bluuebunny/crossref_metadata_2025 huggingface dataset:
Pelvic Pain and Quality of Life Before and After Laparoscopic Bowel Resection for Rectosigmoid Endometriosis: A Prospective, Observational Study
Authors: Riiskjær Mads , Forman Axel , Kesmodel Ulrik S. , Andersen Lars M. , Ljungmann Ken , Seyer-Hansen Mikkel
Published: January 2018

BACKGROUND:

Surgery for rectosigmoid endometriosis carries a substantial risk of short- and long-term complications, which has to be counterbalanced against the potential effect of the procedure. Prospective data are scarce in the field of deep infiltrating endometriosis surgery.

OBJECTIVE:

The study aimed to assess pelvic pain and quality of life before and after laparoscopic bowel resection for rectosigmoid endometriosis.

DESIGN:

The study involved prospectively collected data regarding pelvic pain and quality of life before and after surgery.

SETTINGS:

It was conducted at a tertiary endometriosis referral unit at Aarhus University Hospital.

PATIENTS:

A total of 175 women were included.

INTERVENTION:

Patients underwent laparoscopic bowel resection for endometriosis.

MAIN OUTCOME MEASURES:

Questionnaires for pain (Numerical Rating Scale) and quality of life (RAND Short Form-36) were answered before and 1 year after surgery. Data on analgesic and hormone treatment were collected. Preoperative and postoperative pelvic pain and quality-of-life scores were compared, and risk factors for improvement/worsening were identified.

RESULTS:

A total of 97.1% of the women completed the 1-year follow up. A significant decrease (p= 0.0001) was observed on all pelvic pain parameters. Most profound was the decrease in dyschezia. A significant improvement on all quality-of-life scores was observed (p= 0.0001). A surgical complication did not have a negative impact on outcome 1 year after surgery. The postoperative outcome was not related to the type of surgery.

LIMITATIONS:

This is an observational study without a control group. Risk factor data should be interpreted with caution, because the study was relatively underpowered for some of the rare outcomes.

CONCLUSIONS:

A significant and clinically relevant improvement in pelvic pain and quality of life 1 year after laparoscopic bowel resection for endometriosis was found. We strongly recommend surgery for rectosigmoid endometriosis that is unresponsive to conservative treatment. SeeVideo Abstractat http://links.lww.com/DCR/A472.
Prognostic Factors for Locoregional Recurrence in Neuroendocrine Tumors of the Rectum
Authors: Tsang Erica S. , McConnell Yarrow J. , Schaeffer David F. , Yin Yaling , Speers Caroline H. , Kennecke Hagen F.
Published: January 2018

BACKGROUND:

Optimal management of rectal neuroendocrine tumors is not yet well defined. Various pathologic factors, particularly tumor size, have been proposed as prognostic markers.

OBJECTIVE:

We characterized sequential patients diagnosed with rectal neuroendocrine tumors in a population-based setting to determine whether tumor size and other pathologic markers could be useful in guiding locoregional management.

DESIGN:

This study is a retrospective analysis of data from the British Columbia provincial cancer registry.

SETTINGS:

The study was conducted at a tertiary care center.

PATIENTS:

Sequential patients diagnosed with rectal neuroendocrine tumors between 1999 and 2011 were identified. Neuroendocrine tumors were classified as G1 and G2 tumors with a Ki-67 ≤20% and/or mitotic count ≤20 per high-power field.

MAIN OUTCOME MEASURES:

Baseline clinicopathologic data including TNM staging, depth of invasion, tumor size, treatment modalities, and outcomes including survival data were measured.

RESULTS:

Of 91 rectal neuroendocrine tumors, the median patient age was 58 years, and 35 were men. Median tumor size was 6 mm. Median length of follow-up was 58.1 months, with 3 patients presenting with stage IV disease. Treatment included local ablation (n = 5), local excision (n = 79), surgical resection (n = 4), and pelvic radiation (n = 1; T3N1 tumor). Final margin status was positive in 17 cases. Local relapse occurred in 8 cases and 1 relapse to bone 13 months after T3N1 tumor resection. Univariate analysis demonstrated an association between local relapse and Ki-67, mitotic count, grade, and lymphovascular invasion (p < 0.01). Larger tumor size was associated with decreased disease-free survival.

LIMITATIONS:

Sample size was 91 patients in the whole provincial population over a 13-year time period because of the low incidence of rectal neuroendocrine tumors.

