Persistent Lactatemia in Mauriac Syndrome.

Mauriac syndrome is a rare disorder that occurs in patients with type 1 diabetes mellitus (T1DM) with glucose levels significantly above target, characterized by hepatomegaly, growth delay, and cushingoid features. Another distinguishing feature of Mauriac syndrome is persistent lactatemia during diabetic ketoacidosis (DKA) management. We present a case of an 18-year-old patient with T1DM who presented in DKA and then developed elevated lactate levels leading to a diagnosis of Mauriac syndrome. The cause of the persistent lactatemia is not well understood though it is likely related to glycogenic hepatopathy causing hepatomegaly, abnormalities in glucose metabolism, and subsequent inappropriate lactate production. Since the liver changes seen in Mauriac syndrome are reversible with optimal blood glucose control, these patients should be connected to intensive psychosocial and medical support to help them improve their blood glucose levels.

Factors Influencing Inpatient Insulin Management of Adults With Type 1 and Type 2 Diabetes by Residents and Medical Students.

OBJECTIVES: The day-to-day management of diabetes is often the responsibility of resident physicians in teaching hospitals, yet studies have consistently shown that learners lack confidence and knowledge of inpatient insulin titration. We sought to elucidate factors that influence inpatient management of diabetes by medical learners. We predicted that there would be conscious and unconscious variables at play, and we sought to determine the process by which learners arrived at insulin titration decisions. METHODS: We administered a survey using a hypothetical case based on script concordance testing in 88 medical students and residents at the University of Calgary. We used multilevel, mixed-effects linear regression and random-effects meta-analysis to compare clerks' and residents' insulin prescribing, confidence in prescribing decisions and concordance with endocrinologists. RESULTS: Residents had higher confidence than clerks, yet were less concordant with the insulin decisions of staff endocrinologists. Both residents and clerks prescribed more insulin when the reported blood glucose was higher, or the patient had positive ketones and prescribed less insulin when the patient had hypoglycemic unawareness. Residents prescribed a higher dose of insulin when the charge nurse reported the result compared with a student nurse, but this variable did not significantly impact prescribing by clerks. CONCLUSIONS: We propose a model in which learner factors (knowledge, confidence, experience), patient variables and perceived expectations influence insulin titration decisions via analytical and heuristic processes. We propose that educational interventions designed to improve inpatient glycemic control must, therefore, address both knowledge and systems factors.

Phosphate matters when investigating hypercalcemia: a mutation in SLC34A3 causing HHRH

Summary: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, autosomal recessive disorder caused by mutations in the SLC34A3 gene that encodes the renal sodium-dependent phosphate cotransporter 2c (NaPi-IIc). It may present as intermittent mild hypercalcemia which may attract initial diagnostic attention but appreciation of concomitant hypophosphatemia is critical for consideration of the necessary diagnostic approach. A 21-year-old woman was assessed by adult endocrinology for low bone mass. She initially presented age two with short stature, nephrocalcinosis and mild intermittent hypercalcemia with hypercalciuria. She had no evidence of medullary sponge kidney or Fanconi syndrome and no bone deformities, pain or fractures. She had recurrent episodes of nephrolithiasis. In childhood, she was treated with hydrochlorothiazide to reduce urinary calcium. Upon review of prior investigations, she had persistent hypophosphatemia with phosphaturia, low PTH and a high-normal calcitriol. A diagnosis of HHRH was suspected and genetic testing confirmed a homozygous c.1483G>A (p.G495R) missense mutation of the SLC34A3 gene. She was started on oral phosphate replacement which normalized her serum phosphate, serum calcium and urine calcium levels over the subsequent 5 years. HHRH is an autosomal recessive condition that causes decreased renal reabsorption of phosphate, leading to hyperphosphaturia, hypophosphatemia and PTH-independent hypercalcemia due to the physiologic increase in calcitriol which also promotes hypercalciuria. Classically, patients present in childhood with bone pain, vitamin D-independent rickets and growth delay. This case of a SLC34A3 mutation illustrates the importance of investigating chronic hypophosphatemia even in the presence of other more common electrolyte abnormalities. Learning Points: Hypophosphatemia is an important diagnostic clue that should not be ignored, even in the face of more common electrolyte disorders. HHRH is a cause of PTH-independent hypophosphatemia that may also show hypercalcemia. HHRH is a cause of hypophosphatemic nephrocalcinosis that should not be treated with calcitriol, unlike other congenital phosphate wasting syndromes. Some congenital phosphate wasting disorders may not present until adolescence or early adulthood.

