Readjusting the glucocorticoid balance: an opportunity for modulators of 11beta-hydroxysteroid dehydrogenase type 1 activity?

Glucocorticoids play a pivotal role in the regulation of most essential physiological processes, including energy metabolism, maintenance of electrolyte balance and blood pressure, immune-modulation and stress responses, cell proliferation and differentiation, as well as regulation of memory and cognitive functions. There are several levels at which glucocorticoid action can be modulated. On a tissue-specific level, glucocorticoid action is tightly controlled by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes. The conversion of inactive 11-ketoglucocorticoids (cortisone and 11-dehydrocorticosterone) into active 11beta-hydroxyglucocorticoids (cortisol and corticosterone) is catalyzed by 11beta-HSD1, which is expressed in many tissues and plays an important role in metabolically relevant tissues such as the liver, adipose tissue and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11beta-HSD1 activity rather than elevated systemic glucocorticoid levels has been associated with metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that compounds inhibiting 11beta-HSD1 activity ameliorate the adverse effects of excessive glucocorticoid concentrations on metabolic processes, providing promising opportunities for the development of therapeutic interventions. This review addresses recent findings relevant for the development and application of therapeutically useful compounds that modulate 11beta-HSD1 function.

The role of adrenal steroidogenesis in arterial hypertension

Adrenal aldosterone production, the major regulator of salt and water retention, is discussed with respect to hypertensive diseases. Physiological aldosterone production is tightly regulated, either stimulated or inhibited, in the adrenal zona glomerulosa by both circulating factors and/or by locally derived endothelial factors. Arterial hypertension caused by volume overload is the leading clinical symptom indicating increased mineralocorticoid hormones. Excessive aldosterone production is seen in adenomatous disease of the adrenals. The balance between stimulatory/proliferative and antagonistic signaling is disturbed by expression of altered receptor subtypes in the adenomas. Increased aldosterone production without a detectable adenoma is the most frequent form of primary aldosteronism. Both increased sensitivity to agonistic signals and activating polymorphisms within the aldosterone synthase gene (CYP11B2) have been associated with excessive aldosterone production. 17alpha-Hydroxylase deficiency and glucocorticoidremediable aldosteronism can also cause excessive mineralocorticoid synthesis. In contrast, the severe form of pregnancy-induced hypertension, preeclampsia, is characterized by a compromised volume expansion in the presence of inappropriately low aldosterone levels. Initial evidence suggests that compromised CYP11B2 is causative, and that administration of NaCl lowered blood pressure in pregnant patients with low aldosterone availability due to a loss of function.

Non-alcoholic fatty liver disease associated with hypobetalipoproteinemia: report of three cases and a novel mutation in APOB gene

Background: Non-alcoholic fatty liver disease, the leading cause of chronic liver disease in children, is defined by hepatic fat infiltration >5% of hepatocytes, in the absence of excessive alcohol intake, evidence of viral, autoimmune or drug-induced liver disease. Conditions like rare genetic disorders must be considered in the differential diagnosis. Case Report: Two male brothers, and a non-related girl, all overweight, had liver steatosis. One of the brothers and the girl had elevated transaminases; all three presented with low total cholesterol, low density lipoproteins and very low density lipoproteins cholesterol levels, hypotriglyceridemia and low apolipoprotein B. A liver biopsy performed in the brother with citolysis confirmed steatohepatitis and the molecular study of apolipoprotein B gene showed a novel homozygous mutation (c.9353dup p.Asn3118Lysfs17). Patients with cytolysis lost weight, however liver steatosis persists. Conclusion: Fatty liver disease might be a consequence of hypobetalipoproteinemia. Evidence is scarce due to low number of reported cases.

Assessment of foot health and animal welfare: clinical findings in 229 dairy Mediterranean Buffaloes (Bubalus bubalis) affected by foot disorders.