CONCLUSIONS:

In this population-based cohort, rectal neuroendocrine tumors generally presented with small, early tumors and were treated with local excision or surgical resection without pelvic radiation. Pathologic markers play a role in risk stratification and prognostication. See Video Abstract at http://links.lww.com/DCR/A514.
Seroprevalence of Hepatitis B Among HIV-infected Children and Adolescents Receiving Antiretroviral Therapy in the TREAT Asia Pediatric HIV Observational Database
Authors: Aurpibul Linda , Kariminia Azar , Vibol Ung , Fong Moy Siew , Le Oanh Ngoc , Hansudewechakul Rawiwan , Bunupuradah Torsak , Kurniati Nia , Chokephaibulkit Kulkanya , Kumarasamy Nagalingeswaran , Wati Dewi Kumara , Yusoff Nik Khairulddin Nik , Razali Kamarul Azahar Mohd , Nallusamy Revathy A. , Sohn Annette H. , Lumbiganon Pagakrong
Published: January 2018

Background:

Hepatitis B (HBV)-HIV coinfection is associated with liver inflammation, which can progress to liver fibrosis/cirrhosis and hepatocellular carcinoma. We determined HBV seroprevalence in children and adolescents participating in the TREAT Asia Pediatric HIV Observational Database.

Methods:

A multisite cross-sectional study was conducted in HIV-infected patients currently <25 years old receiving antiretroviral treatment (ART) who had HBV surface antigen (HBsAg), or HBV surface antibody (anti-HBs) or HBV core antibody (anti-HBc) tested during 2012–2013. HBV coinfection was defined as having either a positive HBsAg test or being anti-HBc positive and anti-HBs negative, reflective of past HBV infection. HBV seroprotection was defined as having a positive anti-HBs test.

Results:

A total of 3380 patients from 6 countries (Vietnam, Thailand, Cambodia, Malaysia, Indonesia and India) were included. The current median (interquartile range) age was 11.2 (7.8–15.1) years. Of the 2755 patients (81.5%) with HBsAg testing, 130 (4.7%) were positive. Of 1558 (46%) with anti-HBc testing, 77 (4.9%) were positive. Thirteen of 1037 patients with all 3 tests were anti-HBc positive and HBsAg and anti-HBs negative. One child was positive for anti-HBc and negative for anti-HBs but did not have HBsAg tested. The prevalence of HBV coinfection was 144/2759 (5.2%) (95% confidence interval: 4.4–6.1). Of 1093 patients (32%) with anti-HBs testing, 257 (23.5%; confidence interval: 21.0–26.0) had positive tests representing HBV seroprotection.

Conclusions:

The estimated prevalence of HBV coinfection in this cohort of Asian HIV-infected children and adolescents on ART was 5.2%. The majority of children and adolescents tested in this cohort (76.5%) did not have protective HBV antibody. The finding supports HBV screening of HIV-infected children and adolescents to guide revaccination, the use of ART with anti-HBV activity and future monitoring.
Vision Loss in an 8-Year-Old Immunocompetent Boy with Cryptococcal Meningitis
Authors: Padmanabha Hansashree , Kasinathan Ananthanarayanan , Kumar Anil , Zaman Kamran , Suthar Renu , Suri Deepti , Vyas Sameer , Sankhyan Naveen
Published: January 2018

Cryptococcal meningitis is an opportunistic fungal infection commonly seen in immunocompromised individuals. Information on cryptococcal meningitis is scarce in immunocompetent children. The authors report an 8-year-old immunocompetent boy with cryptococcal meningitis and bilateral vision loss. The role of repeated therapeutic lumbar puncture in the management of raised intracranial pressure in cryptococcal meningitis is discussed.
Continuing Play, Symptom Severity, and Symptom Duration After Concussion in Youth Athletes
Authors: Howell David R. , O'Brien Michael J. , Fraser Joana , Meehan William P.
Published: January 2018

Objective:

To determine whether continuing to play after a concussion is associated with higher symptom burden or prolonged symptom duration.

Design:

Patients who presented for care at a sport concussion clinic within the first 3 weeks of injury were asked whether they continued to play immediately after their injury.

Setting:

Sport concussion clinic within a regional tertiary care hospital.

Main Outcome Measures:

Clinical outcomes including symptom severity, symptom duration, age, time from injury-clinical presentation, sex, sport type, previous concussion history, and whether or not they experienced loss of consciousness or amnesia at the time of injury were recorded. Univariable comparisons between those who did and did not report continuing play were conducted. Multivariable linear regression models were constructed to identify the independent association of continuing to play postinjury with symptom burden and symptom recovery time, while controlling for the effect of potential confounding variables.

Results:

A total of 516 patients were included in the study, assessed a mean of 12.1 ± 5.2 days postinjury (35% female, mean age = 14.5 ± 2.3 years). A total of 227 (44%) continued play after sustaining a concussion. Continuing to play postconcussion was independently associated with higher symptom severity during the initial clinical evaluation [β-coefficient = 6.144, 95% confidence interval (CI), 1.357-10.93], but not with symptom duration evaluation (β-coefficient = 1.794, 95% CI, −15.66 to 19.25).

Conclusion:

Those who continued to play postconcussion presented with more severe symptoms after injury. Recognition of suspected concussion and removal from play on diagnosis confirmation may lead to better initial clinical outcomes after concussion among child and adolescent athletes.
Labyrinthine Sequestrum: A Case Report and Review of the Literature
Authors: Guerin Julie B. , Vork Diana L. , Eguiguren Lourdes , Marston Alexander P. , Driscoll Colin L. W. , Carlson Matthew L. , Henry Nancy K. , Lane John I.
Published: January 2018

Objective:

To report the presentation, diagnosis, management, and convalescence of labyrinthine sequestrum (LS) and summarize all previously published cases.

