Role of transbronchial needle aspiration in patients receiving mechanical ventilation

STUDY OBJECTIVE:s: To evaluate the diagnostic accuracy and safety of transbronchial needle aspiration (TBNA) in patients receiving mechanical ventilation in the ICU. METHODS: Retrospective review of all patients in the medical and surgical ICUs from February 1999 to July 2001 who underwent TBNA while receiving mechanical ventilation. RESULTS: A total of eight histology (19 gauge) and eight cytology (22 gauge) TBNAs were performed on eight patients (four men and four women). TBNA yielded a definitive pathologic diagnosis in five of eight patients (62.5%). Diagnoses were posttransplantation lymphoproliferative disorder, large cell carcinoma, poorly differentiated non-small cell carcinoma, squamous cell carcinoma, and adenocarcinoma. Among patients with negative TBNA results (n = 3), two patients underwent mediastinoscopy. Results of mediastinoscopy were non-small cell carcinoma and inflamed tissue. TBNA led to management changes in five of these patients. Excluding one patient in whom a negative TBNA result could not be further confirmed, TBNA yielded a sensitivity of 83%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 50%. The overall accuracy of the procedure was 75%. There were no complications following any of the TBNAs. CONCLUSIONS: In this small group of patients, TBNA was safe and had a high diagnostic accuracy in selected patients receiving mechanical ventilation in the ICU.     

Primary pulmonary hypertension: an overview of epidemiology and pathogenesis

Pulmonary arterial hypertension (PAH) refers to a group of diseases characterized by high pulmonary artery pressure of unknown mechanism. Primary pulmonary hypertension (PPH) is the idiopathic subset of PAH that affects a mostly young population and is more common in females than in males. A familial form of PPH accounts for about 6% of cases, and its autosomal dominant gene was recently identified. Pulmonary arterial hypertension is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ. The pathogenesis of PAH remains unclear. Elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. Nitric oxide, a locally produced selective pulmonary vasodilator, appears to play a central role in the pathobiology of PAH.     

Helicobacter pylori and autoimmune diseases

It is now widely accepted that Helicobacter pylori may play a role in several extra-gastric diseases. In particular, H. pylori infection seems to be implicated in various autoimmune diseases. Many recent studies have shown a healing or an improvement in different autoimmune disorders after H. pylori eradication therapy in infected patients. The exact mechanisms behind this relationship remain under discussion, but molecular mimicry is a consistent hypothesis. This subject is particularly relevant taking into consideration the high prevalence of H. pylori infection, the existence of inexpensive and noninvasive diagnostic methods, as the urea breath test or the stool antigen test, and the low cost and toxicity of eradication treatment. If this connection becomes confirmed, it can change the diagnostic and therapeutic approach of some autoimmune diseases.     

Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms

Programmed death-1 receptor (PD-1) is expressed on T cells following TCR activation. Binding of this receptor to its cognate ligands, programmed death ligand (PDL)-1 and PDL-2, down-regulates signals by the TCR, promoting T-cell anergy and apoptosis, thus leading to immune suppression. Here, we find that using an anti-PD-1 antibody (CT-011) with Treg-cell depletion by low-dose cyclophosphamide (CPM), combined with a tumor vaccine, induces synergistic antigen-specific immune responses and reveals novel activities of each agent in this combination. This strategy led to complete regression of established tumors in a significant percentage of treated animals, with survival prolongation. We show for the first time that combining CT-011 and CPM significantly increases the number of vaccine-induced tumor-infiltrating CD8(+) T cells, with simultaneous decrease in infiltrating Treg cells. Interestingly, we find that CT-011 prolongs Treg-cell inhibition induced by CPM, leading to a sustainable significant synergistic decrease of splenic and tumor-infiltrated Treg cells. Surprisingly, we find that the anti-tumor effect elicited by the combination of CT-011 and CPM is dependent on both CD8(+) and CD4(+) T-cell responses, although the antigen we used is a class I MHC-restricted peptide. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms.     

