鸟氨酸脱羧酶的生理病理特点及其药物研究概况

鸟氨酸脱羧酶(ornithinedecarboxylase,ODC)是多胺代谢中的关键酶,广泛存在于人体和动物各组织细胞内,其中对肠细胞的增生、移行和分化起重要作用.机体调节因素比较复杂.在黏膜损伤性疾病及某些癌前病变等细胞大量增生的病理情况下ODC的表达发生改变,可以作为这些疾病分期、预后及药物作用靶点或疗效的指标.寻找对ODC有作用的药物对于治疗其相关疾病是非常有意义的.     

Altered response to inflammatory cytokines in hepatic energy metabolism in inducible nitric oxide synthase knockout mice

BACKGROUND/AIMS: Production of nitric oxide (NO) in the liver is believed to be a critical factor for carbohydrate and energy metabolism in endotoxin shock. The present study focuses on the involvement of NO produced by inducible nitric oxide synthase (iNOS) in glycogen synthesis and energy metabolism stimulated by insulin.METHODS: Primary hepatocytes prepared from wild-type and iNOS knockout (iNOS(-/-)) mice were employed.RESULTS: Incubation of wild-type hepatocytes with a combination of cytokines (interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma) and lipopolysaccharide (cytokines/LPS) inhibited insulin-stimulated glycogen synthesis and adenosine triphosphate (ATP) increase, and decreased the ketone body ratio (KBR) at 8-12 h, concomitant with expression of iNOS protein and NO production. While the glycogen synthesis was suppressed by cytokines/LPS, reduction of the ATP increase and a decrease in KBR by cytokines/LPS were not observed in iNOS(-/-) hepatocytes. Further, N(G)-monomethyl-L-arginine, a NOS inhibitor, reversed the inhibition of ATP increase and decrease in KBR by cytokines/LPS, but not the inhibition of glycogen synthesis. Conversely, addition of S-nitroso-N-acetylpenicillamine, a NO donor, inhibited the insulin-stimulated ATP increase synthesis in iNOS(-/-) hepatocytes, but not the insulin-stimulated glycogen synthesis.CONCLUSIONS: These results demonstrate that NO mediates the suppression of insulin-stimulated energy metabolism, but not glycogen synthesis, in cytokines/LPS-treated hepatocytes.     

Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients

Introduction

Delirium occurs in most ventilated patients and is independently associated with more deaths, longer stay, and higher cost. Guidelines recommend monitoring of delirium in all intensive care unit (ICU) patients, though few data exist in non-ventilated patients. The study objective was to determine the relationship between delirium and outcomes among non-ventilated ICU patients.

Method

A prospective cohort investigation of 261 consecutively admitted medical ICU patients not requiring invasive mechanical ventilation during hospitalization at a tertiary-care, university-based hospital between February 2002 and January 2003. ICU nursing staff assessed delirium and level of consciousness at least twice per day using the Confusion Assessment Method for the ICU (CAM-ICU) and Richmond Agitation-Sedation Scale (RASS). Cox regression with time-varying covariates was used to determine the independent relationship between delirium and clinical outcomes.

Results

Of 261 patients, 125 (48%) experienced at least one episode of delirium. Patients who experienced delirium were older (mean ± SD: 56 ± 18 versus 49 ± 17 years; p = 0.002) and more severely ill as measured by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (median 15, interquartile range (IQR) 10–21 versus 11, IQR 6–16; p < 0.001) compared to their non-delirious counterparts. Patients who experienced delirium had a 29% greater risk of remaining in the ICU on any given day (compared to patients who never developed delirium) even after adjusting for age, gender, race, Charlson co-morbidity score, APACHE II score, and coma (hazard ratio (HR) 1.29; 95% confidence interval (CI) 0.98–1.69, p = 0.07). Similarly, patients who experienced delirium had a 41% greater risk of remaining in the hospital after adjusting for the same covariates (HR 1.41; 95% CI 1.05–1.89, p = 0.023). Hospital mortality was higher among patients who developed delirium (24/125, 19%) versus patients who never developed delirium (8/135, 6%), p = 0.002; however, time to in-hospital death was not significant the adjusted (HR 1.27; 95% CI 0.55–2.98, p = 0.58).

