Bronchoprotective tolerance with indacaterol is not modified by concomitant tiotropium in persistent asthma.

BACKGROUND: Tiotropium is a long acting muscarinic antagonist (LAMA), licensed as triple therapy with inhaled corticosteroid and long-acting beta-agonist (ICS/LABA). There may be a synergistic benefit between LAMA and LABA as a consequence of receptor cross-talk, which in turn could modify beta-2 receptor downregulation and associated tolerance induced by LABA. OBJECTIVE: We hypothesize this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy. METHODS: We evaluated 14 non-smoking asthmatics using an open-label, randomized crossover design. ICS with Indacaterol and Tiotropium (IND/TIO) vs ICS with Indacaterol (IND) over 4 weeks with challenge performed after first and last doses at trough. RESULTS: We found no significant difference in mannitol sensitivity, expressed as the provocative dose of mannitol required to reach a 15% drop in FEV1 , or mannitol reactivity, expressed as the response dose ratio (RDR: max % fall in FEV1 /cumulative dose), when comparing ICS/IND/TIO to ICS/IND. Geometric mean fold differences for RDR comparing single and chronic dosing were 3.26-fold (95% CI 1.46-7.29) and 2.51-fold (95% CI 1.32-4.79) for IND and IND/TIO, respectively. Furthermore, salbutamol recovery post-challenge was significantly blunted after chronic compared to single dosing with either ICS/IND (P<.005) or ICS/IND/TIO (P<.05). CONCLUSION AND CLINICAL RELEVANCE: Our data suggest that concomitant tiotropium does not modify the bronchoprotective tolerance induced by Indacaterol, in turn suggesting that cross-talk may not be clinically relevant when using triple therapy. This study was registered on clinicaltrials.gov as NCT02039011.

Effects of the inverse alpha-agonist doxazosin in allergic rhinitis.

BACKGROUND: We examined the paradoxical hypothesis that the alpha-receptor inverse agonist doxazosin might produce beneficial effects in allergic rhinitis. OBJECTIVES: To evaluate single and chronic dosing effects of doxazosin on nasal airflow and symptoms in allergic rhinitis. METHODS: Fifteen patients randomized to receive 3-5 weeks of oral doxazosin 4 mg daily or placebo in crossover fashion. Measurements were taken at baseline and after first and last doses. RESULTS: There was a fall in peak nasal inspiratory flow (PNIF) between baseline vs. first dose of doxazosin: mean difference -19 L/min (95% CI -35 to -2) P = 0.03, with recovery between first and last doses: 21 L/min (95% CI 7-34) P = 0.006. Nasal visual analogue scale (VAS) and blockage scores were worse between baseline vs. first dose of doxazosin: mean difference VAS -10 mm (95% CI -18 to -2) P = 0.02, blockage -0.7 (95% CI -1.3 to -0.1) P = 0.02, with recovery between first and last doses: VAS 15 mm (95% CI 4-25) P = 0.009, blockage 1.1 (95% CI 0.5-1.6) P = 0.001. The oxymetazoline dose-response for PNIF was blunted after single vs chronic dosing with doxazosin: mean difference -17 L/min (95% CI -30 to -4) P = 0.01. Heart rate and diastolic blood pressure showed the same pattern. There was a significant difference between doxazosin and placebo for nasal blockage score and heart rate after single but not chronic dosing. CONCLUSIONS: There was a disconnect between single and chronic dosing effects of doxazosin for nasal symptoms, oxymetazoline response and cardiovascular outcomes, in turn suggesting alpha-1 receptor up-regulation.

Histological Features and Tissue Microarray Taxonomy of Nigerian Breast Cancer Reveal Predominance of the High-Grade Triple-Negative Phenotype.

