bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of Itraconazole with Broad-Spectrum
In Vitro
Antienterovirus Activity That Targets Nonstructural Protein 3A
Authors: Gao Qianqian , Yuan Shilin , Zhang Chao , Wang Ying , Wang Yizhuo , He Guimei , Zhang Shuyi , Altmeyer Ralf , Zou Gang 
Published: February 2015

ABSTRACT

There is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections, which remain a substantial threat to public health. To discover inhibitors that can be immediately repurposed for treatment of enterovirus infections, we developed a high-throughput screening assay that measures the cytopathic effect induced by enterovirus 71 (EV71) to screen an FDA-approved drug library. Itraconazole (ITZ), a triazole antifungal agent, was identified as an effective inhibitor of EV71 replication in the low-micromolar range (50% effective concentrations [EC
50
s], 1.15 μM). Besides EV71, the compound also inhibited other enteroviruses, including coxsackievirus A16, coxsackievirus B3, poliovirus 1, and enterovirus 68. Study of the mechanism of action by time-of-addition assay and transient-replicon assay revealed that ITZ targeted a step involved in RNA replication or polyprotein processing. We found that the mutations (G5213U and U5286C) conferring the resistance to the compound were in nonstructural protein 3A, and we confirmed the target amino acid substitutions (3A V51L and 3A V75A) using a reverse genetic approach. Interestingly, posaconazole, a new oral azole with a molecular structure similar to that of ITZ, also exhibited anti-EV71 activity. Moreover, ITZ-resistant viruses do not exhibit cross-resistance to posaconazole or the enviroxime-like compound GW5074, which also targets the 3A region, indicating that they may target a specific site(s) in viral genome. Although the protective activity of ITZ or posaconazole (alone or in combination with other antivirals) remains to be assessed in animal models, our findings may represent an opportunity to develop therapeutic interventions for enterovirus infection.
Alga-Produced Malaria Transmission-Blocking Vaccine Candidate Pfs25 Formulated with a Human Use-Compatible Potent Adjuvant Induces High-Affinity Antibodies That Block Plasmodium falciparum Infection of Mosquitoes
Authors: Patra Kailash P. , Li Fengwu , Carter Darrick , Gregory James A. , Baga Sheyenne , Reed Steven G. , Mayfield Stephen P. , Vinetz Joseph M. 
Published: February 2015

ABSTRACT

A vaccine to prevent the transmission of malaria parasites from infected humans to mosquitoes is an important component for the elimination of malaria in the 21st century, yet it remains neglected as a priority of malaria vaccine development. The lead candidate for
Plasmodium falciparum
transmission-blocking vaccine development, Pfs25, is a sexual stage surface protein that has been produced for vaccine testing in a variety of heterologous expression systems. Any realistic malaria vaccine will need to optimize proper folding balanced against cost of production, yield, and potentially reactogenic contaminants. Here
Chlamydomonas reinhardtii
microalga-produced recombinant Pfs25 protein was formulated with four different human-compatible adjuvants (alum, Toll-like receptor 4 [TLR-4] agonist glucopyranosal lipid A [GLA] plus alum, squalene–oil-in-water emulsion, and GLA plus squalene–oil-in-water emulsion) and compared for their ability to induce malaria transmission-blocking antibodies. Alga-produced recombinant Pfs25 plus GLA plus squalene–oil-in-water adjuvant induced the highest titer and avidity in IgG antibodies, measured using alga-produced recombinant Pfs25 as the enzyme-linked immunosorbent assay (ELISA) antigen. These antibodies specifically reacted with the surface of
P. falciparum
macrogametes and zygotes and effectively prevented parasites from developing within the mosquito vector in standard membrane feeding assays. Alga-produced Pfs25 in combination with a human-compatible adjuvant composed of a TLR-4 agonist in a squalene–oil-in-water emulsion is an attractive new vaccine candidate that merits head-to-head comparison with other modalities of vaccine production and administration.
Staphylococcus aureus Adapts to Oxidative Stress by Producing H
2
O
2
-Resistant Small-Colony Variants via the SOS Response
Authors: Painter Kimberley L. , Strange Elizabeth , Parkhill Julian , Bamford Kathleen B. , Armstrong-James Darius , Edwards Andrew M. 
Published: February 2015

