Intestinal glucagon-like peptide-1:A new player associated with impaired counterregulatory responses to hypoglycaemia in type 1 diabetic mice

BACKGROUND Impaired hypoglycaemic counterregulation has emerged as a critical concern for diabetic patients who may be hesitant to medically lower their blood glucose levels due to the fear of potential hypoglycaemic reactions.However,the pathogenesis of hypoglycaemic counterregulation is still unclear.Glucagon-like peptide-1(GLP-1)and its analogues have been used as adjunctive therapies for type 1 diabetes mellitus(T1DM).The role of GLP-1 in counterregulatory dysfunction during hypoglycaemia in patients with T1DM has not been reported.AIM To explore the impact of intestinal GLP-1 on impaired hypoglycaemic counterregulation in type 1 diabetic mice.METHODS T1DM was induced in C57BL/6J mice using streptozotocin,followed by intraperitoneal insulin injections to create T1DM models with either a single episode of hypoglycaemia or recurrent episodes of hypoglycaemia(DH5).Immunofluorescence,Western blot,and enzyme-linked immunosorbent assay were employed to evaluate the influence of intestinal GLP-1 on the sympathetic-adrenal reflex and glucagon(GCG)secretion.The GLP-1 receptor agonist GLP-1(7-36)or the antagonist exendin(9-39)were infused into the terminal ileum or injected intraperitoneally to further investigate the role of intestinal GLP-1 in hypoglycaemic counterregulation in the model mice.RESULTS The expression levels of intestinal GLP-1 and its receptor(GLP-1R)were significantly increased in DH5 mice.Consecutive instances of excess of intestinal GLP-1 weakens the sympathetic-adrenal reflex,leading to dysfunction of adrenal counterregulation during hypoglycaemia.DH5 mice showed increased pancreaticδ-cell mass,cAMP levels inδcells,and plasma somatostatin concentrations,while cAMP levels in pancreaticαcells and plasma GCG levels decreased.Furthermore,GLP-1R expression in islet cells and plasma active GLP-1 levels were significantly increased in the DH5 group.Further experiments involving terminal ileal infusion and intraperitoneal injection in the model mice demonstrated that intestinal GLP-1 during recurrent hypoglycaemia hindered the secretion of the counterregulatory hormone GCG via the endocrine pathway.CONCLUSION Excessive intestinal GLP-1 is strongly associated with impaired counterregulatory responses to hypoglycaemia,leading to reduced appetite and compromised secretion of adrenaline,noradrenaline,and GCG during hypoglycaemia.

Nitrate reduction capacity of the oral microbiota is impaired in periodontitis:potential implications for systemic nitric oxide availability

The reduction of nitrate to nitrite by the oral microbiota has been proposed to be important for oral health and results in nitric oxide formation that can improve cardiometabolic conditions. Studies of bacterial composition in subgingival plaque suggest that nitrate-reducing bacteria are associated with periodontal health, but the impact of periodontitis on nitrate-reducing capacity(NRC)and, therefore, nitric oxide availability has not been evaluated. The current study aimed to evaluate how periodontitis affects the NRC of the oral microbiota. First, 16S rRNA sequencing data from five different countries were analyzed, revealing that nitratereducing bacteria were significantly lower in subgingival plaque of periodontitis patients compared with healthy individuals(P < 0.05 in all five datasets with n = 20–82 samples per dataset). Secondly, subgingival plaque, saliva, and plasma samples were obtained from 42 periodontitis patients before and after periodontal treatment. The oral NRC was determined in vitro by incubating saliva with 8 mmol/L nitrate(a concentration found in saliva after nitrate-rich vegetable intake) and compared with the NRC of 15healthy individuals. Salivary NRC was found to be diminished in periodontal patients before treatment(P < 0.05) but recovered to healthy levels 90 days post-treatment. Additionally, the subgingival levels of nitrate-reducing bacteria increased after treatment and correlated negatively with periodontitis-associated bacteria(P < 0.01). No significant effect of periodontal treatment on the baseline saliva and plasma nitrate and nitrite levels was found, indicating that differences in the NRC may only be revealed after nitrate intake. Our results suggest that an impaired NRC in periodontitis could limit dietary nitrate-derived nitric oxide levels, and the effect on systemic health should be explored in future studies.

METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs

Bisphosphonate-related osteonecrosis of jaw(BRONJ)is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells(BMSCs).Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders.However,the role of corin in BRONJ-related BMSCs dysfunction remains unclarified.A m6A epitranscriptomic microarray study from our group shows that the CORIN gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation.Corin knockdown inhibits BMSCs osteogenic differentiation,whereas corin overexpression or soluble corin(sCorin)exerts a promotion effect.Furthermore,corin expression is negatively regulated by bisphosphonates(BPs).Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability.Mechanistically,we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation.PD98059(a selective ERK inhibitor)blocks the corin-mediated promotion effect.With regard to the high methylation level of corin during osteogenic differentiation,we apply a non-selective m6A methylase inhibitor,Cycloleucine,which also blocks the corin-mediated promotion effect.Furthermore,we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function,indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability.To conclude,our study reveals that corin reverses BPs-induced BMSCs dysfunction,and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway.We hope this brings new insights into future clinical treatments for BRONJ.

Prevalence and risk factors for impaired renal function among Asian patients with nonalcoholic fatty liver disease

Background:Nonalcoholic fatty liver disease(NAFLD)is associated with impaired renal function,and both diseases often occur alongside other metabolic disorders.However,the prevalence and risk factors for impaired renal function in patients with NAFLD remain unclear.The objective of this study was to identify the prevalence and risk factors for renal impairment in NAFLD patients.Methods:All adults aged 18-70 years with ultrasound-diagnosed NAFLD and transient elastography examination from eight Asian centers were enrolled in this prospective study.Liver fibrosis and cirrhosis were assessed by FibroScan-aspartate aminotransferase(FAST),Agile 3+and Agile 4 scores.Impaired renal function and chronic kidney disease(CKD)were defined by an estimated glomerular filtration rate(eGFR)with value of<90 mL/min/1.73 m^(2) and<60 mL/min/1.73 m^(2),respectively,as estimated by the CKD-Epidemiology Collaboration(CKD-EPI)equation.Results:Among 529 included NAFLD patients,the prevalence rates of impaired renal function and CKD were 37.4%and 4.9%,respectively.In multivariate analysis,a moderate-high risk of advanced liver fibrosis and cirrhosis according to Agile 3+and Agile 4 scores were independent risk factors for CKD(P<0.05).Furthermore,increased fasting plasma glucose(FPG)and blood pressure were significantly associated with impaired renal function after controlling for the other components of metabolic syndrome(P<0.05).Compared with patients with normoglycemia,those with prediabetes[FPG≥5.6 mmol/L or hemoglobin A1c(HbA1c)≥5.7%]were more likely to have impaired renal function(P<0.05).Conclusions:Agile 3+and Agile 4 are reliable for identifying NAFLD patients with high risk of CKD.Early glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.

Impaired Cognition and Stroke Rehabilitation Outcomes: Are They Related?

