bluuebunny/crossref_metadata_2025 huggingface dataset:
A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Antimalarial Spiroindolone KAE609 (Cipargamin) To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers
Authors: Leong F. Joel , Li Ruobing , Jain Jay Prakash , Lefèvre Gilbert , Magnusson Baldur , Diagana Thierry T. , Pertel Peter
Published: August 2014

This first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC
0–∞
) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUC
last
) and the maximum concentration of drug in plasma (
C
max
) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC
0–24
] on day 3/AUC
0–24
on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (≤0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, the
C
max
was reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses.
Combination of the CCL5-Derived Peptide R4.0 with Different HIV-1 Blockers Reveals Wide Target Compatibility and Synergic Cobinding to CCR5
Authors: Secchi Massimiliano , Vassena Lia , Morin Sébastien , Schols Dominique , Vangelista Luca
Published: August 2014

R4.0, a synthetic CCL5/RANTES-derived peptide, exerts potent anti-HIV-1 activity via its nonactivating interaction with CCR5, the major HIV-1 coreceptor. CCR5 chronic activation may promote undesirable inflammatory effects and enhance viral infection; thus, receptor antagonism is a necessary requisite. HIV-1 gp120, CCL5, and maraviroc dock on CCR5 by sharing two receptor sites: the N terminus and the second extracellular loop. In combination studies, R4.0, CCL5, and maraviroc exhibited concomitant interactions with CCR5 and promoted synergic inhibition of HIV-1 in acute-infection assays. Furthermore, various degrees of additive/synergic HIV-1 inhibition were observed when R4.0 was tested in combination with drugs and lead compounds directed toward different viral targets (gp120, gp41, reverse transcriptase, and protease). In combination with tenofovir, R4.0 provides cross-clade synergic inhibition of primary HIV-1 isolates. Remarkably, an
in vitro
-generated maraviroc-resistant R5 HIV-1 strain was inhibited by R4.0 comparably to the wild-type strain, suggesting the presence of viral resistance barriers similar to those reported for CCL5. Overall, R4.0 appears to be a promising lead peptide with potential for combination in anti-HIV-1 therapy and in microbicide development to prevent sexual HIV-1 transmission.
Masking of β(1-3)-Glucan in the Cell Wall of Candida albicans from Detection by Innate Immune Cells Depends on Phosphatidylserine
Authors: Davis Sarah E. , Hopke Alex , Minkin Steven C. , Montedonico Anthony E. , Wheeler Robert T. , Reynolds Todd B.
Published: August 2014

The virulence of
Candida albicans
in a mouse model of invasive candidiasis is dependent on the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE). Disruption of the PS synthase gene
CHO1
(i.e.,
cho1
Δ/Δ) eliminates PS and blocks the
de novo
pathway for PE biosynthesis. In addition, the
cho1
Δ/Δ mutant's ability to cause invasive disease is severely compromised. The
cho1
Δ/Δ mutant also exhibits cell wall defects, and in this study, it was determined that loss of PS results in decreased masking of cell wall β(1-3)-glucan from the immune system. In wild-type
C. albicans
, the outer mannan layer of the wall masks the inner layer of β(1-3)-glucan from exposure and detection by innate immune effector molecules like the C-type signaling lectin Dectin-1, which is found on macrophages, neutrophils, and dendritic cells. The
cho1
Δ/Δ mutant exhibits increases in exposure of β(1-3)-glucan, which leads to greater binding by Dectin-1 in both yeast and hyphal forms. The unmasking of β(1-3)-glucan also results in increased elicitation of TNF-α from macrophages in a Dectin-1-dependent manner. The role of phospholipids in fungal pathogenesis is an emerging field, and this is the first study showing that loss of PS in
C. albicans
results in decreased masking of β(1-3)-glucan, which may contribute to our understanding of fungus-host interactions.
Characterization of a Lipopolysaccharide-Targeted Monoclonal Antibody and Its Variable Fragments as Candidates for Prophylaxis against the Obligate Intracellular Bacterial Pathogen Coxiella burnetii
Authors: Peng Ying , Schoenlaub Laura , Elliott Alexandra , Mitchell William J. , Zhang Guoquan
Published: August 2014

Our previous study demonstrated that treatment ofCoxiella burnetiiwith the phase I lipopolysaccharide (PI-LPS)-targeted monoclonal antibody (MAb) 1E4 significantly inhibitedC. burnetiiinfection in mice, suggesting that 1E4 is a protective MAb. To determine whether passive transfer of antibodies (Abs) can provide protection againstC. burnetiinatural infection, we examined if passive transfer of 1E4 would protect SCID mice againstC. burnetiiaerosol infection. The results indicated that 1E4 conferred significant protection against aerosolizedC. burnetii, suggesting that 1E4 may be useful for preventingC. burnetiinatural infection. To further understand the mechanisms of 1E4-mediated protection and to test the possibility of using humanized 1E4 to preventC. burnetiiinfection, we examined whether the Fab fragment of 1E4 (Fab1E4), a recombinant murine single-chain variable fragment (muscFv1E4), and a humanized single-chain variable fragment (huscFv1E4) retained the ability of 1E4 to inhibitC. burnetiiinfection. The results indicated that Fab1E4, muscFv1E4, and huscFv1E4 were able to inhibitC. burnetiiinfection in mice but that their ability to inhibitC. burnetiiinfection was lower than that of 1E4. In addition, treatment ofC. burnetiiwith Fab1E4, muscFv1E4, or huscFv1E4 can blockC. burnetiiinfection of macrophages. Interestingly, treatment ofC. burnetiiwith huscFv1E4 can significantly reduceC. burnetiiinfectivity in human macrophages. This report provides the first evidence to demonstrate that the humanized variable fragments of an LPS-specific MAb can neutralizeC. burnetiiinfection and appears to be a promising step toward the potential use of a humanized MAb as emergency prophylaxis againstC. burnetiiexposure.
Glycosylation and Immunoreactivity of the Histoplasma capsulatum Cfp4 Yeast-Phase Exoantigen
Authors: Holbrook Eric D. , Kemski Megan M. , Richer Sarah M. , Wheat L. Joseph , Rappleye Chad A.
Published: August 2014

