Can tissue transglutaminase be a marker of idiopathic inflammatory myopathies?

In the normal striated muscle, tissue transglutaminase (TG2) content is vestigial. However, this protein's presence has been reported to occur in myoblasts and myotubes during the fetal period. Its increased expression has been also found in the muscle tissue in the course of sporadic inclusion body myositis, as well as in polymyositis (PM) and dermatomyositis (DM), which are considered to be diseases of immunological origin. Based on in vitro studies, a substantial TG2 role in the infiltration of some T cell subsets into inflamed tissues has been suggested lately. In this study, the immunohistochemical reactions in the guinea pig experimental myositis specimens and in the ones from PM/DM patients were compared. The guinea pig tissue specimens were taken from muscles affected by experimental myositis induced by intramuscular injections of: 1/sera from 30 neoplasm patients with no metastases; 2/sera from 10 healthy people; 3/sera from 2 DM patients; 4/neuropeptides (SP, NPY or VIP) and from 5/the muscles affected by the reversed passive Arthus reaction (RPAR). The immunostaining for TG2 revealed substantial presence of this protein in single, damaged muscle fibers and a weak reaction in regenerating fibers appearing in PM/DM patients' specimens. From among experimental myositis specimens, a very intensive reaction appeared only in the damaged and regenerating muscle fibers present in the slides from guinea pig muscles injected with DM patients' sera. Such results suggest some presence of a specific factor(s) (the one(s) responsible for TG2 expression in the damaged muscle fibers) in DM patients' sera. The results suggest that transglutaminase can be a marker of inflammatory myopathies. A probable correlation between TG2 expression in muscles and organismal immunological factors, including the complement activation status, requires additional studies.     

Can the disease course in Parkinson’s disease be slowed?

Background

The diagnosis of Parkinson’s disease (PD), which is needed for useful symptomatic therapy, is based on clinical criteria. However, it became quite clear in recent years that the same features can occur through different etiopathogenic mechanisms. Even a pathological diagnosis of PD, based on the demonstration of α-synuclein deposits in a typical distribution, can result from different causes and, vice versa, nigral cell loss can occur without α-synuclein deposition.

Discussion

Thus far, attempts to influence the progression of PD have failed. However, since the clinical manifestations of PD can be the result of diverse mechanisms, a single intervention may not be able to slow the course of the disease in all patients. Indeed, targeting the underlying pathogenic processes, which differ among cases, may be more effective. PD may develop as a consequence of mitochondrial damage, which itself may result from a variety of genetic or environmental factors. Correction of the ensuing oxidative stress may theoretically be useful in these PD patients, but will not affect the progression of the disease among other PD patients in whom an identical clinical syndrome derives from defects in other pathways such as the ubiquitin-proteasome system and lysosomal dysfunction, among others.

Summary

Precision medicine can now be used to identify the underlying pathogenic mechanisms in individual patients, paving the way to the development of real disease modification through a pathway-oriented approach, aimed at the underlying biologic processes of disease occurrence and evolution.

     

Can glucose-insulin-potassium regimen suppress inflammatory bowel disease?

Insulin seems to have the ability to suppress the production of tumor necrosis factor-alpha and superoxide anion, enhance the synthesis of nitric oxide and inhibit the expression of intercellular adhesion molecule-1 (ICAM-1) through stimulation of nitric oxide. This suggests that insulin can behave as an anti-inflammatory molecule. In view of this, it is suggested that insulin in combination with glucose and potassium may be of benefit in the management of inflammatory bowel disease.     

CTCs hemodialysis: Can it be a new therapy for breast cancer?

Circulating tumor cells (CTCs) play an important role in Blood-borne distant metastasis, which is the leading cause of cancer-related death in breast cancer. So far, the impacts of CTCs as a tool for predicting or monitoring the efficacy of systemic therapy and that it is a independent prognostic factor have been confirmed. However, CTCs cannot be generally removed at primary surgery or by systemic therapy. In some EMT (epithelial mesenchymal transition)-related treatment fail, CTCs can be accumulated in the postoperative course of the patient which lead to a bad prognosis. In view of these, considering mature hemodialysis technology, we further propose CTCs hemodialysis (CHD), which filtrate CTCs out of blood, as a new therapy for the breast cancer.     

