Screening for Compositae sensitization with pure allergens: implications of molecular structure, strength of reaction, and time of testing

Background. The sesquiterpene lactone (SL) mix is the only commercial Compositae allergy screening agent that consists of pure allergens; its detection rate is lower than that of Compositae plant extracts. Objective(s). To report a 15‐year experience with routine screening with SL mix and another allergen, parthenolide, the optimal reading times when testing with SL mix constituents, and the advantages and drawbacks of using pure allergens. Materials and methods. The SL mix 0.1% and parthenolide 0.1% petrolatum were included in the baseline series. Results. Of individuals undergoing routine testing, 157/7163 (2.19%) tested positive to SL mix, 161/7162 (2.25%) to parthenolide, and 141 to both in the 15‐year period. The overall detection rate between the two was 177 persons, and 10% would have been missed without parthenolide testing. Two cases of possible active sensitization to parthenolide were recorded. Costunolide elicited positive reactions most frequently, followed by dehydrocostus lactone, and alantolactone. An important observation was that the prevalence of positive reactions to SL mix constituents was lower if they were applied 3–5 days after application of SL mix in those with 1+ or 2+ reactions. Conclusions. The benefit of detecting 10% more Compositae‐sensitive patients with parthenolide in the baseline series must be weighed against a small risk of active sensitization, which may be reduced by lowering the test concentration.     

The role and incidence of facet tropism in lumbar spine degenerative disc disease.

The correlation of posterior intervertebral (facet) joint tropism (asymmetry), degenerative facet disease, and intervertebral disc disease was reviewed in a retrospective study of magnetic resonance images of the lumbar spine from 100 patients with complaints of low back pain and sciatica. Of the 27 of 100 (27%) of patients discovered to have disc disease (either herniation of nuclear material or bulge) at the L4-5 level, an approximately equal number had facet tropism (14 of 27) as did not (13 of 27). Of the 27 of 100 (27%) patients noted to have disc disease at the L5-S1 level, slightly more (16 of 21) had facet tropism than did not (11 of 27). Of the 65 of 100 (65%) of patients who had facet degenerative disease at the L4-5 level, an approximately equal number had facet tropism (33 of 65) as did not (32 of 100). At the L5-S1 level there was slightly more of a difference, with 25 of 41 having facet degenerative joint disease and tropism and 16 of 41 without it. This study raises questions as to the significance of facet joint tropism in intervertebral disc disease and degenerative facet joint disease but did show that asymmetry of the posterior intervertebral joint is far more common than previously thought: 50% of patients were found to have asymmetric facets at the L5-S1 level and 42% at the L4-5 level.     

Perioperative renal function in patients undergoing orthotopic liver transplantation. A randomized trial of the effects of verapamil

Patients who undergo orthotopic liver transplantation often experience a significant drop in GFR postoperatively. Postulated mechanisms include intraoperative hemodynamic changes, suboptimal renal perfusion during the anhepatic stage, and cyclosporine administration. We undertook a prospective double-blind study to investigate these factors, as well as to determine the protective effects of verapamil on perioperative renal function. Twenty-five patients with normal renal function undergoing OLT received either placebo (n = 13) or verapamil (n = 12) intraoperatively and for six weeks post-OLT. No CsA was administered until after reperfusion of the graft liver, and venovenous bypass (VVB) was utilized in all cases. Patients completing six weeks of the study experienced 61% and 48% decreases in GFR within the placebo and verapamil groups respectively. A significant decrease in GFR occurred in the placebo group between one and six weeks post-OLT, and a significant drop in GFR occurred in the verapamil group by one week post-OLT. Differences between the groups were not significant, however. Systemic, renal, and hepatic hemodynamics were similar at all times between groups, and renal hemodynamics and urine output were unchanged during VVB. We conclude that (1) perioperative factors do not contribute to renal dysfunction post-OLT when VVB is used; (2) VVB preserves renal hemodynamics during the anhepatic phase; (3) CsA is the most likely causative agent for post-OLT renal dysfunction; and (4) intraoperative verapamil serves no protective role, as administered in this study.     

Association of a novel regulatory polymorphism (-938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia

Bcl-2 plays a key role in the regulation of apoptosis. We investigated the role of a novel regulatory single-nucleotide polymorphism (-938C>A) in the inhibitory P2 BCL2 promoter in B-cell chronic lymphocytic leukemia (B-CLL). The -938C allele displayed significantly increased BCL2 promoter activity and binding of nuclear proteins compared with the A allele. Concomitantly, Bcl-2 protein expression in B cells from CLL patients carrying the -938 AA genotype was significantly increased compared with CC genotypes. Genotype distribution between 123 CLL patients (42 AA, 55 AC, 26 CC) and 120 genotyped healthy controls (36 AA, 63 AC, 21 CC) was not significantly different, suggesting that genotypes of this polymorphism do not increase the susceptibility for B-CLL. However, median time from first diagnosis to initiation of chemotherapy and median overall survival were significantly shorter in patients with -938AA genotype (38 and 199 months, respectively) compared with AC/CC genotypes (120 and 321 months, respectively; P = .008 and P = .003, respectively). Multivariable Cox regression identified the BCL2-938AA genotype as an independent prognostic factor for the time to first treatment (hazard ratio [HR] 1.9; P = .034) together with disease stage at diagnosis (HR 2.5; P = .004) and ZAP-70 status (HR 3.0; P = .001). The BCL2-938AA genotype is associated with increased Bcl-2 expression and a novel unfavorable genetic marker in patients with B-CLL.     