The yeast phase ofHistoplasma capsulatumis the virulent form of this thermally dimorphic fungal pathogen. Among the secreted proteome ofHistoplasma, culture filtrate protein 4 (Cfp4) is a heavily glycosylated factor produced abundantly and specifically byHistoplasmayeast cells, suggesting its role in pathogenesis. We have generated three monoclonal antibodies as tools for characterization and detection of Cfp4 and determined the epitope each recognizes. Through site-directed mutagenesis of Cfp4, we identified three asparagines that function as the principal sites of N-linked glycan modification. To test the function of Cfp4 inHistoplasmapathogenesis, we generated Cfp4-deficient strains by insertional mutagenesis and by RNA interference. Cfp4-deficient strains are not attenuated in virulence in human macrophages or during lung infection in a murine model of histoplasmosis. Coinfection of differentially marked Cfp4-producing and Cfp4-deficient strains demonstrates that production of Cfp4 does not confer a fitness advantage toHistoplasmayeasts during murine lung infection. Despite no apparent role in acute virulence in mice, secretion of the Cfp4 glycoprotein by yeast cells is consistent across clinical and laboratory isolates of the North American type 1 and type 2 phylogenetic groups as well as a strain from Panama. In addition, human immune sera recognize theHistoplasmaCfp4 protein, confirming Cfp4 production during infection of human hosts. These results suggest the potential utility of Cfp4 as a diagnostic exoantigen for histoplasmosis.
The Serine/Threonine Kinase STK11 Promotes Shigella flexneri Dissemination through Establishment of Cell-Cell Contacts Competent for Tyrosine Kinase Signaling
Authors: Dragoi Ana-Maria , Agaisse Hervé
Published: August 2014

Shigella flexneri
is an intracellular pathogen that disseminates in the intestinal epithelium by displaying actin-based motility. We found that although
S. flexneri
displayed comparable actin-based motilities in the cytosols of HeLa229 and HT-29 epithelial cell lines, the overall dissemination process was much more efficient in HT-29 cells. Time-lapse microscopy demonstrated that as motile bacteria reached the cell cortex in HT-29 cells, they formed membrane protrusions that resolved into vacuoles, from which the bacteria escaped and gained access to the cytosol of adjacent cells. In HeLa229 cells,
S. flexneri
also formed membrane protrusions that extended into adjacent cells, but the protrusions rarely resolved into vacuoles. Instead, the formed protrusions collapsed and retracted, bringing the bacteria back to the cytosol of the primary infected cells. Silencing the serine/threonine kinase STK11 (also known as LKB1) in HT-29 cells decreased the efficiency of protrusion resolution into vacuoles. Conversely, expressing STK11 in HeLa229 cells, which lack the STK11 locus, dramatically increased the efficiency of protrusion resolution into vacuoles.
S. flexneri
dissemination in HT-29 cells led to the local phosphorylation of tyrosine residues in protrusions, a signaling event that was not observed in HeLa229 cells but was restored in STK11-expressing HeLa229 cells. Treatment of HT-29 cells with the tyrosine kinase inhibitor imatinib abrogated tyrosine kinase signaling in protrusions, which correlated with a severe decrease in the efficiency of protrusion resolution into vacuoles. We suggest that the formation of STK11-dependent lateral cell-cell contacts competent for tyrosine kinase signaling promotes
S. flexneri
dissemination in epithelial cells.
The Interleukin-1β/CXCL1/2/Neutrophil Axis Mediates Host Protection against Group B Streptococcal Infection
Authors: Biondo C. , Mancuso G. , Midiri A. , Signorino G. , Domina M. , Lanza Cariccio V. , Mohammadi N. , Venza M. , Venza I. , Teti G. , Beninati C.
Published: August 2014

Previous studies have indicated that group B streptococcus (GBS), a frequent human pathogen, potently induces the release of interleukin-1β (IL-1β), an important mediator of inflammatory responses. Since little is known about the role of this cytokine in GBS disease, we analyzed the outcome of infection in IL-1β-deficient mice. These animals were markedly sensitive to GBS infection, with most of them dying under challenge conditions that caused no deaths in wild-type control mice. Lethality was due to the inability of the IL-1β-deficient mice to control local GBS replication and dissemination to target organs, such as the brain and the kidneys. Moreover, in a model of inflammation induced by the intraperitoneal injection of killed GBS, a lack of IL-1β was associated with selective impairment in the production of the neutrophil chemokines CXCL1 and CXCL2 and in neutrophil recruitment to the peritoneal cavity. Decreased blood neutrophil counts and impaired neutrophil recruitment to the brain and kidneys were also observed during GBS infection in IL-1β-deficient mice concomitantly with a reduction in CXCL1 and CXCL2 tissue levels. Notably, the hypersusceptibility to GBS infection observed in the immune-deficient animals was recapitulated by neutrophil depletion with anti-Gr1 antibodies. Collectively, our data identify a cytokine circuit that involves IL-1β-induced production of CXCL1 and CXCL2 and leads the recruitment of neutrophils to GBS infection sites. Moreover, our data point to an essential role of these cells in controlling the progression and outcome of GBS disease.
Blockade of Indoleamine 2,3-Dioxygenase Reduces Mortality from Peritonitis and Sepsis in Mice by Regulating Functions of CD11b+Peritoneal Cells
Authors: Hoshi Masato , Osawa Yosuke , Ito Hiroyasu , Ohtaki Hirofumi , Ando Tatsuya , Takamatsu Manabu , Hara Akira , Saito Kuniaki , Seishima Mitsuru
Published: August 2014

