Not only for caregivers: intranasal glucagon for severe hypoglycaemia in a simulation study.

AIMS: To evaluate: (i) the propensity of paediatrics and emergency medicine residents to select different therapeutic options and (ii) the speed and administration success in a high-fidelity simulation of severe hypoglycaemia in a child with type 1 diabetes (T1DM). METHODS: In this single-centre high-fidelity simulation study, 51 paediatrics or emergency medicine residents were exposed to a scenario of severe hypoglycaemia in a T1DM child attending an ambulatory setting, before and after a training on the preparation and administration of both injectable and IN glucagon. Time for drug delivery and its effectiveness were collected. RESULTS: Before training, 45.1% of participants chose to administer injectable glucagon, 43.1% intravenous glucose solution, 5.9% intranasal (IN) glucagon, and 5.9% took no action. Administration was successful in 74% of injectable glucagon, 33.3% intravenous glucose solution, and 22.7% IN glucagon. After training, 58.8% of participants chose IN and 41.2% injectable glucagon, with 100% of successful administrations for IN glucagon and 90.5% for injectable glucagon. Time to successful administration was shorter for IN than injectable glucagon (23 ± 10 vs. 38 ± 7 s, p < 0.0001). CONCLUSIONS: IN glucagon is an easy and effective option for severe hypoglycaemia treatment, with an almost zero possibility of failure provided that adequate training is imparted.

Red cell distribution width is a potential predictor of early relapse in polymyalgia rheumatica.

Red blood cell distribution width (RDW) has been studied as a prognostic biomarker for different chronic inflammatory diseases. In this paper we aim to evaluate its potential role in the prediction of early relapse in patients affected by polymyalgia rheumatica (PMR). We revised retrospectively clinical records of patients who received a diagnosis of PMR, according to 2012 ACR/EULAR classification criteria, for whom baseline clinical and laboratory data were available. The baseline RDW variation coefficient was correlated to the risk of relapse, in the first 6 months of the disease. We identified 44 patients [females 15 (34.0%)/males 29 (66.0%); median age 80 (72-83)], 9 of whom had an early relapse. These patients showed a larger median RDW than patients who did not relapse [13.7 (13.5-14.9)% vs 13.5 (12.7-14.2)%; p=0.04). The two groups were comparable for all the other clinical and laboratory parameters considered. Interestingly, patients in the higher half of the RDW distribution showed a shorter relapse-free survival (p<0.03). In a stepwise logistic regression, RDW (p=0.01) predicted the risk of relapse at 6 months, while age, gender, CRP, ESR, Hb, MCV and prednisone dose did not fit the model. Our results show that RDW is an independent biomarker of early relapse, making this parameter a potentially promising predictive marker in PMR.

Association between red cell distribution width and response to methotrexate in rheumatoid arthritis.

Red cell distribution width (RDW) is an unconventional biomarker of inflammation. We aimed to explore its role as a predictor of treatment response in rheumatoid arthritis (RA). Eighty-two RA patients (55 females), median age [interquartile range] 63 years [52-69], were selected by scanning the medical records of a rheumatology clinic, to analyze the associations between baseline RDW, disease activity scores and inflammatory markers, as well as the relationship between RDW changes following methotrexate (MTX) and treatment response. The lower the median baseline RDW, the greater were the chances of a positive EULAR response at three months, 13.5% [13.0-14.4] being among those with good response, vs 14.0% [13.2-14.7] and 14.2% [13.5- 16.0] (p=0.009) among those with moderate and poor response, respectively. MTX treatment was followed by a significant RDW increase (p<0.0001). The increase of RDW was greater among patients with good EULAR response, becoming progressively smaller in cases with moderate and poor response (1.0% [0.4-1.4] vs. 0.7 [0.1-2.0] vs. 0.3 [-0.1-0.8]; p=0.03). RDW is a strong predictor of early response to MTX in RA. RDW significantly increases after MTX initiation in parallel to treatment response, suggesting a role as a marker of MTX effectiveness.

Inflammatory markers predict insulin sensitivity in active rheumatoid arthritis but not in psoriatic arthritis.

