scholarly journals Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Almudena Sacristan-Reviriego ◽  
Hoang Mai Le ◽  
Michalis Georgiou ◽  
Isabelle Meunier ◽  
Beatrice Bocquet ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Disease Onset ◽  
Clinical History ◽  
Hypomorphic Allele ◽  
Functional Assays ◽  
Rich Domain ◽  
History Of ◽  
Functional Analyses ◽  
Retinal Cgmp Phosphodiesterase

Abstract Disease-causing sequence variants in the highly polymorphic AIPL1 gene are associated with a broad spectrum of inherited retinal diseases ranging from severe autosomal recessive Leber congenital amaurosis to later onset retinitis pigmentosa. AIPL1 is a photoreceptor-specific co-chaperone that interacts with HSP90 to facilitate the stable assembly of retinal cGMP phosphodiesterase, PDE6. In this report, we establish unequivocal correlations between patient clinical phenotypes and in vitro functional assays of uncharacterized AIPL1 variants. We confirm that missense and nonsense variants in the FKBP-like and tetratricopeptide repeat domains of AIPL1 lead to the loss of both HSP90 interaction and PDE6 activity, confirming these variants cause LCA. In contrast, we report the association of p.G122R with milder forms of retinal degeneration, and show that while p.G122R had no effect on HSP90 binding, the modulation of PDE6 cGMP levels was impaired. The clinical history of these patients together with our functional assays suggest that the p.G122R variant is a rare hypomorphic allele with a later disease onset, amenable to therapeutic intervention. Finally, we report the primate-specific proline-rich domain to be dispensable for both HSP90 interaction and PDE6 activity. We conclude that variants investigated in this domain do not cause disease, with the exception of p.A352_P355del associated with autosomal dominant cone-rod dystrophy.

Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo [see comments]

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 1965-1971 ◽  
Author(s):  
R Landolfi ◽  
G Ciabattoni ◽  
P Patrignani ◽  
MA Castellana ◽  
E Pogliani ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Clinical History ◽  
Current Treatment ◽  
Lipoxygenase Pathway ◽  
Binding Characteristics ◽  
History Of ◽  
Thrombotic Complications ◽  
Excretion Rates

Abstract Increased thromboxane (TX) production and modified aspirin sensitivity has been detected in vitro in platelets isolated from patients with polycythemia vera. To verify the relevance of these capacity-related measurements to the actual rate of TXA2 biosynthesis in vivo and its suppression by oral aspirin, we have investigated the urinary excretion of major enzymatic metabolites of TXB2 in 17 patients with polycythemia vera and 23 gender- and age-matched controls. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were measured by previously validated radioimmunoassays. In addition, urinary immunoreactive leukotriene (LT) E4 was measured to explore the 5-lipoxygenase pathway of arachidonate metabolism. Polycythemic patients had significantly (P < .001) higher excretion rates of both 11-dehydro-TXB2 (1,033 +/- 1,050 v 117 +/- 45 pmol/mmol creatinine; mean +/- SD) and 2,3-dinor-TXB2 (725 +/- 676 v 82 +/- 43 pmol/mmol creatinine) than controls. In contrast, urinary LTE4 was not significantly different. Enhanced metabolite excretion did not correlate with the platelet count or with the hematocrit value, and was not related to the current treatment or to a clinical history of thrombotic complications. Platelet TX receptor studies did not show any significant changes in the binding characteristics of two different ligands. A platelet-selective regimen of aspirin therapy (50 mg/d for 7 to 14 days) was associated with greater than 80% suppression in metabolite excretion in nine patients. These results are consistent with abnormal stimuli operating in polycythemia vera to induce a selective enhancement in the platelet biosynthesis of TXA2 without changes in receptor binding. This in vivo abnormality in platelet biochemistry can be largely suppressed by low doses of aspirin.

scholarly journals Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo [see comments]

