Does low-dose and short-term glucocorticoids treatment increase the risk of osteoporosis in rheumatoid arthritis female patients?

Rheumatoid arthritis (RA) is frequently complicated by peri-articular and generalized osteoporosis due to increased bone resorption by activated osteoclasts. Pro-inflammatory cytokines, such as TNF-alpha, interleukin 1 (IL1), and interleukin 6 (IL6) are thought, among other factors, to be directly responsible for this extra-articular complication of RA. Glucocorticoids (GCS) commonly prescribed in RA due to their strong anti-inflammatory effect are also well known for causing secondary osteoporosis during a prolonged use. An influence of low-dose GCS therapy (8.7 mg per day) on a bone turnover in female RA patients with or without previous history of GCS treatment was investigated by measuring bone mineral content (BMC), bone mineral density (BMD), and various biochemical markers of inflammation and bone metabolism in comparison to results obtained from: (1) RA patients who have not been treated with GCS and (2) the control group of healthy individuals. Sixty-two female patients with established active RA and 178 healthy individuals from the control group have been investigated. The RA patients were divided into three groups: 21 treated with GCS before the trial—these patients have continued GCS therapy using low doses during the observation; 21 with low-dose GCS therapy launched at the beginning of the trial; and 20 left without GCS treatment. All patients have been assessed twice: at the beginning and after 12 months of observation. BMC and BMD have been measured in all patients in a distal part of forearm. Additionally, several different biochemical markers of osteoporosis and inflammation have been determined.We did not notice any increase in bone metabolism between RA patients receiving GCS therapy for the first time and those treated without GCS after 12 months of observation. Results of BMC, BMD osteocalcin level, total and bone alkaline phosphatase, carboxy-terminal collagen cross links, carboxy-terminal propeptides of type 1 collagen, deoxypyridynoline, and calcium/creatinine ratio were comparable in both groups at the end of the study. There was a significant decrease of the level of IL-6 in patients who had GCS therapy launched at the beginning of observation (p < 0.01). However, levels of C-reactive protein (CRP) and α1-acid-glycoprotein (AGP) have not changed; the level of ESR dropped significantly (p < 0.05) in this group. In contrast, in the group of patients with the previous history of prolonged GCS treatment receiving low doses of GCS during the trial, statistically significant increase of CRP and AGP could be observed (p < 0.05) along with further significant worsening of the primary low BMD (p < 0.05).Based on the obtained data, we came to the conclusion that anti-inflammatory effect of the low-dose GCS therapy in RA patients without previous history of their use may balance their direct negative effect on BMC and BMD. In this group of RA patients, benefits resulting from the 12-month GCS therapy prevail over adverse effects, even if calcium with vitamin D3 supplementation, biphosphonians, or estrogens have not been introduced. On the other hand, low-dose GCS therapy could have no benefit for RA patients with the previous history of their prolonged use, as a rise of markers of inflammation and bone turnover, resulting in the further bone loss, has been observed.     

Switching to Sulphonylureas in Children With iDEND Syndrome Caused by KCNJ11 Mutations Results in Improved Cerebellar Perfusion

OBJECTIVE

Activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the K_ATP channel, result in permanent neonatal diabetes mellitus. They also may cause neurologic symptoms such as mental retardation and motor problems (iDEND syndrome) and epilepsy (DEND syndrome). Sulphonylurea (SU) treatment is reported to alleviate both the neurologic symptoms and diabetes in such cases. The study aimed to establish the magnitude and functional basis of the effect of SUs on the neurologic phenotype in children with iDEND using neuroimaging before and after insulin replacement with glibenclamide.

RESEARCH DESIGN AND METHODS

To localize and quantify the effect of glibenclamide administration, we performed single-photon emission computed tomography in seven patients with different mutations in KCNJ11. In five patients, measurements before and after initiation of SU treatment were performed.

RESULTS

Significant changes in single-photon emission computed tomography signal intensity after transfer to SU therapy were restricted to the cerebellum, consistent with previous data showing high Kir6.2 expression in this brain region. Cerebellar perfusion improved for both left (P = 0.006) and right (P = 0.01) hemispheres, with the mean improvement being 26.7 ± 7.1% (n = 5). No patients showed deterioration of cerebellar perfusion on SU therapy. Electrophysiological studies revealed a good correlation between the magnitude of K_ATP channel dysfunction and the clinical phenotype; mutant channels with the greatest reduction in adenosine 5′-triphosphate inhibition were associated with the most severe neurologic symptoms.

