β-thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up

Background

β-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins β₄, β₄ sulfoxide, and β₁₀ in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters.

Methods

β-thymosins concentrations were determined by Reverse Phase-High Performance Liquid Chromatography-Electrospray-Mass Spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls.

Results

Thymosin β_4, β₄ sulfoxide, and β₁₀ were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin β₄ levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin β₄ levels seem to have a protective role against lung tissue damage. Thymosin β₄ sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis.

Conclusions

We describe for the first time β-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin β₄ seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory status.     

Mitochondrial permeability transition pore: a promising target for the treatment of Parkinson’s disease

Among the neurodegenerative diseases (ND), Parkinson’s disease affects 6.3 million people worldwide characterized by the progressive loss of dopaminergic neurons in substantia nigra. The mitochondrial permeability transition pore (mtPTP) is a non-selective voltage-dependent mitochondrial channel whose opening modifies the permeability properties of the mitochondrial inner membrane. It is recognized as a potent pharmacological target for diseases associated with mitochondrial dysfunction and excessive cell death including ND such as Parkinson’s disease (PD). Imbalance in Ca²⁺ concentration, change in mitochondrial membrane potential, overproduction of reactive oxygen species (ROS), or mutation in mitochondrial genome has been implicated in the pathophysiology of the opening of the mtPTP. Different proteins are released by permeability transition including cytochrome c which is responsible for apoptosis. This review aims to discuss the importance of PTP in the pathophysiology of PD and puts together different positive as well as negative aspects of drugs such as pramipexole, ropinirole, minocyclin, rasagilin, and safinamide which act as a blocker or modifier for mtPTP. Some of them may be detrimental in their neuroprotective nature.     

Occupational musculoskeletal and mental disorders as the most frequent associations to worker’s sickness absence: A 10-year cohort study

Background

Currently in the United Kingdom (UK), there is a mismatch between limited financial resources and the large proportion of patients with suspected allergies actually being referred to specialist allergy clinics. To better understand the case mix of patients being referred, we audited referrals to a regional allergy service over an 8 year period. The main source of data was consultant letters to General Practitioners (GP) summarising the diagnosis of patients, archived from January 2002 to September 2009. Letters were reviewed, extracting the clinic date, doctor seen, gender, date of birth, postcode, GP, and diagnoses. Diagnoses were classified into seven groups and illustrative cases for each group noted.

Findings

Data from 2,028 new referrals with suspected allergy were analysed. The largest group of patients (43%) were diagnosed with a type I hypersensitivity. The other diagnostic groups were chronic idiopathic (spontaneous) urticaria (35%), suspected type I hypersensitivity but no allergen identified (8%), idiopathic (spontaneous) angioedema (8%), physical urticaria (2.5%), non-allergic symptoms (1.6%), type IV hypersensitivity (0.8%) and ACE inhibitor sensitivity (0.5%). Two thirds of patients seen were female with a higher percentage of female patients in the non type-I hypersensitivity group (71%) than the type 1 hypersensitivity (66%) (??² = 5.1, 1df, p = 0.024). The type 1 hypersensitivity patients were younger than other patients (38 Vs 46 years, t = -10.8, p < 0.001)

Conclusions

This study highlights the complexity of specialist allergy practice and the large proportion of patients referred with non-type I hypersensitivities, chronic idiopathic (spontaneous) urticaria being by far the largest group. Such information is critical to inform commissioning decisions, define referral pathways and in primary care education.     

Plasma lipoproteome in Alzheimer’s disease: a proof-of-concept study

Background

Although total plasma lipoproteome consists of proteins that have shown promises as biomarkers that can identify Alzheimer’s disease (AD), effect sizes are modest. The objective of this study is to provide initial proof-of-concept that the plasma lipoproteome more likely differ between AD cases and controls when measured in individual plasma lipoprotein fractions than when measured as total in immunodepleted plasma.

