Pituitary xanthogranulomas: clinical features, radiological appearances and post-operative outcomes.

BACKGROUND: Xanthogranulomas are inflammatory masses most commonly found at peripheral sites such as the skin. Sellar and parasellar xanthogranulomas are rare and present a diagnostic challenge as they are difficult to differentiate from other sellar lesions such as craniopharyngiomas and Rathke's cleft cysts pre-operatively. Their radiological imaging features are yet to be clearly defined, and clinical outcomes after surgery are also uncertain. This study reviews clinical presentation, radiological appearances, and clinical outcomes in a cohort of patients with pituitary xanthogranulomas. METHODS: A prospectively maintained pituitary surgery database was screened for histologically confirmed pituitary xanthogranulomas between May 2011-December 2016. Retrospective case note assessments were then performed by three independent reviewers. Patient demographics, clinical presentations, imaging, and clinical outcomes were analysed. RESULTS: During the study period 295 endoscopic endonasal pituitary surgeries were performed. Six patients had confirmed pituitary xanthogranulomas (2%). Patients most commonly presented with visual field deficits and/or endocrine dysfunction. Common imaging features included: a cystic consistency, hyperintensity on T1-weighted MR images, and contrast enhancement either peripherally (n = 3) or homogenously (n = 3). The most common pre-operative endocrine deficits were hyperprolactinaemia and hypoadrenalism (at least one of which was identified in 4/6 patients; 66%). Thirty-three percent (2/6) of patients presented with diabetes insipidus. The most common post-operative endocrinological deficits were adrenocortical dysfunction (66%) and gonadotropin deficiency (66%). Visual assessments normalised in all six patients post-operatively. Gross total resection was achieved in all patients, and at median follow up of 33.5 months there were no cases of tumour recurrence. CONCLUSIONS: The prevalence of pituitary xanthogranulomas in our series is higher than that suggested in the literature. Surgery restored normal vision to all cases, however four patients (67%) required long-term hormonal replacement post-operatively. Imaging features such peripheral rim enhancement, a suprasellar tumour epicentre, and the absence of both calcification or cavernous sinus invasion were identified as potential indicators that together should alert clinicians to the possibility of pituitary xanthogranuloma when assessing patients with cystic sellar and parasellar tumours.

NF-κB signalling is involved in immune-modulation, but not basal functioning, of the mouse suprachiasmatic circadian clock.

Circadian rhythms are recurring near-24 hour patterns driven by an endogenous circadian timekeeping system. The master pacemaker in this system is the hypothalamic suprachiasmatic nucleus (SCN). Recently interest has been drawn to how the SCN clock responds to immune system stimulation. A major signalling component in the immune system is nuclear factor (NF)-κB. In the present study we examined the role of NF-κB in SCN function. Whilst serum shocked fibroblasts showed rhythmic nuclear localisation of p65 and p65-dependent transcription, there were no circadian changes in the SCN in expression of the NF-κB components p65, c-Rel, p-IκB or p-IKK. Chronic treatment with the NF-κB inhibitor PDTC did not impact on circadian or diurnal rhythms. Phase-shifting light pulses did not impact on SCN expression of p65, and PDTC treatment did not attenuate the behavioural or molecular response to light pulses. Peripheral treatment with lipopolysaccharide resulted in increased NF-κB component expression in the SCN. In vitro experiments with SCN slice cultures showed that treatment with NF-κB inhibitors did not markedly alter rhythmic changes in PER2::LUC expression. Further, SCN slices from nf-κb::luc mice did not show any evidence for circadian rhythms in NF-κB-mediated transcription. Experiments utilising older mice (~16 months old) showed that SCN treatment in vitro with PDTC resulted in increased amplitude of rhythmic PER2::LUC expression, and LPS treatment resulted in altered PER2::LUC rhythm acrophase. Overall, we interpret our results as providing evidence for the involvement of NF-κB in the suprachiasmatic circadian clock following immune stimulation, but not under basal conditions.

Homeostatic migration and distribution of innate immune cells in primary and secondary lymphoid organs with ageing.

