Comparative efficacy of parathyroidectomy and active surveillance in patients with mild primary hyperparathyroidism: a systematic review and meta-analysis.

Counseling for patients with primary hyperparathyroidism (PHPT) and mild hypercalcemia without indications for surgical intervention requires accurate estimates of the potential benefits of parathyroidectomy. We aim to summarize the available evidence regarding the benefits of parathyroidectomy that patients with mild PHPT without indications for surgery experience compared to observation. We searched multiple databases from inception to August 2015. We included randomized controlled trials (RCT) and observational studies that evaluated changes in bone health, quality of life or neuropsychiatric symptoms, or in the risk of nephrolithiasis, cardiovascular events, or death between patients undergoing parathyroidectomy or active surveillance. Eight studies were eligible. Risk differences were not significant, in part due to lack of events (fractures, nephrolithiasis, cardiovascular events, or deaths). No significant differences were observed across measures of bone health, quality of life, and neuropsychiatric symptoms. A single RCT evaluating bone mineral density (BMD) changes at 5 years found a small statistically significant effect favoring parathyroidectomy. Patients with mild PHPT without indications for surgery experience a limited number of adverse consequences during short-term follow-up limiting our ability to estimate the benefit of surgery during this timeframe. This information is helpful as these patients consider surgery versus active surveillance. Long-term data is warranted to determine who benefits in the long run from surgical intervention and the extent to which this benefit affects outcomes that matter to patients.

Shared decision-making in the care of individuals with diabetes.

People with diabetes often live with other chronic conditions and lead complicated lives. Determining what is the best management decision for a patient requires consideration of each individual's personal, social and biomedical context, what he or she values, the reasons he or she has to value the available options, and the relative contribution of each option in terms of benefits, harms, costs and inconveniences. Empathic conversations between patients and clinicians to diagnose the patient situation that necessitates action and the range of evidence-based actions that best address the situation, so-called shared decision-making, are essential to the personalized care of people with diabetes. The aim of the present review was to present key elements of shared decision-making and propose three different approaches for its application. The first approach focuses on transferring information to patients so that they can make decisions. The second approach, choice, focuses on cultivating the individual's ability to give voice to which choice is best for them. The third approach, conversation, establishes an empathic conversational environment through which the individual with diabetes and their clinician think and talk through how to address the problems of living with diabetes and related illnesses. These approaches are manifest in the design of evidence-based decision aids created to support shared decision-making. In randomized trials, decision aids can efficiently improve patient's knowledge, satisfaction, risk awareness, decisional conflict and involvement. Further research, however, is needed to better understand when and how to promote the empathic conversations, patient, clinician and service and policy contexts necessary to routinely implement shared decision-making in different at scale healthcare systems. In the interim, sufficient evidence and tools exist for persons with diabetes and their clinicians to gain expertise in making decisions together.

Early detection of oleic acid-induced lung injury in rats using (111)In-labeled anti-rat intercellular adhesion molecule-1.

UNLABELLED: Previous study of the bleomycin-induced lung injury model suggested that (111)In-labeled antirat intercellular adhesion molecule-1 (aICAM-1) might be a useful acute respiratory distress syndrome (ARDS) diagnostic agent. We further investigated the ability of (111)In-aICAM-1 to detect inflammation in another ARDS lung injury model. METHODS: (111)In-labeled rat polymorphonuclear leukocytes (PMNs), (111)In-aICAM-1, (111)In-labeled normal mouse IgG (nmIgG), and (111)In-labeled rat serum albumin (RSA) were injected into rats 18-24 h before kill. Biodistributions, scintigraphic images, and lung ICAM-1 upregulation were obtained in uninjured rats and in rats after injury with oleic acid. RESULTS: (111)In-RSA and (111)In-nmIgG localized in inflamed lung at 5 min postinjury (PI). (111)In-PMN uptake increased significantly only at 24 h PI. (111)In-aICAM-1 localization increased significantly (30%-60%) at 1 h PI and remained elevated up to 24 h PI. Lung/blood ratios (L/B) at 1 and 4 h PI were very low (<0.6) for (111)In-nmIgG and (111)In-PMN rats; however, for (111)In-aICAM-1 rats, they were >1 and 25%-60% higher than those for the control samples. A low L/B suggests poor inflammation detection on the images. Images and region-of-interest analysis confirmed that only (111)In-aICAM-1 could distinguish inflamed lungs at 4 h PI. ICAM-1 was upregulated at 4 and 24 h PI. CONCLUSION: In this model, (111)In-aICAM-1 detected lung inflammation very early in the course of the disease. These results support the suggestion that (111)In-aICAM-1 could be a very early, highly specific ARDS diagnostic agent and may be useful to detect a wide range of inflammations.