Methods

We first developed a targeted proteomics method based on selected reaction monitoring (SRM) and liquid chromatography and tandem mass spectrometry for measurement of 120 tryptic peptides from 79 proteins that are commonly present in plasma lipoproteins. Then in a proof-of concept case–control study of 5 AD cases and 5 sex- and age-matched controls, we applied the targeted proteomic method and performed relatively quantification of 120 tryptic peptides in plasma lipoprotein fractions (fractionated by sequential gradient ultracentrifugation) and in immunodepleted plasma (of albumin and IgG). Unadjusted p values from two-sample t-tests and overall fold change was used to evaluate a peptide relative difference between AD cases and controls, with lower p values (<?0.05) or greater fold differences (>?1.05 or?<?0.95) suggestive of greater peptide/protein differences.

Results

Within-day and between-days technical precisions (mean %CV [SD] of all SRM transitions) of the targeted proteomic method were 3.95% (2.65) and 9.31% (5.59), respectively. Between-days technical precisions (mean % CV [SD]) of the entire plasma lipoproteomic workflow including plasma lipoprotein fractionation was 27.90% (14.61). Ten tryptic peptides that belonged to 5 proteins in plasma lipoproteins had unadjusted p values?<?0.05, compared to no peptides in immunodepleted plasma. Furthermore, 27, 32, 17, and 20 tryptic peptides in VLDL, IDL, LDL and HDL, demonstrated overall peptide fold differences?>?1.05 or?<?0.95, compared to only 6 tryptic peptides in immunodepleted plasma. The overall comparisons, therefore, suggested greater peptide/protein differences in plasma lipoproteome when measured in individual plasma lipoproteins than as total in immunodepleted plasma. Specifically, protein complement C3’s peptide IHWESASLLR, had unadjusted p values of 0.00007, 0.00012, and 0.0006 and overall 1.25, 1.17, 1.14-fold changes in VLDL, IDL, and LDL, respectively. After positive False Discovery Rate (pFDR) adjustment, the complement C3 peptide IHWESASLLR in VLDL remained statistically different (adjusted p value?<?0.05).

Discussion

The findings may warrant future studies to investigate plasma lipoproteome when measured in individual plasma lipoprotein fractions for AD diagnosis.

     

Arbidol/IFN-α2b therapy for patients with corona virus disease 2019: a retrospective multicenter cohort study

The spread of COVID-19 is accelerating. At present, there is no specific antiviral drugs for COVID-19 outbreak. This is a multicenter retrospective cohort study of patients with laboratory-confirmed COVID-19 infection pneumonia from 3 hospitals in Hubei and Guangdong province, 141 adults (aged ≥18 years) without ventilation were included. Combined group patients were given Arbidol and IFN-α2b, monotherapy group patients inhaled IFN-α2b for 10–14 days. Of 141 COVID-19 patients, baseline clinical and laboratory characteristics were similar between combined group and monotherapy group, that 30% of the patients leucocytes counts were below the normal range and 36.4% of the patients experienced lymphocytopenia. The duration of viral RNA of respiratory tract in the monotherapy group was not longer than that in the combined therapy group. There was no significant differences between two groups. The absorption of pneumonia in the combined group was faster than that in the monotherapy group. We inferred that Arbidol/IFN - 2 b therapy can be used as an effective method to improve the COVID-19 pneumonia of mild patients, although it helpless with accelerating the virus clearance. These results should be verified in a larger prospective randomized environment.     

Patients’ preferences for osteoporosis drug treatment: a discrete-choice experiment

Introduction

The patient’s perspective is becoming increasingly important in clinical and policy decisions. In this study, we aimed to evaluate the preferences of patients with, or at risk of, osteoporosis for medication attributes, and to establish how patients trade between these attributes.

Methods

A discrete choice experiment survey was designed and patients were asked to choose between two hypothetical unlabelled drug treatments (and an opt-out option) that vary in five attributes: efficacy in reducing the risk of fracture, type of potential common side-effects, mode and frequency of administration and out-of-pocket costs. An efficient experimental design was used to construct the treatment option choice sets and a mixed logit panel data model was used to estimate patients’ preferences and trade-offs between attributes.

