Back To Basics: Exercise And Diet In The Management Of Chronic Disease

It is important that physicians understand and relay to their patients the importance of physical activity/exercise and diet/weight control in the management of many common chronic diseases. Instead of just pushing pills, physicians need to stress lifestyle changes for their patients.

Read this; abstract:

INTRODUCTION:The increase in obesity rates in the U.S. and other less developed industrial countries have led to a worldwide epidemic of chronic disease states. Increased obesity rates are implicated in the treatment failures for illnesses such as coronary artery disease, diabetes, heart failure, hypertension and cancer. Effective prevention of obesity through diet and exercise contributes to the successful medical management of multiple chronic disease states.OBJECTIVE:Review the last 10 years of literature (2006-2016) on the effects of diet and exercise as they relate to the prevention of chronic disease.METHOD/DATA REVIEWED:Cochran Database of Systematic Reviews and other original articles using the National Center for Biotechnical Information database.CONCLUSION:The success in management of chronic disease lies in a physician's ability to educate patients and effective utilization of the resources available to that provider. Patient accountability for their individual chronic disease states is a problem related to patient education, patient participation, access to care, and payment resources. Financial, racial, and socioeconomic barriers must be addressed in the creation of an effective plan. Teaching on the importance of diet and exercise needs to occur early in life and be continually reinforced for successful outcomes. In the last 10 years, there has not been a significant study suggesting a single successful model of diet and exercise that can control chronic diseases. Cardiac, diabetic, and cancer patients have reduced hospital admissions, improved diabetic control, and improved quality of life scores related to coordinated diet and exercise programs, however. Patients may be unwilling or unable to be accountable for health care coordination. The development of exercise and obesity prevention policies and the adjustment in financial rewards to health care organizations will have a major impact in implementing these programs over the next 10 years.

Blue Light Activation Of Gene Expression

Here is an interesting study in which human cells are modified so that they react to blue light exposure with altered gene expression.  This has many implications for gene therapy, as well as for stem cell therapy; for the latter, blue light exposure could be used to make stem cells given to the patient differentiate (i.e., transform into) the type of mature cell needed for the relevant therapy.  Abstract:

Our improved CRISPR-Cas9-based photoactivatable transcription systems, CPTS2.0 and Split-CPTS2.0, enable high blue-light-inducible activation of endogenous target genes in various human cell lines. We achieved reversible activation of target genes with CPTS2.0 and induced neuronal differentiation in induced pluripotent stem cells (iPSCs) by upregulating NEUROD1 with Split-CPTS2.0

Fat Tails And Cell Signaling

Cell signaling pathways responsible for fat deposition have been studied in fat-tailed sheep, a breed characterized by an appearance associated with its name.  These findings may have relevance to the human condition.  Of course, the major reasons for fat deposition in humans is diet and inactivity, but research into the problem can be useful.  Abstract:

Adipose tissues are phenotypically, metabolically and functionally heterogeneous based on the sites of their deposition. Undesirable fat deposits in the body are often detrimental to animal and human health. To unravel the potential underlying mechanisms governing accumulation of adipose tissues in various regions of the body, i.e., subcutaneous (SAT), visceral (VAT) and tail (TAT), we profiled transcriptomes from Tan sheep, a Chinese indigenous breed with notable fat tail using RNA-seq. Upon comparison, we identified a total of 1,058 differentially expressed genes (DEGs) between the three adipose types (218, 324, and 795 in SAT/VAT, SAT/TAT, and VAT/TAT, respectively), from which several known key players were identified that are involved in lipid metabolic process, Wnt signals, Vitamin A metabolism, and transcriptional regulation of adipocyte differentiation. We also found that many elevated genes in VAT were notably enriched for key biological processes such as cytokine secretion, signaling molecule interaction and immune systems. Several developmental genes including HOXC11, HOXC12 and HOXC13, and adipose-expressed genes in the tail region, such as HOTAIR_2, HOTAIR_3 and SP9 were specially highlighted, indicating their strong associations with tail fat development in fat-tailed sheep. Our results provide new insight into exploring the specific fat deposition in tail, also contribute to the understanding of differences between adipose depots.

Outside my paycheck prison

"Busy but not productive", this describes my everyday work life for the past six months. Despite that there is no satisfaction in what I do, I need the paycheck. As a result, I have been completely depleted in terms of time, and in terms of contributing with anything useful to this blog. My everyday experiences at work are also demoralizing; therefore, I actively seek sources of moral and ethical strength, and optimism when I am outside my paycheck prison.