Whether the insulin resistance commonly observed in patients with inflammatory arthritis is a disease-specific feature and/or is limited to a disease phase (i.e., it occurs only during phases of high disease activity) is unknown. Fifty-three rheumatoid arthritis (RA) and 44 psoriatic arthritis (PsA) patients were recruited consecutively along with 194 controls matched for age, sex and body mass index for a case-control study. All underwent an oral glucose tolerance test, the results of which were analysed to derive the following indexes: homeostatic model of insulin resistance (HOMA-IR), insulin sensitivity index (ISI) and early insulin sensitivity index (EISI). These data were related to anthropometric, clinical and laboratory findings. Metabolic parameters of patients and controls were similar. Neither inflammatory markers nor disease activity scores were related to glucose metabolism for the generality of RA and PsA patients; however, by restricting the analysis to the subset of RA patients with residual disease activity, an association emerged between erythrocyte sedimentation rate, on the one hand, and fasting insulin (ß=0.46, p=0.047) and HOMA-IR (ß=0.44, p=0.02), on the other. Moreover, C-reactive protein (CRP) levels were associated with plasma glucose and insulin levels measured 120 min after the glucose load (ß=0.91, p=0.0003 and ß=0.77, p=0.0006, respectively); ISI and EISI were predicted by CRP (ß=-0.79, p=0.0006; ß=-0.80, p=0.0001, respectively). The same did not hold true for PsA patients. The association between systemic inflammation and insulin resistance indexes is a feature of RA with residual disease activity, not a universal feature of inflammatory arthritides.

The real evidence for polymyalgia rheumatic as a paraneoplastic syndrome.

Not available.

A case of false positive Troponin I in a patient affected by cryoglobulinemic vasculitis.

Troponin I (TnI) false positive results have been reported in patients affected by immune disorders. We report the case of a 74-year-old woman affected by cryoglobulinemic vasculitis, admitted to the Emergency Room because of a lipotimic episode. A marked elevation of TnI plasma concentration was confirmed in multiple determinations, despite the absence of symptoms or electrocardiogram findings suggesting myocardial infarction. TnI plasma concentration was reported normal after re-testing with a different commercial kit. A false TnI positivity should be considered in patients with immune disorders, especially if seropositive for rheumatoid factor, when the clinical context does not suggest myocardial infarction.

Growth arrest specific gene 6 protein concentration in cerebrospinal fluid correlates with relapse severity in multiple sclerosis.

BACKGROUND: Growth arrest specific gene 6 (Gas6) protein enhances survival of oligodendrocytes and neurons, and it is involved in autoimmunity. Therefore, we aimed to verify whether cerebrospinal-fluid (CSF) Gas6 concentration may represent a biomarker of disease activity in multiple sclerosis. METHODS: Sixty-five patients who underwent a spinal tap during relapse of relapsing/remitting multiple sclerosis (RR-MS)(McDonald-criteria) were studied. Forty patients affected by noninflammatory/nonautoimmune neurological diseases served as controls. Relapse was defined according to Schumacher criteria. Symptoms were grouped according to Kurtzke-Functional System (FS). Clinical characteristics of the relapse, duration, Expanded-Disability-Status Scale (EDSS) change, number of FS involved, completeness of recovery, age, steroid therapy, were categorised. Patients were followed at 6-month intervals to assess relapse rate and EDSS progression. Gas6 was measured (CSF, plasma) by in-house-enzyme-linked immunoassay (ELISA). RESULTS: Higher CSF Gas6 concentrations were observed in relapses lasting ≤60 days (8.7 ± 3.9 ng/mL) versus >60 days (6.5 ± 2.6) or controls (6.5 ± 2.4; P = 0.05), with ≤2 FS involved (8.5 ± 3.8) versus >2 FS (5.6 ± 2.5) (P < 0.05) and EDSS change ≤2.5 points (8.8 ± 3.7) versus >2.5 (6.5 ± 3.5) (P = 0.04). Conversely, CSF Gas6 was not predictive of the completeness of recovery. Plasma and CSF concentrations were not related (R (2) = 0.0003), and neither were predictive of relapse rate or EDSS progression after first relapse. CONCLUSIONS: CSF concentration of Gas6 is inversely correlated with the severity of relapse in RR-MS patients but does not predict the subsequent course of the disease.

Assessing water-electrolyte changes of hyperglycaemic hyperosmolar coma.

