sensation in the right foot in the monofilament test had increased from 22 (84.6%) to 26 (86.7%) (P=0.000), and in the left foot it had increased from 20 (80%) to 25 (86.2%) (P=0.001). The mean and standard deviation of the scores of section A of the Michigan questionnaire showed a statistically significant difference between the two groups (P<0.05), but the B part scores of the Michigan test did not show a significant difference. Conclusion: This study showed that the visible and infra-red LLLT significantly improved the symptoms of diabetic neuropathy without any side effects.

Comparable Outcomes of Pre- Versus Post-Tyrosine Kinase Inhibitor Era Treatment in Chronic Myeloid Leukemia: A Retrospective Cohort Study With Long-term Follow-up.

Imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was introduced after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with chronic myeloid leukemia (CML). However, the long-term effects of allo-HSCT in chronic phase CML patients are mostly unknown. We retrospectively analyzed the outcomes of 204 patients with sibling donors who received peripheral stem cells and underwent allo-HSCT of chronic phase I (CP1) in the pre- and post-TKI era at Shariati Hospital in Tehran, Iran, from 1998 to 2017 and followed up till the end of 2021. The median follow-up time for all patients was 8.7 (SD = 0.54) years. Fifteen-year overall survival (OS), disease-free survival (DFS), graft-versus-host disease-free relapse-free survival (GRFS), relapse, and non-relapse mortality (NRM) incidence were 65.70%, 57.83%, 17.56%, 13.17%, and 28.98%, respectively. Using multivariable analyses, the only risk factor increasing the hazard of death was the time between diagnosis to allo-HSCT greater than 1 year compared to this time less than 1 year by 74% [hazard ratio (HR) = 1.74, P = 0.039]. Also, age is a significant risk factor for DFS (HR = 1.03, P = 0.031). Our findings suggested that allo-HSCT is still an important treatment option for CP1 patients, especially those resistant to TKI treatment. TKI consumption can have a desirable effect on NRM after allo-HSCT for CP1 CML.

Transplantation-based screen identifies inducers of muscle progenitor cell engraftment across vertebrate species.

Stem cell transplantation presents a potentially curative strategy for genetic disorders of skeletal muscle, but this approach is limited by the deleterious effects of cell expansion in vitro and consequent poor engraftment efficiency. In an effort to overcome this limitation, we sought to identify molecular signals that enhance the myogenic activity of cultured muscle progenitors. Here, we report the development and application of a cross-species small-molecule screening platform employing zebrafish and mice, which enables rapid, direct evaluation of the effects of chemical compounds on the engraftment of transplanted muscle precursor cells. Using this system, we screened a library of bioactive lipids to discriminate those that could increase myogenic engraftment in vivo in zebrafish and mice. This effort identified two lipids, lysophosphatidic acid and niflumic acid, both linked to the activation of intracellular calcium-ion flux, which showed conserved, dose-dependent, and synergistic effects in promoting muscle engraftment across these vertebrate species.

Biodegradable chitosan-graphene oxide as an affective green filler for improving of properties in epoxy nanocomposites.

In this work, we investigated the effect of biodegradable Chitosan-encapsulated Graphene Oxide (CGO) on the morphology and properties of epoxy composites prepared using solution mixing with different filler loadings. The microstructures and properties of chitosan-GO and composites were studied using FTIR, XRD, SEM, TEM, tensile, impact, bending analysis, DMTA and TG tests. Microstructural observations confirmed that the CGO composition and its content in the matrix affected the distribution of fillers in the epoxy matrix. Mechanical and thermal tests indicated that the loading level of CGO and the ratio of chitosan to GO were the main factors that changed the strength of epoxy/CGOs composites. The tensile analysis confirmed that nanocomposites containing CGO exhibited a 65 % increase in elastic modulus due to the improved load transfer as a result of interfacial interactions between CGO and the matrix. DMTA analysis showed that the presence of CGO in the epoxy matrix increased Tg of the composite by ~30 °C. In the TGA test, although the introduction of CGO caused higher decomposition temperature of the CGO filled resins. CGO enhanced the final properties of epoxy-based nanocomposites as a result of the synergistic effect of chitosan and GO and the formation of 3-D CGO structures in the epoxy matrix.

Modified combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) as compared with standard ATG protocol in haploidentical peripheral blood stem cell transplantation for acute leukemia.

In haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), the combination of anti-thymocyte globulin and post-transplant cyclophosphamide (ATG/PTCy) has a synergistic impact in preventing graft-versus-host disease (GvHD). However, little is known about the long-term consequences of the new combination approach. Our goal is to evaluate the efficacy of ATG/PTCy versus a standard ATG regimen by focusing at long-term outcomes in a more homogeneous group of patients. We retrospectively included 118 adult patients up to 60 years with acute leukemia who underwent haplo-PBSCT at our single institution, following the same myeloablative conditioning regimen. From 2010 to 2020, 78 patients received a modified combination of ATG (2.5 mg/kg/day, on days -3, -2, and -1) and PTCy (40 mg/kg/day on days +3 and +4) compared to 40 patients who had a standard ATG-based regimen (2.5 mg/kg/day from days -4 to -1) from 2008 to 2015. The median follow-up time for all patients was 5.36 years, respectively. The cumulative incidence (CI) of neutrophil and platelet engraftment, as well as CMV reactivation, did not differ statistically between the two groups. The CI of the acute GvHD of grades II-IV and III-IV and extensive chronic GvHD were considerably lower in the ATG/PTCy (34.6%, 8.97%, and 13.63%) than in the ATG cohort (57.5%, 30%, and 38.23%) as validated by multivariable modeling. Additionally, compared to the ATG arm, the ATG/PTCy was a hazard factor associated with a higher risk of relapse (HR = 2.23, p = 0.039). The probability of 5-year overall survival, disease-free survival, and GvHD-free relapse-free survival in the ATG/PTCy group (53.34%, 49.77%, and 36.04%) was comparable with the ATG group (47.5%, 42.5%, and 22.5%), respectively. Our finding suggested that a modified ATG/PTCy combination resulted in a lower risk of acute and chronic GvHD and a higher risk of relapse than the standard ATG-based protocol but had no effect on long-term outcomes. However, certain adjustments in the immunosuppression protocol are warranted to improve the outcome.

Outcomes of haploidentical peripheral stem cell transplantation with combination of post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) compared to unrelated donor transplantation in acute myeloid leukemia: A retrospective 10-year experience.

In the evolution of haploidentical hematopoietic stem cell transplantation (haplo-HSCT), In vivo T-cell modulation with concomitant use of anti-thymocyte globulin (ATG) and high-dose post-transplant cyclophosphamide (PTCy) provides a novel promising method on transplant outcomes; however, the long-term effects of this therapy are mostly unknown. We retrospectively compared the long-term outcomes of adult acute myeloid leukemia (AML) patients undergoing a haplo-HSCT (n = 92) with a new modified combination of ATG and PTCy in the context of peripheral blood stem cell (PBSC) and myeloablative conditioning (MAC) with an otherwise similar group of AML patients who received an unrelated donor (URD) HSCT (n = 57) with ATG protocol from February 2010 to December 2020 at our single-center (HORCSCT). Median follow-up was 3.73 and 4.28 years for haploidentical and URD-HSCT, respectively. In haplo-HSCT, the cumulative incidence of grades II-IV and III-IV acute graft versus host disease (aGvHD) and extensive chronic GvHD (cGvHD) was much lower than in URD (27% versus 56% for grades II-IV, 8.7% versus 24.5% for grades III-IV, and 15.4% versus 34.7% for extensive cGvHD, respectively). Five-year overall survival (OS) was 54.03% for haplo and 54.48% for URD (p = 0.927); GvHD-free relapse-free survival (GRFS) was 44.1% and 29.86% (p = 0.149); relapse incidence was 15.79% and 26.95% (p = 0.72); and non-relapse mortality (NRM) was 29.48% and 26.32% (p = 0.73), respectively. Using multivariable analyses, when compared to Haplo, URD was a significant predictor of relapse (HR=1.80, p = 0.039); however, no difference in OS, GRFS, and NRM was noted between haplo and URD. Therefore, given the favorable results with haplo-HSCT and considering donor availability promptly with low cost, it conservatively suggested that haplo-HSCT with the introduced protocol could be viewed as the first alternative for patients with AML in the absence of matched sibling donors.

Cell clusters containing intestinal stem cells line, the zebrafish intestine intervillus pocket.