Patient(s):

Eleven-year-old female with LS.

Intervention(s):

Multidisciplinary diagnostic evaluation and treatment.

Main Outcome Measures:

Imaging and laboratory findings, medical and surgical treatment.

Results:

We describe a case of LS secondary to medically recalcitrant suppurative otitis media in an 11-year-old female and review all eight previously reported cases. The index patient presented after 6 months of otitis media, profound unilateral hearing loss, with symptoms suggesting meningitis. Temporal bone CT demonstrated marked bony destruction of the left otic capsule. Gadolinium-enhanced MRI showed an enhancing process with evidence of meningitis and subdural empyema. The patient was treated with surgical debridement and culture directed antibiotic therapy. Posttreatment imaging showed resolution of intracranial infection with fibrous bony healing of the otic capsule resembling fibrous dysplasia.

Conclusion:

LS is a rare form of labyrinthitis characterized by centrifugal destruction of the otic capsule. The current index case highlights the importance of combined medical and surgical treatment and describes for the first time in the literature the fibrous ossification of the otic capsule following disease resolution.
How does ‘metabolic surgery’ work its magic? New evidence for gut microbiota
Authors: Peck Bailey C.E. , Seeley Randy J.
Published: January 2018

Purpose of review

Metabolic surgery is recommended for the treatment of type 2 diabetes for its potent ability to improve glycemic control. However, the mechanisms underlying the beneficial effects of metabolic surgery are still under investigation. We provide an updated review of recent studies into the molecular underpinnings of metabolic surgery, focusing in on what is known about the role of gut microbiota. Over the last 7 years several reports have been published on the topic, however the field is expanding rapidly.

Recent findings

Studies have now linked the regulation of glucose and lipid metabolism, neuronal and intestinal adaptations, and hormonal and nutrient signaling pathways to gut microbiota. Given that the composition of gut microbiota is altered by metabolic surgery, investigating the potential mechanism and outcomes of this change are now a priority to the field.

As evidence for a role for microbiota builds, we expect future patients may receive microbe-based therapeutics to improve surgical outcomes and perhaps one day preclude the need for surgical therapies all together. In this review and perspective, we evaluate the current state of the field and its future.
Induction chemotherapy in acute myeloid leukaemia: origins and emerging directions
Authors: Upadhyay Vivek A. , Fathi Amir T.
Published: January 2018

Purpose of review

This review summarizes the hallmark developments in induction chemotherapy for acute myeloid leukaemia and further describes future directions in its evolution.

Recent findings

We describe the origin of induction chemotherapy. We also describe notable modifications and adjustments to 7+3 induction chemotherapy since its development. Finally, we describe new efforts to modify and add new agents to induction therapy, including ‘7+3 Plus’ combinations.

Induction chemotherapy remains the standard of care for the majority of patients with acute myeloid leukaemia. However, its success is limited in a subset of patients by toxicity, failure to achieve remission and potential for subsequent relapse. Novel agents such as mutant fms like tyrosine kinase 3 inhibitors, mutant isocitrate dehydrogenase inhibitors, CD33-antibody drug conjugates and liposomal formulations have demonstrated significant potential as modifications to traditional induction chemotherapy.
A Systematic Review on Vaginal Laser Therapy for Treating Stress Urinary Incontinence: Do We Have Enough Evidence?
Authors: Pergialiotis Vasilios , Prodromidou Anastasia , Perrea Despina N. , Doumouchtsis Stergios K.
Published: January 2018

(Abstracted from Int Urogynecol J 2017;28:1445–1451)

Treatment options proposed for stress urinary incontinence (SUI) range from conservative approaches, such as pelvic floor exercises, to surgery. When conservative treatment measures fail to improve symptoms, the mainstay of surgical treatment is midurethral slings.
Contraceptive Care of Obese Women
Authors: Morse Jessica Elizabeth , Pathak Prutha Rohit
Published: January 2018

Importance

In the United States, 27% of reproductive-aged women are overweight, and 35% are obese. Until recently, contraceptive research excluded women greater than 130% of their ideal body weight. Gaps in data limit evidence-based decision making for effective contraceptive counseling and management in this rapidly growing population.

Objectives

The aims of this summary are to review the benefits, adverse effects, and risk factors associated with contraceptive methods in obese women, with special attention to effectiveness, and provide contraceptive management and counseling recommendations for best clinical practice.

Evidence Acquisition

We performed a thorough search of PubMed for current literature, including original research articles, review articles, and guidelines on contraceptive counseling and management in obese women in the United States. We reviewed the body of evidence with special attention to studies published since recent Cochrane and systematic reviews on this topic.

