Stable Disease Course Research Articles

Allogeneic Bone Marrow Mesenchymal Stromal Cell Therapy in Patients with Steroid-Refractory Graft Versus Host Disease—a Pilot Study from Pakistan

Mesenchymal stromal cells (MSCs) have emerged as a promising candidate for the treatment of steroid-refractory graft-versus-host disease (GVHD). In this uncontrolled, pilot clinical study, we report safety and efficacy of allogeneic bone marrow MSCs administered intravenously to steroid-refractory GVHD patients. A total of 33 MSC infusions were given to 10 patients suffering from acute GVHD (n = 3), chronic GVHD (n = 5), and overlap syndrome (n = 2). Eight out of ten patients are alive after a median follow-up of 11 months with five having sustained complete remission (CR). Three patients with partial response received further doses to sustain the response. One of them died of lung infection while others are still alive. One out of the two non-responding patients died after 17 days of MSC therapy due to advanced liver GVHD while the other is having a stable disease course. The overall and GVHD-free survival was 80% and 50%, respectively. The patients developed no complication or toxicity related to MSC infusion. Luminex analysis revealed a modest drop after MSC infusion in pro-inflammatory cytokines like TNFα, IL-1β, and IL-6 whereas serum IL-10 levels were slightly raised. Allogeneic donor-derived bone marrow mesenchymal stromal cell therapy is a safe and feasible treatment for steroid-refractory GVHD patients (NCT02824653). We report the safety and efficacy of allogeneic bone marrow mesenchymal stromal cell therapy in 10 patients suffering from steroid-resistant graft-versus-host disease. Eight out of ten patients are alive after a median follow-up of 11 months with five having sustained CR. The response rate was better in acute GVHD patients compared to chronic GVHD patients. MSC therapy within 20 days of steroid-refractory acute GVHD resulted in sustained CR. Initial and sustained response was superior in pediatric patients compared to adults. The Luminex analysis showed a modest decrease in pro-inflammatory cytokines in those responding to MSC therapy.

Randomized phase II study of axitinib versus observation in patients with recurred or metastatic adenoid cystic carcinoma.

6503 Background: Adenoid cystic carcinoma (ACC) does not respond to cytotoxic chemotherapy. Several anti-angiogenic agents were evaluated in single arm phase II trials. However, the role of chemotherapy is still controversial, because of natural stable disease course without chemotherapy and lack of randomized trial. We firstly conducted a randomized trial to evaluate the efficacy of axitinib compared to observation. Methods: In this multicenter, prospective phase II trial, we enrolled recurred, metastatic ACC patients who progressed within 9 months. Patients were randomly assigned either axitinib (5mg twice daily) or observation arm with 1:1 ratio. Crossover to the axitinib arm was permitted for patients in the observation arm who had disease progression. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), overall survival (OS), PFS, duration of response and adverse events. Results: A total of 60 patients randomly allocated to axitinib (N=30) and observation arm (N=30) and response evaluation was conducted in 57 patients. With a median follow-up of 25.4 months, the 6-month PFS rate was 73.2% (95% confidence interval [CI], 54.8 to 88.1%) in the axitinib arm and 23.2% (95% CI, 9.3 to 41.1%) in the observation arm (hazard ratio, 0.19; 95% CI, 0.08 to 0.45; P < 0.001). Median PFS was 10.8 months in axitinib arm and 2.8 months in observation arm ( P < 0.001). The ORR was 3.3% (95% CI, 0.1 to 17.2%) in the axitinib arm, and 0% (95% CI, 0 to 12.8%) in the observation arm. The disease control rate was 100% (95% CI, 88.4 to 100%) in the axitinib arm and 51.9% (95% CI, 32.0 to 71.3%) in the observation arm. After crossover, ORR of axitinib in the observation arm was 11.1% (95% CI, 2.4 to 29.2%). Median OS was not reached in axitinib arm, 28.5 months in observation arm ( P = 0.688). The most frequently reported adverse events of axitinib were grade 1 or 2 oral mucositis and fatigue. Detailed data of adverse events and mutational profile data will be presented. Conclusions: In this first randomized trial in patients with recurred or metastatic ACC, axitinib significantly increased 6-month PFS rate compared to observation. Clinical trial information: NCT02859012 .

Growth differentiation factor 15 is increased in stable MS.

