[Interventionnal bronchoscopy for the treatment of tracheobronchomalacia]. / Place de la bronchoscopie interventionnelle dans la prise en charge des trachéobronchomalacies.

Tracheobronchomalacia is usually characterized by more than 50% expiratory narrowing in diameter of the trachea and the bronchi. The expiratory collapse includes two entities: (1) the TBM related to the weakness of the cartilaginous rings, and (2) the Excessive Dynamic Airway Collapse (EDAC) due to the excessive bulging of the posterior membrane. Patients have nonspecific respiratory symptoms like dyspnea and cough. Diagnosis is confirmed by dynamic tests: flexible bronchoscopy and/or computed tomographic scan of the chest. There are different forms of tracheobronchomalacia in adults: primary (genetic, idiopathic) or secondary to trauma, tracheotomy, intubation, surgery, transplantation, emphysema, infection, inflammation, chronic bronchitis, extrinsic compression; or undiagnosed in childhood vascular rings. Some management algorithms have been proposed, but no specific recommendation was established. Only symptomatic patients should be treated. Medical treatments and noninvasive positive pressure ventilation should be the first line therapy, after evaluation of various quality measures (functional status, performance status, dyspnea and quality of life scores). If symptoms persist, therapeutic bronchoscopy permits: (1) patient's selection by stent trial to determine whether patient benefit for surgical airway stabilization; (2) malacic airways stenting in patients who are not surgical candidates, improving QOL despite a high complication rate; (3) the management of stent-related complication (obstruction, plugging, migration granuloma); (4) alternative therapeutics like thermo-ablative solution. Lasty, the development of new types of stents would reduce the complication rates. These different options remained discussed.

A regime switch analysis on Covid-19 in Romania.

In this paper we propose a three stages analysis of the evolution of Covid19 in Romania. There are two main issues when it comes to pandemic prediction. The first one is the fact that the numbers reported of infected and recovered are unreliable, however the number of deaths is more accurate. The second issue is that there were many factors which affected the evolution of the pandemic. In this paper we propose an analysis in three stages. The first stage is based on the classical SIR model which we do using a neural network. This provides a first set of daily parameters. In the second stage we propose a refinement of the SIR model in which we separate the deceased into a distinct category. By using the first estimate and a grid search, we give a daily estimation of the parameters. The third stage is used to define a notion of turning points (local extremes) for the parameters. We call a regime the time between these points. We outline a general way based on time varying parameters of SIRD to make predictions.

Smart Supra- and Macro-Molecular Tools for Biomedical Applications.

Stimuli-responsive, "smart" polymeric materials used in the biomedical field function in a bio-mimicking manner by providing a non-linear response to triggers coming from a physiological microenvironment or other external source. They are built based on various chemical, physical, and biological tools that enable pH and/or temperature-stimulated changes in structural or physicochemical attributes, like shape, volume, solubility, supramolecular arrangement, and others. This review touches on some particular developments on the topic of stimuli-sensitive molecular tools for biomedical applications. Design and mechanistic details are provided concerning the smart synthetic instruments that are employed to prepare supra- and macro-molecular architectures with specific responses to external stimuli. Five major themes are approached: (i) temperature- and pH-responsive systems for controlled drug delivery; (ii) glycodynameric hydrogels for drug delivery; (iii) polymeric non-viral vectors for gene delivery; (iv) metallic nanoconjugates for biomedical applications; and, (v) smart organic tools for biomedical imaging.

Biocompatibility of Polyimides: A Mini-Review.