ABSTRACT

The development of chronic and recurrent
Staphylococcus aureus
infections is associated with the emergence of slow-growing mutants known as small-colony variants (SCVs), which are highly tolerant of antibiotics and can survive inside host cells. However, the host and bacterial factors which underpin SCV emergence during infection are poorly understood. Here, we demonstrate that exposure of
S. aureus
to sublethal concentrations of H
2
O
2
leads to a specific, dose-dependent increase in the population frequency of gentamicin-resistant SCVs. Time course analyses revealed that H
2
O
2
exposure caused bacteriostasis in wild-type cells during which time SCVs appeared spontaneously within the
S. aureus
population. This occurred via a mutagenic DNA repair pathway that included DNA double-strand break repair proteins RexAB, recombinase A, and polymerase V. In addition to triggering SCV emergence by increasing the mutation rate, H
2
O
2
also selected for the SCV phenotype, leading to increased phenotypic stability and further enhancing the size of the SCV subpopulation by reducing the rate of SCV reversion to the wild type. Subsequent analyses revealed that SCVs were significantly more resistant to the toxic effects of H
2
O
2
than wild-type bacteria. With the exception of heme auxotrophs, gentamicin-resistant SCVs displayed greater catalase activity than wild-type bacteria, which contributed to their resistance to H
2
O
2
. Taken together, these data reveal a mechanism by which
S. aureus
adapts to oxidative stress via the production of a subpopulation of H
2
O
2
-resistant SCVs with enhanced catalase production.
C-Reactive Protein Protects Mice against Pneumococcal Infection via Both Phosphocholine-Dependent and Phosphocholine-Independent Mechanisms
Authors: Gang Toh B. , Hanley Gregory A. , Agrawal Alok 
Published: February 2015

ABSTRACTThe mechanism of action of C-reactive protein (CRP) in protecting mice against lethalStreptococcus pneumoniaeinfection is unknown. The involvement of the phosphocholine (PCh)-binding property of CRP in its antipneumococcal function previously has been explored twice, with conflicting results. In this study, using three different intravenous sepsis mouse models, we investigated the role of the PCh-binding property of CRP by employing a CRP mutant incapable of binding to PCh. The ability of wild-type CRP to protect mice against infection was found to differ in the three models; the protective ability of wild-type CRP decreased when the severity of infection was increased, as determined by measuring mortality and bacteremia. In the first animal model, in which we used 25 μg of CRP and 107CFU of pneumococci, both wild-type and mutant CRP protected mice against infection, suggesting that the protection was independent of the PCh-binding activity of CRP. In the second model, in which we used 25 μg of CRP and 5 × 107CFU of pneumococci, mutant CRP was not protective while wild-type CRP was, suggesting that the protection was dependent on the PCh-binding activity of CRP. In the third model, in which we used 150 μg of CRP and 107CFU of pneumococci, mutant CRP was as protective as wild-type CRP, again indicating that the protection was independent of the PCh-binding activity of CRP. We conclude that both PCh-dependent and PCh-independent mechanisms are involved in the CRP-mediated decrease in bacteremia and the resulting protection of mice against pneumococcal infection.
Disruption of the Membrane Nuclease Gene (MBOVPG45_0215) of Mycoplasma bovis Greatly Reduces Cellular Nuclease Activity
Authors: Sharma Shukriti , Tivendale Kelly A. , Markham Philip F. , Browning Glenn F. 
Published: February 2015