Risk assessment to groundwater of pit latrine rural sanitation policy in developing country settings.

Parallel global rise in pit-latrine sanitation and groundwater-supply provision is of concern due to the frequent spatial proximity of these activities. Study of such an area in Malawi has allowed understanding of risks posed to groundwater from the recent implementation of a typical developing-country pit-latrine sanitation policy to be gained. This has assisted the development of a risk-assessment framework approach pragmatic to regulatory-practitioner management of this issue. The framework involves water-supply and pit-latrine mapping, monitoring of key groundwater contamination indicators and surveys of possible environmental site-condition factors and culminates in an integrated statistical evaluation of these datasets to identify the significant factors controlling risks posed. Our approach usefully establishes groundwater-quality baseline conditions of a potentially emergent issue for the study area. Such baselines are foundational to future trend discernment and contaminant natural attenuation verification critical to policies globally. Attribution of borehole contamination to pit-latrine loading should involve, as illustrated, the use of the range of contamination (chemical, microbiological) tracers available recognising none are ideal and several radial and capture-zone metrics that together may provide a weight of evidence. Elevated, albeit low-concentration, nitrate correlated with some radial metrics and was tentatively suggestive of emerging latrine influences. Longer term monitoring is, however, necessary to verify that the commonly observed latrine-borehole separation distances (29-58m), alongside statutory guidelines, do not constitute significant risk. Borehole contamination was limited and correlation with various environmental-site condition factors also limited. This was potentially ascribed to effectiveness of attenuation to date, monitoring of an emergent problem yet to manifest, or else contamination from other sources. High borehole usage and protective wall absence correlated with observed microbiological contamination incidence, but could relate to increased human/animal activity close to these poorly protected boreholes. Additional to factors assessed, a groundwater-vulnerability factor is recommended that critically relies upon improved proactive securing of underpinning data during borehole/latrine installations. On-going concerns are wide ranging, including poorly constrained pit-latrine input, difficulties in assessing in-situ plume natural attenuation and possible disposal of used motor oils to latrines.

Congenital adrenal hyperplasia causing hypertension: an illustrative review.

Congenital adrenal hyperplasia (CAH) is often considered a pediatric endocrinology condition, but we present two cases of young adults who presented with hypertension. An 18-year-old woman was found to have hypertension and hypokalemia when she presented for gonadectomy for 46, XY gonadal dysgenesis. She was subsequently found to have low cortisol, elevated progesterone, and elevated aldosterone. Genetic testing confirmed 17-alpha hydroxylase deficiency (17OHD). Her case was unique in that 17OHD usually presents with hypoaldosteronism. We also present the case of a 15-year-old man (46, XX) with resistant hypertension due to 11-beta hydroxylase deficiency (11OHD) who underwent bilateral adrenalectomy for control of hypertension. The relevant literature is reviewed including the pathophysiology, clinical presentation, and treatment of the hypertensive variants of congenital adrenal hyperplasia. We also review the unique areas of hyperaldosteronism in 17OHD and the use of bilateral adrenalectomy for control of hypertension in CAH.

Two serines in the distal C-terminus of the human ß1-adrenoceptor determine ß-arrestin2 recruitment.

G protein-coupled receptors (GPCRs) undergo phosphorylation at several intracellular residues by G protein-coupled receptor kinases. The resulting phosphorylation pattern triggers arrestin recruitment and receptor desensitization. The exact sites of phosphorylation and their function remained largely unknown for the human ß1-adrenoceptor (ADRB1), a key GPCR in adrenergic signal transduction and the target of widely used drugs such as ß-blockers. The present study aimed to identify the intracellular phosphorylation sites in the ADRB1 and to delineate their function. The human ADRB1 was expressed in HEK293 cells and its phosphorylation pattern was determined by mass spectrometric analysis before and after stimulation with a receptor agonist. We identified a total of eight phosphorylation sites in the receptor's third intracellular loop and C-terminus. Analyzing the functional relevance of individual sites using phosphosite-deficient receptor mutants we found phosphorylation of the ADRB1 at Ser461/Ser462 in the distal part of the C-terminus to determine ß-arrestin2 recruitment and receptor internalization. Our data reveal the phosphorylation pattern of the human ADRB1 and the site that mediates recruitment of ß-arrestin2.

