Diagnosis, management and therapeutic outcome in prepubertal Cushing's disease.

Objectives: Cushing's disease (CD) in prepubertal children is very rare and presents important diagnostic and therapeutic challenges. We report experience of the management of this subpopulation of CD patients.

Study Design/methods: Retrospective patient case note review.

PPAR control: it's SIRTainly as easy as PGC.

This review describes recent advances in our knowledge of the regulatory interactions influencing the expression of peroxisome proliferator-activated receptor (PPAR)-regulated genes. We address recent advances highlighting the role of PPARgamma (PPARG) coactivator-1 (PGC-1) and lipin-1 in co-ordinating the expression of genes controlling nutrient handling. We evaluate the possibility that SIRT1 lies at the heart of a regulatory loop involving PPARalpha, PGC-1alpha (PPARA, PPARGC1A as given in the HUGO Database), and lipin-1 (LPIN1 as listed in the HUGO Database) that ultimately controls the metabolic response to varying nutrient and physiological signals via a common mechanism mediated by post-translation modifications (deacetylation) of both PPARalpha and PGC-1s.

Characterisation of cystathionine gamma-lyase/hydrogen sulphide pathway in ischaemia/reperfusion injury of the mouse kidney: an in vivo study.

The generation of endogenous hydrogen sulphide may either limit or contribute to the degree of tissue injury caused by ischaemia/reperfusion injury. Here, we have attempted to characterise the endogenous hydrogen sulphide synthesis pathway and the effects of sodium hydrosulphide, a hydrogen sulphide donor, in a mouse model of renal ischaemia/reperfusion injury. Anaesthetised male C57/b mice weighing 20-25 g were divided into two groups; (i) 'Ischaemia/Reperfusion Injury', in which mice were subjected to bilateral renal ischaemia performed by clamping the renal pedicles for 30 min followed by reperfusion for 24 h, (ii) 'Sham', in which mice were subjected to the same surgical procedures as above, except for renal ischaemia/reperfusion.

Challenging dogma: radical conservation surgery for early stage cervical cancer in order to retain fertility.

Introduction: Cervical cancer is the second commonest cancer to affect women with over half a million cases world-wide yearly. Screening programmes have reduced the incidence and death rate dramatically in Western societies. At the same time, professional and social pressures may delay child bearing such that a significant number of women will present with early stage disease, but be anxious to retain their fertility potential.

Activation of macrophage peroxisome proliferator-activated receptor-gamma by diclofenac results in the induction of cyclooxygenase-2 protein and the synthesis of anti-inflammatory cytokines.

Cyclooxygenase-2 (COX-2) is an inducible isoform of the COX family of enzymes central to the synthesis of pro-inflammatory prostaglandins. Induction of COX-2 is mediated by many endogenous and exogenous molecules that include pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS). It has been demonstrated that COX-2 can also be induced by diclofenac in cultured J774.

Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency.

Objective: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations.

Peroxisome proliferator-activated receptor-alpha contributes to the resolution of inflammation after renal ischemia/reperfusion injury.

This study was designed to elucidate the role of peroxisome proliferator-activated receptor (PPAR)-alpha in the development of inflammation after ischemia/reperfusion injury of the kidney. We have evaluated the effects of ischemia/reperfusion on renal dysfunction, injury, and inflammation in wild-type mice or mice in which the gene for PPAR-alpha has been deleted [PPAR-alpha(-/-)] and then treated with the PPAR-alpha agonist fenofibrate. Mice were subjected to bilateral renal ischemia (30 min) and reperfusion (24 h) and received fenofibrate (3 mg/kg i.

SONU20176289, a compound combining partial dopamine D(2) receptor agonism with specific serotonin reuptake inhibitor activity, affects neuroplasticity in an animal model for depression.

We investigated the efficacy of SONU20176289, a member of a group of novel phenylpiperazine derivatives with a mixed dopamine D(2) receptor partial agonist and specific serotonin reuptake inhibitor (SSRI) activity, in a chronic stress model of depression in male tree shrews. Animals were subjected to a 7-day period of psychosocial stress before treatment for 28 days with SONU20176289 (6 mg/kg/day, p.o.