In the mammalian intestine, stem cells (ISCs) replicate in basal crypts, translocate along the villus, and undergo cell death. This pattern of renewal occurs in the zebrafish intestine in which villi are elongated into villar ridges (VR) separated by intervillus pockets (IVP) but lack the infolded crypts. To understand how epithelial dynamics is maintained without crypts, we investigated the origin of epithelial lineage patterns derived from ISCs in the IVP of chimeric and zebrabow recombinant intestines. We found that the VR epithelium and IVP express the same recombinant colors when expression is under the control of ISC marker promoter prmt1. The expression originates from cell clusters that line the IVP and contain epithelial cells including Prmt1-labeled cells. Our data suggest that Prmt1 is a zebrafish ISC marker and the ISCs reside within basal cell clusters that are functionally analogous to crypts.

Variational Approximation-Based Model Selection for Microbial Network Inference.

Microbial associations are characterized by both direct and indirect interactions between the constituent taxa in a microbial community, and play an important role in determining the structure, organization, and function of the community. Microbial associations can be represented using a weighted graph (microbial network), whose nodes represent taxa and edges represent pairwise associations. A microbial network is typically inferred from a sample-taxa matrix that is obtained by sequencing multiple biological samples and identifying the taxa counts in each sample. However, it is known that microbial associations are impacted by environmental and/or host factors. Thus, a sample-taxa matrix generated in a microbiome study involving a wide range of values for the environmental and/or clinical metadata variables may in fact be associated with more than one microbial network. In this study, we consider the problem of inferring multiple microbial networks from a given sample-taxa count matrix. Each sample is a count vector assumed to be generated by a mixture model consisting of component distributions that are multivariate Poisson log-normal. We present a variational expectation maximization algorithm for the model selection problem to infer the correct number of components of this mixture model. Our approach involves reframing the mixture model as a latent variable model, treating only the mixing coefficients as parameters, and subsequently approximating the marginal likelihood using an evidence lower bound framework. Our algorithm is evaluated on a large simulated dataset generated using a collection of different graph structures (band, hub, cluster, random, and scale-free).

Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species.

Replacing or editing disease-causing mutations holds great promise for treating many human diseases. Yet, delivering therapeutic genetic modifiers to specific cells in vivo has been challenging, particularly in large, anatomically distributed tissues such as skeletal muscle. Here, we establish an in vivo strategy to evolve and stringently select capsid variants of adeno-associated viruses (AAVs) that enable potent delivery to desired tissues. Using this method, we identify a class of RGD motif-containing capsids that transduces muscle with superior efficiency and selectivity after intravenous injection in mice and non-human primates. We demonstrate substantially enhanced potency and therapeutic efficacy of these engineered vectors compared to naturally occurring AAV capsids in two mouse models of genetic muscle disease. The top capsid variants from our selection approach show conserved potency for delivery across a variety of inbred mouse strains, and in cynomolgus macaques and human primary myotubes, with transduction dependent on target cell expressed integrin heterodimers.

Strain maps characterize the symmetry of convergence and extension patterns during zebrafish gastrulation.

During gastrulation of the zebrafish embryo, the cap of blastoderm cells organizes into the axial body plan of the embryo with left-right symmetry and head-tail, dorsal-ventral polarities. Our labs have been interested in the mechanics of early development and have investigated whether these large-scale cell movements can be described as tissue-level mechanical strain by a tectonics-based approach. The first step is to image the positions of all nuclei from mid-epiboly to early segmentation by digital sheet light microscopy, organize the surface of the embryo into multi-cell spherical domains, construct velocity fields from the movements of these domains and extract strain rate maps from the change in density of the domains. During gastrulation, tensile/expansive and compressive strains in the axial and equatorial directions are detected as anterior and posterior expansion along the anterior-posterior axis and medial-lateral compression across the dorsal-ventral axis and corresponds to the well characterized morphological movements of convergence and extension. Following gastrulation strain is represented by localized medial expansion at the onset of segmentation and anterior expansion at the onset of neurulation. In addition to linear strain, symmetric patterns of rotation/curl are first detected in the animal hemispheres at mid-epiboly and then the vegetal hemispheres by the end of gastrulation. In embryos treated with C59, a Wnt inhibitor that inhibits head and tail extension, the axial extension and vegetal curl are absent. By analysing the temporal sequence of large-scale movements, deformations across the embryo can be attributed to a combination of epiboly and dorsal convergence-extension.

Selection of Suitable Alternative Donor in the Absence of Matched Sibling Donor: A Retrospective Single-Center Study to Compare between Haploidentical, 10/10 and 9/10 Unrelated Donor Transplantation.