INTRODUCTION: Little is known about the biology, molecular profile and hence optimal treatment of African Nigerian breast cancer. The aim of this work, therefore, was to characterize the histology and molecular profile of Nigerian breast cancer. METHODS: Breast carcinomas from women at 6 centres of similar tribal origin in Nigeria were reviewed and assembled into tissue microarrays (TMAs), and sections were stained for hormone receptors, i.e. estrogen receptor (ER)α, ERß1, ERß progesterone receptor (PR) and androgen receptor, cyclin D, HER2, Ki67 and cytokeratins (CKs), i.e. CK5/6 and CK14 (basal) and CK18 and 19 (luminal). RESULTS: A total of 835 tumours were analysed. The mean age at diagnosis was 48.62 ± 12.41 years. The most common histological subtype was ductal NST (no-special-type) carcinoma (87.3%). Over 90% of the tumours were grade 2 or 3. The predominant molecular phenotype was the non-basal, triple-negative type (47.65%) followed by the HER2-positive group (19.6%). The percentage of ER-, PR- and HER2-positive tumours was 22.4, 18.9 and 18.8%, respectively. CONCLUSION: Nigerian breast cancer predominantly has a high-grade, triple-negative profile. It occurs at a younger age and bears similarities at the molecular level to pre-menopausal breast cancer in white women, with remarkably lower levels of ERß expression. The early presentation and histological and molecular phenotype may explain the poor prognosis, and tailoring treatment strategies to target this unique profile are required.

Association of Streptococcus pneumoniae nasopharyngeal colonization and other risk factors with acute otitis media in an unvaccinated Indian birth cohort.

In order to study the epidemiology of acute otitis media (AOM) and Streptococcus pneumoniae nasopharyngeal colonization in the first 2 years of life, we followed up an unvaccinated birth cohort monthly and at visits when sick, with otoscopy to detect AOM and performed nasopharyngeal swabbing to detect S. pneumoniae. Serotyping of positive cultures was also performed. Of 210 babies who were enrolled at birth, 61 (29·05%) experienced 128 episodes of AOM [relative risk 2·63, 95% confidence interval (CI) 1·21-5·75] with maximum incidence in the second half of the first year of life. Episodes ranged from 1 to 7 (mean 2·1 episodes). Most (86·9%) babies with AOM had a positive culture swab giving an odds ratio (OR) of 1·93 (95% CI 1·03-3·62, P = 0·041) for this association. Other risk factors identified for AOM were winter season (OR 3·46, 95% CI 1·56-7·30, P = 0·001), upper respiratory infection (OR 2·43, 95% CI 1·43-4·51, P = 0·005); residents of small households were less likely to develop AOM (OR 0·32, 95% CI 0·17-0·57, P < 0·01). Common S. pneumoniae serotypes isolated during episodes were 19, 6, 15, 35, 7, 23, 9 and 10 which indicated a theoretical coverage for pneumococcal vaccines PCV10 and PCV13 constituent serotypes of 62·8%. We conclude that AOM in Indian infants is often associated with S. pneumoniae colonization of the nasopharynx as well as other risk factors.

The potential role of direct and indirect bronchial challenge testing to identify overtreatment of community managed asthma.

BACKGROUND: Although airway hyperresponsiveness (AHR) is a defining feature of asthma pathophysiology, bronchial challenge testing is not routinely used in primary care asthma management. OBJECTIVE: The aim of this study was to evaluate the potential role of direct (methacholine) and indirect (mannitol) challenge testing in community managed asthma. METHODS: Patients currently treated for asthma from Tayside and Fife were identified by the Health Informatics Centre (HIC) and invited to take part in the study. At screening, the following tests were carried out: spirometry, methacholine and mannitol challenge, exhaled nitric oxide (FeNO); Asthma Control Questionnaire (ACQ) and Mini Asthma Quality of Life Questionnaire (AQLQ). RESULTS: A total of 3388 asthmatics were initially identified by HIC with 423 positive responses and 123 completing the study. Seventy percent had either a positive methacholine (PC20  < 8 mg/mL) or mannitol challenge (PD15  < 635 mg), and 30% were non-responsive to both challenges. Fourteen percent of methacholine responders (n = 74) were negative to mannitol, and 16% of mannitol responders (n = 76) were negative to methacholine. Spirometry, FeNO, ACQ and AQLQ were significantly better in the non-responder group who were exposed to high-dose inhaled corticosteroids and frequent long-acting beta-agonists. CONCLUSIONS AND CLINICAL RELEVANCE: We found that 30% of unselected patients with community managed asthma were challenge negative and could be potentially misdiagnosed or overtreated, in turn suggesting the need for supervised step-down.

