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Diagnostics (Basel, Switzerland) Jan 2023Acquired haemophilia A (AHA) is a rare bleeding disorder caused by inhibitory autoantibodies against coagulation factor VIII (FVIII). AHA is a disease that most commonly... (Review)
Review
Acquired haemophilia A (AHA) is a rare bleeding disorder caused by inhibitory autoantibodies against coagulation factor VIII (FVIII). AHA is a disease that most commonly affects the elderly but has also been observed in children and in the postpartum period. AHA is idiopathic in 50% of cases and is associated with autoimmune diseases, malignancies, and infections in the remaining 50%. Recently, cases of association between AHA, COVID-19 vaccination, and infection have been reported in the literature. For diagnoses, determining FVIII levels is crucial to distinguish the different causes of aPTT prolongation. Treatment of AHA is based on bypassing agents (recombinant factor VIIa, activated prothrombin complex concentrate) and porcine FVIII to control the bleeding and immunosuppressive therapy (corticosteroids, rituximab, cyclophosphamide) to suppress autoantibody production. It is important to start a prophylactic regimen to prevent further bleeding episodes until the inhibitor is negative. Recently, the series of cases reported in the literature suggest that emicizumab may provide effective and safe haemorrhage prophylaxis in the outpatient setting.
PubMed: 36766524
DOI: 10.3390/diagnostics13030420 -
Lancet (London, England) May 2023Chronic limb-threatening ischaemia is the severest manifestation of peripheral arterial disease and presents with ischaemic pain at rest or tissue loss (ulceration,... (Randomized Controlled Trial)
Randomized Controlled Trial
A vein bypass first versus a best endovascular treatment first revascularisation strategy for patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal revascularisation procedure to restore limb perfusion (BASIL-2):...
BACKGROUND
Chronic limb-threatening ischaemia is the severest manifestation of peripheral arterial disease and presents with ischaemic pain at rest or tissue loss (ulceration, gangrene, or both), or both. We compared the effectiveness of a vein bypass first with a best endovascular treatment first revascularisation strategy in terms of preventing major amputation and death in patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion.
METHODS
Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL)-2 was an open-label, pragmatic, multicentre, phase 3, randomised trial done at 41 vascular surgery units in the UK (n=39), Sweden (n=1), and Denmark (n=1). Eligible patients were those who presented to hospital-based vascular surgery units with chronic limb-threatening ischaemia due to atherosclerotic disease and who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. Participants were randomly assigned (1:1) to receive either vein bypass (vein bypass group) or best endovascular treatment (best endovascular treatment group) as their first revascularisation procedure through a secure online randomisation system. Participants were excluded if they had ischaemic pain or tissue loss considered not to be primarily due to atherosclerotic peripheral artery disease. Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug eluting stents. Participants were followed up for a minimum of 2 years. Data were collected locally at participating centres. In England, Wales, and Sweden, centralised databases were used to collect information on amputations and deaths. Data were analysed centrally at the Birmingham Clinical Trials Unit. The primary outcome was amputation-free survival defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population. Safety was assessed by monitoring serious adverse events up to 30-days after first revascularisation. The trial is registered with the ISRCTN registry, ISRCTN27728689.
FINDINGS
Between July 22, 2014, and Nov 30, 2020, 345 participants (65 [19%] women and 280 [81%] men; median age 72·5 years [62·7-79·3]) with chronic limb-threatening ischaemia were enrolled in the trial and randomly assigned: 172 (50%) to the vein bypass group and 173 (50%) to the best endovascular treatment group. Major amputation or death occurred in 108 (63%) of 172 patients in the vein bypass group and 92 (53%) of 173 patients in the best endovascular treatment group (adjusted hazard ratio [HR] 1·35 [95% CI 1·02-1·80]; p=0·037). 91 (53%) of 172 patients in the vein bypass group and 77 (45%) of 173 patients in the best endovascular treatment group died (adjusted HR 1·37 [95% CI 1·00-1·87]). In both groups the most common causes of morbidity and death, including that occurring within 30 days of their first revascularisation, were cardiovascular (61 deaths in the vein bypass group and 49 in the best endovascular treatment group) and respiratory events (25 deaths in the vein bypass group and 23 in the best endovascular treatment group; number of cardiovascular and respiratory deaths were not mutually exclusive).
INTERPRETATION
In the BASIL-2 trial, a best endovascular treatment first revascularisation strategy was associated with a better amputation-free survival, which was largely driven by fewer deaths in the best endovascular treatment group. These data suggest that more patients with chronic limb-threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion should be considered for a best endovascular treatment first revascularisation strategy.
FUNDING
UK National Institute of Health Research Health Technology Programme.