BACKGROUND Lameness represents the third most important health-related cause of economic loss in the dairy industry after fertility and mastitis. Although, dairy Mediterranean Buffaloes (MB) and dairy cows share similar breeding systems predisposing to similar herd problems, published studies exploring its relevance and role in these ruminants are still rare and incomplete. The aims of this study were to describe the clinical findings of foot disorders (FDs) in dairy MB and their influence on animal welfare, determined by assessment of locomotion score (LS), body condition score (BCS) and cleanliness score (CS). RESULTS Of 1297 multiparous MB submitted to routine trimming procedures, 229 buffaloes showed at least one FD. The prevalence of buffaloes affected by FDs was 17.7 %, while motility and lameness indexes were 84.1 % (1091/1297) and 15.9 % (206/1297), respectively. Overgrowth was present in 17.0 % (220/1297), corkscrew claw in 15.8 % (205/1297), interdigital phlegmon in 0.9 % (12/1297), white line abscess in 0.8 % (11/1297), digital dermatitis in 0.1 % (1/1297) and interdigital hyperplasia in 0.1 % (1/1297). Simultaneous presence of FDs was recorded in 17.0 % of MB (221/1297): overgrowth and corkscrew claw occurred together in 15.8 % of cases (205/1297), overgrowth and interdigital phlegmon in 0.3 % (4/1297), overgrowth and white line abscess in 0.8 % (11/1297), digital dermatitis and interdigital hyperplasia in 0.1 % (1/1297). The presence of FDs was always associated with lameness (LS > 2), except from 23 MB with simultaneous overgrowth and interdigital phlegmon occurrence. The majority of MB within the under-conditioned group (95.5 %, 43/45) and all those with CS > 2 (122/122) had a locomotion score above the threshold of normality (LS > 2). Furthermore, foot diseases such as interdigital hyperplasia, white line abscess and digital dermatitis or interdigital hyperplasia seemed to occur more frequently associated with decreased BCS and increased CS scores. CONCLUSIONS This study describes for the first time the involvement of white line disease, interdigital phlegmona, digital dermatitis and interdigital hyperplasia in foot disorders of dairy Mediterranean buffalo and shows their association with an impairment of animal welfare.

Eating disorders in children and adolescents: an update

Purpose of review Children and adolescents with eating disorders frequently present to child mental health and paediatric services and have significant morbidity, psychosocial impairment and mortality. Efforts to treat these individuals have been hampered by a poor evidence base for effective interventions. This article reviews research published during 2004 with a primary focus on this challenging clinical area. Recent findings Research published during 2004 has replicated past epidemiological findings and expanded our understanding of the relationship of family meal structure and disordered eating. Research has provided assistance in the well known clinical conundrums of excessive exercising in anorexia nervosa and predicting when return of menses will occur. There has also been clarification of adolescent bingeing. Potential advances include a new, noninvasive method of measuring body composition and investigations in adolescents on leptin, neuro and gastrointestinal peptides. Importantly, further evidence of the effectiveness of family therapy for anorexia nervosa and short-term benefits from intervention programs have been published. Summary The research base that will influence clinical practice in child and adolescent eating disorders is increasing. More research is required in all areas of intervention.

Diagnosis of canine bleeding disorders

Canine bleeding disorders arise due to a multitude of conditions and require detailed clinical and laboratory investigation. A productive diagnostic approach depends on a thorough patient history, physical examination, haemostatic screening tests and an array of specific diagnostic tests. Patient history is necessary to assist determination of the onset, severity and possible aetiologies of a bleeding disorder. Similarly, a complete physical examination should ideally allow differentiation between disorders of primary and secondary haemostasis. Following this distinction, a variety of laboratory tests are indicated to further define the nature of the bleeding episode. These tests may be broadly categorised as screening tests of primary haemostasis, secondary haemostasis and fibrinolysis, and specific tests directed at identifying particular disorders. Appropriate utilisation of these tests and interpretation of their results in conjunction with patient signalment, history and clinical signs affords the greatest chance of a successful diagnosis.

An overview of psychological and neurobiological mechanisms by which early negative experiences increase risk of mood disorders

Objective: Early life experiences are associated with severe and long-lasting effects on behavioural and emotional functioning, which in turn are thought to increase the risk for unipolar depression and other disorders of affect regulation. The neurobiological and psychological mechanisms through which adverse early life experiences confer risk are poorly understood. Method: Alterations in brain structure and function in limbic and prefrontal cortical regions have been linked to early negative experiences and to mood disorders. Results: There are a number of psychological domains that may be dysfunctional in people with mood disorders, and which, if the dysfunction occurs prior to onset of mood symptoms, may signify a risk factor for depression. Cognitive dysfunction has been examined in patients with mood disorders, with some suggestion that changes in cognitive function may antedate the onset of mood symptoms, and may be exacerbated in those who experienced early negative trauma. Social cognition, including emotion comprehension, theory of mind and empathy, represent under-studied domains of psychological function that may be negatively influenced by early adverse experience. Temperament and personality factors may also leave people vulnerable to mood instability. Conclusion: This review summarizes the evidence for dysfunction in each of these domains for people with mood disorders.