ObjectiveTo assess whether serum concentrations of the anti-inflammatory cytokine growth differentiation factor 15 (GDF-15) differ in patients with highly active multiple sclerosis (MS) vs patients with stable MS and healthy controls (HCs).MethodsGDF-15 concentrations were measured by ELISA in serum and CSF in a cross-sectional cohort of patients with MS, patients with other inflammatory neurologic diseases (OIND), patients with noninflammatory neurologic diseases (NIND), and healthy controls (HC). Serum GDF-15 concentrations were measured in a longitudinally sampled cohort of clinically and radiologically well-characterized patients with MS and corresponding controls.ResultsCross-sectionally measured median serum GDF-15 concentrations were significantly higher in patients with OIND (n = 42) (600 pg/mL, interquartile range [IQR] = 320–907 pg/mL) compared with HCs (n = 29) (325 pg/mL, IQR = 275–419 pg/mL; p = 0.0007), patients with NIND (n = 46) (304 pg/mL, IQR = 245–493 pg/mL; p = 0.0002), or relapsing MS (n = 42) (356 pg/mL, IQR = 246–460 pg/mL; p = 0.0002). CSF and serum concentrations of GDF-15 were correlated (r = 0.41, 95% CI = 0.25–0.56, p < 0.0001). In a longitudinally sampled cohort of patients with MS (n = 48), deeply phenotyped with quantitative clinical and MRI assessments, mean GDF-15 concentrations were significantly higher in patients with a stable disease course (405 pg/mL, SD = 202) than in patients with intermittent MRI activity (333 pg/mL, SD = 116; p = 0.02).ConclusionsSerum GDF-15 concentrations are increased in patients with MS with a stable disease course. These data suggest that GDF-15 may serve as a biomarker for disease stability in MS.

Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors.

ContextGermline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).ObjectiveTo compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.Design12-year prospective, observational study.Participants & SettingWe studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).ResultsProspectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).ConclusionsProspectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies.

ObjectiveTo investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM).MethodsIn this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance.ResultsWhen compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean ± SD 3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine and 468 ± 134 vs 600 ± 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment (p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] −1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI −5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study.ConclusionIn ambulatory RYR1-RM–affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane.Classification of evidenceThis study provides Class I evidence that, for people with RYR1-RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane.Clinicaltrials.gov identifierNCT02362425.

Characteristics and outcomes of 231 COVID-19 cases admitted at a tertiary facility in India: An observational cohort study.

Background:Ongoing pandemic because of COVID-19 has spread across countries, with varied clinical features and severity. Awareness of clinical course among asymptomatic and symptomatology in symptomatic cases is essential for patients’ management as well as optimal utilization of health services (in resource limited settings) based on clinical status and risk factors. This study aimed to describe the clinical characteristics and outcomes of patients admitted with COVID-19 illness in the initial phase of the pandemic in India.Methods:It was an observational study. Patients aged 18 years or more, with confirmed SARS-CoV-2 infection, asymptomatic or mildly ill, were included. Patients with moderate-severe disease at admission or incomplete clinical symptomatology records were excluded. Data regarding demography, comorbidities, clinical features and course, treatment, results of SARS-CoV-2 RT-PCR, chest radiographs, and laboratory parameters were obtained retrospectively from hospital records. The outcome was noted in terms of course, patients discharged, still admitted (at the time of the study), or death.Results:Out of 231 cases, most were males (78.3%) with a mean age of 39.8 years. Comorbidities were present in 21.2% of patients, diabetes mellitus and hypertension being the most common. The most common symptoms were dry cough (81, 35%), fever (64, 27.7%), sore throat (36, 15.6%); asymptomatic infection noted in 108 (46.8%) patients. The presence of comorbidities was an independent predictor of symptomatic disease (OR-2.66; 95%CI 1.08–6.53, P = 0·03). None of the patients progressed to moderate-severe COVID-19, and there were no deaths.Conclusions:A large proportion of patients remained asymptomatic whereas those with comorbidities were more likely to be symptomatic. Most with mild disease had a stable disease course, barring few complication in those with comorbidities. The pandemic continues to grow as large number of asymptomatic cases may go undiagnosed.

