[Collagen-based biological dressings in the treatment of chronic wounds in diabetic foot syndrome]. / Biologicheskie povyazki na osnove kollagena v lechenii khronicheskikh ran pri sindrome diabeticheskoi stopy.

One of the end-organs of diabetes mellitus (DM) is the skin. Cellular and molecular disorders occurring in the skin due to chronic hyperglycemia, neuropathy, and micro- and macroangiopathy lead to poor-heling foot wounds in patients with diabetes. Consequently, treating wounds in diabetic foot syndrome (DFS) is prolonged, costly, and often ineffective. The research on wound healing and treating wounds in DM with stricter adherence to international guidelines and technological breakthroughs in developing biological materials provide new therapeutic opportunities to solve wound care problems. Collagen is one of the body's many proteins, essential throughout the healing phases for skin repair and remodeling. Collagen is one of the body's many proteins, essential throughout the healing phases for skin repair and remodeling. The article addresses the features of biological dressings based on the lyophilized native triple-helix (non-hydrolyzed) collagen formulation. Also, we present clinical cases of their use in different phases of wound healing in DM.

[Results of a multicentre double-blind randomised placebo-controlled clinical trial evaluating the efficacy and safety of Mexidol in the treatment of Attention Deficit Hyperactivity Disorder in Children (MEGA)]. / Rezul'taty mnogotsentrovogo dvoinogo slepogo randomizirovannogo platsebo-kontroliruemogo klinicheskogo issledovaniya po otsenke effektivnosti i bezopasnosti preparata Meksidol v lechenii sindroma defitsita vnimaniya s giperaktivnost'yu u detei (MEGA).

OBJECTIVES: To evaluate the efficacy and safety of two dosing regimens of Mexidol film-coated tablets, 125 mg («RPC «PHARMASOFT¼ LLC Russia), compared with placebo in children with attention deficit hyperactivity disorder (ADHD) aged 6 to 12 years. MATERIAL AND METHODS: A multicenter randomized, double-blind, placebo-controlled study in 3 parallel groups was conducted in 14 clinical centres of the Russian Federation to assess efficacy and safety of Mexidol film-coated tablets, 125 mg («RPC «PHARMASOFT¼ LLC Russia) in the treatment of attention deficit hyperactivity disorder (ADHD) in children 6-12 years old with different dosing regimens. The study involved 333 boys and girls aged 6 to 12 years with a confirmed diagnosis of ADHD established in accordance with ICD-10 and DSM-5 criteria. After screening (up to 14 days) the patients were randomised into 3 treatment groups in a 1:1:1: Mexidol 125 mg 2 times daily, Mexidol 125 mg daily+placebo and the placebo group. The duration of treatment in all groups was 42 days. 332 children completed the study. ADHD and comorbid disorders assessment scales were used. RESULTS: There were statistically significant changes in the sum of the total scores on the SNAP-IV inattention and hyperactivity/impulsivity subscales after 6 weeks of therapy in all three study groups (p<0.05). There were statistically significant differences between the Mexidol 125 mg and placebo groups and between the Mexidol 125 mg 2 times daily and placebo groups (for the PP population: p=0.000308 and p=0.000024, respectively; for the FAS population: p=0.000198 and p=0.000024, respectively), indicating that Mexidol therapy is superior to placebo. Statistically significant differences (p<0.05) were also obtained for most of the secondary efficacy criteria (average change in SNAP-IV inattention subscale score, average change in SNAP-IV hyperactivity/impulsivity subscale score, average change in SNAP-IV subscale score - Conners index, average change in ADHD-RS-IV score, change in CGI-ADHD-S scores, change in CGI-I score - the Clinical Global Impressions Scale - Improvement) when comparing Mexidol therapy with placebo. The results of statistical analysis of the incidence of adverse events, laboratory values, physical examination show no significant differences between the compared groups in the main safety parameters. CONCLUSIONS: The regimen of Mexidol, 125 mg film-coated tablets twice daily has been shown to be superior to the regimen of Mexidol, 125 mg film-coated tablets once daily and placebo. The safety profiles of the studied dosing regimens of Mexidol and placebo were comparable.