A utilização das análises cefalométricas no diagnóstico dos distúrbios do sono

A Síndrome da Apneia e Hipopneia Obstrutiva do Sono (SAHOS) é uma doença crónica, de carácter progressivo, que atinge cerca de 4% da população adulta. A obstrução parcial ou total das vias aéreas superiores durante o sono pode provocar quadros de hipopneia (uma redução do fluxo aéreo) ou apneia (cessação completa do fluxo aéreo). Os pacientes queixam-se de sonolência diurna excessiva, ronco durante a noite e além destes problemas sociais a preocupação pela redução de funções cognitivas que se podem desencadear, como memória, atenção, hipertensão pulmonar e insuficiência cardíaca. O Médico Dentista está habilitado para avaliar o espaço aéreo oro e nasofaringeo e diagnosticar, além da necessidade de correções dentárias, a presença de obstruções das Vias Aereas Superiores (VAS) orientando assim o seu tratamento. Além do exame clínico, o diagnóstico de distúrbios respiratórios do sono é baseado na história clínica, exame físico e confirmado através da polissonografia e da análise cefalométrica. Esta tem sido considerada como um método importante no diagnóstico, fornecendo características craniofaciais que permitem verificar a existência de pré-disposição de SAHOS. As avaliações com cefalometrias obtidas em telerradiografias em norma lateral é um recurso essencial para realizar o diagnóstico de distúrbios respiratórios do sono, desde que o profissional tenha domínio da técnica e da sua interpretação. Estes distúrbios são caracterizados por diferentes graus de diminuição do espaço das vias aéreas superiores, causado por factores anatómicos e funcionais, que podem ser analisados pelo profissional. A intervenção precoce torna-se crucial, pela diminuição da morbilidade, melhores resultados no tratamento, diminuição de gastos nos serviços de saúde e melhor qualidade de vida do paciente. O presente trabalho teve por objectivo realizar uma revisão bibliográfica sobre a importância da avaliação das vias aéreas superiores através da análise de grandezas cefalométricas obtidas de telerradiografias em norma lateral como padrão de diagnóstico para a identificação de distúrbios respiratórios do sono.

Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality

Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56(low) NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56(low) NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94(hi)/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality.

Outcome Prediction of Consciousness Disorders in the Acute Stage Based on a Complementary Motor Behavioural Tool.

INTRODUCTION: Attaining an accurate diagnosis in the acute phase for severely brain-damaged patients presenting Disorders of Consciousness (DOC) is crucial for prognostic validity; such a diagnosis determines further medical management, in terms of therapeutic choices and end-of-life decisions. However, DOC evaluation based on validated scales, such as the Revised Coma Recovery Scale (CRS-R), can lead to an underestimation of consciousness and to frequent misdiagnoses particularly in cases of cognitive motor dissociation due to other aetiologies. The purpose of this study is to determine the clinical signs that lead to a more accurate consciousness assessment allowing more reliable outcome prediction. METHODS: From the Unit of Acute Neurorehabilitation (University Hospital, Lausanne, Switzerland) between 2011 and 2014, we enrolled 33 DOC patients with a DOC diagnosis according to the CRS-R that had been established within 28 days of brain damage. The first CRS-R assessment established the initial diagnosis of Unresponsive Wakefulness Syndrome (UWS) in 20 patients and a Minimally Consciousness State (MCS) in the remaining13 patients. We clinically evaluated the patients over time using the CRS-R scale and concurrently from the beginning with complementary clinical items of a new observational Motor Behaviour Tool (MBT). Primary endpoint was outcome at unit discharge distinguishing two main classes of patients (DOC patients having emerged from DOC and those remaining in DOC) and 6 subclasses detailing the outcome of UWS and MCS patients, respectively. Based on CRS-R and MBT scores assessed separately and jointly, statistical testing was performed in the acute phase using a non-parametric Mann-Whitney U test; longitudinal CRS-R data were modelled with a Generalized Linear Model. RESULTS: Fifty-five per cent of the UWS patients and 77% of the MCS patients had emerged from DOC. First, statistical prediction of the first CRS-R scores did not permit outcome differentiation between classes; longitudinal regression modelling of the CRS-R data identified distinct outcome evolution, but not earlier than 19 days. Second, the MBT yielded a significant outcome predictability in the acute phase (p<0.02, sensitivity>0.81). Third, a statistical comparison of the CRS-R subscales weighted by MBT became significantly predictive for DOC outcome (p<0.02). DISCUSSION: The association of MBT and CRS-R scoring improves significantly the evaluation of consciousness and the predictability of outcome in the acute phase. Subtle motor behaviour assessment provides accurate insight into the amount and the content of consciousness even in the case of cognitive motor dissociation.