Background: Finding a suitable donor at the optimal time is one of the most challenging issues in many transplant centers. We evaluated the clinical outcomes of 248 patients with acute leukemia and without matched sibling donors (MSD) who underwent alternative transplantation, including haploidentical (n=118), 10/10 matched unrelated (MUD, n=91), 9/10 mismatched unrelated (MMUD, n=21), and 9/10 mismatched related (MMRD, n=18) between January 2010 and November 2019 in our center. Materials and Methods: The myeloablative conditioning regimen was used in most of the patients. Both post-transplant cyclophosphamide (40mg/kg at +3, +4) and pre-transplant ATG were used in most of haploidentical transplantations. Patients with unrelated donors received ATG as a part of the conditioning regimen. Results: The median follow-up was 31.83 months. No significant difference in probability of 3-year leukemia- free survival (LFS) and overall survival (OS) as well as 3-year relapse incidence (RI) was noted among donor sources. A significant difference was found in the 3-year cumulative incidence (CI) of non-relapse mortality (NRM) among the donor sources: 37.89%, 24.20%, 24.30%, and 11.48%, for haplo, 9/10 MMUD, 10/10 MUD, and 9/10 MMRD (p=0.02). Using the multivariable Cox model, the advanced age of patients and Major-ABO mismatched were two risk factors independently associated with lower OS and DFS as well as higher NRM, whereas male donor and AML disease compared to ALL were associated with a better OS and DFS. Conclusion: No significant differences were observed in the overall outcome of haplo with other alternative transplantations, suggesting that haploidentical transplantation is a suitable, accessible, and inexpensive option.

Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthood.

Prenatal alcohol exposure (PAE) affects at least 10% of newborns globally and leads to the development of fetal alcohol spectrum disorders (FASDs). Despite its high incidence, there is no consensus on the implications of PAE on metabolic disease risk in adults. Here, we describe a cohort of adults with FASDs that had an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity. Using a zebrafish model for PAE, we performed population studies to elucidate the metabolic disease seen in the clinical cohort. Embryonic alcohol exposure (EAE) in male zebrafish increased the propensity for diet-induced obesity and fasting hyperglycemia in adulthood. We identified several consequences of EAE that may contribute to these phenotypes, including a reduction in adult locomotor activity, alterations in visceral adipose tissue and hepatic development, and persistent diet-responsive transcriptional changes. Taken together, our findings define metabolic vulnerabilities due to EAE and provide evidence that behavioral changes and primary organ dysfunction contribute to resultant metabolic abnormalities.

Learning a mixture of microbial networks using minorization-maximization.

MOTIVATION: The interactions among the constituent members of a microbial community play a major role in determining the overall behavior of the community and the abundance levels of its members. These interactions can be modeled using a network whose nodes represent microbial taxa and edges represent pairwise interactions. A microbial network is typically constructed from a sample-taxa count matrix that is obtained by sequencing multiple biological samples and identifying taxa counts. From large-scale microbiome studies, it is evident that microbial community compositions and interactions are impacted by environmental and/or host factors. Thus, it is not unreasonable to expect that a sample-taxa matrix generated as part of a large study involving multiple environmental or clinical parameters can be associated with more than one microbial network. However, to our knowledge, microbial network inference methods proposed thus far assume that the sample-taxa matrix is associated with a single network. RESULTS: We present a mixture model framework to address the scenario when the sample-taxa matrix is associated with K microbial networks. This count matrix is modeled using a mixture of K Multivariate Poisson Log-Normal distributions and parameters are estimated using a maximum likelihood framework. Our parameter estimation algorithm is based on the minorization-maximization principle combined with gradient ascent and block updates. Synthetic datasets were generated to assess the performance of our approach on absolute count data, compositional data and normalized data. We also addressed the recovery of sparse networks based on an l1-penalty model. AVAILABILITY AND IMPLEMENTATION: MixMPLN is implemented in R and is freely available at https://github.com/sahatava/MixMPLN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Assessing the prognostic factors, survival, and recurrence incidence of triple negative breast cancer patients, a single center study in Iran.

