Diagnosis of mast cell activation syndrome: a global "consensus-2".

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.

Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy.

Susceptibility to quinoline antimalarial intoxication may reflect individual genetic and drug-induced variation in neuropharmacokinetics. In this report, we describe a case of chloroquine intoxication that appeared to be prolonged by subsequent use of multiple psychotropic medications. This case highlights important new considerations for the management of quinoline antimalarial intoxication.

Efficacy and safety of antifungal additives in Optisol-GS corneal storage medium.

IMPORTANCE: Optisol-GS, the most common corneal storage medium in the United States, contains antibacterial but no antifungal supplementation. Most postkeratoplasty endophthalmitis and keratitis cases are now of a fungal origin. OBJECTIVE: To assess the efficacy and safety of voriconazole and amphotericin B in reducing Candida species contamination of Optisol-GS under normal storage conditions. DESIGN, SETTING, AND PARTICIPANTS: In vitro laboratory study using 15 pairs of research-grade donor corneas and 20-mL vials of Optisol-GS. INTERVENTIONS: Twenty vials of Optisol-GS were supplemented with either voriconazole at 1×, 10×, 25×, or 50× minimum inhibitory concentration (MIC) or amphotericin B at 0.25×, 0.5×, 1×, or 10× MIC. Known concentrations of Candida albicans and Candida glabrata were each added to a set of vials. Safety studies were performed by separating 15 pairs of donor corneas into unsupplemented Optisol-GS or Optisol-GS plus an antifungal. MAIN OUTCOMES AND MEASURES: Efficacy outcomes were viable fungal colony counts determined from samples taken on days 2, 7, and 14 immediately after removal from refrigeration and after warming to room temperature for 2 hours. Safety outcomes included percentage of intact epithelium and endothelial cell density on days 0, 7, and 14, as well as percentage of nonviable endothelial cells by vital dye staining on day 14. RESULTS: Growth of C albicans and C glabrata was observed in all voriconazole-supplemented vials. In contrast, there was no growth of either organism in amphotericin B-supplemented vials, except at 0.25× and 0.5× MIC on day 2, when viable counts of C glabrata were reduced by 99% and 96%, respectively. Compared with paired controls, with the exception of Optisol-GS plus amphotericin B at 10× MIC, donor corneas in supplemented Optisol-GS appeared to have no difference in endothelial cell density reduction, percentage of intact epithelium, or percentage of nonviable endothelial cells. CONCLUSIONS AND RELEVANCE: The addition of amphotericin B to Optisol-GS may significantly improve activity against contamination with Candida species, the primary cause of fungal infection after corneal transplantation. This study found significant endothelial toxic effects at the maximal concentration of amphotericin B.

Validation of cooling effect of insulated containers for the shipment of corneal tissue and recommendations for transport.

PURPOSE: To determine the cooling effect of generic insulated shipping containers in ambient and high-temperature environments. METHODS: Twenty-seven shipping containers were packed with wet ice according to industry standards. The ice in each container was weighed. Ambient temperatures were recorded by data loggers affixed to the exterior. Internal temperatures were recorded by data loggers packed inside the containers, for as long as the data loggers remained at ≤8°C. The cooling effect, or minutes per gram of ice a data logger maintained a temperature of ≤8°C, was calculated using linear regression; 8 similar containers were subjected to elevated summer temperatures. RESULTS: Small, medium, and large containers held mean masses of wet ice of 685, 1929, and 4439 g, respectively. The linear regression equation for grams of ice to duration of time at ≤8°C was y = 0.1994x + 385.13 for small containers, y = 0.1854x + 1273.3 for medium, and y = 0.5892x + 1410.3 for large containers, resulting in a cooling effect of 25.1 hours for small, 58.9 hours for medium, and 85.7 hours for large containers at ambient temperature. The duration of cooling effect in the summer profile group was consistent with that of the ambient temperature group. CONCLUSIONS: All of the container sizes successfully maintained proper cooling when packed with the appropriate grams of wet ice for the needed time interval. This study validates current practice for the shipment of corneal tissue in inexpensive, generic containers that can maintain effective cooling for the duration required for local, national, and international shipment.

Preparation of corneal donor eyes comparing 1% versus 5% povidone-iodine.