Ageing of the innate and adaptive immune system, collectively termed immune senescence, is a complex process. One method to understand the components of ageing involves dissociating the effects of ageing on the cells of the immune system, on the microenvironment in lymphoid organs and tissues where immune cells reside and on the circulating factors that interact with both immune cells and their microenvironment. Heterochronic parabiosis, a surgical union of two organisms of disparate ages, is ideal for this type of study, as it has the power to dissociate the age of the cell and the age of the microenvironment into which the cell resides or is migrating. So far, however, it has been used sparingly to study immune ageing. Here we review the limited literature on homeostatic innate immune cell trafficking in ageing in the absence of chronic inflammation. We also review our own recent data on trafficking of innate immune subsets between primary and secondary lymphoid organs in heterochronic parabiosis. We found no systemic bias in retention or acceptance of neutrophils, macrophages, dendritic cells or natural killer cells with ageing in primary and secondary lymphoid organs. We conclude that these four innate immune cell types migrate to and populate lymphoid organs (peripheral lymph nodes, spleen and bone marrow), regardless of their own age and of the age of lymphoid organs.

A critical review of low-carbohydrate diets in people with Type 2 diabetes.

AIMS: The efficacy of low-carbohydrate diets (LCD) in people with Type 2 diabetes has divided the nutrition community. This review seeks to re-examine the available data to clarify understanding. METHODS: A comprehensive search of databases was used to identify meta-analyses of LCD in Type 2 diabetes. To improve the quality of the studies analysed, the following inclusion criteria were applied: randomized control trials ≥ 4 weeks in people aged > 18 years with Type 2 diabetes; a carbohydrate intake ≤ 45% of total energy intake per day; and a dietary intake assessment at the end of the study. The resulting studies were subjected to a thematic analysis. RESULTS: Nine meta-analyses were identified containing 153 studies. Twelve studies met our amended inclusion criteria. There were no significant differences in metabolic markers, including glycaemic control, between the two diets, although weight loss with a LCD was greater in one study. Carbohydrate intake at 1 year in very LCD (< 50 g of carbohydrates) ranged from 132 to 162 g. In some studies, the difference between diets was as little as 8 g/day of carbohydrates. CONCLUSION: Total energy intake remains the dietary predictor of body weight. A LCD appears no different from a high-carbohydrate diet in terms of metabolic markers and glycaemic control. Very LCDs may not be sustainable over a medium to longer term as carbohydrate intake in diets within studies often converged toward a more moderate level. The variable quality of studies included in earlier meta-analyses likely explains the previous inconsistent findings between meta-analyses.

The Impact of Vitamin D Deficiency on the Severity of Symptoms and Mortality Rate among Adult Patients with Covid-19: A Systematic Review and Meta-Analysis.

INTRODUCTION: We aimed to study the prevalence of vitamin D deficiency (VDD) in patients with COVID-19 infection and evaluate the impact of vitamin D levels on the severity of symptoms and the case fatality rate. EVIDENCE ACQUISITION: A comprehensive literature search was performed up to December 20, 2020, using the following databases: MEDLINE, PubMed, EMBASE, SCOPUS, Web of Science, and preprint databases (BioRxiv and MedRxiv). Any individual observational study related to the prevalence and impact of vitamin D deficiency/insufficiency (VDD/VDI) on the severity of COVID-19 symptoms and mortality rates was included. No language restrictions were applied, and both published and non-published studies were included. EVIDENCE SYNTHESIS: Two of the authors independently performed the literature search and assessed the eligibility of studies. The quality of studies included was assessed using the Newcastle-Ottawa Scale. Data were analyzed using the Review Manager Software (version 5) and Comprehensive Meta-analysis Software (version 3). A total of 43 studies were included with a sample size of 254,963 patients with COVID-19. Pooled analysis showed a higher prevalence of VDD and VDI in patients with COVID-19 (59.0% and 40.1%, respectively). Moreover, a significant association was noticed between vitamin D levels and severity of symptoms (odds ratio [OR] = 3.38, 95% confidence interval [CI]: 1.94-5.87, P < 0.0001), as well as the case fatality rate (OR = 2.30, 95% CI: 1.47-3.59, P < 0.00001). CONCLUSIONS: VDD is highly prevalent in patients with COVID-19 infection. Lower vitamin D levels correlate with disease severity and poor prognosis although most of the data have been derived from moderate-quality observational studies.

Acyl-ghrelin mediated lipid retention and inflammation in obesity-related Type 2 diabetes.

