Regular Clinical Observation Research Articles

Lack of Syndecan-1 promotes the pathogenesis of experimental rheumatoid arthritis.

Syndecan-1 (Sdc-1), a transmembrane heparan sulfate protein, is implicated in several pathophysiological processes including rheumatoid arthritis (RA). The exact role of Syndican-1 in this autoimmune disease is still undetermined. This study explores the involvement level of Sdc-1 in the development of RA in a collagen II-induced arthritis mice model. RA was induced in two mice strains (wild-type BALB/c group and Sdc-1 knockout) by collagen II. Mice underwent regular clinical observations and scoring. After sacrifice, leg biopsies were taken from mice for histological examination, using a variety of stains. In addition, proteins were extracted, and molecular assessment of TNF-α was performed using the western blot technique. In the Sdc-1 knockout group, clinical scoring results showed a significantly more severe experimental RA; histology showed a significant increase in bone erosion, cartilage destruction, inflammation, and less granulated mast cells than the wild-type. In addition, molecular assessment of TNF-α showed more increase in expression in the Sdc-1 knockout models compared to the wild-type. Data suggest that lack of Sdc-1 enhances the inflammatory characteristics in RA. However, more molecular studies and investigations are needed to determine its exact role and possible mechanisms involved.

Image Processing for mHealth-Based Approach to Detect the Local Tissue Inflammation in Cutaneous Leishmaniasis: A Proof of Concept Study.

Skin lesions are a feature of many diseases including cutaneous leishmaniasis (CL). Ulcerative lesions are a common manifestation of CL. Response to treatment in such lesions is judged through the assessment of the healing process by regular clinical observations, which remains a challenge for the clinician, health system, and the patient in leishmaniasis endemic countries. In this study, image processing was initially done using 40 CL lesion color images that were captured using a mobile phone camera, to establish a technique to extract features from the image which could be related to the clinical status of the lesion. The identified techniques were further developed, and ten ulcer images were analyzed to detect the extent of inflammatory response and/or signs of healing using pattern recognition of inflammatory tissue captured in the image. The images were preprocessed at the outset, and the quality was improved using the CIE L∗a∗b color space technique. Furthermore, features were extracted using the principal component analysis and profiled using the signal spectrogram technique. This study has established an adaptive thresholding technique ranging between 35 and 200 to profile the skin lesion images using signal spectrogram plotted using Signal Analyzer in MATLAB. The outcome indicates its potential utility in visualizing and assessing inflammatory tissue response in a CL ulcer. This approach is expected to be developed further to a mHealth-based prediction algorithm to enable remote monitoring of treatment response of cutaneous leishmaniasis.

Monitoring tacrolimus whole blood concentrations

Tacrolimus (TAC) is the primary drug for most immunosuppressive therapy regimens. It has a narrow therapeutic index, meaning that insufficient dose can lead to graft and tissue rejection, while overdose can lead to increased risk of infections, toxicity, and cancerous tumors in organ transplant recipients. TAC belongs to a group of calcineurin inhibitors inhibiting T-cell activation. The use of TAC requires regular clinical observation of recipients and laboratory monitoring of the drug concentrations in the blood. This is to ensure correct dosage of the drug and to limit the potential risk of harmful side effects. The review presents data on some clinical, genetic factors affecting the bioavailability and concentration of TAC in the blood. We also present data on the methodological aspects of TAC laboratory control.

Methotrexate overdose in clinical practice

A folic-acid antagonist, methotrexate, is one of the most commonly prescribed drugs with its expanding use in clinical practice. The drug requires regular monitoring given its wide range of adverse effects including bone marrow suppression, hepatic or renal dysfunction, gastrointestinal distress, mucocutaneous damage, and neurotoxicity. The toxicity usually occurs rapidly and leads to severe neutropenia, sepsis, and advanced renal failure that are difficult to manage. This review is an update for the clinicians to understand the pharmacology, clinical features, laboratory evaluation, and treatment of patients with methotrexate overdose. High-quality literature of the past six decades was collected and reviewed in this article. Several landmark articles were reviewed using PubMed, EMBASE Ovid, and the Cochrane Library, that have important implications in current clinical practice. Methotrexate overdose has complex toxicokinetic and produces myriad clinical features mimicking conditions of lesser severity. Organ dysfunction related to bone marrow, kidney or central nervous system is lifethreatening. The management should focus on high-quality supportive care, antidotal therapy (folinic acid and carboxypeptidase- G2) and plasma alkalization. In accordance with the dictum "prevention is better than cure", the author emphasizes on the role of patient education, regular clinical observation, and laboratory monitoring for prompt recognition and diagnosis of methotrexate overdosing at the earliest stage.

