Expectations and outcomes of varying treatment strategies for CML presenting during pregnancy.

Diagnosing chronic myeloid leukaemia (CML) during pregnancy is rare. Tyrosine kinase inhibitors (TKIs) have traditionally been contraindicated owing to their teratogenicity. Management decisions should consider the risks to mother and foetus of uncontrolled disease and teratogenic medications. Further cases are required to build upon the paucity of current literature. We report 22 cases of CML diagnosed during pregnancy from 2002 to date. Twenty-one pregnancies resulted in healthy babies and one patient miscarried. Some patients remained untreated throughout pregnancy but the majority received one or both of interferon-α and leucapheresis. One patient was started on imatinib at Week 26, and one on hydroxycarbamide in the third trimester. We report haematological parameters during pregnancy to provide clinicians with realistic expectations of management. There were no fetal abnormalities related to treatment during pregnancy. Seventeen patients achieved at least major molecular response on first-line TKI. A diagnosis of CML during pregnancy can be managed without significant consequences for mother or child. Leucapheresis and interferon-α are generally safe throughout pregnancy. Despite having been avoided previously, there is growing evidence that certain TKIs may be used in particular circumstances during the later stages of pregnancy. Future work should aim to further elucidate this safety profile.

Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs.

Short-term memory dysfunction is a key early feature of Alzheimer's disease (AD). Psychiatric patients may be at higher risk for memory dysfunction and subsequent AD due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to discover blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were subsequently prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in AD. The top candidate biomarkers were then tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment. The best overall evidence was for a series of new, as well as some previously known genes, which are now newly shown to have functional evidence in humans as blood biomarkers: RAB7A, NPC2, TGFB1, GAP43, ARSB, PER1, GUSB, and MAPT. Additional top blood biomarkers include GSK3B, PTGS2, APOE, BACE1, PSEN1, and TREM2, well known genes implicated in AD by previous brain and genetic studies, in humans and animal models, which serve as reassuring de facto positive controls for our whole-genome gene expression discovery approach. Biological pathway analyses implicate LXR/RXR activation, neuroinflammation, atherosclerosis signaling, and amyloid processing. Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for brain pathological changes. A majority of top biomarkers also have evidence for involvement in other psychiatric disorders, particularly stress, providing a molecular basis for clinical co-morbidity and for stress as an early precipitant/risk factor. Some of them are modulated by existing drugs, such as antidepressants, lithium and omega-3 fatty acids. Other drug and nutraceutical leads were identified through bioinformatic drug repurposing analyses (such as pioglitazone, levonorgestrel, salsolidine, ginkgolide A, and icariin). Our work contributes to the overall pathophysiological understanding of memory disorders and AD. It also opens new avenues for precision medicine- diagnostics (assement of risk) as well as early treatment (pharmacogenomically informed, personalized, and preventive).

Double-lumen tracheal tubes and bougies: a bench study to investigate factors that influence the risk of shearing.

Tracheal intubation with a double-lumen tube can be more challenging than with a single-lumen tube. A bougie can be used to facilitate intubation. Case reports have described fragment shearing from bougies when they are removed from the tube after intubation. These fragments have the potential to cause harm. It has even been suggested that bougies and double-lumen tubes should not be used together. We conducted a benchtop trial to investigate factors that influence the risk of shearing. We investigated three brands of double-lumen tube (each in three sizes and both lateralities) and four brands of bougie. We simulated one intubation and 29 further insertions/removals of bougie with every bougie-double-lumen tube combination. We inspected the inside of the tube for evidence of shearing after first, tenth and thirtieth removals. We found that brand of bougie, brand of double-lumen tube and size of double-lumen tube (but not its laterality) all influenced the degree of shearing. Certain bougie-double-lumen tube combinations produced a particularly high degree of shearing, so these should be avoided.

Quantitative trait locus mapping and functional genomics of an organophosphate resistance trait in the western corn rootworm, Diabrotica virgifera virgifera.