Topics: Male; Humans; Female; Aged; Chronic Limb-Threatening Ischemia; Ocimum basilicum; Ischemia; Angioplasty, Balloon, Coronary; Peripheral Arterial Disease; Risk Factors; Perfusion; Pain; Treatment Outcome
PubMed: 37116524
DOI: 10.1016/S0140-6736(23)00462-2 -
Medicina (Kaunas, Lithuania) Mar 2023Obesity is a chronic disease that impairs quality of life and leads to several comorbidities. When conservative therapies fail, bariatric surgical options such as... (Review)
Review
Obesity is a chronic disease that impairs quality of life and leads to several comorbidities. When conservative therapies fail, bariatric surgical options such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the most effective therapies to induce persistent weight loss. Over the last two decades, bariatric endoscopy has become a valid alternative to surgery in specific settings. Restrictive gastric procedures, such as intragastric balloons (IGBs) and endoscopic gastroplasty, have been shown to be effective in inducing weight loss compared to diet modifications alone. Endoscopic gastroplasty is usually superior to IGBs in maintaining weight loss in the long-term period, whereas IGBs have an established role as a bridge-to-surgery approach in severely obese patients. IGBs in a minority of patients could be poorly tolerated and require early removal. More recently, novel endoscopic systems have been developed with the combined purpose of inducing weight loss and improving metabolic conditions. Duodenal mucosal resurfacing demonstrated efficacy in this field in its early trials: significant reduction from baseline of HbA1c values and a modest reduction of body weight were observed. Other endoscopic malabsorptive have been developed but need more evidence. For example, a pivotal trial on duodenojejunal bypasses was stopped due to the high rate of severe adverse events (hepatic abscesses). Optimization of these more recent malabsorptive endoscopic procedures could expand the plethora of bariatric patients that could be treated with the intention of improving their metabolic conditions. Weight regain may occur in up to one third of patients after bariatric surgery. Different endoscopic procedures are currently performed after both RYGB and SG in order to modulate post-surgical anatomy. The application of argon plasma coagulation associated with endoscopic full-thickness suturing systems (APC-TORe) and Re-EndoSleeve have shown to be the most effective endoscopic treatments after RYGB and SG, respectively. Both procedures are usually well tolerated and have a very low risk of stricture. However, APC-TORe may sometimes require more than one session to obtain adequate final results. The aim of this review is to explore all the currently available primary and revisional endoscopic bariatric therapies focusing on their efficacy and safety and their potential application in clinical practice.
Topics: Humans; Obesity, Morbid; Quality of Life; Reoperation; Endoscopy; Gastric Bypass; Obesity; Treatment Outcome; Metabolic Diseases; Weight Loss; Retrospective Studies
PubMed: 36984637
DOI: 10.3390/medicina59030636 -
Circulation May 2021The failing heart is energy starved with impaired oxidation of long-chain fatty acids (LCFAs) at the level of reduced CPT1 (carnitine palmitoyltransferase 1) activity at...
BACKGROUND
The failing heart is energy starved with impaired oxidation of long-chain fatty acids (LCFAs) at the level of reduced CPT1 (carnitine palmitoyltransferase 1) activity at the outer mitochondrial membrane. Recent work shows elevated ketone oxidation in failing hearts as an alternate carbon source for oxidative ATP generation. We hypothesized that another short-chain carbon source, short-chain fatty acids (SCFAs) that bypass carnitine palmitoyltransferase 1, could similarly support energy production in failing hearts.
METHODS
Cardiac hypertrophy and dysfunction were induced in rats by transverse-aortic constriction (TAC). Fourteen weeks after TAC or sham operation, isolated hearts were perfused with either the 4 carbon, C-labeled ketone (D3-hydroxybutyrate) or the 4 carbon, C-labeled SCFA butyrate in the presence of glucose and the LCFA palmitate. Oxidation of ketone and SCFA was compared by in vitro C nuclear magnetic resonance spectroscopy, as was the capacity for short-chain carbon sources to compensate for impaired LCFA oxidation in the hypertrophic heart. Adaptive changes in enzyme expression and content for the distinct pathways of ketone and SCFA oxidation were examined in both failing rat and human hearts.
RESULTS
TAC produced pathological hypertrophy and increased the fractional contributions of ketone to acetyl coenzyme-A production in the tricarboxylic acid cycle (0.60±0.02 sham ketone versus 0.70±0.02 TAC ketone; <0.05). However, butyrate oxidation in failing hearts was 15% greater (0.803±0.020 TAC SCFA) than ketone oxidation. SCFA was also more readily oxidized than ketone in sham hearts by 15% (0.693±0.020 sham SCFA). Despite greater SFCA oxidation, TAC did not change short-chain acyl coenzyme-A dehydrogenase content. However, failing hearts of humans and the rat model both contain significant increases in acyl coenzyme-A synthetase medium-chain 3 enzyme gene expression and protein content. The increased oxidation of SCFA and ketones occurred at the expense of LCFA oxidation, with LCFA contributing less to acetyl coenzyme-A production in failing hearts perfused with SCFA (0.190±0.012 TAC SCFA versus 0.3163±0.0360 TAC ketone).
CONCLUSIONS
SCFAs are more readily oxidized than ketones in failing hearts, despite both bypassing reduced CPT1 activity and represent an unexplored carbon source for energy production in failing hearts.