Kinematic and electromyographic analysis of the overhead squat in individuals showing excessive medial knee displacement

Dynamic knee valgus is a multi-planar motion that has been associated with anterior cruciate ligament injuries and patellofemoral pain syndrome. Clinical assessment of dynamic knee valgus can be made by looking for the visual appearance of excessive medial knee displacement (MKD) in the double-leg squat (DLS). The purpose of this dissertation was to identify the movement patterns and neuromuscular strategies associated with MKD during the DLS. Twenty-four control subjects and eight individuals showing MKD during the DLS participated in the study. Significant differences were verified between subjects that demonstrated MKD and a control (CON) group for the eletromyographic amplitude of adductor magnus, biceps femoris, vastus lateralis and vastus medialis muscles (p < 0.05), during the descending phase of the DLS. During the ascending phase were found group differences for adductor magnus and rectus femoris muscles (p < 0.05). Results from kinematic analysis revealed higher minimum and maximum values of ankle abduction and knee internal rotation angles (p < 0.05) for the MKD group. Also, individuals showing excessive MKD had higher hip adduction/abduction excursion. Our results suggested that higher tibial internal rotation and knee internal rotation angles in the initial position of the DLS are associated with MKD. The neuromuscular strategies that contributed to MKD were higher adductor magnus activation, whereas biceps femoris, vastus lateralis and vastus medialis activated more to stabilize the knee in response to the internal rotation moment.

Membrane associated transporter protein gene (SLC45A2) and the genetic basis of normal human pigmentation variation