FAbry STabilization indEX (FASTEX): Clinical evaluation of disease progression in Fabry patients

BackgroundTwo established scores, the Mainz Severity Score Index (MSSI) and Fabry Disease Severity Scoring System (DS3), quantify the disease burden in Fabry disease (FD), while the recent developed FAbry STabilization indEX (FASTEX) aims to detect disease progression. ObjectiveMSSI, DS3 and FASTEX were compared to evaluate disease stability or progression in a prospective cohort of Fabry patients under enzyme replacement therapy (ERT). MethodsDisease load of 62 patients (28 [45%] females) treated with ERT (26 [42%] under agalsidase-alfa) was assessed using the current scores and re-assessed after 12 months of treatment. Fifteen (24%) patients were ERT-naïve at baseline. ResultsAll scores showed a correlation with each other, while MSSI and DS3 showed the strongest (Pearson r: 0.81, p < .0001). Plasma lyso-Gb3 levels in naïve patients correlated with increasing DS3 and MSSI scores (Pearson r: 0.60, p < .05; Pearson r: 0.64, p < .01; respectively), but not with the total weighted FASTEX score. Longitudinal analysis suggested a stable disease course using DS3 and MSSI. Only males long-term-treated with agalsidase-alfa presented with a slight increase of the general MSSI score (p = .0084). By contrast, the FASTEX score demonstrates that only 21 patients (33.9%) were stable, all other patients presented a disease progression. Patients with an unstable FASTEX mainly suffered from a significant loss of renal function (eGFRcreat: −2.7 ± 7.3 ml/min/1.73 m2, p = .0298). ConclusionWe conclude that the FASTEX seems to be a simple and user friendly, valuable tool to assess early changes in disease progression even in smaller patient cohorts and short term surveillance.

Long-term follow-up, quality of life, and survival of patients with Lambert-Eaton myasthenic syndrome.

ObjectiveTo study survival and to characterize long-term functional impairments and health-related quality of life (HRQOL) of patients with Lambert-Eaton myasthenic syndrome (LEMS).MethodsIn this observational study, survival of patients with LEMS, separately for nontumor (NT) and small cell lung cancer (SCLC), was compared to that of the Dutch general population and patients with SCLC. Disease course in patients with LEMS was recorded retrospectively. Several scales for functional impairments and health-related quality of life were assessed.ResultsWe included 150 patients with LEMS. Survival was similar to that of the general population in 65 patients with NT-LEMS. Tumor survival was significantly longer in 81 patients with SCLC-LEMS compared to patients with non-LEMS SCLC (overall median survival 17 vs 7.0 months, p < 0.0001). At diagnosis, 39 (62%) of 63 patients with complete follow-up data were independent for activities of daily living, improving to 85% at the 1-year follow-up. The physical HRQOL composite score (55.9) was significantly lower than in the general population (76.3, p < 0.0001) and comparable to that of patients with myasthenia gravis (60.5). The mental HRQOL composite score was 71.8 in patients with LEMS, comparable to that of the general population (77.9, p = 0.19) and patients with myasthenia gravis (70.3).ConclusionsThis study shows that patients with NT-LEMS have normal survival. Patients with SCLC-LEMS have an improved tumor survival, even after correction for tumor stage. A majority of patients with LEMS report a stable disease course and remain or become independent for self-care after treatment.

Risk factors associated with poor outcome after medial rectus resection for recurrent intermittent exotropia.

To describe characteristics of recurrent intermittent exotropia after bilateral lateral rectus (BLR) recession, and identify factors associated with poor outcome after unilateral medial rectus (MR) resection for recurrent intermittent exotropia. We retrospectively reviewed 124 patients who have undergone unilateral MR resection for recurrent intermittent exotropia after BLR recession. Patients were followed for at least 2years after MR resection. Clinical characteristics and risk factors associated with poor outcome after unilateral MR resection were evaluated. Successful outcome was defined as distant deviation within the range of 4 prism diopters (PD) esotropia and 10 PD exotropia at last visit after MR resection. Among 124 patients, 50 patients (41.1%) were male, and the mean age at the time of MR resection was 9.5 ± 3.1years. The average follow-up period after MR resection was 43.8 ± 23.7months. Forty-seven patients (37.9%) were classified to have poor outcome at last visit, and 29 patients (23.4%) underwent third operation. None of the patients was overcorrected after MR resection. Multiple logistic regression analyses showed that distant deviation at post-operative 3months and male gender were associated with poor outcome (OR 1.49; 95% CI 1.27-1.73; P < 0.001, and OR 5.19; 95% CI 1.42-18.98; P = 0.013, respectively). Ocular deviation at 3months after unilateral MR resection for recurrent intermittent exotropia may play a valuable role in anticipating poor outcome. Patients whose exotropia exceeded 9 PD at distance at 3months' follow-up tended to recur while those whose exotropia remained below 9 PD at distance showed a stable disease course.