Early detection of bleomycin-induced lung injury in rat using indium-111-labeled antibody directed against intercellular adhesion molecule-1.

UNLABELLED: We have investigated whether an (111)In-labeled mouse monoclonal antibody to rat intercellular adhesion molecule-1 ((111)In*aICAM-1) could detect lung injury early in rats treated with bleomycin. METHODS: Rats received an intravenous injection of either (111)In*aICAM-1 or (111)In-labeled normal mouse IgG ((111)In*nmIgG) and were imaged and killed 24 hr later. Lung injury was induced by an intratracheal injection of bleomycin 4 or 24 hr before the rats were killed. After death, tissue was removed and activity was measured, lungs were cryostat-sectioned to detect the presence of ICAM-1 by immunofluorescence, and the up-regulation of LFA-1alpha was examined on blood polymorphonuclear leukocytes (PMNs) using fluorescence-activated cell-sorter (FACS) analysis. RESULTS: In rats injected with (111)In*aICAM-1, the percent injected dose/organ in lungs both at 4 and 24 hr postbleomycin increased significantly compared to the values in either uninjured rats or rats that received (111)In*nmIgG. At 4 and 24 hr postinjury, the target-to-blood (T/B) ratio was 8/1 and 6/1, respectively. For (111)In*nmIgG, the T/B ratio at 4 hr was 0.5/1 and 0.4/1 at 24 hr. In (111)In*aICAM-1 rats injured at 4 or 24 hr, images could easily be distinguished from uninjured rats. All images of (111)In*nmIgG rats showed only cardiac blood-pool and liver activity with little lung activity. Lung ICAM-1 immunofluorescence intensity increased in the bleomycin-treated samples compared to uninjured lungs. Expression of LFA-1alpha on PMNs increased 19% and 210% at 4 hr and 24 hr postinjury, respectively, compared to control values. CONCLUSION: Biodistribution and imaging data demonstrate that (111)In*aICAM-1 can detect early acute bleomycin-induced lung injury. Immunofluorescence and FACS data suggest that (111)In*ICAM-1 uptake is a specific process. This antibody has potential as an early radionuclide detector of acute inflammations.

Biodistribution of indium-111-labeled antibody directed against intercellular adhesion molecule-1.

UNLABELLED: We examined the biodistribution in normal rats of an 111In-labeled mouse monoclonal antibody to rat intercellular adhesion molecule-1 (111In-alCAM-1), as a potential detector of inflammation. METHODS: Indium-111-alCAM-1 or 111In-labeled normal mouse polyclonal immunoglobulin G (111In-nmIgG) was injected into rats. Groups of three to four rats were killed up to 18 hr after injection, and activity was measured in various tissues. Rats were also imaged at 1 and 18 hr after injection. RESULTS: Uptake of 111In-alCAM-1 was greatest in the lung (approximately 10% injected dose [ID]/g at 15 min) and then declined steadily (to approximately 2% ID/g at 18 hr). Lung uptake of 111In-nmIgG was eightfold less than that for 111In-alCAM-1 and did not change throughout the 18 hr. At all time points, blood activity for 111In-alCAM-1 was only 30% to 40% of that for 111In-nmIgG, whereas the percent injected dose per gram was increased more than twofold in the major organs. Compared with 111In-nmIgG, the 111In of alCAM-1 was shifted from the blood and was distributed among the lung kidney, spleen and liver. CONCLUSION: Indium-111-alCAM-1 may be useful as an early inflammation detection agent. Intercellular adhesion molecule-1 upregulation is a very early event in inflammation and rapid removal from the blood of this antibody provides low background in contrast to the usual high background with whole antibodies.

Eprazinone alters lung lavage lipid levels and transtracheal ion transport.