Disseminated superficial actinic porokeratosis (DSAP): significant improvement after local administration of calcipotriol/betamethasone gel?

Porokeratosis is defined as a disorder of keratinization characterized by one or more atrophic patches surrounded by a clinically and histologically distinctive hyperkeratotic ridgelike border called the cornoid lamella. Lesions are most commonly located on the sun-exposed sides of trunk and extremities, while exclusive facial involvement has been also reported. Despite that the exact risk of cutaneous malignancy developing in porokeratosis is unknown, it is confirmed by series of case reports, including squamous cell carcinoma, basal cell carcinoma and even melanoma. Although no definite cure exists, a number of treatment modalities, from topical medications to laser and light devices, have been reported with variable success. Although promising, reports of disseminated superficial actinic porokeratosis treated with vitamin D3 analogs are rare. No satisfactory enough effect is obtained also with calcipotriol monotherapy.We report a case of disseminated superficial actinic porokeratosis in a 80-year-old female patient, successfully treated with combination of topical calcipotriol/betamethasone gel. A significant improvement was noticed after 3 weeks; almost full resolution of the clinical symptoms without appearance of fresh lesions was achieved in the second month. To the best of our knowledge, this is the first report of successful treatment with full resolution in a short interval, by simultaneous application of vitamin D3 analog (calcipotriol) and corticosteroid (betamethasone), combined in a one commercial product as a gel for treatment of keratinocyte proliferation's disorder such as psoriasis vulgaris. This promising new entity seems to be more effective, because of the simultaneous synergetic effects of the substations, namely the normalization of the proliferation of the keratinocytes by calcipotriol on one hand, and the reducing of the inflammation by the corticosteroid on another. Sun protection stays always mandatory, as well as the regular clinical observation, regarding the risk of malignant transformation.

Metabolomics analysis and biomarker identification for brains of rats exposed subchronically to the mixtures of low-dose cadmium and chlorpyrifos.

Cadmium (Cd) and chlorpyrifos (CPF) are widespread harmful environmental pollutants with neurotoxicity to mammals. Although the exposure to Cd and CPF at the same time may pose a significant risk to human health, the subchronic combined neurotoxicity of these two chemicals at low levels in the brain is poorly understood. In this study, we treated rats with three doses (low, middle, and high) of Cd, CPF, or their mixture for 90 days. No obvious symptom was observed in the treated animals except those treated with high-dose CPF. Histological results showed that middle and high doses of the chemicals caused neuronal cell damage in brains. GC-MS-based metabonomics analysis revealed that energy and amino acid metabolism were disturbed in the brains of rats exposed to the two chemicals and their combinations even at low doses. We further identified the unique brain metabolite biomarkers for rats treated with Cd, CPF, or both. Two amino acids, tyrosine and l-leucine, were identified as the biomarkers for Cd and CPF treatment, respectively. In addition, a set of five unique biomarkers (1,2-propanediol-1-phosphate, d-gluconic acid, 9H-purine, serine, and 2-ketoisovaleric acid) was identified for the mixtures of Cd and CPF. Therefore, the metabolomics analysis is more sensitive than regular clinical observation and pathological examination for detecting the neurotoxicity of the individual and combined Cd and CPF at low levels. Overall, these results identified the unique biomarkers for Cd and CPF exposure, which provide new insights into the mechanism of their joint toxicity.

Home-based system for physical activity monitoring in patients with multiple sclerosis (Pilot study)

