Introduction: Recently, right bundle branch block (RBBB) was proved to be an important predictor of mortality in heart failure (HF) patients as much as left bundle branch block (LBBB). We ...characterized endocardial right ventricular (RV) and left ventricular (LV) activation sequence in HF patients with RBBB using a three‐dimensional non‐fluoroscopic electroanatomic contact mapping system (3D‐Map) in order to provide the electrophysiological background to understand whether these patients can benefit from cardiac resynchronization therapy (CRT).
Methods and Results: Using 3D‐Map, RV and LV activation sequences were studied in 100 consecutive HF patients. Six of these patients presented with RBBB QRS morphology. The maps of these patients were analyzed and compared post hoc with those of the other 94 HF patients presenting with LBBB. Clinical and hemodynamic profile was significantly worse in RBBB group compared to LBBB. Patients with RBBB showed significantly longer time to RV breakthrough (P < 0.001), longer activation times of RV anterior and lateral regions (P < 0.001), and longer total RV endocardial activation time (P < 0.02) compared to patients with LBBB. Time to LV breakthrough was significantly shorter in patients with RBBB (P < 0.001), while total and regional LV endocardial activation times were not significantly different between the two groups.
Conclusions: Degree of LV activation delay is similar between HF patients with LBBB and RBBB. Moreover, patients with RBBB have larger right‐sided conduction delay compared to patients with LBBB. The assessment of these electrical abnormalities is important to understand the rationale for delivering CRT in HF patients with RBBB.
Human lung carcinomas express Fas ligand Niehans, G A; Brunner, T; Frizelle, S P ...
Cancer research (Chicago, Ill.),
03/1997, Letnik:
57, Številka:
6
Journal Article
Recenzirano
To reach a clinically detectable size, neoplasms must be able to suppress or evade a host immune response. Activated T cells may enter apoptosis in the presence of Fas ligand (FasL) (1), and tissue ...expression of FasL has been shown to contribute to immune privilege in the eye and testis (2, 3). We have demonstrated that all human lung carcinoma cell lines tested (16 of 16) express a Mr 38,000 protein consistent with FasL by immunoblotting, whereas the majority of resected tumors (23 of 28) show positive staining for FasL by immunohistochemistry. DNA sequencing of reverse transcription-PCR products from lung cancer cells and resected lung tumors confirms the presence of human FasL mRNA in these neoplastic tissues. Furthermore, lung carcinoma cells are capable of killing a Fas-sensitive human T cell line (Jurkat) in coculture experiments; this killing was inhibited by a recombinant form of the soluble portion of the Fas receptor (FasFc). FasL expression by neoplastic cells represents a potential mechanism for peripheral deletion of tumor-reactive T-cell clones.
Low rectal cancers (<5 cm from the anal verge), compared with all others, have greater positive resection margin rates, attributed to mesorectal tapering and higher perforation risk. The aim of this ...study was to assess positive resection margin prediction by using magnetic resonance imaging staging.
The following features were analyzed by using preoperative magnetic resonance imaging from 101 consecutive patients with low rectal tumors: tumor location (posterior/anterior) and magnetic resonance stage (Stage 1-2, tumor within the intersphincteric plane; Stage 3-4 tumor extending into the intersphincteric plane). Magnetic resonance imaging tumor regression grade was measured where posttreatment magnetic resonance imaging was available and compared with histopathologic findings.
Seventy of 101 patients had abdominoperineal excisions, and 31 of 101 had low anterior resections. Using logistic regression, positive resection margin odds were higher for magnetic resonance Stages 3 to 4 than Stages 1 to 2 by a factor of 17.7 (P < 0.001), and positive resection margin odds were higher by a factor of 2.8 for anterior vs. posterior tumors (P = 0.026). Magnetic resonance imaging tumor regression grade strongly predicted for positive resection margins; 11 of 15 patients with little treatment response had positive resection margins, compared with 2 of 15 with >50 percent complete treatment response on magnetic resonance imaging (P < 0.001).
Significant magnetic resonance imaging positive resection margin predictors are tumor into or beyond the intersphincteric plane and magnetic resonance imaging tumor regression grade.
Background
Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (
AIRE
) gene mutations and characterized by three major ...manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison’s disease (AD).
Methods
Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years.
AIRE
mutations were determined.
Results
The prevalence of APS-1 was 2.6 cases/million (range 0.5–17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The
AIRE
mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases.
Conclusions
In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different
AIRE
gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.
It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock.
To determine whether the combination of vitamin C, ...hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.
Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019.
Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days.
The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality.
Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years SD, 15.0; 133 men 63%). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range IQR, 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported.
In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.
ClinicalTrials.gov Identifier: NCT03333278.
Endocrine complications have been described in patients affected by RASopathies but no systematic assessment has been reported. In this study, we investigate the prevalence of endocrine disorders in ...a consecutive unselected cohort of patients with RASopathies.
