Adrenal venous sampling in primary aldosteronism: lessons from over 600 single-operator procedures.

Adrenal vein sampling (AVS) is a recommended if not required final diagnostic step in the investigation of primary aldosteronism, the most common cause of remediable secondary hypertension. Successful adrenal vein sampling is operator-dependent. Having performed over 600 such procedures at our centre over 20 years, our single-operator experience is described in detail for the purpose of training future radiologists as well as for use by those who are planning to start an AVS programme of their own. This updated review considers new developments in primary aldosteronism disease understanding that are relevant for AVS performance and protocols, along with technical enhancements that may be used for special cases. Detailed understanding of variant anatomy and tips for successful cannulation are keys to success, along with an endocrinology and clinical chemistry partnership for continuous quality control. A successful AVS programme offers patients a hope for cure of resistant hypertension.

Prevalence of growth hormone deficiency in patients with unexplained chronic fatigue after undergoing bone marrow transplantation in adulthood.

PURPOSE: Many patients who undergo bone marrow transplantation (BMT) in adulthood experience unexplained chronic fatigue which can have a major impact on their health-related quality of life (QoL). Pre-BMT treatment regimens increase the risk of developing acquired growth hormone deficiency (GHD), which results in a clinical syndrome with decreased energy and has additionally been linked to metabolic syndrome. METHODS: Using the gold-standard insulin hypoglycemic test (IHT), we evaluated the prevalence of GHD in 18 post-BMT adult patients with unexplained chronic fatigue, as well as the correlation between peak serum GH response and QoL scores, the metabolic syndrome, and insulin resistance. Peak serum GH cut-point less than 3.0 ug/L was used for the diagnosis of severe GHD. The Fatigue Severity Scale and Quality of Life in Adult GHD Assessment questionnaires were used to quantify fatigue symptoms. RESULTS: The prevalence of severe GHD within this sample of 18 patients was 50%. A trend between lower peak serum GH response and higher fatigue and QoL-AGHDA scores was observed. CONCLUSIONS: GHD may represent a remediable contributor to post-BMT chronic fatigue in adults, further studies are needed to evaluate the potential role of screening and GH replacement therapy in this vulnerable patient population. IMPLICATIONS FOR CANCER SURVIVORS: GHD may be a treatable explanation for disabling post-BMT fatigue pending results of intervention studies.

Pharmacotherapy decisions among postmenopausal women attending a group medical consultation or a one-on-one specialist consultation at an osteoporosis center: an observational cohort study.

Group medical visits for osteoporosis can improve access to care while being highly accepted by patients. In this study, a similar proportion of women planned to initiate pharmacotherapy after attending a group or traditional one-on-one osteoporosis consultation, indicating that the group consultation model does not produce unexpected treatment decisions. INTRODUCTION: Group medical consultations for osteoporosis are time-efficient and highly accepted by patients, but effects on treatment decisions are unknown. We aimed to compare women's decisions to initiate or decline osteoporosis pharmacotherapy after attending either a group or transitional one-on-one osteoporosis consultation. METHODS: In this observational study, we prospectively evaluated postmenopausal women referred to an osteoporosis clinic who attended a group medical visit and compared their decisions regarding pharmacologic osteoporosis treatment with retrospective data from a cohort of women who attended a traditional consultation. Both consultation types involved interaction with a specialist physician, individualized fracture risk estimation (using FRAX®), and education regarding fracture consequences and available osteoporosis medications. Both forms of consultation emphasized shared decision-making; however, group consultation attendees did not receive personalized treatment recommendations from the physician. RESULTS: We reviewed the records of 125 women (median age 63 years) who attended a group consultation and 83 women (median age 64 years) who attended a traditional consultation between 2016 and 2019. Twenty-four (19%) of the group cohort and 16 (19%) of the traditional cohort were at high 10-year risk of major osteoporotic fracture (FRAX® ≥ 20.0%). A similar proportion planned to initiate pharmacologic therapy after the group and traditional consultations (23% vs 16%, p = 0.22); these proportions were comparable among women at high risk (42% vs 50%, p = 0.75) and moderate risk (19% vs 15%, p = 0.77), but a higher proportion of low-risk women planned to initiate therapy after the group consultation (18% vs 0%, p = 0.009). CONCLUSION: Patient decisions to initiate pharmacologic treatment made during a group visit are similar to those made during traditional one-on-one consultation. The group consultation model represents an alternative to one-on-one assessment for delivering osteoporosis consultative services.

