Enzyme-mediated one-pot synthesis of hydrogel with the polyphenol cross-linker for skin regeneration.

Polyphenols can trigger immunity that activates intracellular anti-inflammatory signaling and prevents external infections. In this study, we report the fabrication of chitosan-based hydrogels with epigallocatechin gallate (EGCG) using enzyme-mediated one-pot synthesis. The tyrosinase-mediated oxidative reaction of the phenolic rings of EGCG with the primary amines on chitosan results in stable EGCG-chitosan hydrogels. The EGCG concentrations contributed to the cross-linking density and physical properties of EGCG-chitosan hydrogels. Furthermore, EGCG-chitosan hydrogels maintained intrinsic properties such as antibacterial and antioxidant effects. When endotoxin-activated RAW 264.7 macrophage cells were cultured with EGCG-chitosan hydrogels, the hydrogels reduced the inflammatory response of the RAW 264.7 cells. Furthermore, subcutaneous implantation of EGCG-chitosan hydrogels reduced endogenous macrophage and monocyte activation. When the EGCG-chitosan hydrogels were applied to a full-skin defect wound, they facilitated skin regeneration. Our study demonstrates that the one-pot synthesized EGCG-chitosan hydrogels can be applied in broad tissue regeneration applications that require immune modulation.

Febrile neutropenia and its associated hospitalization in breast cancer patients on docetaxel-containing regimen: A retrospective cohort study on duration of prophylactic GCSF administration.

PURPOSE: To compare febrile neutropenia (FN) incidence and hospitalization among breast cancer patients on docetaxel with no granulocyte colony-stimulating factors (GCSF) primary prophylaxis (PP), 4/5-day PP, or 7-day PP. METHODS: We identified 3916 breast cancer patients using docetaxel-cyclophosphamide (TC), doxorubicin-cyclophosphamide then docetaxel (AC-T), fluorouracil-epirubicin-cyclophosphamide then docetaxel (FEC-T), docetaxel-carboplatin-trastuzumab (TJH), or docetaxel-doxorubicin-cyclophosphamide (TAC) from a hospital pharmacy dispensing database in Hong Kong between 2014 and 2016. Patients were offered GCSF within 5 days since administering docetaxel. Outcomes included FN incidence, time to first hospitalization, hospitalization rate, and duration. RESULTS: In TC regimen, FN incidence (with odds ratio, OR) of patients with no PP, 4/5-day PP, and 7-day PP was 21.69%, 7.95% (OR 0.31, p < 0.001), and 5.33% (OR 0.20, p < 0.001), respectively. In TJH regimen, FN incidence of patients with no PP, 4/5-day PP, and 7-day PP was 38.26%, 8.33% (OR 0.15, p < 0.001), and 8.57% (OR 0.15, p < 0.001), respectively. FN incidence of patients on AC-T regimen with no PP and 4/5-day PP was 20.93% and 6.84%, respectively (OR 0.28, p = 0.005); with FEC-T regimen, the incidence was 9.91% and 4.77%, respectively (OR 0.46, p = 0.035). Only 3.27% FN cases were not hospitalized. Mean (±standard deviation, SD) time to first hospitalization was 8.21 ± 2.44 days. Mean (±SD) duration of hospitalization for patients with no PP, 4/5-day PP, and 7-day PP was 4.66 ± 2.60, 4.37 ± 2.85, and 5.12 ± 2.97 days, respectively. CONCLUSION: GCSF prophylaxis in breast cancer patients on docetaxel could reduce FN incidence and hospitalization. 4/5-day PP demonstrated similar efficacy to 7-day PP with superior saving benefits on healthcare expenditure.

Mortality and morbidity of extremely low birth weight infants in Hong Kong, 2010-2017: a single-centre review.