Indoleamine 2,3-dioxygenase-1 (Ido), which catalyzes the first and limiting step of tryptophan catabolism, has been implicated in immune tolerance. However, the roles of Ido in systemic bacterial infection are complicated and remain controversial. To explore this issue, we examined the roles of Ido in bacterial peritonitis and sepsis after cecal ligation and puncture (CLP) in mice by using the Ido inhibitor 1-methyl-d,l-tryptophan (1-MT), by comparing Ido+/+and Ido−/−mice, or by using chimeric mice in which Ido in the bone marrow-derived cells was deficient. Ido expression in the peritoneal CD11b+cells and its metabolitel-kynurenine in the serum were increased after CLP. 1-MT treatment or Ido deficiency, especially in bone marrow-derived cells, reduced mortality after CLP. Compared to Ido+/+mice, Ido−/−mice showed increased recruitment of neutrophils and mononuclear cells into the peritoneal cavity and a decreased bacterial count in the blood accompanied by increased CXCL-2 and CXCL-1 mRNA in the peritoneal cells. Ido has an inhibitory effect on LPS-induced CXCL-2 and CXCL-1 production in cultured peritoneal cells. These findings indicate that inhibition of Ido reduces mortality from peritonitis and sepsis after CLP via recruitment of neutrophils and mononuclear cells by chemokine production in peritoneal CD11b+cells. Thus, blockade of Ido plays a beneficial role in host protection during bacterial peritonitis and sepsis.
Tick Passage Results in Enhanced Attenuation of Babesia bovis
Authors: Sondgeroth Kerry S. , McElwain Terry F. , Ueti Massaro W. , Scoles Glen A. , Reif Kathryn E. , Lau Audrey O. T.
Published: August 2014

Serial blood passage of virulent
Babesia bovis
in splenectomized cattle results in attenuated derivatives that do not cause neurologic disease. Tick transmissibility can be lost with attenuation, but when retained, attenuated
B. bovis
can revert to virulence following tick passage. This study provides data showing that tick passage of the partially attenuated
B. bovis
T2Bo derivative strain further decreased virulence compared with intravenous inoculation of the same strain in infected animals. Ticks that acquired virulent or attenuated parasites by feeding on infected cattle were transmission fed on naive, splenectomized animals. While there was no significant difference between groups in the number of parasites in the midgut, hemolymph, or eggs of replete female ticks after acquisition feeding, animals infected with the attenuated parasites after tick transmission showed no clinical signs of babesiosis, unlike those receiving intravenous challenge with the same attenuated strain prior to tick passage. Additionally, there were significantly fewer parasites in blood and tissues of animals infected with tick-passaged attenuated parasites. Sequencing analysis of select
B. bovis
genes before and after tick passage showed significant differences in parasite genotypes in both peripheral blood and cerebral samples. These results provide evidence that not only is tick transmissibility retained by the attenuated T2Bo strain, but also it results in enhanced attenuation and is accompanied by expansion of parasite subpopulations during tick passage that may be associated with the change in disease phenotype.
LcrV Delivered via Type III Secretion System of Live Attenuated Yersinia pseudotuberculosis Enhances Immunogenicity against Pneumonic Plague
Authors: Sun Wei , Sanapala Shilpa , Henderson Jeremy C. , Sam Shandiin , Olinzock Joseph , Trent M. Stephen , Curtiss Roy
Published: August 2014

Here, we constructed aYersinia pseudotuberculosismutant strain with arabinose-dependent regulated and delayed shutoff ofcrpexpression (araCPBADcrp) and replacement of themsbBgene with theEscherichia colimsbBgene to attenuate it. Then, we inserted theasdmutation into this construction to form χ10057 [Δasd-206ΔmsbB868::PmsbBmsbB(EC)ΔPcrp21::TTaraCPBADcrp] for use with a balanced-lethal Asd-positive (Asd+) plasmid to facilitate antigen synthesis. A hybrid protein composed of YopE (amino acids [aa]1 to 138) fused with full-length LcrV (YopENt138-LcrV) was synthesized in χ10057 harboring an Asd+plasmid (pYA5199,yopENt138-lcrV) and could be secreted through a type III secretion system (T3SS)in vitroandin vivo. Animal studies indicated that mice orally immunized with χ10057(pYA5199) developed titers of IgG response to whole-cell lysates ofY. pestis(YpL) and subunit LcrV similar to those seen with χ10057(pYA3332) (χ10057 plus an empty plasmid). However, only immunization of mice with χ10057(pYA5199) resulted in a significant secretory IgA response to LcrV. χ10057(pYA5199) induced a higher level of protection (80% survival) against intranasal (i.n.) challenge with ∼240 median lethal doses (LD50) (2.4 × 104CFU) ofY. pestisKIM6+(pCD1Ap) than χ10057(pYA3332) (40% survival). Splenocytes from mice vaccinated with χ10057(pYA5199) produced significant levels of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-17 (IL-17) after restimulation with LcrV and YpL antigens. Our results suggest that it is possible to use an attenuatedY. pseudotuberculosisstrain delivering the LcrV antigen via the T3SS as a potential vaccine candidate against pneumonic plague.
Towards an Informative Mutant Phenotype for Every Bacterial Gene
Authors: Deutschbauer Adam , Price Morgan N. , Wetmore Kelly M. , Tarjan Daniel R. , Xu Zhuchen , Shao Wenjun , Leon Dacia , Arkin Adam P. , Skerker Jeffrey M.
Published: August 2014