Data on compounding lopinavir and ritonavir suspension for non-cooperative COVID-19 patients.

The COVID-19 outbreak is now one of the most critical crises to manage for most of national healthcare systems in the world. The situation is complicated by the absence of vaccines and authorized pharmacological treatments, except for remdesivir. In this context, many medicaments, including different Ebola and HIV antivirals, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Authorized medicaments manipulation is sometimes necessary because they are not always formulated to be administered to non-cooperative patients or they are in shortage. It is this the case of the fixed combination of lopinavir/ritonavir, which was extensively used in the first phase of the outbreak inducing a shortage of the oral solution available in the EU market. This work provides data on size distribution, osmolarity other than drug chemical stability of a lopinavir/ritonavir extemporaneous preparation made by using the solid dosage form (i.e., tablet) available on the market as drug source. The reported data indicate that such preparation is suitable to be delivered through a nasogastric tube, and enough stable for two weeks from the preparation at room temperature.

Data on chloroquine/hydroxychloroquine content in compounded oral suspension after filtration and centrifugation.

The COVID-19 outbreak is spreading worldwide pushing the national healthcare systems to find effective protocols to prevent contagion and to reduce the patients' mortality and the severity of long-term effects. In the absence of authorised pharmacological treatments, chloroquine, and hydroxychloroquine, which are known as anti-malaria drugs, had been widely used off-label until concerns about their efficacy/safety limited their use to hospitalized patients affected by severe COVID-19. Regardless of their clinical use, their manipulation is necessary since the pure drug substance is not always promptly available and most of the drug products available on the market are tablets designed to be ingested; no liquid dosage forms are available. These are needed for children and the enteral nutrition of inpatients of intensive care units. Considering that both chloroquine and hydroxychloroquine are BCS class I, proper procedures for purifying the preparation from the insoluble excipients may be adopted to avoid clogging of a nasogastric tube and to reduce the drug content variability in the administered doses. The data in this article indicate that compounded oral suspensions containing chloroquine and hydroxychloroquine can be filtered and/or centrifuged without altering the drug assay of the preparation.

Data on the stability of darunavir/cobicistat suspension after tablet manipulation.

The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. In the absence of authorised pharmacological treatments, many antiretrovirals, including darunavir/cobicistat fixed combination, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortunately, for most of them, the drug products available on the market are not designed to be administered by a nasogastric tube to inpatients of intensive care units. Therefore, their manipulation, even if it can strongly affect the product quality, is necessary for the preparation of suspension to meet patients' need. In this situation, it is urgent to provide data and guidance to support hospital pharmacists and clinicians in their activity. The data in this article indicate that darunavir/cobicistat suspensions compounded by pharmacists using as active ingredient a commercially available tablet can be stable at least for one week.

Prevalence and Prognostic Value of Depression and Anxiety in Patients with Diabetic Foot Ulcers and Possibilities of their Treatment.

BACKGROUND: Depression and anxiety can potentially influence treatment results of diabetic complications. OBJECTIVE: Of our study was to explore: (1) prevalence of these disorders in patients with diabetic foot ulcers (DFU); (2) possible risk factors of depression and anxiety; (3) possible links between ulcer treatment results and depression/anxiety status. METHODS: 285 outpatients with diabetes and foot or leg ulcers were tested for depression and anxiety with self-report scales: CES-D and the anxiety subscale from HADS. Ulcer treatment results, incidence of new ulcers and number of hospital admissions were assessed after 1.5 years of follow-up. RESULTS: Depression was detected in 110 patients (39%), anxiety in 103 (36%). Females had depression and anxiety more often than males (48% and 46% vs. 27% and 25% respectively). A combined score based on diabetes duration, insulin treatment, history of myocardial infarction, history of foot ulcers and recent foot surgery was higher in patients with than without depression (3.0 vs. 2.0, p=0.02). Every of these or other potential risk factors alone was not associated with depression or anxiety. Patients with depression did not demonstrate poorer prognosis except higher mortality in subgroup of severely depressed patients without ulcer history. For anxiety we got similar results as its presence strongly correlated with depression. CONCLUSION: The overall prevalence of depression and anxiety in DFU patients is compatible with other diabetic populations. Various parameters of ulcer severity and duration did not influence the probability of depression and anxiety occurrence. Depression in general was not associated with poorer ulcer treatment results.

