Amyloid beta accumulations and enhanced neuronal differentiation in cerebral organoids of Dutch-type cerebral amyloid angiopathy patients

IntroductionADutch-type cerebral amyloid angiopathy (D-CAA) is a hereditary brain disorder caused by a point mutation in the amyloid precursor protein (APP) gene. The mutation is located within the amyloid beta (Aβ) domain of APP and leads to Aβ peptide accumulation in and around the cerebral vasculature. There lack of disease models to study the cellular and molecular pathological mechanisms of D-CAA together with the absence of a disease phenotype in vitro in overexpression cell models, as well as the limited availability of D-CAA animal models indicates the need for a D-CAA patient-derived model.MethodsWe generated cerebral organoids from four D-CAA patients and four controls, cultured them up to 110 days and performed immunofluorescent and targeted gene expression analyses at two time points (D52 and D110).ResultsD-CAA cerebral organoids exhibited Aβ accumulations, showed enhanced neuronal and astrocytic gene expression and TGFβ pathway de-regulation.ConclusionsThese results illustrate the potential of cerebral organoids as in vitro disease model of D-CAA that can be used to understand disease mechanisms of D-CAA and can serve as therapeutic intervention platform for various Aβ-related disorders

Deep versus Moderate Neuromuscular Blockade in Gynecologic Laparoscopic Operations: Randomized Controlled Trial

Background: To investigate whether deep neuromuscular blockade (NMB) improves surgical conditions and postoperative pain compared to moderate block, in patients undergoing gynecologic laparoscopic surgery. Methods: A single blind, randomized, controlled trial was undertaken with laparoscopic gynecologic surgical patients, who were randomly assigned to one of the following two groups: patients in the first group received deep NMB (PTC 0-1) and in the other, moderate NMB (TOF 0-1). Primary outcomes included assessing the surgical conditions using a four-grade scale, ranging from 0 (extremely poor) to 3 (optimal), and patients’ postoperative pain was evaluated with a five-grade Likert scale and the analgesic consumption. Results: 144 patients were analyzed as follows: 73 patients received deep NMB and 71 moderate NMB. Mean surgical field scores were comparable between the two groups (2.44 for moderate vs. 2.68 for deep NMB). Regarding postoperative pain scores, the patients in the deep NMB experienced significantly less pain than in the group of moderate NMB (0.79 vs. 1.58, p p = 0.007). From the secondary endpoints, an interesting finding of the study was that patients on deep NMB had significantly fewer incidents of subcutaneous emphysema. Conclusions: Our data show that, during the performance of gynecologic laparoscopic surgery, deep NMB offers no advantage of operating filed conditions compared with moderate NMB. Patients may benefit from the deep block as it may reduce postoperative pain

Deep versus Moderate Neuromuscular Blockade in Gynecologic Laparoscopic Operations: Randomized Controlled Trial

Background: To investigate whether deep neuromuscular blockade (NMB) improves surgical conditions and postoperative pain compared to moderate block, in patients undergoing gynecologic laparoscopic surgery. Methods: A single blind, randomized, controlled trial was undertaken with laparoscopic gynecologic surgical patients, who were randomly assigned to one of the following two groups: patients in the first group received deep NMB (PTC 0-1) and in the other, moderate NMB (TOF 0-1). Primary outcomes included assessing the surgical conditions using a four-grade scale, ranging from 0 (extremely poor) to 3 (optimal), and patients’ postoperative pain was evaluated with a five-grade Likert scale and the analgesic consumption. Results: 144 patients were analyzed as follows: 73 patients received deep NMB and 71 moderate NMB. Mean surgical field scores were comparable between the two groups (2.44 for moderate vs. 2.68 for deep NMB). Regarding postoperative pain scores, the patients in the deep NMB experienced significantly less pain than in the group of moderate NMB (0.79 vs. 1.58, p < 0.001). Moreover, when the consumption of analgesic drugs was compared, the moderate NMB group needed more extra opioid analgesia than the deep NMB group (18.3% vs. 4.1%, p = 0.007). From the secondary endpoints, an interesting finding of the study was that patients on deep NMB had significantly fewer incidents of subcutaneous emphysema. Conclusions: Our data show that, during the performance of gynecologic laparoscopic surgery, deep NMB offers no advantage of operating filed conditions compared with moderate NMB. Patients may benefit from the deep block as it may reduce postoperative pain

Laparoscopic Cystectomy In-a-Bag of an Intact Cyst: Is It Feasible and Spillage-Free After All?

