Tyrosinase, could it be a missing link in ochronosis in alkaptonuria?

The hypothesis that is proposed is that tyrosinase, an enzyme widely found within the human body is implicated in the ochronosis that occurs in alkaptonuria; an autosomal recessive condition first used by Archibald Garrod to describe the theory of “Inborn Errors of Metabolism.” The disease results from the absence of a single enzyme in the liver that breaks down homogentisic acid; this molecule becomes systemically elevated in sufferers. The condition is characterised by a clinical triad of symptoms; homogentisic aciduria from birth, ochronosis (darkening) of collagenous tissues (from ∼30years of age) and ochronotic osteoarthropathy in weight bearing joints due to long term ochronosis in them (from ∼40years of age). Tyrosinase, a polyphenol oxidase has been shown in many species to contribute to the darkening of tissues in many organisms; including humans in the production of melanin. Tyrosinase under the right conditions shows alterations in its substrate specificity and may contribute to the darkening seen in AKU where it moves away from polymerising tyrosine but also homogentisic acid, the causative molecule in alkaptonuria, that is present in excess

Ultrasound entropy may be a new non-invasive measure of pre-clinical vascular damage in young hypertensive patients

BACKGROUND: The identification of pre-clinical microvascular damage in hypertension by non-invasive techniques has proved frustrating for clinicians. This proof of concept study investigated whether entropy, a novel summary measure for characterizing blood velocity waveforms, is altered in participants with hypertension and may therefore be useful in risk stratification. METHODS: Doppler ultrasound waveforms were obtained from the carotid and retrobulbar circulation in 42 participants with uncomplicated grade 1 hypertension (mean systolic/diastolic blood pressure (BP) 142/92 mmHg), and 26 healthy controls (mean systolic/diastolic BP 116/69 mmHg). Mean wavelet entropy was derived from flow-velocity data and compared with traditional haemodynamic measures of microvascular function, namely the resistive and pulsatility indices. RESULTS: Entropy, was significantly higher in control participants in the central retinal artery (CRA) (differential mean 0.11 (standard error 0.05 cms(−1)), CI 0.009 to 0.219, p 0.017) and ophthalmic artery (0.12 (0.05), CI 0.004 to 0.215, p 0.04). In comparison, the resistive index (0.12 (0.05), CI 0.005 to 0.226, p 0.029) and pulsatility index (0.96 (0.38), CI 0.19 to 1.72, p 0.015) showed significant differences between groups in the CRA alone. Regression analysis indicated that entropy was significantly influenced by age and systolic blood pressure (r values 0.4-0.6). None of the measures were significantly altered in the larger conduit vessel. CONCLUSION: This is the first application of entropy to human blood velocity waveform analysis and shows that this new technique has the ability to discriminate health from early hypertensive disease, thereby promoting the early identification of cardiovascular disease in a young hypertensive population. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov, NCT0104742

Statin therapy does not significantly alter microvascular function in uncomplicated hypertension

Objective Young patients with uncomplicated hypertension are frequently exempt from statin therapy as they generally fall below current treatment thresholds. This study examined whether there may be evidence of improved microvascular function in young patients with grade 1 hypertension after 12 weeks of statin therapy. Methods This was a randomized double-blind placebo-controlled crossover study in which 42 statin-naïve participants with grade 1 hypertension (mean systolic/diastolic blood pressure 142/92 mmHg) were randomized to receive either simvastatin 40 mg or a placebo for 12 weeks, followed by a 4-week washout period, after which the arms crossed for a further 12 weeks. Measures of vascular function were recorded at the beginning and end of each study period equating to four measures in total. The brachial artery was studied by flow-mediated dilatation (FMD) together with the resistive and pulsatility indices and mean velocity of flow. Results Statin therapy did not significantly alter the change in FMD seen in the brachial artery [standardized differential mean = 0.02 (0.23), confidence interval (CI) = −0.45 to 0.48, p = 0.932]. No significant changes were seen in the brachial artery mean velocity (CI = −9.68 to 11.51, p = 0.861), resistive index (CI = −0.11 to 0.12, p = 0.903), or pulsatility index (CI = −5.82 to 4.91, p = 0.864). Conclusion This study did not demonstrate any significant changes in established measures of microvascular function after treatment with a statin in a young hypertensive population with no antecedent cardiovascular disease. This may indicate that either the intervention was insufficiently vasoactive to produce a clinically detectable improvement in vascular function, or that the means used to assess the microvasculature were insufficiently sensitive to detect what may have been quite minor changes. </jats:sec

Outcome study of the Pipeline Vantage Embolization Device (second version) in unruptured (and ruptured) aneurysms (PEDVU(R) study)

Background The Pipeline Vantage Embolization Device (PEDV) is the fourth-generation pipeline flow diverter for intracranial aneurysm treatment. There are no outcome studies for the second PEDV version. We aimed to evaluate safety and efficacy outcomes. Primary and secondary objectives were to determine outcomes for unruptured and ruptured cohorts, respectively.Methods In this multicenter retrospective and prospective study, we analyzed outcome data from eight centers using core laboratory assessments. We determined 30-day and ≥3-month mortality and morbidity rates, and 6- and 18-month radiographic aneurysm occlusion rates for procedures performed during the period July 2021–March 2023.Results We included 121 consecutive patients with 131 aneurysms. The adequate occlusion rate for the unruptured cohort at short-term and medium-term follow up, and also for the ruptured cohort at short-term follow up, was &gt;90%. Two aneurysms (1.5%) underwent retreatment. When mortality attributed to a palliative case in the unruptured cohort, or subarachnoid hemorrhage in the ruptured cohort, was excluded then the overall major adverse event rate in respective cohorts was 7.5% and 23.5%, with 0% mortality rates for each. When all event causes were included on an intention-to-treat basis, the major adverse event rates in respective cohorts were 8.3% and 40.9%, with 0.9% and 22.7% mortality rates.Conclusions For unruptured aneurysm treatment, the second PEDV version appears to have a superior efficacy and similar safety profile to previous-generation PEDs. These are acceptable outcomes in this pragmatic and non-industry-sponsored study. Analysis of ruptured aneurysm outcomes is limited by cohort size. Further prospective studies, particularly for ruptured aneurysms, are needed

T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant.

To access publisher's full text version of this article click on the hyperlink belowRelapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features1-3. When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells4. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease5. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens6. We therefore isolated a high-affinity Wilms' Tumor Antigen 1-specific TCR (TCRC4) from HLA-A2+ normal donor repertoires, inserted TCRC4 into Epstein-Bar virus-specific donor CD8+ T cells (TTCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival7,8, and infused these cells prophylactically post-HCT into 12 patients ( NCT01640301 ). Relapse-free survival was 100% at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival (P = 0.002). TTCR-C4 maintained TCRC4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.Juno Therapeutics Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Research Center Damon Runyon Guillot Family ZachAttacksLeukemia Foundatio