BackgroundLimitations in physical activity are considered as a key problem in patients with multiple sclerosis (PwMS). Contemporary methods to assess the level of physical activity in PwMS are regular clinical observation. However, these methods either rely on high recall and accurate reporting from the patients (e.g. self-report questionnaires), or they are conducted during a particular clinical assessment with predefined activities. Therefore, the main aim of this pilot study was to develop an objective method to gather information about the real type and intensity of daily activities performed by PwMS in every-day living situations using an accelerometer. Furthermore, the accelerometer-derived measures are investigated regarding their potential for discriminating between different MS groups.MethodsEleven PwMS that were able to walk independently (EDSS ≤ 5) were divided into two groups: mild disability (EDSS 1–2.5; n = 6) and moderate disability (EDSS 3 –5; n = 5). Participants made use of an activity monitor device attached to their waist during their normal daily activities over 4 measurements. Activity parameters were assessed and compared for the time of each participant’s first measurement and follow-up measurement. Furthermore, differences between both subgroups, and the correlation of activity parameters with the clinical neurological variable (EDSS) were investigated.ResultsParticipants showed significant decline in step count (p = 0.008), maximum walking speed (p = 0.02) and physical activity intensity (p = 0.03) throughout the study period. Compared to the mild subgroup, moderate affected participant accumulated less number of steps (G1: 9214.33 ± 2439.11, G2: 5018.13 ± 2416.96; p < 0.005) and were slower (G1: 1.48 ± 0.19, G2: 1.12 ± 0.44; p = 0.03). Additionally, the EDSS correlated negatively with mean walking speed (r = - 0.71, p = 0.01) and steps count (r = - 0.54, p = 0.08).ConclusionsIn this study, we used a portable activity monitoring sensor to gather information about everyday physical activity in PwMS at home. We showed that objective measurements using simple 3D accelerometers can track daily physical activity fluctuation. Furthermore, they track disability changes better than clinical measures. Thus, they can help to develop activity based treatments for PwMS.

Anti tumor necrosis factor therapy of ankylosing spondylitis in clinical practice

Purpose: The aim of this study was to analize ankylosing spondylitis (AS) patients who were using tumor necrosis factor-alpha (TNF-α) blocking agents and present the data on the efficacy and safety of this treatment in clinical practice. Materials and methods: AS patients using TNF-α blockers for at least six months were included in this retrospective study. Regular clinical observations were used to evaluate the efficacy and safety of the anti-TNF-α drugs. Adverse events were recorded. Reasons for discontinuation of treatment were also closely followed-up. All the patients had a baseline comprehensive rheumatologic assessment and were repeatedly monitored every three months in the routine clinic practice for AS spesific disease indexes as well as laboratory tests. Results: A total of 41 patients with AS were reviewed of whom 26 were male and 15 were female, with a mean age of 43.22 years. The number of AS patients who were treated with etanercept was 18 (43.9%), adalimumab was 15 (36.6%), golimumab was 3 (7.3%) and finally infliximab was 5 (12.2%). Mean duration of the TNF-α bloker usage for AS patients was 39.56 months. 7 of the 11 (26.8%) AS patients who did not respond to the first anti-TNF-α therapy were switched to another anti-TNF-α agent. On the other hand 4 AS patients gave up antiTNF-α therapy. AS spesific disease index scores and laboratory tests improved at the third and the sixth months when compared with the scores at the initiation of the TNF-α bloker therapy. Conclusion: Follow-up of patients with AS in our clinical setting showed that anti-TNF therapy is an effective and safe way of treatment with good adherence rates. Pam Med J 2014;7(3):218-224

Testing toxicity of multiple intravitreal injections of bevacizumab in rabbit eyes

Objective: To evaluate the potential toxicity of repeated intravitreal injections of bevacizumab in rabbit eyes. Design: Randomized, placebo-controlled experimental animal study. Participants: Fourteen chinchilla rabbits; 12 assigned to the experimental group and 2 assigned to the normal control group. Methods: Three sequential, biweekly, intravitreal injections of bevacizumab in doses of 2.5 mg/0.1 mL or 5.0 mg/0.2 mL were performed on each rabbit. Evaluations included intraocular pressure (IOP), aqueous flare, B-scan ultrasound, fundus photography, ultrasound biomicroscopy, electroretinography (ERG), and visually evoked potentials (VEPs) performed at baseline and during the follow-up period. The eyes were enucleated at 1 week and 4 weeks after the last intravitreal injection, and underwent light and electron microscopic evaluations, as well as testing for apoptotic activity. Results: After intravitreal injections, no changes were found by regular clinical observation and IOP tests. There was no significant difference in the anterior chamber inflammatory activity evaluated by the laserflare meter. No evidence of retinal toxicity was seen after intravitreal bevacizumab at doses of 2.5 and 5.0 mg by either ERG or flash VEPs. Electron microscopy did show the presence of inflammatory cells and some ultrastructural changes in the photo-receptor cells in the 5.0 mg experimental group 1 week after the third injection. Mild to moderate apoptosis of photoreceptors was detected in the 5.0 mg group at the same time. Conclusions: The biweekly, multiple intravitreal injections of bevacizumab did not result in evidence of toxicity in regular clinical and functional observations at both 2.5 mg and 5.0 mg doses. The 5.0 mg dose may induce transient inflammation, ultrastructural abnormalities, and apoptosis.