An outbreak of post-partum breast abscesses in Mumbai, India caused by ST22-MRSA-IV: genetic characteristics and epidemiological implications.

A cluster of methicillin-resistant Staphylococcus aureus (MRSA) breast abscesses in women who had given birth at a hospital in Mumbai, India was investigated retrospectively. Nineteen of 20 cases were caused by a single clone: pvl-positive, spa type 648 (Ridom t852), ccrB:dru subtype 3:0, ST22-MRSA-IV. Despite the presence of pvl and SCCmec type IV, which are common genetic markers in community-associated MRSA, this outbreak was caused by a healthcare-associated, community-onset MRSA that was common in the hospital environment. Thus, infection control practices may have an important role in limiting the spread of this virulent clone.

Toppled Pediatric Radial Neck Fracture Treated by Open Reduction with Good Functional Outcome: A Rare Case Report with Review of Literature.

Introduction: 180 °rotated and displaced fracture neck of radius with displacement is rare case in pediatric age as the cartilaginous head absorbs the force and transmits it to the weaker physis or metaphysis of the neck. These fractures characteristically produce an angular deformity of the head with the neck. Case Report: This case report describes a rare case of 180° rotated and displaced fracture neck of radius with displacement. A 12-year-old female presented to OPD with history of self-fall over right elbow while playing and started complaining of pain over right elbow for about 2 h. She underwent open reduction internal fixation with k wire fixation procedures. She made an uneventful recovery and reported full range of motion after a follow-up of 3 months. Conclusion: The best treatment options in pediatric age suffering from a displaced (Judet classification type 4b) radial neck fracture with displacement in childhood is open reduction and fixation of fracture to avoid further joint stiffness and growth related deformity.

A case report of an angiomyxoma in the liver.

Angiomyxomas are uncommon myxoid tumours arising most commonly from the pelvis. A 46-year-old woman with a history of polycystic kidney disease presented asymptomatically for surveillance ultrasonography; changes were noted in the size and morphology of her liver cysts. Subsequent radiological assessment displayed features suspicious of malignancy and a right hemihepatectomy was performed with curative intent. Pathological examination of the resected specimen found histology consistent with an angiomyxoma arising primarily from the liver parenchyma. Follow-up review of the patient has been uneventful with annual imaging showing no evidence of recurrence. Angiomyxomas do not characteristically invade other tissues. However, any liver lesion displaying suspicious features of malignancy should be resected in the absence of disseminated disease.

Cardiopulmonary interactions with beta-blockers and inhaled therapy in COPD.

BACKGROUND: Beta-blockers remain underused in patients with chronic obstructive pulmonary disease (COPD) and cardiovascular disease. AIM: We compared how different inhaled therapies affect tolerability of bisoprolol and carvedilol in moderate to severe COPD. DESIGN: A randomized, open label, cross-over study. METHODS: We compared the cardiopulmonary interactions of bisoprolol 5 mg qd or carvedilol 12.5 mg bid for 6 weeks in conjunction with: (i) triple: inhaled corticosteroid/long acting beta-agonist/long acting muscarinic antagonist (ICS + LABA + LAMA), (ii) dual: ICS + LABA and (iii) ICS alone. RESULTS: Eighteen patients completed, all ex-smokers, mean age 65 years, forced expiratory volume in 1 s (FEV1) 52% predicted. Bisoprolol and carvedilol produced comparable significant reduction in resting and exercise heart rate. FEV1, forced vital capacity and lung compliance (AX) were significantly lower with carvedilol vs. bisoprolol while taking concomitant ICS/LABA (P < 0.05) but not ICS/LABA/LAMA. CONCLUSIONS: In summary, bisoprolol was better tolerated than carvedilol on pulmonary function at doses which produced equivalent cardiac beta-1 blockade. Worsening of pulmonary function with carvedilol was mitigated by concomitant inhaled LAMA (tiotropium) with LABA (formoterol), but not LABA alone. Registered at clinicaltrials.gov: NCT01656005.