Topics: Animals; Disease Models, Animal; Fatty Acids, Volatile; Heart Failure; Humans; Ketones; Male; Oxidation-Reduction; Rats; Rats, Sprague-Dawley
PubMed: 33601938
DOI: 10.1161/CIRCULATIONAHA.120.052671 -
Molecular Cell Jan 2023Endogenous and exogenous agents generate DNA-protein crosslinks (DPCs), whose replication-dependent degradation by the SPRTN protease suppresses aging and liver cancer....
Endogenous and exogenous agents generate DNA-protein crosslinks (DPCs), whose replication-dependent degradation by the SPRTN protease suppresses aging and liver cancer. SPRTN is activated after the replicative CMG helicase bypasses a DPC and polymerase extends the nascent strand to the adduct. Here, we identify a role for the 5'-to-3' helicase FANCJ in DPC repair. In addition to supporting CMG bypass, FANCJ is essential for SPRTN activation. FANCJ binds ssDNA downstream of the DPC and uses its ATPase activity to unfold the protein adduct, which exposes the underlying DNA and enables cleavage of the adduct. FANCJ-dependent DPC unfolding is also essential for translesion DNA synthesis past DPCs that cannot be degraded. In summary, our results show that helicase-mediated protein unfolding enables multiple events in DPC repair.
Topics: DNA; DNA Damage; DNA Helicases; DNA Repair; DNA Replication; DNA-Binding Proteins; Protein Unfolding
PubMed: 36608669
DOI: 10.1016/j.molcel.2022.12.005 -
Drugs Oct 2023Ovarian cancer is the leading cause of gynecological cancer death. Improved understanding of the biologic pathways and introduction of poly (ADP-ribose) polymerase... (Review)
Review
Ovarian cancer is the leading cause of gynecological cancer death. Improved understanding of the biologic pathways and introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) during the last decade have changed the treatment landscape. This has improved outcomes, but unfortunately half the women with ovarian cancer still succumb to the disease within 5 years of diagnosis. Pathways of resistance to PARPi and chemotherapy have been studied extensively, but there is an unmet need to overcome treatment failure and improve outcome. Major mechanisms of PARPi resistance include restoration of homologous recombination repair activity, alteration of PARP function, stabilization of the replication fork, drug efflux, and activation of alternate pathways. These resistant mechanisms can be targeted to sensitize the resistant ovarian cancer cells either by rechallenging with PARPi, overcoming resistance mechanism or bypassing resistance pathways. Augmenting the PARPi activity by combining it with other targets in the DNA damage response pathway, antiangiogenic agents and immune checkpoint inhibitors can potentially overcome the resistance mechanisms. Methods to bypass resistance include targeting non-cross-resistant pathways acting independent of homologous recombination repair (HRR), modulating tumour microenvironment, and enhancing drug delivery systems such as antibody drug conjugates. In this review, we will discuss the first-line management of ovarian cancer, resistance mechanisms and potential strategies to overcome these.
Topics: Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Drug Resistance, Neoplasm; Ovarian Neoplasms; DNA Repair; Recombinational DNA Repair; Tumor Microenvironment
PubMed: 37737434
DOI: 10.1007/s40265-023-01934-0 -
Biophysical Journal Dec 2021Loop extrusion convincingly describes how certain structural maintenance of chromosome (SMC) proteins mediate the formation of large DNA loops. Yet most of the existing...
Loop extrusion convincingly describes how certain structural maintenance of chromosome (SMC) proteins mediate the formation of large DNA loops. Yet most of the existing computational models cannot reconcile recent in vitro observations showing that condensins can traverse each other, bypass large roadblocks, and perform steps longer than their own size. To fill this gap, we propose a three-dimensional (3D) "trans-grabbing" model for loop extrusion, which not only reproduces the experimental features of loop extrusion by one SMC complex but also predicts the formation of so-called Z-loops via the interaction of two or more SMCs extruding along the same DNA substrate. By performing molecular dynamics simulations of this model, we discover that the experimentally observed asymmetry in the different types of Z-loops is a natural consequence of the DNA tethering in vitro. Intriguingly, our model predicts this bias to disappear in the absence of tethering and a third type of Z-loop, which has not yet been identified in experiments, to appear. Our model naturally explains roadblock bypassing and the appearance of steps larger than the SMC size as a consequence of non-contiguous DNA grabbing. Finally, this study is the first, to our knowledge, to address how Z-loops and bypassing might occur in a way that is broadly consistent with existing cis-only 1D loop extrusion models.
Topics: Cell Cycle Proteins; Chromosomes; DNA; Molecular Dynamics Simulation
PubMed: 34793758
DOI: 10.1016/j.bpj.2021.11.015 -
Endocrine Journal Apr 2022Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has...
Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.
Topics: Adrenalectomy; Aldosterone; Humans; Hyperaldosteronism; Hypertension; Japan; Mineralocorticoid Receptor Antagonists; Renin
PubMed: 35418526
DOI: 10.1507/endocrj.EJ21-0508