The western corn rootworm, Diabrotica virgifera virgifera, is an insect pest of corn and population suppression with chemical insecticides is an important management tool. Traits conferring organophosphate insecticide resistance have increased in frequency amongst D. v. virgifera populations, resulting in the reduced efficacy in many corn-growing regions of the USA. We used comparative functional genomic and quantitative trait locus (QTL) mapping approaches to investigate the genetic basis of D. v. virgifera resistance to the organophosphate methyl-parathion. RNA from adult methyl-parathion resistant and susceptible adults was hybridized to 8331 microarray probes. The results predicted that 11 transcripts were significantly up-regulated in resistant phenotypes, with the most significant (fold increases ≥ 2.43) being an α-esterase-like transcript. Differential expression was validated only for the α-esterase (ST020027A20C03), with 11- to 13-fold greater expression in methyl-parathion resistant adults (P < 0.05). Progeny with a segregating methyl-parathion resistance trait were obtained from a reciprocal backcross design. QTL analyses of high-throughput single nucleotide polymorphism genotype data predicted involvement of a single genome interval. These data suggest that a specific carboyxesterase may function in field-evolved corn rootworm resistance to organophosphates, even though direct linkage between the QTL and this locus could not be established.

Dead space: the physiology of wasted ventilation.

An elevated physiological dead space, calculated from measurements of arterial CO2 and mixed expired CO2, has proven to be a useful clinical marker of prognosis both for patients with acute respiratory distress syndrome and for patients with severe heart failure. Although a frequently cited explanation for an elevated dead space measurement has been the development of alveolar regions receiving no perfusion, evidence for this mechanism is lacking in both of these disease settings. For the range of physiological abnormalities associated with an increased physiological dead space measurement, increased alveolar ventilation/perfusion ratio (V'A/Q') heterogeneity has been the most important pathophysiological mechanism. Depending on the disease condition, additional mechanisms that can contribute to an elevated physiological dead space measurement include shunt, a substantial increase in overall V'A/Q' ratio, diffusion impairment, and ventilation delivered to unperfused alveolar spaces.

Performance of influenza-specific triage tools in an H1N1-positive cohort: P/F ratio better predicts the need for mechanical ventilation and critical care admission.

BACKGROUND: Pandemic influenza presents a major threat to global health and socioeconomic well-being. Future demand for critical care may outstrip supply and force clinicians to triage patients for admission. We evaluated the Simple Triage Scoring System (STSS), Ontario Health Plan for an Influenza Epidemic (OHPIP) and PaO2 /FiO2  (P/F) ratio to determine utility in predicting need for mechanical ventilation. METHODS: We conducted a retrospective case note review of patients admitted to two centres, Royal Liverpool University Hospital and Countess of Chester Hospital, during the UK influenza pandemic of 2010-11. Demand for critical care during this period forced hospitals in Cheshire and Merseyside to implement escalation policies and increase capacity. Inclusion criteria were polymerase chain reaction-confirmed H1N1 influenza and age >18 years. Exclusion criteria were no evidence of treatment for influenza, patient not admitted to hospital or the inability to locate case notes. RESULTS: One hundred and one patients were included, 29 were admitted to critical care and 23 required mechanical ventilation. The P/F ratio predicted the need for mechanical ventilation with a receiver operating characteristic area under the curve (ROC AUC) of 0.885 (CI 0.817-0.952). Predictive ability was not reduced when the P/F ratio had to be estimated using the Pandharipande tool. The STSS score predicted the need for mechanical ventilation [ROC AUC 0.798 (CI 0.704-0.891)]. The reverse triage component of the OHPIP tool was a poor predictor of patient outcome. CONCLUSIONS: The P/F ratio was a better predictor of need for mechanical ventilation than STSS. The P/F ratio is a simple and accepted determinant of hypoxaemia and should be used if secondary triaging becomes necessary during future influenza pandemics.

Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials.