AIM: We reported new methods to accurately estimate salt and water deficits during hyperglycaemic hyperosmolar coma (HC), valid under restricted boundary conditions. The accuracy of these estimates is herein verified over the unrestricted spectrum of abnormalities, to correctly evaluate any patient with just one algorithm that recognizes the boundary conditions pertaining to each abnormality, choosing the appropriate calculations. METHODS: A large number of cases of HC was simulated on computer by subtracting an exhaustive combination of water, sodium and chloride losses coupled to a large variety of gains in glucose. Altered solute concentrations were generated. From these true plasma concentrations generated by the computer, the losses of water and electrolytes were back-calculated with our new computational algorithm, by knowing in addition only the normal total body water and extra-cellular volume. The accuracy of the method was tested by comparing true to calculated values over the entire range of deranged values. In 100 patients admitted to hospital for HC these same computations were performed, where calculated data were validated by comparing them to true data obtained by balance studies performed during correction of the abnormality. RESULTS: Both in simulated and real cases of HC true and calculated data for the changes in Na and volume were significantly correlated (R (2)=0.76 and 0.50, respectively, P<0.01), while their mean values were not significantly different by paired "t" tests (P>0.05 for all). CONCLUSION: Our new computation algorithm, applicable to the bed-side, useful in accurately assessing the average water-electrolyte deficits of HC, can be used to guide correct re-infusion strategies.

Computation of Na and water deficit of iso-osmolar dehydration.

BACKGROUND AND AIMS: The presence of altered plasma Na concentration (PNa) allows calculations of changes in water and electrolyte contents, which are not feasible during normonatremic derangements. We have developed a computational algorithm whereby the changes in solute (ΔNa and ΔCl) and solvent (ΔV) contents can be computed exactly when Na is lost entirely as NaCl (or NaHCO(3)) and nearly exactly in all other circumstances, except when the losses of Na and Cl occur in the same proportions as those of the normal plasma concentration of these ions. METHODS: In computer experiments, we simulated different fluid depletions containing 140 mEq/l of Na (which is to say, ΔNa/ΔV ≈ 140), coupled with variable ratios in Na to Cl losses (variable ΔNa/ΔCl). The data were back-calculated with our algorithms from the ensuing plasma ion concentrations (PNa(1), PCl(1) and POAN(1), where subscript (0) and (1) indicate normal and deranged plasma concentration values, respectively, and OAN indicates anions other than Cl), as if they had been measured on patients, and from known normal values (TBW(0), ECV(0), Na(0)). These were compared to the true values used to build the simulations. This procedure was reproduced in 17 patients suffering from iso-osmolar dehydration, where true data were obtained by balance studies. RESULTS: True and calculated data were compared with linear regression analysis. We obtained significant correlations both in computer-simulated and real patients (R(2) = 0.83, p < 0.005 and R(2) = 0.63, p < 0.05, respectively). CONCLUSION: This new math model and its related computational method are useful in the correct evaluation and treatment of iso-osmolar dehydration.

Quantitative assessment of the abnormalities of hyperosmolar coma when glucose excess is larger than Na deficit.

Computing Na and water deficits of hyperosmolar coma (HC) is important in correcting the derangement, to avoid unwanted iatrogenic electrolyte derangements and brain oedema. This paper derives and applies formulas valid when GA (glucose accumulation) >2.DeltaNa (sodium loss), with or without DeltaV (water depletion). We built a model system and wrote the equations describing the relationships between volume and concentration of solutes within the body water compartments. HC was simulated on computer experiments by adding GA in different amounts combined with a large variety of DeltaNa and DeltaV. The ensuing concentrations in Na (PNaNone. (1)) and glucose (PG (1)) were used to identify the condition GA >2 . DeltaNa, DeltaV=0 or not equal 0, and then, with original formulas, to back calculate GA, DeltaNa and DeltaV. These same calculations were applied to 31 patients with HC. The procedure to recognize the conditions under investigation unerringly discarded all simulations except those characterized by GA >2 . DeltaNa, with or without DeltaV. When DeltaV=0, the computations yielded values identical to the true ones for GA and DeltaNa (R (2)=1.00, p<0.0001). When DeltaV was present, the correlation coefficients between calculated and true values were 0.92 (p<0.001) for GA, 0.73 (p<0.001) for DeltaNa, 0.74 (p<0.001) for DeltaV in computer experiments, while they were R (2)>0.47<0.95 (p<0.001) in patient studies. The accuracy in computing solute and water changes demonstrates the validity of our model system of HC, and of the calculation formulas, which can be used to quantitatively evaluate the deficits in Na and volume, as well as the addition of glucose, improving the effectiveness of treatment.