Conclusion

Delirium occurred in nearly half of the non-ventilated ICU patients in this cohort. Even after adjustment for relevant covariates, delirium was found to be an independent predictor of longer hospital stay.     

Age-Related Hip Proprioception Declines: Effects on Postural Sway and Dynamic Balance

Objective

To evaluate the effects of age on hip proprioception, and determine whether age-related hip proprioception declines disrupt balance.

Design

Survey of proprioception and balance differences between 3 age groups.

Setting

University balance laboratory.

Participants

Volunteer sample of independent community-dwelling adults (N=102) without sensory or other neurologic impairments in 3 age groups: younger (mean age, 24.6y; range, 19–37y), mid-aged (mean age, 53.3y; range, 40–64y), and older adults (mean age, 76.3y; range, 65–94y).

Interventions

Not applicable.

Main Outcome Measures

Hip joint position sense (JPS) and kinesthesia were measured using a custom-built device. JPS error was determined by the magnitude of matching errors during vision and no-vision conditions. Kinesthesia was evaluated by the ability to detect passive limb rotation without vision. Postural sway was assessed during static stance and measured using root mean square of center of pressure (COP) displacement and velocity of COP displacement. Clinical balance and fear of falling were assessed with the mini-Balance Evaluation Systems Test (mini-BESTest) and Activities-specific Balance Confidence Scale, respectively.

Results

Both older and mid-aged adults had significantly increased JPS error compared with younger adults (P<.05). Kinesthesia accuracy was significantly decreased in older adults compared with mid-aged and younger adults (P≤.01). Both measures of proprioception error correlated with age (P≤.001). There were no relationships between hip proprioception error and postural sway during static stance. However, older adults with lower proprioceptive error had significantly higher mini-BESTest scores of dynamic balance abilities (P=.005).

Conclusions

These results provide evidence of significant hip proprioception declines with age. Although these declines are not related to increases in postural sway, participants with hip proprioception declines demonstrated disrupted dynamic balance, as indicated by decreased mini-BESTest scores.     

Development of hydrophobic reduced graphene oxide as a new efficient approach for photochemotherapy

Nowadays, chemotherapy is one of the crucial and common therapies in the world. So far, it has been revealed to be highly promising, yet patients suffer from the consequences of severe negative medical dosages. In order to overcome these issues, the enhancement of photothermal chemotherapy with reduced graphene oxide (rGO) as a photothermal agent (PTA) is widely utilised in current medical technologies. This is due to its high near-infrared region (NIR) response, in vitro or in vivo organism biocompatibility, low risk of side effects, and effective positive results. Moreover, rGO not only has the ability to ensure that selective cancer cells have a higher mortality rate but can also improve the growth rate of recovering tissues that are untouched by necrosis and apoptosis. These two pathways are specific diverse modalities of cell death that are distinguished by cell membrane disruption and deoxyribonucleic acid (DNA) disintegration of the membrane via phosphatidylserine exposure in the absence of cell membrane damage. Therefore, this review aimed to demonstrate the recent achievements in the modification of rGO nanoparticles as a PTA as well as present a new approach for performing photochemotherapy in the clinical setting.

rGO of QD-rGO nanocomposite could absorb and convert into heat when harvested under NIR radiation, resulting cell death with reduction of fluorescence.     