How Good is Our Best Guess? Clinical Application of the WHO FRAX Tool in Osteoporotic Fracture Risk Determination and Treatment Decisions.

Historically, treatment decisions for osteoporosis were based on bone mineral density. However, many fractures occur in patients with T-scores outside the osteoporotic range, emphasizing the importance of multi-factorial risk assessments. The World Health Organization Fracture Risk Assessment Tool (FRAX) predicts 10-year risk of osteoporotic fracture. We hypothesized that physicians' clinical estimates of osteoporotic fracture risk would differ significantly from that calculated by FRAX. Thus, treatment decisions would differ depending whether or not physicians used FRAX. A survey consisting of five clinical scenarios was administered to 76 endocrinologists, family physicians, internists, and internal medicine residents. They were asked to estimate the osteoporotic fracture risk and decide whether they would offer preventative treatment. Their estimates were compared to the risk predicted by FRAX and national treatment threshold guidelines. The primary outcome was the difference between the participant's estimate and the FRAX-based estimate of the 10-year risk of osteoporotic fracture for each scenario. In each scenario, physicians statistically significantly over-estimated fracture risk compared to that predicted by FRAX. Estimates for hip fracture risk were 2-4 times higher than FRAX estimates. The major osteoporotic fracture risk at which participants would offer treatment varied with physician group, with endocrinologists, family physicians, and residents requiring a 10-20 % 10-year risk, while internal medicine physician thresholds ranged from 2 to 20 %. Physicians greatly over-estimated the risk of hip fracture based on clinical information. FRAX is necessary to accurately quantify risk, but because physicians varied in the level of risk required before they would offer treatment, uniform approaches to risk estimation may still not result in uniform clinical treatment decisions.

Addison's Disease in Evolution: An Illustrative Case and Literature Review.

OBJECTIVE: To present a case of symptomatic autoimmune adrenal insufficiency with initially normal serum cortisol and to caution about limitations of the current diagnostic algorithm for adrenal insufficiency, which does not reflect the pathophysiology of early disease. METHODS: We describe the clinical presentation and relevant investigations of a patient ultimately found to have Addison's disease, which is followed by a focused review of the literature. RESULTS: A 41-year-old Caucasian woman with autoimmune hypothyroidism, premature ovarian failure, and microscopic colitis presented with nausea, salt craving, increased skin pigmentation, and postural hypotension. Initial bloodwork revealed a normal morning cortisol of level of 19.2 µg/dL (normal, 7.2 to 25 µg/dL) but an adrenocorticotropic hormone (ACTH) level 10 times normal, at 513.6 pg/mL (normal, <52.5 pg/mL). Her potassium was normal, but her aldosterone level was 4.12 ng/dL (normal, 12.3 to 62.5 ng/dL) and her renin activity was increased (23.0 mg/dL/hour; normal, <6.0 mg/dL/hour). Six weeks after initial presentation, she was found to have anti-adrenal antibodies. It was not until 10 weeks after her initial symptomatic presentation that her morning cortisol level was found to be subnormal and a formal diagnosis of adrenal insufficiency was made. CONCLUSION: The present case and literature review reveal that common diagnostic approaches will miss patients with (possibly symptomatic) early adrenal insufficiency. We suggest that serum ACTH level testing or tests of mineralocorticoid function be included in the initial step of investigation for suspected primary adrenal insufficiency.

A novel CXCL10-based GPI-anchored fusion protein as adjuvant in NK-based tumor therapy.