Clinically stable disease is associated with a lower risk of both income loss and disability pension for patients with multiple sclerosis

ObjectiveTo assess the risk of losing income from salaries and risk disability pension for multiple sclerosis patients with a clinically stable disease course 3 years after the start of disease-modifying...

Various protocols of extracorporeal shock wave therapy in the treatment of stable angina

Aim. To evaluate effects of various protocols of cardiac shock wave therapy (CSWT) on quality of life and exercise tolerance in patients with stable angina against the background of optimal medication therapy (OMT). Material and methods . Overall 53 patients (37 men, 16 women) were included in the study. The mean age of examined patients was 67,3 ±8,1 years. Inclusion criteria: CCS class I-IV angina pectoris, stable therapy for at least 1 month before inclusion in the study and a stable course of coronary artery disease for more than 3 months (no cardiovascular events) before inclusion in the study. Patients were divided into 2 groups. The Group 1 (n=37) received OMT+CSWT standard-modified protocol, Group 2 (n=16) received OMT+CSWT rapid-modified protocol. Electrocardiography, echocardiography, treadmill test, and Seattle quality of life questionnaire (SAQ) were performed at inclusion and 6 months follow up. Results. Both CSWT with rapid-modified protocol and standard-modified protocol significantly reduced the number of short-acting nitrates from 2 (2; 7) to 1 (0; 2) (p=0,04) and from 2 (0; 6) to 0 (0; 2) (p ≤0,001) at 6 months, respectively, as well as the number of angina attacks per week (from 4 (2; 7) to 1 (1; 1) (p=0,007) and 6 (2; 20) to 1 (0; 5) (p ≤0,001). Treadmill test total exercise duration was significantly increased from 393 (326; 574) to 561 (411; 650) seconds (p=0,007) and 365+140,4 to 411,5±156,1 seconds (p=0,01), respectively. Time to 1 mm ST segment depression was also significantly increased from 399,8+169 to 460+182 seconds (p ≤0,05) and from 303,1+179 to 389,9+203 seconds (p=0,001), respectively. Conclusion. In our study, CSWT with rapid-modified protocol improved quality of life and exercise tolerance in patients with stable angina similar to the standard-modified protocol. Rapid-modified protocol of CSWT reduced total duration of the treatment.

Treatment of Patients with Stable Manifestations of Atherosclerotic Vascular Disease: New Possibilities (Conclusion of the Council of Experts from November 16, 2018, Rostov-on-Don)

In the conclusion of the council of experts (list of participants see text) the following issues are discussed: regional specifics of diagnosticsand therapy of patients with ischemic heart disease (IHD) and / or peripheral arterial disease (PAD), methods of risk assessment in patientswith stable course of atherosclerotic disease, pathogenetic validity of simultaneous inhibition of coagulation and platelet thrombus formation,as well as clinical significance of a novel therapeutic approach - combined use of rivaroxaban and acetylsalicylic acid (ASA). Possible problemsand ways to their solution at implementation in clinical practice of the novel scheme of antithrombotic therapy are presented. Importanceof multidisciplinary approach to management of patients with IHD and concomitant diseases is stressed. Experts have noted that after registrationof the corresponding indication therapy with rivaroxaban 2.5 mg twice daily and ASA 75-100 mg once daily might be recommendedto majority of patients with atherosclerotic involvement of blood vessels. In real clinical practice prescription of this therapy is appropriate firstof all in patients with IHD and high risk of complications - with multifocal atherosclerosis, with history of myocardial infarction after stoppageof dual antiplatelet therapy, - patients with concomitant diabetes, heart failure, and other prognosis worsening comorbid diseases. Experts expresshope that in the nearest time combined antithrombotic therapy will be included into corresponding national clinical recommendations.