Polyimides (PIs) represent a benchmark for high-performance polymers on the basis of a remarkable collection of valuable traits and accessible production pathways and therefore have incited serious attention from the ever-demanding medical field. Their characteristics make them suitable for service in hostile environments and purification or sterilization by robust methods, as requested by most biomedical applications. Even if PIs are generally regarded as "biocompatible", proper analysis and understanding of their biocompatibility and safe use in biological systems deeply needed. This mini-review is designed to encompass some of the most robust available research on the biocompatibility of various commercial or noncommercial PIs and to comprehend their potential in the biomedical area. Therefore, it considers (i) the newest concepts in the field, (ii) the chemical, (iii) physical, or (iv) manufacturing elements of PIs that could affect the subsequent biocompatibility, and, last but not least, (v) in vitro and in vivo biocompatibility assessment and (vi) reachable clinical trials involving defined polyimide structures. The main conclusion is that various PIs have the capacity to accommodate in vivo conditions in which they are able to function for a long time and can be judiciously certified as biocompatible.

Modeling the development of the post-natal mouse thymus in the absence of bone marrow progenitors.

Many mathematical models have been published with the purpose of explaining aspects of T-cell development in the thymus. In this manuscript we adapted a four-compartment model of the thymus and used a range of mathematical approaches with the aim of explaining the dynamics of the four main thymocyte populations in the mouse thymus, from the emergence of the first fetal thymocyte until the death of the animal. At various pre-natal and post-natal stages we investigated experimentally the number and composition of thymocytes populations, their apoptosis and proliferation, along with data from literature, to create and validate the model. In our model the proliferation processes are characterized by decreasing proliferation rates, which allows us to model the natural involution of the thymus. The best results were obtained when different sets of parameters were used for the fetal and post-natal periods, suggesting that birth may induce a discontinuity in the modeled processes. Our model is able to model the development of both pre-natal and post-natal thymocyte populations. Also, our findings showed that the post-natal thymus is able to develop in the absence of the daily input of bone marrow progenitors, providing more evidence to support the autonomous development of the post-natal thymus.

[A case of mediastinum actinomycosis by Aggregatibacter actinomycetemcomitans]. / Un cas d'actinomycose médiastinale à Aggregatibacter actinomycetemcomitans.

The actinomycosis is a suppurative infection due to an anaerobic and microaerophillic bacteria called actinomyces. Only few case reports are described for the mediastinal locations of this rare entity. We report a new case of inflammatory pseudotumor in the mediastinum due to Aggregatibacte actinomycetemcomitans revealed by hemoptysis. The mediastinoscopy procedure with biopsy was needed to confirm the definitive bacteriological diagnosis by a positive culture. During the postoperative course, a cutaneous fistula was found which had a favourable evolution after appropriate antibiotherapy. Through this case report, the authors insist upon the importance of considering the diagnosis of mediastinal actinomycosis when facing non-specfic mediastinal mass symptoms and also about the interest of systematic bacterioscopic examination and histopathologic examination on nodes' biopsies to avoid to be lost on pathology of mediastinal tumor or tuberculosis. In practise, we caution the non-expert during biopsies because of this lesion's invasive characteristic especially in the confined space of the mediastinum.

Drain tip cultures do not predict infections in primary total knee arthroplasty.

BACKGROUND AND AIM: The possibility to predict surgical site infections development could be of high prognostic value. We aimed to investigate whether cultures obtained from the tip of the closed passive wound drain may provide early signs of progression towards periprosthetic joint infections. MATERIALS AND METHODS: We performed an observational study on consecutive primary total knee arthroplasties performed in our department over 4 years by two high volume surgeons (it means they do a lot of arthroplasties/year; it is orthopedics specific). A total of 284 knees in 257 patients were included. Follow up was available for an average of 18.7 months. There were no simultaneous procedures. RESULTS: Nineteen (6.69%) drain tips yielded positive cultures, for a mean duration, from surgery to sample collection, of 1.63 (0.5) days. None of the positive drain tip cultures developed clinical signs of infection and all knees were healed at discharge after a mean of 13.78 days (SD= 3.34; range= 8-18). None of the 7 (2.46%) cases who developed deep infections had positive drain tip cultures. A true positive value of 0 led to a positive predictive value of 0, a negative predictive value of 97.34%, sensitivity of 0% and specificity of 93.14. CONCLUSIONS: The diagnostic use of passive drain tip cultures to detect early infections after total knee replacement is therefore absolutely useless.