Mutant phenotypes provide strong clues to the functions of the underlying genes and could allow annotation of the millions of sequenced yet uncharacterized bacterial genes. However, it is not known how many genes have a phenotype under laboratory conditions, how many phenotypes are biologically interpretable for predicting gene function, and what experimental conditions are optimal to maximize the number of genes with a phenotype. To address these issues, we measured the mutant fitness of 1,586 genes of the ethanol-producing bacterium
Zymomonas mobilis
ZM4 across 492 diverse experiments and found statistically significant phenotypes for 89% of all assayed genes. Thus, in
Z. mobilis
, most genes have a functional consequence under laboratory conditions. We demonstrate that 41% of
Z. mobilis
genes have both a strong phenotype and a similar fitness pattern (cofitness) to another gene, and are therefore good candidates for functional annotation using mutant fitness. Among 502 poorly characterized
Z. mobilis
genes, we identified a significant cofitness relationship for 174. For 57 of these genes without a specific functional annotation, we found additional evidence to support the biological significance of these gene-gene associations, and in 33 instances, we were able to predict specific physiological or biochemical roles for the poorly characterized genes. Last, we identified a set of 79 diverse mutant fitness experiments in
Z. mobilis
that are nearly as biologically informative as the entire set of 492 experiments. Therefore, our work provides a blueprint for the functional annotation of diverse bacteria using mutant fitness.
Mutations in the Primary Sigma Factor σ
A
and Termination Factor Rho That Reduce Susceptibility to Cell Wall Antibiotics
Authors: Lee Yong Heon , Helmann John D.
Published: August 2014

Combinations of glycopeptides and β-lactams exert synergistic antibacterial activity, but the evolutionary mechanisms driving resistance to both antibiotics remain largely unexplored. By repeated subculturing with increasing vancomycin (VAN) and cefuroxime (CEF) concentrations, we isolated an evolved strain of the model bacterium
Bacillus subtilis
with reduced susceptibility to both antibiotics. Whole-genome sequencing revealed point mutations in genes encoding the major σ factor of RNA polymerase (
sigA
), a cell shape-determining protein (
mreB
), and the ρ termination factor (
rho
). Genetic-reconstruction experiments demonstrated that the G-to-C substitution at position 336 encoded by
sigA
(
sigA
G336C
), in the domain that recognizes the −35 promoter region, is sufficient to reduce susceptibility to VAN and works cooperatively with the
rho
G56C
substitution to increase CEF resistance. Transcriptome analyses revealed that the
sigA
G336C
substitution has wide-ranging effects, including elevated expression of the general stress σ factor (σ
B
) regulon, which is required for CEF resistance, and decreased expression of the
glpTQ
genes, which leads to fosfomycin (FOS) resistance. Our findings suggest that mutations in the core transcriptional machinery may facilitate the evolution of resistance to multiple cell wall antibiotics.
PTEN hamartoma tumour syndrome: early tumour development in children
Authors: Smpokou Patroula , Fox Victor L , Tan Wen-Hann
Published: August 2014

Objective

The aim of this study was to report the earliest age of diagnosis of common clinical findings in children with PTEN hamartoma tumour syndrome (PHTS).

Design

Medical records of children with PHTS were reviewed; data included growth measurements, presence or absence of specific clinical manifestations and tumours, and documented ages of diagnosis.

Setting

Children with PHTS evaluated at Boston Children's Hospital from 1996 to 2011.

Patients

The cohort included 34 children diagnosed with PHTS via genetic testing, under the age of 21 years. Of these, 23 were male and 11 female. The mean age at their last documented clinical evaluation was 13.6 years. The mean follow-up time was 7.5 years.

Results

Macrocephaly and developmental/intellectual disability were consistent findings. Pigmented penile macules were noted in all males examined for this finding. Thyroid nodules, found in half the children screened with ultrasound, were diagnosed as early as at 5 years of age. Thyroid carcinoma, identified in 12% of the children in this cohort, was diagnosed as early as at 7 years of age. Other tumours included renal cell carcinoma diagnosed at 11 years of age and granulosa cell tumour of the ovary and colonic ganglioneuroma, each diagnosed at 16 years of age.

Conclusions

Specific clinical findings and tumours are characteristic in children with PHTS. Tumour development occurs in young children with this condition, which necessitates early surveillance, especially of the thyroid.
Contraceptive confidence and timing of first birth in Moldova: an event history analysis of retrospective data
Authors: Lyons-Amos Mark , Padmadas Sabu S , Durrant Gabriele B
Published: August 2014

Objectives

To test the contraceptive confidence hypothesis in a modern context. The hypothesis is that women using effective or modern contraceptive methods have increased contraceptive confidence and hence a shorter interval between marriage and first birth than users of ineffective or traditional methods. We extend the hypothesis to incorporate the role of abortion, arguing that it acts as a substitute for contraception in the study context.