Conclusions

Contraceptive use is safer than pregnancy, especially for obese women who have increased pregnancy risks. Baseline health is compromised by obesity, but contraceptive risks remain low. Long-acting, reversible contraceptive methods offer superior effectiveness, minimal risk, and numerous noncontraceptive benefits across body mass index groups. No substantial evidence supports ineffectiveness of any method in obese women except oral emergency contraception and the patch. Pharmacokinetic changes of obesity associated with other oral methods do not seem to result in clinically significant declines in effectiveness. Future contraceptive efficacy studies should include obese women to better discuss their contraceptive needs.

Relevance

This review is beneficial for all providers caring for reproductive-aged women wanting to avoid unintended pregnancy.

Target Audience

Obstetricians and gynecologists, family physicians, and internal medicine physicians.

Learning Objectives

After completing this CME activity, physicians should be better able to (1) identify the general health, fertility, and pregnancy implications of obesity in reproductive-aged women; (2) describe the epidemiology and recent trends in unintended pregnancy rates in the United States; (3) discuss the significance of weighing risks, advantages, and adverse effects of all contraceptive methods compared with risks of unintended pregnancy in obese women; and (4) recognize evidence-based contraceptive counseling and management guidelines for obese women.
Accidental Rivaroxaban Intoxication in a Boy
Authors: Weirthein Julieta , Scolnik Dennis , Milshtein Nili Yanai , Capua Tali , Glatstein Miguel
Published: January 2018

Novel oral anticoagulants offer equivalent or improved therapeutic profiles compared with warfarin, with less risk of bleeding, no interactions with food, and no need for routine laboratory monitoring. Caution must be exercised in using these drugs in certain patient populations, for example, renal insufficiency, those receiving additional antithrombotic therapy, those with questionable compliance, children, and those with a high risk of gastrointestinal bleeding. One of the novel oral anticoagulants, rivaroxaban, is a direct Factor Xa inhibitor, used to reduce risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, deep vein thrombosis, and pulmonary embolism. We report a child who presented abnormal coagulation tests after unintended ingestion of 4 tablets of rivaroxaban. The patient was treated with fresh frozen plasma as well as admitted to intensive care and improved several hours later. We discuss his presentation and review of the literature on this topic.
The what, when and how in performing and interpreting microbiological diagnostic tests in skin and soft tissue infections
Authors: Navarro-San Francisco Carolina , Ruiz-Garbajosa Patricia , Cantón Rafael
Published: January 2018

Purpose of review

To summarize and classify the most recent and relevant microbiological studies for each type of skin and soft tissue infection (SSTI).

Recent findings

Following Infectious Diseases Society of America and Food and Drug Administration classifications of SSTIs, we differentiate between two large groups, the superficial or uncomplicated infections and the complicated infections with deep involvement. It is not usually necessary to obtain microbiological samples in uncomplicated infections, except in cases of recurrences or for epidemiological control purposes. In the case of complicated infections, the samples are of two different types: those obtained from the affected area (surgical samples, punctures of abscesses or swabs) and systemic samples (i.e. blood cultures). The clinical condition also determines the type of samples to be obtained. In cases of systemic involvement, blood cultures are mandatory. For immunocompromised patients, who may present atypical infections, detection of antigens, serologies or molecular biology techniques may be helpful. The rapid diagnosis is currently the goal to be pursued by implementing techniques such as matrix assisted laser desorption ionization-time of flight, commercial real-time PCR or the promising metagenomics.

Microbiological diagnosis is one of the cornerstones of the management of SSTIs. Prompt obtaining and processing of the necessary samples, depending on the clinical situation of the patient, is of relevance in the decision-making process. Rapid and fluid reporting of the results (identification, mechanisms of resistance and antibiogram) will improve the management of these patients.
Telomeres and genomic evolution
Authors: Baird Duncan M.
Published: January 2018

The terminal regions of eukaryotic chromosomes, composed of telomere repeat sequences and sub-telomeric sequences, represent some of the most variable and rapidly evolving regions of the genome. The sub-telomeric regions are characterized by segmentally duplicated repetitive DNA elements, interstitial telomere repeat sequences and families of variable genes. Sub-telomeric repeat sequence families are shared among multiple chromosome ends, often rendering detailed sequence characterization difficult. These regions are composed of constitutive heterochromatin and are subjected to high levels of meiotic recombination. Dysfunction within telomere repeat arrays, either due to disruption in the chromatin structure or because of telomere shortening, can lead to chromosomal fusion and the generation of large-scale genomic rearrangements across the genome. The dynamic nature of telomeric regions, therefore, provides functionally useful variation to create genetic diversity, but also provides a mechanism for rapid genomic evolution that can lead to reproductive isolation and speciation. This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.