[Genetic Variability and Structure of SNP Haplotypes in the DMPK Gene in Yakuts and Other Ethnic Groups of Northern Eurasia in Relation to Myotonic Dystrophy].

The genetic variability of the DMPK locus has been studied in relation to six SNP markers (rs2070736, rs572634, rs1799894, rs527221, rs915915, and rs10415988) in Yakuts with myotonic dystrophy (MD) in the Yakut population and in populations of northern Eurasia. Significant differences were observed in the allele frequencies between patients and a population sample of Yakuts for three SNP loci (rs915915, rs1799894, and rs10415988) associated with a high chance of disease manifestation. The odds ratios (OR) of MD development in representatives of the Yakut population for these three loci were 2.59 (95% CI, p = 0,004), 4.99 (95% CI, p = 0.000), and 3.15 (95% CI, p = 0.01), respectively. Haplotype TTTCTC, which is associated with MD, and haplotype GTCCTT, which was observed only in Yakut MD patients (never in MD patients of non-Yakut origin), were revealed. A low level of variability in the locus of DMRK gene in Yakuts (H(e) = 0.283) compared with other examined populations was noted. An analysis of pairwise genetic relationships between populations revealed their significant differentiation for all the examined loci. In addition, a low level of differentiation in territorial groups of Yakut populations (F(ST) = 0.79%), which was related to the high subdivision of the northern Eurasian population (F(ST) = 11.83%), was observed.

[Length and structure of telomeric DNA in three species of Baikal gastropods (Caenogastropoda: Hydrobioidea: Benedictiidae)].

The structure of telomeric repeat (TTAGGG)n was determined and the length of telomeric DNA (tDNA) was measured in three species of gastropods from the family Benedictiidae that are endemic to Lake Baikal. Fluorescence in situ hybridization (FISH) confirmed the localization of a telomeric repeat at the chromosome ends. The sizes of tDNA in "giant" eurybathic, psammo-pelobiontic species Benedictia fragilis and shallow water litho-psammobiontic species B. baicalensis with medium shell sizes were similar (16 ± 2.9 and 15 ± 2.1 kb, respectively), but they had a greater length than that of the shallow water spongio-litobiontic species Kobeltocochlea martensiana with small shells (10.5 ± 1.5 kb). We discuss tendencies in age-related changes in tDNA length in snails and a possible mechanism for maintaining tDNA size in ontogeny.

[Monoamine-hormonal interactions in the pathogenesis of anxious depression]. / Monoamino-gormonal'nye sviazi v patogeneze trevozhnoi depressii.

Biochemical aspects of the relationship between monoaminergic and hormonal systems in the pathogenesis of anxious depression are analyzed on the basis of literature and own results published earlier. Significant alterations in biogenic monoamine metabolism and changes in the hormonal status, that reflects homeostasis disturbance in whole, are inherent to anxious depression. The biochemical mechanisms of imbalance between serotonergic and noradrenergic systems and a role of cortisol in this process are discussed.

Experience from a single paediatric transplant centre with identification of some protective and risk factors concerning the development of hepatic veno-occlusive disease in children after allogeneic hematopoietic stem cell transplant.

Hepatic veno-occlusive disease (VOD) is a frequent and severe complication of hematopoietic stem cell transplantation (HSCT) affecting 9.6-17.3 % of cases. 200 HSCT, performed between January 1995 and March 2013 in our Paediatric HSCT Centre in Trieste, were retrospectively analysed to evaluate the frequency of VOD and to identify the associated risk factors. The frequency of VOD according to the Seattle criteria was 17 %, within the range reported in literature. The mortality rate was 37.5 % (75 out of 200 transplantations) in the general population and 73.5 % (25 out of 34) in VOD patients (p < 0.05). Veno-occlusive disease significantly decreased from 38 % (1995-2000) to 8 % (2007-2013) p < 0.05. Univariate and multivariate analyses identified sepsis and pre-transplant ferritin levels above 1000 ng/ml as two significant risk factors for VOD, while the use of tacrolimus appeared to be associated with a lower VOD risk. Veno-occlusive disease still remains an important cause of transplant-related mortality even if it appears to have decreased over the last few years.