CONCLUSIONS

We conclude it is likely that at least some of the beneficial effects of SU treatment on neurodevelopment in iDEND patients result from improved cerebellar perfusion.Approximately 50% of cases of permanent neonatal diabetes mellitus are caused by mutations in the genes encoding either the pore-forming (Kir6.2, KCNJ11) or regulatory (SUR1, ABCC8) subunits of the ATP-sensitive K⁺ (K_ATP) channel (1). In some patients with these mutations, neurologic symptoms such as mental retardation, impaired motor development, and hypotonia coexist with neonatal diabetes (iDEND syndrome); if epilepsy is also present, then the condition is called DEND syndrome (2). Previous studies have shown that it is possible to alleviate diabetes and some of the neurologic symptoms by substituting insulin therapy with orally ingested sulphonylurea (SU) drugs (3). In one patient, the improvement in neurologic function was associated with enhanced perfusion of the brain, particularly of the cerebellum, as measured by single-photon emission computed tomography (SPECT). To determine if this effect is common to patients treated with SU, we performed SPECT in patients with different mutations in KCNJ11 and varying clinical phenotypes.     

The use of neural networks in evaluation of the direction and dynamics of changes in lipid parameters in kidney transplant patients on the Mediterranean diet.

OBJECTIVE: The objective of the study was to assess whether neural networks can be a tool useful in the evaluation of the effect of the Mediterranean diet (MD) on the direction and dynamics of selected parameters. DESIGN: Randomized, prospective study. SETTING: Outpatient Clinic of the Department of Nephrology, Transplantology, and Internal Medicine. PATIENTS AND INTERVENTION: The study group consisted of 21 patients after kidney transplantation whose diet complied with the MD; the control group included 16 patients (also after transplantation) on a low-fat diet, isocaloric with the study diet. MAIN OUTCOME MEASURES: Anthropometry, plasma lipids, chromatography of triacylglycerols and fatty acids, and activity of superoxide dismutase and catalase were measured in both groups. Statistical analysis was done with the SNN (Statistica Neural Networks) StatSoft software package. RESULTS: The advantage of neural networks is the possibility of the dynamic presentation of a process taking place in a biological system. In the MD group in the first months of use of the diet, the cholesterol level was reduced only in the group of young and middle-aged patients. This tendency was not observed among elderly patients, among whom a small reduction of the total cholesterol level was noted only at the end of the observation period. In control group at the beginning of the observation, the plasma total cholesterol level was proportional to the patient's age. After 6 months, the total cholesterol increased in young patients and redacted in the group of elderly patients. CONCLUSIONS: We concluded that the MD diet would be ideal for posttransplantation patients without serious pathologic dyslipidemia. In the case of patients with substantial dyslipidemia, appropriate pharmacologic treatment lowering proatherosclerotic lipid levels should be used in combination with the MD. Artificial neural networks (ANNs) were a useful tool in modeling biological parameters, showing dynamics of the studied interactions in a very detailed way. ANN is the most suitable method for investigations with many variables, interconnected nonlinearly; therefore, this method allows for a more general approach to biological problems. However, it should be noted that considerable data sets are required to obtain a satisfactory fit to the data. Moreover, to ensure the predictive power of this method for new cases, the representative database is indispensable. In spite of these demands, ANN is a prospective tool for reliable, quick assessments and predictions.     

MLP (muscle LIM protein) as a stress sensor in the heart

Muscle LIM protein (MLP, also known as cysteine rich protein 3 (CSRP3, CRP3)) is a muscle-specific-expressed LIM-only protein. It consists of 194 amino-acids and has been described initially as a factor involved in myogenesis (Arber et al. Cell 79:221–231, 1994). MLP soon became an important model for experimental cardiology when it was first demonstrated that MLP deficiency leads to myocardial hypertrophy followed by a dilated cardiomyopathy and heart failure phenotype (Arber et al. Cell 88:393–403, 1997). At this time, this was the first genetically altered animal model to develop this devastating disease. Interestingly, MLP was also found to be down-regulated in humans with heart failure (Zolk et al. Circulation 101:2674–2677, 2000) and MLP mutations are able to cause hypertrophic and dilated forms of cardiomyopathy in humans (Bos et al. Mol Genet Metab 88:78–85, 2006; Geier et al. Circulation 107:1390–1395, 2003; Hershberger et al. Clin Transl Sci 1:21–26, 2008; Kn?ll et al. Cell 111:943–955, 2002; Kn?ll et al. Circ Res 106:695–704, 2010; Mohapatra et al. Mol Genet Metab 80:207–215, 2003). Although considerable efforts have been undertaken to unravel the underlying molecular mechanisms—how MLP mutations, either in model organisms or in the human setting cause these diseases are still unclear. In contrast, only precise knowledge of the underlying molecular mechanisms will allow the development of novel and innovative therapeutic strategies to combat this otherwise lethal condition. The focus of this review will be on the function of MLP in cardiac mechanosensation and we shall point to possible future directions in MLP research.     

Nucleotide Excision Repair Capacity and XPC and XPD Gene Polymorphism Modulate Colorectal Cancer Risk

Background

Colorectal cancer (CRC) is leading malignant tumors to occur mainly in industrialized countries, where it exhibits one of the highest mortality rates. Up to 80% of all CRCs characterize a chromosomal instability (CIN) phenotype. The main challenge faced by scientist is to reveal the mechanism of CIN development. An often proposed model is defects in DNA repair in terms of efficiency and genetic variations that modulate the response to stimuli from the environment. The objectives of this research were to determine whether nucleotide excision repair (NER) might affect CRC risk.