•Sex hormones modify auditory processing to facilitate mating.•Hormonal level changes with age can influence age-related hearing loss.•Prospective studies reveal that hormone therapies can alter ...hearing abilities.•Combining hormones with other supplements may be a key for future therapies.•Co-morbid medical conditions can have a negative impact on hearing in the elderly.
Provocative research has revealed both positive and negative effects of hormones on hearing as we age; with in some cases, mis-regulation of hormonal levels in instances of medical comorbidities linked to aging, lying at the heart of the problem. Animal model studies have discovered that hormonal fluctuations can sharpen hearing for improved communication and processing of mating calls during reproductive seasons. Sex hormones sometimes have positive effects on auditory processing, as is often the case with estrogen, whereas combinations of estrogen and progesterone, and testosterone, can have negative effects on hearing abilities, particularly in aging subjects. Too much or too little of some hormones can be detrimental, as is the case for aldosterone and thyroid hormones, which generally decline in older individuals. Too little insulin, as in Type 1 diabetics, or poor regulation of insulin, as in Type 2 diabetics, is also harmful to hearing in our aged population. In terms of clinical translational possibilities, hormone therapies can be problematic due to systemic side effects, as has happened for estrogen/progestin combination hormone replacement therapy (HRT) in older women, where the HRT induces a hearing loss. As hormone therapy approaches are further developed, it may be possible to lower needed doses of hormones by combining them with supplements, such as antioxidants. Another option will be to take advantage of emerging technologies for local drug delivery to the inner ear, including biodegradeable, sustained-release hydrogels and micro-pumps which can be implanted in the middle ear near the round window. In closing, exciting research completed to date, summarized in the present report bodes well for emerging biomedical therapies to prevent or treat age-related hearing loss utilizing hormonal strategies.
The microstructure of green-emitting InGaN/GaN quantum well (QW) samples grown at different temperatures was studied using cross-section scanning transmission electron microscopy (STEM) and plan-view ...cathodoluminescence (CL). The sample with the lowest InGaN growth temperature exhibits microscale variations in the CL intensity across the sample surface. Using STEM analysis of such areas, the observed darker patches do not correspond to any observable extended defect. Instead, they are related to changes in the extent of gross-well width fluctuations in the QWs, with more brightly emitting regions exhibiting a high density of such fluctuations, whilst dimmer regions were seen to have InGaN QWs with a more uniform thickness.
Summary
In a phase 2 study, continued denosumab treatment for up to 8 years was associated with continued gains in bone mineral density and persistent reductions in bone turnover markers. Denosumab ...treatment was well tolerated throughout the 8-year study.
Introduction
The purpose of this study is to present the effects of 8 years of continued denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTM) from a phase 2 study.
Methods
In the 4-year parent study, postmenopausal women with low BMD were randomized to receive placebo, alendronate, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo for two more years. The parent study was then extended for 4 years where all subjects received denosumab.
Results
Of the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab treatment, BMD at the lumbar spine (
N
= 88) and total hip (
N
= 87) increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in BTM were sustained over the course of continued denosumab treatment. Reductions also were observed when the placebo group transitioned to denosumab. Adverse event profile was consistent with previous reports and an aging cohort.
Conclusion
Continued denosumab treatment for 8 years was associated with progressive gains in BMD, persistent reductions in BTM, and was well tolerated.
Inappropriate prescription of intravenous fluid therapy is highly prevalent in hospitals, with up to 1 in 5 patients suffering from preventable, additional morbidity. Since trainee physicians are ...frequently responsible for prescribing intravenous fluids, it is possible that common medical student resources do not sufficiently cover the topic. There is a paucity of recent literature on this issue, which this study was designed to address.
Two original evaluation tools were created by the authors to evaluate reference books, official guidelines, and online reference sources commonly used by medical students in the United States of America, Australia, and the United Kingdom on their coverage of foundational and clinically relevant principles of intravenous fluid prescription. The choice of student resources was guided by a literature search and personal experience. A total of 10 resources was assessed.
Resources were generally deficit in their coverage of basic intravenous fluid topics. The total points each topic accumulated ranged from 0.5 (5%) to 7.5 (75%), with the median score being 4.5 (45%), on a scale from 0 to 10 points.
Popular medical student resources poorly cover intravenous fluid therapy topics. This may be contributing to inadequate fluid prescribing practices.