PURPOSE: To compare the effect of 1% versus 5% polyvinylpyrrolidone-iodine (PVP-I) chemical preparation (prep) of the eye on the recovery of organisms from donor globes before in situ recovery of donor corneal tissue. METHODS: One hundred consecutive pairs of donor corneas (200 eyes) were randomized to receive either 1% or 5% PVP-I drops applied to the conjunctival cul-de-sac, which was left in place for 2 minutes. Limbal cultures were obtained before and after prepping of the eye. RESULTS: Twenty-five different species of organisms were recovered. Native flora of the eye included coagulase-negative staphylococci (62%), Corynebacterium species (27%), streptococcal species (9.5%), gram-negative bacilli (14.5%), Staphylococcus aureus (5%), anaerobes (10%), and yeast (2%). After PVP-I instillation of the donor eye, 74 isolates were recovered from the 1% P-I group and 76 isolates from the 5% PVP-I group. Cultures were sterile after PVP-I prep in 49 eyes and 47 eyes in the 1% PVP-I group and 5% PVP-I group, respectively. Microorganism colony forming units were similar among post-prep cultures from both PVP-I groups. The effect of the PVP-I prep on the number of negative cultures and on the reduction in the number of isolates was highly significant for both the 1% PVP-I group and the 5% PVP-I group when compared with the limbal cultures taken before PVP-I instillation. CONCLUSIONS: This study found that 1% and 5% PVP-I solutions are equally effective for chemical prep of the donor eye. Because PVP-I is known to be toxic to the corneal endothelium and corneal fibroblasts, this study suggests that 1% PVP-I should be the preferred disinfectant for the recovery of corneal donors.

Hypercholesterolemia impairs exercise capacity in mice.

We previously reported an attenuation of both exercise hyperemia and measures of aerobic capacity in hypercholesterolemic mice. In this study, we expanded upon the previous findings by examining the temporal and quantitative relationship of hypercholesterolemia to aerobic and anaerobic capacity and by exploring several potential mechanisms of dysfunction. Eight-week-old wild type (n = 123) and apoE knockout (n = 79) C57BL/6J mice were divided into groups with distinct cholesterol levels by feeding with regular or high-fat diets. At various ages, the mice underwent treadmill ergospirometry. To explore mechanisms, aortic ring vasodilator function and nitrate (NO(x)) activity, urinary excretion of NO(x), running muscle microvascular density and citrate synthase activity, as well as myocardial mass and histologic evidence of ischemia were measured. At 8 weeks of age, all mice had similar measures of exercise capacity. All indices of aerobic exercise capacity progressively declined at 12 and 20 weeks of age in the hypercholesterolemic mice as cholesterol levels increased while indices of anaerobic capacity remained unaffected. Across the four cholesterol groups, the degree of aerobic dysfunction was related to serum cholesterol levels; a relationship that was maintained after correcting for confounding factors. Associated with the deterioration in exercise capacity was a decline in measures of nitric oxide-mediated vascular function while there was no evidence of aberrations in functional or oxidative capacities or in other components of transport capacity. In conclusion, aerobic exercise dysfunction is observed in murine models of genetic and diet-induced hypercholesterolemia and is associated with a reduction in vascular nitric oxide production.

NOS inhibition accelerates atherogenesis: reversal by exercise.

In this study, we assessed the effects of chronic exercise training (12 wk) on atherosclerotic lesion formation in hypercholesterolemic apolipoprotein E-deficient mice (n = 31). At the age of 9 wk, mice were assigned to the following groups: sedentary (Sed; n = 9); exercise (Ex; n = 12); sedentary and oral NG-nitro-L-arginine (L-NNA, Sed-NA; n = 4), or exercise and oral L-NNA (Ex-NA; n = 6). Chronic exercise training was performed on a treadmill for 12 wk (6 times/wk and twice for 1 h/day) at a final speed of 22 m/min, and an 8 degrees grade. L-NNA was discontinued 5 days before final treadmill testing. The farthest distance run to exhaustion was observed in Ex-NA mice (Sed: 306 +/- 32 m; Ex: 640 +/- 87; Sed-NA: 451 +/- 109 m; Ex-NA: 820 +/- 49 m; all P < 0.05). Lesion formation was assessed in the proximal ascending aorta by dissection microscopy after oil red O staining. The aortas of Sed-NA mice manifested a threefold increase in lesion formation compared with the other groups. This L-NNA-induced lesion formation was reduced by chronic exercise training (Sed, 786 +/- 144; Ex, 780 +/- 206; Sed-NA, 2,147 +/- 522; Ex-NA, 851 +/- 253; Sed-NA vs. all other groups: P < 0.001). In conclusion, treatment with oral L-NNA (an nitric oxide synthase antagonist) leads to accelerated atherogenesis in genetically determined hypercholesterolemic mice. This adverse effect can be overcome by chronic exercise training.

