Effect of infusion and withdrawl of glucose and insulin on gas exchange in injured ventilated patients

To evaluate the effect induced on gas exchange and on urea excretion by glucose and insulin infusion in injured patients. The magnitude and time necessary for the full development of the metabolic effect were investigated. Six injured patients were investigated. During the first 24 hours, the fasting period, patients received 1 mg/kg^*min of glucose; during the second 24 hours, the treatment period, infusion was increased to about the 95% of the energy production rate; during the last 8 hours, (stop period) the infusion rate was again set to 1 mg/kg^*min. Gas exchange was determined in two consecutive 12-hour series, for 30 minutes every hour, either during a stabilized treatment or after its variation. Urea excretion was determinated on 4-hour samples. With respect to the fasting period, during the last 4 hours of the treatment period, the energy production rate did not vary; urea excretion (−25%) and oxygen consumption (−9%) decreased significantly. Carbon dioxide production (+16%), total respiratory quotient, and minute ventilation (+5%) increased significantly. Carbon dioxide production varied linearly with time (glucose infusion ⁺1.74 mL/min^*m2^*h, P <.05; glucose withdrawal −1.89 mL/min^*m2^*h, P < .01). Minute ventilation decreased only during the withdrawal period by 65 mL/ min^*m2^*h (P < .05). The infusion of glucose and insulin, in an amount slightly lower than the metabolic expenditure, leads to a consistently reduced amino acid catabolism and to a decreased oxygen consumption, without affecting energy requirements. Although it leads to an increase of carbon dioxide production, the measured change is so small and slow that it is not harmful unless there is severe respiratory insufficiency.     

Melanoma risk alleles are associated with downregulation of the MTAP gene and hypermethylation of a CpG island upstream of the gene in dermal fibroblasts

Several association studies and GWAS on melanoma skin cancer risk have reported statistically significant signals on 9p21.3 region, where MTAP gene maps. None of the associated SNPs identified in these studies lie in the coding region of the gene and the causative relation of risk alleles with melanoma predisposition has not been elucidated. MTAP has a tumor suppressor activity and epigenetic silencing has been described in melanoma cell lines. In the present study, we show that melanoma risk alleles correlate with a MTAP allele‐specific hyper‐methylation and down‐regulation of gene expression.     

The 17-year single-center experience with the use of azathioprine to maintain remission in ulcerative colitis

Despite the accumulation of positive data, the role of azathioprine (AZA) in the maintenance of remission of ulcerative colitis is still controversial. We looked at the follow-up of the ulcerative colitis patients who, after responding to either steroids or cyclosporin (CsA), received AZA at our referral center for over a decade. The 39 patients (29 m/10f) were treated between 1991 and 2007. Twenty-five of them had responded to CsA, the remaining 14 to corticosteroids. AZA was usually overlapped with either of the two agents at the initial dose of 2 mg/kg/day. The definitions of remission, relapse, and AZA toxicity followed commonly agreed criteria. The median duration of the AZA treatment was 14 months (<1–201). Fifty-two percent and 14%, respectively, of the CsA and the steroid responders needed surgery (overall rate = 38%). The figures were 32 and 15 at the first year. The majority of the patients had 1–2 relapses often in connection with withdrawal of AZA; only 3 of these relapsers needed hospitalization. AZA caused toxicity in 16/39 (41%) patients, requiring withdrawal in 23% of the cases; leukopenia (17%) and hepatitis/cholestasis (10%) ranked first and second for frequency. All of the patients in whom AZA was stopped (or reduced) relapsed. In conclusion, the 1-year colectomy rates compare favorably with the figures reported by the literature. By contrast, the toxicity rates were higher than expected. Failure to genotype or to use escalating AZA doses can only be hypothesized as causes.     

Treatment of psoriasis with topical agents: Recommendations from a Tuscany Consensus

Psoriasis is a chronic and relapsing inflammatory skin disease, clinically characterized by erythematous and scaly plaques. Treatment approach is mainly driven by disease severity, though several factors should be considered in order to identify the optimal therapeutic choice. Mild psoriasis may be treated with a wide array of topical agents including corticosteroids, vitamin D analogs, keratolytics, and calcipotriol/betamethasone propionate compound. Because guidelines may not provide practical indications regarding the therapeutic approach, the use of topical agents in psoriasis is more individually tailored. In order to homogenize the standard of care, at least in a local setting, we collected the real‐life‐based recommendations for the use of topical therapies from an expert panel, the Tuscany Consensus Group on Psoriasis, representing all leading centers for psoriasis established in Tuscany. With this document, this consensus group sought to define principles guiding the selection of therapeutic agents with straightforward recommendations derived from a real‐life setting.     