ABSTRACTAlthough the complete genome sequences of three strains ofMycoplasma bovisare available, few studies have examined gene function in this important pathogen. Mycoplasmas lack the biosynthetic machinery for thede novosynthesis of nucleic acid precursors, so nucleases are likely to be essential for them to acquire nucleotide precursors. Three putative membrane nucleases have been annotated in the genome ofM. bovisstrain PG45, MBOVPG45_0089 and MBOVPG45_0310, both of which have the thermonuclease (TNASE_3) functional domain, and MBOVPG45_0215 (mnuA), which has an exonuclease/endonuclease/phosphatase domain. While previous studies have demonstrated the function of TNASE_3 domain nucleases in several mycoplasmas, quantitative comparisons of the contributions of different nucleases to cellular nuclease activity have been lacking. Mapping of a library of 319 transposon mutants ofM. bovisPG45 by direct genome sequencing identified mutants with insertions in MBOVPG45_0310 (the Δ0310 mutant) and MBOVPG45_0215 (the Δ0215 mutant). In this study, the detection of the product of MBOVPG45_0215 in the Triton X-114 fraction ofM. boviscell lysates, its cell surface exposure, and its predicted signal peptide suggested that it is a surface-exposed lipoprotein nuclease. Comparison of a ΔmnuAmutant with wild-typeM. bovison native and denatured DNA gels and in digestion assays using double-stranded phage λ DNA and closed circular plasmid DNA demonstrated that inactivation of this gene abolishes most of the cellular exonuclease and endonuclease activity ofM. bovis. This activity could be fully restored by complementation with the wild-typemnuAgene, demonstrating that MnuA is the major cellular nuclease ofM. bovis.IMPORTANCENucleases are thought to be important contributors to virulence and crucial for the maintenance of a nutritional supply of nucleotides in mycoplasmas that are pathogenic in animals. This study demonstrates for the first time that of the three annotated cell surface nuclease genes in an important pathogenic mycoplasma, the homologue of the thermostable nuclease identified in Gram-positive bacteria is responsible for the majority of the nuclease activity detectablein vitro.
Evolution of insulin resistance in coronary artery disease patients on four different pharmacological therapies
Authors: Piédrola Gonzalo , Novo Enrique , Serrano-Gotarredona Joaquín , de Teresa Maria Luisa , García-Robles Rafael 
Published: February 2015

Summary
The objective of the study was to examine the evolution of insulin sensitivity in a group of patients with stable coronary artery disease receiving one of four different pharmacological therapies. Insulin sensitivity was evaluated using an insulin suppression test in 40 newly diagnosed patients with coronary artery disease and no previous history of metabolic disorders, who were not taking any medication which might affect insulin sensitivity. The insulin suppression test consisted of a constant infusion of glucose, insulin and somatostatin for 150 min; insulin resistance was estimated by determining the steady-state plasma glucose concentrations during the last 60 minutes of the test. The insulin sensitivity index was calculated by the formula: insulin sensitivity index = (glucose infusion rate/steady state plasma glucose concentrations) × 103. A second insulin suppression test was performed after 6 months' therapy with either isosorbide mononitrate, atenolol, diltiazem or captopril in 30 of the 40 patients.
There were no differences between any of the groups before therapy was initiated. After 6 months, patients treated with captopril and, to a lesser extent, those treated with diltiazem showed statistically significantly decreased steady state plasma glucose concentrations and increased insulin sensitivity index compared to basal values. No statistically significant differences were found in the other two groups. We conclude that captopril and, to a lesser extent, diltiazem improve insulin sensitivity in patients with stable coronary artery disease.
Red-man syndrome after vancomycin: potential cross-reactivity with teicoplanin
Authors: Khurana C , de Belder M A 
Published: February 2015

Summary
We report a patient with infective endocarditis who developed a severe form of Red-man syndrome after vancomycin. On substituting the antibiotic to teicoplanin, the patient went on to develop a dramatic pyrexia which settled only after the teicoplanin was discontinued. This suggested that there may be an element of cross-reactivity between teicoplanin and vancomycin in such patients and that teicoplanin may not be the most appropriate substitute in all cases of vancomycin-induced Red-man syndrome.
Unilateral gestational macromastia − an unusual presentation of a rare disorder
Authors: Zargar Abdul Hamid , Laway Bashir Ahmad , Masoodi Shariq Rashid , Chowdri Nisar Ahmad , Bashir Mir Iftikhar , Wani Arshad Iqbal 
Published: February 2015

Summary
Macromastia (mammary gigantism) is an uncommon clinical entity. Macromastia occurring during pregnancy (gestational macromastia) is rare. A case of unilateral gestational macromastia is reported which required reduction mammoplasty. We documented hyperprolactinaemia in the patient. This case report is particularly interesting because, to our knowledge, no such case has previously been reported.
Modern management of eclampsia
Authors: Salha Osama , Walker James J 
Published: February 2015