Background: Stroke survivors who exhibit impaired cognition at admission to inpatient rehabilitation may experience participation challenges and poorer functional outcomes than those without impaired cognition. Differences in functional outcomes between stroke survivors with and without impaired cognition may be attributed to age, level of cognitive impairment, and severity of stroke. Materials and Methods: A retrospective secondary data analysis was conducted using health-related administrative data acquired from a Southwestern Ontario hospital’s stroke rehabilitation database. The aim was to explore potential linkages between post-stroke impaired cognition and functional gains, rehabilitation stays, and living settings after discharge from rehabilitation. Results: An aggregate sample of 393 males and 314 females subclassified as experiencing mild, moderate, and severe stroke was analyzed. At inpatient rehabilitation admission, 21.5% (n = 152) of these patients had no impaired cognition, 33.7% (n = 238) had mild impaired cognition, 22.2% (n = 157) had moderate impaired cognition, and 22.6% (n = 160) had severe impaired cognition. Cognitively impaired stroke patients were significantly (p 0.001) older, had (mostly) moderate to severe stroke with significantly (p = 0.012) more moderate cognitive impairment, had significantly (p 0.001) longer rehabilitation stays, and a high propensity for being discharged to longer-term care facilities compared to non-cognitively impaired patients. Conclusion: Presence of significant dissimilarity in rehabilitation stays and post-discharge destinations among stroke survivors with and without cognitive impairment is attributed to the age of the patient, level of cognitive impairment, and rigorous rehabilitation interventions.

Red Deer Optimization with Artificial Intelligence Enabled Image Captioning System for Visually Impaired People

The problem of producing a natural language description of an image for describing the visual content has gained more attention in natural language processing(NLP)and computer vision(CV).It can be driven by applications like image retrieval or indexing,virtual assistants,image understanding,and support of visually impaired people(VIP).Though the VIP uses other senses,touch and hearing,for recognizing objects and events,the quality of life of those persons is lower than the standard level.Automatic Image captioning generates captions that will be read loudly to the VIP,thereby realizing matters happening around them.This article introduces a Red Deer Optimization with Artificial Intelligence Enabled Image Captioning System(RDOAI-ICS)for Visually Impaired People.The presented RDOAI-ICS technique aids in generating image captions for VIPs.The presented RDOAIICS technique utilizes a neural architectural search network(NASNet)model to produce image representations.Besides,the RDOAI-ICS technique uses the radial basis function neural network(RBFNN)method to generate a textual description.To enhance the performance of the RDOAI-ICS method,the parameter optimization process takes place using the RDO algorithm for NasNet and the butterfly optimization algorithm(BOA)for the RBFNN model,showing the novelty of the work.The experimental evaluation of the RDOAI-ICS method can be tested using a benchmark dataset.The outcomes show the enhancements of the RDOAI-ICS method over other recent Image captioning approaches.

Vascular endothelial growth factor B improves impaired glucose tolerance through insulin-mediated inhibition of glucagon secretion

BACKGROUND Impaired glucose tolerance(IGT)is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes.When IGT occurs,insulin sensitivity decreases,causing a reduction in insulin secretion and an increase in glucagon secretion.Recently,vascular endothelial growth factor B(VEGFB)has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity.Therefore,we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion,thus contributing to the prevention and cure of prediabetes.AIM To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.METHODS We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression.Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay,and the protein expression of phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)was determined using western blot.Further,mRNA expression of forkhead box protein O1,phosphoenolpyruvate carboxykinase,and glucose-6 phosphatase was detected via quantitative polymerase chain reaction,and the correlation between the expression of proteins was analyzed via bioinformatics.RESULTS In mice with IGT and VEGFB knockout,glucagon secretion increased,and the protein expression of PI3K/AKT decreased dramatically.Further,in mice with VEGFB overexpression,glucagon levels declined,with the activation of the PI3K/AKT signaling pathway.CONCLUSION VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.

IoT-Driven Optimal Lightweight RetinaNet-Based Object Detection for Visually Impaired People