Right ventricular septal pacing- clinical and electrical predictors for LV contraction asynchrony.

PURPOSE: Prolonged pacing from the right ventricular apex (RV) is associated with the LV dyssynchrony leading to progressive left ventricular dysfunction and increased morbidity and mortality. Alternate RV pacing sites-in particular the mid- RV septum and the RV outflow tract (RVOT) septum were considered, but no clear benefit was proven till now for this pacing sites. This may be due to the heterogeneity of the RV septal positions and to the significant number of leads placed on the RV free wall. The aim of this study is to find a reliable method of septal lead placement and to identify those pacing sites which provide better LV electrical activation Methods: 50 consecutive patients referred for pacemaker implants due to AV block were included. Patients with history of heart failure or LVEF < 50% at the implant were excluded. All patients had RV leads placed in septal position. This was achieved with a double curved stilet with the distal curve aimed posteriorly. RV septum and RVOT were mapped during implant aiming for a narrow paced QRS with an axis as close to normal as possible. Pacing lead position was evaluated during the implant using fluoroscopy (AP and LAO 40 °) and than by 12 lead ECG and echo. IntraLV dyssynchrony was evaluated during pacing using SPWMD in short axis parasternal view and the TDI septal to lateral ∆ t. Paced QRS duration and axis were also recorded. The correlation was sought between lead position evaluated by Rx and by echo and between paced QRS duration and axis and LV dyssynchrony. RESULTS: 92%(46) of the patients had the lead in septal position RV (32 in the mid-septal RV and 14 in RVOT), while 8% (4 pts) had the lead on the RVOT RV free wall as shown by echo. An anterior-oriented lead in the left anterior oblique fluoroscopic projection was specific for free wall position while positive QRS in DI in RVOT position was suggestive for free wall position on the ECG. No correlation was made between paced QRS axis and LV dyssynchrony while the QRS duration of > 160 ms was associated with significant LV dyssynchrony (SPWMD > 130 ms and to lateral septal ∆ t > 70 ms). CONCLUSIONS: RV lead placement on the RV septum can be reliably achieved using a specially curved stilet and the LAO projection for confirmation. The wide paced QRS is correlated with significant intra LV dyssynchrony and therefore the RV pacing site with the narrowest QRS should be sought.

[Obstructive jaundice by genodermatosis--case report]. / Icter obstructiv prin genodermatoza--caz clinic.

BACKGROUND: Neurofibromatosis type I, or Recklinnghausen disease, is the most frequently occurring neurofibromatosis, in 1/3000-11,5000 of children born. This disease is a genodermatosis with 1/3000-1/5000 autosomal dominant transmission. Incriminated in the pathological appearance of the disease gene is located on chromosome 17, gene product, neurofibromina, is a protein involved in controlling cell differentiation and proliferation. Skin manifestations can be associated with the same papillary tumors and the internal organ. Treatment is surgery for larger tumors. Worse prognosis in malignant developpment, with the lower quality of life in the presence of complications, as in this case: mechanical obstructive jaundice. MATERIAL AND METHOD: Patients aged 75 years, admitted for obstructive jaundice (progressive, pruritic), cutaneous papillomas (0.5-3 cm) on the trunk and several hyperpigmented brown spots (5-6 cm diameter). Cutaneous lesions (45 years old) have been previously diagnosed by histological examination. RESULTS: We did surgery under general anesthesia: cholecystectomy, intraoperative choledocoscopy of bile duct. In the last portion of bile duct we found pedicled tumors. We did partial excision of tumors and coledoco-duodenoanastomosis in healthy tissue. Histological examination showed neurofibrodermatoza type I. Discharge 12 days postoperatively. CONCLUSIONS: Preoperative diagnosis suggested the possibility of mechanical jaundice by malignancy. Etiologic diagnosis of this rare form of obstructive jaundice could not be established before surgery, only by histological examination of the excised tumors.