This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
Characterization in humans ofin vitroleucocyte maximal telomerase activity capacity and association with stress
Authors: de Punder Karin , Heim Christine , Przesdzing Ingo , Wadhwa Pathik D. , Entringer Sonja
Published: January 2018

The goal of this study was to develop and validate a measure ofmaximal telomerase activity capacity(mTAC) for use in human studies of telomere biology, and to determine its association with measures of stress and stress responsivity. The study was conducted in a population of 28 healthy young women and men who were assessed serially across two separate days, at multiple time points, and in response to a standardized laboratory stressor. Venous blood was collected at each of these multiple assessments, and anin vitromitogen challenge (phytohaemagglutinin supplemented with interleukin-2) was used to stimulate telomerase activity in leucocytes. After first establishing the optimal post-stimulation time course to characterize mTAC, we determined the within-subject stability and the between-subject variability of mTAC. The major findings of our study are as follows: (i) the optimal time point to quantify human leucocyte mTAC appears to be at 72 h after mitogen stimulation; (ii) mTAC exhibits substantial within-subject stability (correlations were in the range ofr0.68–0.82) and between-subject variability, with a high intra-class coefficient (0.70), indicating greater between-subject relative to within-subject variability; (iii) mTAC is not influenced by situational factors including time of day, cortisol, acute stress exposure and immune cell distribution in the pre-stimulation blood sample; and (iv) a significant proportion of the between-subject variability in mTAC is associated with measures of stress and stress responsivity (mTAC is lower in subjects reporting higher levels of perceived (chronic) stress and exhibiting higher psychophysiological stress reactivity). Based collectively on these findings, it appears that mTAC, as proposed and operationalized, empirically meets the key criteria to represent a potentially useful individual difference measure of telomerase activity capacity of human leucocytes.

This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
The rate of telomere loss is related to maximum lifespan in birds
Authors: Tricola Gianna M. , Simons Mirre J. P. , Atema Els , Boughton Raoul K. , Brown J. L. , Dearborn Donald C. , Divoky G. , Eimes John A. , Huntington Charles E. , Kitaysky Alexander S. , Juola Frans A. , Lank David B. , Litwa Hannah P. , Mulder Ellis G. A. , Nisbet Ian C. T. , Okanoya Kazuo , Safran Rebecca J. , Schoech Stephan J. , Schreiber Elizabeth A. , Thompson Paul M. , Verhulst Simon , Wheelwright Nathaniel T. , Winkler David W. , Young Rebecca , Vleck Carol M. , Haussmann Mark F.
Published: January 2018

Telomeres are highly conserved regions of DNA that protect the ends of linear chromosomes. The loss of telomeres can signal an irreversible change to a cell's state, including cellular senescence. Senescent cells no longer divide and can damage nearby healthy cells, thus potentially placing them at the crossroads of cancer and ageing. While the epidemiology, cellular and molecular biology of telomeres are well studied, a newer field exploring telomere biology in the context of ecology and evolution is just emerging. With work to date focusing on how telomere shortening relates to individual mortality, less is known about how telomeres relate to ageing rates across species. Here, we investigated telomere length in cross-sectional samples from 19 bird species to determine how rates of telomere loss relate to interspecific variation in maximum lifespan. We found that bird species with longer lifespans lose fewer telomeric repeats each year compared with species with shorter lifespans. In addition, phylogenetic analysis revealed that the rate of telomere loss is evolutionarily conserved within bird families. This suggests that the physiological causes of telomere shortening, or the ability to maintain telomeres, are features that may be responsible for, or co-evolved with, different lifespans observed across species.

This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.
All's well that ends well: why large species have short telomeres
Authors: Risques Rosa Ana , Promislow Daniel E. L.
Published: January 2018

Among mammal species, almost all life-history traits are strongly size dependent. This size dependence even occurs at a molecular level. For example, both telomere length and telomerase expression show a size-dependent threshold. With some exceptions, species smaller than approximately 2 kg express telomerase, while species larger than that do not. Among species greater than approximately 5 kg, telomeres tend to be short—less than 25 kb—while among smaller species, some species have short and some have long telomeres. Here, we present a model to explore the role of body size-dependent trade-offs in shaping this threshold. We assume that selection favours short telomeres as a mechanism to protect against cancer. At the same time, selection favours long telomeres as a protective mechanism against DNA damage and replicative senescence. The relative importance of these two selective forces will depend on underlying intrinsic mortality and risk of cancer, both of which are size-dependent. Results from this model suggest that a cost–benefit model for the evolution of telomere length could explain phylogenetic patterns observed within the Class Mammalia. In addition, the model suggests a general conceptual framework to think about the role that body size plays in the evolution of tumour suppressor mechanisms.

This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.
Ectothermic telomeres: it's time they came in from the cold
Authors: Olsson Mats , Wapstra Erik , Friesen Christopher
Published: January 2018

We review the evolutionary ecology and genetics of telomeres in taxa that cannot elevate their body temperature to a preferred level through metabolism but do so by basking or seeking out a warm environment. This group of organisms contains all living things on earth, apart from birds and mammals. One reason for our interest in this synthetic group is the argument that high, stable body temperature increases the risk of malignant tumours if long, telomerase-restored telomeres make cells ‘live forever’. If this holds true, ectotherms should have significantly lower cancer frequencies. We discuss to what degree there is support for this ‘anti-cancer’ hypothesis in the current literature. Importantly, we suggest that ectothermic taxa, with variation in somatic telomerase expression across tissue and taxa, may hold the key to understanding ongoing selection and evolution of telomerase dynamics in the wild. We further review endotherm-specific effects of growth on telomeres, effects of autotomy (‘tail dropping’) on telomere attrition, and costs of maintaining sexual displays measured in telomere attrition. Finally, we cover plant ectotherm telomeres and life histories in a separate ‘mini review’.