Visual impairment is one of the major problems among people of all age groups across the globe.Visually Impaired Persons(VIPs)require help from others to carry out their day-to-day tasks.Since they experience several problems in their daily lives,technical intervention can help them resolve the challenges.In this background,an automatic object detection tool is the need of the hour to empower VIPs with safe navigation.The recent advances in the Internet of Things(IoT)and Deep Learning(DL)techniques make it possible.The current study proposes IoT-assisted Transient Search Optimization with a Lightweight RetinaNetbased object detection(TSOLWR-ODVIP)model to help VIPs.The primary aim of the presented TSOLWR-ODVIP technique is to identify different objects surrounding VIPs and to convey the information via audio message to them.For data acquisition,IoT devices are used in this study.Then,the Lightweight RetinaNet(LWR)model is applied to detect objects accurately.Next,the TSO algorithm is employed for fine-tuning the hyperparameters involved in the LWR model.Finally,the Long Short-Term Memory(LSTM)model is exploited for classifying objects.The performance of the proposed TSOLWR-ODVIP technique was evaluated using a set of objects,and the results were examined under distinct aspects.The comparison study outcomes confirmed that the TSOLWR-ODVIP model could effectually detect and classify the objects,enhancing the quality of life of VIPs.

Prevalence of Uropathogenic Escherichia coli among Adult Male Patients 40 Years and above with Haematuria and Impaired Kidney Attending General Hospitals in Benue State

Haematuria is the presence of red blood cells in urine. It is most often caused by urinary tract infections of which Escherichia coli is frequently implicated. Impairment of kidney functions could occur as a result of infection or other complications of the kidney. The aim of the study was to determine the prevalence of uropathogenic Escherichia coli among adult male patients with haematuria and impaired kidneys attending a general hospital in Benue state. Three hundred and sixty-eight (368) samples of urine were collected from 368 male patients (≥ 40 years) attending the 23 general hospitals in Benue state. Each of the urine samples was divided into two parts for haematuria and isolation and identification of Escherichia coli. Blood samples (368) were also collected from the patients and used for quantitative determination of creatinine and estimation of glomerular filtration rate. The presence of haematuria was 45.1% and ranges from 12.5% to 100%. Prevalence of haematuria with respect to age shows that patients within the age group of 90 - 99 years had the highest rate (100%) and the least were those within the ages of 40 - 49 years (20.0%). Isolation rate of uropathogenic Escherichia coli was 16.3% and ranged from 6.3 to 37.5%. Patients within the age group of 90 - 99 years had the highest elevated impaired renal function of 4 (80%), followed by patients within the ages of 80 - 89 years [17 (77.3%)] and the lowest were those within the ages of 40 - 49 [6 (10.0%)]. The overall presence of haematuria in the patients was high (45.1%) with similar high Escherichia coli isolation rate and impaired renal function which could mean that acute or chronic kidney disease may set in.

Profiling and Determinants of Impaired Lipid Profile Parameters among Breast Cancer Women of Childbearing Age Living in Douala, Cameroon

Objective: Breast cancer in women of childbearing age (WCBA) is a major public health concern. This study aimed to determine variation and determinants in lipid profile among Cameroonian WCBA diagnosed with breast cancer. Materials and Methods: A case-control study took place at two reference hospitals in Douala, Cameroon. A total of 176 WCBA (88 cases and 88 controls) were finally enrolled. Interviewer-administered questionnaires were used to collect sociodemographic, behavioural, clinical and anthropometric data. Three millilitres of venous blood were collected for analysis of total cholesterol (TC), high density lipoprotein cholesterol (HDL-c), low density lipoprotein cholesterol (LDL-c) and triglycerides (TG). Results: Overweight was predominantly seen in cases and controls. Serum levels of TC and LDL-c were significantly lower in cancer women (167.02 ± 45.46 vs 183.12 ± 27.38 mg/dL, p = 0.005 for TC;85.83 ± 40.34 vs 105.25 ± 29.95 mg/dL, p = 0.0004 for LDL-c), while HDL-c levels were higher in controls (45.09 ± 7.20 vs 38.24 ± 11.14 mg/dL, p Conclusion: This study suggests the influence of breast cancer on lipid profile parameters especially HDL-c and LDL-c, and possibly their putative clinical utility for early diagnosis in premenopausal women in Cameroon.