In the evenings, I try to replenish my spiritual life by listening to talks and podcasts, usually delivered by wise men. It helps somewhat, and I have recently shared some of my favorites.

Today I have a Google talk to share. Google talks are always good, but this one is a top-notch, Frank Abagnale: "Catch Me IfYou Can" | Talks at Google:

First, I listened to the talk by myself, then I listened to it again with my family. I have not seen the movie based upon the life of Frank Abagnale, but I am glad that I have not. It is so much better to first understand what is there behind the dynamic and astonishing story of a swindler. And behind the façade, is the story of a child whose entire world of family, school and love suddenly collapses. And as the story goes, the loss of love turns into pain, and then miraculously, the pain is transformed into love.

There are many life lessons in the 27-minute narrative: the love of a parent and its impact on the children, the reminder that at 16, our children still do lots of stupid, inconsiderate things and we, the parents, become easily disappointed at them, the lesson of meaningless and sudden death, the lesson of rebirth when one can finally reveal his identity and and be loved for who he truly is.

I am looking forward to listening to all questions that follow Frank's narrative, as I walk by my Christmas tree in my living room:

Propofol In Septic Patients

Danger of Propofol in septic patients. 

Abstract:

BACKGROUND:

Critical illness polyneuropathy (CIN) and critical illness myopathy (CIM), together "ICU-Acquired weakness (ICUAW)," occur frequently in septic patients. One of the proposed mechanisms for ICUAW includes prolonged inactivation of sodium channels. Propofol, used commonly in patients with acute respiratory failure (ARF), primarily acts via enhancement of GABAergic transmission but may also increase sodium channel inactivation, suggesting a potential interaction.

METHODS:

Electronic medical records and EMG reports of patients with ICUAW and a diagnosis of either sepsis, septicaemia, severe sepsis, or septic shock, concurrent with a diagnosis of acute respiratory failure (ARF), were retrospectively analyzed in a single center university hospital.

RESULTS:

74 cases were identified (50.0% men, age 58±14 years), and compared to age- and sex-matched controls. Of these, 51 (69%) had CIN, 19 (26%) had CIM, and 4 (5%) had both. Propofol exposure was significantly higher in patients with ICUAW compared to controls (63.5% vs. 33.8%, p<0.001). The odds ratio of developing ICUAW with propofol exposure was 3.4 (95% CI:1.7-6.7, p<0.001). Patients with ICUAW had significantly more days in hospital (59±44 vs. 30±23) and ICU (38±26 vs. 17±13), days dependent on mechanical ventilation (27±21 vs. 13±16), and rates of tracheostomy (79.7% vs. 36.5%) and gastrostomy (75.7% vs. 25.7%) (all p<0.001). They also received a significantly higher number of distinct intravenous antibiotics, cumulative days of antibiotic therapy, and exposure to vasopressors and paralytics.

CONCLUSIONS:

Propofol exposure may increase the risk of ICUAW in septic patients. An interaction through sodium channel inactivation is hypothesized.

If you or a loved one are in this position of being a septic patient, this information may be useful. It may be (or not) that the benefits of Propofol treatment outweigh the risks in a particular case, but it is best to be informed, and ask questions of your physician whenever possible.  Of course, in emergency situations, physicians must use their best judgment, and you can ask questions only after the fact.

Nephrolithiasis In Children

By Robert R. Wal - http://en.wikipedia.org/wiki/Kidney_stone, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3101185

Kidney/urinary stone disease is a serious disorder, and this paper discusses dietary interventions to avoid this disease in children.  As the abstract below makes clear, there hasn’t been any real positive findings apart from some limited data in favor of oral potassium citrate supplementation.  I have had kidney stones myself; that was one of the most painful experiences of my life.  Upon advice from an urologist, my own major preventive technique is drinking a lot of water during the day (up to 2 liters per day or more).  That’s inconvenient of course – what goes in must come out – and requires many bathroom visits per day.  A problem with children is that they go to school and can’t be spending much time in the bathroom, and keep in mind that drinking too much water can be a problem, and children, with smaller bodies than adults, have to be more careful with that.  The bottom line: follow your doctor’s advice on this subject, for both adults and children. Speaking only for myself as an adult, drinking water has helped, and I also eat a healthy diet as well.  Abstract:

BACKGROUND:

Nephrolithiasis, or urinary stone disease, in children causes significant morbidity, and is increasing in prevalence in the North American population. Therefore, medical and dietary interventions (MDI) for recurrent urinary stones in children are poised to gain increasing importance in the clinical armamentarium.