BACKGROUND: Breast cancer is the second leading cause of death due to cancer in women. Triple negative breast cancer (TNBC) is a subgroup with unique behavior. There is a controversy in organ involvement in metastasis. In this study, we planned to define the prognostic factors, survival, and recurrence incidence of patients. MATERIALS AND METHOD: Among the 583 patients with breast mass referred to hematology and oncology clinic in Shariati hospital, Tehran, Iran from March 2005 to March 2015, fifty four patients entered the survival analysis whom we followed for two years until March 2017. Overall survival (OS) and disease-free survival (DFS) and Cumulative recurrence incidences (RI) were estimated. Univariate and multivariate Cox proportional hazards regression was performed to assess risk factors in predicting OS and DFS. RESULTS: Median follow up for the patients was 5.00 years. The five-year OS, DFS and RI were 86.13% (95% CI (71.42-93.59), 63.09% (95% CI (47.04-75.49) and 32.15% (95% CI (19.52-47.43) respectively. Among the factors studied OS, DFS and RI differed significantly only between patients with and without nodal involvement (P = 0.004, P = 0.003, and P = 0.02 respectively). On the other hand, based on the univariate modeling, patients with nodal involvement had a higher risk of breast cancer-specific death (HR: 17.99, P = 0.004). Furthermore, patients with nodal involvement had a higher risk of breast cancer-specific death or recurrence (HR = 5.64, P = 0.008). In Multivariate model, just the nodal involvement significantly changed the hazard for OS (HR = 23.91, P = 0.001). As the nodal involvement was the only significant risk factor at the 0.2 level of significance, we can consider the hazard ratio of lymph node positivity in DFS univariate models as adjusted hazard. CONCLUSION: The only factor with significant effect on OS, DFS and RI was nodal involvement in the pathology report.

The Prevalence of Allergic Rhinitis, Eczema and Asthma in Students of Guidance Schools in Mazandaran Province, Iran.

BACKGROUND: Eczema, allergic rhinitis and asthma are common chronic allergic disorders in childhood. AIM: The aim of this study was to determine the prevalence of common allergic disorders among Iranian guidance schools students in Mazandaran Province, northern Iran. METHODS: This analytical cross-sectional study was performed on 3000 children aged 11-14 years old during 2012-13 according to ISAAC study. Of 3000 recruited children 1576 (52.54%) were female and 1424 (47.46%) were male. Data gathered by ISAAC first phase questionnaire analysed by SPSS software 20. RESULTS: The prevalence of wheezing, allergic rhinitis symptoms (sneezing and pruritus) and atopic dermatitis symptoms (pruritus skin lesion) were 30.5%, 30% and 15% respectively. History of pets contact and smoking was positive 6.6% and 36 % respectively. About 52% was born with caesarian section. There was wheezing in 32.5% during sport. The diagnosis of asthma, allergic rhinitis and eczema were 12.2%, 28.5% and 15% respectively. Eczema, asthma and allergic rhinitis were significantly more common in boys students (p < 0.05). CONCLUSIONS: The results of this study showed that asthma, allergic rhinitis and eczema have a high prevalence and they are more common in boys.

Central venous pressure catheter for large-volume paracentesis in refractory ascites.

BACKGROUND AND AIMS: About 10 % of cirrhotic patients are unresponsive to sodium restriction and diuretics and develop refractory ascites. Such patients usually require recurrent large-volume paracentesis and lots of hospital admissions. Hereby, we introduce a method applying a central vein (CV) catheter for large-volume paracentesis in patients with refractory ascites in up to 4 days associated with sodium restriction and high dose of diuretics. METHODS: Non-tunneled triple lumen CV catheter was used to drain the ascites fluid of 30 cirrhotic patients. After precise percussion, the point of highest fluid accumulation was marked for puncture. Then, the skin and subcutaneous tissue were anesthetized. CV catheter set guide wire was entered into the peritoneal cavity and the dilator of the CV catheter set was passed through the guide wire and extracted after some rotations around its insertion site on the skin. The catheter was passed over the guide wire and the guide wire was extracted gradually from one of the lumens and fixed to the skin. RESULTS: Nineteen males and 11 females with mean (±SD) age of 59.4 ± 11.7 years old underwent the procedure. A minimum of 9 and maximum of 29 L (12 ± 6.6 L) ascites fluid drained during a minimum of 2 and maximum of 5 days of hospital stay. All catheters were patent during the drainage. None of the patients developed hemodynamic instability. Number of re-hospitalizations for paracentesis was 1.9 times during the following year. No complication occurred. CONCLUSIONS: This technique is a simple noninvasive method that can be performed in the endoscopy unit or even at the patient's bedside and may reduce the need for repeated admissions.