Ultrasound screening for abdominal aortic aneurysm in high-risk women.

BACKGROUND: Population-wide ultrasound screening programmes for abdominal aortic aneurysm (AAA) for men have already been established in some countries. Women account for one third of aneurysm-related mortality and are four times more likely to experience an AAA rupture than men. Whole-population screening for AAA in women is unlikely to be clinically or economically effective. The aim of this study was to determine the outcomes of a targeted AAA screening programme for women at high risk of AAA. METHOD: Women aged 65-74 years deemed at high risk of having an AAA (current smokers, ex-smokers, or with a history of coronary artery disease) were invited to attend ultrasound screening (July 2016 to March 2019) for AAA in the Female Aneurysm screening STudy (FAST). Primary outcomes were attendance for screening and prevalence of AAA. Biometric data, medical history, quality of life (QoL) and aortic diameter on ultrasound imaging were recorded prospectively. RESULTS: Some 6037 women were invited and 5200 attended screening (86.7 per cent). Fifteen AAAs larger than 29 mm were detected (prevalence 0.29 (95 per cent c.i. 0.18 to 0.48) per cent). Current smokers had the highest prevalence (0.83 (95 per cent c.i. 0.34 to 1.89) per cent) but lowest attendance (75.2 per cent). Three AAAs greater than 5.5 cm were identified and referred for consideration of surgical repair; one woman underwent repair. There was a significant reduction in patient-reported QoL scores following screening. CONCLUSION: A low prevalence of AAA was detected in high-risk women, with lowest screening uptake in those at highest risk. Screening for AAA in high-risk women may not be beneficial.

The South Asian Health Foundation (UK) guidelines for managing diabetes during Ramadan.

BACKGROUND: Fasting in the holy month of Ramadan is among the five pillars of Islam and is considered as a religious obligation by the Muslim population. People with diabetes observing the practice of fasts are at a higher risk of complications such as hypoglycaemia, hyperglycaemia and ketoacidosis due to changes in eating patterns and circadian rhythms. With the objective of mitigating these complications, the South Asian Health Foundation (UK) has developed the present guidelines based on robust evidence derived from epidemiological studies and clinical trials. METHODS: We have highlighted the role of pre-Ramadan risk stratification and counselling by healthcare professionals with emphasis on the need for advice on adequate dietary and fluid intake, blood glucose monitoring and awareness of when to break the fast. RESULTS: We reviewed the current literature and have given clinically-relevant recommendations on lifestyle modifications and glucose-lowering therapies such as metformin, sulphonylureas, dipeptidyl peptidase-4 inhibitors, sodium glucose co-transporter-2 inhibitors, thiazolidinediones, glucagon-like peptide-1 receptor agonists and insulin. CONCLUSIONS: An individualised patient-centric treatment plan is essential to not only achieve optimal glycaemic outcomes but also enable people with diabetes to observe a risk-free month of fasting during Ramadan.

Comorbid depression and risk of cardiac events and cardiac mortality in people with diabetes: A systematic review and meta-analysis.

OBJECTIVE: To examine the association of comorbid occurrence of diabetes and depression with risk of cardiovascular endpoints including cardiovascular mortality, coronary heart disease and stroke. RESEARCH DESIGN AND METHODS: A systematic review and metaanalysis. We searched PUBMED/MEDLINE, Medscape, Cochrane Library, CINAHL, EMBASE and Scopus databases assessing cardiac events and mortality associated with depression in diabetes up until 1 December 2018. Pooled hazard ratios were calculated using random- effects models. RESULTS: Nine studies met the inclusion criteria. The combined pooled hazard ratios showed a significant association of cardiac events in people with depression and type 2 diabetes, compared to those with type 2 diabetes alone. For cardiovascular mortality the pooled hazard ratio was 1.48 (95% CI: 1.185, 1.845), p = 0.001, for coronary heart disease 1.37 (1.165, 1.605), p < 0.001 and for stroke 1.33 (1.291, 1.369), p < 0.001. Heterogeneity was high in the meta-analysis for stroke events (I-squared = 84.7%) but was lower for coronary heart disease and cardiovascular mortality (15% and 43.4% respectively). Meta-regression analyses showed that depression was not significantly associated with the study level covariates mean age, duration of diabetes, length of follow-up, BMI, sex and ethnicity (p < 0.05 for all models). Only three studies were found that examined the association of depression in type 1 diabetes, there was a high degree of heterogeneity and data synthesis was not conducted for these studies. CONCLUSIONS: We have demonstrated a 47.9% increase in cardiovascular mortality, 36.8% increase in coronary heart disease and 32.9% increase in stroke in people with diabetes and comorbid depression. The presence of depression in a person with diabetes should trigger the consideration of evidence-based therapies for cardiovascular disease prevention irrespective of the baseline risk of cardiovascular disease or duration of diabetes.

