Objective
To test whether long‐term antihypertensive treatment with metoprolol succinate (a β1‐adrenoceptor blocker) or olmesartan medoxomil (an angiotensin II AT1‐receptor blocker) reverses ...microvascular dysfunction in hypertensive patients.
Methods
This study included 44 hypertensive outpatients and 20 age and sex‐matched healthy controls. We used skin capillaroscopy to measure capillary density and recruitment at rest and during PORH. Endothelium‐dependent vasodilation of skin microcirculation was evaluated with a LDPM system in combination with ACh iontophoresis, PORH, and LTH.
Results
Pretreatment capillary density in hypertensive patients was significantly reduced compared with controls (71.3 ± 1.5 vs. 80.6 ± 1.8 cap/mm2; p < 0.001), as was PORH (71.7 ± 1.5 vs. 79.5 ± 2.6 cap/mm2; p < 0.05). After treatment for six months, capillary density increased to 75.4 ± 1.1 cap/mm2 (p < 0.01) at rest and 76.8 ± 1.1 cap/mm2 during PORH. During LTH, CVC in perfusion units (PU)/mmHg was similar in patients (1.71 1.31–2.12) and controls (1.60 1.12–1.91) and increased significantly (1.82 1.30–2.20) after treatment. Maximal CVC during PORH was reduced in hypertensive patients (0.30 0.22–0.39) compared to controls (0.39 0.31–0.49, p < 0.001) and increased (0.41 0.29–0.51, p < 0.001) after treatment.
Conclusions
Capillary rarefaction and microvascular endothelial dysfunction in hypertensive patients responded favorably to long‐term pharmacological treatment.
Despite the noteworthy advancements and the introduction of new technologies in diagnostic tools for cardiovascular disorders, the electrocardiogram (ECG) remains a reliable, easily accessible, and ...affordable tool to use. In addition to its crucial role in cardiac emergencies, ECG can be considered a very useful ancillary tool for the diagnosis of many non-cardiac diseases as well. In this narrative review, we aimed to explore the potential contributions of ECG for the diagnosis of non-cardiac diseases such as stroke, migraine, pancreatitis, Kounis syndrome, hypothermia, esophageal disorders, pulmonary embolism, pulmonary diseases, electrolyte disturbances, anemia, coronavirus disease 2019, different intoxications and pregnancy.
Background: Early recognition of heart disease in diabetics is a highly desirable goal, and diastolic dysfunction, one of its earliest manifestations, can be readily assessed by tissue Doppler ...imaging. We tested in normotensive diabetics without signs of coronary artery disease whether tissue Doppler imaging would improve the diagnosis of diastolic dysfunction beyond classical criteria and identify patients already presenting impaired cardiac performance. Methods: We studied 79 patients (56 males, 55 type‐2 diabetes mellitus) who underwent Doppler echocardiography, and exercise testing. Diastolic dysfunction was diagnosed either based on European Study Group on Diastolic Heart Failure guidelines or by tissue Doppler imaging provided that both of the following criteria were met: Em/Am ratio <1; and Em < 8.5 cm/sec. Results: Tissue Doppler imaging identified diastolic dysfunction in 26.6% of diabetics, while classical criteria did so in 40.5% of the cases. The group identified by classical criteria did not differ significantly from patients without diastolic dysfunction, while in the group identified by Tissue Doppler imaging, significant differences were highlighted, including worse exercise tolerance and higher left ventricular mass index. Moreover, in multiple regression analysis, Em myocardial velocity and body mass index were the only variables independently related to exercise tolerance. Conclusion: Differently from classical criteria based on pulsed Doppler, Tissue Doppler imaging identifies a group of asymptomatic normotensive diabetics with diastolic dysfunction and reduced exercise tolerance. Confirmation of the prognostic importance of our findings could justify the use of Tissue Doppler imaging for diastolic function assessment in diabetics with otherwise healthy hearts.
Background Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options. Objective We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE. ...Methods Patients (18-50 years) with proton pump inhibitor–resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months. The primary end point was the responder rate for a greater than 75% decrease in peak eosinophil counts at week 12. Efficacy was to be declared if the lower 90% confidence limit for the proportion of responders on QAX576 was 35% or greater. Secondary end points included changes in esophageal eosinophil counts, symptoms assessed by questionnaire scores, and quantification of a series of biomarkers. Results Twenty-three patients completed the study up to week 12, and 18 continued to the end of the study. For the proximal and distal esophageal biopsies combined, the responder rate was 12.5% (90% confidence limit, 1% to 43%) with placebo, compared to 40.0% (90% confidence limit, 22% to 61%) with QAX576. Although the primary end point was not met, the mean esophageal eosinophil count decreased by 60% with QAX576 versus an increase of 23% with placebo ( P = .004), and the decrease was sustained up to 6 months. There was a trend for improved symptoms, particularly dysphagia. QAX576 improved expression of EoE-relevant esophageal transcripts, including eotaxin-3, periostin, and markers of mast cells and barrier function, for up to 6 months after treatment. QAX576 was well tolerated. Conclusions QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease–related transcripts in adults with EoE in a sustained manner.