SIMIFF study: Italian fungal registry of mold infections in hematological and non-hematological patients.

PURPOSE: We compared the risk factors, the diagnostic tools and the outcome of filamentous fungal infections (FFIs) in hematological patients (HAEs) and non-hematological patients (non-HAEs). METHODS: Prospective surveillance (2009-2011) of proven and probable FFIs was implemented in 23 Italian hospitals. RESULTS: Out of 232 FFIs, 113 occurred in HAEs and 119 in non-HAEs. The most frequent infection was invasive aspergillosis (76.1 % for HAEs, 56.3 % for non-HAEs), and the localization was principally pulmonary (83.2 % for HAEs, 74.8 % for non-HAEs). Neutropenia was a risk factor for 89.4 % HAEs; the main underlying condition was corticosteroid treatment (52.9 %) for non-HAEs. The distribution of proven and probable FFIs was different in the two groups: proven FFIs occurred more frequently in non-HAEs, whereas probable FFIs were correlated with the HAEs. The sensitivity of the galactomannan assay was higher for HAEs than for non-HAEs (95.3 vs. 48.1 %). The overall mortality rate was 44.2 % among the HAEs and 35.3 % among the non-HAEs. The etiology influenced the patient outcomes: mucormycosis was associated with a high mortality rate (57.1 % for HAEs, 77.8 % for non-HAEs). CONCLUSIONS: The epidemiological and clinical data for FFIs were not identical in the HAEs and non-HAEs. The differences should be considered to improve the management of FFIs according to the patients' setting.

Changes in the retina in induced hypoestrogenia (according to optical coherent tomography data).

Ultrastructural changes in the retina under conditions of experimental hypoestrogenia were studied. Hypoestrogenic status was induced in female rabbits by extirpation of both uterine horns with appendages. Clinical status of the eyes was evaluated after 9 months by ophthalmoscopy and optical coherent tomography. Changes in the retinal layers under conditions of experimental estrogenia were detected: thickened retinal pigmented epithelium layer, a lesser layer of nerve fibrils, and thinning of the choriocapillary layer. A relationship between thinning of the choroid and thickening of the pigmented epithelium of the retina was detected.

[Depressive symptoms diagnosis and treatment of schizophrenia and schizophrenia spectrum disorders in Russian clinical practice].

A cohort study of depression in schizophrenia and schizophrenia spectrum disorders was conducted in four Russian regional mental health services with the use of simultaneous one-day census on October 20, 2011. The total number of patients in this study was 1269: 753 patients were receiving outpatient treatment, 143 patients were served in day clinics and 373 patients were in-patients in psychiatric hospitals. Depressive symptoms were present in 6.0% of outpatients, 50.3% of day clinic patients, and 36.5% of inpatients. The average duration of current depressive symptoms in weeks was 10.0, 8.1, 9.0, respectively. The periods of depressive symptoms during the last 2 years were revealed in 30.8% of outpatients, 67.8% of day clinic patients, and 42.1% of inpatients with the average duration of each such period in weeks 10.9, 12.2, 8.3, respectively. In outpatient settings, 28.8% of patients received antidepressants in addition to antipsychotic therapy. The proportion of inpatients receiving this treatment was 42.1%, and two thirds of patients received antidepressants in day clinics.

Haematopoietic SCT in autoimmune diseases in children: rationale and new perspectives.

The possible role of haematopoietic SCT (HSCT) for the treatment of severe autoimmune diseases was originally supported by animal experiments and remission of concomitant autoimmune diseases in patients undergoing transplantation for haematological disorders. Since 1996, over 100 procedures were performed in children with different severe autoimmune diseases such as juvenile idiopathic arthritis, systemic lupus erythematosus, systemic sclerosis, immune cytopaenias and Crohn's disease. This review tries to summarize the published data on efficacy and toxicity of HSCT in this group of patients.

Characteristics of albumin molecule binding centers in patients with anxious depression. Study by the fluorescence quenching method.