BACKGROUND: Extremely low birth weight (ELBW) infants exhibit high rates of mortality and morbidity. We retrospectively assessed factors associated with mortality and morbidity among ELBW infants. METHODS: Perinatal demographic data were reviewed for all ELBW infants born between 2010 and 2017 at a tertiary neonatal unit. RESULTS: For non-survivors (21% of ELBW infants) and survivors, the median gestational ages were 24.1 and 26.2 weeks, respectively, and median birth weights were 650 g and 780 g, respectively (all P<0.001). Regression analyses showed that non-survival was positively associated with lower gestational age (adjusted odds ratio [aOR]=6.71 for every 1-week decrease; 95% confidence interval [CI]=1.73-26.00; P=0.006) and grade 3 or 4 intraventricular haemorrhage (aOR=29.23; 95% CI=1.39-613.84; P=0.030); non-survival was negatively associated with the presence of bronchopulmonary dysplasia (aOR=0.01; 95% CI= <0.001-0.23; P=0.005); length of neonatal intensive care unit stay for survivors was positively associated with the presence of necrotising enterocolitis (B-coefficient=89.60; 95% CI=43.86-135.34; P<0.001); and length of hospital stay for survivors was positively associated with the presence of necrotising enterocolitis (B-coefficient=2.08; 95% CI=0.43-3.73; P=0.015) and a low Apgar score at 1 minute (B-coefficient=-0.63; 95% CI=-1.04 to -0.22; P=0.003). CONCLUSION: Extremely low birth weight infants exhibited significant mortality and morbidity; there was no survival prior to 23.6 weeks' gestation or below 550 g birth weight. The presence of grade 3 or 4 intraventricular haemorrhage was independently associated with non-survival. Survivors were significantly more likely to exhibit bronchopulmonary dysplasia; survivors with necrotising enterocolitis were more likely to require longer stays in the neonatal intensive care unit and in hospital.

Effects of Swaddled and Sponge Bathing Methods on Signs of Stress and Pain in Premature Newborns: Implications for Evidence-Based Practice.

AIMS: To determine the effects of sponge baths and swaddled bathing on premature infants' vital signs, oxygen saturation levels, crying times, pain, and stress levels. METHODS: This study was a clinical trial with a crossover design. Data were conducted in the neonatal intensive care unit of a public hospital in Denizli, Turkey. A total of 35 premature infants, who were born at 33-37 weeks gestation with a birth weight <1,500 g, were enrolled in the study. Two bathing methods were applied at 3-day intervals. Vital signs and oxygen saturation levels were measured before and at minutes 1, 5, 15, 30 after bathing. Infants' bathing was video recorded to assess pain and stress behaviors. The pain and stress behaviors of infants were evaluated by independent observers. A significance level of .05 was used for all statistical analyses. RESULTS: There were statistically significant differences between bathing methods on vital signs, oxygen saturation levels, and crying times. Levels of stress and pain according to bathing type were significantly higher in the sponge bath condition (p < .05). LINKING EVIDENCE TO ACTION: Swaddled bathing has a positive effect on the infant's vital signs, oxygen saturation levels, crying time, and level of stress and pain compared to the sponge bath condition. Swaddled bathing is a harmless and safe nursing practice.

Sagittal alignment and mobility of the thoracolumbar spine are associated with radiographic progression of secondary hip osteoarthritis.

OBJECTIVE: To identify predictors of radiographic progression of hip osteoarthritis (OA) over 12 months among functional hip impairments and spinal alignment and mobility. DESIGN: Fifty female patients with secondary hip OA, excluding those with end-stage hip OA, participated in this prospective cohort study. Joint space width (JSW) of the hip was measured at baseline and 12 months later. With radiographic progression of hip OA over 12 months (>0.5 mm in JSW) as dependent variable, logistic regression analyses were performed to identify predictors for hip OA progression among functional impairments of the hip and spine with and without adjustment for age, body mass index (BMI), and minimum JSW at baseline. The independent variables were hip pain, Harris hip score (HHS), hip morphological parameters, hip passive range of motion (ROM) and muscle strength, and alignment and mobility of the thoracolumbar spine at baseline. RESULTS: Twenty-one (42.0%) patients demonstrated radiographic progression of hip OA. Multivariable logistic regression analysis showed that larger anterior inclination of the spine in standing position (adjusted OR [95% CI], 1.37 [1.04-1.80]; P = 0.028) and less thoracolumbar spine mobility (adjusted OR [95% CI], 0.96 [0.92-0.99]; P = 0.037) at baseline were statistically significantly associated with radiographic progression of hip OA, even after adjustment for age, BMI, and minimum JSW. CONCLUSIONS: The findings suggest that spinal alignment and mobility should be considered when assessing risk and designing preventive intervention for radiographic progression of secondary hip OA.