The Dose-Response Effects of Consuming High Fructose Corn Syrup-Sweetened Beverages on Hepatic Lipid Content and Insulin Sensitivity in Young Adults

Increased hepatic lipid content and decreased insulin sensitivity have critical roles in the development of cardiometabolic diseases. Therefore, our objective was to investigate the dose-response effects of consuming high fructose corn syrup (HFCS)-sweetened beverages for two weeks on hepatic lipid content and insulin sensitivity in young (18–40 years) adults (BMI 18–35 kg/m²). In a parallel, double-blinded study, participants consumed three beverages/day providing 0% (aspartame: n = 23), 10% (n = 18), 17.5% (n = 16), or 25% (n = 28) daily energy requirements from HFCS. Magnetic resonance imaging for hepatic lipid content and oral glucose tolerance tests (OGTT) were conducted during 3.5-day inpatient visits at baseline and again at the end of a 15-day intervention. During the 12 intervening outpatient days participants consumed their usual diets with their assigned beverages. Significant linear dose-response effects were observed for increases of hepatic lipid content (p = 0.015) and glucose and insulin AUCs during OGTT (both p = 0.0004), and for decreases in the Matsuda (p = 0.0087) and Predicted M (p = 0.0027) indices of insulin sensitivity. These dose-response effects strengthen the mechanistic evidence implicating consumption of HFCS-sweetened beverages as a contributor to the metabolic dysregulation that increases risk for nonalcoholic fatty liver disease and type 2 diabetes.     

MK-8237: a house dust mite vaccine for treating allergic rhinitis,asthma and atopic dermatitis

ABSTRACT

Introduction: Since its introduction in clinical practice one century ago for the treatment of respiratory allergic diseases, allergen-specific immunotherapy (AIT) has exhibited a relevant clinical efficacy that was subsequently confirmed in controlled trials. Thus, AIT has been accepted worldwide, as testified by guidelines and international documents. AIT is considered pivotal in the management of allergic rhinitis with or without conjunctivitis and with or without asthma. These conditions, in addition to hymenoptera venom allergy, currently are the accepted indications. The use of AIT in house-dust mite allergy still remains debated, especially due to the methodological problems in assessing this form of respiratory allergy. The more recent experimental data on MK-8237 sublingual tablets provided evidence that AIT, in the sublingual form, is effective in dust mite allergy.

Areas covered: At present, the evidence of the efficacy of AIT in conditions other than respiratory allergy are not conclusive, but encouraging results have been obtained in food allergy and atopic dermatitis. Herein, the authors discuss the data for these indications.

Expert opinion: Not all patients respond to AIT in the same way. Accordingly, AIT represents a promising path to precision medicine and hopefully will be able to reduce this burden of non-responding patients.     

Platelet mitochondrial dysfunction in critically ill patients: comparison between sepsis and cardiogenic shock

IntroductionPlatelet mitochondrial respiratory chain enzymes (that produce energy) are variably inhibited during human sepsis. Whether these changes occur even during other acute critical illness or are associated with impaired platelet aggregation and secretion (that consume energy) is not known. The aims of this study were firstly to compare platelet mitochondrial respiratory chain enzymes activity between patients with sepsis and those with cardiogenic shock, and secondly to study the relationship between platelet mitochondrial respiratory chain enzymes activity and platelet responsiveness to (exogenous) agonists in patients with sepsis.MethodsThis was a prospective, observational, case–control study. Platelets were isolated from venous blood of 16 patients with severe sepsis or septic shock (free from antiplatelet drugs) and 16 others with cardiogenic shock, within 48 hours from admission to Intensive Care. Platelet mitochondrial respiratory chain enzymes activity was measured with spectrophotometry and expressed relative to citrate synthase activity, a marker of mitochondrial density. Platelet aggregation and secretion in response to adenosine di-phosphate (ADP), collagen, U46619 and thrombin receptor activating peptide were measured with lumiaggregometry only in patients with sepsis. In total, 16 healthy volunteers acted as controls for both spectrophotometry and lumiaggregometry.ResultsPlatelets of patients with sepsis or cardiogenic shock similarly had lower mitochondrial nicotinamide adenine dinucleotide dehydrogenase (NADH) (P < 0.001), complex I (P = 0.006), complex I and III (P < 0.001) and complex IV (P < 0.001) activity than those of controls. Platelets of patients with sepsis were generally hypo-responsive to exogenous agonists, both in terms of maximal aggregation (P < 0.001) and secretion (P < 0.05). Lower mitochondrial NADH (R² 0.36; P < 0.001), complex I (R² 0.38; P < 0.001), complex I and III (R² 0.27; P = 0.002) and complex IV (R² 0.43; P < 0.001) activity was associated with lower first wave of aggregation with ADP.ConclusionsSeveral platelet mitochondrial respiratory chain enzymes are similarly inhibited during human sepsis and cardiogenic shock. In patients with sepsis, mitochondrial dysfunction is associated with general platelet hypo-responsiveness to exogenous agonists.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00541827","term_id":"NCT00541827"}}NCT00541827. Registered 8 October 2007.     