The state of binding centers in albumin molecule in patients with anxious depression was studied by the method of quenching of fluorescence of molecular probe (dimethyl-aminonaphthaleic acid carboxyphenylimide) with nitrate ions. Serum samples from 24 donors without somatic and mental diseases and 26 patients were analyzed. In the absence of the quenching agent, specific fluorescence of the probe (standardized by albumin concentration) was lower in patients with depression. The fluorescence quenching constant and the percentage of fluorescence available for quenching were also lower in serum samples from patients. These data indicate that the parameters of binding centers in albumin molecule in patients with anxious depression are significantly modified in comparison with normal subjects. The detected changes can play a role in the pathogenesis of depressive disorders.

Suppression of programmed cell death by intracellular cAMP is not mediated by expression of genes encoding an inhibitor of apoptosis.

The elevation of intracellular cAMP content is accompanied by expression of genes whose promoter contains a Ca(2+)-cAMP responsive element. In vascular smooth muscle cells (VSMC), activation of cAMP signaling blocks apoptosis triggered by serum deprivation. In the present study we investigated the role of gene expression in the inhibition of apoptosis by cAMP. In VSMC transfected with E1A adenovirus, incubation in the absence of serum for 6 h led to 20-fold elevation of chromatin fragmentation and 10-fold activation of caspase-3 activity, these being employed as markers of apoptosis. Forskolin-induced activation of cAMP signaling was accompanied by 50% elevation of RNA synthesis and completely abolished the development of apoptosis during the initial 6 h incubation in growth factor-free medium. In 12 h apoptosis in forskolin-treated VSMC was slowly developed and after 24 h the content of chromatin fragments was 2-fold less than in control cells. Addition of actinomycin D and cycloheximide completely blocked RNA synthesis and decreased protein synthesis by 80%, respectively. Neither compound affected baseline apoptosis or its inhibition by forskolin. More than 70 newly phosphorylated proteins were observed by 2D-electrophoresis of VSMC after incubation with forskolin for 3 h; in 24 h the number of phosphoproteins triggered by forskolin was decreased by 2-3-fold. These results show that suppression of VSMC apoptosis under activation of cAMP signaling is mediated via posttranslational modification of pre-existing intermediates of the apoptotic machinery rather than by de novo synthesis of inhibitors of programmed cell death.

Increased Na(+)/H(+) exchanger isoform 1 activity in spontaneously hypertensive rats: lack of mutations within the coding region of NHE1.

Enhanced Na(+)/H(+) exchange, measured as amiloride derivative-sensitive Na(+) and H(+) fluxes in cells with a preliminary acidified cytoplasm (Deltamu(H+)-induced Na(+)/H(+) exchange), is one of the most prominent intermediate phenotypes of altered vascular smooth muscle cell (VSMC) function in spontaneously hypertensive rats (SHR). Analysis of Na(+)/H(+) exchange in F(2) hybrids of SHR and normotensive rats seems to be the most appropriate approach in the search for the genetic determinants of abnormal activity of this carrier. However, the measurement of Deltamu(H+)-induced Na(+)/H(+) exchange is hardly appropriate for precise analysis of the carrier's activity in VSMC derived from several hundred F(2) hybrids. To overcome this problem, we compared the rate of (22)Na influx under baseline conditions and in Na(+)-loaded (ouabain-treated) VSMC. The dose-dependency of the rate of Deltamu(H+)-induced H(+) efflux as well as of (22)Na influx in control and ouabain-treated cells on ethylisopropylamiloride (EIPA) concentration were not different (K(0.5) approximately 0.3 microM), suggesting that these ion transport pathways are mediated by the same carrier. EIPA-sensitive (22)Na influx in Na(+)-loaded cells was approximately 6-fold higher than in ouabain-untreated VSMC and was increased by 50-70% in two different substrains of SHR. About the same increment of EIPA-sensitive (22)Na influx in Na(+)-loaded VSMC was observed in 5- to 6-week-old SHR (an age at which hypertension has not yet developed) as well as in stroke-prone SHR (SHRSP) with severe hypertension, indicating that the heightened activity of Na(+)/H(+) exchange is not a consequence of long-term blood pressure elevation. To examine whether or not the augmented activity of Na(+)/H(+) exchange in SHR is caused by mutation of NHE1, i.e. the only isoform of this carrier expressed in VSMC, we undertook single-stranded conformational polymorphism analysis of 23 NHE1 cDNA fragments from SHR and SHRSP and sequencing of the 456-2421 NHE1 cDNA fragment. This study did not reveal any mutation in the entire coding region of NHE1. The lack of mutation in the coding region of NHE1 indicates that the augmented activity of the ubiquitous Na(+)/H(+) exchanger in primary hypertension is caused by altered regulation of carrier turnover number or/and its plasma membrane content.