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 1965-1971 ◽  
Author(s):  
R Landolfi ◽  
G Ciabattoni ◽  
P Patrignani ◽  
MA Castellana ◽  
E Pogliani ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Clinical History ◽  
Current Treatment ◽  
Lipoxygenase Pathway ◽  
Binding Characteristics ◽  
History Of ◽  
Thrombotic Complications ◽  
Excretion Rates

Increased thromboxane (TX) production and modified aspirin sensitivity has been detected in vitro in platelets isolated from patients with polycythemia vera. To verify the relevance of these capacity-related measurements to the actual rate of TXA2 biosynthesis in vivo and its suppression by oral aspirin, we have investigated the urinary excretion of major enzymatic metabolites of TXB2 in 17 patients with polycythemia vera and 23 gender- and age-matched controls. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were measured by previously validated radioimmunoassays. In addition, urinary immunoreactive leukotriene (LT) E4 was measured to explore the 5-lipoxygenase pathway of arachidonate metabolism. Polycythemic patients had significantly (P < .001) higher excretion rates of both 11-dehydro-TXB2 (1,033 +/- 1,050 v 117 +/- 45 pmol/mmol creatinine; mean +/- SD) and 2,3-dinor-TXB2 (725 +/- 676 v 82 +/- 43 pmol/mmol creatinine) than controls. In contrast, urinary LTE4 was not significantly different. Enhanced metabolite excretion did not correlate with the platelet count or with the hematocrit value, and was not related to the current treatment or to a clinical history of thrombotic complications. Platelet TX receptor studies did not show any significant changes in the binding characteristics of two different ligands. A platelet-selective regimen of aspirin therapy (50 mg/d for 7 to 14 days) was associated with greater than 80% suppression in metabolite excretion in nine patients. These results are consistent with abnormal stimuli operating in polycythemia vera to induce a selective enhancement in the platelet biosynthesis of TXA2 without changes in receptor binding. This in vivo abnormality in platelet biochemistry can be largely suppressed by low doses of aspirin.

scholarly journals Retention of dopamine 2 receptor mRNA and absence of the protein in craniospinal and extracranial metastasis of a malignant prolactinoma: a case report

2002 ◽  
pp. 81-88 ◽  
Author(s):  
J Winkelmann ◽  
U Pagotto ◽  
M Theodoropoulou ◽  
K Tatsch ◽  
W Saeger ◽  
...  
Keyword(s):  
Single Case ◽  
Clinical History ◽  
Extracranial Metastasis ◽  
Invasion And Metastasis ◽  
History Of ◽  
Dopamine 2 Receptor ◽  
Immunohistochemical Techniques

OBJECTIVES: The case presented here describes the clinical evolution of a malignant prolactinoma with occurrence of intra- and extra-cranial metastases. In this case, the presence of dopamine 2 receptor (D2R) was studied at the mRNA and protein level, in order to understand the pathological background of the resistance to treatment with different dopamine agonists. DESIGN: Together with an extensive description of the clinical history of this case, a combination of in vitro and in vivo techniques was performed to provide the basis of the dopamine resistance developed in the course of the disease. METHOD: A comparison of the D2R was performed in specimens obtained at presentation of the disease compared with autoptic specimens derived from local invasion and metastasis using in situ hybridization and immunohistochemical techniques. RESULTS: Intact D2R mRNA was found in the primitive tumor and metastatic tissues, whereas protein for the same receptor was present only in the tissues derived from neurosurgical operations and not in the metastases obtained post-mortem. CONCLUSION: This is the first report of the absence of D2R protein despite the retention of the transcript in an advanced stage of a malignant prolactinoma. The findings of this single case suggest the hypothesis that postranscriptional mechanisms may contribute to the development of dopamine resistance in prolactinomas.

scholarly journals Karyotypically distinct subpopulations in acute leukemia with specific growth requirements