Acyl-ghrelin has various peripheral effects including the potential role in mediating cellular lipid removal and macrophage polarization. Previous reports are contradictory as to how glycaemia and acyl-ghrelin mediates lipid retention and inflammation within individuals with Type 2 diabetes (T2D). Our aim was to explore acyl-ghrelin levels and ghrelin expression in relation to lipid and inflammatory markers within an ex vivo human model, biopsied visceral adipose tissue. Results indicated that acyl-ghrelin was associated with a decline in key lipid homeostasis genes ABCG1 and LXRß expression. Within T2D there was also a down regulation of these genes which was independent of acyl-ghrelin levels. Circulatory pro-inflammatory markers (IL-6 and TNFα) had no association with ghrelin expression nor circulating acyl-ghrelin levels. Anti-inflammatory marker (IL-10) and total antioxidant status (TAOS%) were positively associated with ghrelin expression across samples from all groups combined (total sample cohort) and specifically within the obesity sample cohorts. Data supported the hypothesis that hyperglycaemia and acyl-ghrelin have a regulatory role in lipid retention. Furthermore, that both acyl- and desacyl-ghrelin is responsible for a protective inflammatory response; however this response is diminished in T2D.

Regulatory Architecture of the Neuronal Cacng2/Tarpγ2 Gene Promoter: Multiple Repressive Domains, a Polymorphic Regulatory Short Tandem Repeat, and Bidirectional Organization with Co-regulated lncRNAs.

CACNG2 (TARPγ2, Stargazin) is a multi-functional regulator of excitatory neurotransmission and has been implicated in the pathological processes of several brain diseases. Cacng2 function is dependent upon expression level, but currently, little is known about the molecular mechanisms that control expression of this gene. To address this deficit and investigate disease-related gene variants, we have cloned and characterized the rat Cacng2 promoter and have defined three major features: (i) multiple repressive domains that include an array of RE-1 silencing transcription factor (REST) elements, and a calcium regulatory element-binding factor (CaRF) element, (ii) a (poly-GA) short tandem repeat (STR), and (iii) bidirectional organization with expressed lncRNAs. Functional activity of the promoter was demonstrated in transfected neuronal cell lines (HT22 and PC12), but although selective removal of REST and CaRF domains was shown to enhance promoter-driven transcription, the enhanced Cacng2 promoter constructs were still about fivefold weaker than a comparable rat Synapsin-1 promoter sequence. Direct evidence of REST activity at the Cacng2 promoter was obtained through co-transfection with an established dominant-negative REST (DNR) construct. Investigation of the GA-repeat STR revealed polymorphism across both animal strains and species, and size variation was also observed in absence epilepsy disease model cohorts (Genetic Absence Epilepsy Rats, Strasbourg [GAERS] and non-epileptic control [NEC] rats). These data provide evidence of a genotype (STR)-phenotype correlation that may be unique with respect to proximal gene regulatory sequence in the demonstrated absence of other promoter, or 3' UTR variants in GAERS rats. However, although transcriptional regulatory activity of the STR was demonstrated in further transfection studies, we did not find a GAERS vs. NEC difference, indicating that this specific STR length variation may only be relevant in the context of other (Cacna1h and Kcnk9) gene variants in this disease model. Additional studies revealed further (bidirectional) complexity at the Cacng2 promoter, and we identified novel, co-regulated, antisense rat lncRNAs that are paired with Cacng2 mRNA. These studies have provided novel insights into the organization of a synaptic protein gene promoter, describing multiple repressive and modulatory domains that can mediate diverse regulatory inputs.

The Impact of Ghrelin on the Survival and Efficacy of Dopaminergic Fetal Grafts in the 6-OHDA-Lesioned Rat.

Ghrelin is a peptide produced in the gut with a wide range of physiological functions. Recent studies have suggested it may have potential as a neuroprotective agent in models of Parkinson's disease, reducing the impact of toxic challenges on the survival of nigral dopaminergic neurons. The presence of the ghrelin receptor (GHSR1a) on the dopaminergic neurons of the substantia nigra raises the possibility that a potential application for this property of ghrelin may be as an adjunctive neuroprotective agent to enhance and support the survival and integration of dopaminergic cells transplanted into the striatum. Thus far, inconsistent outcomes in clinical trials for fetal cell transplantation have been linked to low rates of cell survival which we hypothesize could be ameliorated by the presence of ghrelin. To explore this, we confirmed the expression of the GHSR1a and related enzymes on e14 ventral mesencephalon. To determine a functional effect, five groups of female Sprague-Dawley rats received a unilateral 6-OHDA lesion to the medial forebrain bundle and four received an intrastriatal graft of e14 ventral mesencephalic cells. Grafted rats received saline; acyl-ghrelin (10 µg/kg); acyl-ghrelin (50 µg/kg) or the ghrelin agonist JMV-2894 (160 µg/kg) i.p. for 8 weeks. An effect of ghrelin at low dose on hippocampal neurogenesis indicated blood-brain barrier penetrance and attainment of biologically relevant levels but neither acyl-ghrelin nor JMV-2894 improved graft survival or efficacy.