Generation of endogenous hydrogen sulfide by cystathionine gamma-lyase limits renal ischemia/reperfusion injury and dysfunction.

The generation of endogenous hydrogen sulfide may either limit or contribute to the degree of tissue injury caused by ischemia/reperfusion. A total of 74 male Wistar rats were used to investigate the effects of endogenous and exogenous hydrogen sulfide in renal ischemia/reperfusion. Administration of the irreversible cystathionine gamma-lyase (CSE) inhibitor, dL-propargylglycine, prevented the recovery of renal function after 45 min ischemia and 72 h reperfusion.

Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R.

Hydrogen sulfide (H2S) is a novel gaseous mediator produced by cystathionine-beta-synthase and cystathionine-gamma-lyase in the cardiovascular system, including the heart. Using a rat model of regional myocardial ischemia/reperfusion, we investigated the effects of an H2S donor (sodium hydrogen sulfide [NaHS]) on the infarct size and apoptosis caused by ischemia (25 min) and reperfusion (2 h). Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by NaHS.

Clinical value of immunohistochemically detected lymphovascular space invasion in early stage cervical carcinoma.

Background: This study investigates the clinical significance of lymphovascular space invasion (LVSI) as detected by hematoxylin and eosin (LVSI-H&E) and immunohistochemistry (LVSI-IHC) in early stage cervical carcinoma.

Methods: Single representative sections from 97 patients with early stage squamous cell cervical cancer were immunostained with pancytokeratin and CD31 endothelial cell marker antibodies. The H&E sections and their corresponding immunostained sections were reexamined to identify LVSI.

Conservative surgery for carcinoma of the cervix.

Cancer of the cervix is the second most common female cancer, with more than half a million cases worldwide occurring annually. Although screening programmes have significantly reduced the incidence and death rates in the western world, social pressures have led to the delay in childbearing, increasing numbers of cervix cancer present early in reproductive life and at an early stage. These women are often anxious to retain their fertility potential, if at all possible.

Vaccine Oka variants and sequence variability in vaccine-related skin lesions.

As with most live attenuated viral vaccines, varicella vaccine comprises a mixture of variant strains. Knowledge about the pathogenic potential of individual strains in the varicella vaccine is limited. Vaccination against chickenpox causes a usually modified varicella-like rash in a small percentage of healthy children, and vaccine virus reactivates on rare occasions to cause herpes zoster (HZ).

Use and limitations of varicella-zoster virus-specific serological testing to evaluate breakthrough disease in vaccinees and to screen for susceptibility to varicella.

A plethora of tests for determining the presence of antibodies to varicella-zoster virus (VZV) have been developed over the years, with a wide range of performance standards. There is general agreement that the presence of VZV antibodies in serum indicates immunity to varicella and protection from chickenpox, although the role of specific antibody in mediating protection remains unclear. Both antibodies and cellular immunity probably interact to mediate immunity to the virus.

Sphingosylphosphorylcholine reduces the organ injury/dysfunction and inflammation caused by endotoxemia in the rat.

Objective: Sphingosylphosphorylcholine (SPC) has been reported to activate a variety of G-protein coupled receptors, including S1P(1-5), G2A, GPR4, and OGR1 (GPR68). Interestingly, other structurally related lysophospholipid agonists of these receptors have been shown to exhibit immunomodulatory properties both in vitro and in vivo. These include prevention of tumor necrosis factor-alpha-induced monocyte adhesion to aortic endothelium in mice (sphingosine-1-phosphate via S1P(1-5) receptors) and reduction of organ injury and/or mortality in animal models of sepsis and endotoxemia (lysophosphatidylcholine via G2A).

Pediatric Cushing's syndrome: clinical features, diagnosis, and treatment.

Cushing's syndrome (CS) results from prolonged exposure to supraphysiological levels of circulating glucocorticoids, endogenously or exogenously derived. Although rare in childhood, CS remains a difficult condition to diagnose and treat. A multidisciplinary approach and close collaboration with adult colleagues is adopted at most large centres that manage pediatric CS patients.