Simulated effects of early menopausal bone mineral density preservation on long-term fracture risk: a feasibility study.

Prevention of early menopausal bone loss may reduce the future burden of osteoporosis. In this modelling exercise, an osteoporosis prevention strategy involving 5-year infusions of zoledronic acid, beginning early in menopause, reduced long-term fracture risk and the proportion of aging women with femoral neck densitometric osteoporosis. This strategy warrants further evaluation. INTRODUCTION: Preventing early menopausal bone loss may substantially reduce the future burden of osteoporosis. We modelled the effects of infrequent zoledronic acid infusions on long-term fracture risk. METHODS: Data from the Canadian Multicentre Osteoporosis Study (CaMos) were used to determine the expected natural history of femoral neck areal bone mineral density (BMD) and fracture risk (using FRAX®) from ages 50-80 for women with no antiresorptive drug exposures. We modelled the effects of three infusions of zoledronic acid (at ages 50, 55, 60) on long-term fracture risk, assuming this intervention would preserve BMD until age 65 years, followed by losses mirroring early menopausal BMD loss. RESULTS: At age 65, untreated women and zoledronic acid recipients had expected mean (SD) femoral neck T-scores of - 1.5(1.0) and - 0.8(1.0), 10-year major osteoporotic fracture (MOF) risks of 9.8%(5.0) and 8.0%(3.7) and hip fracture risks of 1.7%(2.4) and 0.8%(1.2), respectively. At age 80, untreated women and zoledronic acid recipients had expected femoral neck T-scores of - 1.9(0.9) and - 1.4(0.9), MOF risks of 17.9%(8.2) and 14.9%(6.4) and hip fracture risks of 6.3%(6.2) and 4.4%(4.5), respectively. The expected proportion of women with femoral neck T-score ≤ - 2.5 was 14.9% for untreated women and 3.8% for zoledronic acid recipients at age 65, increasing to 28.1% and 12.0%, respectively, at age 80. Numbers-needed-to-treat to prevent one case of densitometric osteoporosis were 9 at age 65 and 5 at age 80. CONCLUSION: Infrequent infusions of zoledronic acid, initiated early in menopause, are expected to reduce long-term fracture risk and result in a substantial reduction in the proportion of women with densitometric osteoporosis after age 65.

Very high rate of false positive biochemical results when screening for pheochromocytoma in a large, undifferentiated population with variable indications for testing.

OBJECTIVE: Pheochromocytoma/Paraganglioma (PPGL) is a rare tumor with non-specific presentations overlapping common entities like anxiety, hypertension, acute illness and episodic "spells." Assessment of urine normetanephrine or metanephrine (UNM-UMN) in real-life, where PPGL is very rare and PPGL mimics extremely common, may show overlap in results with loss of specificity depending on the reference range. We determined the extent to which UNM-UMN are high in people undergoing screening for PPGL. DESIGN AND METHODS: Retrospective review of all UNM-UMN performed in a central lab serving Southern Alberta over 8 years. RESULTS: After excluding pediatric ages and patients with CKD, there were 12,572 unique patients with 14,383 measures of UNM-UMN. 85 patients (0.7%) had markedly high UNM-UMN compatible with likely PPGL. Depending on the age category (in decades), 10-22% of all UNM results were above the upper reference limit(URL), particularly between ages of 40-60. Less than 3% had elevations in both UNM and UMN. Of those with high UNM, 99% were less than 3-fold the URL. Based on the population data, a potential new reference range for UNM is suggested, which may be more appropriate to the types of patient who undergo this form of testing. CONCLUSIONS: There is an extraordinarily high prevalence of high UNM seen in real-life use of the test. However, the vast majority of high UNM are unlikely to be PPGL given the disease rarity and the massive number of tests ordered. This suggests the current laboratory URL may be too low (poor specificity) and/or the reference range may not be appropriate to the type of patient being screened for PPGL. Depending on the frequency of use of any screening test in a population, if the disease is rare and the specificity of the test is poor, a high rate of false positive results will be expected.

