2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells

2-Methoxyestradiol (2ME2) an estrogen derivative, induces growth arrest and apoptosis in leukemic cells and is also antiangiogenic. In this study, we demonstrate that 2ME2 inhibits growth and induces apoptosis in multiple myeloma (MM) cell lines and patient cells. Significantly, 2ME2 also inhibits growth and induces apoptosis in MM cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40 and Dox-6), and dexamethasone (MM.1R). In contrast to its effects on MM cells, 2ME2 does not reduce the survival of normal peripheral blood lymphocytes. Moreover, 2ME2 enhances Dex-induced apoptosis, and its effect is not blocked by interleukin-6 (IL-6). We next examined the effect of 2ME2 on MM cells in the bone marrow (BM) milieu. 2ME2 decreases survival of BM stromal cells (BMSCs), as well as secretion of vascular endothelial growth factor (VEGF), and IL-6 triggered by the adhesion of MM cells to BMSCs. We show that apoptosis induced by 2ME2 is mediated by the release of mitochondrial cytochrome-c (cyto-c) and Smac, followed by the activation of caspases-8, -9, and -3. Finally, 2ME2 inhibits MM cell growth, prolongs survival, and decreases angiogenesis in a murine model. These studies, therefore, demonstrate that 2ME2 mediates anti-MM activity directly on MM cells and in the BM microenvironment. They provide a framework for the use of 2ME2, either alone or in combination with Dex, to overcome drug resistance and to improve outcome in MM.     

Rifaximin,a pregnane X receptor (PXR) activator regulates apoptosis in a murine model of breast cancer

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized and divided among four groups of six animals each. Group I (control 0.9% normal saline, 3 ml kg⁻¹, p.o.); Group II (toxic control, MNU 47 mg kg⁻¹, i.v.); Group III (RFX, 25 mg kg⁻¹, p.o.); Group IV (RFX, 50 mg kg⁻¹, p.o.). Toxicity was induced by single i.v. injection of MNU. MNU treatment was evident with increased alveolar bud count, differentiation score, up-regulated inflammatory enzyme markers (COX, LOX, NO and H₂S) and oxidative stress markers (TBAR''s, protein carbonyl, SOD, catalase and Ach). The mammary gland surface architecture was studied using SEM, carmine staining and H&E staining. The treatment with RFX elicited noticeable restoration of the overall histological architecture in the experimental animals similar to the control. In the MNU treated toxic group, the levels of oxidative stress markers significantly increased in comparison to the control, which was subsequently restored after RFX treatment. Furthermore, RFX up regulated the levels of caspase 3 and caspase 8, when compared to the MNU treated animals. MNU associated toxicity was also ascertained, when determined for UCHL-1, COX, NF-κBp65, BAD, and BCL-xl expression, while RFX demonstrated modulation of the same.

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats.     

HIV and Sexually Transmitted Infection Testing Among High-Risk Youths: Supporting Positive Opportunities With Teens (SPOT) Youth Center