BACKGROUND: Cellular therapy is a promising therapeutic strategy for malignant diseases. The efficacy of this therapy can be limited by poor infiltration of the tumor by immune effector cells. In particular, NK cell infiltration is often reduced relative to T cells. A novel class of fusion proteins was designed to enhance the recruitment of specific leukocyte subsets based on their expression of a given chemokine receptor. The proteins are composed of an N-terminal chemokine head, the mucin domain taken from the membrane-anchored chemokine CX3CL1, and a C-terminal glycosylphosphatidylinositol (GPI) membrane anchor replacing the normal transmembrane domain allowing integration of the proteins into cell membranes when injected into a solid tumor. The mucin domain in conjunction with the chemokine head acts to specifically recruit leukocytes expressing the corresponding chemokine receptor. METHODOLOGY/PRINCIPAL FINDINGS: A fusion protein comprising a CXCL10 chemokine head (CXCL10-mucin-GPI) was used for proof of concept for this approach and expressed constitutively in Chinese Hamster Ovary cells. FPLC was used to purify proteins. The recombinant proteins efficiently integrated into cell membranes in a process dependent upon the GPI anchor and were able to activate the CXCR3 receptor on lymphocytes. Endothelial cells incubated with CXCL10-mucin-GPI efficiently recruited NK cells in vitro under conditions of physiologic flow, which was shown to be dependent on the presence of the mucin domain. Experiments conducted in vivo using established tumors in mice suggested a positive effect of CXCL10-mucin-GPI on the recruitment of NK cells. CONCLUSIONS: The results suggest enhanced recruitment of NK cells by CXCL10-mucin-GPI. This class of fusion proteins represents a novel adjuvant in cellular immunotherapy. The underlying concept of a chemokine head fused to the mucin domain and a GPI anchor signal sequence may be expanded into a broader family of reagents that will allow targeted recruitment of cells in various settings.

Costs of recalled and recommended diets for pregnant women with type 1, type 2 and gestational diabetes.

OBJECTIVE: The costs associated with nutritious foods may be a barrier to healthy dietary choices and of particular concern to pregnancies complicated by diabetes. Therefore, a survey was conducted in a tertiary care diabetes and pregnancy clinic to compare the associated costs of actual food choices versus the cost of a constructed recommended diet. METHODS: Women with types 1, 2 and gestational diabetes mellitus (GDM) completed 24-hour dietary recalls under the supervision of the research coordinator (Actual Diet). A Recommended Diet for this population was constructed independent of participant responses. Actual and Recommended Diets were standardized per 2000 kcal, priced and compared for content and cost. RESULTS: Seventy-five women participated: 27 with GDM, 29 with type 1 diabetes and 19 with type 2 diabetes. There were no significant cost differences between Recommended and Actual Diets food choices expressed per 2000 kcal: Recommended Diet $10.14±3.72; Actual Diet GDM: $11.30±3.88; Actual Diet type 1 diabetes: $9.00±3.16; Actual Diet type 2 diabetes: $10.24±3.92. Percentage of fibre intake was lower for Actual Diets than Recommended Diet for all groups, while percentage of protein intake was lower in Actual than Recommended Diet for women with type 1 diabetes. CONCLUSION: Clinical recommendations for healthy food choices may not be more expensive than actual choices made by pregnant women with diabetes.

Clinical relevance of hindfoot alignment view in total ankle replacement.

BACKGROUND: Alignment is instrumental for success and long-term survival of Total Ankle Replacement (TAR). At this point in TAR, only coronal alignment in the region of the tibiotalar joint or above has been assessed because inframalleolar deformity is difficult to visualize radiographically. The Hindfoot Alignment View (HAV) allows visualization of the hindfoot position relative to the tibia. The purpose of this study was to evaluate the clinical relevance of this view in assessing patients with TAR. MATERIALS AND METHODS: Twenty-eight consecutive patients with a Hintegra-TAR with an average followup of 4.1 ± 1.5 years were followed with (1) AOFAS and SF-36 scores, (2) visual judgment of the hindfoot position, (3) HAV and AP/lateral radiographs, (4) dynamic pedobarography (Novel emed m/E, Munich, Germany). RESULTS: The HAV position correlated well with different load parameters on heel strike (r = 0.44 to 0.62) but not with the varus-valgus load pattern of the rest of the foot. Visual judgment and TAR joint line did not correlate to radiographic hindfoot alignment or to pedobarographic load distribution. The hindfoot alignment measured by the HAV correlated significantly to the Physical Function and Role Physical of SF-36. No correlation was found to other SF36-qualities or the AOFAS-score. CONCLUSION: Inframalleolar alignment, as assessed by the HAV, influenced the dynamic pedobarographic load pattern and clinical outcome. Visual judgment and TAR joint line were not accurate enough to estimate the hindfoot alignment or dynamic load pattern. We believe adjusting the hindfoot correctly with HAV might improve long-term outcome and survival of TAR.