Haploidentical bone marrow transplantation in leukemia and genetic diseases.

From 1986 to June 2000, sixty children suffering from acute and chronic leukemia (n = 42, 33 of which in resistant relapse), genetic diseases (n = 11), aplastic anemia (n = 2, one of which with platelet refractoriness and bleeding), myelodysplasia (n = 5) received an haploidentical bone marrow, mismatched for 2-3 HLA loci. The donor's marrow was treated in vitro with vincristine and methylprednisolone to obtain a functional T depletion (MLC and CTL inhibition, functional blockade of Th1 and Th2). The prevalence of infectious complications and GVHD was similar to that recorded in matched unrelated donor (MUD) transplants. In situations of high risk of rejection (chronic leukemia, genetic diseases) we infused immediately one half of the harvest and then frozen aliquots from the second week. Of the 25 ALL and 8 AML in resistant relapse, 3 survived, disease-free at 14, 8 and 1 years respectively. Of the 3 ALL, transplanted during remission, 1 is surviving at 18 months. Of the 6 CML, 1 had fractionated bone marrow and is surviving at 3 years, and 5 had standard single dose infusion and died of progression of their disease after rejection of the graft (4) or blast crisis after complete engraftment (1). The 2 patients with aplastic anemia, those with myelodysplasia, and 6 of the 10 with genetic disorders died of transplant-related complications or disease progression. 4 patients with osteopetrosis (n = 2), MLD (n = 1), Wiskott Aldrich dis. (n = 1) survive at 8, 2, 5 and 1.5 years respectively. In patients transplanted with fractionated marrow GVHD > 2nd grade occurred in 15%. Only one patient rejected the graft. Compared with MUD transplantation, mismatched BMT whenever performed in patients in good conditions provides similar outcome and widens the donor availability.

Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the tolerability and effectiveness of a non-myeloablative conditioning regimen followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune diseases. DESIGN AND METHODS: From 1996 patients with severe autoimmune disease not responsive to conventional immunosuppressive treatment were selected. The patients' blood or marrow cells were harvested after incubation with vincristine and methylprednisolone. Two different immunoablative conditioning regimens were employed. The first used cyclophosphamide (2500 mg/m2 in one day) and antilymphocyte globulin (ALG) (15 vials/m2 in three days) and the second used fludarabine (300 mg/m2 in two courses of 5 days) plus ALG (25 vials/m2 in 5 days). RESULTS: Nineteen patients (14 female, 5 male) with severe autoimmune diseases were treated. Nine had a rheumatologic disorder (5 juvenile chronic arthritis, 1 rheumatoid arthritis, 1 systemic vasculitis, 1 Sjögren's syndrome, 1 Behçt's disease), 4 a neurologic disorder (3 multiple sclerosis, 1 myasthenia), 3 a haematologic disease (2 pure red cell aplasia, 1 autoimmune thrombocytopenia), 2 had a gastrointestinal disease (1 Crohn's disease, 1 autoimmune enteropathy) and 1 had a multiple autoimmune disorder. There was no regimen-related toxicity and no opportunistic infections occurred. Ninety percent of the patients improved and/or had a complete remission after the procedure. Fifty percent of the subjects went into complete or partial remission after a median follow-up of 15 months (range 3-25) while 50% relapsed after a median follow-up of 11 months, (range 6-16). The incidence of relapse in the group treated with fludarabine was lower (30%). INTERPRETATION AND CONCLUSIONS: A non-myeloablative conditioning regimen was able to induce persistent remission in some patients with severe autoimmune diseases. There was no mortality or morbidity related to the procedure. The extent of remission does, however, remain to be established.