The effect of broadband and monochromatic stimuli on the photopic negative response of the electroretinogram in normal subjects and in open-angle glaucoma patients

The aim was to investigate the effects of monochromatic and broadband stimuli on the amplitude of the photopic negative response (PhNR) and to compare the sensitivities of these stimuli for the detection of ganglion cell damage in glaucoma patients. Forty-one healthy subjects were studied, along with 16 patients with open-angle glaucoma. Photopic electroretinograms (ERGs) were elicited with monochromatic red, amber, green, and broadband white stimuli of progressively brighter intensities in a blue background. Pattern ERGs were also recorded using a 0.8° checkerboard pattern on a 21.6° × 27.8° screen. In the photopic ERGs of the control subjects, the PhNR amplitude was significantly higher (P < 0.01) to red than to monochromatic amber, green, and broadband white stimuli of the same intensity. In glaucoma patients, the percentage of amplitude reduction was greater for the PhNR to red (68%, P < 0.001) than to the broadband stimulus (38%, P = 0.001). The PhNR to red monochromatic stimulus appeared to be a more sensitive parameter, with a larger area enclosed by the receiver-operating characteristic curve (0.97) than for the PhNR to broadband stimulus (0.76). Also, the PhNR to red stimulus showed a more significant correlation with the pattern ERG and the visual field defects (P < 0.05) than the PhNR elicited with broadband stimulus. These findings suggest that ganglion cell activity can be more efficiently evaluated with the PhNR elicited with a red than with a broadband stimulus. The PhNR thus appears to be a promising test for the diagnostics of the ganglion cell dysfunction.     

Sodium-glucose cotransporter 2 inhibitors' mechanisms of action in heart failure

Three major cardiovascular outcome trials(CVOTs) with a new class of antidiabetic drugs-sodium-glucose cotransporter 2(SGLT2) inhibitors(EMPAREG OUTCOME trial with empagliflozin, CANVAS Program with canagliflozin, DECLARE-TIMI 58 with dapagliflozin) unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk, which seems to be the most sensitive outcome of SGLT2 inhibition. No other CVOT to date has shown any significant benefit on heart failure events. Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure: Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status. Nevertheless, despite their possible wide clinical implications, there is much doubt about the mechanisms of action and a lot of questions to unravel, especially now when their benefits translated to nondiabetic patients, rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucoselowering and antiatherosclerotic-mediated effects and multiple other mechanisms, direct cardiac as well as systemic, are suggested to explain their early cardiorenal benefits. These are: Anti-inflammatory, antifibrotic, antioxidative, antiapoptotic properties, then renoprotective and hemodynamic effects, attenuation of glucotoxicity, reduction of uric acid levels and epicardial adipose tissue, modification of neurohumoral system and cardiac fuel energetics, sodiumhydrogen exchange inhibition. The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis. All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.     

The WHO diagnostic criteria for polycythemia vera—role of red cell mass versus hemoglobin/hematocrit level and morphology

Regarding diagnosis of polycythemia vera (PV), discussion persists about hemoglobin (Hb) and/or hematocrit (Hct) threshold values as surrogate markers for red cell mass (RCM) and the diagnostic impact of bone marrow (BM) morphology. We performed a retrospective study on 290 patients with PV (151 males, 139 females; median age 65 years) presenting with characteristic BM features (initial biopsies, centralized evaluation) and endogenous erythroid colony (EEC) formations. This cohort included (1) a group of 229 patients when following the 2008 versus 256 patients diagnosed according to the 2016 World Health Organization (WHO) guidelines, all presented with increased RCM; (2) masked PV patients with low Hb (n?=?143)/Hct (n?=?45) recruited from the 2008 WHO cohort; (3) a cohort of 17 PV patients with elevated diagnostic Hb/Hct levels but low RCM; and (4) nine PV patients with increased RCM, opposing low Hb/Hct values. All patients were treated according to current PV guidelines (phlebotomies 87%, hydroxyurea 79%, and acetylsalicylic acid 87%). Applying the 2016 WHO criteria significantly increased concordance between RCM and Hb values compared with the 2008 WHO criteria (90 vs. 43% in males and 83 vs. 64% in females). Further analysis of the WHO 2016 PV cohort revealed that increased RCM is associated with increased Hb/Hct (93.8/94.6%). Our study supports and extends the diagnostic impact of the 2016 revised WHO classification for PV by highlighting the importance of characteristic BM findings and implies that Hb/Hct threshold values may be used as surrogate markers for RCM measurements.     

Intravenous iron therapy restores functional iron deficiency induced by infliximab

Background and aimsInfliximab (IFX) and iron sucrose (FeS) are of high value in inflammatory bowel disease (IBD). We aimed to assess the relative role of both therapies in IBD related anaemia and their safety when used in combination.MethodsIBD patients with anaemia receiving a first series of FeS infusions in addition to IFX were prospectively followed. We investigated serum kinetics of erythropoietin (EPO), soluble transferrin receptors (sTFRs) and vascular endothelial growth factor (VEGF).ResultsData analysis included 87 patients of whom 49.4% achieved the target Hb level of 12.0 g/dL. IFX resulted in a significant increase of EPO and sTFR compared to baseline pre-IFX levels (p = 0.029 and p = 0.005 respectively) and after a 12-week combined FeS and IFX treatment, EPO and sTFR levels dropped significantly compared to pre-FeS levels (p < 0.001 for both). Infusion related adverse events were recorded in 2 IFX treated patients (2.3%, 0.7% of the infusions) and were mild. Disease activity and quality of life were not affected.ConclusionsIn anaemic IBD patients treated with IFX, combined administration of FeS is safe. Infliximab significantly increases serum EPO and sTFR levels resulting in an increased functional iron deficiency, which is restored after combined treatment with I.V. iron sucrose.