OBJECTIVES:

To assess the effects of medical and dietary interventions (MDI) for the prevention of idiopathic urinary stones in children aged from one to 18 years.

SEARCH METHODS:

We searched multiple databases using search terms relevant to this review, including studies identified from the Cochrane Central Register of Controlled Trials (CENTRAL, 2017, Issue 1), MEDLINE OvidSP (1946 to 14 February 2017), Embase OvidSP (1980 to 14 February 2017), International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Additionally, we handsearched renal-related journals and the proceedings of major renal conferences, and reviewed weekly current awareness alerts for selected renal journals. The date of the last search was 14 February 2017. There were no language restrictions.

SELECTION CRITERIA:

Randomized controlled trials of at least one year of MDI versus control for prevention of recurrent idiopathic (non-syndromic) nephrolithiasis in children.

DATA COLLECTION AND ANALYSIS:

We used standard methodologic procedures expected by Cochrane. Titles and abstracts were identified by search criteria and then screened for relevance, and then data extraction and risk of bias assessment were carried out. We assessed the quality of evidence using GRADE.

MAIN RESULTS:

The search identified one study of 125 children (72 boys and 53 girls) with calcium-containing idiopathic nephrolithiasis and normal renal morphology following initial treatment with shockwave lithotripsy (SWL). Patients were randomized to oral potassium citrate 1 mEq/kg per day for 12 months versus no specific medication or preventive measure with results reported for a total of 96 patients (48 per group). This included children who were stone-free (n = 52) or had residual stone fragments (n = 44) following SWL. Primary outcomes:Medical therapy may lower rates of stone recurrence with a risk ratio (RR) of 0.19 (95% confidence interval (CI) 0.06 to 0.60; low quality evidence). This corresponds to 270 fewer stone recurrences per 1000 (133 fewer to 313 fewer) children. We downgraded the quality of evidence by two levels for very serious study limitations related to unclear allocation concealment (selection bias) and a high risk of performance, detection and attrition bias. While the data for adverse events were incomplete, they reported that six of 48 (12.5%) children receiving potassium citrate left the trial because of adverse effects. This corresponds to a RR of 13.0 (95% CI 0.75 to 224.53; very low quality evidence); an absolute effect size estimate could not be generated. We downgraded the quality of evidence for study limitations and imprecision.We found no information on retreatment rates.

SECONDARY OUTCOMES:

We found no evidence on serum electrolytes, 24-hour urine collection parameters or time to new stone formation.We were unable to perform any preplanned secondary analyses.

AUTHORS' CONCLUSIONS:

Oral potassium citrate supplementation may reduce recurrent calcium urinary stone formation in children following SWL; however, our confidence in this finding is limited. A substantial number of children stopped the medication due to adverse events. There is no trial evidence on retreatment rates. There is a critical need for additional well-designed trials in children with nephrolithiasis.

Exercise For Peripheral Artery Disease

Perhaps we should not be surprised by the findings reported in this paper: exercise alone, but not a sophisticated new treatment (granulocyte-macrophage colony-stimulating factor) was helpful for patients with lower extremity peripheral artery disease.  There is a lesion there I think for people paying attention. Abstract:

IMPORTANCE:Benefits of granulocyte-macrophage colony-stimulating factor (GM-CSF) for improving walking ability in people with lower extremity peripheral artery disease (PAD) are unclear. Walking exercise may augment the effects of GM-CSF in PAD, since exercise-induced ischemia enhances progenitor cell release and may promote progenitor cell homing to ischemic calf muscle.OBJECTIVES:To determine whether GM-CSF combined with supervised treadmill exercise improves 6-minute walk distance, compared with exercise alone and compared with GM-CSF alone; to determine whether GM-CSF alone improves 6-minute walk more than placebo and whether exercise improves 6-minute walk more than an attention control intervention.DESIGN, SETTING, AND PARTICIPANTS:Randomized clinical trial with 2 × 2 factorial design. Participants were identified from the Chicago metropolitan area and randomized between January 6, 2012, and December 22, 2016, to 1 of 4 groups: supervised exercise + GM-CSF (exercise + GM-CSF) (n = 53), supervised exercise + placebo (exercise alone) (n = 53), attention control  + GM-CSF (GM-CSF alone) (n = 53), attention control + placebo (n = 51). The final follow-up visit was on August 15, 2017.INTERVENTIONS:Supervised exercise consisted of treadmill exercise 3 times weekly for 6 months. The attention control consisted of weekly educational lectures by clinicians for 6 months. GM-CSF (250 μg/m2/d) or placebo were administered subcutaneously (double-blinded) 3 times/wk for the first 2 weeks of the intervention.MAIN OUTCOMES AND MEASURES:The primary outcome was change in 6-minute walk distance at 12-week follow-up (minimum clinically important difference, 20 m). P values were adjusted based on the Hochberg step-up method.RESULTS:Of 827 persons evaluated, 210 participants with PAD were randomized (mean age, 67.0 [SD, 8.6] years; 141 [67%] black, 82 [39%] women). One hundred ninety-five (93%) completed 12-week follow-up. At 12-week follow-up, exercise + GM-CSF did not significantly improve 6-minute walk distance more than exercise alone (mean difference, -6.3 m [95% CI, -30.2 to +17.6]; P = .61) or more than GM-CSF alone (mean difference, +28.7 m [95% CI, +5.1 to +52.3]; Hochberg-adjusted P = .052). GM-CSF alone did not improve 6-minute walk more than attention control + placebo (mean difference, -1.4 m [95% CI, -25.2 to +22.4]; P = .91). Exercise alone improved 6-minute walk compared with attention control + placebo (mean difference, +33.6 m [95% CI, +9.4 to +57.7]; Hochberg-adjusted P = .02).CONCLUSIONS AND RELEVANCE:Among patients with PAD, supervised treadmill exercise significantly improved 6-minute walk distance compared with attention control + placebo, whereas GM-CSF did not significantly improve walking performance, either when used alone or when combined with supervised treadmill exercise. These results confirm the benefits of exercise but do not support using GM-CSF to treat walking impairment in patients with PAD.

Shared And Open-Plan Office Spaces Spread Disease

There’s been a trend for offices to be more “shared” and “open-plan” (academic laboratories at some institutions follow this model as well).  There’s probably some sort of underlying social and political motivation in this (“collective team-building” and “cooperation” – although for some strange reason administration keep their own private offices, with Deans having their own private bathrooms), as well as "cost-cutting" financial reasons, but the overall experience for workers seems to be negative. Now, we see that such “open-plan” spaces are hotbeds of disease transmission, as anyone could have expected.  Abstract:

OBJECTIVE:

The aim of this study was to examine whether shared and open-plan offices are associated with more days of sickness absence than cellular offices.

METHODS:

The analysis was based on a national survey of Danish inhabitants between 18-59 years of age (response rate 62%), and the study population consisted of the 2403 employees that reported working in offices. The different types of offices were characterized according to self-reported number of occupants in the space. The log-linear Poisson model was used to model the number of self-reported sickness absence days depending on the type of office; the analysis was adjusted for age, gender, socioeconomic status, body mass index, alcohol consumption, smoking habits, and physical activity during leisure time.

RESULTS:

Sickness absence was significantly related to having a greater number of occupants in the office (P<0.001) when adjusting for confounders. Compared to cellular offices, occupants in 2-person offices had 50% more days of sickness absence [rate ratio (RR) 1.50, 95% confidence interval (95% CI) 1.13-1.98], occupants in 3-6-person offices had 36% more days of sickness absence (RR 1.36, 95% CI 1.08-1.73), and occupants in open-plan offices (>6 persons) had 62% more days of sickness absence (RR 1.62, 95% CI 1.30-2.02).

CONCLUSION:

Occupants sharing an office and occupants in open-plan offices (>6 occupants) had significantly more days of sickness absence than occupants in cellular offices.