Ten years’ experience of enzyme infusion therapy of Norrbottnian (type 3) Gaucher disease

Abstract Aim: To study the long‐term effects of enzyme replacement therapy on the neurological signs of chronic neuronopathic Gaucher disease and to evaluate some biochemical parameters for monitoring the treatment. Methods: Eight patients from the Norrbottnian cohort were followed during 10 y of treatment. They were followed with regular clinical observations, biochemical tests and psychometric testing. Results: After the start of treatment, their general well‐being improved and was stable during the follow‐up. In three of the patients there were some indications of slow neurological deterioration. The mean results of psychometric testing did not decrease. Glucosylceramide and chitotriosidase levels were useful in monitoring the treatment. The chemokine CCL18 also seems to be a useful parameter for future monitoring. Conclusions: Enzyme replacement therapy seems to slow down further neurological and mental deterioration in mild chronic neuronopathic (type 3) Gaucher disease.

Ten years’ experience of enzyme infusion therapy of Norrbottnian (type 3) Gaucher disease

To study the long-term effects of enzyme replacement therapy on the neurological signs of chronic neuronopathic Gaucher disease and to evaluate some biochemical parameters for monitoring the treatment. Eight patients from the Norrbottnian cohort were followed during 10 y of treatment. They were followed with regular clinical observations, biochemical tests and psychometric testing. After the start of treatment, their general well-being improved and was stable during the follow-up. In three of the patients there were some indications of slow neurological deterioration. The mean results of psychometric testing did not decrease. Glucosylceramide and chitotriosidase levels were useful in monitoring the treatment. The chemokine CCL18 also seems to be a useful parameter for future monitoring. Enzyme replacement therapy seems to slow down further neurological and mental deterioration in mild chronic neuronopathic (type 3) Gaucher disease.

Uranyl nitrate: 91-day exposure and recovery studies in the male New Zealand white rabbit.

This study was undertaken to examine the reversibility of renal injury in the male New Zealand White rabbit subsequent to a 91-day exposure to uranyl nitrate (UN) in drinking water, followed by various recovery periods. Specific pathogen-free (SPF) animals were exposed for 91 days to UN in their drinking water (24 or 600 mg UN/L). Control groups were given municipal tap water (< 0.001 mg U/L). Regular clinical observations were recorded, and urine was collected periodically. Recovery periods between the last UN exposure and termination were 0, 8, 14, 45, or 91 days. Following the study, all animals were anesthetized and terminated by exsanguination, and multiple hematological and biochemical parameters were determined. Necropsies were conducted, and histopathological examination was performed. Exposure-related histopathological changes were observed only at much higher doses than in our previous male rabbit study where non-SPF-free animals had been used. Minor increases in kidney to body weight ratios were observed in the high-dose groups following exposure and early recovery. Renal tubular injury with degenerative nuclear changes, cytoplasmic vacuolation, and tubular dilation was seen in the high-dose group, without consistent resolution even after 91 days recovery. Animals ingested approximately 33% more uranium per day in this study than did males in a comparable dose group in the previous study, yet their kidney tissue uranium residues were 30% lower. These results suggest that SPF rabbits are less sensitive to uranyl injury than the non-SPF animals. The lowest-observed-adverse-effect level is estimated to lie at or below 24 mg UN/L.

Frequency of hepatitis B after open heart surgery: a retrospective study over a three-year period (1974--1976).

In spite of intensive efforts to reduce the risk of hepatitis B after heart operations, this complication is observed in 40 % or more of the cases. Over a period of three years (1974--1976) we examined 588 patients who had undergone open heart surgery. The following results were found: In 1974 the hepatitis frequency was 2.0 %, while in 1975 and 1976 it was 0.6 % hepatitis B and 0.6 % non-B hepatitis. We believe the reason for this improvement is a more careful selection of blood donors and their continuous control according to the following parameters: regular clinical observation; regular chest x-ray; determination of BSR, hemoglobin and aminotransferase; TPHA test; and search for antibodies. In 1974 hepatitis-B-surface-antigen (HBsAg) was detected by means of reverse hemagglutination tests. Since 1975 a modified radioimmunoassay has been used for this purpose. No donor blood with abnormal results was transfused, except for a very small number of extreme emergencies. The good results demonstrated can only be obtained by following the described program and by strictly avoiding pool preparations.