Cell biology of osteoarthritis: The chondrocyte’s response to injury

Cartilage is comprised of a large amount of functional extracellular matrix that is made and maintained by a small number of chondrocytes, the sole resident cell type. Normal cartilage exists in a relatively steady state: that is, the anabolic processes (those that result in the synthesis of cartilage matrix components) are in equilibrium with the catabolic processes (those that result in the normal turnover of matrix molecules). If the functional extracellular matrix is disturbed by physical or molecular means, the cells respond in an attempt to repair the matrix. This stimulated activity does not result in repair due to the extent and complexity of the extracellular matrix. Eventually, the newly synthesized and activated catabolic enzymes degrade the matrix components. This review presents the cellular and molecular mechanisms that account for this activity and provides some possible solutions.     

The Artificial Pancreas: Is It Important to Understand How the β Cell Controls Blood Glucose?

It has been more than 7 years since the first fully automated closed-loop insulin delivery system that linked subcutaneous insulin delivery and glucose sensing was published. Since the initial report, the physiologic insulin delivery (PID) algorithm used to emulate the β cell has been modified from the original proportional-integral-derivative terms needed to fit the β cell’s biphasic response to a hyperglycemic clamp to include terms emulating cephalic phase insulin release and the effect of insulin per se to inhibit insulin secretion. In this article, we compare the closed-loop glucose profiles obtained as each new term has been added, reassess the ability of the revised PID model to describe the β cells’ insulin response to a hyperglycemic clamp, and look for the first time at its ability to describe the response to a hypoglycemic clamp. We also consider changes that might be added to the model based on perfused pancreas data. We conclude that the changes introduced in the PID model have systematically improved the closed-loop meal response. We note that the changes made do not adversely affect the ability of the model to fit hyperglycemic clamp data but are necessary to fit the response to a hypoglycemic clamp. Finally, we note a number of β cell characteristics observed in the perfused pancreas have not been included in the model. We suggest that continuing the effort to understand and incorporate aspects of how the β cell achieves glucose control can provide valuable insights into how improvements in future artificial pancreas algorithms might be achieved.     

Recent Findings in the Genetics of Blood Pressure: How to Apply in Practice or Is a Moonshot Required?

Purpose of Review

Hypertension is recognised as the biggest contributor to the global burden of disease, but it is controlled in less than a fifth of patients worldwide, despite being relatively easy to detect and the availability of inexpensive safe generic drugs. Blood pressure is regulated by a complex network of physiologic pathways with currently available drugs targeting key receptors or enzymes in the top pathways. Major advances in the dissection of both monogenic and polygenic determinants of blood pressure regulation and variation have not resulted in rapid translation of these discoveries into clinical applications or precision medicine.

Recent Findings

Uromodulin is an example of a novel gene for hypertension identified from genome-wide association studies, currently the basis of a clinical trial to reposition loop diuretics in hypertension management. Gene-editing studies have established a genome-wide association studies (GWAS) SNP in chromosome 6p24, implicated in six conditions including hypertension, as a distal regulator of the endothelin-1 gene around 3000 base pairs away. Genomics of aldosterone-producing adenomas bring to focus the paradox in genomic medicine where availability of cheap generic drugs may render precision medicine uneconomical.

Summary

The speed of technology-driven genomic discoveries and the sluggish traditional pathways of drug development and translation need harmonisation to make a timely and early impact on global public health. This requires a directed collaborative effort for which we propose a hypertension moonshot to make a quantum leap in hypertension management and cardiovascular risk reduction by bringing together traditional bioscience, omics, engineering, digital technology and data science.

     

The Management of Hypertension for an Acute Stroke: What Is the Blood Pressure Goal?