Assessing the Relationship between Vitamin D Status and Impairments in Cognitive and Physical Performance in Older Adults Using a Dual Task Physical Performance Test.

BACKGROUND: Vitamin D deficiency has been associated with an increased risk of falls in older adults. Several studies have demonstrated an association between vitamin D deficiency and gait and cognitive impairments, which are two risk factors for falls in the elderly. There is lack of research about the role of vitamin D in cognitive function in the context of mobility. OBJECTIVE: The purpose of this study was to evaluate the association between vitamin D status with the age-related changes in mobility through higher order cognitive function using a dual task physical performance test. DESIGN: Cross-sectional. SETTING: Community-dwelling older adult population located in Miami, Fl. PARTICIPANTS: Healthy participants over the age of 55 (n=97) who participated in the parent interventional study. MEASUREMENTS: Participants completed assessments that included serum levels of vitamin D, surveys, and dual task physical performance tests. Spearman's correlations, independent t-tests, repeated measures ANOVAs and multiple logistic regressions were used to examine the relationship between vitamin D insufficiency (25-hydroxyvitamin D <30 ng/ml) and sufficiency (≥30 ng/ml) and dual task physical performance variables. The significance level was set at α=0.05. RESULTS: There were no significant associations between vitamin D insufficiency and gait velocity during either task. Using Spearman correlations, slower single (P=0.011) and dual task counting rates (P=0.006) were significantly associated with vitamin D insufficiency. Independent t-tests showed dual and single task counting rates were significantly lower in the vitamin D insufficient group compared to the sufficient group (P=0.018 and P=0.028, respectively). The results for the ANOVAs indicated that velocities and counting rates were not significantly different by vitamin D status (Wilk's Lambda =0.999; F (1, 95) =.11, P=.740) (Wilk's Lambda =.999, F(1,95)=.13, P=.718). Vitamin D status was not significantly associated with dual task physical performance (defined as the difference in dual and single task) in gait velocity (OR=1.00, 95% CI: 0.98; 1.02, P=0.772) and counting rate (OR=1.684, 95% CI: 0.15; 19.57, P=0.677), when controlling for confounders. CONCLUSIONS: Since counting backward is a mental tracking task, which is a component of executive function, our results suggest a relationship between vitamin D insufficiency and executive dysfunction. Executive dysfunction has been previously associated with fall risks in the elderly, and it could be a possible mediator between vitamin D and falls. Our data suggest that cognition may play a significant role in vitamin D's influence on falls, while motor function may play a lesser role.

Regulation of signaling pathways by tanshinones in different cancers.

Past several years have witnessed dramatic leaps in our understanding of rewiring of gene expression at the translation level during cancer developmentthat provides linchpin support to the transformed phenotype. Most recent and ground-breaking developments in the field of molecular oncology aredriven by an explosion in technological advancements and have started to reveal previously unimagined regulatory mechanisms and how they intricately co-ordinate to modulate cancer progression, loss of apoptosis and development of resistance against different therapeutics. However, the insights gained from work in this natural product research have far-reaching impact because of rapidly increasing repertoire of medicinally and biologically efficient phytochemicals. How Tanshinones mediate targeting of JAK-STAT, ER stress associated signaling cascade,PI3K/AKT/mTOR pathway,autophagy, TRAIL pathway and microRNAs are being discovered and will prove to be helpful in getting a step closer to personalized medicine.

Signaling networks in TMPRSS2-ERG positive prostate cancers: Do we need a Pied Piper or sharpshooter to deal with "at large" fused oncoprotein.