Hyponatraemia in clinical practice.

Hyponatraemia is defined as a serum sodium concentration below 135 mmol/l. It causes major diagnostic and management problems in practice. Hyponatraemic disorders are divided into euvolaemic, hypervolaemic and hypovolaemic. In the evaluation of the hyponatraemic patient, history taking should focus on identifying the potential cause, duration and symptomatology. Clinical examination should include assessment of volume status. Acute hyponatraemia of less than 48 h duration requires prompt correction. Treatment may involve hypertonic saline, isotonic saline and appropriate hormone replacement therapy depending on the aetiology. Chronic hyponatraemia should be treated with caution because of the risk of central pontine myelinolysis.

Less is more: Caloric regulation of neurogenesis and adult brain function.

Calorie intake is essential for regulating normal physiological processes and is fundamental to maintaining life. Indeed, both extremes of calorie intake result in increased morbidity and mortality. In this review, we discuss the effect of calorie intake on adult brain function, with an emphasis on the beneficial effects of mild calorie restriction. Recent findings relating to the regenerative and protective effects of the gastrointestinal hormone, ghrelin, suggest that it may underlie the beneficial effects of calorie restriction. We discuss the putative cellular mechanisms underlying the action of ghrelin and their possible role in supporting healthy brain ageing.

Ghrelin function in human obesity and type 2 diabetes: a concise review.

The 28 amino acid hormone, ghrelin, has been found to have various effects on metabolism. This review will focus on the pathways integrated into ghrelin's effect within the hypothalamus, pancreas and adipocytes. The identification of molecules and pathways that regulate ghrelin-mediated lipid retention could establish new mechanisms underlying cellular energy homeostasis. The impact of acyl-ghrelin on glucose metabolism and lipid homeostasis may allow for novel preventative or early intervention therapeutic strategies to treat obesity related type 2 diabetes and associated metabolic dysfunction.

Acyl ghrelin improves cognition, synaptic plasticity deficits and neuroinflammation following amyloid ß (Aß1-40) administration in mice.

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild-type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid ß peptide 1-40 (Aß1-40 ) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aß1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y-maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aß1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aß1-40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aß1-40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium-binding adapter expressing microglial in the rostral hippocampus. Finally, Aß1-40 blocked long-term potentiation induced by high-frequency stimulation and this effect could be acutely blocked with co-administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.

Comparative analysis of the effects of ghrelin and unacylated ghrelin on luteinizing hormone secretion in male rats.

Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of diverse biological functions, including energy homeostasis and, recently, reproduction. Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.

Protein/DNA interaction profiling reveals novel regulators of the pineal transcriptome.

The rat pineal gland transcriptome exhibits dynamic daily variation that reflects nocturnally restricted hormone production. Here we have used a protein/DNA interaction array to screen for day-night changes in DNA binding activity that are associated with transcriptional rhythms. Overall, 47 of 54 potential consensus binding sequence activities were detected, and of these, 29 (62%) were found to exhibit day:night differences in level. In addition to known, rhythmic pineal DNA binding activities (CRE and AP-1), multiple novel activities were observed including nocturnally elevated AP-2 consensus sequence binding activity. This array result was validated using conventional DNA binding assays, and we have also demonstrated AP-2beta and AP-2gamma proteins in the pineal gland, in addition to a nocturnally elevated AP-2alpha isoform. Our results have confirmed the presence of a complex assembly of transcriptional rhythms in the rat pineal gland and have provided details of more factors that contribute to this aspect of circadian neuroendocrine function.

Hypothalamic expression of human growth hormone induces post-pubertal hypergonadotrophism in male transgenic growth retarded rats.

