Antimicrobial technology in orthopedic and spinal implants

Infections can hinder orthopedic implant function and retention.Current implant-based antimicrobial strategies largely utilize coating-based approaches in order to reduce biofilm formation and bacterial adhesion.Several emerging antimicrobial technologies that integrate a multidisciplinary combination of drug delivery systems,material science,immunology,and polymer chemistry are in development and early clinical use.This review outlines orthopedic implant antimicrobial technology,its current applications and supporting evidence,and clinically promising future directions.     

Dysfunction of the vocal cords simulating exercise-induced asthma

Vocal cord dysfunction is a respiratory condition characterized by anomalous adduction of the vocal cords during inspiration, causing significant air flow limitation in the larynx. Few such cases have been described in which dysfunction is triggered by exercise. We report the case of a young women with severe dyspnea appearing as a result of physical activity. We first deal with issues of differential diagnosis in relation to several other diseases, particularly exercise-induced asthma and then discuss therapeutic approaches.     

Impact of a standardized patient simulation on undergraduate nursing student knowledge and perceived competency of the care of a patient diagnosed with schizophrenia

Background

Undergraduate nursing students may not have the opportunity to assess and intervene with a patient diagnosed with schizophrenia during their clinical rotation. Provision of a standardized patient simulation experience affords students this opportunity in a safe setting without risk to the patient or student.

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single‐dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end‐stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre‐ and post‐dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.     

PTEN regulates natural killer cell trafficking in vivo

Phosphatase and tensin homolog (PTEN) is a critical negative regulator of the phosphoinositide-3 kinase pathway, members of which play integral roles in natural killer (NK) cell development and function. However, the functions of PTEN in NK cell biology remain unknown. Here, we used an NK cell-specific PTEN-deletion mouse model to define the ramifications of intrinsic NK cell PTEN loss in vivo. In these mice, there was a significant defect in NK cell numbers in the bone marrow and peripheral organs despite increased proliferation and intact peripheral NK cell maturation. Unexpectedly, we observed a significant expansion of peripheral blood NK cells and the premature egress of NK cells from the bone marrow. The altered trafficking of NK cells from peripheral organs into the blood was due to selective hyperresponsiveness to the blood localizing chemokine S1P. To address the importance of this trafficking defect to NK cell immune responses, we investigated the ability of PTEN-deficient NK cells to traffic to a site of tumor challenge. PTEN-deficient NK cells were defective at migrating to distal tumor sites but were more effective at clearing tumors actively introduced into the peripheral blood. Collectively, these data identify PTEN as an essential regulator of NK cell localization in vivo during both homeostasis and malignancy.Natural killer (NK) cells are innate lymphoid cells critical for host defense against pathogens and antitumor responses (1–3). In the naïve mouse, NK cells are distributed among a number of hematopoietic and nonhematopoietic organs, including major reservoirs within the spleen, blood, and bone marrow (BM). Factors that orchestrate NK cell trafficking during homeostasis, including chemokine receptors and adhesion molecules, remain largely unknown. The majority of studies have focused on receptors controlling NK cell migration out of the BM, such as CXCR4 and S1P₅ (4–6). During inflammatory states, other receptors have defined roles for specific tissue homing, including CCR1, CCR5, CXCR3, CX3CR1, and CXCR6 (7). Integrin molecules, such as very late antigen-4 (VLA-4), also have specific functions in retaining NK cells within BM sinusoids (8). However, the downstream intracellular signaling pathways important for trafficking remain unclear, especially in light of the complex interplay of multiple chemotactic signals during an immune response.One family of enzymes regulating a number of chemokine receptors includes the phosphoinositide 3-kinase (PI3K) signaling pathway, which plays a broad role in regulating cellular proliferation, gene expression, survival, cytoskeleton rearrangement, and migration (9). In immune cells, the PI3K pathway may be activated downstream of a number of receptors, including cytokine receptors and G protein-coupled receptors (GPCRs), the latter of which include most chemokine receptors. Stimulation of the PI3Ks results in the generation of phosphatidylinositol phosphate lipids, such as PI(3,4,5)P₃, and subsequent recruitment and activation of downstream signaling proteins, including Vav, Akt, and PDK1 (9, 10). Exogenous inhibition of PI3Ks suppresses perforin and granzyme B polarization and NK cell cytotoxicity (11). Additionally, deficiency of the leukocyte-selective PI3K p110γ or p110δ subunit results in defective NK cell development and maturation and alters the production of IFN gamma (IFN-γ) and cytotoxicity (12–14). New evidence has also linked IL-15 to the mammalian target of rapamycin (mTOR) pathway via PI3K activation (15, 16). Thus, PI3K signaling is a critical pathway for NK cell biological processes.Two primary phosphatases oppose PI3K generation of the active secondary messenger PI(3,4,5)P₃: SH2-containing inositol-5′-phosphatase 1 (SHIP1) and phosphatase and tensin homolog (PTEN). SHIP1 specifically dephosphorylates PI(3,4,5)P₃ to PI(3,4)P₂, whereas PTEN dephosphorylates the 3′ inositol phosphate on PI(3,4,5)P₃, PI(3,4)P₂, and PI(3)P, thereby also counteracting other classes of PI3Ks (10). SHIP1^−/− BM-chimeric mice have no overt alterations in NK cell distribution, and its intrinsic role in NK cell development only affects the terminal differentiation of mature NK cells (17). However, there are no reported studies of PTEN function in NK cells to date. The effects of lymphocyte-selective PTEN deficiency in T and B cells result from increased PI3K signaling and include increased cell survival and proliferation, lowered activation threshold through the B-cell receptor (18), and loss of costimulatory requirements in T cells (19). The role of phosphatases, particularly SHIP1 and PTEN, in cellular migration, however, remains controversial and appears to be dependent on both the cell studied and the mode of stimulation (20–22). Furthermore, unique aspects of PTEN function have been reported, including protein phosphatase activity (23) and regulation via intracellular sequestration to the cytoplasmic membrane (24). As PTEN is a major nonredundant regulator of PI3K signaling, we hypothesized that disruption of PI3K inhibition would uniquely impact NK cell developmental and functional pathways.In this study, we generated NK cell-specific PTEN-deficient mice, which have diminished opposing lipid phosphatase activity to all known PI3K family members. PTEN-deficient mice display significant defects in peripheral organ and BM NK cell compartments, with a large proportion of NK cells being inappropriately localized to the blood. These effects were due in part to alterations in NK cell trafficking in vivo, a defect that also prevented their recruitment to a localized tumor challenge. These results identify a previously unidentified role for PTEN in regulating NK cell tissue distribution during both homeostasis and malignancy in vivo.     