Overwhelmingly increasing scientific evidence has provided near complete resolution of prostate cancer landscape and it is now more understandable that wide ranging factors underlies its development and progression. Increasingly it is being realized that genetic/epigenetic factors, Intra-tumoral and inter-tumoral heterogeneity, loss of apoptosis, dysregulations of spatio-temporally controlled signaling cascades, Darwinian evolution in response to therapeutic pressures play instrumental role in prostate carcinogenesis. Moreover, multi-directional patterns of spread between primary tumors and metastatic sites have also been studied extensively in prostate cancer. Research over the years has gradually and systematically revealed closer association between tumor phenotype and type of gene fusion. Latest developments in deep sequencing technologies have shown that gene fusions originate in a non-random, cell type dependent manner and are much more frequent than previously surmised. These findings enabled sub-classification and categorization of seemingly identical diseases. Furthermore, research methodologies have shown that many gene fusions inform us about risk stratification and many chimeric proteins encoded by the fused genes are being studied as drug target/s. We partition this multi-component review into the molecular basis of formation of fusion transcripts, how protein network is regulated in fusion positive prostate cancer cells and therapeutic strategies which are currently being investigated to efficiently target fusion transcript and its protein product.

Peripherally inserted central catheter in extremely preterm infants: Characteristics and influencing factors.

OBJECTIVE: To evaluate the duration of catheter stay, incidence of non-elective removal and rates of complications associated with peripherally inserted central catheters (PICCs) in relation to different catheter positions in extremely preterm infants (EPT, <28 weeks of gestation). METHODS: A retrospective analysis of Peripherally Inserted Central Catheters (PICCs) inserted in EPT infants over a 10-year period, from January 2004 through December 2013 (mean gestational age, 25.2 weeks; mean birth weight, 727 g). RESULTS: Of the 379 PICCs analyzed, the majority of lines (68%) were placed in the central position, and 259 PICCs (56%) were removed electively after fulfilment of the treatment. Significantly more PICCs in the lower extremities compared to the upper extremities were in central positions (86% vs 61%, p < 0.001, respectively). Significantly more PICCs that were removed electively after fulfilment of the treatment were in a central position compared to a non-central position (p < 0.001). Of the 166 catheters that were removed because of complications, most (71%) of them had mechanical problems, and 13% had sepsis resulting in an incidence rate of 4.4/1000 catheter days. CONCLUSION: PICCs inserted in the lower extremity were more likely to have a centrally placed tip position compared to PICC lines inserted in the upper extremities.

Evaluating the impact of an enhanced primary care diabetes service on diabetes outcomes: A before-after study.

Diabetes is an ambulatory care-sensitive condition and a high quality primary care or risk factor control can lead to a decrease in the risk of non-elective hospitalisations while ensuring continuity of care with usual primary care teams. AIMS AND METHODS: In this before and after study, eight primary care practices providing a newer enhanced diabetes model of care in Leicester UK, were compared with matched neighbouring practices with comparable demographic features providing a more expensive integrated specialist-community care diabetes service. The primary outcome at twelve months was to demonstrate equivalence in non-elective bed days. The enhanced practices had primary care physicians and nurses with an interest in diabetes who attended monthly diabetes education meetings and provided care plans and audits. The control practices provided an integrated primary-specialist care service. RESULTS: The difference between the mean change in the non-elective bed days from baseline and at follow up in core and enhanced practices was not statistically significant (mean=2.20 per 100 patients, 95% CI=-0.92 to 5.31 per 100 patients, p=0.14). The analogous change for first outpatients' attendance were 0.23 per 100 patients (95% CI=-0.47 to 0.52 per 100 patients p=0.92) and for diabetes related complications admissions was 0.30 per 100 patients (95% CI=-0.85 to 1.45 per 100 patients p=0.55). CONCLUSION: A model of enhanced primary care based diabetes care appears unlikely to increase hospitalisations, outpatients' attendance or admissions for diabetes related complications.

Targeting of BCR-ABL: Lessons learned from BCR-ABL inhibition.