Stroke is the 4th leading cause of death in the US and a leading cause of disability among adults. Stroke is broadly classified into ischemic and hemorrhagic subtypes. Although the pathogenesis may differ between ischemic and hemorrhagic stroke subtypes, a unifying feature is that hypertension is a major risk factor for most ischemic and hemorrhagic strokes. Prevention of first and recurrent stroke is substantially dependent on blood pressure control. There is controversy about blood pressure management in acute stroke. In this review we discuss controversies about and guidelines for management of blood pressure in acute stroke. We subdivide our discussion to address important questions about acute blood pressure management in ischemic stroke, intraparenchymal hemorrhage, and subarachnoid hemorrhage. In addition, we address BP control recommendations when tissue plasminogen activator administration is being contemplated for treatment of acute ischemic stroke.     

The current therapeutic options for Crohn’s disease: from medical therapy to intestinal transplantation

Introduction: Crohn’s disease (CD) has an annual incidence per 100.000 person-year of 20.2 in North America and 12.7 in Europe, and the purpose of this review is to evaluate its medical management, from diagnosis to transplant. Pharmacologic manipulation with nutritional care aims to achieve and maintain remission, but more than half of patients will undergo an intestinal resection, very often repeated over time. They could experience short bowel syndrome (SBS) requiring total parenteral nutrition (TPN). Intestinal transplantation (ITx) represents an alternative in case of irreversible intestinal failure (IF) with life-threatening TPN complications. Patient survival after ITx is 79%, 53% and 43% at 1, 3 and 5 years respectively, with no differences among ITx for other disorders.

Areas covered: The research discussed medical therapy with nutritional support, evaluating the role of endoscopy, surgery and transplant in CD. A systematic literature review was conducted using the PubMed search engine up to May 31^th, 2017 without restriction of the language. The decision on paper’s eligibility was reached by consensus between the 3 screening authors.

Expert commentary: CD treatment is mainly medical, leaving endoscopy and surgery for a complex course. ITx represents a therapeutic option if TPN complications with IF arise.     

Is snoring intensity responsible for the sleep partner’s poor quality of sleep?

Purpose

This study aimed to determine if the intensity of breathing noise (including snoring) and/or the presence of abnormal breathing events (ABE) are factors that trigger arousal/awakening of a snorer??s bed partner.

Methods

We conducted a prospective multicenter study investigating couples where the male had a chronic disturbing snoring. We simultaneously recorded the male??s respiration and snoring and the female?? sleep. We counted the number of arousals and awakenings during N2 sleep and randomly took nine of each. Then, for periods before, during, and after each arousal and awakening, we observed on the respiratory tracings what was happening in terms of breathing noise intensity and presence/absence of snoring and/or ABE.

Results

Thirteen couples were analyzed. The intensity of breathing noise and the presence/absence of snoring and/or ABE were comparable before and at initiation of arousal/awakening and between arousal and awakening. However, breathing volume intensity was lower and the presence of snoring and/or ABE was less frequent when the bed partner returned back to sleep from awakening compared to the other periods (p always <0.001).

Conclusions

The intensity of breathing noise or the presence of ABE does not seem to be essential to trigger an arousal or an awakening. However, the persistence of noise or events may prolong the duration of wakefulness during the sleep period and could be one factor that explains the bothersome snoring.     

Speckle Tracking Echocardiography for the Assessment of the Athlete’s Heart: Is It Ready for Daily Practice?

Purpose of review

To describe the use of speckle tracking echocardiography (STE) in the biventricular assessment of athletes’ heart (AH). Can STE aid differential diagnosis during pre-participation cardiac screening (PCS) of athletes?

Recent findings

Data from recent patient, population and athlete studies suggest potential discriminatory value of STE, alongside standard echocardiographic measurements, in the early detection of clinically relevant systolic dysfunction. STE can also contribute to subsequent prognosis and risk stratification.

Summary

Despite some heterogeneity in STE data in athletes, left ventricular global longitudinal strain (GLS) and right ventricular longitudinal strain (RV ?) indices can add to differential diagnostic protocols in PCS. STE should be used in addition to standard echocardiographic tools and be conducted by an experienced operator with significant knowledge of the AH. Other indices, including left ventricular circumferential strain and twist, may provide insight, but further research in clinical and athletic populations is warranted. This review also raises the potential role for STE measures performed during exercise as well as in serial follow-up as a method to improve diagnostic yield.