Setting

Moldova, a country in South-East Europe. Moldova exhibits high use of traditional contraceptive methods and abortion compared with other European countries.

Participants

Data are from a secondary analysis of the 2005 Moldovan Demographic and Health Survey, a nationally representative sample survey. 5377 unmarried women were selected.

Primary and secondary outcome measures

The outcome measure was the interval between marriage and first birth. This was modelled using a piecewise-constant hazard regression, with abortion and contraceptive method types as primary variables along with relevant sociodemographic controls.

Results

Women with high contraceptive confidence (modern method users) have a higher cumulative hazard of first birth 36 months following marriage (0.88 (0.87 to 0.89)) compared with women with low contraceptive confidence (traditional method users, cumulative hazard: 0.85 (0.84 to 0.85)). This is consistent with the contraceptive confidence hypothesis. There is a higher cumulative hazard of first birth among women with low (0.80 (0.79 to 0.80)) and moderate abortion propensities (0.76 (0.75 to 0.77)) than women with no abortion propensity (0.73 (0.72 to 0.74)) 24 months after marriage.

Conclusions

Effective contraceptive use tends to increase contraceptive confidence and is associated with a shorter interval between marriage and first birth. Increased use of abortion also tends to increase contraceptive confidence and shorten birth duration, although this effect is non-linear—women with a very high use of abortion tend to have lengthy intervals between marriage and first birth.
Effects of the First Line Diabetes Care (FiLDCare) self-management education and support project on knowledge, attitudes, perceptions, self-management practices and glycaemic control: a quasi-experimental study conducted in the Northern Philippines
Authors: Ku Grace Marie V , Kegels Guy
Published: August 2014

Objectives

To investigate the effects of implementing a context-adapted diabetes self-management education and support (DSME/S) project based on chronic care models in the Philippines, on knowledge, attitudes, self-management practices, adiposity/obesity and glycaemia of people with diabetes.

Design

Prospective quasi-experimental before–after study.

Participants

203 people with type 2 diabetes mellitus from two local government units in the Northern Philippines fulfilling set criteria.

Outcome measures

Context-adapted DSME/S was given to a cohort of people with diabetes by trained pre-existing local government healthcare personnel. Changes in knowledge, attitudes and self-management practices, body mass index, waist circumference, waist-hip ratio (WHR) and glycosylated haemoglobin (HbA1c) were measured 1 year after full project implementation. Non-parametric and parametric descriptive and inferential statistics including logistic regression analysis were done.

Results

Complete data were collected from 164 participants. Improvements in glycaemia, waist circumference, WHR, knowledge, some attitudes, adherence to medications and exercise, and an increase in fear of diabetes were significant. Reductions in HbA1c, regardless of level of control, were noted in 60.4%. Significant increase in knowledge (p<0.001), positive attitude (p=0.013), perceived ability to control blood glucose (p=0.004) and adherence to medications (p=0.001) were noted among those whose glycaemia improved. Significant differences between the subgroups whose HbA1c improved and those whose HbA1c deteriorated include male gender (p=0.042), shorter duration of diabetes (p=0.001) and increased perceived ability to control blood glucose (p=0.042). Significant correlates to improved glycaemia were male gender (OR=2.655; p=0.034), duration of diabetes >10 years (OR=0.214; p=0.003) and fear of diabetes (OR=0.490; p=0.048).

Conclusions

Context-adapted DSME/S introduced in resource-constrained settings and making use of established human resources for health may improve knowledge, attitudes, self-management practices and glycaemia of recipients. Further investigations on addressing fear of diabetes and tailoring DSME/S to females with diabetes and those who have had diabetes for a longer period of time may help improve glycaemia.
Pneumococcal colonisation density: a new marker for disease severity in HIV-infected adults with pneumonia
Authors: Albrich Werner C , Madhi Shabir A , Adrian Peter V , van Niekerk Nadia , Telles Jean-Noel , Ebrahim N , Messaoudi Melina , Paranhos-Baccalà Glaucia , Giersdorf Sven , Vernet Guy , Mueller Beat , Klugman Keith P
Published: August 2014

Objective

A high genomic load ofPneumococcusfrom blood or cerebrospinal fluid has been associated with increased mortality. We aimed to analyse whether nasopharyngeal colonisation density in HIV-infected patients with community-acquired pneumonia (CAP) is associated with markers of disease severity or poor outcome.

Methods

QuantitativelytAreal-time PCR was performed on nasopharyngeal swabs in HIV-infected South African adults hospitalised for acute CAP at Chris Hani Baragwanath Hospital, Soweto, South Africa. Pneumonia aetiology was considered pneumococcal if any sputum culture or Gram stain, urinary pneumococcal C-polysaccharide-based antigen, blood culture or whole bloodlytAreal-time PCR revealed pneumococci.

Results

There was a moderate correlation between the mean nasopharyngeal colonisation densities and increasing CURB65 scores among all-cause patients with pneumonia (Spearman correlation coefficient r=0.15, p=0.06) or with the Pitt bacteraemia score among patients with pneumococcal bacteraemia (p=0.63). In patients with pneumococcal pneumonia, nasopharyngeal pneumococcal colonisation density was higher among non-survivors than survivors (7.7 vs 6.1 log10copies/mL, respectively, p=0.02) and among those who had pneumococci identified from blood cultures and/or by whole bloodlytAreal-time PCR than those with non-bacteraemic pneumococcal pneumonia (6.6 vs 5.6 log10copies/mL, p=0.03). Nasopharyngeal colonisation density correlated positively with the biomarkers procalcitonin (Spearman correlation coefficient r=0.37, p<0.0001), proadrenomedullin (r=0.39, p=0.008) and copeptin (r=0.30, p=0.01).