In 1960 researchers reported that balanced translocation between chromosomes 22 and 9 resulted in the generation of Philadelphia chromosome. This breakthrough revolutionized our knowledge related to leukemia biology and contemporary studies revealed that chromosomal translocation resulted in the fusion between the 5' segment of BCR gene and 3' segment of the ABL gene to form BCR/ABL fusion gene. Research over the years has progressively and systematically improved our understanding of the genetic and proteomic basis of Leukemia. Genome-wide profiling studies, including genome sequencing and microarray analysis, have helped us in identification of different intracellular signaling cascades that are frequently mutated in Leukemia.  We partition this multi-component review into different sections related to biochemical characteristics of BCR-ABL+ cells, underlying mechanism of generation of mutations and crosstalk of BCR-ABL with various intracellular signaling cascades. We also summarize how BCR-ABL encoding mRNA is negatively regulated by different miRNAs and the strategies which are currently being used to effectively target BCR-ABL protein. We also provide an overview of the natural products which have been used for targeting of BCR-ABL protein. Better understanding of the protein network of Philadelphia positive leukemic cells will prove to be helpful in getting a step closer to personalized medicine.

How sesquiterpenes modulate signaling cascades in cancers.

Data obtained from high-throughput technologies has started to shed light on the interplay between signal transduction cascades and chromatin modifications thus adding another layer of complexity to the already complex regulation of the protein network. Based on the insights gleaned from almost a decade of research, it has now been convincingly revealed that sesquiterpenes effectively modulated different intracellular signaling cascades in different cancers. In this review we summarize how sesquiterpenes mediated Wnt, Shh, Notch and TRAIL induced signaling cascades.

Two-thirds of adolescents who received active perinatal care after extremely preterm birth had mild or no disabilities.

AIM: Active perinatal care (APC) increases the survival of extremely preterm (EPT) infants, but may increase the rate of disabilities. We examined neurodevelopmental outcomes in adolescents aged 10-15 years who were born EPT and received APC in two Swedish tertiary care centres. METHODS: Cognitive function was assessed using the Wechsler Intelligence Scale for Children, and neurosensory impairments were assessed by reviewing the case records and a standard parent health questionnaire. The outcomes were compared to term-born controls. RESULTS: We assessed 132 EPT adolescents and 103 controls. The rates of cerebral palsy, moderate to severe visual impairment and moderate to severe hearing impairment were 9%, 4% and 6%, respectively, for the EPT children and zero for the controls. Serious cognitive impairment was present in 31% of the EPT adolescents and 5% of the controls. Combining impairments across domains showed that 34% of EPT adolescents had moderate and severe disabilities compared with 5% of the controls. Impairments were more common at 23-24 weeks of gestational age (43%) than at 25 weeks (28.4%). CONCLUSION: Two-thirds (66%) of adolescents born EPT who received APC had mild or no disabilities. Our results are relevant for healthcare providers and clinicians counselling families.

Editorial.

To optimize treatment, we need to understand biology of different diseases in much more detail with emphasis on morphological, proteomic, genetic and epigenetic grounds. Keeping in view the facts and stimulating developments in molecular pathology, it is worthwhile to present an up-date on this topic.It is becoming progressively more understandable that exciting fields of pharmacogenomics and pharmacogenetics have revolutionized field of medicine. Better understanding of underlying mechanisms of different diseases has provided us with better ways to treat illnesses. There cannot be a distinct definition of 'discipline' of pathology, mainly because investigation of human disease encompasses all the scientific disciplines of biomedical research. Sen et al reported that hyperbaric oxygen (HBO) administration affected the endocrinological functions of fat tissue. Observation of significant increases in leptin, visfatin and IL-10 levels, leads to the consideration that in near future HBO administration may be applied as treatment for obesity, DM, eating disorders and obesity related diseases...

The effect of glycyrrhizic acid on traumatic spinal cord injury in rats.