Summary
Eclampsia, the occurrence of a seizure in association with pre-eclampsia, remains an important cause of maternal mortality and morbidity. Despite being recognised since antiquity, consistent management practices are still lacking. Given that the aim of good care is to prevent seizures, it is disappointing that in the majority of cases the first eclamptic convulsion occurs after admission to hospital. This indicates that either the women who are likely to have a convulsion were not identified accurately, or the treatment given was ineffective. The answer to poor management of eclampsia lies in better education and training of all obstetricians, anaesthetists, midwives, and general practitioners in the diagnosis and treatment of severe pre-eclampsia and eclampsia. Protocols for the management of fluid balance, antihypertensive and anticonvulsant therapies should be available and reviewed regularly. The universal adoption of such guidelines in all obstetric units would substantially reduce elements of substandard care which have repeatedly been identified in the triennial reports of the confidential enquiries into maternal deaths in the UK.
Physician attitudes and behaviour regarding erectile dysfunction in at-risk patients from a rural community
Authors: Perttula Eric 
Published: February 2015

SummaryErectile dysfunction affects many men in the United States. A 34% prevalence is estimated among male family practice patients. It is associated with a loss of self-image, self-confidence, and even chronic anger. Several risk factors increases the risk of erectile dysfunction. Prevalence is increased by 20–40% in patients with diabetes, hypertension, and those over 65 years old. While erectile dysfunction is generally acknowledged as an important health problem, misconceptions remain as to the need for clinician-initiated discussion regarding the issue. A retrospective chart review of patients at three health clinics in a predominately rural area was conducted. Subjects (n=102) were those at risk of erectile dysfunction who had undergone a complete physical exam between October 1995 and December 1996. All physician encounters were examined for documentation of physician inquiry about erectile dysfunction. A survey of physician perceptions on initiating discussions of erectile dysfunction was also conducted. Physician-initiated discussion of erectile dysfunction was documented in 17% of patients with hypertension, 18% with diabetes mellitus, and 30% of patients &gt; 65 years. The physician survey (11 respondents) showed 27% reported asking all male patients about erectile dysfunction at routine physical, while 45% reported asking 80% of their male patients. A ‘lack of time’ or belief that the ‘patient will initiate discussions’ was cited by several practitioners as reasons why inquiries were not initiated. All physicians in the study agreed that sexual function is an integral part of overall health. They either overestimated the percentage of patients asked about erectile dysfunction or they had not documented results consistently.
Carcinoid-associated ectopic ACTH syndrome with variable response to octreotide
Authors: Gill Geoffrey V , Yong Alice , Power Eileen , Ramage John 
Published: February 2015

Summary
The case is presented of a 31-year-old woman who developed florid clinical and biochemical Cushing's syndrome due to metastatic hepatic carcinoid tumour from a probable pancreatic primary. Hypercortisolaemia was controlled with metyrapone and ketoconazole, but high doses of octreotide failed to affect plasma cortisol and urinary 5-hyroxyindole acetic acid (5HIAA) levels, or prevent rapid tumour growth. Hepatic polystyrene embolisation failed, and she was treated by liver transplantation with initial excellent results, and normalisation of cortisol and 5HIAA levels. Ten months later, however, she relapsed with bony and pelvic tumour recurrence, and high and symptomatic levels of cortisol and 5HIAA. At this time, octreotide in similar doses to those used previously appeared to normalise her biochemically, although she died soon after. This variable responsiveness to octreotide could be related to somatostatin receptor changes, or cyclical tumour secretion patterns.
Primary antibody deficiency and Crohn's disease
Authors: Conlong P , Rees Wynne , Shaffer J L , Nicholson David , Jewell Derek , Heaney Mansel , Jones Aled , Snowden Neil 
Published: February 2015

Summary
Five patients with primary antibody deficiency were investigated because of intermittent but persistent diarrhoea of several years duration despite immunoglobulin replacement therapy. We found no evidence of Giardia lambia or other intestinal pathogens to explain their gastrointestinal symptoms. All five had definite radiological evidence of small bowel Crohn's disease and three had histological specimens available with abnormalities consistent with Crohn's disease. One patient had a non-caseating granuloma in an oral ulcer. A second patient with stricturing disease in the small bowel had a mucosal inflammatory infiltrate with non-caseating granulomas. A third had transmural inflammation but no granulomas. All five patents were diagnosed as having Crohn's disease and have responded symptomatically to steroid therapy.
Evaluation of renal function in elderly heart failure patients on ACE inhibitors
Authors: Jolobe O M P 
Published: February 2015