Familial glucocorticoid deficiency: advances in the molecular understanding of ACTH action.

Familial glucocorticoid deficiency (FGD), otherwise known as hereditary unresponsiveness to ACTH, is a rare autosomal recessive disease characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Mutations of the ACTH receptor, also known as the melanocortin-2 receptor (MC2R), account for approximately 25% of FGD cases. More recently a second gene, MRAP (melanocortin-2 receptor accessory protein), was identified and found to account for a further 15-20%.

Is the modulation of retinoid and retinoid-associated signaling a future therapeutic strategy in neurological trauma and neurodegeneration?

The complex molecular pathways that mediate the effects of vitamin A and its derivatives, are increasingly recognized as a component of the repair capacity that could be activated to induce protection and regeneration in the mature nervous tissue. Retinoid and retinoid-associated signaling plays an essential role in normal neurodevelopment and appears to remain active in the adult CNS. In this paper, we review evidence which supports the hypothesis of an activation of retinoid-associated signaling molecular pathways in the mature nervous tissue and its significance in the context of neurodegenerative, trauma-induced and psychiatric disorders, at spinal and supra-spinal levels.

Consistency of labial finish line preparation for metal ceramic crowns: an investigation of a new bur.

Purpose: Previous studies have reported on the difficulties inherent in preparing the labial aspect of teeth for metal ceramic crowns with consistency and also the implications for the definitive restoration of underprepared and overangled finish lines. In this study, a bur designed to prepare a 1.2-mm deep chamfer was tested and compared with two other bur kits.

Muramyl dipeptide enhances the response to endotoxin to cause multiple organ injury in the anesthetized rat.

Nucleotide oligomerization domain (NOD) proteins recognize peptidoglycan fragments, resulting in up-regulation of transcription factors, and may enhance the inflammatory response to infection. Specifically, NOD2 has been shown to sense muramyl dipeptide (MDP), which is released during bacterial cell growth and replication. Activation of NOD2 by MDP enhances the inflammatory response caused by LPS (endotoxin).

Erythropoietin and carbamylated erythropoietin are neuroprotective following spinal cord hemisection in the rat.

The cytokine erythropoietin (EPO) has been shown to be neuroprotective in a variety of models of central and peripheral nervous system injury. Derivatives of EPO that lack its erythropoietic effects have recently been developed, and the initial reports suggest that they have a neuroprotective potential comparable to that of EPO. One such derivative is carbamylated EPO (CEPO).

Unilateral laparoscopic ovarian diathermy in infertile women with clomiphene citrate-resistant polycystic ovary syndrome.

We evaluated the efficacy of unilateral versus bilateral laparoscopic ovarian diathermy in infertile women with clomiphene citrate-resistant polycystic ovary syndrome. Recall follow-up 18 to 48 months after laparoscopic ovarian diathermy showed that unilateral ovarian diathermy was as effective and long lasting as bilateral ovarian diathermy in the resumption of menstruation and pregnancy rates.

Abnormal puberty in paediatric Cushing's disease: relationship with adrenal androgen, sex hormone binding globulin and gonadotrophin concentrations.

Objective: Paediatric Cushing's disease is frequently associated with abnormal puberty. We addressed the hypothesis that prepubertal patients show excessive virilization and pubertal patients show suppression of LH and FSH secretion.

Design And Measurements: Serum androstenedione (A4), dehydroepiandrosterone sulphate (DHEAS), testosterone (T), and sex hormone binding globulin (SHBG) were determined at diagnosis and converted to standard deviation scores.

Long-term anterior pituitary function in patients with paediatric Cushing's disease treated with pituitary radiotherapy.

Background/objective: Pituitary radiotherapy (RT) is an effective second-line treatment for paediatric Cushing's disease (CD). Although the short-term effects of pituitary RT are well documented, there are less data on possible long-term sequelae. We report the long-term anterior pituitary function in a cohort of paediatric CD patients treated with pituitary RT.