Spine injury associated with traumatic spinal cord injury eventuates in oxidative stress, inflammation and neuronal apoptosis. The aim of this study is to find out whether the glycyrrhizic acid treatment protects spinal cord from traumatic injuries in rats. To this end, the rats were divided into three groups: group I; control group (no drug or operation, n=8), group II; traumatic spinal cord injury group (TSCI, n=8) and group III; glycyrrhizic acid group (TSCI-GA, 80 mg/kg, n=8). Total laminectomy was performed at T10 level. A balloon angioplasty catheter was inserted into the T9 level thoracic spinal cord extradurally. The rats were evaluated with the Tarlov Scale. After 24 hours, spinal cord tissues were taken for biochemical and histopathological examinations. TSCI effectuates unwanted results on tissues, antioxidant systems and cell membranes. Antioxidant enzyme level decreased and lipid peroxidation increased. However, TSCI led to inflammation and apoptosis. Glycyrrhizic acid treatment provided a significant decrease in lipid peroxidation in group III in comparison with group II. Moreover, nuclear respiratory factor 1 levels and superoxide dismutase activity of group III were significantly higher than group II (p<0.05). The histopathological and immunohistochemical results revealed that the numbers of apoptotic and necrotic neuron, edema, hemorrhage, inflammatory cells, NF-κB and S100B expressions were significantly lower than group II (p<0.05). Our study showed that the glycyrrhizic acid treatment reduced oxidative stress and inflammation, and promoted the neuronal functions in traumatic spinal cord injury.

Are there possible associations between MnSOD and GPx1 gene variants for laryngeal cancer risk or disease progression?

Laryngeal squamous cell carcinoma (LSCC) is a multifaceted and genomically complex disease and cellular and preclinical studies have demystified wide ranging molecular mechanisms which underpin its development and progression and resistance against wide ranging molecular therapeutics. Oxidative stress is a widely studied molecular mechanism and reportedly involved in carcinogenesis. Increasingly it is being realized that accumulation of Reactive Oxygen Species (ROS) activates defensive mechanism to counteract oxidative stress induced damage. Manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx) are important members of defensive machinery. We investigated whether the polymorphisms of MnSOD (Ala-9Val, rs4880) and GPx1 (Pro198Leu, rs1050450) are associated with LSCC and also evaluated possible interactions between these polymorphisms and various lifestyle factors or pathological features of patients. For this purpose, 67 LSCC patients and 73 healty controls were enrolled. Molecular assessment of MnSOD and GPx1 variants were determined with polymerase chain reaction-restriction fragment length polymorphism techniques. We found that the frequency of both heterozygous PL genotype and P allele was considerably higher in patients with advanced tumor stage (T3/T4) than in those with early tumor stage (T1/T2) (OR= 5.106; 95% CI=1.372-19.004; p<0.001, OR=5.787; 95% CI =1.564-21.414; p<0.001 respectively). Although the frequency of ValVal/LL combine genotype was significantly decreased (OR=0.204, 95% CI=0.055-0.760; p=0.021), the frequency of ValAla/PL combine genotypes was higher in patients with stage T3/T4 than in those patients with stage T1/T2 (p=0.027). Consequently, we have concluded that variants of GPx1 and MnSOD should not be considered as a risk factor of LSCC, only may be accepted as a prognostic markers. Use of new technologies such as metabolomics and deep DNA sequencing will prove to be helpful in developing a deeper knowledge related to how cancer cell metabolism adapts and provides a buffer against increased oxidative stress.

Tudor tells about new twists in the story tale of SMURFs.

Smad ubiquitin regulatory factors (SMURFS) belong to the HECT- family of E3 ubiquitin ligases. This family has two members, SMURF1 and SMURF2. SMURFs have emerged as well studied negative regulators of TGF induced intracellular signaling. However, increasingly it is being realized that SMURFs tactfully modulate an array of proteins in different cancers. This review sets spotlight on how SMURF1 and SMURF2 communicate with effectors of different signaling pathways during the multistep progression to cancer. We also summarize how microRNAs (miRNAs) effectively control SMURFs in different cancers. Role of SMURFs is context dependent in different cancers and better concepts related to miRNA regulation of SMURFs in different stages and steps of cancer will be helpful in efficient translation of laboratory findings to clinic.

Anticancer activity of Cynodon dactylon and Oxalis corniculata on Hep2 cell line.