INTRODUCTION: Botulinum toxin A (BTA) injection into the glabellar region is currently being studied as a treatment for major depressive disorder (MDD). Here we explore efficacy data of this novel approach in a pooled analysis. METHODS: A literature search revealed 3 RCTs on this topic. Individual patient data and clinical end points shared by these 3 trials were pooled and analyzed as one study (n=134) using multiple regression models with random effects. RESULTS: In the pooled sample, the BTA (n=59) and the placebo group (n=75) did not differ in the baseline variables. Efficacy outcomes revealed BTA superiority over placebo: Improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale 6 weeks after baseline was 45.7% for BTA vs. 14.6% for placebo (p<0.0001), corresponding to a BTA response rate of 54.2% (vs. 10.7%) and a BTA remission rate of 30.5% (vs. 6.7%). DISCUSSION: Equalling the status of a meta-analysis, this study increases evidence that a single treatment of BTA into the glabellar region can reduce symptoms of MDD. Further studies are needed to better understand how BTA exerts its mood-lifting effect.

Biliary epithelial senescence and plasticity in acute cellular rejection.

Biliary epithelial cells (BEC) are important targets in some liver diseases, including acute allograft rejection. Although some injured BEC die, many can survive in function compromised states of senescence or phenotypic de-differentiation. This study was performed to examine changes in the phenotype of BEC during acute liver allograft rejection and the mechanism driving these changes. Liver allograft sections showed a positive correlation (p < 0.0013) between increasing T cell mediated acute rejection and the number of BEC expressing the senescence marker p21(WAF1/Cip) or the mesenchymal marker S100A4. This was modeled in vitro by examination of primary or immortalized BEC after acute oxidative stress. During the first 48 h, the expression of p21(WAF1/Cip) was increased transiently before returning to baseline. After this time BEC showed increased expression of mesenchymal proteins with a decrease in epithelial markers. Analysis of TGF-ß expression at mRNA and protein levels also showed a rapid increase in TGF-ß2 (p < 0.006) following oxidative stress. The epithelial de-differentiation observed in vitro was abrogated by pharmacological blockade of the ALK-5 component of the TGF-ß receptor. These data suggest that stress induced production of TGF-ß2 by BEC can modify liver allograft function by enhancing the de-differentiation of local epithelial cells.

Odorant receptors of a primitive hymenopteran pest, the wheat stem sawfly.

The wheat stem sawfly, Cephus cinctus, is an herbivorous hymenopteran that feeds exclusively on members of the Graminae family. Synanthropically, it has become one of the most important insect pests of wheat grown in the northern Great Plains region of the USA and Canada. Insecticides are generally ineffective because of the wheat stem sawfly's extended adult flight period and its inaccessible larval stage, during which it feeds within the wheat stems, making it virtually intractable to most pest management strategies. While research towards integrated pest management strategies based on insect olfaction has proved promising, nothing is known about the molecular basis of olfaction in this important pest species. In this study we identified 28 unique odorant receptor (Or) transcripts from an antennal transcriptome. A phylogenetic analysis with the predicted Ors from the honey bee and jewel wasp genomes revealed at least four clades conserved amongst all three Hymenoptera species. Antennal expression levels were analysed using quantitative real-time PCR, and one male-biased and five female-biased Ors were identified. This study provides the basis for future functional analyses to identify behaviourally active odours that can be used to help develop olfactory-mediated pest management tools.

Cardiopulmonary exercise testing for heart failure: pathophysiology and predictive markers.

Despite the numerous recent advancements in therapy, heart failure (HF) remains a principle cause of both morbidity and mortality. HF with preserved ejection fraction (HFpEF), a condition that shares the prevalence and adverse outcomes of HF with reduced ejection fraction, remains poorly recognised in its initial manifestations. Cardiopulmonary exercise testing (CPET), defined as a progressive work exercise test that includes non-invasive continuous measurement of cardiovascular and respiratory parameters, provides a reliable mode to evaluate for early features and for the assessment of prognostic features of both forms of HF. While CPET measurements are standard of care for advanced HF and transplant programmes, they merit a broader clinical application in the early diagnosis and assessment of patients with HFpEF. In this review, we provide an overview of the pathophysiology of exercise intolerance in HF and discuss key findings in CPETs used to evaluate both severity of impairment and the prognostic implications.