This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.
Heritability of telomere variation: it is all about the environment!
Authors: Dugdale Hannah L. , Richardson David S.
Published: January 2018

Individual differences in telomere length have been linked to survival and senescence. Understanding the heritability of telomere length can provide important insight into individual differences and facilitate our understanding of the evolution of telomeres. However, to gain accurate and meaningful estimates of telomere heritability it is vital that the impact of the environment, and how this may vary, is understood and accounted for. The aim of this review is to raise awareness of this important, but much under-appreciated point. We outline the factors known to impact telomere length and discuss the fact that telomere length is a trait that changes with age. We highlight statistical methods that can separate genetic from environmental effects and control for confounding variables. We then review how well previous studies in vertebrate populations including humans have taken these factors into account. We argue that studies to date either use methodological techniques that confound environmental and genetic effects, or use appropriate methods but lack sufficient power to fully separate these components. We discuss potential solutions. We conclude that we need larger studies, which also span longer time periods, to account for changing environmental effects, if we are to determine meaningful estimates of the genetic component of telomere length.

This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.
Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis
Authors: Halama Anna , Kulinski Michal , Dib Shaima S. , Zaghlool Shaza B. , Siveen Kodappully S. , Iskandarani Ahmad , Satheesh Noothan J. , Bhagwat Aditya M. , Uddin Shahab , Kastenmüeller Gabi , Elemento Olivier , Gross Steven S. , Suhre Karsten
Published: January 2018

Suppressing glutaminolysis does not always induce cancer cell death in glutamine-dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis. We conducted metabolic profiling in the triple-negative breast cancer cell line MB-MDA-231, treated with different dosages of glutaminase inhibitor C.968 at multiple time points. We found that multiple molecules involved in lipid catabolism responded directly to glutamate deficiency as a presumed compensation for energy deficit. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. We therefore simultaneously inhibited glutaminolysis and autophagy, which induced cancer cell death. Our study emphasizes the potential of non-targeted metabolomics to characterize and identify metabolic escape mechanisms contributing to cancer cell survival under treatment. Our findings add to the increasing evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers.
Metabolic co-dependence drives the evolutionary ancientHydra-Chlorellasymbiosis
Authors: Hamada Mayuko , Schröder Katja , Bathia Jay , Kürn Ulrich , Fraune Sebastian , Khalturina Mariia , Khalturin Konstantin , Shinzato Chuya , Satoh Nori , Bosch Thomas C.G.
Published: January 2018

Many multicellular organisms rely on symbiotic associations for support of metabolic activity, protection, or energy. Understanding the mechanisms involved in controlling such interactions remains a major challenge. In an unbiased approach we identified key players that control the symbiosis betweenHydra viridissimaand its photobiontChlorellasp. A99. We discovered significant upregulation ofHydragenes encoding a phosphate transporter and glutamine synthetase suggesting regulated nutrition supply between host and symbionts. Interestingly, supplementing the medium with glutamine temporarily supports in vitro growth of the otherwise obligate symbioticChlorella, indicating loss of autonomy and dependence on the host. Genome sequencing ofChlorellaA99 revealed a large number of amino acid transporters and a degenerated nitrate assimilation pathway, presumably as consequence of the adaptation to the host environment. Our observations portray ancient symbiotic interactions as a codependent partnership in which exchange of nutrients appears to be the primary driving force.
Inherited BRCA1 epimutation as a novel cause of breast and ovarian cancer
Authors: Evans D. Gareth R. , van Veen Elke M. , Byers Helen J. , Wallace Andrew J. , Ellingford Jamie M. , Beaman Glenda , Santoyo-Lopez Javier , Aitman Timothy J. , Eccles Diana M. , Lalloo Fiona I. , Smith Miriam J. , Newman William G.
Published: January 2018

Background

Pathogenic variants in BRCA1 or BRCA2 are identified in ~20% of families with multiple individuals with early-onset breast/ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1/2 have not explained the missing heritability. For the first time, we report transgenerational epigenetic silencing of BRCA1 due to promoter hypermethylation in two families with breast/ovarian cancer.

Methods

BRCA1 promoter methylation of ten CpG dinucleotides in breast/ovarian cancer families without germline BRCA1/2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants.

Findings

BRCA1 promoter hypermethylation was identified in two of 49 families with multiple women affected with grade 3 breast/high grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa and hair follicles. Methylation levels were ~50%, consistent with the silencing of one allele and confirmed by clonal bisulfite sequencing. RNA sequencing revealed allelic loss of BRCA1 expression in both families and this segregated with a novel heterozygous variant c.-107A>T in the BRCA1 5’UTR.