Objectives. We investigated the development of and service utilization at Supporting Positive Opportunities with Teens (SPOT)—a community-based health and social service facility in St. Louis, Missouri, for youths that focuses on increasing HIV and sexually transmitted infection (STI) testing.Methods. We identified the US-based, co-located youth health and social service models that guided the establishment of the SPOT. We analyzed the first 5 years (2008–2013) of service delivery and utilization data.Results. During the study period, the SPOT provided services for 8233 youths in 37 480 visits. The 5 most utilized services included HIV and STI screening, food, transportation, contraception, and case management. A total of 9812 gonorrhea and chlamydia screenings revealed 1379 (14.1%) cases of chlamydia and 437 (4.5%) cases of gonorrhea, and 5703 HIV tests revealed 59 HIV infections (1.0%); 93.0% of patients found to have an STI were treated within a 5-day window.Conclusions. Co-locating health and social services in informal community settings attracts high-risk youths to utilize services and can prove instrumental in reducing STI burden in this population.Sexual behaviors that contribute to unintended pregnancy and sexually transmitted infections (STIs), including HIV, are considered a priority health-risk behavior among youths in the United States.1 In 2008, St. Louis, Missouri, had some of the highest rates of Neisseria gonorrheae and Chlamydia trachomatis infections of all US cities.2 The majority of STIs in youths aged 15 to 24 years in Missouri are seen disproportionately among African American youths. HIV infection rates among youths continue to rise.3 From 2008 to 2010 new cases of HIV/AIDS among male youths in St. Louis increased by 33%, compared with a 2% increase among adult males.3,4These high rates of STIs and HIV highlight gaps in services for youths in our region. Evidence suggests that it is best to co-locate health and social services when providing care to a very needy population of youths.5–7 There are programs that do this in multiple sites across the country. Studies found that peer-to-peer information sharing and outreach, peer advisory groups, tightly linked medical and social services, and active case management to assess need and link youths to services were critical for keeping youths engaged.6,7 Despite the obvious needs of youths in St. Louis, no social service agency or health facility has ever combined these services for youths aged 13 to 24 years.We describe the development of our youth center, the SPOT (Supporting Positive Opportunities with Teens), and report screening outcomes and service utilization measures for the first 5 years of the center. We focus on identifying STI and HIV infections in youths and ensuring access to timely treatment.     

Quantification of allospecific and nonspecific corneal endothelial cell damage after corneal transplantation

Purpose

To investigate the effect of host immunity (allospecific) and surgical manipulation (non-allospecific) on corneal endothelial cells (CECs) in corneal transplantation.

Methods

Draining lymph nodes and grafted C57BL/6 corneas were harvested from syngeneic recipients, allograft acceptors, and allograft rejectors (BALB/c) 1, 3, and 8 weeks after transplantation. We analyzed CEC apoptosis using an ex vivo cornea-in-the-cup assay, and visualized cell-to-cell junctions using immunohistochemical staining (ZO-1). Automatic cell analysis using Confoscan software was used to measure CEC density as well as changes in CEC morphology by quantifying the coefficient of variation in cell size (polymegethism) and shape (pleomorphism).

Results

The cornea-in-the-cup assay showed that allogeneic acceptor T cells and to an even greater extent rejector T cells (but not syngeneic T cells) induced CEC apoptosis. CEC density after corneal transplantation was significantly reduced in allogeneic acceptors compared with syngeneic grafts (P<0.001), and CEC density was even further reduced in the allo-rejector group compared with the allo-acceptor group. Allogeneic grafts showed a greater increase in the coefficient of variation in cell size (polymegethism) when compared with syngeneic grafts 1 week after transplantation (P=P<0.001). However, pleomorphism was not significantly different between syngeneic and allo-acceptor grafts, indicating that polymegethism (but not pleomorphism or cell density) is a sensitive indicator of the effect of alloimmunity on CECs.

Conclusions

Our data demonstrate that host alloimmunity rather than surgical manipulation alone is the major cause of CEC damage in corneal transplantation, and such morphologic changes of CECs can be detected before the clinically visible onset of allograft rejection.     

Effect of ionic size compensation by Ag+ incorporation in homogeneous Fe-substituted ZnO: studies on structural,mechanical, optical,and magnetic properties

Substituting an ion of different size from that of the host element introduces lattice strain and defects. However, this mismatch may be significantly reduced by substituting an additional ion with a compensating size relative to the dopant. Such a double substitution might offer better solubility irrespective of the local distortions as well as the formation of defects in the valence states. Fe-substituted ZnO has been widely reported with conflicting results primarily arising from lack of chemical and structural homogeneity originating from preparation techniques, compositional fluctuations, and equivocal comprehension of actual solubility limits of the dopants. In this study, Ag ion has been incorporated in Fe-substituted ZnO to compensate the ionic size of Zn_1−x[Fe_0.8Ag_0.2]_xO (0 ≤ x ≤ 0.03125) by determining the solubility limit of the homogeneous material and their corresponding structural, mechanical, optical and magnetic properties have been investigated thoroughly. Co-substitution rearranges the lattice and leads to better crystal structures with tunable properties related to the amount of substitution.

Substituting an ion of different size from that of the host element introduces lattice strain and defects.     

