Chronic Venous Disease and Its Intersections With Diabetes Mellitus.

Chronic venous disease (CVD) is a vascular disorder in which blood return is severely compromised and CVD is usually characterized by venous hypertension. Along with obesity and diabetes mellitus, CVD is one of the most common civilization diseases. In general, the estimated prevalence of CVD ranges from 60-80 %. Early diagnosis and adequate treatment are important for preventing progression to more severe stages of the disease like venous leg ulcers. Clinical manifestations of CVD in initial stages of the disease are often asymptomatic. However, as CVD progresses, symptoms begin to develop. Treatment of CVD could be divided into conservative and surgical. Conservative therapy consists of compression, pharmacological treatment and lifestyle change. In cases where conservative therapy is ineffective, surgical or endovascular treatment may be required. The intersections between diabetes mellitus (DM) and CVD are not to be underestimated. CVD and DM have often the same risk factors. Symptoms of CVD can be modified by late complications of DM, but the incidence of different CVD degrees seems to be the same as in diabetics as in non-diabetics population. We are particularly concerned in diabetics about worse compliance with treatment due to their often-poorer adherence to treatment of DM and lifestyle changes. Moreover, there exist a higher risk of CVD and peripheral arterial disease in diabetics patients. Patients with CVD should always be inspected for the presence of DM, considering its presence can have a bearing on CVD symptoms, diagnostic procedures, and therapeutic strategies.

Factors Influencing the Risk of Major Amputation in Patients with Diabetic Foot Ulcers Treated by Autologous Cell Therapy.

Introduction: Autologous cell therapy (ACT) is one of the last options for limb salvage in patients with chronic limb-threatening ischemia (CLTI) and diabetic foot ulcers (DFU). However, some patients may still undergo a major amputation even after ACT, but the risk factors for this are not known. Therefore, the aim of our study was to assess the risk factors for major amputation in patients with CLTI and DFU during a 2-year follow-up after ACT. Methods: One hundred and thirteen patients after ACT were included in our study and divided into two groups: Group 1 with major amputation (AMP; n = 37) and Group 2 without amputation (nAMP, n = 76). The risk factors for major amputation were evaluated before ACT and included factors relating to the patient, the DFU, and the cell product. Results: The AMP group had significantly higher C-reactive protein (CRP) levels compared to the nAMP group (22.7 vs. 10.7 mg/L, p = 0.024). In stepwise logistic regression, independent predictors for major amputation were mutation of the gene for methylenetetrahydrofolate reductase (MTHFR) with heterozygote and homozygote polymorphism 1298 (OR 4.33 [95% CI 1.05-17.6]), smoking (OR 3.83 [95% CI 1.18-12.5]), and CRP > 10 mg/L (OR 2.76 [95% CI 0.93-8.21]). Lower transcutaneous oxygen pressure (TcPO2) values were observed in AMP patients compared to the nAMP group at one month (24.5 vs. 33.2, p = 0.012) and at 3 months (31.1 vs. 40.9, p = 0.009) after ACT. Conclusion: Our study showed that the risk for major amputation after ACT in patients with CLTI and DFU is increased by the presence of MTHFR heterozygote and homozygote gene mutations, smoking, and higher CRP at baseline. Lower TcPO2 at one and 3 months after ACT may also have a predictive value. Therefore, it is necessary to stop smoking before ACT, treat any infection, and, above all, consider antiaggregation or anticoagulant treatment after the procedure.

Incidence and Risk Factors of Diabetic Foot Syndrome in Patients Early After Pancreas or Kidney/Pancreas Transplantation and its Association with Preventive Measures.