Treadmill exercise suppressed stress-induced dendritic spine elimination in mouse barrel cortex and improved working memory via BDNF/TrkB pathway.

Stress-related memory deficit is correlated with dendritic spine loss. Physical exercise improves memory function and promotes spinogenesis. However, no studies have been performed to directly observe exercise-related effects on spine dynamics, in association with memory function. This study utilized transcranial two-photon in vivo microscopy to investigate dendritic spine formation and elimination in barrel cortex of mice under physical constrain or naive conditions, followed by memory performance in a whisker-dependent novel texture discrimination task. We found that stressed mice had elevated spine elimination rate in mouse barrel cortex plus deficits in memory retrieval, both of which can be rescued by chronic exercise on treadmill. Exercise also elevated brain-derived neurotrophic factor (BDNF) expression in barrel cortex. The above-mentioned rescuing effects for both spinognesis and memory function were abolished after inhibiting BDNF/tyrosine kinase B (TrkB) pathway. In summary, this study demonstrated the improvement of stress-associated memory function by exercise via facilitating spine retention in a BDNF/TrkB-dependent manner.

Daily cumulative hip moment is associated with radiographic progression of secondary hip osteoarthritis.

OBJECTIVE: To investigate whether higher daily cumulative hip moment at baseline is associated with subsequent radiographic progression of hip osteoarthritis (OA) over 12 months. DESIGN: Fifty patients with secondary hip OA, excluding patients with end-stage hip OA, participated in this prospective cohort study. Joint space width (JSW) of the hip was measured at baseline and 12 months later. With radiographic progression of hip OA (>0.5 mm/year in JSW) as dependent variable (yes/no), univariable and multivariable logistic regression analyses were performed to assess the association between load-related parameters during gait (i.e., peak hip moment, hip moment impulse, and daily cumulative hip moment [product of hip moment impulse and mean steps/day]) and hip OA progression with and without adjustment for age, body weight, and minimum JSW. RESULTS: Of the 50 patients (47.4 ± 10.7 years old), 21 (42.0%) were classified into the progression group. The higher daily cumulative hip moment in the frontal plane at baseline was statistically significantly associated with radiographic progression of hip OA (adjusted odds ratio (OR) [95% confidence interval (CI)], 1.34 [1.06-1.70]; P = 0.013). The higher daily cumulative hip moment in the sagittal plane was also approaching significance in its association with hip OA progression (adjusted OR, 1.80 [0.99-3.26]; P = 0.052). CONCLUSIONS: In the female patients with secondary hip OA, higher daily cumulative hip moment, particularly in the frontal plane, was a predictor of radiographic progression of hip OA over 12 months. Reduction in daily cumulative hip moment by modification in gait and physical activity may potentially slow hip OA progression.

Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac.

Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1(-/-)) or Epac2 (Epac2(-/-)) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2(-/-) mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2(-/-) mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2(-/-) mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis.

Lowering levels of bed occupancy is associated with decreased inhospital mortality and improved performance on the 4-hour target in a UK District General Hospital.

OBJECTIVE: To evaluate whether there is an association between an intervention to reduce medical bed occupancy and performance on the 4-hour target and hospital mortality. METHODS: This before-and-after study was undertaken in a large UK District General Hospital over a 32 month period. A range of interventions were undertaken to reduce medical bed occupancy within the Trust. Performance on the 4-hour target and hospital mortality (hospital standardised mortality ratio (HSMR), summary hospital-level mortality indicator (SHMI) and crude mortality) were compared before, and after, intervention. Daily data on medical bed occupancy and percentage of patients meeting the 4-hour target was collected from hospital records. Segmented regression analysis of interrupted time-series method was used to estimate the changes in levels and trends in average medical bed occupancy, monthly performance on the target and monthly mortality measures (HSMR, SHMI and crude mortality) that followed the intervention. RESULTS: Mean medical bed occupancy decreased significantly from 93.7% to 90.2% (p=0.02). The trend change in target performance, when comparing preintervention and postintervention, revealed a significant improvement (p=0.019). The intervention was associated with a mean reduction in all markers of mortality (range 4.5-4.8%). SHMI (p=0.02) and crude mortality (p=0.018) showed significant trend changes after intervention. CONCLUSIONS: Lowering medical bed occupancy is associated with reduced patient mortality and improved ability of the acute Trust to achieve the 95% 4-hour target. Whole system transformation is required to create lower average medical bed occupancy.

