Variational Problems Involving a Caputo-Type Fractional Derivative

We study calculus of variations problems, where the Lagrange function depends on the Caputo-Katugampola fractional derivative. This type of fractional operator is a generalization of the Caputo and the Caputo–Hadamard fractional derivatives, with dependence on a real parameter ρ. We present sufficient and necessary conditions of first and second order to determine the extremizers of a functional. The cases of integral and holomonic constraints are also considered

Investigations of the novel checkpoint kinase 1 inhibitor SRA737 in non-small cell lung cancer and colorectal cancer cells of differing tumour protein 53 gene status

Aim: In response to DNA damage the serine/threonine-specific protein kinase checkpoint kinase 1 (CHK1) is activated allowing cells to enter S phase (S) and G2 phase (G2) cell-cycle arrest. CHK1 inhibitors are expected to prevent cells from entering such arrest, thereby enhancing DNA damage-induced cytotoxicity. In contrast, normal cells with intact ataxia–telangiectasia mutated (ATM), CHK2 and tumour suppressor protein 53 (P53) signalling are still able to enter cell-cycle arrest using the functioning G1/S checkpoint, thereby being rescued from enhanced cytotoxicity. The main objective of this work is to investigate the in vitro effects of the novel CHK1 inhibitor SRA737 on pairs of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cell lines, all with genetic aberrations rendering them susceptible to replication stress but of differing tumour protein 53 (TP53) gene status, focusing on DNA damage induction and the subsequent effects on cell proliferation and viability. Methods: NSCLC cell lines H23 [TP53 mutant (MUT)] and A549 [TP53 wild-type (WT)] and CRC cell lines HT29 (TP53 MUT) and HCT116 (TP53 WT) were incubated with differing micromolar concentrations of SRA737 for 24 h and then analysed using alkaline comet and phosphorylated H2A.X variant histone (γH2AX)-foci assays to assess mostly DNA single strand break and double strand break damage, respectively. Cell-counting/trypan blue staining was also performed to assess cell proliferation/viability. Results: Clear concentration-dependent increases in comet formation and γH2AX-foci/cell were noted for the TP53 MUT cells with no or lower increases being noted in the corresponding TP53 WT cells. Also, greater anti-proliferative and cell killing effects were noted in the TP53 MUT cells than in the TP53 WT cells. Conclusions: This study’s data suggests that P53 status/functioning is a key factor in determining the sensitivity of NSCLC and CRC cancer cells towards CHK1 inhibition, even in circumstances conducive to high replicative stress

Vascular effects of apelin in vivo in man

ObjectivesThis study was designed to establish the direct vascular effects of apelin in vivo in man.BackgroundApelin is the endogenous ligand for the previously orphaned G-protein–coupled receptor, APJ. This novel pathway is widely expressed in the cardiovascular system and is emerging as an important mediator of cardiovascular homeostasis. In pre-clinical models, apelin causes venous and arterial vasodilation.MethodsVascular effects of apelin were assessed in 24 healthy volunteers. Dorsal hand vein diameter was measured by the Aellig technique during local intravenous infusions (0.1 to 3 nmol/min) of apelin-36, (Pyr1)apelin-13, and sodium nitroprusside (0.6 nmol/min). Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of apelin-36 and (Pyr1)apelin-13 (0.1 to 30 nmol/min) and subsequently in the presence or absence of a “nitric oxide clamp” (nitric oxide synthase inhibitor, L-NG-monomethylarginine [8 μmol/min], coinfused with nitric oxide donor, sodium nitroprusside [90 to 900 ng/min]), or a single oral dose of aspirin (600 mg) or matched placebo.ResultsAlthough sodium nitroprusside caused venodilation (p < 0.0001), apelin-36 and (Pyr1)apelin-13 had no effect on dorsal hand vein diameter (p = 0.2). Both apelin isoforms caused reproducible vasodilation in forearm resistance vessels (p < 0.0001). (Pyr1)apelin-13–mediated vasodilation was attenuated by the nitric oxide clamp (p = 0.004) but unaffected by aspirin (p = 0.7).ConclusionsAlthough having no apparent effect on venous tone, apelin causes nitric oxide–dependent arterial vasodilation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis

An overview of the cutaneous porphyrias

This is an overview of the cutaneous porphyrias. It is a narrative review based on the published literature and my personal experience; it is not based on a formal systematic search of the literature. The cutaneous porphyrias are a diverse group of conditions due to inherited or acquired enzyme defects in the porphyrin–haem biosynthetic pathway. All the cutaneous porphyrias can have (either as a consequence of the porphyria or as part of the cause of the porphyria) involvement of other organs as well as the skin. The single commonest cutaneous porphyria in most parts of the world is acquired porphyria cutanea tarda, which is usually due to chronic liver disease and liver iron overload. The next most common cutaneous porphyria, erythropoietic protoporphyria, is an inherited disorder in which the accumulation of bile-excreted protoporphyrin can cause gallstones and, rarely, liver disease. Some of the porphyrias that cause blistering (usually bullae) and fragility (clinically and histologically identical to porphyria cutanea tarda) can also be associated with acute neurovisceral porphyria attacks, particularly variegate porphyria and hereditary coproporphyria. Management of porphyria cutanea tarda mainly consists of visible-light photoprotection measures while awaiting the effects of treating the underlying liver disease (if possible) and treatments to reduce serum iron and porphyrin levels. In erythropoietic protoporphyria, the underlying cause can be resolved only with a bone marrow transplant (which is rarely justifiable in this condition), so management consists particularly of visible-light photoprotection and, in some countries, narrowband ultraviolet B phototherapy. Afamelanotide is a promising and newly available treatment for erythropoietic protoporphyria and has been approved in Europe since 2014

A single-center, observational study of 607 children & young people presenting with Differences in Sex Development (DSD)

Context Differences in sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family and developing a management plan are important. Objective We aimed to better understand the presentation and prevalence of pediatric DSD. Design A retrospective, observational cohort study was undertaken of all children and young people (CYP) referred to a DSD multi-disciplinary team over 25 years (1995-2019). Setting A single tertiary paediatric center. Participants In total, 607 CYP (520 regional referrals) were included. Main Outcome Measures Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results Amongst the three major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45, X/46, XY mosaicism), 46, XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46, XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or herniae. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46, XY children, usually due to complex associated features (46, XY girls, 8.3%; 46, XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6,347 births, and 1 in 5,101 overall throughout childhood. Conclusions DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care

Emergency and perioperative management of adrenal insufficiency in children and young people: British Society for Paediatric Endocrinology and Diabetes consensus guidance

Adrenal insufficiency (AI) is characterised by lack of cortisol production from the adrenal glands. This can be a primary adrenal disorder or secondary to adrenocorticotropic hormone deficiency or suppression from exogenous glucocorticoids. Symptoms of AI in children may initially be non-specific and include growth faltering, lethargy, poor feeding, weight loss, abdominal pain, vomiting and lingering illnesses. AI is treated with replacement doses of hydrocortisone. At times of physiological stress such as illness, trauma or surgery, there is an increased requirement for exogenous glucocorticoids, which if untreated can lead to an adrenal crisis and death. There are no unified guidelines for those <18 years old in the UK, leading to substantial variation in the management of AI. This paper sets out guidance for intercurrent illness, medical, dental and surgical procedures to allow timely and appropriate recognition and treatment of AI and adrenal crisis for children and young people

Identifying the best predictive diagnostic criteria for psoriasis in children (< 18 years): a UK multicentre case-control diagnostic accuracy study (DIPSOC study).

BACKGROUND: In children, psoriasis can be challenging to diagnose. Difficulties arise from differences in the clinical presentation compared with adults. OBJECTIVES: To test the diagnostic accuracy of previously agreed consensus criteria and to develop a shortlist of the best predictive diagnostic criteria for childhood psoriasis. METHODS: A case-control diagnostic accuracy study in 12 UK dermatology departments (2017-2019) assessed 18 clinical criteria using blinded trained investigators. Children (< 18 years) with dermatologist-diagnosed psoriasis (cases, N = 170) or a different scaly inflammatory rash (controls, N = 160) were recruited. The best predictive criteria were identified using backward logistic regression, and internal validation was conducted using bootstrapping. RESULTS: The sensitivity of the consensus-agreed criteria and consensus scoring algorithm was 84·6%, the specificity was 65·1% and the area under the curve (AUC) was 0·75. The seven diagnostic criteria that performed best were: (i) scale and erythema in the scalp involving the hairline, (ii) scaly erythema inside the external auditory meatus, (iii) persistent well-demarcated erythematous rash anywhere on the body, (iv) persistent erythema in the umbilicus, (v) scaly erythematous plaques on the extensor surfaces of the elbows and/or knees, (vi) well-demarcated erythematous rash in the napkin area involving the crural fold and (vii) family history of psoriasis. The sensitivity of the best predictive model was 76·8%, with specificity 72·7% and AUC 0·84. The c-statistic optimism-adjusted shrinkage factor was 0·012. CONCLUSIONS: This study provides examination- and history-based data on the clinical features of psoriasis in children and proposes seven diagnostic criteria with good discriminatory ability in secondary-care patients. External validation is now needed