Diffuse large B-cell lymphoma (DLBCL) consists of at least 2 phenotypic subtypes; that is, the germinal center B-cell–like (GCB-DLBCL) and the activated B-cell–like (ABC-DLBCL) groups. It has been ...shown that GCB-DLBCL responds favorably to chemotherapy and expresses high levels of BCL6, a transcription repressor known to play a causative role in lymphomagenesis. In comparison, ABC-DLBCL has lower levels of BCL6, constitutively activated nuclear factor-κB, and tends to be refractory to chemotherapy. Here, we report that the STAT3 gene is a transcriptional target of BCL6. As a result, high-level STAT3 expression and activation are preferentially detected in ABC-DLBCL and BCL6-negative normal germinal center B cells. Most importantly, inactivating STAT3 by either AG490 or small interference RNA in ABC-DLBCL cells inhibits cell proliferation and triggers apoptosis. These phenotypes are accompanied by decreased expression of several known STAT3 target genes, including c-Myc, JunB, and Mcl-1, and increased expression of the cell- cycle inhibitor p27. In addition to identifying STAT3 as a novel BCL6 target gene, our results define a second oncogenic pathway, STAT3 activation, which operates in ABC-DLBCL, suggesting that STAT3 may be a new therapeutic target in these aggressive lymphomas.
This study was conducted to investigate the effects of Lonicera flos and Cnicus japonicus extracts (LCE) on the laying performance, egg quality, morphology, antioxidant status, inflammatory-related ...cytokines, and shell matrix protein expression of oviduct in laying hens. A total of 1,728 Roman Pink laying hens aged 73-wk-old were randomly assigned into 4 groups (18 replicates/group, 24 layers/replicate) fed basal diets supplemented with 0, 300, 500, and 1,000 mg of LCE per kg of diet, respectively. The trial lasted for 11 wk, including 2-wk adjustment period and 9-wk testing period. The results indicated that laying hens fed diets supplemented with LCE linearly increased egg weight, yolk color and shell thickness at wk 78 and albumen height, Haugh unit and shell thickness at wk 83 (P < 0.05). At wk 78, LCE groups linearly affected the hydrogen peroxide content in magnum (P < 0.05) and 300 mg/kg LCE groups had the highest catalase activity in isthmus (P < 0.05). At wk 83, LCE groups linearly reduced (P < 0.05) hydrogen peroxide content in the magnum and isthmus and malondialdehyde content in the uterus whereas increased catalase activity in isthmus (P < 0.05). Furthermore, LCE levels quadratically affected glutathione peroxidase activity in isthmus at wk 83 (P < 0.05). At wk 78, the mRNA expressions of inducible nitric oxide synthase and interferon-γ in isthmus and ovalbumin and ovocleidin-116 in uterus had linear effects in response to LCE levels (P < 0.05) and 1,000 mg/kg LCE group had the lowest mRNA expression of interleukin-6 in magnum (P < 0.05). At wk 83, LCE supplementation linearly decreased the mRNA expression of interleukin-1β, interferon-γ and tumor necrosis factor-α in magnum and tumor necrosis factor-α and inducible nitric oxide synthase in uterus (P < 0.05). It is concluded that LCE improved egg quality partly by modulating antioxidant status, inflammatory-related cytokines and shell matrix protein expression of oviduct in laying hens.
Diffuse large B-cell lymphomas (DLBCLs) contain 2 major molecular subtypes; namely, the germinal center B-cell-like (GCB) and the activated B-cell-like (ABC) DLBCLs. It is well documented that ...ABC-DLBCL cases have a significantly poorer survival response than GCB-DLBCLs in both the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and the rituximab (R)-CHOP eras. However, the underlying cause of this subtype disparity is poorly understood. Nevertheless, these clinical observations raise the possibility for an ABC-DLBCL–specific resistance mechanism that is directed toward 1 of the CHOP components and is inadequately addressed by rituximab. Here, we report that the main cytotoxic ingredient in CHOP, doxorubicin (Dox), has subtype-specific mechanisms of cytotoxicity in DLBCLs resulting from differences in the subcellular distribution pattern. Specifically, in cell line models of ABC-DLBCL, Dox is often enriched in the cytoplasm away from the nuclear DNA. As a result, Dox-induced cytotoxicity in ABC-DLBCLs is often dependent on oxidative stress, rather than DNA damage response. These findings are corroborated by gene signature analysis, which demonstrates that basal oxidative stress status predicts treatment outcome among patients with ABC-DLBCL, but not patients with GCB-DLBCL. In terms of redox-related resistance mechanism, our results suggest that STAT3 confers Dox resistance in ABC-DLBCLs by reinforcing an antioxidant program featuring upregulation of the SOD2 gene. Furthermore, a small-molecule STAT3 inhibitor synergizes with CHOP to trigger oxidative stress and kill ABC-DLBCL cells in preclinical models. These results provide a mechanistic basis for development of novel therapies that target either STAT3 or redox homeostasis to improve treatment outcomes for ABC-DLBCLs.