Interpretation

Our results indicate a novel mechanism for familial breast/ovarian cancer, caused by epigenetic silencing of the BRCA1 promoter, segregating with an in cis 5’UTR variant in two independent families. We propose that methylation analyses are indicated in all families affected by early onset breast/ovarian cancer without a BRCA1/2 pathogenic variant.

Funding

Funded by Prevent Breast Cancer (GA 12-006 and GA 15-002) and the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007).
Mutation accumulation differentially impacts ageing in mammalian tissues
Authors: Turan Zeliha Gözde , Parvizi Poorya , Dönertaş Handan Melike , Tung Jenny , Khaitovich Philipp , Somel Mehmet
Published: January 2018

Medawar’s mutation accumulation (MA) hypothesis explains ageing by the declining force of natural selection with age: slightly deleterious germline mutations that are functional in old age are not effectively eliminated by selection and therefore lead to ageing-related phenotypes. Although widely cited, empirical support for the MA hypothesis, particularly molecular evidence, has remained limited. Here we test one of its predictions, that genes relatively highly expressed in old adults vs. young adults should be under weaker purifying selection than those relatively highly expressed in young adults. To do so, we combine 23 RNA-sequencing and 35 microarray gene expression datasets (including 9 tissues from 5 mammalian species) with protein and regulatory sequence conservation estimates across mammals. We identify age-related decrease in transcriptome conservation (ADICT) in four tissues, brain, liver, lung, and artery, but not in other tissues, most notably muscle and heart. ADICT is driven both by decreased expression of highly conserved genes and up-regulation of poorly conserved genes during ageing, in line with the MA hypothesis. Lowly conserved and up-regulated genes in ADICT-associated tissues have overlapping functional properties, particularly involving apoptosis and inflammation, with no evidence for a history of positive selection. Our results suggest that tissues vary in how evolution has shaped their ageing patterns. We find that in some tissues, genes up-regulated during ageing, possibly in response to accumulating cellular and histological damage, are under weaker purifying selection than other genes. We propose that accumulation of slightly deleterious substitutions in these genes may underlie their suboptimal regulation and activity during ageing, shaping senescent phenotypes such as inflammaging.
Epigenetic Drift of H3K27me3 in Aging Links Glycolysis to Healthy Longevity
Authors: Ma Zaijun , Wang Hui , Cai Yuping , Wang Han , Niu Kongyan , Wu Xiaofen , Ma Huanhuan , Yang Yun , Tong Wenhua , Liu Feng , Liu Zhandong , Zhang Yaoyang , Liu Rui , Zhu Zheng-Jiang , Liu Nan
Published: January 2018

Epigenetic alteration has been implicated in aging. However, the mechanism by which epigenetic change impacts aging is unclear. H3K27me3, a highly conserved histone modification signifying transcriptional repression, is marked and maintained by Polycomb Repressive Complexes (PRCs). Here, we explore the mechanism by which age-modulated increase of H3K27me3 impacts adult lifespan. Using Drosophila, we reveal that aging leads to loss of fidelity in epigenetic marking and drift of H3K27me3 and consequential reduction in the expression of glycolytic genes with negative effects on energy production and redox state. Moreover, we show that a reduction of H3K27me3 by PRCs-deficiency promotes glycolysis and healthy lifespan. While perturbing glycolysis by gene mutation diminishes the pro-lifespan benefits mediated by PRCs-deficiency, transgenic increase of glycolytic genes in wild-type animals extends longevity. Together, we propose that epigenetic drift of H3K27me3 defines a new aging mechanism and that stimulation of glycolysis promotes metabolic health and longevity.
Noise-resistant developmental reproducibility in vertebrate somite formation
Authors: Naoki Honda , Akiyama Ryutaro , Ishii Shin , Bessho Yasumasa , Matsui Takaaki
Published: January 2018

The reproducibility of embryonic development is remarkable, although molecular processes are intrinsically stochastic at the single-cell level. How the multi-cellular system resists the inevitable noise to acquire developmental reproducibility constitutes a fundamental question in developmental biology. Toward this end, we focused on vertebrate somitogenesis as a representative system, because somites are repeatedly reproduced within a single embryo whereas such reproducibility is lost in segmentation clock gene-deficient embryos. However, the effect of noise on developmental reproducibility has not been fully investigated, because of the technical difficulty in manipulating the noise intensity in experiments. In this study, we developed a computational model of ERK-mediated somitogenesis, in which bistable ERK activity is regulated by an FGF gradient, cell-cell communication, and the segmentation clock, subject to the intrinsic noise. The model simulation generated our previousin vivoobservation that the ERK activity was distributed in a step-like gradient in the presomitic mesoderm, and its boundary was posteriorly shifted by the clock in a stepwise manner, leading to regular somite formation. Here we showed that this somite regularity was robustly maintained against the noise. Removing the clock from the model predicted that the stepwise shift of the ERK activity occurs at irregular timing with irregular distance owing to the noise, resulting in somite size variation. Through theoretical analysis, we presented a mechanism by which the clock reduces the inherent somite irregularity observed in clock-deficient embryos. Therefore, this study indicates a novel role of the segmentation clock in noise-resistant developmental reproducibility.
Control of non-homeostatic feeding in sated mice using associative learning of contextual food cues
Authors: Stern Sarah A. , Doerig Katherine R. , Azevedo Estefania P. , Stoffel Elina , Friedman Jeffrey M.
Published: January 2018