Blood ◽  
1982 ◽  
Vol 59 (3) ◽  
pp. 641-645 ◽  
Author(s):  
B Lowenberg ◽  
A Hagemeijer ◽  
K Swart
Keyword(s):  
Leukemic Cell ◽  
Clinical History ◽  
Malignant Cell ◽  
Biological Properties ◽  
Myeloid Differentiation ◽  
Tumor Stem Cells ◽  
Growth Requirements ◽  
Acute Monoblastic Leukemia ◽  
History Of

Bone marrow and blood cells of a patient with acute monoblastic leukemia with subclones marked with specific karyotypic abnormalities were investigated. In order to more precisely evaluate the proliferative abilities of these populations, leukemic cell enriched fractions were prepared and incubated in two colony assays. Colony forming cells of the disparate clones had growth advantages in different systems which shows that their proliferation depended on the presence of selective stimulatory factors in culture. In one assay, at diagnosis, colonies from the minor clone were demonstrated exclusively. It is suggested that the assays measured distinct cellular stages of myeloid differentiation and the findings indicate that prior to diagnosis the neoplasm had evolved into subsets with progressive dedifferentiation. Differences of growth in vitro correlated with the different roles of these clones in the clinical history of the disease. Approaches based on differential cloning of tumor stem cells as in this example, may be useful for discriminating biological properties of heterogeneous subpopulations within neoplasms, and may facilitate the cytogenetic recognition of minimal clones among composite malignant cell specimens.

Karyotypically distinct subpopulations in acute leukemia with specific growth requirements

Blood ◽  
1982 ◽  
Vol 59 (3) ◽  
pp. 641-645 ◽  
Author(s):  
B Lowenberg ◽  
A Hagemeijer ◽  
K Swart
Keyword(s):  
Leukemic Cell ◽  
Clinical History ◽  
Malignant Cell ◽  
Biological Properties ◽  
Myeloid Differentiation ◽  
Tumor Stem Cells ◽  
Growth Requirements ◽  
Acute Monoblastic Leukemia ◽  
History Of

Abstract Bone marrow and blood cells of a patient with acute monoblastic leukemia with subclones marked with specific karyotypic abnormalities were investigated. In order to more precisely evaluate the proliferative abilities of these populations, leukemic cell enriched fractions were prepared and incubated in two colony assays. Colony forming cells of the disparate clones had growth advantages in different systems which shows that their proliferation depended on the presence of selective stimulatory factors in culture. In one assay, at diagnosis, colonies from the minor clone were demonstrated exclusively. It is suggested that the assays measured distinct cellular stages of myeloid differentiation and the findings indicate that prior to diagnosis the neoplasm had evolved into subsets with progressive dedifferentiation. Differences of growth in vitro correlated with the different roles of these clones in the clinical history of the disease. Approaches based on differential cloning of tumor stem cells as in this example, may be useful for discriminating biological properties of heterogeneous subpopulations within neoplasms, and may facilitate the cytogenetic recognition of minimal clones among composite malignant cell specimens.

Component resolved diagnostics in peanut sensitized children with and without a history of clinical reaction

2020 ◽  
Vol 41 (5) ◽  
pp. 336-340
Author(s):  
Yasmin Hamzavi Abedi ◽  
Cristina P. Sison ◽  
Punita Ponda
Keyword(s):  
Retrospective Chart Review ◽  
Clinical History ◽  
Specific Ige ◽  
Exact Test ◽  
Ara H 1 ◽  
Sige Level ◽  
History Of ◽  
Laboratory Procedures ◽  
Ige Mediated ◽  
The Relationship