Patient engagement in clinical guidelines development: input from > 1000 members of the Canadian Osteoporosis Patient Network.

Patient engagement in clinical guidelines development is essential. The results of a self-administered online survey identified themes important to people living with osteoporosis and will inform the development of Osteoporosis Canada clinical guidelines recommendations. INTRODUCTION: Patient engagement is essential in the development of high-quality and relevant guidelines for osteoporosis management. Osteoporosis Canada (OC) is updating its national clinical practice guidelines in collaboration with people living with osteoporosis in the process. METHODS: Using electronic mail, we contacted 6937 members of the Canadian Osteoporosis Patient Network (COPN) to provide input on the selection of relevant content, outcomes, and research questions via a self-administered online survey. Close-ended questions were analyzed using descriptive statistics, and conventional content analysis was conducted for open-ended questions. RESULTS: A total of 1108 individuals completed the survey (97% women, 86% stated they lived with osteoporosis). Most participants considered it critical to have recommendations on physical activity and exercise (74%), fall prevention (69%), nutrition (68%), and initial bone mineral density testing (67%). In addition to preventing fractures, over 75% of respondents stated that consideration of preserving quality of life and ability to perform daily activities, preventing admission to long-term care and fracture-related death, and avoiding serious harms from medications were essential outcomes to consider in evaluating the evidence. In terms of selection of research questions, seven themes emerged from the content analysis including pharmacotherapy, screening and monitoring, diet and supplements, education, exercise, alternative therapies, and pain management. CONCLUSIONS: Patients emphasized that autonomy, mobility, and quality of life are highly valued outcomes and must be integral to practice guideline development. As expected, guidance on pharmacotherapy, screening and monitoring, and fracture prevention were priorities identified to be included in osteoporosis management guidelines.

Parathyroid hormone-dependent familial hypercalcemia with low measured PTH levels and a presumptive novel pathogenic mutation in CaSR.

Familial hypocalciuric hypercalcemia (FHH) is a benign autosomal dominant condition characterized by lifelong asymptomatic hypercalcemia. FHH is typically caused by a heterozygous inactivating mutation of the calcium-sensing receptor (CaSR) and characterized by moderate hypercalcemia, inappropriately normal or elevated serum parathyroid hormone (PTH), and relative hypocalciuria (FeCa < 2%) with histologically normal parathyroid glands. FHH should be distinguished from primary hyperparathyroidism so that unnecessary parathyroid surgery is avoided. We report a case that presented with asymptomatic, familial hypercalcemia but low PTH and normal (non-low) urinary calcium excretion found to be secondary to a novel pathogenic inactivating mutation of the CaSR gene. We present an asymptomatic 54-year-old Malaysian woman with incidentally discovered hypercalcemia, intermittent hypophosphatemia, and FeCa > 2%. PTH levels were repeatedly below the mean of the reference range (on two separate assays) and sometimes even below the lower reference limit. Two siblings, one niece, and her son had hypercalcemia without nephrolithiasis. Cinacalcet, used as a PTH-suppression test, normalized serum total and ionized calcium after 7 days of cinacalcet 30 mg BID, confirming her hypercalcemia was PTH-mediated. Given her family history, genetic testing was pursued and discovered a novel pathogenic mutation of the CaSR gene confirming the diagnosis of FHH type 1. Our case represents an atypical presentation of FHH1 with low PTH and FeCa > 2%. This contributes to the expanding clinical and biochemical spectrum of CaSR inactivating mutations and presents an innovative approach to evaluating biochemically uncertain familial hypercalcemia with cinacalcet before pursuing expensive genetic analysis.

Diffuse, fracturing systemic skeletal histiocytosis of unknown type: a novel metabolic bone disease.

We describe a novel disease of diffuse skeletal histiocytosis associated with multiple fragility fractures and high osteoclast activity. Clinical, radiographic, biochemical, genetic, and histopathological investigations were performed to characterize the diagnosis of an Asian man who presented with hip fracture and diffuse skeletal lytic lesions. After excluding malignancy and other common metabolic bone diseases, open bone biopsy yielded several pathological samples all showing extensive skeletal histiocytosis likely to explain the diffuse axial and appendicular lytic lesions. Rare disorders such as Langerhans histiocytosis, Erdheim-Chester disease, and diffuse cystic skeletal angiomatosis were excluded through careful pathological examination and lack of CD1a and S-100 staining. Whole exome sequencing did not yield diagnostic findings to explain this likely acquired disease. High markers of osteoclast activity suggested excessive focal bone resorption but normalized after zoledronic acid treatment. A novel disease of skeletal histiocytosis with high bone turnover is differentiated from other histiocytic and lytic skeletal diseases.