Diabetic foot (DF) can develop in diabetic patients after organ transplantation (Tx) due to several factors including peripheral arterial disease (PAD), diabetic neuropathy and inappropriate DF prevention. Aim: To assess the occurrence of DF and associated risk factors in transplant patients. Methods: Fifty-seven diabetic patients were enrolled as part of this prospective study. All patients underwent organ Tx (01/2013-12/2015) and were followed up for minimum of 12 months up to a maximum of 50 months. Over the study period we evaluated DF incidence and identified a number of factors likely to influence DF development, including organ function, presence of late complications, PAD, history of DF, levels of physical activity before and after Tx, patient education and standards of DF prevention. Results: Active DF developed in 31.6% (18/57) of patients after organ Tx within 11 months on average (10.7 ± 8 months). The following factors significantly correlated with DF development: diabetes control (p = .0065), PAD (p<0.0001), transcutaneous oxygen pressure (TcPO2;p = .01), history of DF (p = .0031), deformities (p = .0021) and increased leisure-time physical activity (LTPA) before Tx (p = .037). However, based on logistic stepwise regression analysis, the only factors significantly associated with DF during the post-transplant period were: PAD, deformities and increased LTPA. Education was provided to patients periodically (2.6 ± 2.5 times) during the observation period. Although 94.7% of patients regularly inspected their feet (4.5 ± 2.9 times/week), only 26.3% of transplant patients used appropriate footwear. Conclusions: Incidence of DF was relatively high, affecting almost 1/3 of pancreas and kidney/pancreas recipients. The predominant risk factors were: presence of PAD, foot deformities and higher LTPA before Tx. Therefore, we recommend a programme involving more detailed vascular and physical examinations and more intensive education focusing on physical activity and DF prevention in at-risk patients before transplantation.

Rational use of mucoactive medications to treat pediatric airway disease.

Many airway diseases in children, notably bronchiolitis, cystic fibrosis (CF), non-CF bronchiectasis including primary ciliary dyskinesia, pneumonia, and severe asthma are associated with retention of airway secretions. Medications to improve secretions clearance, the mucoactive medications, are employed to treat these diseases with varying degrees of success. This manuscript reviews evidence for the use of these medications and future directions of study.

Human respiratory syncytial virus infection in the pre-clinical calf model.

Human respiratory syncytial virus (hRSV) is the most important respiratory pathogen in young children worldwide. Experimental modelling of hRSV disease by bovine RSV (bRSV) infection in calves provides an important tool for developing new strategies for prevention and treatment. Depending on the scientific hypothesis under investigation, this cognate host-virus model might have the disadvantage of using a highly related but not genetically identical virus. In this study, we aim to describe viral kinetics and (clinical) disease characteristics in calves inoculated with hRSV. Our results show that hRSV infects the upper and, to a lesser extent, the lower respiratory tract of calves. Infection causes upper airway clinical disease symptoms and neutrophilic infiltration of the lower airways. We conclude that a hRSV model in calves may aid future research involving distinct scientific questions related to hRSV disease in children.

Clinical and (31)P magnetic resonance spectroscopy characterization of patients with critical limb ischemia before and after autologous cell therapy.

Autologous cell therapy (ACT) is a new treatment method for diabetic patients with critical limb ischemia (CLI) not eligible for standard revascularization. After intramuscular injection of bone marrow-derived mononuclear cells local arteriogenesis in the ischemic tissue occurs. Studies assessing visualization of this therapeutic vasculogenesis after ACT by novel imaging techniques are lacking. The aim of our study was to assess the effect of ACT on possible metabolic changes and perfusion of critically ischemic limbs using (31)P magnetic resonance spectroscopy ( (31)P MRS) and its possible correlation with changes of transcutaneous oxygen pressure (TcPO(2)). Twenty-one patients with diabetes and no-option CLI treated by ACT in our foot clinic over 8 years were included in the study. TcPO(2) as well as rest (phosphocreatine, adenosine triphosphate and inorganic phosphate) and dynamic (mitochondrial capacity and phosphocreatine recovery time) (31)P-MRS parameters were evaluated at baseline and 3 months after cell treatment. TcPO(2) increased significantly after 3 months compared with baseline (from 22.4±8.2 to 37.6±13.3 mm Hg, p=0.0002). Rest and dynamic (31)P MRS parameters were not significantly different after ACT in comparison with baseline values. Our study showed a significant increase of TcPO(2) on the dorsum of the foot after ACT. We did not observe any changes of rest or dynamic (31)P MRS parameters in the area of the proximal calf where the cell suspension has been injected into.

Impact of severe diabetic kidney disease on the clinical outcome of autologous cell therapy in people with diabetes and critical limb ischaemia.

