Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology.

Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modeling TDP-43 pathology has been challenging in vivo and in vitro. We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm-mature brain organoids (mbOrg)-composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN-/- iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.

A Retrospective Study of a Multi-Center Case Series of 452 Zygomatic Implants Placed Over 5 Years for Treatment of Severe Maxillary Atrophy.

BACKGROUND: Treatment of the severely resorbed maxilla traditionally has been managed with such protocols as sinus elevation, bone and soft-tissue grafting, and osteotomy procedures. The use of zygomatic implants has made it possible to circumvent such procedures, allowing immediate loading of implants with fixed prostheses. OBJECTIVE: This study reports the success rate of 452 zygomatic implants placed and restored in 249 patients over 5 years in a multi-center setting. Additionally, case examples are presented. METHODS: The authors conducted a multi-center case series study. Inclusion criteria were ASA 1 or ASA 2, nonsmoking adults over age 30, fully or partially edentulous, with severely atrophic maxillae. These patients had zygomatic implants placed over a 5-year period with a follow-up of 5 years. The survival rate of these implants is described. RESULTS: A total of 249 patients, aged 34 to 80, had 452 zygomatic implants placed. Survival rate was 95% for quad zygoma; 99.1% for unilateral zygoma with additional premaxillary implants; 98.7% for bilateral single zygoma with additional premaxillary implants; and 100% for unilateral zygoma as a distal extension in implant-supported fixed prostheses. Overall implant survival rate was 97.6%. CONCLUSION: This study supports reports of zygomatic implants having a high success rate while allowing an array of ancillary procedures to be avoided. CLINICAL IMPLICATIONS: The use of zygomatic implants in the atrophic maxilla has shown to be a reliable treatment option for patients selecting to not undergo advanced bone-replacing protocols.

Zygomatic Implants for the Management of Severe Alveolar Atrophy in the Partial or Completely Edentulous Maxilla.

Treatment of severely resorbed partially or completely edentulous maxillae can include the utilization of the zygomatic process for immediate implant fixation and stabilization with immediate function. This approach may alleviate the need for significant grafting to enable implant placement in the posterior maxilla and allow implants to be placed into denser, more stable bone. Zygomatic implants, which have been used clinically for the past 20 years in the treatment of the severely resorbed maxilla, allow implant placement to support fixed prosthetics. Their usage can potentially shorten treatment time and reduce costs, as the need to wait for osseous graft maturation is eliminated. Guided surgical approaches are being utilized to maximize placement of the prosthetic platform of these implants.