Results

A total of 257 patients with, or at risk of, osteoporosis completed the experiment. As expected, patients preferred treatment with higher effectiveness and lower cost. They also preferred either an oral monthly tablet or 6-month subcutaneous injection above weekly oral tablets, 3-month subcutaneous, 3-month intravenous or yearly intravenous injections. Patients disliked being at risk of gastro-intestinal disorders more than being at risk of skin reactions and flu-like symptoms. There was significant variation in preferences across the sample for all attributes except subcutaneous injection.

Conclusions

This study revealed that osteoporotic patients preferred 6-month subcutaneous injection and oral monthly tablet, and disliked gastro-intestinal disorders. Moreover, patients were willing to pay a personal contribution or to trade treatment efficacy for better levels of other attributes. Preferences for treatment attributes varied across patients and this highlights the importance of clinical decision-making taking individual preferences into account to improve osteoporosis care.     

New approaches for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the ‘Aβ hypothesis’, there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.     

Sleep problems in Parkinson’s disease: a community-based study in Norway

Background

Neurogenic claudication (NC) is a common symptom in patients with lumbar spinal stenosis (LSS). The Neurogenic Claudication Outcome Score (NCOS) is a very short instrument for measuring functional status in these patients. This study aimed to translate and validate the NCOS in Iran.

Methods

This was a prospective clinical validation study. The 'forward-backward' procedure was applied to translate the NCOS from English into Persian (Iranian language). A total of 84 patients with NC were asked to respond to the questionnaire at two points in time: at preoperative and at postoperative (6 months follow-up) assessments. The Oswestry Disabiltiy Index (ODI) also was completed for patients. To test reliability, the internal consistency was assessed by Cronbach's alpha coefficient. Validity was evaluated using known groups comparison and criterion validity (convergent validity). Internal responsiveness of the NCOS to the clinical intervention (surgery) also was assessed comparing patients?? pre- and postoperative scores.

Results

The Cronbach??s alpha coefficients for the NCOS at preoperative and postoperative assessments were 0.77 and 0.91, respectively. Known groups analysis showed satisfactory results. The instrument discriminated well between sub-groups of patients who differed in claudication distance as measured by the Self-Paced Walking Test (SPWT). The change in the ODI after surgery was strongly correlated with change in the NCOS, lending support to its good convergent validity (r?=?0.81; P?<?0.001). Further analysis also indicated that the questionnaire was responsive to the clinical intervention (surgery) as expected (P?<?0.0001).

Conclusion

In general, the Iranian version of the NCOS performed well and the findings suggest that it is a reliable and valid measure of functionality in patients with lumbar spinal stenosis who are suffering from neurogenic claudication.     

131I Radioiodine therapy in Graves’ disease: Us et coutumes,controversies and guidelines

For almost 80 years ¹³¹I radioiodine (RAI) therapy has proven to be an efficient and well-tolerated therapeutic option in patients with Graves’ disease (GD). Along with anti-thyroid drugs (ATD) and thyroidectomy, RAI is one the three major therapeutic tools for this autoimmune disease. The objective of this article is to review how RAI treatment is usually conducted in clinical routine and to discuss the main controversies surrounding this treatment in the light of recent national or international guidelines. This will be an opportunity to discuss the indications and contraindications for this treatment, its advantages and limits, and more generally its practical organization by a specialized team.     

Outcome predictors of intra-articular glucocorticoid treatment for knee synovitis in patients with rheumatoid arthritis – a prospective cohort study

Introduction

Intra-articular glucocorticoid treatment (IAGC) is widely used for symptom relief in arthritis. However, knowledge of factors predicting treatment outcome is limited. The aim of the present study was to identify response predictors of IAGC for knee synovitis in patients with rheumatoid arthritis (RA).

Methods

In this study 121 RA patients with synovitis of the knee were treated with intra-articular injections of 20 mg triamcinolone hexacetonide. They were followed for six months and the rate of clinical relapse was studied. Non-responders (relapse within 6 months) and responders were compared regarding patient characteristics and knee joint damage as determined by the Larsen-Dale index. In addition, matched samples of serum and synovial fluid were analysed for factors reflecting the inflammatory process (C-reactive protein, interleukin 6, tumour necrosis factor alpha, vascular endothelial growth factor), joint tissue turnover (cartilage oligomeric matrix protein, metalloproteinase 3), and autoimmunity (antinuclear antibodies, antibodies against citrullinated peptides, rheumatoid factor).