Conclusions

In addition to its previously reported role as a diagnostic tool for pneumococcal pneumonia, quantitative nasopharyngeal colonisation density also correlates with mortality and prognostic biomarkers. It may also be useful as a severity marker for pneumococcal pneumonia in HIV-infected adults.
Urate urolithiasis and hyperuricosuria in a Weimaraner, secondary to the SLC2A9 transporter defect
Authors: Westropp Jodi L. , Johnson Eric G. , Fuller Mark C. , Safra Noa , Bannasch Danika L.
Published: August 2014

In this case, we describe a middle‐aged, male Weimaraner that presented with upper and lower urinary tract urate urolithiasis. The dog required surgical intervention to remove the obstruction in the right ureter as well as medical management to prevent recurrent calculi. While the genetic defect that causes this disease in Dalmatians is well known among clinicians, this is the first clinical case documented in the Weimaraner breed. This dog shared the same SLC2A9 mutation as Dalmatians, which likely predisposed this dog to developing urate calculi. For dogs where urate uroliths are suspected on imaging studies, genetic testing may be warranted to help elucidate any predisposing factors for stone formation. Knowing the aetiology of the stone formation will alter the therapeutic approach for treatment and management.
Fanconi syndrome in a Bichon Maltese dog: a quantitative approach to acid–base analysis
Authors: Mesa‐Sánchez Ignacio , Purzycka Katarzyna , Isidoro‐Ayza Marcos , Ruiz de Gopegui‐Fernández Rafael
Published: August 2014

A three‐year‐old female Bichon Maltese dog presented with inappetence, polyuria, polydipsia, weakness, weight loss, seborrhoea and hypotrichosis. Diagnostic test results were consistent with Fanconi syndrome (euglycaemic glucosuria, hypophosphataemia, hyponatraemia, hypokalaemia, normal anion gap metabolic acidosis, proteinuria, aminoaciduria and increased urinary excretion of electrolytes). The dog died eight months after diagnosis and histopathological findings consisted of diffuse renal tubular necrosis. Fanconi syndrome is a rare disorder in veterinary medicine associated with a reabsorption defect of the proximal renal tubules, resulting in renal tubular acidosis. A quantitative approach to acid–base analysis was applied in this patient. Initial presentation of acidaemia was mainly due to hyponatraemia (increased free water effect) and increased Cl− effect. The severe acidaemia observed seven months after initial presentation was primarily associated with hypoperfusion (raised lactate effect), increased unmeasured anions effects and hyponatraemia. A quantitative approach could be more appropriate than a traditional approach in Fanconi syndrome because it considers more of the individual factors affecting the acid–base balance (sodium, chloride, lactate, albumin, phosphate and unmeasured anions), all of which are altered in affected patients.
Disseminated histiocytic sarcoma in an English springer spaniel presenting as primary cardiac disease
Authors: Cobb Malcolm , Ingram Babs , Brower Alexandra
Published: August 2014

A four‐year‐old female English springer spaniel presented following an episode of weakness at home. On examination, the heart rate was very rapid and irregular, the pulses weak, and there were pulse deficits. An ECG showed a wide complex tachycardia, and echocardiography showed eccentric left ventricular dilatation and poor systolic function, serum troponin level was elevated. A presumptive diagnosis of myocarditis or dilated cardiomyopathy was made and the dog had a good initial response to treatment with mexiletine and later sotalol. Fifteen weeks later the dog developed respiratory difficulty, and a diffuse, nodular, interstitial lung pattern was evident throughout the lung fields on thoracic radiographs, and the owners elected to have the dog euthanased. On postmortem examination, a diagnosis of disseminated histiocytic sarcoma was made, with lesions found most extensively in the heart. Infiltrative myocardial disease should be considered as a potential diagnosis in patients with unexplained structural cardiac disease.
Histiocytic sarcoma in a flat‐coated retriever with central and peripheral nervous system sarcomatosis
Authors: Marcinowska A. , Constantino‐Casas F. , Dobson J. M.
Published: August 2014

A six‐year‐old male, neutered, flat‐coated retriever presented with a suspicion of localised histiocytic sarcoma (HS) in the right axillary region, fine needle aspirate was suggestive of HS. The dog was prescribed four doses of radiotherapy (4×850 cGy). At the first treatment tru‐cut biopsies of the mass were taken, and histopathology was consistent with the cytological diagnosis. At the third treatment, the dog developed five cutaneous nodules, and microscopy confirmed HS. Seven weeks after radiotherapy, the patient presented with severe progressive hind limb ataxia and a flaccid tail. Due to the severity of clinical signs, euthanasia was performed. Postmortem examination revealed neoplastic cells within the right axillary mass, liver, kidney, adrenal gland and diffusely infiltrating the brain, lumbar spinal cord, cauda equina and spinal nerves, consistent with metastatic HS. This case is unusual in the diffuse and infiltrative dissemination of the tumour throughout the CNS and nerve roots.
Biaxial plantar process fractures of the distal phalanx in a horse
Authors: Meehan Lucinda Jayne , Cillan‐Garcia Eugenio , Parker Russell
Published: August 2014