Growth hormone (GH) is known to regulate peripheral components of the hypothalamo-pituitary gonadal (HPG) axis, but it remains unclear whether GH exerts a significant influence on the activity of the hypothalamo-pituitary components of the HPG axis. In this study, we investigated the development of HPG axis function in the male transgenic growth retarded (Tgr) rat, a model of moderate systemic GH deficiency caused by hypothalamic expression of human (h)GH. Impaired postnatal somatotroph expansion and moderate GH deficiency in male Tgr rats were accompanied by a two- to three-fold increase in pituitary gonadotrophin content, but without a significant change in the pituitary gonadotroph population. A three- to nine-fold elevation in basal circulating luteinising hormone concentration was seen in postpubertal Tgr rats, with a smaller increase in follicle-stimulating hormone. Despite this hypergonadotrophism, there was no corresponding increase in steroidogenic (circulating testosterone and seminal vesicle weights) or gametogenic (spermatozoa counts in seminiferous tubules) activity in the postpubertal Tgr testis. Following puberty, the plasma leptin concentration also became progressively elevated in Tgr males. Circulating gonadotrophin and leptin levels were normalised in Tgr rats by peripheral physiological replacement of rat GH, but plasma testosterone concentration was unaffected. These results confirm that hGH exerts a positive influence on the central control of gonadotrophin secretion in the Tgr rat, but the absence of a corresponding elevation in the steroidogenic or gametogenic function of the Tgr testis implies that the peripheral GH/insulin-like growth factor I axis may also exert a permissive influence on testicular function. The relative contribution of somatogenic and lactogenic mechanisms and the potential influence of elevated leptin and decreased sensitivity to androgen feedback to the development of postpubertal hypergonadotrophism in Tgr males remain to be determined.

Cost-effectiveness and budget impact of Empirical vitamin D therapy on unintentional falls in older adults in the UK.

OBJECTIVES: To evaluate the health outcomes and economics associated with the current guidance relating to the prevention of falls in the elderly through vitamin D supplementation. SETTING: UK. PARTICIPANTS: UK population aged 60 years and above. INTERVENTIONS: A Markov health state transition model simulated patient transitions between key fall-related outcomes using a 5-year horizon and annual cycles to assess the costs and benefits of empirical treatment with colecalciferol 800 iu daily. PRIMARY AND SECONDARY OUTCOME MEASURES: Costs and health outcomes attributable to fall prevention following vitamin D supplementation. RESULTS: Our model shows that treating the UK population aged 60 years and above with 800 iu colecalciferol would, over a 5-year period: (1) prevent in excess of 430,000 minor falls; (2) avoid 190,000 major falls; (3) prevent 1579 acute deaths; (4) avoid 84,000 person-years of long-term care and (5) prevent 8300 deaths associated with increased mortality in long-term care. The greatest gains are seen among those 75 years and older. Based on reduction in falls alone, the intervention in all adults aged 65+ is cost-saving and leads to increased quality adjusted life years. Treating all adults aged 60+ incurs an intervention cost of £2.70bn over 5 years, yet produces a -£3.12bn reduction in fall-related costs; a net saving of £420M. Increasing the lower bound age limit by 5-year increments increases budget impact to -£1.17bn, -£1.75bn, and -£2.06bn for adults 65+, 70+ and 75+, respectively. CONCLUSIONS: This study shows that treatment of the elderly UK population with colecalciferol 800 iu daily would be associated with reductions in mortality and substantial cost-savings through fall prevention.

The validity of estimating total body fat and fat-free mass from skinfold thickness in adults with growth hormone deficiency.

The regression equations of Durnin and Womersley for estimating total body fat (TBF) and fat-free mass (FFM) from skinfold thickness were validated for adult GH-deficient (GHD) patients by comparing the values of TBF and FFM from the prediction equations with the directly measured values from dual energy x-ray absorptiometry. Twenty-seven male and 24 female patients (aged 21-61 yr) were studied. GHD was isolated in 5 cases and was part of a spectrum of hypopituitarism due to a variety of causes in 46 cases. The mean period of GHD was 6.9 +/- 4.6 yr. All patients were receiving stable replacement therapy. The validation statistics showed no significant differences (P > 0.05) between measured and predicted values of TBF and FFM in either males (24.5 vs. 24.9 and 65.5 vs. 65.8 kg) or females (24.6 vs. 26.3 and 44.7 vs. 43.9 kg). Mean differences were smaller in males (0.4 and 0.2 kg) than females (1.7 and -0.8 kg); they were less than 1% in males and less than 2% in females. Therefore, the Durnin and Womersley equations are suitable for general use with GHD patients. Using TBF (kilograms) from dual energy x-ray absorptiometry as the dependent variable and the log of the sum of skinfold thickness as the independent variable, linear regression equations were formulated to predict TBF in GHD patients. The lowest SE of estimate was 3.8 kg in males and 4.6 kg in females. To determine their general applicability, these equations will need to be cross-validated.