Eprazinone therapy improves pulmonary function and arterial pO2 in patients with chronic bronchitis; however, the mechanism of action is unknown. The purpose of this study was to determine if eprazinone alters either lung surfactant levels in bronchoalveolar lavage fluid (BAL) of normal rats, or ion transport across canine tracheal epithelium mounted in Ussing chambers. In the surfactant studies, normal rats were force fed three doses (50, 100, and 200 mg/kg) of eprazinone for 4 days. Eprazinone at a dose of 200 mg/kg significantly increased total and individual (with the exception of phosphatidylinositol) phospholipid levels and decreased total neutral lipids. Lower doses of eprazinone significantly decreased neutral lipid levels without affecting the phospholipids. There was no change in BAL levels of protein or cells and no abnormal histology. In airway epithelial studies, mucosal addition of eprazinone produced a dose-dependent partially reversible decrease in short-circuit current (Isc). The decrease in Isc at lower eprazinone concentrations was accounted for entirely by a decrease in net chloride secretion while at higher concentrations both sodium and chloride transport were affected. Submucosal eprazinone had no affect on ion transport. These studies suggest that eprazinone influences both BAL lipid levels and ion transport, either of which could lead to a beneficial therapeutic effect.

A model of pulmonary granulomata induced by beryllium sulfate in the rat.

In humans beryllium is known to cause pulmonary granulomata which are histologically indistinguishable from sarcoidosis. There is some evidence in man that beryllium-induced pulmonary granulomata are immunologically mediated. We set out to develop an animal model to study the immunopathogenesis of beryllium-induced granulomatous lung disease. Beryllium sulfate (BeSO4) was injected intratracheally (i.t.) into F344 rats previously immunized to BeSO4. This results in well-formed, sarcoid-like lung granulomata at 6 weeks post BeSO4. There was a conspicuous presence at 4 weeks post BeSO4 of numerous, perivascularly located Langhans' giant cells which preceded the development of well-formed granulomas at 6 weeks. Rats were sacrificed at 4, 6, 8 and 12 weeks after i.t. BeSO4. At the time of sacrifice bronchoalveolar lavage (BAL) was performed; B and T (W3/25+ helper 0X8+ suppressor/cytotoxic) lymphocyte populations were quantitated and compared to lymphocyte populations obtained from lung tissue. Both B and T cells were significantly elevated in lung tissue post BeSO4. At 4 weeks when granulomata were just developing, a W3/25+ to 0X8+ ratio of 20:1 in lavage and 2:1 in lung tissue was seen. At 6 weeks when granulomata were well-formed there was a predominance of W3/25+ cells in lavage but not in lung tissue. At 8 and 12 weeks, when the granulomata were regressing, lavage fluid still contained a W3/25+ predominance in contrast to lung tissue which contained a predominance of 0X8+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Atracurium: clinical strategies for preventing histamine release and attenuating the haemodynamic response.

This study was designed to determine the effects of a rapid bolus dose of atracurium 0.6 mg kg-1 on arterial pressure, heart rate and plasma histamine concentration (n = 9), and to compare these values with those obtained by (a) giving the same dose of atracurium slowly (over 75 s) (n = 9), or (b) pre-treating with H1- and H2- antagonists (n = 9). The rapid (5-s) bolus dose of atracurium i.v. resulted in a significant increase in plasma histamine concentration (P less than 0.05) and was associated with a decrease in mean arterial pressure and an increase in heart rate. Administering the same dose of atracurium slowly (over 75 s) prevented the increase in plasma histamine concentration, and abolished the subsequent haemodynamic response. Pretreatment with cimetidine 4 mg kg-1 i.v. and chlorpheniramine 0.1 mg kg-1 i.v. abolished the haemodynamic response despite a moderate increase in histamine concentration (0.1 greater than P greater than 0.05).

Safety and efficacy of vecuronium in adolescents and children.