[Surgical lung biopsy: Indications and therapeutic implications]. / Biopsie pulmonaire chirurgicale : indications et incidences thérapeutiques.

Surgical biopsy of lung parenchyma can be used to establish a diagnosis in interstitial lung disease both of acute and chronic presentation. The present article summarizes the current indications, the therapeutic implications, the different surgical techniques and postoperative complications of the procedure. Common controversies and problems related to surgical lung biopsy are also presented.

[Advances in tracheal surgery: are we close to finding the ideal tracheal substitute?]. / Avancées en chirurgie trachéale : a-t-on enfin trouvé le substitut idéal à la trachée ?

Tracheal surgery has evolved progressively with advances in anaesthesia, the understanding of tracheal pathology and the efforts made by surgeons all over the world. In the era of organ transplantation, tracheal replacement remains an unsolved problem and one of the most important challenges in thoracic surgery. In animals, the use of a stent supported aortic graft as a tracheal substitute led to unexpected tissue regeneration in the form of a functional "neo-trachea" with respiratory epithelium and cartilage. These results led to the first clinical applications in France in patients with extensive, incurable, malignant tracheal tumors. Experimental and clinical research programs have to be increased in order, firstly to provide a standardized surgical technique for complex tracheal lesions and secondly to understand better the mechanisms of tracheal regeneration.

Role of local production of endothelium-derived nitric oxide on cGMP signaling and S-nitrosylation.

Nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), exerts control over vascular function via two distinct mechanisms, the activation of soluble guanylate cyclase (sGC)/cGMP-dependent signaling or through S-nitrosylation of proteins with reactive thiols (S-nitrosylation). Previous studies in cultured endothelial cells revealed that eNOS targeted to the plasma membrane (PM) releases greater amounts of NO compared with Golgi tethered eNOS. However, the significance of eNOS localization to sGC-dependent or -independent signaling is not known. Here we show that PM-targeted eNOS, when expressed in human aortic endothelial cells (HAEC) and isolated blood vessels, increases sGC/cGMP signaling to a greater extent than Golgi-localized eNOS. The ability of local NO production to influence sGC-independent mechanisms was also tested by monitoring the secretion of Von Willebrand factor (vWF), which is tonically inhibited by the S-nitrosylation of N-ethylmaleimide sensitive factor (NSF). In eNOS "knockdown" HAECs, vWF secretion was attenuated to a greater degree by PM eNOS compared with a Golgi-restricted eNOS. Moreover, the PM-targeted eNOS induced greater S-nitrosylation of NSF vs. Golgi eNOS. To distinguish between the amount of NO generated and the intracellular location of synthesis, we expressed Golgi and PM-targeted calcium-insensitive forms of eNOS in HAEC. These constructs, which generate equal amounts of NO regardless of location, produced equivalent increases in cGMP in bioassays and equal inhibition of vWF secretion. We conclude that the greater functional effects of PM eNOS are due to the increased amount of NO produced rather than effects derived from the local synthesis of NO.

A new model calculation of the peak efficiency for HPGe detectors used in assays of radioactive waste drums.

In this paper we present a new semi-empirical model calculation of the peak efficiency for unshielded HPGe detectors based on the virtual point detector and the attenuation factor concepts. The validity of the model calculation was checked by comparison with Monte Carlo efficiency values and experimental efficiencies determined for a HPGe detector type GEM 25P4 using a calibration drum. The discrepancy between experimental and calculated efficiencies is smaller than 10% in the energy range 122-1408 keV.

The novel arthritis-drug substance MCS-18 attenuates the antibody production in vivo.