Angiopoietin-like 4 Stimulates STAT3-mediated iNOS Expression and Enhances Angiogenesis to Accelerate Wound Healing in Diabetic Mice

Impaired wound healing is a major source of morbidity in diabetic patients. Poor outcome has, in part, been related to increased inflammation, poor angiogenesis, and deficiencies in extracellular matrix components. Despite the enormous impact of these chronic wounds, effective therapies are lacking. Here, we showed that the topical application of recombinant matricellular protein angiopoietin-like 4 (ANGPTL4) accelerated wound reepithelialization in diabetic mice, in part, by improving angiogenesis. ANGPTL4 expression is markedly elevated upon normal wound injury. In contrast, ANGPTL4 expression remains low throughout the healing period in diabetic wounds. Exogenous ANGPTL4 modulated several regulatory networks involved in cell migration, angiogenesis, and inflammation, as evidenced by an altered gene expression signature. ANGPTL4 influenced the expression profile of endothelial-specific CD31 in diabetic wounds, returning its profile to that observed in wild-type wounds. We showed ANGPTL4-induced nitric oxide production through an integrin/JAK/STAT3-mediated upregulation of inducible nitric oxide synthase (iNOS) expression in wound epithelia, thus revealing a hitherto unknown mechanism by which ANGPTL4 regulated angiogenesis via keratinocyte-to-endothelial-cell communication. These data show that the replacement of ANGPTL4 may be an effective adjunctive or new therapeutic avenue for treating poor healing wounds. The present finding also confirms that therapeutic angiogenesis remains an attractive treatment modality for diabetic wound healing.     

High risk of Mycobacterium tuberculosis infection during the Hajj pilgrimage

INTRODUCTION: Annually more than 2 million pilgrims from all over the world attend the Hajj in Saudi Arabia. Overcrowding during this pilgrimage leads to a high risk of transmission of airborne infectious diseases. Tuberculosis (TB) is common among hospitalized pilgrims, but the overall risk of acquiring Mycobacterium tuberculosis infection during this pilgrimage is not known. We conducted a prospective study to assess the risk of M. tuberculosis infection among Hajj pilgrims. METHODS: We measured the immune response to TB antigens using a whole-blood assay (QuantiFERON TB assay) prior to departure and 3 months after return from the Hajj pilgrimage. RESULTS: Of 357 paired assays, 149 pilgrims were negative prior to the Hajj and 15 (10%) of these had a significant rise in immune response to TB antigens. CONCLUSIONS: Pilgrims may be at high risk of acquiring M. tuberculosis infection during the Hajj. This has significant public health implications for TB control in countries with large Muslim populations.     

Dual-Channel Photoplethysmography to Monitor Local Changes in Vascular Stiffness

Objectives. Monitoring arterial distensibility changes is important to understand the cardiovascular status of patient. Pulse transit time (PTT), which is an inverse equivalent of pulse wave velocity (PWV), has shown its potential in such studies. However, its methodological approach in using an electrocardiogram and a peripheral photoplethysmography (PPG) is limited due to the inclusion of pre-ejection period (PEP) in its computation. Previous studies have suggested the using the transit time difference between two peripheral measuring sites (PTT-D) instead. However, it requires two medical instruments and may not be efficient in terms of equipment utility, especially in prolonged clinical studies. Methods. Postural changes are known to cause complex haemodynamics adaptation and thereby affecting transit time measurements. A customised dual-channel PPG system based on discrete electronic devices was constructed to evaluate against conventional peripheral-based PTT. 10 healthy adults (7 male; mean age 27.0 yr) were recruited to assess the differences observed in PTT and PTT-D during two postural change test activities. Results. PTT-D derived from the customised PPG system registered 43.3± 5.6 ms and − 31.1± 3.8 msrelativechangesforthetworegulatedactivitieswhileconventionalPTTrecorded 43.6± 10.3 msand -31.0±m 6.5 msrespectively. Theformermayhavesimilarresultsbuthavesignificantlylowervariance (< EmphasisType =Italic p </Emphasis 0.05). Conclusions. Findings herein suggest that PTT-D derived from the customised PPG system shows potential. It can be used as an alternative to conventional peripheral-based PTT and possibly as a direct assessment of arterial distensibility or PWV variations as it does not include PEP in its time-related computations.