Clinical implications for biochemical diagnostic thresholds of adrenal sufficiency using a highly specific cortisol immunoassay.

OBJECTIVES: Recent guidelines recommend a diagnosis of adrenal insufficiency when a stimulated peak cortisol level falls below 500nmol/L. This may not be valid using a highly specific cortisol immunoassay or liquid chromatography-mass spectroscopy (LCMS/MS). We sought to determine the diagnostic threshold for adrenal insufficiency using a new and widely available, highly specific cortisol immunoassay. DESIGN: All patients having a dynamic test of adrenal reserve had results measured using the historical cortisol assay (Roche Cortisol) and the newer assay (Roche Cortisol II). MEASUREMENTS: Subjects were categorized according to the traditional assay (normal>500nmol/L) with clinical case adjudication where necessary. Results from Cortisol II assay were concomitantly measured along with cortisol levels measured by LCMS/MS. ROC curve analysis was performed to generate new diagnostic thresholds. RESULTS: The Roche Cortisol II compared favourably with measures by LCMS/MS, generating cortisol levels approximately 30% lower than the older immunoassay. Many normal subjects had peak cortisols as low as 300nmol/L with Cortisol II. The optimized diagnostic threshold for adrenal insufficiency was 350nmol/L with a sensitivity of 91% and specificity 97%. Use of the old diagnostic threshold with the Cortisol II assay would have inappropriately doubled the rate of patient-classification as adrenal insufficient. CONCLUSIONS: Transition to a more specific cortisol assay requires revision of diagnostic thresholds for dynamic tests of adrenal insufficiency. With the Roche Cortisol II assay, a cut-off of 350nmol/L should replace the traditional 500nmol/L although some healthy subjects may be very close to this level.

Severe hyperkalemia following adrenalectomy for aldosteronoma: prediction, pathogenesis and approach to clinical management- a case series.

BACKGROUND: As the field of Primary Aldosteronism (PA) becomes ever expanded, diagnosis of PA is increasingly diagnosed by endocrinologists. With increased PA screening, many of the cases are now found in patients with complex co-morbidities in addition to their hypertension. Post adrenalectomy renal impairment with hyperkalemia is now increasingly seen in these complex patients, as evidenced by the numerous reports on this issue that have appeared within the past 3 years. We present a small case series to illustrate the breadth of the problem, along with a discussion about how such CKD/hyperkalemic events may be predicted. CASE PRESENTATION: We present three cases of primary aldosteronism with long standing hypertension (more than 10 years) hypokalemia (2.0-3.0 mmol/l). Serum aldosterone was high with low renin activity leading to high aldosterone to renin ratio (ARR). They underwent abdominal CT scan revealing adrenal mass and adrenal vein sample confirmed lateralization. None of the patients had evidence of renal disease before surgery (as evident by normal eGFR and serum creatinine). Post adrenalectomy they had reduction in the blood pressure and became eukalemic. Serum aldosterone and renin activity were low leading to a low ARR. Case 1 developed hyperkalemia and increased serum creatinine 6 weeks post operatively which resolved with initiation of fludrocortisone and every attempt to discontinue fludrocortisone resulted in hyperkalemia and rising creatinine. Her hyperkalemia is under control with oral sodium bicarbonate. Case 2 developed hyperkalemia and increasing creatinine 2 months post operatively transiently requiring fludrocortisone and later on managed with furosemide for hyperkalemia. Case 3 developed renal impairment and hyperkalemia 2 weeks post operatively requiring fludrocortisone. CONCLUSION: Post APA resection severe hyperkalemia may be a common entity and screening should be actively considered in high risk patients. Older age, longer duration of hypertension, impaired pre-op and post-op GFR and higher levels of pre-op aldosterone and are all risk factors which predict the likelihood of developing post-operative hyperkalemia. Fludrocortisone, sodium bicarbonate, loop diuretics and potassium binders can be used for treatment. Treatment choice should be tailored to patient characteristics including fluid status, blood pressure and serum creatinine. Potassium binders should be avoided in patients with history of recent abdominal surgery, opioid use and constipation. Serum electrolytes and creatinine should be monitored every 1-2 weeks after starting treatment to ensure an adequate response. Prolonged management may be necessary in some cases and at-risk patients should be counselled as to the meaning and importance of post-operative changes in measured renal function and potassium.

