Development of a Microarray-Based Tool To Characterize Vaginal Bacterial Fluctuations and Application to a Novel Antibiotic Treatment for Bacterial Vaginosis

The healthy vaginal microbiota is generally dominated by lactobacilli that confer antimicrobial protection and play a crucial role in health. Bacterial vaginosis (BV) is the most prevalent lower genital tract infection in women in reproductive age and is characterized by a shift in the relative abundances of Lactobacillus spp. to a greater abundance of strictly anaerobic bacteria. In this study, we designed a new phylogenetic microarray-based tool (VaginArray) that includes 17 probe sets specific for the most representative bacterial groups of the human vaginal ecosystem. This tool was implemented using the ligase detection reaction-universal array (LDR-UA) approach. The entire probe set properly recognized the specific targets and showed an overall sensitivity of 6 to 12 ng per probe. The VaginArray was applied to assess the efficacy of rifaximin vaginal tablets for the treatment of BV, analyzing the vaginal bacterial communities of 22 BV-affected women treated with rifaximin vaginal tablets at a dosage of 25 mg/day for 5 days. Our results showed the ability of rifaximin to reduce the growth of various BV-related bacteria (Atopobium vaginae, Prevotella, Megasphaera, Mobiluncus, and Sneathia spp.), with the highest antibiotic susceptibility for A. vaginae and Sneathia spp. Moreover, we observed an increase of Lactobacillus crispatus levels in the subset of women who maintained remission after 1 month of therapy, opening new perspectives for the treatment of BV.     

Recombinant protein meningococcal serogroup B vaccine combined with outer membrane vesicles

Introduction: Meningococcal infection is a major cause of morbidity and mortality worldwide. Infection with Neisseria meningitidis is most common in young children, teenagers and people with certain medical conditions. Effective polysaccharide and glycoconjugate vaccines for serogroups A, C, W135 and Y have been developed. A similar capsular polysaccharide approach for serogroup B (MenB) has by most been judged as unsuitable, hence, no broad coverage vaccine has been licensed to date. The novel vaccine Bexsero (previously 4CMenB) has been developed and proven safe and immunogenic in clinical trials.

Areas covered: The authors outline the constituents of Bexsero and immunogenicity and safety data from preclinical and clinical trials published in peer-reviewed literature, meeting proceedings and publicly-available clinical trial websites from 2000 to 2010.

Expert opinion: Bexsero is well tolerated with a proven safety profile, and has demonstrated a robust immune response across different age groups against a range of diverse MenB strains. These data suggest that Bexsero has the ability to provide protection in infants, who are at the greatest risk of developing meningococcal disease.     

Multidrug-resistant Escherichia coli in Asia: epidemiology and management

Escherichia coli has become multiresistant by way of production of a variety of β-lactamases. The prevalence of CTX-M–producing E. coli has reached 60–79% in certain parts of Asia. The acquisition of CTX-M plasmids by E. coli sequence type 131, a successful clone of E. coli, has caused further dissemination of CTX-M–producing E. coli. The prevalence of carbapenemase-producing E. coli, especially Klebsiella pneumoniae carbapenemase, and New Delhi metallo-β-lactamase (NDM)-producing E. coli has been increasing in Asia. K. pneumoniae carbapenemase and NDM have now been found in E. coli sequence type 131. The occurrence of NDM-producing E. coli is a major concern particularly in the Indian subcontinent, but now elsewhere in Asia as well. There are multiple reasons why antibiotic resistance in E. coli in Asia has reached such extreme levels. Approaches beyond antibiotic therapy, such as prevention of antibiotic resistance by antibiotic stewardship and protecting natural microbiome, are strategies to avoid further spread of antibiotic resistance.     

EUCALYPTUS IN THE BRITISH ISLES

In recent years Australia has imported considerable quantities of soft wood timber, a proportion of which has been found to be infested with various species of siricid wasps. In view of the difficulties associated with the adequate inspection of such imports by quarantine officers it is not surprising that one species, Sirex noctilio F., which has been in New Zealand for many years, has now become established in a plantation of Pinus radiata in Tasmania.

The location and history of the Pittwater plantation is given together with details of the known distribution of the insect within the area.

The life cycle of the insect in Tasmania would appear to be similar to that reported in New Zealand, i.e. 1–2 years. From the available information it appears that the insect gained entry not later than the summer of 1950/51, but this may have occurred earlier.