Aberrant seed development in Litchi chinensis is associated with the impaired expression of cell wall invertase genes

Cell wall invertase(CWIN)are known to play important roles in seed development.However,most reports to date have focused on a single gene family member,and have mainly investigated CWIN functions during the filling stage of seed development.In this study,we found significant lower levels of CWIN protein and activity associated with seed abortion in the Litchi chinensis cultivar“Nuomici.”We identified five litchi CWIN genes and observed that the expression of LcCWIN5 was limited to the flower tissues and decreased sharply with fruit development.Silencing of LcCWIN5 expression before 28 DAA(cell division stage)resulted in perturbed liquid endosperm development,smaller seeds,and higher seed abortion rate,while silencing after 28 DAA(filling stage)had no effect on seed development.In contrast,LcCWIN2 was mostly expressed in the funicle and seed coat,and increased with fruit development.Decreased LcCWIN2 expression and CWIN activity during early seed filling coincided with smaller seeds in the cultivar“Feizixiao.”Silencing of LcCWIN2 caused a reduction in the seed size without inducing seed abortion.We propose that CWIN activity in seed maternal tissues during cell division stage is likely due to LcCWIN5 expression,which regulates early seed development.On the other hand,CWIN activity during the filling stage is due to the expression of LcCWIN2,which may promote carbon import by creating a sucrose gradient.Comparable LcCWIN5 expression,but much lower CWIN activity,detected in the funicle of“Nuomici”is consistent with post-translational regulation.

APOE4 expression is associated with impaired autophagy and mitophagy in astrocytes

Among the risk factors for late onset sporadic Alzheimer's disease(AD)is the expression ofε4 allele of apolipoprotein E(APOE4)gene(Mahley et al.,2006).Elevated amyloid processing and reduced degradation of Aβ,which lead to Ap plaque deposition,are evident in APOE4-positive AD patients and mice(Mahley et al.,2006).These features correlate with neuronal cell loss.Impaired mitochondrial activity and increased oxidative stress have long been recognized as additional hallmarks of AD pathology(Mahley et al.,2006).The effect of APOE4 expression on autophagy and mitochondrial dynamics and activity in astrocytes is discussed in this perspective and is summarized in Figure 1.

Effects of Impaired Glucose Metabolism on Heart Rate Variability and Blood Pessure Variability in Essential Hpertensive Patients

To investigate the effects of impaired glucose metabolism （IGM） on cardiovascular autonomic nervous systems in essential hypertensive （EH） patients by comparing heart rate variability （HRV） and blood pressure variability （BPV） in EH patients with or without type 2 diabetes mellitus （T2DM）. Simultaneous 24-h recordings of ambulatory ECG and blood pressure monitoring were performed in 36 male old patients with simple EH and 33 male old patients with EH combined with T2DM. HRV analysis included time domain parameters such as SDNN, SDANN, SDNNi, rMSSD and pNN50, and total spectral power （TP） of HRV, which mainly consists of VLF, LF and HF component along with LF/HF ratio, was also obtained. The value of ambulatory blood pressure was represented as the mean blood pressure （mean systolic/mSBP, diastolic/mDBP and pulse pressure/mPP） during different periods （24 h/24 h, day time/d and night time/n）. Standard deviation （SD） as well as coefficient of variance （CV） of blood pressure during each above-mentioned period were obtained to reflect the long-term BPV. Our result showed that SDNN, SDNNi, SDANN, rMSSD, PNN50, TP and HF of HRV in cases of EH with T2DM were all significantly lower than those in simple EH subjects （P〈0.05）. No significant differences in VLF or LF was found between the two groups （P〉0.05）, while LF/HF ratio was significantly higher in EH with T2DM patients than in simple EH subjects （P〈0.01）. Moreover, dmSBP, 24 h-mPP and dmPP were all significantly higher in EH with T2DM patients than in simple EH subjects （P〈0.05）, while nmSBP, 24 h-mSBP, 24 h-mDBP, dmDBP, nmDBP or nmPP showed no significant difference between this two groups of patients （P〉0.05）. And dSBPSD, dSBPCV and 24 h-SBPSD were all significantly higher in EH with T2DM patients than in simple EH subjects （P〈0.05）, while the other BPV indexes showed no significant difference between this two groups （P〉0.05）. It is concluded that the cardiovascular autonomic nervous systems in EH patients was further impaired by T2DM, displaying lowering of HRV and enlargement of BPV, which in turn induced abnormal structural and functional changes of cardiovascular systems. Therefore, improving cardiovascular autonomic nervous systems might reduce the occurrence of cardiovascular complications in the EH patients with IGM.