Can depression be a menopause-associated risk?

There is little doubt that women experience a heightened psychiatric morbidity compared to men. A growing body of evidence suggests that, for some women, the menopausal transition and early postmenopausal years may represent a period of vulnerability associated with an increased risk of experiencing symptoms of depression, or for the development of an episode of major depressive disorder. Recent research has begun to shed some light on potential mechanisms that influence this vulnerability. At the same time, a number of studies and clinical trials conducted over the past decade have provided important data regarding efficacy and safety of preventative measures and treatment strategies for midlife women; some of these studies have caused a shift in the current thinking of how menopausal symptoms should be appropriately managed.     

Will a new vaccine be used?

Despite the fact that vaccines are successful at preventing disease as well as cost-effective, many factors prevent their uptake. These factors are different for different regions. In the United States and Europe, several factors have been identified. The first of these factors is complacency. Both patients and parents lack the knowledge of disease. In addition, physicians are often apathetic about vaccines. There is a lack of training in public health and preventive medicine in that the mind-set of physicians is not directed toward prevention but rather toward treatment. Younger physicians are often less aware of disease controlled by vaccines than their older colleagues are because they have not seen them. One of the paradoxes of vaccines is that success leads to decreased use. Despite the Vaccine for Children's Program, which has provided ample funding for the purchase of vaccines, there are limits on funding for people, facilities, and systematized approaches to maintaining high levels of immunizations. Finally, and perhaps most important, there is fear, real and unfounded. Additionally, in many developing countries there is a lack of focus on preventive medicine, including immunization, as well as limited funding available. Reasonable steps can be taken to overcome these obstacles.     

Homocysteine in cardiovascular disease: a culprit or an innocent bystander?

Whether hyperhomocysteinemia is a cardiovascular risk factor or is just an epiphenomenon is a subject of debate. More than 20 prospective and 30 retrospective studies on the topic have been published. Despite huge literature available, an unequivocal view has not been firmly established. Medical fraternity is still witnessing differing opinions regarding need to treat hyperhomocysteinemia. A medical practitioner needs to be well informed of developments and current opinion on this subject as it has a strong bearing on a major emerging public health problem of cardiovascular disease (CVD). This review presents the two views - for and against the acceptance of association between hyperhomocysteinemia and cardiovascular disease - and their basis. The two views are examined in the light of clinical, epidemiologic and genetic studies, reviews and meta-analyses available. Following conclusion was drawn from the exercise: The available evidence indicates that homocysteine is not an innocent bystander; it is an independent risk factor for CVD. The need for homocysteine-lowering therapy is however not yet unequivocally established. Physicians need to be vigilant of the updates on this much-debated topic thrusted on them time and again.     

Can NK cells be a therapeutic target in human diseases?

Our current knowledge of NK-cell recognition and effector function suggests that it will be possible to design various new NK-cell-based immunotherapies against human cancer. The application of NK cells is already showing promise using HLA-mismatched haematopoietic stem cell transplantation for treatment of haematological malignancies. A better understanding of NK-cell heterogeneity and function will only broaden the applications for human cancer. Here we review the key developments that will propel this field.     

Can exhaled inflammatory markers predict a steroid response in wheezing preschool children?