To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in
, a tRNA processing enzyme, and to ...explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.
We studied nine patients with biallelic mutations in
and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).
We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.
Mutations of
lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may ...represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5.
We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear beta-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF).
Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and between-modules for next-generation combinatorial therapeutics and improved mouse models.
Human immunodeficiency virus type 1 (HIV-1) non-B subtype infections occurred in Belgium since the 1980s, mainly amongst migrants and heterosexuals, whereas subtype B predominated in ...men-having-sex-with-men (MSM). In the last decade, the diagnosis of F1 sub-subtype in particular has increased substantially, which prompted us to perform a detailed reconstruction of its epidemiological history. To this purpose, the Belgian AIDS Reference Laboratories collected HIV-1
sequences from all sub-subtype F1-infected patients for whom genotypic drug resistance testing was requested as part of routine clinical follow-up. This data was complemented with HIV-1
sequences from countries with a high burden of F1 infections or a potential role in the global origin of sub-subtype F1. The molecular epidemiology of the Belgian subtype F1 epidemic was investigated using Bayesian phylogenetic inference and transmission dynamics were characterized based on birth-death models. F1 sequences were retained from 297 patients diagnosed and linked to care in Belgium between 1988 and 2015. Phylogenetic inference indicated that among the 297 Belgian F1 sequences, 191 belonged to a monophyletic group that mainly contained sequences from people likely infected in Belgium (OR 26.67, 95% CI 9.59-74.15), diagnosed in Flanders (OR 7.28, 95% CI 4.23-12.53), diagnosed at a recent stage of infection (OR 7.19, 95% CI 2.88-17.95) or declared to be MSM (OR 34.8, 95% CI 16.0-75.6). Together with a Spanish clade, this Belgian clade was embedded in the genetic diversity of Brazilian subtype F1 strains and most probably emerged after one or only a few migration events from Brazil to the European continent before 2002. The origin of the Belgian outbreak was dated back to 2002 (95% higher posterior density 2000-2004) and birth-death models suggested that its extensive growth had been controlled (
< 1) by 2012, coinciding with a time period where delay in antiretroviral treatment initiation substantially declined. In conclusion, phylogenetic reconstruction of the Belgian HIV-1 sub-subtype F1 epidemic illustrates the introduction and substantial dissemination of viral strains in a geographically restricted risk group that was most likely controlled by effective treatment as prevention.
Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing ...to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates and exhibit diverse alterations in expression of pRb, p53, p14(Arf), and p16(INK4a) proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100beta protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool.
Background With the expanding eligibility for endovascular therapy (EVT) of patients presenting in the late window (6–24 hours after last known well), we aimed to derive a score to predict favorable ...outcomes associated with EVT versus best medical management. Methods and Results A multinational observational cohort of patients from the CLEAR (Computed Tomography for Late Endovascular Reperfusion) study with proximal intracranial occlusion (2014–2022) was queried (n=58 sites). Logistic regression analyses were used to derive a 9‐point score for predicting good functional outcome (modified Rankin Scale score 0–2 or return to premorbid modified Rankin Scale score) at 90 days, with sensitivity analyses for prespecified subgroups conducted using bootstrapped random forest regressions. Secondary outcomes included 90‐day functional independence (modified Rankin Scale score 0–2), poor outcome (modified Rankin Scale score 5–6), and 90‐day survival. The score was externally validated with a single‐center cohort (2014–2023). Of the 3231 included patients (n=2499 EVT), a 9‐point score included age, early computed tomography ischemic changes, and stroke severity, with higher points indicating a higher probability of a good functional outcome. The areas under the curve for the primary outcome among EVT and best medical management subgroups were 0.72 (95% CI, 0.70–0.74) and 0.87 (95% CI, 0.84–0.90), respectively, with similar performance in the external validation cohort (area under the curve, 0.71 95% CI, 0.66–0.76). There was a significant interaction between the score and EVT for good functional outcome, functional independence, and poor outcome (all P interaction <0.001), with greater benefit favoring patients with lower and midrange scores. Conclusions This score is a pragmatic tool that can estimate the probability of a good outcome with EVT in the late window. Registration URL: https://www.Clinicaltrials.gov ; Unique identifier: NCT04096248.
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