Although an unidentified fungus has been found in association with S. noctilio in Tasmania the rapid and extensive wood rotting reported from New Zealand has not been observed.

The presence of S. noctilio may introduce a new factor into plantation management in Tasmania.     

Pharmacology and clinical applications of human recombinant antithrombin

Importance of the field: Antithrombin therapy (AT) has been tested in various medical applications. With advances in genetics and biotechnology, large-scale production of human recombinant antithrombin (rhAT) is now feasible. The prospect of administering a recombinant protein rather than a pooled blood component, has rekindled interest in antithrombin therapy. However, many known properties of human pooled antithrombin (hpAT) still need to be investigated and established for rhAT.

Areas covered in this review: The manufacture and clinical pharmacology of antithrombin. The literature, evidence and our own views about the future of this drug and its potential clinical applications.

What the reader will gain: The reader will appreciate the biological rationale underpinning antithrombin administration in various clinical settings. The potential benefits and harms of the intervention are addressed. Novel future applications of recombinant antithrombin are broached.

Take home message: rhAT has been approved for its use in congenital antithrombin deficiency. rhAT has also been used off-label to treat heparin-resistance in cardiac surgery and sepsis. It is a promising adjuvant for immunosuppression in organ transplantation, and may have role as an anti-angiogenic, anti-tumor and anti-viral agent. rhAT has clear safety advantages over phAT, such as the avoidance of infection transmission.     

Campylobacters: the most common bacterial enteropathogens in the Nordic countries

Campylobacters have been known as important human pathogens since the late 1970s. Campylobacter jejuni and coli are the most common bacterial enteropathogens in the developed countries. During the past years an increasing incidence of campylobacteriosis has been reported in many developed countries. C. jejuni is the most common Campylobacter species while C. coli accounts for about 5–10% of the cases. Although the genome of C. jejuni NCTC 11168 strain was sequenced recently, the exact pathogenetic mechanisms are still not known. Furthermore, there are no reliable animal models available. The epidemiology of this common infection is not well understood; however, eating and handling poultry, contaminated drinking water, and contact with pet animals have been recognized as important risk factors. Most of the cases are sporadic although large water-borne outbreaks have also been reported. Discriminatory typing methods are helpful in tracing the sources and transmission routes. In addition to traditional serotyping, genotyping methods, such as pulsed-field gel electrophoresis, have been developed. As Campylobacter infections probably precede Guillan-Barré syndrome in many cases, a great interest has lately been focused on the possible triggering mechanisms underlying this phenomenon.     

The use of ustekinumab in autoimmune disease

Importance of the field: The advent of biologic therapies has revolutionized the treatment of autoimmune diseases including psoriasis, autoimmune arthritides and inflammatory bowel disease. With recent advances in our understanding of the immunogenetic pathways involved in the pathogenesis of these conditions, newer, more targeted biologic therapies have been developed. Ustekinumab is an antibody to the common p40 subunit of IL-12 and IL-23, which has been studied in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Areas covered in this review: This review details the efficacy and safety of ustekinumab in all clinical studies to date, using PubMed listed publications and official product websites.

What the reader will gain: Readers will gain a comprehensive understanding of the mechanism of action of ustekinuamb, its pharmacodynamic and pharmacokinetic profile, and its clinical efficacy and safety in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Take home message: Ustekinumab has shown significant efficacy in the treatment of chronic plaque psoriasis in Phase III studies, and promising results in Phase II studies in psoriatic arthritis. Efficacy has been shown in Crohn's disease only in non-responders to infliximab. Ustekinumab did not show benefit in the treatment of multiple sclerosis.     

A review of the newer aromatase inhibitors in the management of metastatic breast cancer

Background: Breast cancer remains a major cause of morbidity and mortality world-wide. While aminoglutethimide, a first-generation aromatase inhibitor, has equivalent efficacy to first-line tamoxifen in the palliative treatment of metastatic breast cancer, its toxicity profile has relegated this drug to a second- or third-line agent in this setting. Recently, several aromatase inhibitors have been released onto the market while others are in phase II and III clinical trials Aim: To review the role of the new aromatase inhibitors in the management of metastatic breast cancer Methods: Current literature, abstracts from meetings and information from pharmaceutical manufacturers have been summarized Content: A review of the clinical pharmacology of the new aromatase inhibitors has been provided in addition to a synopsis of phase III clinical studies Conclusion: The newer aromatase inhibitors have several advantages compared to aminoglutethimide and are a useful addition to the armamentarium of therapies employed in the palliative management of advanced breast cancer     

Beyond the wheelchair: development of motorised transport for people with severe mobility impairments in developing countries

Purpose.?In developing countries, lack of over-the-road transportation reduces a vast number of disabled people to a life of begging, dependency and social isolation. Although there have been some excellent efforts to provide low-cost wheelchairs and hand-powered tricycles, little has been done to further provide transport for disabled people.