Managing women of childbearing age with chronic myeloid leukemia: safety and treatment considerations.

INTRODUCTION: TKIs are paradigmatic in CML management and offer patients the prospect of a normal life expectancy. As a consequence, the focus of both the clinician and patient has shifted to considerations of quality of life, including the ability to parent children. Unfortunately, TKIs are teratogenic so that alternative treatment options may be required during pregnancy to adequately control disease and minimize risk. AREAS COVERED: In this review, we summarize and provide an overview of the literature on the management of CML in women of childbearing age. We discuss the various treatment options as well as their advantages, disadvantages, and safety considerations. We discuss CML in the context of: 1) planned pregnancies with CML; 2) unplanned pregnancies with CML; 3) CML diagnosed during pregnancy. EXPERT OPINION: Confidence in managing pregnancy and CML continues to grow. In the majority of cases, with careful planning and counseling, no treatment is required and disease control can be safely regained after pregnancy ends. For those who require treatment, various options are available and there is growing evidence to suggest that some TKIs may be safe in the later stages of pregnancy.

No compelling evidence that sibutramine prolongs life in rodents despite providing a dose-dependent reduction in body weight.

OBJECTIVE: The health and longevity effects of body weight reduction resulting from exercise and caloric restriction in rodents are well known, but less is known about whether similar effects occur with weight reduction from the use of a pharmaceutical agent such as sibutramine, a serotonin-norepinephrine reuptake inhibitor. RESULTS AND CONCLUSION: Using data from a 2-year toxicology study of sibutramine in Sprague-Dawley CD rats and CD-1 mice, despite a dose-dependent reduction in food intake and body weight in rats compared with controls, and a body weight reduction in mice at the highest dose, there was no compelling evidence for reductions in mortality rate.

In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial.

BACKGROUND: Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial. METHODS: Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling (ATP supply per O2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions. RESULTS: A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATPmax; P = 0.055, %ΔATPmax; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI. CONCLUSIONS: These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

A new experimental model for the investigation of sequential hermaphroditism.

The stunning sexual transformation commonly triggered by age, size or social context in some fishes is one of the best examples of phenotypic plasticity thus far described. To date our understanding of this process is dominated by studies on a handful of subtropical and tropical teleosts, often in wild settings. Here we have established the protogynous New Zealand spotty wrasse, Notolabrus celidotus, as a temperate model for the experimental investigation of sex change. Captive fish were induced to change sex using aromatase inhibition or manipulation of social groups. Complete female-to-male transition occurred over 60 days in both cases and time-series sampling was used to quantify changes in hormone production, gene expression and gonadal cellular anatomy. Early-stage decreases in plasma 17ß-estradiol (E2) concentrations or gonadal aromatase (cyp19a1a) expression were not detected in spotty wrasse, despite these being commonly associated with the onset of sex change in subtropical and tropical protogynous (female-to-male) hermaphrodites. In contrast, expression of the masculinising factor amh (anti-Müllerian hormone) increased during early sex change, implying a potential role as a proximate trigger for masculinisation. Collectively, these data provide a foundation for the spotty wrasse as a temperate teleost model to study sex change and cell fate in vertebrates.

Therapy with nonglycosaminoglycan-binding mutant CCL7: a novel strategy to limit allograft inflammation.

Chemokines are immobilized by binding to glycosaminoglycans (GAGs). A non-GAG-binding mutant CCL7 (mtCCL7) was developed that retained its affinity for chemokine receptors. This mtCCL7 induced leukocyte chemotaxis in diffusion gradients but did not stimulate trans-endothelial migration (p<0.01). Unlike wild-type CCL7, mtCCL7 persisted in the circulation of BALB/c mice for more than 6 h and prevented leukocyte infiltration of skin isografts (p<0.05). Treatment with mtCCL7 marginally increased the survival of C57BL/6 to BALB/c skin allografts and reduced graft infiltration by CD3+ cells (p<0.05). Importantly, mtCCL7 promoted long-term (>40 day) graft survival following minor histocompatibility (HY) antigen mismatched C57BL/6 skin transplantation; control grafts were rejected by day 24. Treatment with mtCCL7 produced a significant decrease in the frequency of IFN-gamma producing donor-reactive splenic T cells, reduced CCR2 expression by circulating leukocytes for 6 h (p<0.01) and blocked the normal increase in affinity of alpha4beta1 integrins for VCAM-1 following transient chemokine stimulation. These data suggest that mtCCL7 persists in the circulation and reduces both specific T-cell priming and the capacity of circulating immune cells to respond to GAG-bound chemokine at sites of developing inflammation.