Feeding is a complex motivated behavior controlled by a distributed neural network that processes sensory information to generate adaptive behavioral responses. Accordingly, studies using appetitive Pavlovian conditioning confirm that environmental cues that are associated with food availability can induce feeding even in satiated subjects. However, in mice, appetitive conditioning generally requires intensive training and thus can impede molecular studies that often require large numbers of animals. To address this, we developed and validated a simple and rapid context-induced feeding (ctx-IF) task in which cues associated with food availability can later lead to increased food consumption in sated mice. We show that the associated increase in food consumption is driven by both positive and negative reinforcement and that spaced training is more effective than massed training. Ctx-IF can be completed in ∼1 week and provides an opportunity to study the molecular mechanisms and circuitry underlying non-homeostatic eating. We have used this paradigm to map brain regions that are activated during Ctx-IF with cFos immunohistochemistry and found that the insular cortex, and other regions, are activated following exposure to cues denoting the availability of food. Finally, we show that inhibition of the insular cortex using GABA agonists impairs performance of the task. Our findings provide a novel assay in mice for defining the functional neuroanatomy of appetitive conditioning and identify specific brain regions that are activated during the development of learned behaviors that impact food consumption.
Early diverging insect pathogenic fungi of the order Entomophthorales possess diverse and unique subtilisin-like serine proteases
Authors: Arnesen Jonathan A. , Malagocka Joanna , Gryganskyi Andrii , Grigoriev Igor V. , Voigt Kerstin , Stajich Jason E. , De Fine Licht Henrik H.
Published: January 2018

Insect-pathogenic fungi use subtilisin-like serine proteases (SLSPs) to degrade chitin-associated proteins in the insect procuticle. Most insect-pathogenic fungi in the order Hypocreales (Ascomycota) are generalist species with a broad host-range, and most species possess a high number of SLSPs. The other major clade of insect-pathogenic fungi is part of the subphylum Entomophthoromycotina (Zoopagomycota, formerly Zygomycota) which consists of high host-specificity insect-pathogenic fungi that naturally only infect a single or very few host species. The extent to which insect-pathogenic fungi in the order Entomophthorales rely on SLSPs is unknown. Here we take advantage of recently available transcriptomic and genomic datasets from four genera within Entomophthoromycotina: the saprobic or opportunistic pathogens Basidiobolus meristosporus, Conidiobolus coronatus, C. thromboides, C. incongruus, and the host-specific insect pathogens Entomphthora muscae and Pandora formicae, specific pathogens of house flies (Muscae domestica) and wood ants (Formica polyctena), respectively. We use phylogenetics and protein domain analysis to show that the obligate biotrophic fungi E. muscae, P. formicae and the saprobic human pathogen C. incongruus all contain “classical” fungal SLSPs and a unique group of SLSPs that loosely resembles bacillopeptidase F-like SLSPs. This novel group of SLSPs is found in the genomes of obligate insect pathogens and a generalist saprobic opportunistic pathogen why they are unlikely to be responsible for the host specificity of Entomophthorales. However, this class represent a unique group of SLSPs so far only observed among Bacteria, Oomycetes and early diverging fungi such as Cryptomycota, Microsporidia, and Entomophthoromycotina and missing in the sister fungal lineages of Kickxellomycotina or the fungal phyla Mucoromyocta, Ascomycota and Basidiomycota fungi suggesting interesting gene loss patterns.
A pupillary index of susceptibility to decision biases
Authors: Eldar Eran , Felso Valkyrie , Cohen Jonathan D. , Niv Yael
Published: January 2018

Under what conditions do humans systematically deviate from rational decision making? Here we show that pupillary indices of low neural gain are associated with strong and consistent biases across six different extensively-studied decision making tasks, whereas indices of high gain are associated with weak or absent biases. Lower susceptibility to biases, however, comes at the cost of indecisiveness, or alternatively, prolonged deliberation time. We explain the association between low gain and strong biases as reflecting a broader information integration process that gives greater weight to weak biasing influences. The findings underscore the role of pupil-linked brain states in the generation of decision making biases.

Significance

“Framing effects” are demonstrations that people’s decisions can be biased by the way a decision problem is presented, and consequently, people can make decisions that violate the principles of rationality. Using a set of classic decision-making tasks, we show that pupil dilation, previously linked to levels of the neuromodulator norepinephrine and to a tradeoff between narrowly focused and broadly integrative modes of information processing, distinguishes between people who are consistently biased and people who are relatively immune to these effects. Our findings suggest that norepinephrine may drive these individual differences, and that a narrowly focused mode of information processing confers relative immunity to these decision making biases, whereas the integration of a wider range of information results in greater susceptibility.