This prospective study was conducted to assess the feasibility of laparoscopic cystectomy of an intact adnexal cyst performed inside a water proof endoscopic bag, aiming to avoid intraperitoneal spillage in case of cyst rupture. 102 patients were recruited. Two of them were pregnant. In 8 of the patients the lesions were bilateral, adding up to a total of 110 cysts involved in our study. The endoscopic sac did not rupture in any case. Mean diameter of the cysts was 5.7 cm (range: 2.3–10.5 cm). In 75/110 (68.2%) cases, cystectomy was completed without rupture, whereas in the remaining 35/110 (31.8%) cases the cyst ruptured. Minimal small spillage occurred despite every effort only in 8/110 (7.2%) cases with large (>8 cm) cystic teratomas. There were no intraoperative or postoperative complications. We concluded that laparoscopic cystectomy in-a-bag of an intact cyst is feasible and oncologically safe for cystic tumors with a diameter < 8 cm. Manipulation of larger tumors with the adnexa into the sac may be more difficult, and in such cases previous puncture and evacuation of the cyst contents should be considered

Image_9_Amyloid beta accumulations and enhanced neuronal differentiation in cerebral organoids of Dutch-type cerebral amyloid angiopathy patients.jpg

IntroductionADutch-type cerebral amyloid angiopathy (D-CAA) is a hereditary brain disorder caused by a point mutation in the amyloid precursor protein (APP) gene. The mutation is located within the amyloid beta (Aβ) domain of APP and leads to Aβ peptide accumulation in and around the cerebral vasculature. There lack of disease models to study the cellular and molecular pathological mechanisms of D-CAA together with the absence of a disease phenotype in vitro in overexpression cell models, as well as the limited availability of D-CAA animal models indicates the need for a D-CAA patient-derived model.MethodsWe generated cerebral organoids from four D-CAA patients and four controls, cultured them up to 110 days and performed immunofluorescent and targeted gene expression analyses at two time points (D52 and D110).ResultsD-CAA cerebral organoids exhibited Aβ accumulations, showed enhanced neuronal and astrocytic gene expression and TGFβ pathway de-regulation.ConclusionsThese results illustrate the potential of cerebral organoids as in vitro disease model of D-CAA that can be used to understand disease mechanisms of D-CAA and can serve as therapeutic intervention platform for various Aβ-related disorders.</p

Image_8_Amyloid beta accumulations and enhanced neuronal differentiation in cerebral organoids of Dutch-type cerebral amyloid angiopathy patients.jpg

IntroductionADutch-type cerebral amyloid angiopathy (D-CAA) is a hereditary brain disorder caused by a point mutation in the amyloid precursor protein (APP) gene. The mutation is located within the amyloid beta (Aβ) domain of APP and leads to Aβ peptide accumulation in and around the cerebral vasculature. There lack of disease models to study the cellular and molecular pathological mechanisms of D-CAA together with the absence of a disease phenotype in vitro in overexpression cell models, as well as the limited availability of D-CAA animal models indicates the need for a D-CAA patient-derived model.MethodsWe generated cerebral organoids from four D-CAA patients and four controls, cultured them up to 110 days and performed immunofluorescent and targeted gene expression analyses at two time points (D52 and D110).ResultsD-CAA cerebral organoids exhibited Aβ accumulations, showed enhanced neuronal and astrocytic gene expression and TGFβ pathway de-regulation.ConclusionsThese results illustrate the potential of cerebral organoids as in vitro disease model of D-CAA that can be used to understand disease mechanisms of D-CAA and can serve as therapeutic intervention platform for various Aβ-related disorders.</p

Image_2_Amyloid beta accumulations and enhanced neuronal differentiation in cerebral organoids of Dutch-type cerebral amyloid angiopathy patients.TIF

IntroductionADutch-type cerebral amyloid angiopathy (D-CAA) is a hereditary brain disorder caused by a point mutation in the amyloid precursor protein (APP) gene. The mutation is located within the amyloid beta (Aβ) domain of APP and leads to Aβ peptide accumulation in and around the cerebral vasculature. There lack of disease models to study the cellular and molecular pathological mechanisms of D-CAA together with the absence of a disease phenotype in vitro in overexpression cell models, as well as the limited availability of D-CAA animal models indicates the need for a D-CAA patient-derived model.MethodsWe generated cerebral organoids from four D-CAA patients and four controls, cultured them up to 110 days and performed immunofluorescent and targeted gene expression analyses at two time points (D52 and D110).ResultsD-CAA cerebral organoids exhibited Aβ accumulations, showed enhanced neuronal and astrocytic gene expression and TGFβ pathway de-regulation.ConclusionsThese results illustrate the potential of cerebral organoids as in vitro disease model of D-CAA that can be used to understand disease mechanisms of D-CAA and can serve as therapeutic intervention platform for various Aβ-related disorders.</p