A mature horse was presented for investigation of severe acute hindlimb lameness with soft tissue swelling, a full thickness wound to the dorsal metatarsus and no other localising signs. Survey radiographs of the metatarsophalangeal region were unremarkable. Nuclear scintigraphy was required to reach a diagnosis of biaxial plantar process fractures of the distal phalanx, which to the authors’ knowledge is previously unreported. Flexed dorsal 45° lateral‐plantaromedial and flexed dorsal 45° medial‐plantarolateral oblique projections confirmed the diagnosis of both a type I and II fracture in the same foot. Treatment with cast immobilisation and corrective farriery was successful, and the horse became sound at six‐month follow‐up.
The use of bougie‐guided insertion of a laryngeal mask airway device in neonatal piglets after unexpected complications
Authors: Morath Ute , Skogmo Hege Kippenes , Ranheim Birgit , Levionnois Olivier Louis
Published: August 2014

After marked airway obstruction with laryngeal mask (LM) placement in neonate piglets, anatomical observations in cadavers revealed a large epiglottis advancing markedly over the soft palate. CT imaging in vivo confirmed that the LM pushes the epiglottis caudally thereby obstructing the larynx. As a new approach, in 20 piglets a flexible PVC bougie placed under laryngoscopy was used to guide the LM to the correct position at the larynx. Placement of the bougie was easy and the LM was positioned successfully in all piglets at first attempt. In 14 piglets, the epiglottis was positioned dorsal to the soft palate before LM insertion and had to be pushed downwards to advance the bougie. In case of failure of LM placement with potential airway obstruction, the use of a bougie to guide the LM over the epiglottis was simple, rapid, and improved the success rate without complication.
Maxillectomy for the treatment of a recurrent nasal adenocarcinoma in a cat
Authors: Janovec Jan , L'Eplattenier Henry
Published: August 2014

An 11‐year‐old, male neutered, domestic shorthair cat was referred with recurrence of unilateral epistaxis, approximately three years after radiotherapy treatment for low‐grade nasal adenocarcinoma. A CT scan of the head showed a mass localised within the left nasal cavity invading the left maxillary bone. Maxillectomy was performed to allow removal of all visible neoplastic tissue and an oesophagostomy tube was placed after the procedure to facilitate feeding in the early postoperative period. During the first 24 hours after surgery, epistaxis was noted, and five days after maxillectomy, the nasal discharge became purulent so the cat was administered broad‐spectrum antibiotic. The cat was discharged from hospital 11 days after surgery. The owner reported a good clinical outcome 12 months after surgery. Even though surgery is not the preferred treatment for nasal adenocarcinoma, this case report shows that surgery represents a reasonable treatment option to manage selected cases of recurrent nasal tumours after radiotherapy, and that a good outcome can be obtained despite all the pitfalls associated with this type of surgery in cats. No report discussing treatment options for locally recurrent non‐lymphoproliferative nasal tumours in the cat has been published to date.
Use of acoustoelastography to evaluate tendon healing after surgical repair of an Achilles mechanism laceration and rehabilitation with a custom tarsal orthotic splint in a dog
Authors: Hans E. C. , Sample S. J. , Duenwald‐Kuehl S. E. , Vanderby R. , Muir P.
Published: August 2014

Achilles mechanism laceration in dogs is commonly treated by suture repair and temporary tarsal immobilisation. Acoustoelastography is an ultrasound technique that can relate changes in ultrasonic wave amplitude to a tendon's mechanical properties. This report describes use of this novel technique for monitoring mechanical healing of an Achilles tendon laceration in a dog after suture repair. A three‐year‐old spayed female Duck Tolling Retriever was diagnosed with complete laceration of the Achilles mechanism after traumatic injury. Suture repair was performed with temporary tarsal immobilisation by use of a custom hinged orthotic splint. Acoustoelastography examination was performed immediately after surgery, 6, 16, 22 and 29 weeks after surgery. Tarsal range of motion was gradually increased after surgery by staged modification of the splint. Serial acoustoelastography examinations demonstrated improving mechanical properties throughout the recovery period. At 29 weeks, mechanical properties of the repaired tendon approximated that of the normal contralateral Achilles mechanism.
Monozygotic incomplete caudal duplication in a German Holstein calf
Authors: Freick M. , Behn H. , Hardt M. , Knobloch S. , Eftekharzadeh B. , Schütz E. , Brenig B.
Published: August 2014

Congenital duplications are rare entities in cattle. This report deals with an incomplete caudal duplication case of a dairy calf, which exhibited a supernumerary limb attached to the pelvic region, a polydactyly, a bifid scrotum containing one testis each, a diphallus, an atresia ani and a recto‐vesical fistula. Genotyping of the tissues of the calf and the pygomelus using the bovine SNP50 v2 BeadChip demonstrated that the origin of this malformation was from one zygote.
Idiopathic eosinophilic enteritis in a pet goat
Authors: Groenevelt Margit , Busschers Evita , Fews Debra , Grogono‐Thomas Rose
Published: August 2014