Coming untied? Narrative accounts of social network dynamics from first‐time mental health clients

Existing research demonstrates a relationship between mental illness and social network attrition over time – a pattern attributed to dysfunctional psychosocial and interpersonal processes and rejection. Yet, according to the social network perspective, personal network dynamics naturally accompany important biographical transitions or events, suggesting that our current understanding of mechanisms underlying network instability in mental illness may be incomplete. This research uses data from the Indianapolis Network Mental Health Study, a longitudinal study of social network dynamics spanning five years. It focuses on in‐depth interviews with 135 individuals making their first major contact with the mental health treatment system. First, levels of tie attrition and replacement in the core discussion networks of individuals with mental illness are compared to a sample with no self‐reported history of mental illness. Second, using open‐ended responses describing why specific individuals mentioned in previous waves were not listed again, respondents’ explanations of attrition are analysed qualitatively. In addition to providing support for existing perspectives, the themes suggest a need to also consider: (i) interaction strategies that maximise the supportiveness of social networks and minimise burden and (ii) changing life circumstances external to social networks that influence opportunities for social interaction.     

Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model

A simple and efficient synthetic method for the preparation of quinazoline type phosphodiesterase 7 (PDE7) inhibitors, based on microwave irradiation, has been developed. The use of this methodology improved yields and reaction times, providing a scalable procedure. These compounds are pharmacologically interesting because of their in?vivo efficacy both in spinal cord injury and Parkinson's disease models, as shown in previous studies from our group. Herein we describe for the first time that administration of one of the PDE7 inhibitors here optimized, 3-phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline (compound 5), ameliorated brain damage and improved behavioral outcome in a permanent middle cerebral artery occlusion (pMCAO) stroke model. Furthermore, we demonstrate that these PDE7 inhibitors are potent anti-inflammatory as well as neuroprotective agents in primary cultures of neural cells. These results led us to propose PDE7 inhibitors as a new class of therapeutic agents for neuroprotection.     

Treatment and follow-up of HIV-negative multidrug-resistant tuberculosis patients in an infectious diseases reference hospital, Buenos Aires, Argentina.

SETTING: An Argentinean reference hospital specialising in infectious diseases. OBJECTIVE: To assess the outcomes of all human immunodeficiency virus (HIV) negative multidrug-resistant tuberculosis (MDR-TB) patients referred to or diagnosed at Hospital Mu?iz. DESIGN: Clinical study for the period 1996-1999, with follow-up until June 2002. RESULTS: One hundred and forty-one adult patients (52.5% female) with resistance to two to seven drugs were studied. Fifty patients (35.5%) had not been treated previously. The most frequently used second-line drugs were 5-F-quinolones, cycloserine and ethionamide in susceptibility based individually tailored three- to five-drug regimens. Hospital admission was associated with treatment success. Forty-five episodes of severe toxicity occurred. Treatment was successful in 51.8% of cases, but follow-up of 73 patients yielded 11.9% relapse. The mortality rate was 19.1% and default was 19.9%. Logistic regression analysis was statistically significant for treatment success in relation to patient admission, residence and resistance pattern. CONCLUSION: The burden of MDR-TB in this setting--prolonged infection, treatment cost and difficulties, low rates of cure and treatment adherence and high rates of fatality and relapse--can be improved by strengthening TB control programme activities and fighting against poverty and HIV/AIDS.