Diffusivity of the uncinate fasciculus in heroin users relates to their levels of anxiety.

Heroin use is closely associated with emotional dysregulation, which may explain its high comorbidity with disorders such as anxiety and depression. However, the understanding of the neurobiological etiology of the association between heroin use and emotional dysregulation is limited. Previous studies have suggested an impact of heroin on diffusivity in white matter involving the emotional regulatory system, but the specificity of this finding remains to be determined. Therefore, this study investigated the association between heroin use and diffusivity of white matter tracts in heroin users and examined whether the tracts were associated with their elevated anxiety and depression levels. A sample of 26 right-handed male abstinent heroin users (25 to 42 years of age) and 32 matched healthy controls (19 to 55 years of age) was recruited for this study. Diffusion tensor imaging data were collected, and their levels of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Our findings indicated that heroin users exhibited higher levels of anxiety and depression, but the heroin use-associated left uncinate fasciculus was only related to their anxiety level, suggesting that association between heroin and anxiety has an incremental organic basis but that for depression could be a threshold issue. This finding improves our understanding of heroin addiction and its comorbid affective disorder and facilitates future therapeutic development.

The regulation of oxytocin receptor gene expression during adipogenesis.

Although it has been reported that oxytocin stimulates lipolysis in adipocytes, changes in the expression of oxytocin receptor (OTR) mRNA in adipogenesis are still unknown. The present study aimed to investigate the expression of OTR mRNA during adipocyte differentiation and fat accumulation in adipocytes. OTR mRNA was highly expressed in adipocytes prepared from mouse adipose tissues compared to stromal-vascular cells. OTR mRNA expression was increased during the adipocyte differentiation of 3T3-L1 cells. OTR expression levels were higher in subcutaneous and epididymal adipose tissues of 14-week-old male mice compared to 7-week-old male mice. Levels of OTR mRNA expression were higher in adipose tissues at four different sites of mice fed a high-fat diet than in those of mice fed a normal diet. The OTR expression level was also increased by refeeding for 4 h after fasting for 16 h. Oxytocin significantly induced lipolysis in 3T3-L1 adipocytes. In conclusion, a new regulatory mechanism is demonstrated for oxytocin to control the differentiation and fat accumulation in adipocytes via activation of OTR as a part of the hypothalamic-pituitary-adipose axis.

The injury resistant ability of melanopsin-expressing intrinsically photosensitive retinal ganglion cells.

Neurons in the mammalian retina expressing the photopigment melanopsin have been identified as a class of intrinsically photosensitive retinal ganglion cells (ipRGCs). This discovery more than a decade ago has opened up an exciting new field of retinal research, and following the initial identification of photosensitive ganglion cells, several subtypes have been described. A number of studies have shown that ipRGCs subserve photoentrainment of circadian rhythms. They also influence other non-image forming functions of the visual system, such as the pupillary light reflex, sleep, cognition, mood, light aversion and development of the retina. These novel photosensitive neurons also influence form vision by contributing to contrast detection. Furthermore, studies have shown that ipRGCs are more injury-resistant following optic nerve injury, in animal models of glaucoma, and in patients with mitochondrial optic neuropathies, i.e., Leber's hereditary optic neuropathy and dominant optic atrophy. There is also an indication that these cells may be resistant to glutamate-induced excitotoxicity. Herein we provide an overview of ipRGCs and discuss the injury-resistant character of these neurons under certain pathological and experimental conditions.

Functional performance of female patients more than 6 months after total hip arthroplasty shows greater improvement with weight-bearing exercise than with non-weight-bearing exercise. Randomized controlled trial.