•Dox causes DNA damage inefficiently in ABC-DLBCL because of preferential cytoplasmic localization.•STAT3 promotes resistance to ROS-mediated Dox cytotoxicity by upregulating the expression of SOD2.
We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether ...STAT3 activation can risk stratify patients with DLBCL.
By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival.
PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non-germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P = .025).
STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype.
This study was to determine the effects of the mixture of glycerol monolaurate and cinnamaldehyde (GCM) supplementation on the intestinal morphology, immunity, antioxidant status and cecal microbiota ...of laying hens. A total of 1,120 healthy laying hens (Jingfen-1 strain) at the age of 14 wk were randomly divided into 4 groups with 10 replicates of 28 layers in each and layers were fed diets containing 0 (control group), or 250, 500, and 1,000 mg/kg GCM for 12 wk. The results showed that dietary supplementation with GCM significantly increased intestinal villus height and villus height/crypt depth, duodenal villus area, total superoxide disumutase activities in the liver and jejunum, jejunal glutathione peroxidase activities while decreased duodenal and jejunal crypt depth, hydrogen peroxide content in the liver and jejunal malondialdehyde content of laying hens aging 28 wk (P < 0.05). Meanwhile, GCM addition significantly increased serum immunoglobulin A and immunoglobulin M concentration of layers at the age of 20, 24, and 28 wk (P < 0.05). Moreover, it was observed in the 16S rRNA sequencing that the addition of GCM elevated the abundance and diversity of gut microbiota in laying hens. The predominant bacteria from each group were Bacteroidota and Firmicutes at the phylum level and Bacteroides and Lactobacillus were the dominant genera. The composition and structure of cecal microflora were changed by the addition of GCM to the diet of laying hens. In conclusion, the addition of GCM (500–1,000 mg/kg diet) can improve intestinal morphology, immune function, intestinal and liver antioxidant status and intestinal flora of laying hens, thereby improving intestinal digestion and absorption capacity. These findings provide a new way to further explore the mechanism of GCM improving intestinal health.
The purpose of this study was to investigate the epidemiological characteristics of carbapenem-resistant
Klebsiella pneumoniae
(CRKP) in Shanghai Children’s Hospital in China. Twenty-two ...non-duplicate CRKP strains were collected from pediatric patients between March and June in 2014. Antimicrobial susceptibility testing was conducted by the agar dilution method. Beta-lactamases were characterized by polymerase chain reaction (PCR) and DNA sequencing. The transferability of
bla
NDM-1
was investigated by conjugation experiment. The plasmids bearing antibiotic resistance genes were characterized by S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and Southern hybridization. Clonal relatedness was evaluated by PFGE and multilocus sequence typing (MLST). The clinical data of patients were retrospectively reviewed. The 22 CRKP strains were resistant to most of the antimicrobial agents tested, except tigecycline and colistin. Overall, 59, 77, and 100 % of these strains were resistant to imipenem, meropenem, and ertapenem, respectively. The
bla
NDM-1
was positive in 77.3 % (17/22) of the CRKP strains, of which the 16 isolates from inpatients were designated as ST37 (
n
= 9) and ST76 (
n
=7) and one isolate from an outpatient belonged to ST846. The 17
bla
NDM-1
-positive isolates belonged to PFGE type A (
n
= 9), type C (
n
= 7), or type B (
n
= 1). The plasmids bearing
bla
NDM-1
could be transferred into recipient
Escherichia coli
J53 through conjugation in 88.2 % (15/17) of the strains. The hybridization results showed that the plasmids carrying the
bla
NDM-1
gene were approximately 50–240 kb in size. This is the first report of an outbreak caused by NDM-1-producing
K. pneumoniae
ST76 and ST37 among neonates.
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