Methods.?To address this problem directly we devised a low-cost motorised wheelchair transporter prototype (the Skeeter) using a combination of bicycle parts, a custom built frame, and an inexpensive small engine for propulsion.

Results.?The Skeeter can provide independent operation and travel by a wheelchair user. It is an economically feasible solution to the lack of over-the-road transportation for people with mobility impairments in developing countries.

Conclusions.?The Skeeter has the potential to provide a major enhancement in the quality of life for people with disabilities in developing countries around the world.     

Bevacizumab for the treatment of cervical cancer

ABSTRACT

Introduction: Cervical cancer is still a major cause of morbidity and mortality in women. Early stages and locally advanced cervical cancer are currently treated respectively with surgery and chemoradiation with good prognosis. Persistent, recurrent and metastatic cervical cancers have a poor prognosis. Angiogenesis has been identified as a crucial factor for cervical cancer growth. Recently, research has increasingly focused on the development of targeted therapies, such as anti-angiogenic drugs. Amongst such drugs, bevacizumab, a recombinant humanized monoclonal antibody has been the subject of extensive investigation, including its use in cervical cancer. This was recently approved for the treatment of patients with metastatic, recurrent, or persistent cervical cancer.

Areas covered: The aim of this review is to discuss the role of bevacizumab in both locally advanced and metastatic or recurrent cervical cancer and to analyze the studies that have led to the approval of bevacizumab in cervical cancer.

Expert opinion: The use of bevacizumab in combination with other chemotherapies in cervical cancer has been proven safe and effective, with a significant improvement in overall survival of patients with advanced cervical cancer. Combination therapy using bevacizumab has been demonstrated to increase toxicity rates but it does not impair patient’s quality of life.     

N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility

Background: Glutathione is an endogenous antioxidant and has a ubiquitous role in many of the body's defences. Treatment with N-acetylcysteine (NAC) has been shown to increase levels of glutathione. NAC has been proposed as a treatment for several illnesses. Objectives: The efficacy and tolerability of NAC was examined across a range of conditions to evaluate the evidence supporting the use of NAC for each indication. Methods: A literature search was conducted using PubMed. Information was also collected from other online sources including the websites of the Therapeutic Goods Administration of Australia and the FDA. Results: Reports ranged from case studies to clinical trials. There is strong evidence to support the use of NAC for the treatment of paracetamol overdose and emerging evidence suggesting it has utility in psychiatric disorders, particularly schizophrenia and bipolar disorder. NAC is safe and well tolerated when administered orally but has documented risks with intravenous administration.     

The treatment of pulmonary Wangiella dermatitidis infection with oral voriconazole

What is known and Objective: Wangiella dermatitidis is a darkly pigmented fungus that has been isolated from the soil, dead plant material and areas of high humidity. Infection from the pathogen has not been extensively documented and few published cases report survival. Of the antifungal agents used in previous reports, none has been proven to improve outcomes. Voriconazole is known to have in vitro activity against the organism, but clinical experience for the treatment of W. dermatitidis infection is limited. The objective of this case report is to describe the use of voriconazole for the treatment of W. dermatitidis infection. Case summary: An 86‐year‐old American woman with a past medical history significant only for mild dementia is successfully treated for pulmonary W. dermatitidis infection using oral voriconazole monotherapy with minimal adverse effects. What is new and Conclusion: Voriconazole appears to be effective as monotherapy for the treatment of pulmonary W. dermatitidis infections. A minimum of 3–4 months of antifungal treatment should be given. Adverse effects with prolonged voriconazole use do not appear to be a barrier to treatment.     