AIM: To assess the impact of autologous cell therapy on critical limb ischaemia in people with diabetes and diabetic kidney disease. METHODS: A total of 59 people with diabetes (type 1 or type 2) and critical limb ischaemia, persisting after standard revascularization, were treated with cell therapy in our foot clinic over 7 years; this group comprised 17 people with and 42 without severe diabetic kidney disease. The control group had the same inclusion criteria, but was treated conservatively and comprised 21 people with and 23 without severe diabetic kidney disease. Severe diabetic kidney disease was defined as chronic kidney disease stages 4-5 (GFR <30 ml/min/1.73 m²). Death and amputation-free survival were assessed during the 18-month follow-up; changes in transcutaneous oxygen pressure were evaluated at 6 and 12 months after cell therapy. RESULTS: Transcutaneous oxygen pressure increased significantly in both groups receiving cell therapy compared to baseline (both P<0.01); no significant change in either of the control groups was observed. The cell therapy severe diabetic kidney disease group had a significantly longer amputation-free survival time compared to the severe diabetic kidney disease control group (hazard ratio 0.36, 95% CI 0.14-0.91; P=0.042); there was no difference in the non-severe diabetic kidney disease groups. The severe diabetic kidney disease control group had a tendency to have higher mortality (hazard ratio 2.82, 95% CI 0.81-9.80; P=0.062) than the non-severe diabetic kidney disease control group, but there was no difference between the severe diabetic kidney disease and non-severe diabetic kidney disease cell therapy groups. CONCLUSIONS: The present study shows that autologous cell therapy in people with severe diabetic kidney disease significantly improved critical limb ischaemia and lengthened amputation-free survival in comparison with conservative treatment; however, the treatment did not influence overall survival.

Perfusion scintigraphy in the assessment of autologous cell therapy in diabetic patients with critical limb ischemia.

Perfusion scintigraphy with technetium-99-methoxy-isobutyl-isonitrile ((99m)Tc-MIBI) is often used for assessing myocardial function but the number of studies concerning lower limb perfusion is limited. The aim of our study was to assess whether (99m)Tc-MIBI was an eligible method for evaluation of the effect of cell therapy on critical limb ischemia (CLI) in diabetic patients. (99m)Tc-MIBI of calf muscles was performed before and 3 months after autologous cell therapy (ACT) in 24 diabetic patients with CLI. Scintigraphic parameters such as rest count and exercising count after a stress test were defined. These parameters and their ratios were compared between treated and untreated (control) limbs and with changes in transcutaneous oxygen pressure (TcPO(2)) that served as a reference method. The effect of ACT was confirmed by a significant increase in TcPO(2) values (p<0.001) at 3 months after ACT. We did not observe any significant changes of scintigraphic parameters both at rest and after stress 3 months after ACT, there were no differences between treated and control limbs and no association with TcPO(2) changes. Results of our study showed no significant contribution of (99m)Tc-MIBI of calf muscles to the assessment of ACT in diabetic patients with CLI over a 3-month follow-up period.

Anti-parietal cell antibodies in patients with autoimmune thyroid diseases.

BACKGROUND: Autoimmune thyroid disease (ATD) patients may have a higher prevalence of anti-parietal cell antibodies (APCA) than normal population. OBJECTIVE: To study the prevalence of APCA in a cohort of ATD patients to know its association with patient's clinical profile and gastrointestinal complaints. METHODS: APCA was sought for by indirect immunofluorescence test in 243 ATD patients: 136 (55.9%) with Graves' disease and 107 (44.0%) with Hashimoto's thyroiditis. A structured questionnaire for gastrointestinal symptoms, previous history of thrombosis, arthralgia and other autoimmune diseases in the patients and their families was applied. Positive and negative APCA individuals were compared. Positive patients were invited to perform upper gastrointestinal endoscopy and biopsy of duodenum segments. Sera from 100 healthy individuals from the same geographic area were used as controls. RESULTS: APCA was present in 20.1% (49/243) of ATD patients: 21.3% (29/136) in the Graves' sample and 18.6% (20/107) in the Hashimoto's sample (p = 0.61). Patients with positive APCA had more anemia (p = 0.03; OR = 2.89; 95% CI = 1.03-8.07) and less heartburn (p = 0.01; OR = 0.4; 95% CI = 0.20-0.83). Among the group of 49 APCA-positive patients, 24 agreed with upper endoscopy and it was found that 54.1% had atrophic gastritis. CONCLUSIONS: There is a high prevalence of positive APCA in ATD patients. APCA are more common in those with anemia and less common in those with complaints of heartburn. Almost half of positive APCA patients had atrophic gastritis.