Methods for the quantitative assessment of electrolyte disturbances in hyperglycaemia.

AIM: While empirical calculations are presently used, exact solutions to compute volume and solute changes of hyperosmolar coma (HC) can be obtained by subdividing the patients according to well defined clinical and laboratory conditions. These are represented by PNa(G), the plasma Na concentration that would be present if there were only glucose addition (GA), that discloses prevalent Na depletion when >PNa(1), prevalent water deficit when , = or

Metabolic characteristics of glucose intolerance: the critical role of obesity.

INTRODUCTION: Obesity enhances insulin secretion and resistance. We investigated its importance in linking insulin metabolism to glucose intolerance. MATERIAL AND METHODS: We studied 700 subjects referred by general practitioners for possible metabolic abnormalities. Plasma glucose was measured before (FPG) and after (2h-PG) OGTT, together with insulin. Insulin resistance was estimated by HOMA-IR, insulin sensitivity using ISI(gly) and ISI(Stumvoll) indexes, insulin secretion by first (1stPH est) and second phase (2ndPH est) estimates. RESULTS: Sixty three subjects had impaired glucose tolerance (IGT), 132 impaired fasting glucose (IFG), 63 a mixed disorder (IFG/IGT). Insulin resistance was present only in IGT and IFG/IGT. IFG sub-jects had inappropriately low insulin secretionexclusively during fasting. In a stepwise logistic regression analysis BMI>or=27, female sex and hy-pertension were associated to an altered 2h-PG during OGTT, while hypertension and age were linked to alterations in FPG. While overweight prevalence (BMI>or=7) was higher in all glucose intolerance groups, obesity (BMI>or=30) was typical of IGT. Overweight and obesity were related to higher insulin concentration, secretion and resistance. Obese normal glucose tolerant subjects were more insulin resistant than lean IFG patients. DISCUSSION: OGTT is essential to correctly establish the metabolic derangement of glucose intolerance. Obesity is significantly connected with the impairment of insulin metabolism even in subjects with normal FPG. Considering that both obesity and insulin resistance are independently associated to an increased cardiovascular risk, all overweight subjects, even with normal FPG, should be referred for OGTT evaluation to define glucose tolerance status in order to enforce adequate preventive actions.

A new method to distinguish the hyponatremia of electrolyte loss from that due to pure solvent changes.

Estimates of solute and solvent changes during electrolyte abnormalities are valid only when either total body water (TBW) or solute content do not change, while it cannot be established which one of these is altered. The present paper provides a method capable of distinguishing these two different conditions. When only solvent changes, the respective concentration ratios of plasma (P) solutes PCl/PNa, POAN: /PNa, PCl/POAN: (POAN: = anions other than Cl) remain unchanged. Moreover, PNa(1)/PNa(0) (the ratio of PNa during the derangement over the normal value, indicated by subfix (1) and (0), respectively) = PCl(1)/PCl(0) = POAN: (1)/POAN: (0.) When these constraints are met, the abnormality is due only to a TBW change, which is easily calculated and corrected. When they are not met, the exact change in Na content is correctly calculated assuming no variation in TBW. These calculations could still be useful even in the presence of TBW modifications, where they represent minimum estimates of electrolyte losses. The formulas were validated by computer simulations generating true electrolyte concentrations, which were then used to back calculate the changes in their contents and extra/intra-cellular volumes. Since the predicted results were significantly correlated with the true data, the method was transferred to 24 patients with electrolyte disturbances, who met the above constraints. The calculated volume changes were significantly correlated with those obtained by body weight measurements (regression coefficient = 0.94, P < 0.0001), while the quantitative estimates of Na deficit predicted the PNa values measured after corrective treatment (P < 0.0001). This new method may prove valuable in diagnosing and treating electrolyte derangements.

Poor specificity of fasting plasma glucose cut-off values in ruling out glucose intolerance: the complementary usefulness of OGTT.