UNLABELLED: Influence of the novel arthritis drug-substance MCS-18 on the antibody (Ab) production against tetanus toxoid (TT) and diphtheria toxoid (DT) antigens was tested in vivo. Possible involvement of MCS-18 in Toll-like receptor (TLR) signalling pathway was further considered. MATERIALS AND METHODS: Immunization of male CD1 mice was done with subcutaneous injection of TT emulsified in Freund's Complete (FCA) or Incomplete Adjuvant (FIA) and mixed diversly with MCS-18 and different test substances. To investigate the influence of TLR activation Pam3Cys and lipopolysaccharide (LPS) emulsified in FIA were tested in combinations with MCS-18. Antibody production was analysed in vivo by tetanus- or diphtheria-toxin neutralization test. RESULTS: Immunogenicity of TT was significantly enhanced if administered together with FCA or TLR agonists Pam3Cys or LPS emulsified in FIA. It was shown that MCS-18 attenuated strongly the production of anti-TT Ab if administered together with the Ab elicitor FCA or TLR agonists in various combinations. MCS-18 was also active via oral administration. DISCUSSION: These findings suggest that MCS-18 could be a potent, non-toxic antagonist or a down-regulator of TLR signalling pathway. Investigations on further models are needed to establish ifMCS-18 may influence particularly the production of RA-specific auto-antibodies, too.

Peripheral circadian clock rhythmicity is retained in the absence of adrenergic signaling.

OBJECTIVE: The incidence of heart attack and stroke undergo diurnal variation. Molecular clocks have been described in the heart and the vasculature; however it is largely unknown how the suprachiasmatic nucleus (SCN) entrains these peripheral oscillators. METHODS AND RESULTS: Norepinephrine and epinephrine, added to aortic smooth muscle cells (ASMCs) in vitro, altered Per1, E4bp4, and dbp expression and altered the observed oscillations in clock gene expression. However, oscillations of Per1, E4bp4, dbp, and Per2 were preserved ex vivo in the aorta, heart, and liver harvested from dopamine beta-hydroxylase knockout mice (Dbh-/-) that cannot synthesize either norepinephrine or epinephrine. Furthermore, clock gene oscillations in heart, liver, and white adipose tissue phase shifted identically in Dbh-/- mice and in Dbh+/- controls in response to daytime restriction of feeding. Oscillation of clock genes was similarly preserved ex vivo in tissues from Dbh+/- and Dbh-/- chronically treated with both propranolol and terazosin, thus excluding compensation by dopamine in Dbh-/- mice. CONCLUSIONS: Although adrenergic signaling can influence circadian timing in vitro, peripheral circadian rhythmicity is retained despite its ablation in vivo.

Pancreatic beta cell allotransplant in double transgenic mouse model of type 1 diabetes mellitus.

The purpose of this study was to evaluate the therapeutic response to intra-hepatic and intra-portal allotransplant with pancreatic beta cells in double transgenic mice (dTg) with autoimmune diabetes. The results showed an improvement in metabolic and somatic parameters and an increase in survival rate. Histopathology analysis revealed the presence of transplanted islets and the absence of the inflammatory infiltrate 5 days after the procedure and an increase in insulinemia. In the absence of immunosuppressive drugs, rejection of the transplanted islet seems to appear after 10 weeks, being marked by an increase in blood glucose level. A re-transplantation was performed in one mouse of each group and the glycemia levels recorded after the second transplant were less successful.

Molecular analysis of the first avian influenza H5N1 isolates from fowl in Romania.

Since the events of avian influenza (AI) caused by H5N1 subtype from Hong Kong (1997), the people worldwide have been confronted with new waves of epizootic influenza. In 2005 in Romania an unprecedent H5N1 epizootic occurred in domestic and wild birds. Therefore an immediate investigation by molecular approach of this highly pathogenic H5N1 strain was necessary. The virus isolation and the RNA extraction were performed in the Institute of Diagnosis and Animal Health while PCR and sequencing were carried out in Cantacuzino Institute. Herein we report the first evidence of H5N1 presence in Romanian fowls. The phylogenetic analysis of haemagglutinin and neuraminidase gene indicated a close relationship of Romanian strains to those from Siberia and China. The virological and molecular analysis of the first strains of avian virus from Romania confirmed the presence of H5N1 subtype, belonging to the genetic line Z. These results indicate that the avian virus from this genetic line is directly derived from the highly pathogenic viruses isolated in China and Russia in 2005.