     

The importance of rectal washout for the oncological outcome after Hartmann’s procedure for rectal cancer: analysis of population-based data from the Swedish Colorectal Cancer Registry

Background

During rectal cancer surgery the bowel may contain viable, exfoliated cancer cells, a potential source for local recurrence (LR). The amount and viability of these cells can be reduced using intraoperative rectal washout, a procedure that reduces the LR risk after anterior resection. The aim of this study was to analyse the impact of washout on oncological outcome when performed in Hartmann’s procedure (HP) for rectal cancer.

Methods

A national cohort study on data for patients registered from 1995 to 2007 in the Swedish Colorectal Cancer Registry was carried out. The final analysis included patients belonging to TNM stages I–III who had undergone R0 HP with a registered 5-year follow-up. Multivariate analysis was performed.

Results

A total of 1188 patients were analysed (686 washout and 502 no washout). No differences were detected between the washout group and the no washout group concerning rates of LR [7% (49/686) vs. 10% (49/502); p = 0.13], distant metastasis (DM) [17% (119/686) vs. 18% (93/502); p = 0.65], and overall recurrence (OAR) [21% (145/686) vs. 24% (120/502); p = 0.29]. For both groups, the 5-year cancer-specific survival was below 50%. In multivariate analysis, washout neither decreased the risk of LR, DM, or OAR nor increased overall or the cancer-specific 5-year survival.

Conclusions

The oncological outcome did not improve when washout was performed in HP for rectal cancer.

     

Evaluation of Applying a Combination of Red Cell Indexes and Formulas to Differentiate β-Thalassemia Trait from Iron Deficiency Anemia in the Thai Population

Red cell indexes and formulas have been established as simple, fast, and inexpensive tools to differentiate β-thalassemia (β-thal) trait from iron deficiency anemia. However, none of them showed 100.0% sensitivity and specificity. Moreover, one index may show greater sensitivity and specificity in one population but is ineffective in another population. This study evaluated the diagnostic reliability of a combination of two red cell indexes [red blood cell (RBC) and red blood cell distribution width (RDW)] and nine formulas called ‘11T score’ for differentiation of β-thal trait and iron deficiency anemia in the Thai population. A total of 103 cases, 67 β-thal trait and 36 iron deficiency anemia, Thai subjects with microcytic hypochromic anemia [mean corpuscular volume (MCV) <80.0?fL and mean corpuscular hemoglobin (Hb) (MCH) <27.0?pg] were involved in this retrospective study. The results showed that the 11T score with a cutoff value of 7 was able to discriminate between β-thal trait and iron deficiency anemia with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and efficiency (EFF) higher than 70.0%. It also had 85.4% of correctly identified cases and the highest value of Youden’s Index (YI) (73.8%) when compared to the 11T score with other cutoff values (5, 6, 8 and 9) and other indexes. Thus, the 11T score with the cutoff value of 7 could be used to differentiate β-thal trait from iron deficiency anemia in the Thai population.     

Clinical score system in the treatment of Cushing’s disease: failure to identify discriminative variables from the German Cushing’s Registry

Pituitary - To develop a multidimensional and integrated clinical scoring instrument, that encompasses, summarizes and weights appropriately the desired clinical benefits of a treatment for...     

Update on Omalizumab for Urticaria: What’s New in the Literature from Mechanisms to Clinic

Purpose of Review

Since omalizumab has been approved for urticaria, numerous randomized and real-life observational trials have been published. We reviewed the period January 2017–February 2018.

Recent Findings

Omalizumab is effective for the control of urticaria recalcitrant to antihistamines in different populations globally. The ratio of total serum IgE 4-week/baseline ≥2 can predict response with a high likelihood. In observational real-life trials, doses have been adjusted on an individual basis: in some populations, up to two-thirds of the patients can be controlled with 150 mg/month; however, others are still not controlled with 300 mg/month. In these, 150 mg bimonthly could be tried, before up-dosing to 450 mg/month. On the long run (up to 3 years) omalizumab kept its efficacy. In many patients, dosing intervals could be augmented (6–8 weeks, some even more). After a 12-month treatment, about 20% showed long-term remission without relapse.