INTRODUCTION: With the objective to assess the diagnostic power of the ADA criteria in detecting glucose intolerance, we studied 654 patients by performing an oral glucose tolerance test (OGTT). MATERIAL AND METHODS: The design required computing sensitivity, specificity and predictive values for different cut-off levels of fasting plasma glucose (FPG). The patients were recruited in an outpatient facility of a General Internal Medicine department affiliated to a Medical School. RESULTS: Lowering the threshold from 7.0 to 6.1, 5.6, 5.0 and 4.4 mmol/l (126 to 110, 100, 90 and 80 mg/dl) respectively, resulted in a progressive fall in specificity (99.6, 91.6, 76.0, 45.3 and 15.8%) combined to a rise in sensitivity (8.6, 30.7, 56.4, 76.4 and 92.9%). Two subjects with FPG <5.0 mmol/l were diabetic. At the lowest FPG of 4.4 mmol/l the percentage of glucose intolerant patients by OGTT was still 11% while at 6.1 mmol/l the false positive rate was 50%. DISCUSSION: The simple screening based on FPG alone, as suggested by ADA, is ineffective, not detecting an unacceptable number of subjects with glucose intolerance, and conveys the high cost of working up an excessively large number of false positives. Only the OGTT represents the effective screening procedure.

Quantitative treatment of the hyponatremia of cirrhosis.

BACKGROUND: Hyponatremia represents a frequent complication of liver cirrhosis, associated with adverse events and death. It is caused either by excessive water retention or solute depletion, or a combination of both. AIMS: To determine the cause of hyponatremia clinically and to examine the usefulness of quantitative calculations of water excess and Na deficit to guide treatment. METHODS: We studied 23 patients with liver cirrhosis and PNa < or =131 meq/L to determine the cause of hyponatremia and results of quantitative treatment. RESULTS: The most frequent cause of hyponatremia was diuretic-induced Na depletion, which occurred in 14 out of 23 instances, while four patients had water excess. Hyponatremia was corrected after a quantitative estimate of the Na deficit or relative water excess by algebraic formulas. The former was quantitatively replenished as 3% NaCl, the latter was excreted with the technique of furosemide-induced diuresis and re-infusion of solute, but not water, losses. After quantitative replacement, there was a significant correlation (R=0.98, P< 0.001) between the Na concentration predicted mathematically and that actually measured. CONCLUSIONS: The hyponatremia of cirrhosis is frequently caused by diuretics. Its treatment can be effectively guided with the aid of quantitative estimates of Na deficit and/or water excess in all instances, although the methods of correction described are indicated in severe clinical conditions.

Hyponatremia in liver cirrhosis: pathophysiological principles of management.

Hyponatremia is common in cirrhosis, where it impairs encephalopathy. It could be either due to excess water, or reduced Na, or a combination of both. The diagnosis can be established with clinical skills aided by simple data like weight, blood pressure and plasma electrolytes. The quantitative estimates of the water surfeit or solute deficit, easily performed with simple formulas and measurements, guide accurate and programmed treatment procedures, avoiding the occurrence of the ominous central pontine myelinolysis.

Pathways of glomerular toxicity of cyclosporine-A: an "in vitro" study.

BACKGROUND/AIMS: Knowledge of renal toxicity of cyclosporine-A (CyA) is clouded by multiple effects on different glomerular and tubular cells and on kidney and systemic hemodynamics. To focus on glomerular action of CyA we used glomeruli isolated in vitro, with the aim of dissecting the effects on recruitment of glomerular vasoconstricting systems, like endothelin-1 (ET) and angiotensins (AI and AII). METHODS: We studied the pathways of CyA damage on pig glomeruli isolated in vitro with the technique of sieving through mesh filters of different sizes, and incubated in an appropriate culture medium. The supernatant was sampled at different time intervals to measure ET, AI and AII concentrations upon addition of ET 10(-12) or CyA 4x10(-7)M, with or without either selective endothelin receptor A (ETA) or B (ETB), or unselective ETA-ETB receptor inhibitors. RESULTS: CyA increased ET concentration (from 9.7+/-0.3 to 11.4+/-0.4 pgxml-1, p<0.002), and the added ET released AI in the medium (from 26.6+/-4.7 to 39.1+/-4.6 pgxml-1, p<0.05) when ETB receptors were blocked. In contrast, CyA stimulated angiotensins release independent of ET receptors blockade, hence, irrespective of ET concentration in the medium, from 26.6+/-4.7 to 38.0+/-2.1 pgxml-1 for AI, p<0.05, and from 12.3+/-1.0 to 14.8+/-0.9 pgxml-1 for AII, p<0.05. CONCLUSION: CyA releases ET and angiotensins independently by a direct action. Glomerular CyA toxicity might be mediated by recruitment of vasoconstricting peptides and modulated by relative ETA and ETB receptor occupancy.