Safety and efficacy of Ahmed glaucoma valve implantation in refractory glaucomas in Northern Indian eyes

Purpose

To evaluate the safety and efficacy of Ahmed glaucoma valve (AGV) implantation in refractory glaucoma in Northern Indian eyes.

Background

The success rate of trabeculectomy remains low in cases of refractory glaucoma even with the use of antifibrotics. Glaucoma drainage devices have proven to be more efficacious in reducing intraocular pressure (IOP) in these glaucomas.

Methods

Retrospective records of 55 consecutive patients who underwent AGV implantation at Dr. Shroff’s Charity Eye Hospital, New Delhi, India from January 2003 to December 2012 were reviewed. Pre-operative data included age, gender, eye laterality, specific diagnosis, number of anti-glaucoma medications, number of prior incisional surgeries, visual acuity and IOP on medical treatment. Postoperative data included visual acuity and IOP on day one, 1 week, 1 month, 3 months, 6 months, 1 year and yearly thereafter, number of anti-glaucoma medications, any complication or additional surgical intervention required. Success was defined as IOP >5 and <22 mmHg with or without treatment.

Results

Mean IOP decreased from 39.71 ± 8.99 pre-operatively to 17.52 ± 5.72 mmHg at last follow-up (p < 0.001) and number of medications reduced from 3.27 ± 0.84 to 1.25 ± 0.88 (p < 0.001). Visual acuity remained within one Snellen line or improved at last follow-up in 47 cases (85.4%). The cumulative probability of success was 85.45% at 1 year and 79.63% at 3 years. The incidence of post-operative complications was 25.45%.

Conclusion

AGV implantation has proven to be safe and is effective in controlling IOP in refractory glaucoma in Northern Indian eyes.     

Kyasanur Forest Disease Outbreak and Vaccination Strategy,Shimoga District,India, 2013–2014

We investigated a Kyasanur Forest disease outbreak in Karnataka, India during December 2013–April 2014. Surveillance and retrospective study indicated low vaccine coverage, low vaccine effectiveness, and spread of disease to areas beyond those selected for vaccination and to age groups not targeted for vaccination. To control disease, vaccination strategies need to be reviewed.     

Small molecule generators of biologically reactive sulfur species

Sulfur metabolism is integral to cellular growth and survival. The presence of a wide range of oxidation states of sulfur in biology coupled with its unique reactivity are some key features of the biology of this element. In particular, nearly all oxidation states of sulfur not only occur but are also inter-convertible. In order to study the chemical biology of reactive sulfur species, tools to reliably detect as well as generate these species within cells are necessary. Herein, an overview of strategies to generate certain reactive sulfur species is presented. The donors of reactive sulfur species have been organized based on their oxidation states. These interesting small molecules have helped lay a strong foundation to study the biology of reactive sulfur species and some may have therapeutic applications in the future as well.

Reactive sulfur species (RSS) are integral to cellular survival and growth. Here, small molecule generators of RSS are reviewed.     

COVID 19 infection associated with thrombotic thrombocytopenic purpura

Journal of Thrombosis and Thrombolysis - Thrombotic thrombocytopenic purpura (TTP) which can cause significant mortality is a thrombotic microangiopathy due to deficiency of VWF cleaving protease...     

Neurological manifestations of hepatitis E virus infection: An overview

Hepatitis E virus (HEV) is an important cause of repeated waterborne outbreaks of acute hepatitis. Recently, several extrahepatic manifestations (EHMs) have been described in patients with HEV infection. Of these, neurological disorders are the most common EHM associated with HEV. The involvement of both the peripheral nervous system and central nervous system can occur together or in isolation. Patients can present with normal liver function tests, which can often be misleading for physicians. There is a paucity of data on HEV-related neurological manifestations; and these data are mostly described as case reports and case series. In this review, we analyzed data of 163 reported cases of HEV-related neurological disorders. The mechanisms of pathogenesis, clinico-demographic profile, and outcomes of the HEV-related neurological disorders are described in this article. Nerve root and plexus disorder were found to be the most commonly reported disease, followed by meningoencephalitis.