Discontinuation of disease-modifying therapy for patients with relapsing-remitting multiple sclerosis: Effect on clinical and MRI outcomes

BackgroundDisease-modifying therapy (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS) have been shown to reduce relapses and new MRI lesions. However, few studies have assessed the impact of discontinuing DMT after a period of disease inactivity. ObjectiveTo investigate the impact of DMT discontinuation on clinical and radiological outcomes in RRMS patients. Methods69 RRMS patients who discontinued DMT after a period of disease inactivity were identified from the Comprehensive Longitudinal Investigation of MS study at the Brigham and Women's Hospital, based on the following inclusion criteria: age 18 or older; treated with DMT ≥2 years; no clinical and radiological relapse ≥2 years until the discontinuation; not restarting DMT for ≥6 months after discontinuation. Patients matched by age, gender, treatment, treatment duration, disease duration and Expanded Disability Status Scale score who remained on DMT were identified. Univariate and multivariable Cox proportional hazard models with robust standard errors to account for the paired data were used to test the differences based on DMT discontinuation with the outcome measures: time to clinical relapse, MRI event, disability progression, and disease activity (either clinical relapse or MRI event). ResultsBased on the 69 pairs of patients, discontinuation was not associated with time to clinical relapse (HR = 0.87, 95% CI = 0.44–1.72, p = 0.69), MRI event (HR = 0.95, 95% CI = 0.57 to 1.59, p = 0.84), disability progression (HR = 1.24, 95% CI = 0.61 to 2.53, p = 0.55) and disease activity (HR = 0.89, 95% CI = 0.56 to 1.42, p = 0.62). When we performed subgroup analysis to compare the impact of DMT discontinuation between older (age > 45) and younger (age ≤ 45) patients, we found a significant difference in the association between young and old for time to MRI event (p = 0.012) and time to new disease activity (p = 0.0005). ConclusionsThis study found that patients who discontinued treatment after a period of disease inactivity had a similar time to next event compared to subjects who remained on first-generation DMTs. In our cohort, we found that discontinuation after age 45 was associated with a stable disease course, while patients younger than age 45 who discontinued treatment were more likely to experience a new clinical relapse or MRI event.

Faecal Microbiota Dynamics and their Relation to Disease Course in Crohn's Disease.

BackgroundMicrobial shifts have been associated with disease activity in Crohn’s disease [CD], but findings on specific taxa are inconsistent. This may be due to differences in applied methods and cross-sectional study designs. We prospectively examined the faecal microbiota in adult CD patients with changing or stable disease course over time.MethodsFaeces were collected at two time-points from 15 healthy control individuals [HCs], 35 CD patients who were in remission and who maintained remission [RRs], and 22 CD patients during remission and also during subsequent exacerbation [RAs]. The microbial composition was assessed by 16S rRNA [V4] gene sequencing.ResultsCompared with HCs, patients with CD had a lower microbial richness [p = 0.0002] and diversity [p = 0.005]. Moreover, the microbial community structure of a subset of patients, clustered apart from HCs, was characterized by low microbial diversity and Faecalibacterium abundance. Patients within this cluster did not differ with respect to long-term disease course compared with patients with a ‘healthy-appearing’ microbiota.Over time, microbial richness and diversity did not change in RR versus RA patients. Although the microbial community structure of both RR and RA patients was less stable over time compared with that of HCs, no differences were observed between the patient groups [p = 0.17]; nor was the stability impacted by Montreal classification, medication use, or surgery.ConclusionThe altered microbiota composition and stability in CD was neither associated with disease activity nor long-term disease course, questioning its involvement in the development of an exacerbation. The aberrant microbiota composition in a subset of CD patients warrants further exploration of a more microbiota-driven etiology in this group.

Dandy-Walker malformation in Polish hunting dogs: long term prognosis and quality of life

In the last few years, it has become easier to diagnose congenital brain malformations in dog’s ante-mortem. This is probably due to the wider availability of advanced diagnostic imaging, in particular computed tomography or magnetic resonance imaging (MRI). Despite this, there is still not much literature available about potential treatments, outcome and overall prognosis with respect to the patient’s quality of life. We present three cases of Dandy-Walker malformation in Polish hunting dogs with up to five years follow up including assessment of their quality of life. A nine-week-old Polish hunting dog was presented with progressive signs of ataxia that had developed over the preceding few weeks. MRI revealed a Dandy-Walker malformation. The dog underwent MRI at the ages of 12 and 36 months, and his neurological condition was followed for five years. No other subsequent abnormities were found on further diagnostic tests. The dog showed transient behavioural problems which improved after castration and training. The ataxia seen at first visit improved with time and intensive physiotherapy, and the dog was considered to have a good quality of life in the owner’s eyes. A further two cases shared a similar disease course. Dandy-Walker malformation was confirmed with MRI, but diagnostic imaging could not be reported here because the owner did not consent to publication. The Dandy-Walker malformations described in these three Polish hunting dogs had a stable disease course and revealed that dogs suffering from this condition may have a good quality of life, providing no other abnormalities are detected and rehabilitation is performed.