The expansion of megakaryocyte progenitors from CD34+-enriched mobilized peripheral blood stem cells is inhibited by Flt3-L.

This study aimed to determine the optimal growth factor combination for expansion of megakaryocyte (Mk) progenitors with clonogenic potential from CD34+-enriched mobilized peripheral blood stem cells (PBSC). Mobilized PBSC were monocyte depleted and CD34+ enriched, then cultured with various combinations of interleukin-3 (IL-3), IL-6, IL-11, Flt3 ligand (Flt3-L), stem cell factor (SCF), granulocyte-macrophage colonystimulating factor (GM-CSF), and erythropoietin (EPO), using a 2(7-3) IV fractional factorial design. Expansion of Mk committed progenitors (CD41+) and primitive precursors (CD61+ CD34+) was determined using FACS and colony-forming assays. Amplification of Mk progenitor production was attributed to IL-3 (p < 0.002), SCF (p < 0.001), and GM-CSF (p < 0.05). Flt3-L inhibited the production of total CD61+ cells (p < 0.05), CD61+CD34+ cells (p < 0.03), and total CD41a+ cells (p < 0.01). Addition of Flt3-L to the optimum growth factor combination of megakaryocyte growth and development factor (MGDF), SCF, IL-3, and GM-CSF caused the greatest increase in total nucleated cells but reduced Mk progenitor expansion. There was also a 20% reduction in Mk+ colonies from cells expanded in the presence of Flt3-L. Factorial analysis identified the optimal combination of growth factors required to expand Mk precursors with clonogenic potential. The addition of Flt3-L to the optimal combination of MGDF, SCF, IL-3, and GM-CSF reduced both the fold expansion of Mk progenitors and Mk colony numbers.

Multidrug resistance mediated by co-carriage of extended-spectrum beta-lactamases, AmpC and New Delhi metallo-beta-lactamase-1 genes among carbapenem-resistant Enterobacteriaceae at five Indian medical centres.

In this study, we evaluated the coexistence of extended-spectrum beta-lactamases (ESBL), AmpC and New Delhi metallo-beta-lactamase-1 (NDM-1) genes among carbapenem-resistant Enterobacteriaceae (CRE) recovered prospectively from patients at multiple sites. The study included 285 CRE strains from 2782 Gram-negative Bacilli collected from multiple centres during 2007-2010, of which 87 were characterised. Standard and reference laboratory methods were used for resistance determination. Detection of blaNDM-1 , blaAmpC , blaTEM , blaSHV and blaCTX-M was done by polymerase chain reaction. High levels of antimicrobial resistance observed among study isolates. Co-carriage of ESBLs, AmpC and NDM-1 was 26.3%. Nosocomial origin among the co-carriage isolates was 64.3%, with 9.2% associated mortality.

Splenic blood flow measurements by Doppler ultrasound: a preliminary report.

Splenic blood flow and splenic volume were measured by Doppler and cross sectional ultrasound in 72 human subjects consisting of 61 patients with splenomegaly and 11 normal subjects. This non-invasive and relatively simple method yielded satisfactory results in 76% of the subjects studied; failures were due to obesity, debility, distorted vascular anatomy, and excessive gas in the stomach. These preliminary results suggest that the Doppler ultrasound technique is a practical clinical method for measuring splenic blood flow.

Clinical and radiographic assessment of the efficacy of calcium silicate indirect pulp capping: a randomized controlled clinical trial.