Subjective experiences of transient ischaemic attack: a repertory grid approach

Abstract

Purpose: Research on the psychosocial reactions to stroke has been used to inform rehabilitation programmes. Yet much less research has been conducted into experiences of, and reactions to, transient ischaemic attack (TIA), despite its link with secondary stroke. This study aimed to investigate the subjective psychological experiences of TIA.?Method: Repertory grid technique was used because of its capacity to make individual implicit experiences explicit. Using the standard repertory grid protocol, 12 post-TIA patients were asked to consider how five everyday activities had been affected by TIA. Each participant generated six constructs or personal perspectives, which were analysed using proprietary (RepGrid IV) software.?Results: Despite the individualised nature of the responses, six themes emerged from the constructs. These included deep-seated anxiety about future uncertainties/disruption to normality, loss of confidence, frustration, TIA as a wake-up call, a sense of loss and sadness, and embarrassment.

• Implications for Rehabilitation

• Research has shown that the patient’s subjective experience and perspective are important to the rehabilitation process post-stroke.

• Relatively little research has been conducted into the subjective experiences of TIA patients.

• This study has revealed a range of subjective reactions to TIA, which could be used to inform individualised post-TIA management, adaptation and rehabilitation.

     

The Bactrocera tryoni homologue of the Drosophila melanogaster sex-determination gene doublesex

A homologue of the bifunctional sex-determining gene, doublesex (dsx), has been identified in the tephritid fruit fly, Bactrocera tryoni, and has been found to be expressed in a sex-specific manner in adult flies. The male- and female-specific cDNAs are identical at their 5′ ends but differ at their 3′ ends and appear to be the products of alternate splicing. The level of identity of the sex-specific DSX proteins of B. tryoni with the D. melanogaster DSX proteins, across the region corresponding to the DNA binding domain and the oligomerization domains, is greater than 85%. Four sequence motifs which are ten to thirteen bases identical to the TRA/TRA-2 binding sites (thirteen-nucleotide repeat sequences) are present in the female-specific exon of the B. tryoni dsx gene.     

Moose, a new family of LTR-retrotransposons in the mosquito Anopheles gambiae

A novel LTR retrotransposable element called moose has been cloned and characterized from the malaria transmitting mosquito, Anopheles gambiae. This element has all the characteristic features of LTR retroelements and is related to retroelements from other insects and nematodes, belonging to a subgroup of retroelements distinct from the copia/Ty1 and gypsy/Ty3 groups. The moose element appears to be active in A. gambiae, and strong RNA expression is detected in the male and female gonads. The use of this retroelement as a potential vector for germ line transformation is discussed.     

Efficacy of telavancin,a lipoglycopeptide antibiotic,in experimental models of Gram-positive infection

Telavancin is a parenteral lipoglycopeptide antibiotic with a dual mechanism of action contributing to bactericidal activity against multidrug-resistant Gram-positive pathogens. It has been approved for the treatment of complicated skin and skin structure infections due to susceptible Gram-positive bacteria and hospital-acquired/ventilator-associated bacterial pneumonia due to Staphylococcus aureus when other alternatives are unsuitable. Telavancin has been demonstrated to be efficacious in multiple animal models of soft tissue, cardiac, systemic, lung, bone, brain and device-associated infections involving clinically relevant Gram-positive pathogens, including methicillin-resistant S. aureus, glycopeptide-intermediate S. aureus, heterogeneous vancomycin-intermediate S. aureus and daptomycin non-susceptible methicillin-resistant S. aureus. The AUC_0–24h/MIC ratio is the primary pharmacodynamically-linked pharmacokinetic parameter. The preclinical data for telavancin supports further investigative clinical evaluation of its efficacy in additional serious infections caused by susceptible Gram-positive pathogens.     

Acinetobacter baumannii: an emerging multidrug-resistant threat

Amid the recent attention focused on the growing impact of methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa infections, the pathogen Acinetobacter baumannii has been stealthily gaining ground as an agent of serious nosocomial and community-acquired infection. Historically, Acinetobacter spp. have been associated with opportunistic infections that were rare and of modest severity; the last two decades have seen an increase in both the incidence and seriousness of A. baumannii infection, with the main targets being patients in intensive-care units. Although this organism appears to have a predilection for the most vulnerable patients, community-acquired A. baumannii infection is an increasing cause for concern. The increase in A. baumannii infections has paralleled the alarming development of resistance it has demonstrated. The persistence of this organism in healthcare facilities, its inherent hardiness and its resistance to antibiotics results in it being a formidable emerging pathogen. This review aims to put into perspective the threat posed by this organism in hospital and community settings, describes new information that is changing our view of Acinetobacter virulence and resistance, and calls for greater understanding of how this multifaceted organism came to be a major pathogen.