Coronary heart disease and inflammation.

The increased content of inflammation markers in the blood is a significant prognostic sign of coronary events in persons with stable or asymptomatic course of coronary heart disease (CHD) and suggests that the inflammation underlying the destabilization of CHD has an independent character and is largely independent of the severity of stenotic lesions of coronary vessels. Activation of the local inflammatory process in the atherosclerotic plaque leads to the destruction of the fibrous capsule in combination with an increase in the activity of cellular and plasma factors of the coagulation system and inhibition of the fibrinolytic system. Cytomegalovirus, Chlamydia pneumoniae, pathogens of periodontal disease are nominated for the role of inducers of inflammatory reactions. The synergistic effect of several pathogens is reflected in the concept of burden of infection (“infectious burden”). Immuno-inflammatory rheumatic diseases are characterized by a high risk of cardiovascular complications. An important place in their prevention is an effective anti-inflammatory therapy: methotrexate, suppressing the formation of interleukin 1ft and tumor necrosis factor a, allows not only to modify the course of the disease, but also to reduce the risk of cardiovascular accidents. Chronic inflammation, as a key element of atherosclerosis pathogenesis, can be caused not only by infectious and immune factors, but also by metabolic factors. The activation of inflammasomes induced by cholesterol crystals in macrophages is an important link between cholesterol metabolism and inflammation in atherosclerotic plaques. Confirmation of the important pathogenetic role of inflammation is to reduce the risk of cardiovascular complications (CVD) on the background of anti-inflammatory therapy. In statin therapy, the decrease in The level of C-reactive protein (CRP) was significantly correlated with the suppression of atherosclerosis progression and a decrease in the risk of SSR, regardless of the degree of lowering the low-density lipoprotein cholesterol level. Taking colchicine in a low dose in patients with stable coronary artery disease, who received standard therapy, reduced the risk of acute coronary syndrome and sudden cardiac death. Secondary prevention of cardiovascular complications by human monoclonal antibodies to interleukin 1ft (kanakinumab) led to a decrease in the risk of SSR regardless of sex, Smoking, and lipid levels.

Clinical and molecular characterization of Korean children with infantile and late-onset Pompe disease: 10 years of experience with enzyme replacement therapy at a single center.

PurposePompe disease (PD) is an autosomal recessive disorder caused by a deficiency of acid alphaglucosidase resulting from pathogenic GAA variants. This study describes the clinical features, genotypes, changes before and after enzyme replacement therapy (ERT), and long-term outcomes in patients with infantile-onset PD (IOPD) and late-onset PD (LOPD) at a tertiary medical center.MethodsThe medical records of 5 Korean patients (2 male, 3 female patients) diagnosed with PD between 2002 and 2013 at Samsung Medical Center in Seoul, Republic of Korea were retrospectively reviewed for data, including clinical and genetic characteristics at diagnosis and clinical course after ERT.ResultsCommon initial symptoms included hypotonia, cyanosis, and tachycardia in patients with IOPD and limb girdle weakness in patients with LOPD. Electrocardiography at diagnosis revealed hypertrophic cardiomyopathy in all patients with IOPD who showed a stable disease course during a median follow-up period of 10 years. Patients with LOPD showed improved hepatomegaly and liver transaminase level after ERT.ConclusionAs ERT is effective for treatment of PD, early identification of this disease is very important. Thus, patients with IOPD should be considered candidates for clinical trials of new drugs in the future.

Clinical Heterogeneity of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A French Multicenter Retrospective Study.