Neutrophil Extracellular Traps in Respiratory Disease: guided anti-microbial traps or toxic webs?

Neutrophil recruitment to the airways and lungs is a major hallmark of many respiratory diseases. One of the more recently discovered unique innate immune effector mechanisms of neutrophils is the formation of neutrophil extracellular traps (NETs), consisting of an extracellular network of DNA fibers studded with nuclear and granule proteins. Although in the respiratory system NETs contribute to capture and inactivation of bacteria, fungi and viruses, there is a delicate 'balance' between aid and damage to the host. Accumulating evidence now suggests that NETs can have direct cytotoxic effects to lung epithelial and endothelial cells and can contribute to airway obstruction. As such, NETs may play an important role in the pathogenesis of respiratory diseases. The purpose of this review is to give an up-to-date overview of the current status of NETs in respiratory diseases. We examine both experimental and clinical data concerning the role of NETs in host defence as well as immunopathology, with special attention paid to the literature relevant for the paediatric pulmonology community. Finally, we discuss future treatment strategies that may target the formation of NETs in the airways and lungs.

[Special contact splints in postoperative care for patients with the diabetic foot]. / Pouzití speciálních kontaktních dlah v pooperacní péci u syndromu diabetické nohy.

UNLABELLED: Adequate stabilization and off-loading of the lower limb is an integral part of postoperative care for patients with the diabetic foot. Off-loading can accelerate the healing process and reduce the number of complications and reoperations. The newly introduced method of the performance of removable contact splints (modified contact removable casts) seems to fulfil a number of requirements for stabilization and off-loading devices - the method is safe and can actually reduce the healing time and the number of reoperations in patients with the diabetic foot. KEY WORDS: diabetic foot - off-loading - splints.

Low hepatitis B vaccine response in children with Down syndrome from Brazil.

BACKGROUND: It has been reported that vaccination against hepatitis B is less effective among people with Down syndrome than in the general population. We aimed to evaluate the rate of seroconversion to hepatitis B vaccine in children with Down syndrome from Brazil. METHODS: A total of 120 people with Down syndrome were included. All of them received the vaccine at intervals of 0, 30 and 180 days and serum samples were tested for the presence of antibodies to the hepatitis B surface antigen (anti-HBs) 30 days after the last dose. RESULTS: In the studied group, 58.3% (70/120) were male and 41.7% (50/120) female, with the median age of 5 years (range 2-15 years). Fifty-eight of 120 (48.3%) developed anti-HBs after vaccination. No association was found between gender and/or age and vaccine response. CONCLUSIONS: The low rate of seroconversion in response to hepatitis B vaccine suggests that all patients with Down syndrome immunized against hepatitis B should be followed and monitored by clinicians.

Both autologous bone marrow mononuclear cell and peripheral blood progenitor cell therapies similarly improve ischaemia in patients with diabetic foot in comparison with control treatment.

BACKGROUND: The aim of our study was to compare the effect of bone marrow mononuclear cell and peripheral blood progenitor cell therapies in patients with diabetic foot disease and critical limb ischaemia unresponsive to revascularization with conservative therapy. METHODS: Twenty-eight patients with diabetic foot disease (17 treated by bone marrow cells and 11 by peripheral blood cell) were included into an active group and 22 patients into a control group without cell treatment. Transcutaneous oxygen pressure and rate of major amputation, as the main outcome measures, were compared between bone marrow cells, peripheral blood cell and control groups over 6 months; both cell therapy methods were also compared by the characteristics of cell suspensions. Possible adverse events were evaluated by changes of serum levels of angiogenic cytokines and retinal fundoscopic examination. RESULTS: The transcutaneous oxygen pressure increased significantly (p < 0.05) compared with baseline in both active groups after 6 months, with no significant differences between bone marrow cells and peripheral blood cell groups; however, no change of transcutaneous oxygen pressure in the control group was observed. The rate of major amputation by 6 months was significantly lower in the active cell therapy group compared with that in the control group (11.1% vs. 50%, p = 0.0032), with no difference between bone marrow cells and peripheral blood cell. A number of injected CD34+ cells and serum levels of angiogenic cytokines after treatment did not significantly differ between bone marrow cells and peripheral blood cell. CONCLUSIONS: Our study showed a superior benefit of bone marrow cells and peripheral blood cell treatments of critical limb ischaemia in patients with diabetic foot disease when compared with conservative therapy. There was no difference between both cell therapy groups, and no patient demonstrated signs of systemic vasculogenesis.