Anti-BCMA CAR-T Cell Therapy in Relapsed or Refractory Multiple Myeloma Patients with Impaired Renal Function

Anti-B cell maturation antigen(BCMA)chimeric antigen receptor(CAR)T-cell therapyis effective and well-tolerated for refractory or relapsed multiple myeloma(RRMM).The purposcof the present study was to analyze efficacy in RRMM patients with renal impairment treated byanti-BCMA CAR-T cell therapy.A total of 59 RRMM patients were selected,and divided intoimpaired renal function(lRF)group[basclinc cstimated giomerular filtration rate(eSFR)<90 m/min/1.73 m^2(n=18)]and normal renal function(NRF)group(baseline eGFR≥90 mL/min/1.73 m,n=41).For patients with IRF,eGFR at the 6th month post-CAR-T cells infusion was significantlyhigher than the baseline(P<0.05).The multivariate analysis showed that light chain type and beta-2 micro-globulin(bcta-2M)were associated factors with the decrease of serum creatinine.Medianprogression-free survival(PFS)in the NRF group and IRF group was 266 days and 181 daysrespectively.Overall survival(OS)in the NRF group and lRF group was 877 days and 238 daysrespectively.There was no significant difference in the objective response rate(ORR)between thelRF group and the NRF group.It is suggested that CAR-T cells therapy could improve the renalfunction during the treatment of RRMM.The renal function could be more significantly improvedin RRMM patients with light chain type than with other types.

PREVALENCE OF IMPAIRED GLUCOSE REGULATION IN THE POPULATION OF TIANJIN

Objective To investigate the prevalence of impaired glucose regulation （IGR） in the population of Tianjin. Methods A cross-sectional study was conducted in Tianjin from June to September in 2005. The multi-phasic stratified cluster sampling method was adopted. Totally, 21454 people were selected as survey sample. Information on risk factors was collected through face-to-face questionnaire interview. Fasting capillary whole blood glucose level and other clinical indexes were tested. Results The prevalence of impaired fasting glucose （IFG） in the population was 5.61% （5.32% in male, 5.89% in female）. The prevalence of impaired glucose tolerance （IGT） was 2.91% （2.59% in male, 3.20% in female） in whole population, and the prevalence of female was significantly higher than that of male （P = 0.04）. The prevalences of IFG and IGT increased with the increasing of age. And the prevalences were also influenced by the profession, educational level, and income level. Conclusion The prevalences oflGT and IFG in Tianjin are similar to those in the other big cities of China.

Impaired consciousness caused by injury of the lower ascending reticular activating system: evaluation by diffusion tensor tractography

A 34-year-old male patient underwent conservative management for traumatic hemorrhage in the right frontal lobe（Figure 1A）.The patient lost consciousness for approximately 4 weeks and experienced post-traumatic amnesia continuously from the time of the accident.The patient’s Glasgow Coma Scale score（Teasdale et al.,1974）was 6

Development of Nursing Protocol for Preventing Discontinuation of Treatments by Methods Other than Physical Restraint during Acute Exacerbation of Chronic Heart Failure in Patients with Impaired Cognitive Function