Defining contralateral adrenal suppression in primary aldosteronism: implications for diagnosis and outcome.

OBJECTIVE: Unilateral primary aldosteronism (PA) should have a contralaterally normal and therefore suppressed adrenal zona glomerulosa. However, there is no validated definition of adrenal suppression. We created two biochemical hypotheses of adrenal suppression based upon measurements taken during adrenal vein sampling (AVS) to determine whether either proved useful for interpretation of AVS or prediction of hypertension outcome in operated cases. DESIGN: Retrospective database analysis. PATIENTS: Ninety-nine cases of PA from a tertiary hypertension unit. MEASUREMENTS: Hypothesis 1 was the proportional suppression of the uninvolved/lowest adrenal(aldo/cortisol) to IVC(aldo/cortisol) ratio pre- and post cosyntropin. Hypothesis 2 was the absolute decrease in the uninvolved adrenal(aldo/cortisol) ratio after cortrosyn injection. ROC analysis performed using lateralization and hypertension resolution as the outcomes of interest. RESULTS: Hypothesis 1 proved highly predictive of lateralization with a ROC AUC of 0.958, P < 0.0001, giving adrenal(aldo/cortisol):IVC(aldo/cortisol) <1.4 as the optimized criterion (sensitivity 90%, specificity 94%). For blood pressure outcomes in the surgical subgroup (n = 52), hypertension resolution was most commonly seen among subjects with adrenal suppression by both definitions although there was significant overlap with subjects requiring ongoing medication. CONCLUSIONS: Post cosyntropin suppression of the uninvolved adrenal-to-IVC ratio is a highly useful definition of adrenal suppression that accurately predicts unilateral PA. This may be particularly useful in a case where AVS fails to catheterize one of the adrenal veins but suppression is seen on the other side. Adrenal suppression may also predict blood pressure outcome, however, a much larger PA database is likely necessary to determine the relative contribution of this predictor.

Despite limited specificity, computed tomography predicts lateralization and clinical outcome in primary aldosteronism.

BACKGROUND: Computed tomography (CT) of the adrenals is a common first step for investigation of primary aldosteronism (PA). However, prior studies report poor specificity, necessitating adrenal vein sampling (AVS) prior to surgical consideration. METHODS: We examined our AVS database to determine whether CT adrenal findings could help select patients with a high likelihood of lateralization by AVS or high-value blood pressure (BP) outcomes. Subjects (N = 113) with validated outcomes were divided into groups of CT 'positive' or CT 'negative' according to the presence or absence of an adrenal mass and compared for the outcomes of lateralization by AVS or proportions achieving normotension off medications following surgery. RESULTS: For patients with CT adrenal masses, there was a significantly higher odds ratio (OR) for both outcomes (6.3 and 9.7, p < 0.01). In subgroup analysis, age <40 years carried particularly high odds for lateralization and cure when a CT mass was present (ORs 45 and 26, p < 0.01). Young individuals with normal CT adrenals rarely lateralized (10 %) and, in such patients, even factors like hypokalemia, body mass index (BMI), and plasma aldosterone level did not change the result on regression analysis. CONCLUSIONS: CT-imaged adrenal masses strongly predicted lateralization by AVS and normotension with surgical treatment of lateralized PA. In PA, CT-positive patients should indeed be offered AVS and/or surgery given the high chance of good outcomes; younger CT-negative patients should be advised of a low chance of finding surgical disease by AVS.

Use of dexamethasone in patients with high-grade glioma: a clinical practice guideline.