Summary
A total of 187 heart failure patients aged 65–92 years, with pretreatment serum creatinine levels below 200 μmol/l, were monitored for more than 12 months on angiotensin-converting enzyme (ACE) inhibitor therapy. Optimal ACE inhibitor dosage was found in 27% of patients, while a significant deterioration in renal function, characterised by &gt;20% increase in serum creatinine to &gt;200 μmol/l, occurred in 25 patients. This was most closely attributable to ACE inhibitor treatment per se (implying co-existence of bilateral renal artery stenosis) in only four cases, including one in whom renal deterioration was reproducible on inadvertent rechallenge. In the other 21, renal deterioration was attributable to diuretic-related blood volume depletion (two cases), nonsteroidal anti-inflammatory drugs (two cases), obstructive uropathy (two cases), preterminal renal shutdown (two cases), and the interaction between diuretic and ACE inhibitor dosage (including long-acting vs short-acting drugs) (13 cases). This study could serve as the basis for future comparisons of ACE-inhibitor-related renal deterioration when the entry requirement is optimal ACE inhibitor dosage.
Lobular carcinoma-in-situ within a fibroadenoma of the breast
Authors: Shah Ajay K , Pathak Ranganath , Banerjee Subhendra N , Kaul Ashutosh , Niazi Masooma , Girishkumar Hanasoge T 
Published: February 2015

Summary
We present a case of an in-situ lobular carcinoma within an otherwise benign fibroadenoma in a 45-year-old woman.
Induction for senior house officers. Part I: The hospital programme
Authors: Ward Simon J , Stanley Paula 
Published: February 2015

Summary
The study was set up to examine how an induction programme can be designed to meet the needs and expectations of senior house officers (SHOs) beginning a new post in a hospital. A total of 63 SHOs, in five hospitals in the Anglia region, participated in standardised structured interviews up to 3 months after starting their post, by sorting a list of 38 possible induction topics in order of priority. Trainees' early induction needs were found to centre on day-one service activities, ie, information that enables them to undertake their service work efficiently and effectively, is particularly valued and required early. Information related to clinical education and training is also valued, but many trainees prefer it to be provided after they have been in post for a week or two. Much induction information can also be effectively conveyed in writing, with little or no need for additional formal presentation. We conclude that first-day induction programmes which strive to satisfy the range of trainee needs in one session fail to take account of the different priorities that trainees attach to induction information. Trainees do not want all information at once. Information of prime concern to clinical tutors, namely education, training and generic skills, is generally favoured after a week or two. To ensure that trainees' hospital induction needs are met in an efficient and effective way, programmes must be flexible and timely, and supported by comprehensive written information.
Hypersensitivity pneumonitis associated with co-proxamol (paracetamol + dextropropoxyphene) therapy
Authors: Matusiewicz S P , Wallace W A H , Crompton G K 
Published: February 2015

Summary
A 61-year-old man developed hypersensitivity pneumonitis and skin rash in close association with taking co-proxamol. These problems occurred in spite of being treated with prednisolone 40 mg daily (20 mg daily at the time of presentation) for assumed cranial arteritis. A therapeutic challenge with paracetamol was negative and the patient continues to take this drug. It seems likely that this patient's rash and hypersensitivity pneumonitis was caused by dextropropoxyphene. Dextropropoxyphene has not been reported previously as a cause of hypersensitivity pneumonitis.
Hereditary hypophosphataemic rickets: report of a family from the Indian subcontinent
Authors: Zargar Abdul Hamid , Laway Bashir Ahmad , Masoodi Shariq Rashid , Hakim Fayaz Ahmad , Wani Arshad Iqbal , Bashir Mir Iftikhar , Mithal Ambrish 
Published: February 2015

Summary
Nutritional deficiency continues to be an important cause of rickets in the underdeveloped and developing parts of the world. In the western hemisphere, predominantly non-nutritional forms of rickets and osteomalacia are now seen. In this report we discuss a family with X-linked hypophosphataemic rickets from the Kashmir region of the Indian subcontinent (which is an uncommon entity here).