[Treatment of critical limb ischemia and diabetic foot disease by the use of autologous stem cells]. / Terapie kritické koncetinové ischemie u pacientu se syndromem diabetické nohy pomocí autologních kmenových bunek.

AIM: The aim of our study was to assess safety and effectiveness of therapy of critical limb ischaemia by autologous stem cells and evaluation of potential adverse events. METHODS: Fourteen patients were included into the study (11 men, 3 women, mean age 61.9 +/- 9.6 years, mean diabetes duration 23.5 +/- 11.1 years, mean glycated hemoglobin 6 +/- 1%). Eight patients were treated by bone marrow stromal cells, 6 patients by peripheral blood progenitor cells after stimulation by filgrastim. The suspension of stem cells was then applied into the muscles of ischemic limbs. We evaluated transcutaneous oxygen tension (TcPO2), subjective pain sensation assessed by Visual Analog Scale (VAS) and wound healing. RESULTS: TcPO2 significantly increased in all patients from 10 +/- 8.7 mm Hg before the treatment to 39.4 +/- 9.5 mm Hg after 6 months (p = 0.0005) after stem cell therapy. We also observed significant area defect reduction and pain decrease during the follow-up period. Median of area defect was reduced from 4.3 (0.7 - 31.7) before the treatment to 0.06 (0 - 0.5) cm2 after 6 months from the treatment (p = 0.0078). Decrease in rest pain was observed in all patients, mean VAS decreased from 5.3 +/- 1.8 to 1.1 +/- 1.3 after 6 months (p = 0.002). CONCLUSION: Our study suggests that stem cell therapy of diabetic foot disease is an effective therapeutic option with no adverse events for patients with severe peripheral arterial disease. This treatment leads to increase of transcutaneous oxygen tension, improves wound healing and decreases the rest pain.

Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice.

Activation of the Fas/Fas ligand (FasL) system in the lungs results in a form of injury characterized by alveolar epithelial apoptosis and neutrophilic inflammation. Studies in vitro show that Fas activation induces apoptosis in alveolar epithelial cells and cytokine production in alveolar macrophages. The main goal of this study was to determine the contribution of alveolar macrophages to Fas-induced lung inflammation in mice, by depleting alveolar macrophages using clodronate-containing liposomes. Liposomes containing clodronate or PBS were instilled by intratracheal instillation. After 24 h, the mice received intratracheal instillations of the Fas-activating monoclonal antibody Jo2 or an isotype control antibody and were studied 18 h later. The Jo2 MAb induced increases in bronchoalveolar lavage fluid (BALF) total neutrophils, lung caspase-3 activity, and BALF total protein and worsened histological lung injury in the macrophage-depleted mice. Studies in vitro showed that Fas activation induced the release of the cytokine KC in a mouse lung epithelial cell line, MLE-12. These results suggest that the lung inflammatory response to Fas activation is not primarily dependent on resident alveolar macrophages and may instead depend on cytokine release by alveolar epithelial cells.

Epilepsy in children with cerebral palsy.

OBJECTIVE: To describe the prevalence and characteristics of epilepsy in patients with cerebral palsy in a tertiary center. METHODS: a total of 100 consecutive patients with cerebral palsy were retrospectively studied. Criteria for inclusion were follow-up period for at least 2 years. Types and incidence of epilepsy were correlated with the different forms of cerebral palsy. Other factors associated with epilepsy such as age of first seizure, neonatal seizures and family history of epilepsy were also analysed. RESULTS: follow-up ranged between 24 and 151 months (mean 57 months). The overall prevalence of epilepsy was 62%. Incidence of epilepsy was predominant in patients with hemiplegic and tetraplegic palsies: 70.6% and 66.1%, respectively. First seizure occurred during the first year of life in 74.2% of patients with epilepsy. Generalized and partial were the predominant types of epilepsy (61.3% and 27.4%, respectively). Thirty-three (53.2%) of 62 patients were seizure free for at least 1 year. Neonatal seizures and family history of epilepsy were associated with a higher incidence of epilepsy. CONCLUSIONS: epilepsy in cerebral palsy can be predicted if seizures occur in the first year of life, in neonatal period and if there is family history of epilepsy.