The aims of this study were to assess the effectiveness of calcium silicate cement (Biodentine) versus glass ionomer cement (GIC; control group) as indirect pulp capping materials in patients with reversible pulpitis and to compare the effectiveness of cone beam computed tomography (CBCT) versus periapical (PA) radiographs in detecting PA changes at baseline (T0) and at 12 mo (T12) postoperatively. Seventy-two restorations (36 Biodentine, 36 Fuji IX) were placed randomly in 53 patients. CBCT/PA radiographs were taken at T0 and T12. Two calibrated examiners assessed the presence/absence and increase/decrease in the size of existing PA radiolucencies under standardized conditions. The Kappa coefficient evaluated statistically the effectiveness of CBCT versus PA radiographs in detecting PA changes. Chi-square/Mann-Whitney tests were used to evaluate the association between PA changes in CBCT with various clinical measures. Significance was predetermined at α = 0.05. Clinical success rates for Biodentine and Fuji IX GIC were 83.3%. CBCT was significantly more effective in detecting PA radiolucencies compared with radiographs (P = 0.0069). Of the teeth, 65.4% and 90.4% were deemed healthy using CBCT and PA radiographs, respectively, at T12. Healing/healed rates were 17.3%/0%, while new/progressed radiolucency were 30.8%/9.6% with CBCT/PA radiographs, respectively. Seventy-one percent of healed lesions had received Biodentine; 88% of new/progressed lesions received Fuji IX GIC. Teeth presenting with an initial CBCT PA lesion had a failure rate of 63%, whereas teeth with no initial lesion had a failure rate of 16%. Although no statistically significant difference was detected in the clinical efficacy of Biodentine/Fuji IX when used as indirect pulp capping materials in patients with reversible pulpitis, CBCT showed a significant difference in that most healed CBCT lesions had received Biodentine while most that did not heal received Fuji IX. Longer-term follow-up is needed to establish their effect on the healing dynamics of PA tissues (ClinicalTrials.gov NCT02201641).

Syndrome of myelofibrosis and osteosclerosis: a series of case reports and review of the literature.

Myelofibrosis (MF) is a chronic disorder characterized by bone marrow evidence of myeloid metaplasia associated with reactive fibrosis, angiogenesis, and osteosclerosis. We report serum biochemistry, noninvasive markers of bone turnover, tetracycline-labeled bone histomorphometry, and bone densitometry (DXA) data of four men presenting with newly diagnosed biopsy-proven MF and osteosclerosis. The mechanisms and putative growth factors responsible for this syndrome are examined.

Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study.

AIM: To compare clinical outcomes in a randomised comparison of treatment with danaparoid sodium (a heparinoid), or dextran 70, for heparin-induced thrombocytopaenia (HIT) plus thrombosis. METHODS: Forty-two patients with recent thrombosis and a clinical diagnosis of probable HIT who presented at ten Australian hospitals during a study period of six and one half years were randomly assigned to open-label treatment with intravenous danaparoid or dextran 70, each combined with oral warfarin. Thirty-four patients (83%) had a positive platelet aggregation or 14C-serotonin release test for HIT antibody. Twenty-five received danaparoid as a bolus injection of 2400 anti-Xa units followed by 400 units per hour for 2 h, 300 units per hour for 2 h, and then 200 units per hour for five days. Seventeen received 1000 mL dextran 70 on day one and then 500 mL on days 2-5. Patients were reviewed daily for clinical evidence of thrombus progression or resolution, fresh thrombosis or embolism, bleeding or other complications. The primary trial endpoint was the proportion of thromboembolic events with complete clinical resolution by the time of discharge from hospital. RESULTS: With danaparoid, there was complete clinical recovery from 56% of thromboembolic events compared to 14% after dextran 70 (Odds Ratio 10.53, 95% Confidence Interval 1.6-71.4; p = 0.02). Clinical recovery with danaparoid was complete or partial in 86% of thromboembolic events compared with 53% after dextran 70 (Odds Ratio 4.55, 95% Confidence Interval 1.2-16.7; p = 0.03). Overall clinical effectiveness of danaparoid was rated as high or moderate in 88% of patients compared with 47% for dextran 70 (p = 0.01). One patient given danaparoid died of thrombosis compared with three patients given dextran 70. The platelet count returned to normal after a mean of 6.7 days with danaparoid and 7.3 days with dextran 70. There was no major bleeding with either treatment. CONCLUSION: danaparoid plus warfarin treatment for HIT with thrombosis is effective, safe, and superior to dextran 70 plus warfarin.