Kisspeptin Is a Novel Regulator of Human Fetal Adrenocortical Development and Function: A Finding With Important Implications for the Human Fetoplacental Unit

CONTEXT: The human fetal adrenal (HFA) is an integral component of the fetoplacental unit and important for the maintenance of pregnancy. Low kisspeptin levels during pregnancy are associated with miscarriage, and kisspeptin and its receptor are expressed in the HFA. However, the role of kisspeptin in fetal adrenal function remains unknown. OBJECTIVE: To determine the role of kisspeptin in the developing HFA. Design: Experiments using H295R and primary HFA cells as in vitro models of the fetal adrenal. Association of plasma kisspeptin levels with HFA size in a longitudinal clinical study. SETTING: Academic research center and tertiary fetal medicine unit. Participants: Thirty-three healthy pregnant women were recruited at their 12-week routine antenatal ultrasound scan. Main Outcome MEASURES: The spatiotemporal expression of Kiss1R in the HFA. The production of dehydroepiandrosterone sulfate (DHEAS) from HFA cells after kisspeptin treatment, alone or in combination with adrenocorticotropic hormone or corticotropin-releasing hormone. Fetal adrenal volume (FAV) and kisspeptin levels at four antenatal visits (∼20, 28, 34, and 38 weeks' gestation). RESULTS: Expression of Kiss1R was present in the HFA from 8 weeks after conception to term and was shown in the inner fetal zone. Kisspeptin significantly increased DHEAS production in H295R and second-trimester HFA cells. Serial measurements of kisspeptin confirmed a correlation with FAV growth in the second trimester, independent of sex or estimated fetal weight. CONCLUSIONS: Kisspeptin plays a key role in the regulation of the HFA and thus the fetoplacental unit, particularly in the second trimester of pregnancy

Pirt, a TRPV1 Modulator, Is Required for Histamine-Dependent and -Independent Itch

Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood. Recent work has begun to identify genes that contribute to detecting itch at the molecular level. Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation. Pirt−/− mice exhibit deficits in cellular and behavioral responses to various itch-inducing compounds, or pruritogens. Pirt contributes to both histaminergic and nonhistaminergic itch and, crucially, is involved in forms of itch that are both TRPV1-dependent and -independent. Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways

A Concerted Kinase Interplay Identifies PPARγ as a Molecular Target of Ghrelin Signaling in Macrophages

The peroxisome proliferator-activator receptor PPARγ plays an essential role in vascular biology, modulating macrophage function and atherosclerosis progression. Recently, we have described the beneficial effect of combined activation of the ghrelin/GHS-R1a receptor and the scavenger receptor CD36 to induce macrophage cholesterol release through transcriptional activation of PPARγ. Although the interplay between CD36 and PPARγ in atherogenesis is well recognized, the contribution of the ghrelin receptor to regulate PPARγ remains unknown. Here, we demonstrate that ghrelin triggers PPARγ activation through a concerted signaling cascade involving Erk1/2 and Akt kinases, resulting in enhanced expression of downstream effectors LXRα and ABC sterol transporters in human macrophages. These effects were associated with enhanced PPARγ phosphorylation independently of the inhibitory conserved serine-84. Src tyrosine kinase Fyn was identified as being recruited to GHS-R1a in response to ghrelin, but failure of activated Fyn to enhance PPARγ Ser-84 specific phosphorylation relied on the concomitant recruitment of docking protein Dok-1, which prevented optimal activation of the Erk1/2 pathway. Also, substitution of Ser-84 preserved the ghrelin-induced PPARγ activity and responsiveness to Src inhibition, supporting a mechanism independent of Ser-84 in PPARγ response to ghrelin. Consistent with this, we found that ghrelin promoted the PI3-K/Akt pathway in a Gαq-dependent manner, resulting in Akt recruitment to PPARγ, enhanced PPARγ phosphorylation and activation independently of Ser-84, and increased expression of LXRα and ABCA1/G1. Collectively, these results illustrate a complex interplay involving Fyn/Dok-1/Erk and Gαq/PI3-K/Akt pathways to transduce in a concerted manner responsiveness of PPARγ to ghrelin in macrophages