Body composition derived from whole body counting of potassium in growth hormone-deficient adults: a possible low intracellular potassium concentration.

The validity of total body potassium (TBK) measurement in estimating fat mass and fat-free mass (FFM) in GHD adults was assessed by comparison with the reference technique of dual energy x-ray absorptiometry (DEXA). The TBK and FFM values determined by DEXA were used to calculate the potassium concentration per kg FFM in GH-deficient (GHD) adults and compared with standard values for normal subjects of 59.6 mmol for females and 66.4 mmol for males. There were considerable differences between predicted and measured TBK values for both males (3972 vs. 3577 mmol; P < 0.001) and females (2526 vs. 2277 mmol; P < 0.001). Similarly, the estimation of FFM and fat mass by TBK measurement was significantly inaccurate for both sexes compared to values determined by DEXA. These discrepancies may be accounted for by the lower calculated potassium concentrations compared with standard values for both males (56.2 vs. 66.4 mmol; P < 0.001) and females (53.1 vs. 59.6 mmol; P < 0.001). These observations suggest that caution should be exercised in the interpretation of TBK in GHD adults, and the reduced potassium concentrations would alleviate inaccuracies in the estimation of body composition. Secondly, the decreased intracellular potassium concentration of GHD adults may account for the decreased muscle strength and ease of fatigueability seen in GHD adults.

AMP is a component of the low molecular weight mitogenic activity present in human pituitary tumours.

The mitogenic activity of extracts of human non-functional pituitary tumours has been studied. Previously we have reported that the tumour extracts could be resolved into both high (> 13,000) and low (< 3,000) molecular weight fractions using Sephadex G-50 chromatography. Mitogenic activity was assayed by looking at trichloroacetic acid precipitable 3H-thymidine incorporation into GH3 cells. We have now purified the major component of the low molecular weight mitogenic fraction using reversed phase HPLC: the material was identified and found to be 5'-adenosine monophosphate (5'-AMP) using electron spray mass spectrometry. The mitogenic activity of 5'-AMP and the purified tumour extract was confirmed as both produced an increase in GH3 cell number after 4 days of treatment. In conclusion our results show that the major component of the low molecular weight mitogenic activity in human non-functional pituitary tumour extracts is 5'-AMP.

Increased central arterial stiffness in hypothyroidism.

Hypothyroidism is associated with cardiovascular dysfunction. It is increasingly apparent that stiffening of central arteries may lead to increased afterload and cardiac dysfunction. We noninvasively studied the peripheral and central pressure waveforms in 12 untreated hypothyroid patients as well as in 12 age-, sex-, and body mass index-matched controls using the technique of pulse wave analysis from recordings at the radial artery. Indexes of arterial stiffness, augmentation index (AI) and augmentation of central arterial pressure (AG), were derived as well as time of travel of the reflected wave (TR), a direct estimate of aortic pulse wave velocity. At baseline, there were no significant differences between the 2 groups in brachial and aortic blood pressures. Hypothyroid patients had significantly higher AI than controls (mean +/- SEM[SCAP], 32.0 +/- 3.4% vs. 17.0 +/- 2.4%; P < 0.0005) even when corrected for heart rate (AI(C); 28.0 +/- 3.2% vs. 17.0 +/- 2.4%; P < 0.006) and AG (13.0 +/- 2.2 vs. 7.0 +/- 2.1 mm Hg; P < 0.03) together with a lower TR (132.0 +/- 4.1 vs. 142.0 +/- 1.5 msec; P < 0.03). After 6 months of therapy with T(4), all patients were euthyroid. AI(C) had decreased in the patient group (23.0 +/- 3.2% vs. 28.0 +/- 3.2%; P < 0.01) as had AG (9.0 +/- 1.5 vs. 13.0 +/- 2.2 mm Hg; P < 0.008), but TR was significantly higher (142.0 +/- 3.0 vs. 132.0 +/- 4.1 msec; P < 0.008). AI correlated with age in all groups (hypothyroid group: r = 0.937; P < 0.0005; control group: r = 0.804; P < 0.0005), but correlated with TSH level only among controls (r = 0.591; P < 0.05). This study confirms that hypothyroidism is associated with increased cardiovascular risk, as evidenced by increased augmentation of central aortic pressures and central arterial stiffness. Furthermore, these abnormalities are reversed after adequate T(4) replacement.