Summary

Some biomarkers are being detected. Adjusting omalizumab doses in urticaria patients could enhance efficacy (shortening dosing interval and/or augmenting dose) and save costs (after 12 months: extending dosing interval and/or reducing dose).

     

Tocilizumab for the treatment of adult-onset Still’s disease: results from a case series

Adult-onset Still’s disease (AOSD) is a chronic inflammatory disease of unknown etiology which commonly affects young adults. Treatment of AOSD patients includes nonsteroidal anti-inflammatory drugs, corticosteroids, and DMARDs. Interleukin (IL)-6 blockade is an attractive therapeutic option for AOSD because this cytokine contributes to the pathogenesis of major AOSD symptoms. Tocilizumab (TCZ) is a humanized anti-IL-6 receptor antibody that blocks the effects of IL-6. Preliminary results of TCZ in AOSD have been promising. Here, we reported our experience evaluating both the safety and the efficacy of 12 months therapy with TCZ in 11 patients with AOSD refractory to corticosteroids and MTX therapy, followed for 18 months, including the first 12 months of active treatment and the last 6 months to evaluate the activity of the disease when the treatment was discontinued. The main outcome measures were the European League Against Rheumatism (EULAR) improvement criteria and improvement of systemic symptoms at the 3, 6, 12, and 18-months follow-up periods. Our patients rapidly responded and experienced a sustained clinical remission over time during active treatment. Disease Activity Score 28 decreased from 5.62 (3.75–8.28) [median (range)] at baseline to 1.61(0.49–3.5) at month 12. EULAR remission was achieved in 81.82 % at 12 months. Tender joint and swollen joint counts displayed a progressive reduction during active therapy study period. During treatment, we observed a resolution of fever in our AOSD patient. In conclusion, TCZ might represent a suitable option for the therapy of refractory AOSD patients.     

Cord Blood Analysis for Rapid Prenatal Confirmation of Hb Bart’s Disease Using the Sebia Capillary Electrophoresis System

Prenatal diagnosis of severe α-thalassemia (α-thal) diseases is usually performed by DNA analysis. To establish a simple and rapid method, we evaluated the reliability of cord blood hemoglobin (Hb) analysis using an automated capillary electrophoresis (CE) system. Our results demonstrated that analysis of fetal Hb using the Sebia CapillaryS 2 is an effective, accurate and simple alternative for prenatal diagnosis of Hb Bart’s (γ4) disease.     

The Molecular Basis for the Generation of Hodgkin and Reed-Sternberg Cells in Hodgkin’s Lymphoma

Hodgkin's lymphoma (HL) is a lymphoid neoplasm with a low frequency of malignant tumor cells, known as Hodgkin and Reed-Sternberg (H-RS) cells, in a background of mixed cellular infiltrates. Despite extensive studies on H-RS cells, the molecular mechanisms of their growth and regulation have remained uncertain for a long period. Recently, constitutively activated nuclear factor-kappaB (NF-kappaB) was reported to be a unique and common characteristic of H-RS cells that prevents the cells from undergoing apoptosis. NF-kappaB triggers proliferation and provides a molecular basis for these cells' aberrant growth and cytokine gene expression. In HL pathogenesis associated with Epstein-Barr virus infection, the activation of NF-kappaB is induced by viral latent membrane protein 1 (LMP1). Coupled with recent insights into the molecular mechanisms of activation of NF-kappaB signaling in H-RS cells, this review discusses a linkage between LMP1 and HL via CD99, which has recently been reported to be down-regulated by LMP1 through the NF-kappaB signaling pathway. This down-regulation leads to the generation of cells with H-RS phenotypes related to the clinical and histologic characteristics of HL.