The purpose of this study is to prepare a nursing protocol for preventing discontinuation of treatments using a method other than physical restraint during acute exacerbation of chronic heart failure in patients with impaired cognitive function. For the first stage of the study, we prepared a draft of the nursing protocol based on a basic survey. For the second stage, semi-structured interviews were conducted with 5 nurses specialized in chronic heart failure and 10 nurses in dementia case to ensure content validity of the draft protocol. For the third stage, we examined the possibility of clinical application of the revised version of the protocol draft prepared in the second stage of the study. For assessment items, significant points of nursing care, and specific nursing care practice in this revised version, 154 subjects (93.9%) considered effective for patients, in terms of prevention of treatment discontinuation using a method other than physical restraint. All items and contents were considered useful by more than 60% of the nurses. Considering that the nurses working in the clinical setting reported 93.9% of usefulness, we concluded that this nursing protocol remained valid at a certain level. We also received a comment from the certified nurses that we should include the basic contents for newly graduated nurses. We consider that this nursing protocol will be also useful for newly graduated nurses to acquire knowledge. It helped to standardize nursing care in order to predict potential risks for patients with impaired cognitive function.

Mice with a heterozygous Lrp6 deletion have impaired fracture healing

Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/fl-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 （LRP6）, a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 （Lrp6~/-） and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6~^- mice and wild-type controls （Lrp6~/~）. Fractures were analyzed using micro-computed tomography （~CT） scans, biomechanical testing, and histological analysis. Lrp6~/- mice had significantly decreased stiffness and strength at 28 days post fracture （PF） and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.

Accelerated tooth movement in Rsk2-deficient mice with impaired cementum formation

Coffin–Lowry–Syndrome(CLS)is a X-linked mental retardation characterized by skeletal dysplasia and premature tooth loss.We and others have previously demonstrated that the ribosomal S6 kinase RSK2,mutated in CLS,is essential for bone and cementum formation;however,it remains to be established whether RSK2 plays also a role in mechanically induced bone remodeling during orthodontic tooth movement(OTM).We,therefore,performed OTM in wild-type(WT)mice and Rsk2-deficient mice using Nitinol tension springs that were fixed between the upper left molars and the incisors.The untreated contralateral molars served as internal controls.After 12 days of OTM,the jaws were removed and examined by micro-computed tomography(μCT),decalcified histology,and immunohistochemistry.Our analysis of the untreated teeth confirmed that the periodontal phenotype of Rsk2-deficient mice is characterized by alveolar bone loss and hypoplasia of root cementum.Quantification of OTM usingμCT revealed that OTM was more than two-fold faster in Rsk2-deficient mice as compared to WT.We also observed that OTM caused alveolar bone loss and root resorptions in WT and Rsk2-deficient mice.However,quantification of these orthodontic side effects revealed no differences between WT and Rsk2-deficient mice.Taken together,Rsk2 loss-of-function accelerates OTM in mice without causing more side effects.

Investigation of the transcriptomic and metabolic changes associated with superficial scald physiology impaired by lovastatin and 1-methylcyclopropene in pear fruit(cv.“Blanquilla”)

To elucidate the physiology underlying the development of superficial scald in pears,susceptible“Blanquilla”fruit was treated with different compounds that either promoted(ethylene)or repressed(1-methylcyclopropene and lovastatin)the incidence of this disorder after 4 months of cold storage.Our data show that scald was negligible for the fruit treated with 1-methylcyclopropene or lovastatin,but highly manifested in untreated(78%incidence)or ethylenetreated fruit(97%incidence).The comparison between the fruit metabolomic profile and transcriptome evidenced a distinct reprogramming associated with each treatment.In all treated samples,cold storage led to an activation of a cold-acclimation-resistance mechanism,including the biosynthesis of very-long-chain fatty acids,which was especially evident in 1-methylcyclopropane-treated fruit.Among the treatments applied,only 1-methylcyclopropene inhibited ethylene production,hence supporting the involvement of this hormone in the development of scald.However,a common repression effect on the PPO gene combined with higher sorbitol content was found for both lovastatin and 1-methylcyclopropene-treated samples,suggesting also a non-ethylene-mediated process preventing the development of this disorder.The results presented in this work represent a step forward to better understand the physiological mechanisms governing the etiology of superficial scald in pears.