Background The efficacy of inhaled corticosteroids (ICS) varies among wheezing preschool children. Currently, it is not possible to predict which fraction of wheezing children will benefit from an ICS treatment. Objective We explored whether fractional exhaled nitric oxide (FeNO) and inflammatory markers in exhaled breath condensate (EBC) can predict an ICS response in preschool wheezers. Methods An 8‐week ICS study (registered at Clinicaltrial.gov: NCT 00422747; 200 μg; beclomethasone extra‐fine daily) was performed in 93 wheezing children (age range 2.0–4.4 years). At baseline, FeNO was determined off‐line. EBC was collected using a closed glass‐condenser. The acidity of EBC was determined and other EBC markers [interleukin (IL)‐1α, IL‐2, IL‐4, IL‐5, IL‐10, soluble intercellular adhesion molecule, interferon‐γ, eotaxin] were measured using a multiplex immunoassay. The change in airway resistance (Rint) and symptom score following ICS treatment was related to atopy (positive Phadiatop Infant test), FeNO and EBC markers. Results Airway resistance and symptoms mildly improved after ICS treatment [median (IQR): 1.4 (1.2–1.7) to 1.3 (1.1–1.5) kPa s/L, symptom score: 26 (23–28) to 28 (24–29), P<0.01, respectively]. Only IL‐10 and atopy had limited predictive value regarding a change in symptoms [β (SE)=?0.13 (0.07), P=0.08, β (SE)=2.05 (1.17), P=0.08, respectively]. Conclusions and Clinical Relevance We did not find convincing evidence that FeNO and EBC markers could predict an ICS response in preschool wheezers. Recommendations for future studies on this topic are given. Cite this as: K. D. G. van de Kant, K. Koers, G. T. Rijkers, V. Lima Passos, E. M. M. Klaassen, M. Mommers, P. C. Dagnelie, C. P. van Schayck, E. Dompeling and Q. Jöbsis, Clinical & Experimental Allergy, 2011 (41) 1076–1083.     

Baroreflex function is reduced in Alzheimer’s disease: a candidate biomarker?

The baroreflex (BR) reflects autonomic blood pressure control. Alzheimer’s disease (AD) affects the autonomic system. Detailed properties of BR in AD are unknown. We hypothesized that BR is reduced in AD, and is influenced by autonomic effects of cholinesterase inhibitors (ChEI). BR was determined in 18 AD patients, 11 patients with mild cognitive impairment (MCI) and 19 healthy control subjects. In AD, BR was measured again after ChEI treatment. Receiver operating characteristic analysis was used to define a BR cutoff value, which was then tested in an independent validation sample of 16 AD, 18 MCI, and 18 control subjects. BR was lower in AD compared with MCI (p < 0.05) and in MCI compared with healthy control subjects (p < 0.01). Receiver operating characteristic analysis between AD and healthy control subjects yielded a sensitivity of 89% and a specificity of 94%. ChEI treatment increased BR with 66% (p < 0.01). BR was reduced in AD and increased after treatment with ChEI. BR might be a good biomarker to further explore the link between cardiovascular disease and AD.     

Is interleukin-6 important in inflammatory bowel disease?

The IL-6 gene maps to an area of chromosome 7 known to be significant for susceptibility to inflammatory bowel disease. The functional effects of interleukin-6 (IL-6) polymorphisms in the 4th intron and in the 3' flanking region of IL-6 gene were studied in 192 inflammatory bowel disease patients and healthy subjects. A polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to determine a G to A polymorphism (* at position 4470 in intron 4 of IL-6 gene). Four alleles in the 3' flanking region were studied using a variable number of tandem repeats PCR (VNTR-PCR) amplification. Production of IL-6 was measured in lipopolysaccharide (LPS) stimulated whole blood samples by an enzyme-linked immunosorbent assay (ELISA). A modest increase in the frequency of the IL-6*G allele was noted in Crohn's disease (CD) patients (50%) and ulcerative colitis (UC) patients (46.1%) as compared to controls (39.8%, P = 0.025). We were unable to find any significant functional effect of the IL-6 polymorphisms tested on IL-6 protein production. We postulate that the IL-6 polymorphisms investigated here may be in linkage disequilibrium with a susceptibility gene and that they may be utilised as genetic markers.     

Clinical challenges in thyroid disease: Time for a new approach?

Thyroid disease is common, and the prevalence is rising. Traditional diagnosis and monitoring relies on thyroid stimulating hormone (TSH) levels. This does not always result in symptomatic improvement in hypothyroid symptoms, to the disappointment of both patients and physicians. A non-traditional therapeutic approach would include evaluation of GI function as well as a dietary history and micronutrient evaluation. This approach also includes assessment of thyroid peroxidase (TPO) antibodies, T3, T4, and reverse T3 levels, and in some cases may require specific T3 supplementation in addition to standard T4 therapy. Both high and low TSH levels on treatment are associated with particular medical risks. In the case of high TSH this is primarily cardiac, whereas for low TSH it is predominantly bone health. This article discusses these important clinical issues in more detail, with some practical tips especially for an approach to the “non-responders” to the current traditional therapeutic approach.