A young goat referred to Langford Veterinary Services presented with chronic diarrhoea and weight loss with good appetite. Previous treatment with anthelmintics, coccidiostats and two courses of antibiotics had not resulted in improvement. On clinical examination, no abnormalities were detected except diarrhoea. Haematology revealed an elevated white blood cell count; biochemistry, faecal egg counts and an abdominal ultrasound revealed no abnormalities. A course of trimethoprim‐sulfadiazine and meloxicam was started for a suspected chronic intestinal inflammation. Twelve days after start of treatment, the goat presented with lethargy, inappetance and abdominal pain. Abdominal radiographs revealed distended large intestines with free fluid in the abdomen. An exploratory laparotomy was performed. Small quantities of fibrin around the colon were detected. Histological biopsies taken from the mid jejunum, caecum and colon revealed severe eosinophilic enteritis and typhlitis and a mild eosinophilic colitis. On the first day of immunosuppressive treatment, the animal deteriorated and was euthanised.
Rapidly growing primary malignant teratoid medulloepithelioma of the ciliary body in a gelding
Authors: van Bergen Thomas , De Vries Cynthia , Ducatelle Richard , Martens Ann , Gasthuys Frank
Published: August 2014

Intraocular medulloepithelioma is a relatively rare tumour in horses which is difficult to differentiate from retinoblastoma. The rate of growth of this tumour has not been investigated so far. We present a case of a primary intraocular teratoid malignant medulloepithelioma in a four‐year‐old gelding that was unilaterally blind at presentation. Repeated examination revealed rapid growth of the tumour. After enucleation of the affected eye, the horse returned to its former level of performance without recurrence for 12 months postoperatively. The histological and immunohistochemical examination of the mass clearly confirmed the malignancy of the tumour. Clinicians should be aware of the potential malignant behaviour of intraocular neoplasias. Immunohistochemistry plays an important role in the final diagnosis.
A case of infectious pericardial effusion and tamponade in a guinea pig (Cavia porcellus) associated with a multiresistant staphylococcus
Authors: Quinton Jean‐François , Valentin Suzy , Ruel Yannick
Published: August 2014

A three‐year‐old female guinea pig was presented for an acute onset of lethargy and dyspnoea and was subsequently diagnosed with pericardial effusion and cardiac tamponade. Bacterial culture of the fluid obtained from ultrasound‐guided pericardiocentesis revealed a coagulase‐negative multiresistant staphylococcus. Pericardiocentesis and antibiotic therapy resulted in complete resolution of the pericardial effusion. As the staphylococcus was resistant to many antibiotics and the owner was diagnosed a few weeks prior with cutaneous multiresistant staphylococcal infection, it was speculated that the source of the septic pericardial effusion may have been the owner.
Unusual presentation of a T‐cell‐rich large B‐cell lymphoma in the nictitating membrane in a seven‐year‐old Bavarian warmblood gelding
Authors: Rushton James Oliver , Fuchs‐Baumgartinger Andrea , Nell Barbara
Published: August 2014

A seven‐year‐old, 550‐kg, Bavarian warmblood gelding was referred to the Ophthalmology Service of the Veterinary University Vienna, due to a mass on the bulbar aspect of the nictitating membrane of the left eye. Thorough ophthalmic examination of the left eye revealed a red‐pink mass, about 1 cm in diameter and 4 mm thickness, on the bulbar aspect of the nictitating membrane. Histopathological and immunohistological examination of the excised mass identified a T‐cell‐rich large B‐cell lymphoma. Follow‐up examination revealed no recurrence of the mass 18 months after initial presentation. To the authors' knowledge this is the first report of a histopathologically confirmed T‐cell‐rich large B‐cell lymphoma of the ocular adnexa in the horse, with no recurrence or metastasis 18 months after initial presentation.
BoLA‐1 antibodies and the induction of bovine neonatal pancytopenia: a twin calves study
Authors: Kasonta Rahel , Sauter‐Louis Carola , Holsteg Mark , Cussler Klaus , Bastian Max
Published: August 2014

Bovine neonatal pancytopenia (BNP) is a vaccine‐induced alloimmune disease. The syndrome affects young calves and is characterised by haemorrhages, pancytopenia and severe destruction of the haematopoietic tissue. Recent evidence indicates that vaccine‐induced alloantibodies target bovine major histocompatibility complex class I (MHC‐I) antigens (bovine leucocyte antigen 1 (BoLA‐1)). However, whether BoLA‐1‐specific antibodies suffice to induce BNP is still a matter of debate. In the current case study, we investigate samples from twin calves where only one calf succumbed to BNP. The fraternal twin also ingested high amounts of BoLA‐1‐specific alloantibodies but it did not develop BNP because the maternal antibodies did not recognise its BoLA‐1 alleles. This association between lack of BoLA‐1 binding and the absence of disease provides another important piece of evidence that BoLA‐1‐specific alloantibodies play a role in the induction of BNP.
Successful management of infected wounds in a fallow deer (Dama dama)
Authors: Tsioli Vassiliki , Galatos Apostolos D , Papadimitriou Seraphim , Ballomenos Dimitrios
Published: August 2014

A two‐year‐old female fallow deer (Dama dama) weighing 29.6 kg was presented with multiple, large and heavily infected wounds at the right mammary, inguinal and femoral areas, caused by the antlers of a male fallow deer five days earlier, lameness of the right hindlimb, anorexia and general dullness. Radiography revealed no fractures. The deer was anaesthetised with a mixture of pethidine, xylazine, ketamine and isoflurane and the wounds were lavaged under pressure and debrided. Some of the wounds were sutured and drained, while others were left to heal by second intention. Topical and systemic antibiotics were administered. Two days postoperatively the deer's condition was greatly improved and one month later all the wounds were completely healed. It seems that following the principles of wound management may effectively treat large and heavily infected wounds in cervids.