Gene Therapy Advance

An important methodological advance that can be of use for gene therapy is described here.  This is a modification of the CRISPR system that now allows targeted base editing of DNA with high efficiency and low off-target effects.  In practical terms, this would allow targeted correction of DNA mutations, assuming an efficient and safe delivery system could be devised.  These are exciting days for the development of potential gene therapy approaches.  Abstract:

The spontaneous deamination of cytosine is a major source of C•G to T•A transitions, which account for half of known human pathogenic point mutations. The ability to efficiently convert target A•T base pairs to G•C could therefore advance the study and treatment of genetic diseases. While the deamination of adenine yields inosine, which is treated as guanine by polymerases, no enzymes are known to deaminate adenine in DNA. Here we report adenine base editors (ABEs) that mediate conversion of A•T to G•C in genomic DNA. We evolved a tRNA adenosine deaminase to operate on DNA when fused to a catalytically impaired CRISPR-Cas9. Extensive directed evolution and protein engineering resulted in seventh-generation ABEs (e.g., ABE7.10), that convert target A•T to G•C base pairs efficiently (~50% in human cells) with very high product purity (typically ≥ 99.9%) and very low rates of indels (typically ≤ 0.1%). ABEs introduce point mutations more efficiently and cleanly than a current Cas9 nuclease-based method, induce less off-target genome modification than Cas9, and can install disease-correcting or disease-suppressing mutations in human cells. Together with our previous base editors, ABEs advance genome editing by enabling the direct, programmable introduction of all four transition mutations without double-stranded DNA cleavage.

"Mutation-Independent" Cancer Therapy: Targeting Mitochondria

By Kelvinsong - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=27715320

Mitochondria are the “powerhouses of the cell” and problems with mitochondria have been associated with cancer.  So, putting stress on mitochondria can mimic the effects of aberrant gene expression to stimulate breast cancer stem cell activity.  This effect can be inhibited by the antibiotic doxycycline, demonstrating that “mutation-independent” cancer therapy approaches can be used against cancer – approaches that target such phenomena such as mitochondrial function and reproduction, or some other aspects of cell phenotype, as opposed to targeting specific gene mutations and the aberrant products of such mutated genes.  Abstract:

Here, we used MCF7 cells as a model system to interrogate how MYC/RAS co-operativity contributes to metabolic flux and stemness in breast cancer cells. We compared the behavior of isogenic MCF7 cell lines transduced with c-Myc or H-Ras (G12V), either individually or in combination. Cancer stem cell (CSC) activity was measured using the mammosphere assay. c-Myc augmented both mammosphere formation and mitochondrial respiration, without any effects on glycolytic flux. In contrast, H-Ras (G12V) synergistically augmented both mammosphere formation and glycolysis, but only in combination with c-Myc, directly demonstrating MYC/RAS co-operativity. As c-Myc is known to exert its effects, in part, by stimulating mitochondrial biogenesis, we next examined the effects of another stimulus known to affect mitochondrial biogenesis, i.e. ROS production. To pharmacologically induce oxidative stress, we used Rotenone (a mitochondrial inhibitor) to target mitochondrial complex I. Treatment with Rotenone showed bi-phasic effects; low-dose Rotenone (1 to 2.5 nM) elevated mammosphere formation, while higher doses (10 to 100 nM) were inhibitory. Importantly, the stimulatory effects of Rotenone on CSC propagation were blocked using a mitochondrial-specific anti-oxidant, namely Mito-tempo. Thus, "mild" mitochondrial oxidative stress, originating at Complex I, was sufficient to pheno-copy the effects of c-Myc, effectively promoting CSC propagation. To validate the idea that mitochondrial biogenesis is required to stimulate CSC propagation, we employed Doxycycline, a well-established inhibitor of mitochondrial protein translation. Treatment with Doxycycline was indeed sufficient to block the stimulatory effects of H-Ras (G12V), c-Myc, and Rotenone on CSC propagation. As such, Doxycycline provides a strong rationale for designing new therapeutics to target mitochondrial biogenesis, suggesting a new "mutation-independent" approach to cancer therapy. In support of this notion, most currently successful anti-cancer agents therapeutically target "cell phenotypes", such as increased cell proliferation, rather than specific genetic mutations. Remarkably, we demonstrated that Doxycycline inhibits the effects of diverse oncogenic stimuli, of both i) genetic (MYC/RAS) and ii) environmental (Rotenone) origins. Finally, we discuss the advantages of our "Proteomics-to-Genomics (PTG)" approach for in silico validation of new biomarkers and novel drug targets. In this context, we developed a new Myc-based Mito-Signature consisting of 3 mitochondrial genes (HSPD1; COX5B; TIMM44) for effectively predicting tumor recurrence (HR=4.69; p=2.4e-08) and distant metastasis (HR=4.94; p=2.8e-07), in ER(+) in breast cancer patients. This gene signature could serve as a new companion diagnostic for the early prediction of treatment failure in patients receiving hormonal therapy.