This work is concerned with the genetic basis of normal human pigmentation variation. Specifically, the role of polymorphisms within the solute carrier family 45 member 2 (SLC45A2 or membrane associated transporter protein; MATP) gene were investigated with respect to variation in hair, skin and eye colour ― both between and within populations. SLC45A2 is an important regulator of melanin production and mutations in the gene underly the most recently identified form of oculocutaneous albinism. There is evidence to suggest that non-synonymous polymorphisms in SLC45A2 are associated with normal pigmentation variation between populations. Therefore, the underlying hypothesis of this thesis is that polymorphisms in SLC45A2 will alter the function or regulation of the protein, thereby altering the important role it plays in melanogenesis and providing a mechanism for normal pigmentation variation. In order to investigate the role that SLC45A2 polymorphisms play in human pigmentation variation, a DNA database was established which collected pigmentation phenotypic information and blood samples of more than 700 individuals. This database was used as the foundation for two association studies outlined in this thesis, the first of which involved genotyping two previously-described non-synonymous polymorphisms, p.Glu272Lys and p.Phe374Leu, in four different population groups. For both polymorphisms, allele frequencies were significantly different between population groups and the 272Lys and 374Leu alleles were strongly associated with black hair, brown eyes and olive skin colour in Caucasians. This was the first report to show that SLC45A2 polymorphisms were associated with normal human intra-population pigmentation variation. The second association study involved genotyping several SLC45A2 promoter polymorphisms to determine if they also played a role in pigmentation variation. Firstly, the transcription start site (TSS), and hence putative proximal promoter region, was identified using 5' RNA ligase mediated rapid amplification of cDNA ends (RLM-RACE). Two alternate TSSs were identified and the putative promoter region was screened for novel polymorphisms using denaturing high performance liquid chromatography (dHPLC). A novel duplication (c.–1176_–1174dupAAT) was identified along with other previously described single nucleotide polymorphisms (c.–1721C>G and c.–1169G>A). Strong linkage disequilibrium ensured that all three polymorphisms were associated with skin colour such that the –1721G, +dup and –1169A alleles were associated with olive skin in Caucasians. No linkage disequilibrium was observed between the promoter and coding region polymorphisms, suggesting independent effects. The association analyses were complemented with functional data, showing that the –1721G, +dup and –1169A alleles significantly decreased SLC45A2 transcriptional activity. Based on in silico bioinformatic analysis that showed these alleles remove a microphthalmia-associated transcription factor (MITF) binding site, and that MITF is a known regulator of SLC45A2 (Baxter and Pavan, 2002; Du and Fisher, 2002), it was postulated that SLC45A2 promoter polymorphisms could contribute to the regulation of pigmentation by altering MITF binding affinity. Further characterisation of the SLC45A2 promoter was carried out using luciferase reporter assays to determine the transcriptional activity of different regions of the promoter. Five constructs were designed of increasing length and their promoter activity evaluated. Constitutive promoter activity was observed within the first ~200 bp and promoter activity increased as the construct size increased. The functional impact of the –1721G, +dup and –1169A alleles, which removed a MITF consensus binding site, were assessed using electrophoretic mobility shift assays (EMSA) and expression analysis of genotyped melanoblast and melanocyte cell lines. EMSA results confirmed that the promoter polymorphisms affected DNA-protein binding. Interestingly, however, the protein/s involved were not MITF, or at least MITF was not the protein directly binding to the DNA. In an effort to more thoroughly characterise the functional consequences of SLC45A2 promoter polymorphisms, the mRNA expression levels of SLC45A2 and MITF were determined in melanocyte/melanoblast cell lines. Based on SLC45A2’s role in processing and trafficking TYRP1 from the trans-Golgi network to stage 2 melanosmes, the mRNA expression of TYRP1 was also investigated. Expression results suggested a coordinated expression of pigmentation genes. This thesis has substantially contributed to the field of pigmentation by showing that SLC45A2 polymorphisms not only show allele frequency differences between population groups, but also contribute to normal pigmentation variation within a Caucasian population. In addition, promoter polymorphisms have been shown to have functional consequences for SLC45A2 transcription and the expression of other pigmentation genes. Combined, the data presented in this work supports the notion that SLC45A2 is an important contributor to normal pigmentation variation and should be the target of further research to elucidate its role in determining pigmentation phenotypes. Understanding SLC45A2’s function may lead to the development of therapeutic interventions for oculocutaneous albinism and other disorders of pigmentation. It may also help in our understanding of skin cancer susceptibility and evolutionary adaptation to different UV environments, and contribute to the forensic application of pigmentation phenotype prediction.

Fathers as informants of children’s fears and worries

The recognition of excessive fears and worries in children is important for early intervention. Despite current knowledge about the important contribution fathers make to their children’s emotional, social and cognitive development, more emphasis is often given to the views of mothers in both research and practice. This paper reports on a community study of 220 families. Fathers, mothers and children reported on children’s fears and worries using three different methods. While father and mother ratings were moderately correlated on two of the measures, there was relatively poor parent-child agreement. Implications for the role of fathers in the assessment of childhood fears and worries are discussed.

Determinants and market impact of seasoned equity offerings : the case of A-REITs

The paper examines the decision by Australian Real Estate Trusts (A-REITs) to issue seasoned equity offerings from 2000 - 2008 and stock market reaction to the offerings. The findings reveal that highly leveraged A-REITs with variable earnings are less likely to issue seasoned equity offerings. Inconsistent results for structure and type of properties held by the A-REIT do not allow for inference to be drawn. Similar to previous studies of seasoned equity offerings, we find a significant negative abnormal return associated with their announcement and no evidence of excessive leakage of information. Furthermore, market reaction differences to announcements of SEOs for the pre-global financial crisis (GFC) (2000-2006) and GFC eras (2007-2008) are noted with GFC era shareholders incurring larger abnormal return losses at 1.13% in comparison to the pre-GFC era shareholder loss of 0.34% on the SEO announcement day. Cross-sectional regressions show that the issued amount, leverage and profitability are significant factors affecting abnormal returns. Growth opportunities, tangibility, operating risk, size of A-REIT and other variables capturing A-REIT structure and property types held do not have an impact on abnormal returns

Anxiety and Aboriginal and Torres Strait Islander young people

This chapter outlines issues of excessive anxiety in Indigenous youth. It describes what an anxiety disorder is and its consequences and how Indigenous youth seem to be at risk for developing such disorders. Issues concerning the delivery of traditional prevention and intervention programs are discussed and possible interventions are provided.