Responses of CDKs and p53 in Delayed Ischemic Neuronal Death

Stroke is a debilitating disease that affects millions each year.While in many cases cerebral ischemic in jury can be limited by effectivw resuscitation or thrombolytic treatment,the injured neurons wither in a process known as delayed neuronal death(DND).Mounting evidence indicates that DND is not simply necrosis played out in slow motion but apoptosis is triggered.Of particular interest are two groups of signal proteins that participate in apoptosis-cyclin dependent kinases(CDKs) and p53-among a myriad of signaling events after an ischemic insult.Recent investigations have shown that CDKs,a family of enzymes initially known for their role in cell cycle regulation,are activated in injured neurons in DND.As for p53,new reports suggest that its up-regulation may represent a failed attempt to rescue in jured neurons,although its up-regulation was previously considered an indication of apoptosis.These observations thus rekindle an old quest to identify new neuroprotective targets to minimize the stroke damage.In this review,the author will examine the evidence that indicates the participation of CDKs and p53 in DND and then introduce pre-clinical data to explore CDK inhibition as a potential neuroprotective target.Finally,using CDK inhibition as an example,this paper will discuss the pertinent criteria for a viable neuroprotective strategy for ischemic in jury.     

中国人与白种人鼻咽癌的发病和治疗

对1971—1990年间加拿大不列颠哥伦比亚癌症中心收治的428例鼻咽癌病人的发病和治疗情况进行分析。其中,中国人占303例(71％),白种人116例(27％)。中国人在该省鼻咽癌的年发病率是白种人的64倍,其中又以在中国出生的发病率最高,分别为白种人的104倍和北美出生的中国人的16倍。本组总的5年和10年生存率分别为51％和39％,颈淋巴结阴性的病人5年生存率达64％;而阳性的病人只有44％。鼻咽癌的预后与它的临床分期、病理类型、治疗前有无做颈淋巴结活检,以及性别有关,而与病人的人种和出生地无关。     

Neu–Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis

Neu–Laxova syndrome (NLS) is a lethal autosomal recessive microcephaly syndrome associated with intrauterine growth restriction (IUGR) and multiple congenital anomalies. Clinical features include central nervous system malformations, joint contractures, ichthyosis, edema, and dysmorphic facial features. Biallelic pathogenic variants in either the PHGDH or PSAT1 genes have been shown to cause NLS. Using exome sequencing, we aimed to identify the underlying genetic diagnosis in three fetuses (from one family) with prenatal skin edema, severe IUGR, micrognathia, renal anomalies, and arthrogryposis and identified a homozygous c.1A>C (p.Met1?, NM_006623.3) variant in the PHGDH gene. Loss of the translation start codon is a novel genetic mechanism for the development of NLS. Prenatal diagnosis of NLS is challenging and few reports describe the fetal pathology. Fetal neuropathologic examination revealed: delayed brain development, congenital agenesis of the corticospinal tracts, and hypoplasia of the hippocampus, cerebellum and brainstem. Each pregnancy also showed increased nuchal translucency (NT) or cystic hygroma. While NLS is rare, it may be a cause of recurrent increased NT/cystic hygroma. This finding provides further support that cystic hygroma has many different genetic causes and that exome sequencing may shed light on the underlying genetic diagnoses in this group of prenatal patients.     

Influence of an injury reduction program on injury and fitness outcomes among soldiers

OBJECTIVE: This study evaluated the influence of a multiple injury control intervention on injury and physical fitness outcomes among soldiers attending United States Army Ordnance School Advanced Individual Training. METHODS: The study design was quasiexperimental involving a historical control group (n = 2559) that was compared to a multiple intervention group (n = 1283). Interventions in the multiple intervention group included modified physical training, injury education, and a unit based injury surveillance system (UBISS). The management responsible for training independently formed an Injury Control Advisory Committee that examined surveillance reports from the UBISS and recommended changes to training. On arrival at school, individual soldiers completed a demographics and lifestyle questionnaire and took an army physical fitness test (APFT: push-ups, sit-ups, and two mile run). Injuries among soldiers were tracked by a clinic based injury surveillance system that was separate from the UBISS. Soldiers completed a final APFT eight weeks after arrival at school. RESULTS: Cox regression (survival analysis) was used to examine differences in time to the first injury while controlling for group differences in demographics, lifestyle characteristics, and physical fitness. The adjusted relative risk of a time loss injury was 1.5 (95% confidence interval 1.2 to 1.8) times higher in the historical control men and 1.8 (95% confidence interval 1.1 to 2.8) times higher in the historical control women compared with the multiple intervention men and women, respectively. After correcting for the lower initial fitness of the multiple intervention group, there were no significant differences between the multiple intervention and historical control groups in terms of improvements in push-ups, sit-ups, or two mile run performance. CONCLUSIONS: This multiple intervention program contributed to a reduction in injuries while improvements in physical fitness were similar to a traditional physical training program previously used at the school.     

Medicare's hospital readmissions reduction program and the rise in observation stays

Objective

To evaluate whether Medicare's Hospital Readmissions Reduction Program (HRRP) is associated with increased observation stay use.

Data Sources and Study Setting

A nationally representative sample of fee-for-service Medicare claims, January 2009–September 2016.

Study Design

Using a difference-in-difference (DID) design, we modeled changes in observation stays as a proportion of total hospitalizations, separately comparing the initial (acute myocardial infarction, pneumonia, heart failure) and subsequent (chronic obstructive pulmonary disease) target conditions with a control group of nontarget conditions. Each model used 3 time periods: baseline (15 months before program announcement), an intervening period between announcement and implementation, and a 2-year post-implementation period, with specific dates defined by HRRP policies.

Data Collection/Extraction Methods

We derived a 20% random sample of all hospitalizations for beneficiaries continuously enrolled for 12 months before hospitalization (N = 7,162,189).

Principal Findings

Observation stays increased similarly for the initial HRRP target and nontarget conditions in the intervening period (0.01% points per month [95% CI −0.01, 0.3]). Post-implementation, observation stays increased significantly more for target versus nontarget conditions, but the difference is quite small (0.02% points per month [95% CI 0.002, 0.04]). Results for the COPD analysis were statistically insignificant in both policy periods.

Conclusions

The increase in observation stays is likely due to other factors, including audit activity and clinical advances.     

Clinical approaches to non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)ranges from simple steatosis to nonalcoholic steatohepatitis(NASH),leading to fibrosis and potentially cirrhosis,and it is one of the most common causes of liver disease worldwide.NAFLD is associated with other medical conditions such as metabolic syndrome,obesity,cardiovascular disease and diabetes.NASH can only be diagnosed through liver biopsy,but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis,reducing the need for liver biopsy and risk to patients.Disease progression varies between individuals and is linked to a number of risk factors.Mechanisms involved in the pathogenesis are associated with diet and lifestyle,influx of free fatty acids to the liver from adipose tissue due to insulin resistance,hepatic oxidative stress,cytokines production,reduced very low-density lipoprotein secretion and intestinal microbiome.Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD.Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial.Omega 3 polyunsaturated fatty acids and statins may offer additional benefits.Bariatric surgery should be considered in morbidly obese patients.More research is needed to assess the impact of these treatments on a long-term basis.The objective of this article is to briefly review the diagnosis,management and treatment of this disease in order to aid clinicians in managing these patients.