ObjectiveImmune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disease caused by mutations in the forkhead box protein 3 gene (FOXP3), which encodes a key regulator of immune tolerance. The aim of this study was to describe the clinical heterogeneity of the disease in a national French cohort.MethodsMulticenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3.ResultsThirty children from 26 families were included. Age at disease onset (median [first to third quartile]) was 1.5 mo [0–84] and at death 3.5 years [0–10.5] (n = 15) indicating a high heterogeneity. Initial presentation was diarrhoea (68%), type 1 diabetes (T1D; 25%), skin lesions (7%) and nephropathy (3%). During the course of the disease the following main symptoms were observed: diarrhoea (100%), skin lesions (85%), T1DM (50%), severe food allergies (39%), haematological disorders (28%), nephropathies (25%), hepatitis (14%) as well as the presence of a variety of autoantibodies. Immunosuppressive mono- or combination therapy led to improvement in eight children. Three boys displayed a stable disease course without any immunosuppressive medication. Overall 10-year survival rate was 43% (42% in transplanted patients and 52% in patients on immunosuppressive therapy). Five out of 22 identified FOXP3 mutations have not been described yet: c.−23 + 1G > A, c.−23 + 5G > A, c.264delC, c.1015C > T and c.1091A > G. The first two produced atypical, attenuated phenotypes. Missense and frameshift mutations affecting the forkhead domain were associated with poor survival (Gehan–Wilcoxon p = 0.002).ConclusionThe broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.

Influence of tobacco smoking on clinical efficacy of a 1-year rehabilitation programme for myocardial infarction patients of economically active age

Aim. Evaluation of the efficacy of 1-year exercise based program (EP) in coronary heart disease (CHD) patients of economically active age after acute myocardial infarction (MI), depending on smoking status.Material and methods. To the study, males included (n=338) after MI (not later than 3 weeks from the event). Four groups shaped by randomization: EP patients smokers (group 1, n=84), EP non-smokers (group 2, n=85); no EP smokers (group 3, n=85) and no EP non-smokers (group 4, n=84). All patients received standard medication treatment. The EP were added, of moderate intensity (50-60% from the load in exercise test) 3 times a week during 1 year.Results. After EP in smokers (n=41) and non-smokers (n=85) there was an increase of load duration by 30,3% (p&lt;0,001) and by 28,4% (p&lt;0,001), and its intensity by 31,2% (p&lt;0,001) and 30,8% (p&lt;0,001), with 3,8% (p&lt;0,01) increase of economicity of physical work, but only in smokers. With no EP only in non-smokers there was slight increase of exercise duration by 10,1% (p&lt;0,01) and its intensity by 11,1% (p&lt;0,05), but milder, and in smokers, in contrary, the economicity parameter declined by 13,3% (p&lt;0,05). This was linked with the heart size enlargement and the left ventricle ejection fraction increase in smokers and non-smokers; in the absence of EP there were no changes, just slight (by 1,9%) (p&lt;0,05) increase of the left ventricle ejection fraction in non-smokers. Only at EP, with similar grade in smokers and non-smokers there was decrease of atherogenic lipids levels and high density cholesterol increase. In 1 year of EP, all cases of cardiovascular adverse events significantly decreased in smokers by 44,8% (р&lt;0,05) and in nonsmokers by 50,9% (р&lt;0,05).Conclusion. Long term (1 year) EP of moderate intensity, in both smokers and non-smokers MI patients lead to stable disease course, decrease the rate of cardiovascuar complications and improve patients life quality. However the “smoking factor” decreases rehabilitational potentional of patient and interferes with better results achievement in cardiorehabilitation.

Optimal Treatment of Osteofibrous Dysplasia of the Tibia.

Our study of a large patient group reports on the behavior and postoperative recurrence of osteofibrous dysplasia (OFD). We reviewed the medical records of 55 patients who were diagnosed with OFD of the tibia and showed typical features of this tumor. The patients' presentation, disease course, history of pathologic fracture, typical radiographic features, surgical treatment history, and surgical results were investigated. The longitudinal OFD lesion size peaks at a mean 13.3 years of age with a mean maximum proportionate size of 0.33. These lesions in 92% of the patients spontaneously presented with a stable disease course, while those in the other 8% continued increasing. There were no significant predictive factors of disease course. Among surgically treated lesions, we noted a higher rate of recurrence after curettage than after excision (P<0.001). Patients who underwent curettage and developed recurrence were significantly younger than those who did not (P=0.01). Our data suggest that observation can be the primary form of treatment for patients with OFD and that the disease would stop advancing with time. During observation, clinicians should carefully observe all patients with OFD because the relation between OFD and adamantinoma is unclear. If surgery is necessary due to severe morbidity, we recommend excision rather than curettage to prevent recurrence, especially for younger patients. Level III.