The insect chemoreceptor superfamily of the parasitoid jewel wasp Nasonia vitripennis.

Chemoreception is important for locating food, mates and other resources in many insects, including the parasitoid jewel wasp Nasonia vitripennis. In the insect chemoreceptor superfamily, Nasonia has 58 gustatory receptor (Gr) genes, of which 11 are pseudogenes, leaving 47 apparently intact proteins encoded. No carbon dioxide receptors, two candidate sugar receptors, a DmGr43a orthologue, and several additional Gr lineages were identified, including significant gene subfamily expansions related to the 10 Grs found in the honey bee Apis mellifera. Nasonia has a total of 301 odorant receptor (Or) genes, of which 76 are pseudogenes, leaving 225 apparently intact Ors. Phylogenetic comparison with the 174 honey bee Ors reveals differential gene subfamily expansion in each hymenopteran lineage, along with a few losses from each species. The only simple orthologous relationship is the expected single DmOr83b orthologue. The large number of Nasonia Ors is the result of several major subfamily expansions, including one of 55 genes. Nasonia does not have the elaborate social chemical communication of honey bees, nor the diversity of floral odours honey bees detect, however, Nasonia wasps might need to detect a diversity of odours to find potential mates and hosts or avoid harmful substances in its environment.

A functional DNA methylation system in the pea aphid, Acyrthosiphon pisum.

Methylation of cytosine is one of the main epigenetic mechanisms involved in controlling gene expression. Here we show that the pea aphid (Acyrthosiphon pisum) genome possesses homologues to all the DNA methyltransferases found in vertebrates, and that 0.69% (+/-0.25%) of all cytosines are methylated. Identified methylation sites are predominantly restricted to the coding sequence of genes at CpG sites. We identify twelve methylated genes, including genes that interact with juvenile hormone, a key endocrine signal in insects. Bioinformatic prediction using CpG ratios for all predicted genes suggest that a large proportion of genes are methylated within the pea aphid.

Severe hypoglycaemia during pregnancy in women with Type 1 diabetes is common and planning pregnancy does not decrease the risk.

AIMS: The aim of this study was to identify risk factors for severe hypoglycaemia (SH) in pregnancy in Type 1 diabetes, including associations with pregnancy planning and glycaemic control. METHODS: Clinical data including details of the pregnancy and its outcome, glycaemic control, frequency of SH and evidence of pregnancy planning were collected prospectively as part of a national audit of 160 pregnancies in women with Type 1 diabetes. RESULTS: An episode of SH was experienced by 29.4% of women at some point during the pregnancy, with the percentage of women experiencing SH decreasing from 21.9% in the first trimester to 18.1% in trimester 2 and 10.9% in trimester 3. Longer duration of diabetes was associated with increased frequency of SH during pregnancy (r = 0.191, P = 0.012). A greater fall in glycated haemoglobin (HbA(1c)) between pre-pregnancy and the first trimester was not associated with increased risk of SH in trimester 1. Planned pregnancies had better glycaemic control but higher risk of SH in trimester 1 (P = 0.047). Women with pre-pregnancy retinopathy and current smokers had an increased risk of SH in trimester 3 (P = 0.029, P = 0.033). CONCLUSIONS: SH is common during pregnancy and particularly in the first trimester. Planning pregnancy does not decrease the risk of SH. Improvements in glycaemic control at the start of pregnancy do not appear to increase the risk of SH. Education of women and their partners about the risks of SH and its management is essential when planning pregnancy.