Drainage of pleural effusion in mechanically ventilated patients: Time to measure chest wall compliance?

Purpose

Pleural effusion (PE) is commonly encountered in mechanically ventilated, critically ill patients and is generally addressed with evacuation or by fluid displacement using increased airway pressure (P_AW). However, except when massive or infected, clear evidence is lacking to guide its management. The aim of this study was to investigate the effect of recruitment maneuvers and drainage of unilateral PE on respiratory mechanics, gas exchange, and lung volume.

Materials and methods

Fifteen critically ill and mechanically ventilated patients with unilateral PE were enrolled. A 3-step protocol (baseline, recruitment, and effusion drainage) was applied to patients with more than 400 mL of PE, as estimated by chest ultrasound. Predefined subgroup analysis compared patients with normal vs reduced chest wall compliance (C_CW). Esophageal and P_AWs, respiratory system, lung and C_CWs, arterial blood gases, and end-expiratory lung volumes were recorded.

Results

In the whole case mix, neither recruitment nor drainage improved gas exchange, lung volume, or tidal mechanics. When C_CW was normal, recruitment improved lung compliance (81.9 [64.8-104.1] vs 103.7 [91.5-111.7] mL/cm H₂O, P < .05), whereas drainage had no significant effect on total respiratory system mechanics or gas exchange, although it measurably increased lung volume (1717 vs 2150 mL, P < .05). In the setting of reduced C_CW, however, recruitment had no significant effect on total respiratory system mechanics or gas exchange, whereas pleural drainage improved respiratory system and C_CWs as well as lung volume (42.7 [38.9-50.0] vs 47.0 [43.8-63.3], P < .05 and 97.4 [89.3-97.9] vs 126.7 [92.3-153.8] mL/cm H₂O, P < .05 and 1580 vs 1750 mL, P < .05, respectively).

Conclusions

Drainage of a moderate-sized effusion should not be routinely performed in unselected population of critically ill patients. We suggest that measurement of C_CW may help in the decision-making process.     

Magnetic resonance imaging of the pancreas at 3.0 tesla: qualitative and quantitative comparison with 1.5 tesla

OBJECTIVES: We sought to perform a preliminary comparison of signal-to-noise ratio (SNR) and image quality for magnetic resonance imaging (MRI) of the pancreas at 1.5 and 3 T. MATERIALS AND METHODS: Two imaging cohorts were studied using a T2-weighted, single-shot fast spin-echo pulse sequence and a T1-weighted, fat-suppressed 3D gradient-echo pulse sequence. In the first cohort, 4 subjects were imaged using identical imaging parameters before and after contrast administration at 1.5 and 3.0 T. The SNR was quantified for the pancreas as well as for the liver, spleen, and muscle. In a second cohort of 12 subjects in whom the receiver bandwidth was adjusted for field strength, SNR measurements and qualitative rankings of image quality were performed. RESULTS: In the study cohort using identical imaging parameters at both magnetic field strengths, the mean (SD) ratios of SNR at 3.0 to 1.5 T of the single-shot fast spin-echo images for the pancreas, liver, spleen, and muscle were 1.63 (0.39), 1.82 (0.39), 1.45 (0.18), 2.01 (0.16), respectively. For the precontrast fat-suppressed 3D gradient-echo sequence, the corresponding ratios were 1.28 (0.29), 1.26 (0.30), 1.16 (0.27), and 1.76 (0.45), respectively; for the arterial phase, the corresponding ratios were 2.02 (0.28), 1.60 (0.42), 1.47 (0.26), and 1.94 (0.32), respectively; and for the delayed postcontrast phase, the corresponding ratios were 1.63 (0.51), 2.01 (0.25), 1.66 (0.06), and 2.31 (0.47), respectively. The SNR benefit of 3.0 T was significantly greater on contrast-enhanced as compared with noncontrast T1-weighted 3D gradient-echo images. In the second study cohort, SNR was superior at 3.0 T, although the use of a reduced readout bandwidth at 1.5 T substantially diminished the advantage of the higher field system. With qualitative comparison of images obtained at the 2 magnetic field strengths, the fat-suppressed 3D gradient-echo images obtained at 3.0 T were preferred, whereas the single shot fast spin-echo images obtained at 1.5 T were preferred because of better signal homogeneity. CONCLUSIONS: Our results in a small cohort of volunteers and patients demonstrate a marked improvement in SNR at 3.0 T compared with 1.5 T (by a factor of 2 in some cases) when identical imaging parameters were used. The SNR advantage at 3.0 T is diminished but persists when the receiver bandwidth is adjusted for magnetic field strength. The results suggest that 3.0 T may offer promise for improved body MRI, although further technical development to optimize SNR and improve signal homogeneity will be needed before its full potential can be achieved.