Rehabilitation of orthopedic patients after hip replacement

A comparative analysis of the treatment of 120 patients after endoprosthesis for degenerative-destructive diseases of the hip joint was carried on. All the patients were divided into two groups: the main group included 74 patients who underwent a full course of rehabilitation, the control group consisted of 46 patients without rehabilitation. The results of a comparative assessment of the static-dynamic function in the two groups of patients after operation of endoprosthesis have shown the inclusion of an obligatory program of rehabilitation to be expedient for the restorative treatment in addition to the operation of endoprosthesis.     

Analogs of methyllycaconitine as novel noncompetitive inhibitors of nicotinic receptors: pharmacological characterization, computational modeling, and pharmacophore development

As a novel approach to drug discovery involving neuronal nicotinic acetylcholine receptors (nAChRs), our laboratory targeted nonagonist binding sites (i.e., noncompetitive binding sites, negative allosteric binding sites) located on nAChRs. Cultured bovine adrenal cells were used as neuronal models to investigate interactions of 67 analogs of methyllycaconitine (MLA) on native alpha3beta4* nAChRs. The availability of large numbers of structurally related molecules presents a unique opportunity for the development of pharmacophore models for noncompetitive binding sites. Our MLA analogs inhibited nicotine-mediated functional activation of both native and recombinant alpha3beta4* nAChRs with a wide range of IC(50) values (0.9-115 microM). These analogs had little or no inhibitory effects on agonist binding to native or recombinant nAChRs, supporting noncompetitive inhibitory activity. Based on these data, two highly predictive 3D quantitative structure-activity relationship (comparative molecular field analysis and comparative molecular similarity index analysis) models were generated. These computational models were successfully validated and provided insights into the molecular interactions of MLA analogs with nAChRs. In addition, a pharmacophore model was constructed to analyze and visualize the binding requirements to the analog binding site. The pharmacophore model was subsequently applied to search structurally diverse molecular databases to prospectively identify novel inhibitors. The rapid identification of eight molecules from database mining and our successful demonstration of in vitro inhibitory activity support the utility of these computational models as novel tools for the efficient retrieval of inhibitors. These results demonstrate the effectiveness of computational modeling and pharmacophore development, which may lead to the identification of new therapeutic drugs that target novel sites on nAChRs.     

Differential detection of Entamoeba histolytica, Entamoeba dispar and Entamoeba moshkovskii in fecal samples by nested PCR in the United Arab Emirates (UAE)

Amoebiasis is one of the most important infectious diseases afflicting mainly tropical and subtropical countries. This study was carried out in the Sharjah Emirate, UAE in order to accurately detect and differentiate Entamoeba histolytica, Entamoeba dispar and E. moshkovskii in fecal samples collected from the Sharjah municipality public health clinic by ELISA and nested polymerase chain reaction (PCR). One hundred and twenty specimens were examined and the PCR was positive for E. histolytica, E. dispar and E. moshkovskii (collectively referred to as Entamoeba complex) in 19.2% (23 out of 120). Of those, 10% (12/120) were mono — infection with E. histolytica; 2.5% (3/120) with E. dispar; and 2.5% (3/120) E. moshkovskii. The nested PCR also detected mixed infections by both E. histolytica and E. dispar in 3.3% (4/120) and E. dispar and E. moshkovskii in 0.8% (1/120). The TechLab ELISA kit failed to detect E. histolytica in any of the E. histolytica PCR positive samples. Overall, the percentage of E. histolytica including those found in mixed infections was 13.3% (16/120). Compared to nested PCR, microscopy was found to have an overall sensitivity of 52.2% and a specificity of 75.2% for detection of Entamoeba complex. The present study indicates that E. histolytica is present in the UAE with an average incidence rate of 13.3%. However, larger studies need to be conducted in order to confirm these findings. We propose the use of PCR in both the routine diagnosis of amoebiasis and epidemiological survey in the UAE.