BACKGROUND: Impaired functional performance and decreased muscle strength and muscle atrophy generally persist for a long period after total hip arthroplasty (THA). AIM: To investigate the effects of weight-bearing (WB) and non-weight-bearing (NWB) exercises on functional performance, Harris hip score (HHS), muscle strength and muscle thickness in women after THA. DESIGN: A randomised, controlled trial. SETTING: Community. POPULATION: Sixty-five women who had undergone unilateral or bilateral THA at least 6 months before enrolment in the study. METHODS: Participants were randomly allocated to the following groups: WB (n = 22), NWB (n = 21) and control (n = 22) groups. Participants in the WB and NWB groups performed daily home exercise programs for 8 weeks. Functional performance (timed up and go, sit-to-stand, stair climbing, walking speed and 3-min walk test), HHS, isometric muscle strength of the hip and knee muscle and gluteus and quadriceps muscle thickness were measured at baseline and after 8 weeks. RESULTS: An intention-to-treat analysis revealed that both the intervention groups exhibited significant improvements in almost all functional performance measures compared with the control group. Furthermore, the WB group showed significantly greater pre-post changes in the sit-to-stand and 3-min walk test compared with the NWB group. In terms of HHS, only the WB group showed significantly greater improvement compared with the control group. Relative to the control group, improvements in all isometric strength measures were observed in both the intervention groups. Significant improvement in quadriceps muscle thickness was observed in the WB group compared with the control group. However, no significant difference was observed among the three groups in pre-post changes in gluteus muscle thickness. CONCLUSION: WB and NWB home exercise programs were both effective for improving functional performance and muscle strength in women after THA. However, the WB exercise was more effective than the NWB exercise for improving sit-to-stand ability and walking endurance. CLINICAL REHABILITATION IMPACT: In this study, we demonstrated that the WB exercise was more effective than the NWB exercise for improving functional performance in patients after THA.

Spinal cord maturation and locomotion in mice with an isolated cortex.

The spinal cord plays a key role in motor behavior. It relays major sensory information, receives afferents from supraspinal centers and integrates movement in the central pattern generators. Spinal motor output is controlled via corticofugal pathways including corticospinal and cortico-subcortical projections. Spinal cord injury damages descending supraspinal as well as ascending sensory pathways. In adult rodent models, plasticity of the spinal cord is thought to contribute to functional recovery. How much spinal cord function depends on cortical input is not well known. Here, we address this question using Celsr3/Foxg1 mice, in which cortico-subcortical connections (including corticospinal tract (CST) and the terminal sensory pathway, the thalamocortical tract) are genetically ablated during early development. Although Celsr3/Foxg1 mice are able to eat, walk, climb on grids and swim, open-field tests showed them to be hyperactive. When compared with normal littermates, mutant animals had reduced number of spinal motor neurons, with atrophic dendritic trees. Furthermore, motor axon terminals were decreased in number, and this was confirmed by electromyography. The number of cholinergic, calbindin, and calretinin-positive interneurons was moderately increased in the mutant spinal cord, whereas that of reelin and parvalbumin-positive interneurons was unchanged. As far as we know, our study provides the first genetic evidence that the spinal motor network does not mature fully in the absence of corticofugal connections, and that some motor function is preserved despite congenital absence of the CST.

Calcium binding protein expression in the optic tectum of Alligator during development.

The onset and distribution of the calcium binding proteins, calretinin, calbindin, and parvalbumin, were examined in the optic tectum of Alligator mississipiensis embryos between Stages 18 and 26-28. The immunoreactivity of each calcium binding protein correlated well with the results from the Western blot experiments. In terms of onset and distribution, calretinin expressison was the most widespread of the three calcium binding proteins that were examined, and was also the earliest to be visualized. Calbindin expression occurred next, whereas parvalbumin expression was the most limited and appeared last. For small calretinin (+) neurons, the pattern of immunoreactivity during development was from inside to outside, whereas for the larger cells, it was from outside to inside. For calbindin immunoreactive cells in the superficial zone, the pattern was from outside to inside. The distribution of the parvalbumin immunopositive neurons did not change significantly over the time period examined. Similar data on other amniotes is limited. However, the pattern in Alligator shares some similarities with kittens in regards to the distribution of calbindin and parvalbumin in the developing superior colliculus.