Bioactive chemicals isolated from plants have attracted considerable attention over the years and overwhelmingly increasing laboratory findings are emphasizing on tumor suppressing properties of these natural agents in genetically and chemically induced animal carcinogenesis models. We studied in vitro anticancer activity of organic extracts of Cynodon dactylon and Oxalis corniculata on Hep2 cell line and it was compared with normal human corneal epithelial cells (HCEC) by using MTT assay. Real Time PCR was conducted for p53 and PTEN genes in treated cancer cell line. DNA fragmentation assay was also carried out to note DNA damaging effects of the extracts. The minimally effective concentration of ethanolic extract of Cynodon dactylon and methanolic extract of Oxalis corniculata that was nontoxic to HCEC but toxic to Hep2 was recorded (IC50) at a concentration of 0.042mg/ml (49.48 % cell death) and 0.048mg/ml (47.93% cell death) respectively, which was comparable to the positive control. Our results indicated dose dependent increase in cell death. P53 and PTEN did not show significant increase in treated cell line. Moreover, DNA damaging effects were also not detected in treated cancer cell line. Anticancer activity of these plants on the cancer cell line showed the presence of anticancer components which should be characterized to be used as anticancer therapy.

Executive Functioning and Learning Skills of Adolescent Children Born at Fewer than 26 Weeks of Gestation.

AIMS: To assess the cognitive and behavioral aspects of executive functioning (EF) and learning skills in extremely preterm (EPT) children compared with term control children aged 10 to 15 years. METHODS: A total of 132 of 134 (98% of all eligible survivors) EPT children born at the 2 Swedish regional tertiary care centers from 1992 to 1998 (mean age = 12 years, mean birth weight = 718 g, and mean gestational age = 24.4 weeks) and 103 matched term controls were assessed. General intelligence was assessed using the Wechsler Intelligence Scale for Children (WISC-III-R), and cognitive aspects of EF were analyzed using EF-sensitive subscales of the WISC-III-R and Tower test of the Delis-Kaplan Executive Function Scale (D-KEFS). Behaviors related to EF and learning skills were assessed using the Five to Fifteen questionnaire, which is a validated parent and teacher instrument. Academic performance in school was assessed by teachers' responses on Achenbach's Teachers Report Form. Analyses performed included multivariate analyses of covariance (ANCOVA and MANCOVA) and logistic regression analyses. RESULTS: The EPT children displayed significant deficits in cognitive aspects of EF compared with the controls, exhibiting decreases on the order of 0.9 SD to 1.2 SD for tasks of verbal conceptual reasoning, verbal and non-verbal working memory, processing speed and planning ability (P <0.001 for all). After excluding the children with major neurosensory impairment (NSI) or a Full Scale intelligence quotient (FSIQ) of < 70, significant differences were observed on all tests. Compared with controls, parents and teachers of EPT children reported significantly more EF-related behavioral problems. MANCOVA of teacher-reported learning skills in children with FSIQ >70 and without major NSI revealed no interactions, but significant main effects were observed for the behavioral composite executive function score, group status (EPT vs control) and FSIQ, for which all effect sizes were medium to large. The corresponding findings of MANCOVA of the parent-reported learning skills were very similar. According to the teachers' ratings, the EPT children were less well adjusted to the school environment. CONCLUSION: EPT children born in the 1990s who received active perinatal care are at an increased risk of executive dysfunction, even after excluding children with significant neurodevelopmental disabilities. Even mild to moderate executive dysfunctions has a significant impact on learning skills. These findings suggest the need for timely interventions that address specific cognitive vulnerabilities and executive dysfunctions.

Signaling lansdscape of prostate cancer.

Research over the decades has gradually and sequentially shown that both intratumor heterogeneity and multifocality make prostate cancer difficult to target. Different challenges associated with generation of risk-stratification tools that correlate genomic landscape with clinical outcomes severely influence clinical efficacy of therapeutic strategies. Androgen receptor mediated signaling has gained great appreciation and rewiring of AR induced signaling cascade in absence of androgen, structural variants of AR have provided near complete resolution of genomic landscape and underlying mechanisms of prostate cancer. In this review we have attempted to provide an overview of most recent advancements in our knowledge related to different signaling cascades including TGF, SHH, Notch, JAK-STAT in prostate cancer progression and development.