72 patients with a genetically confirmed RASopathy (Noonan syndrome NS, N=53; 29 LEOPARD syndrome LS, N=2; cardiofaciocutaneous syndrome CFCS, N=14; subjects showing co-occurring pathogenic variants in
and
, N=3) and an age- and sex-matched healthy controls were included in the study. Endocrine system involvement was investigated by assessing the thyroid function, pubertal development, auxological parameters, adrenal function and bone metabolism.
Short stature was detected in 40% and 64% of the NS and CFCS subcohorts, respectively. Patients showed lower Z-scores at DXA than controls (p<0.05) when considering the entire case load and both NS and CFCS groups. Vitamin D and Calcitonin levels were significantly lower (p< 0.01), Parathormone levels significantly higher (p<0.05) in patients compared to the control group (p<0.05). Patients with lower BMD showed reduced physical activity and joint pain. Finally, anti-TPO antibody levels were significantly higher in patients than in controls when considering the entire case load and both NS and CFCS groups.
The collected data demonstrate a high prevalence of thyroid autoimmunity, confirming an increased risk to develop autoimmune disorders both in NS and CFCS. Reduced BMD, probably associated to reduced physical activity and inflammatory cytokines, also occurs. These findings are expected to have implications for the follow-up and prevention of osteopenia/osteoporosis in both NS and CFCS.
Tellurium compounds have shown several biological properties and recently the leishmanicidal effect of one organotellurane was demonstrated. These findings led us to test the effect of the ...organotellurium compound RF07 on Leishmania (Leishmania) chagasi, the agent of visceral leishmaniasis in Latin America. In vitro assays were performed in L. (L.) chagasi-infected bone marrow derived macrophages treated with different concentrations of RF07. In in vivo experiments Golden hamsters were infected with L. (L.) chagasi and injected intraperitoneally with RF07 whereas control animals received either Glucantime or PBS. The effect of RF07 on cathepsin B activity of L. (L.) chagasi amastigotes was assayed spectrofluorometrically using fluorogenic substrates. The main findings were: 1) RF07 showed significant leishmanicidal activity against intracellular parasites at submicromolar concentrations (IC50 of 529.7±26.5 nM), and the drug displayed 10-fold less toxicity to macrophages (CC50 of 5,426±272.8 nM); 2) kinetics assays showed an increasing leishmanicidal action of RF07 at longer periods of treatment; 3) one month after intraperitoneal injection of RF07 L. (L.) chagasi-infected hamsters showed a reduction of 99.6% of parasite burden when compared to controls that received PBS; 4) RF07 inhibited the cathepsin B activity of L. (L.) chagasi amastigotes. The present results demonstrated that the tellurium compound RF07 is able to destroy L. (L.) chagasi in vitro and in vivo at concentrations that are non toxic to the host. We believe these findings support further study of the potential of RF07 as a possible alternative for the chemotherapy of visceral leishmaniasis.
Background:
Autoantibodies to tryptophan hydroxylase (TPHAbs) directed against serotonin-producing enterochromaffin cells (EC) have been reported in autoimmune-polyendocrine-syndrome type 1 (APS-1) ...patients with gastrointestinal dysfunction (GID). Serotonin plays a critical role in enteric function and its peripheral blood levels reflect serotonin release from the gastrointestinal tract.
Aims:
We test the hypothesis that TPHAbs mark a distinct autoimmune component of APS-1 characterized by an autoimmune attack toward EC, which results in clinical GID.
Methods:
TPHAbs were measured in 64 APS-1 patients. Endoscopy with gastric (antrum/body) and duodenal biopsy was carried in 16 TPHAbs+ patients (8 with and 8 without GID) and in 2 TPHAbs− patients (without GID). Immunohistochemistry of biopsy specimens was carried out using antibodies to serotonin, chromogranin-A, CD3, CD4, CD8, and CD20. Serotonin serum levels were measured in TPHAbs+ and TPHAbs− patients who had endoscopy.
Results:
Thirty-seven of 64 patients were TPHAbs+ (11/12 with GID and 26/52 without GID; P < .001). Gastric and duodenal biopsies in all 8 TPHAb+ patients with GID showed lymphocytic infiltration with increased CD3+CD8+ intraepithelial lymphocytes and absence of EC. Furthermore, mean serotonin serum levels were below the normal range in TPHAb+ patients with GID (P < .01). In 8 TPHAb+ patients without GID gastric and duodenal biopsies showed different grades of inflammatory infiltration and reduced number of EC. Mean serotonin serum levels were near the lower limit of the normal range. In all TPHAbs+ patients the biopsies showed a reduced number of chromogranin-A positive cells consistent with enteroendocrine cells depletion. TPHAbs− patients without GID showed normal gastrointestinal mucosa and serotonin serum levels.
Conclusions:
TPHAbs appear to be markers of a distinct autoimmune component of APS-1. Progressive involvement of the gastrointestinal EC leads to the transition from preclinical to clinical disease, characterized by GID and reduced serotonin serum levels.
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