Mechanisms of dysfunction of the nitric oxide pathway in vascular diseases.

Vascular nitric oxide (NO) is involved in many physiologic and pathophysiologic processes throughout the body. Many vascular diseases have a reduction in the activity of endothelium-derived NO as an important component involved in the initiation and/or progression of the disease. It is now known that there are multiple mechanisms for this reduction in NO activity with one or more mechanisms operating depending on the specific condition or stage of a disease. In other instances, the therapy for certain diseases is responsible for the reduction in NO activity and contributes to the acceleration of vascular disease. This review details the known mechanisms of dysfunction of the NO pathway leading to vascular diseases, which provides the rationale for why certain therapies can improve while other therapies adversely affect vascular health.

Randomized trial of a medical food for the dietary management of chronic, stable angina.

OBJECTIVES: We determined the electrocardiographic, vascular and clinical effects of a medical food bar enriched with L-arginine and a combination of other nutrients known to enhance endothelium-derived nitric oxide (NO) in patients with stable angina. BACKGROUND: Enhancement of vascular NO by supplementation with L-arginine and other nutrients has been shown to have clinical benefits in patients with angina secondary to atherosclerotic coronary artery disease (CAD). However, the amounts and combinations of these nutrients required to achieve a clinical effect make traditional delivery by capsules and pills less suitable than alternative delivery methods such as a specially formulated nutrition bar. METHODS: Thirty-six stable outpatients with CAD and class II or III angina participated in a randomized, double-blind, placebo-controlled, crossover trial with two treatment periods each of two weeks' duration (two active bars or two placebo bars per day). Flow-mediated brachial artery dilation was measured by ultrasound. Electrocardiographic measures of ischemia, exercise capacity and angina onset time were measured by treadmill exercise testing and by Holter monitor during routine daily activities. Quality of life was assessed by SF-36 and Seattle Angina Questionnaires and by diary. RESULTS: The medical food improved flow-mediated vasodilation (from 5.5 +/- 4.5 to 8.0 +/- 4.9, p = 0.004), treadmill exercise time (by 20% over placebo, p = 0.05) and quality-of-life scores (SF-36 summary score; 68 +/- 13 vs. 63 +/- 21 after placebo, p = 0.04, Seattle Angina Questionnaire summary score; 67 +/- 10 vs. 62 +/- 18, p = 0.04) without affecting electrocardiographic manifestations of ischemia or angina onset time. CONCLUSIONS: These findings reveal that this arginine-rich medical food, when used as an adjunct to traditional therapy, improves vascular function, exercise capacity and aspects of quality of life in patients with stable angina.

Pediatric Primary Pulmonary Hypertension.

Primary pulmonary hypertension is a disease for which there is no single best therapy. Rather, it is a process that progresses inexorably to disability and death, for which there are a variety of palliative therapies, all with significant side effects, and none curative. Nevertheless, it is clear that the available therapies improve the quality of life and prolong life; failure to offer therapy for patients with this disease in the current era is indefensible. As primary pulmonary hypertension progresses, one must chose from among the available therapies the regimen that provides the most benefit for the patient with the least associated morbidity. Organ replacement is appropriate only after all other available therapies have been exhausted. The recommended hierarchy of therapy is 1) anticongestive therapy, anticoagulation, and supplemental oxygen, 2) calcium channel blockade, 3) continuous intravenous prostacyclin, 4) beta-receptor agonists for cardiac support, and 5) lung transplantation. Newer therapies, described in this review, soon will be incorporated into this hierarchy.