The neuromuscular and cardiovascular effects of vecuronium (Norcuron, ORG NC45) were studied in 40 adolescents (10-17 yr) and children (2-9 yr) anesthetized with 1.5% inspired halothane. Ten adolescents and ten children were given 20 micrograms/kg incremental doses of vecuronium to establish a cumulative dose-response curve during train-of-four stimulation. The ED95 dose was 56 micrograms/kg in children and 40 micrograms/kg in adolescents, children being significantly (P less than 0.01) more resistant to the neuromuscular effects of vecuronium than adolescents. Another group of 10 children and 10 adolescents received a bolus dose of 80 micrograms/kg. This dose provided satisfactory conditions for endotracheal intubation with complete suppression of train-of-four response in all adolescents and children within 2 min. Thereafter, the twitch tension recovered to 5% of control twitch height in 18.5 +/- 1.5 min, to 25% in 24.4 +/- 1.6 min, and to 95% in 43.3 +/- 2.1 min. Vecuronium (20-80 micrograms/kg) did not significantly alter the heart rate or blood pressure nor did it affect kidney or liver function as assessed by routine clinical laboratory tests. Vecuronium is a useful nondepolarizing neuromuscular blocking agent with a short to intermediate duration of action, which can be used safely in children and adolescents.

Evaluation of cumulative properties of three new nondepolarizing neuromuscular blocking drugs BW A444U, atracurium and vecuronium.

Comparative patterns of recovery during successive doses of three new, relatively non-cumulative, intermediate-duration non-depolarizing neuromuscular blocking drugs, BW A444U, atracurium (BW33A) and vecuronium (Org NC 45), were studied in 94 surgical patients during thiopentone in nitrous oxide and oxygen with narcotic anaesthesia. The train-of-four (TOF) pattern of nerve stimulation was used. The spontaneous 5-25% recovery time of the first twitch of TOF showed a statistically significant difference between the initial dose and the fifth incremental dose in the cases of atracurium and vecuronium, but not in the case of BW A444U. The 25-75% recovery times for the final doses were significantly longer than the corresponding times for each drug after the initial doses. The percent TOF ratio at the point of recovery of the first twitch to 95% of the control height was compared for the initial and final doses in a series of doses of each drug. The difference was significant only when the final dose of vecuronium was compared with the initial dose (TOF ratio 79.3 +/- 2.3% v. 64.3 +/- 4.4%; P less than 0.005). Analysis of variance indicates that the TOF ratio at 95% recovery of the first twitch of TOF after the final dose of vecuronium (64.3%) is significantly smaller (P less than 0.001) than that of either BW A444U (78%) or atracurium (84%), indicating that vecuronium appears to show more residual fade and greater cumulative effect after incremental doses than BW A444U or atracurium. The data suggest that the cumulative properties of the new drugs may be ranked as follows: atracurium less than BW A444U less than vecuronium.

Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant.

Atracurium, a new non-depolarizing neuromuscular blocking agent, was studied in 70 patients anesthetized with fentanyl, thiopental, and nitrous oxide-oxygen. The dose found to produce 95% twitch inhibition (ED95) was 0.2 mg/kg. The onset time from injection to maximum depression of twitch was 4.0 minutes at this dose; the duration to 95% recovery was 44.1 minutes. Twice the ED95 dose (0.4 mg/kg) had an onset time of 1.7 minutes and a duration of 63.5 minutes. No cardiovascular effects were observed in this dosage range. At higher doses (0.5 and 0.6 mg/kg) arterial pressure decreased 13% and 20% and heart rate increased 5% and 8%, respectively. Sixteen patients received at least four successive doses of atracurium. No clinically significant cumulative effect could be shown when recovery from 25% to 75% of control twitch height was compared for initial and final doses in the series. Atracurium spontaneously decomposes at physiologic pH via the Hofmann elimination reaction and may also undergo ester hydrolysis independent of plasma cholinesterase. These proposed pathways of inactivation may explain the lack of cumulative effect and the drug's intermediate duration of action. Based on the results of this study, atracurium offers several clinical advantages and should undergo more extensive clinical trials.

Treatment of NZB/W ("lupus") mice with 15(S)-15 methyl PGE1.

The F1 hybrid of New Zealand black and New Zealand white mice--the NZB/W mouse--spontaneously develops a disease similar to human systemic lupus erythematosus. Male NZB/W mice with established disease were treated with a stable derivative of prostaglandin E1, 15(S)-15 methyl PGE1 (4 micrograms twice daily) from 7 months of age. The pge analog prolonged survival of these mice: At 14 months 7 of 10 control mice had died, whereas 9 of 10 15(S)-15 methyl PGE1 treated mice remained alive. Thus a dose of 200 micrograms/Kg/day 14(S)-15 methyl PGE1 retards progression of murine lupus.