Results

During the observation period, 48 knees relapsed (40%). Non-responders had more radiographic joint damage than responders (P = 0.002) and the pre-treatment vascular endothelial growth factor (VEGF) level in synovial fluid was significantly higher in non-responders (P = 0.002).

Conclusions

Joint destruction is associated with poor outcome of IAGC for knee synovitis in RA. In addition, higher levels of VEGF in synovial fluid are found in non-responders, suggesting that locally produced VEGF is a biomarker for recurrence of synovial hyperplasia and the risk for arthritis relapse.     

CCR5Δ32 variant and cardiovascular disease in patients with rheumatoid arthritis: a cohort study

Introduction  

The aim of our study was to analyze the influence of the CCR5Δ32 polymorphism in the risk of cardiovascular (CV) events and subclinical atherosclerosis among patients with rheumatoid arthritis (RA).     

Risk factors for bovine periodontal disease – a preliminary study

The work presented in this pilot study aimed to identify potential risk factors associated with bovine periodontitis development. Bovine periodontitis is a multifactorial polymicrobial infectious disease for which the aetiopathogenesis and risk factors are not fully understood. From cattle slaughtered in an abattoir in Scotland, 35 dental arcades with periodontal lesions and 40 periodontally healthy arcades were selected over seven visits for study. Multivariable logistic regression analysis was used to evaluate the association between periodontitis and the independent variables, gender, age and breed. For every increase in year of age, cattle were 1.5 times more likely to have periodontitis. A graphical analysis indicated that within the limits of this study, we could not detect any major influence of breed on the age-effect. Although logistic regression analysis demonstrated that periodontitis lesions are more prevalent with increasing age of cattle the underlying mechanisms remain unclear. It is likely that periodontitis is an important cause of oral pain in older cattle and can contribute to reduced productivity/performance. Further studies with a larger sample size are necessary to elucidate the associations between potential risk factors and periodontitis in cattle and to define its effects on animal welfare and productivity.     

Synthesis and biological study of new galanthamine-peptide derivatives designed for prevention and treatment of Alzheimer’s disease

Amino Acids - The Alzheimer’s disease leads to neurodegenerative processes and affecting negatively million people worldwide. The treatment of the disease is still difficult and incomplete in...     

Current viral-mediated gene transfer research for treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia and has affected millions of individuals worldwide. The hallmarks of AD include the amyloid beta plaque deposits, tau neurofibrillary tangles, altered neuronal signaling, alongside decline in memory and cognitive functions. Conventional drug therapies do exist, such as donepezil or aducanumab, but these drugs mostly focus on halting AD progression instead of causing a reversal within the disease. In an effort to ameliorate and ultimately cure AD, researchers have delved into viral-mediated gene therapy to fix this disease from its root molecular causes. To date, adeno-associated virus and lentiviral vectors have remained the most vastly studied among other viral vectors to combat AD. These vectors could be employed alongside various genetic materials based on the types of processes we want to alter to yield a positive effect, such as disruption of amyloidogenic pathway, neuroprotection and lipid metabolism pathways. Recent studies and trials were reviewed in this article, highlighting their clinical significance, differences and limitations between each method. By learning from the different combinations and possibilities of viral-mediated gene transfer, researchers would then get a step closer in ameliorating symptoms and possibly in curing AD.     

2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease

Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.     

Autologous bone marrow–derived cells for venous leg ulcers treatment: a pilot study

Background

Chronic venous leg ulcers (VLUs) are a common problem in clinical practice and available treatments are not satisfactory. The use of adjuvant therapies in combination with lower limb compression may lead to improved healing rates. Chronic wounds are candidates for new strategies in the emergent field of regenerative medicine. Bone marrow–derived cells (BMDCs) contain cells and secrete cytokines known to participate in wound healing. Thus, BMDC therapy seems a logical strategy for the treatment of chronic wounds. Our objective was to evaluate feasibility, safety and initial clinical outcome of autologous BMDC therapy associated with standard treatment in patients with VLUs.