Methysergide-induced retroperitoneal fibrosis: successful outcome and two new laboratory features.

A 25-year-old woman sought medical attention because of iliocaval manifestations of retroperitoneal fibrosis while she was taking methysergide. Laboratory studies yielded substantially increased serum procollagen III levels and anticardiolipin antibodies accompanied with anti-beta(2) glycoprotein I, findings not previously described with this disorder. Clinical and laboratory manifestations resolved after cessation of methysergide therapy.

Lymphoma-like presentation of acute monocytic leukaemia.

Four patients in whom a diagnosis of acute monocytic leukaemia (M5) was subsequently made presented with extramedullary disease clinically resembling lymphoma. In all patients histological sections were initially misinterpreted as showing malignant lymphoma or anaplastic carcinoma. The diagnosis of M5 leukaemia was subsequently made on the basis of morphological and cytochemical studies of peripheral blood and bone marrow. The histological diagnosis of the soft tissue lesions of M5 leukaemia (monocytic sarcoma) is difficult, although features such as abundant cytoplasm and the presence of some reniform nuclei are helpful. If there is no peripheral blood or bone marrow involvement and only fixed paraffin-embedded tissues are available, demonstration of lysozyme by an immunoperoxidase technique may confirm the diagnosis but results are not invariably positive. An early diagnosis of M5 leukaemia has therapeutic implications since the disease evolves through a progressive leukaemia phase and systemic therapy is essential.

Rates of acquisition and loss of Wuchereria bancrofti infection in Culex quinquefasciatus.

Rates of acquisition and loss of parasitic infection in the vector host of Wuchereria bancrofti were estimated using a new method. The age of parasitic infections was estimated from the abdominal condition, determined on the basis of Sella's stages of blood digestion and ovary development, and parity of the vector host and larval stages of the parasite. A negative exponential relationship between age and number of W. bancrofti infections provided estimated daily losses of 25.3% and 33.2% of the initial infection from the resting and biting populations, respectively, of the mosquito Culex quinquefasciatus. The rates per day of acquisition of infection estimated from resting and biting female Cx. quinquefasciatus were found to be 9.6% and 8.6%, respectively. The mean minimum developmental time for W. bancrofti infective larvae estimated from the natural resting and biting populations were 8.9 +/- 1.41 (+/- SEM) and 8.33 +/- 0.85 days, respectively, which was somewhat less than the duration observed under laboratory conditions. Comparisons of the estimates (mean age, rates of acquisition, and loss of infections) based on the resting and biting data suggest that the rates are independent of the method of collecting mosquitoes.

Streptococcus pneumoniae from ophthalmic infections: serotype distribution and penicillin susceptibility.

Streptococcus pneumoniae is one of the pathogens causing infection of the conjunctiva and the uveal tract. The present study began with the observation of two ophthalmic S. pneumoniae isolates showing intermediate resistance to penicillin. Among the 25 isolates of S. pneumoniae from 617 ophthalmic specimens, during the period of 14 months, four were found to exhibit an intermediate resistance to penicillin. Minimum Inhibitory Concentration values ranging from 0.125 microg/mL to 0.25 microg/mL was observed. No multidrug resistant strains were isolated. Serogrouping/typing of the S. pneumoniae revealed the following serogroups/types; 6A (n = 3), 6B (n = 2), 22 (n = 3), 14 (n = 3), 23A (n = 2), and 1 each of 23B, 19A, 7B, 32, 9, 42, 21, 39, 10, 3, and 34. One strain showed cross reaction in pool 29, 35, and 47. These findings represent the first such observation of ophthalmic isolates from India.