COX-2 inhibitors can down-regulate in vivo antibody response against T-dependent antigens.

There are many studies demonstrating by different experimental models that non-steroidal antiinflammatory drugs (NSAIDs), also known as cyclooxygenase-2 (COX-2) inhibitors, can modulate immune response such as lymphoid cells differentiation and proliferation. There are experimental data which show that activated B cells can express mRNA COX-2, release prostaglandins (PGs) and produce immunoglobulins in PGs dependent manner. In this study, using different COX-2 inhibitors and applying personalized immunization scheme, we confirmed that it is possible to modulate in vivo antibody response against T cell dependent antigens, substantiating the importance of PGE2 and E prostanoid receptor (EP-R) in antibody generation. Our results point out the fact that we must be more careful when we apply vaccines containing T-cell dependent antigens, such as tetanus or diphteric anatoxin, to the patients under an intense antiinflammatory treatment.

Microbiological and immunological study of staphylococcus vaccine effects in periodontitis.

The aim of this study was to evaluate the immunomodulatory effect of the staphylococcal vaccine inoculated subcutaneously in 15 patients with chronic periodontitis. Bacteriological investigation of samples collected from the periodontal pocket for aerobic and anaerobic microorganisms was performed by classic bacteriological procedures before and after vaccination. The following immune system parameters were evaluated: C reactive protein (CRP), serum level of C3 complement fraction, IgG, IgA, and IgM by immunodiffusion, PMN granulocytes ROS release after in vitro stimulation with opsonized zymosan (OZ) and Concanavalin A (ConA) by chemiluminescence assay and lymphocytes sets and subsets by flow-cytometry immunophenotyping. The microbiological investigations revealed high frequency of Staphylococcus spp isolation and the presence of the most common anaerobe agents incriminated in human periodontitis like Fusobacterium, Porphyromonas, Peptostreptococcus, Veillonella spp and the reduction of this flora in the periodontal pocket after therapy. The immunological parameters quantification showed the absence of CRP, normal values of C3, IgG, IgA, IgM in the majority of cases. All patients presented normal values of lymphocytes sets and subsets. Significant increase of PMN respiratory burst after ConA stimulation was observed before vaccination which turned to normal values after therapy and a low ROS level both before and after therapy suggesting PMN Fc receptors dysfunction in this group of patients. The data presented in our study suggest an immunomodulatory effect of staphylococcal vaccine therapy in periodontitis and high frequency of Staphylococcus spp recovering from the periodontal pocket of investigated subjects.

Double transgenic mice with type 1 diabetes mellitus develop somatic, metabolic and vascular disorders.

The double transgenic mice (dTg) were obtained by mating: (i) transgenic mice expressing the hemagglutinin of influenza virus under the insulin promoter with (ii) transgenic mice expressing specific T lymphocytes with receptor for the immunodominant epitope of the same virus. In this study we show that dTg mice developed type 1 diabetes mellitus associated with hyperglycemia, low level of plasma insulin, glucosuria, weight loss and approximately 90% mortality (at 3 months biological age). The membrane of red blood cells was more sensitive to osmotic shock in diabetic mice, compared to non-diabetic mice, assessing systemic oxidative stress. Both vasoconstriction and vasorelaxation of the renal arteries decreased significantly in diabetic mice (compared to the control group of non-diabetic mice) related to the phenotypic change of endothelium and smooth muscle cells within the artery wall. This animal model, may be used in developing various strategies to study pancreatic beta-cell function, as well as for a better metabolic control conducting to a reduced risk of vascular complications.