Background: Serum Peanut-specific-IgE (PN-sIgE) and peanut-component-resolved-diagnostics (CRD) are often ordered simultaneously in the evaluation for peanut allergy. Results often guide the plans for peanut oral challenge. However, the clinical utility of CRD at different total PN-sIgE levels is unclear. A commonly used predefined CRD Ara h2 cutoff value in the literature predicting probability of peanut challenge outcomes is 0.35kUA/L. Objective: To examine the utility of CRD in patients with and without a history of clinical reactivity to peanut (PN). Methods: This was a retrospective chart review of 196 children with PN-sIgE and CRD testing, of which, 98 patients had a clinical history of an IgE-mediated reaction when exposed to PN and 98 did not. The Fisher's exact test was used to assess the relationship between CRD and PN-sIgE at different cutoff levels, McNemar test and Gwet’s approach (AC1 statistic) were used to examine agreement between CRD and PN-sIgE, and logistic regression was used to assess differences in the findings between patients with and without reaction history. Results: Ara h 1, 2, 3, or 9 (ARAH) levels ≤0.35 kUA/L were significantly associated with PN-sIgE levels <2 kUA/L rather than ≥2 kUA/L (p < 0.0001). When the ARAH threshold was increased to 1 kUA/L and 2 kUA/L, these thresholds were still significantly associated with PN-sIgE levels of <2, <5, and <14 kUA/L. These findings were not significantly different in patients with and without a history of clinical reactivity. Conclusion: ARAH values correlated with PN-sIgE. Regardless of clinical history, ARAH levels are unlikely to be below 0.35, 1, or 2 kUA/L if the PN-sIgE level is >2 kUA/L. Thus, if possible, practitioners should consider PN-sIgE rather than automatically ordering CRD with PN-sIgE every time. Laboratory procedures that allow automatically and reflexively adding CRD when the PN-sIgE level is ≤5 kUA/L can be helpful. However, further studies are needed in subjects with challenge-proven PN allergy.

Stepping up detection, response, preparedness and readiness measures for “COVID-19”- A Pandemic

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 1042-1047
Author(s):  
Khushbu Balsara ◽  
Deepankar Shukla
Keyword(s):  
Health Care ◽  
Health Care Workers ◽  
Clinical History ◽  
Frontline Workers ◽  
Diagnostic Assays ◽  
Care Workers ◽  
Short Period ◽  
History Of ◽  
Detection Response ◽  
Care Worker

In a very short period of time, “COVID-19” has seized the consciousness globally by making remarkable changes in our day to day living and has superintended as a public health emergency globally. It has high radar of transmission, affecting an individual at work to frontline workers. The measures and planning for a response plays a key role from drawing up an emergency committee and this follows an equation which broadly deals with epidemiological to clinical history of the patient, management steps from isolation, screening, diagnostic assays for identification and treatment. The application of an organized plan with secure structure aids in better performance, increases efficacy of management and saves time. Also saves time for a health care worker to g through routine levels of channels of administration if already a familiar way of operation is known for such situations. Thus, planning and developing a ‘blueprint of approach’ towards management of patient while facing such situation is a must. This review provides an insight to the measures for detection, response and preparedness of the hospital and health care workers should largely be inclusive of; also highlights the measures to be taken at every step after coming in contact with a positive case of “COVID-19”.

On the Power of the Object

2017 ◽  
Author(s):  
Liubov Vetoshkina ◽  
Yrjö Engeström ◽  
Annalisa Sannino
Keyword(s):  
Point Of View ◽  
The Political ◽  
Material Objects ◽  
Human Beings ◽  
Work Activities ◽  
Skilled Performance ◽  
Rich Domain ◽  
Boat Building ◽  
Building Activity ◽  
History Of

By skillfully shaping and producing objects human beings externalize and make real their future-oriented imaginaries and visions. Material objects created by skilled performance make human lifeworlds durable. From the point of view of history making, wooden boat building is a particularly rich domain of skilled performance. This chapter is based on two research sites, one in Finland and the other in Russia. The analysis is divided into four layers or threads of history making, namely personal history, the history of the wooden boat community, the political history of the nations and their relations, and the history of the boats themselves as objects of boat-building activity. The chapter ends by discussing our findings and their implications for the understanding of skilled performance and history making in work activities and organizations.

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