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.     

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.     

Potent relaxant effect of a Celastrus paniculatus extract in the rat and human ileum

Ethnopharmacological importance

Celastrus paniculatus Willd. (Celastraceae) is an Ayurvedic remedy used for the treatment of a number of diseases, including bowel spasms.

Aim of the study

To investigate the mode of the relaxing action of a methanolic extract prepared from the seeds of Celastrus paniculatus (CPE, 0.0001–10 μg/mL) in the rat ileum and to try to confirm on human tissues the intestinal pharmacological activity of the extract.

Materials and methods

The relaxant effect of CPE was studied in vitro by evaluating its effect on the spontaneous contractions of the isolated ileum.

Results

CPE exerted a tetrodotoxin- and ω-conotoxin-resistant inhibitory effect on rat ileum motility (IC₅₀: 0.24 ± 0.02 μg/mL; E_max: 99.0 ± 0.60%). The inhibitory effect was reduced by nifedipine but not by cyclopiazonic acid. Experiments with specific antagonists enabled us to exclude the involvement of the main endogenous spasmogenic (i.e. acetylcholine and tachykinins) and relaxing (noradrenaline, nitric oxide, ATP) compounds. CPE also relaxed the isolated human ileum (IC₅₀: 0.26 ± 0.02 μg/mL; E_max: 99.1 ± 0.46%).

Conclusion

It is concluded that (i) CPE exerted a powerful myogenic and L-type Ca²⁺-dependent relaxing effect in the isolated rat ileum and that (ii) the human ileum is sensitive to the inhibitory effect of CPE. If confirmed in vivo, our data could explain the traditional use of this herb in the treatment of intestinal spasms.     

Untersuchungen über die Veränderungen der Blutgefässe bei der Entzündung

Ohne Zusammenfassung     

Prognostic value of persistent thallium-201 defects that become reversible after reinjection in patients with chronic myocardial infarction

Background

The presence of defects at stress-redistribution thallium-201 scintigraphy is related to a higher risk of cardiac events. However, the prognostic value of defects that become reversible after reinjection is not known. In this study we evaluated the prognostic contribution of stress-redistribution-reinjection with special regard to 3-hour fixed defects that become reversible after reinjection.

Methods and Results

We studied 122 patients with chronic myocardial infarction (>2 months) and suspected or known residual ischemia, with stress-redistribution-reinjection planar scintigraphy. Thallium scans were analyzed by three observers (three segments per view, 5-point score) and classified as normal, fixed, and reversible. The lung/heart ratio was also calculated. At a median follow-up of 47 months, 10 patients had hard events (four deaths and six myocardial infarctions) (group I), 12 patients had unstable angina (group II), 12 patients underwent planned coronary artery bypass grafting or percutaneous transluminal coronary angioplasty (group III), and 86 patients had no events (group IV). The presence of fixed defects that became reversible after reinjection did not identify patients at higher risk. The number of reversible defects at 3 hours was significantly higher only in patients who underwent revascularization. Unstable angina was not predicted by any scintigraphic pattern. The variables that were statistically related to hard events by univariate analysis were increased lung uptake, reversible cavity dilation, and the number of fixed defects that remained fixed after reinjection. By Cox multivariate analysis, the strongest predictor of hard events was the presence of more than three fixed defects that remained fixed after reinjection as a marker of irreversible myocardial damage.

Conclusions

²⁰¹TI reinjection is a useful approach for not only detecting viable myocardium but also risk stratification in patients with chronic myocardial infarction.     

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.     

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.