BACKGROUND: Dexamethasone is the corticosteroid most commonly used for the management of vasogenic edema and increased intracranial pressure in patients with brain tumours. It is also used after surgery (before embarking on radiotherapy), particularly in patients whose tumours exert significant mass effect. Few prospective clinical trials have set out to determine the optimal dose and schedule for dexamethasone in patients with primary brain tumours, and subsequently, fewer clinical practice guideline recommendations have been formulated. METHODS: A review of the scientific literature published to November 2012 considered all publications that addressed dexamethasone use in adult patients with brain tumours. Evidence was selected and reviewed by a working group comprising 3 clinicians and 1 methodologist. The resulting draft guideline underwent internal review by members of the Alberta Provincial cns Tumour Team, and feedback was incorporated into the final version of the guideline. RECOMMENDATIONS: Based on the evidence available to date, the Alberta Provincial cns Tumour Team makes these recommendations: Treatment with dexamethasone is recommended for symptom relief in adult patients with primary high-grade glioma and cerebral edema.After surgery, a maximum dose of 16 mg daily, administered in 4 equal doses, is recommended for symptomatic patients. This protocol should ideally be started by the neurosurgeon.A rapid dexamethasone tapering schedule should be considered where appropriate.Patients who have high-grade tumours, are symptomatic, or have poor life expectancy, can be maintained on a 0.5-1.0 mg dose of dexamethasone daily.Side effects with dexamethasone are common, and they increase in frequency and severity with increased dose and duration of therapy. Patients should be carefully monitored for endocrine, muscular, skeletal, gastrointestinal, psychiatric, and hematologic complications, and for infections and other general side effects.

A marked proportional rise in IVC aldosterone following cosyntropin administration during AVS is a signal to the presence of adrenal hyperplasia in primary aldosteronism.

We hypothesized aldosteronoma responsiveness to cosyntropin may be a characterizing feature that could be determined in addition to standard adrenal vein sampling (AVS) data. We reviewed an AVS database from June 2005 to October 2011 including 65 patients with confirmed primary aldosteronism (PA) who underwent AVS and, if applicable, unilateral adrenalectomy. Patients were divided into confirmed lateralized and non-lateralized groups and subgrouped by histology. Plasma aldosterone in inferior vena cava (IVC) pre- and post-cosyntropin infusion during AVS was measured. Peak aldosterone and proportional change was compared between groups. Baseline and peak IVC aldosterone was higher in lateralized patients but incremental aldosterone rise was much greater in subjects with bilateral hyperplasia. From receiver operator characteristics (ROC) analysis, the optimized diagnostic cut point of peak IVC aldosterone of >649 pmol l(-1) would have a sensitivity of 94% for surgical disease although specificity of just 59%. A 250% increase in IVC aldosterone following cosyntropin would be specific enough to exclude 87% of surgical/lateralized disease. These diagnostic capabilities are similar to other results with non-AVS tests performed for diagnosis of lateralization. Although not specific enough to replace standard AVS interpretation, a marked IVC aldosterone increase after cosyntropin during AVS is a useful additional test to diagnose non-lateralizing forms of PA. Such a calculation requires no additional expense or tests.

Medical or surgical therapy for primary aldosteronism: post-treatment follow-up as a surrogate measure of comparative outcomes.

BACKGROUND: In primary aldosteronism (PA), lateralized aldosterone excess can be treated with aldosterone antagonists or surgery, which raises the question as to whether surgery or medications should be the preferred management. A difference in required patient follow-up/clinic resource utilization might provide a surrogate estimate of the comparative outcome efficacy of medical versus surgical therapy. METHODS: From a retrospective review of our adrenal vein sampling (AVS) database June 2005 to August 2011, we chose all patients with PA who were surgical candidates and investigated with AVS. There were 77 subjects; 38 (with aldosteronoma) had unilateral adrenalectomy, and 39 (7 aldosteronoma and 32 hyperplasia) were treated with primary medical therapy. After AVS, patients with nonsurgical disease immediately started mineralocorticoid antagonists and follow-up measured from the AVS date. Surgical patients were seen in the clinic immediately after hospital discharge and follow-up measured from the operative date. Target BP was <140/90 before discharge to the community. RESULTS: Total follow-up ranged from 1 to 55 months, and 4 subjects were lost to follow-up. Mean follow-up in the medical and surgical groups was 13.4 versus 6.5 months (p < 0.004). There was a trend toward more clinic visits for the medical group (7.0 vs 5.2, p = 0.17). CONCLUSIONS: Most PA patients can be managed by medical or surgical approaches. Medically treated patients require much longer-term follow-up to manage their condition, whereas most surgical patients can be successfully discharged shortly after surgery. When possible, surgical management may represent a more expeditious means of treating PA.

Errors in patient perception of caloric deficit required for weight loss--observations from the Diet Plate Trial.

Persons with obesity may be poor estimators of caloric content of food. Health care professionals encourage patients to consult nutritional labels as one strategy to assess and restrict caloric intake. Among subjects enrolled in a weight loss clinical trial, the objective is to determine the accuracy of subjects' estimates of caloric deficit needed to achieve the desired weight loss. A 6-month controlled trial demonstrated efficacy of a portion control tool to induce weight loss in 130 obese people with type 2 diabetes. All subjects had previously received dietary teaching from a dietician and a nurse. At baseline, patients were asked how much weight they would like to lose and to quantitatively estimate the caloric deficit required to achieve this weight loss. The stated amount of weight loss desired ranged from 4.5 to 73 kg, with an average of 26.6 kg (n = 127 respondents). Only 30% of participants were willing to estimate the required caloric deficit to lose their target weight. Subjects' per kilograms estimate of caloric deficit required ranged from 0.7 to 2,000,000 calories/kg with a median of 86 calories/kg. Nearly half of subjects (47.4%) underestimated the total required caloric deficit to achieve their target weight loss by greater than 100,000 calories. Despite attendance at a diabetes education centre, this population of obese individuals had a poor understanding of the quantitative relationship between caloric deficit and weight loss. Educational initiatives focused upon quantitative caloric intake and its impact on weight change may be needed to assist obese patients in setting appropriate weight loss goals and achieving the appropriate daily caloric restriction required for success.

Contraction-sensitive skeletal muscle afferents inhibit arterial baroreceptor signalling in the nucleus of the solitary tract: role of intrinsic GABA interneurons.

Arterial baroreceptor and skeletal muscle receptor afferents relay sensory information to the nucleus of the solitary tract (NTS) during exercise. Previous studies have suggested that skeletal muscle afferent input inhibits baroreflex function; however, detailed information on the role of muscle afferents and GABAergic mechanisms in the NTS is limited. Furthermore, identification of specific afferent modalities that activate GABAergic neurons in the NTS remains unknown. In the present study, we examined the neuroanatomical and physiological interactions between spinal dorsal horn cells that transmit contraction-sensitive input from skeletal muscle and GABAergic interneurons in the NTS. Biotinylated dextran amine (BDA, 10%, 25-100 nL) microinjection into dorsal horn of the cervical spinal cord was combined with glutamate decarboxylase (GAD) immunohistochemistry to visualize the nature of the relationship of BDA-labeled fibers in the NTS with GAD immunoreactivity (GAD-ir). BDA-labeled axons and terminal processes were localized in the medial, commissural, dorsomedial and dorsolateral subdivisions of the caudal NTS. Moreover, BDA-labeled fibers were observed in close proximity to GAD-ir structures throughout these regions of the NTS. The physiological interaction between skeletal muscle receptor and arterial baroreceptor afferents was investigated using an arterially perfused, decerebrate rat preparation. Activation of skeletal muscle afferents by electrically evoked twitch contraction of the forelimb attenuated baroreflex responsiveness (BR, calculated as the ratio of changes in heart rate to systemic pressure) from -1.5+/-0.3 bpm.mm Hg(-1) to -0.1+/-0.1 bpm.mm Hg(-1) (control versus contraction, P<0.05, n=15). However, forelimb contraction failed to inhibit the reflex bradycardia evoked by activation of peripheral chemoreceptor afferents, indicating a reflex-specific action. Bilateral microinjection of bicuculline methiodide (BIC, 10 microM, 40-60 nL) into the caudal NTS restored baroreflex responsiveness during contraction (-1.6+/-0.2 versus -0.1+/-0.1 versus -1.5+/-0.2 bpm.mmHg(-1), control versus contraction versus contraction+BIC P<0.05, n=8). We conclude that activation of ascending spinal neurons from the cervical dorsal horn by contraction-sensitive skeletal muscle afferents selectively inhibits arterial baroreceptor signaling in the NTS via activation of a GABAergic mechanism.