The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations

The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified to mark long-lived multipotent ISCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmi1 and Lgr5 mark two functionally distinct ISCs in vivo. Lgr5 marks mitotically active ISCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmi1 marks quiescent ISCs that are insensitive to Wnt perturbations, contribute weakly to homeostatic regeneration, and are resistant to high-dose radiation injury. After irradiation, however, the normally quiescent Bmi1(+) ISCs dramatically proliferate to clonally repopulate multiple contiguous crypts and villi. Clonogenic culture of isolated single Bmi1(+) ISCs yields long-lived self-renewing spheroids of intestinal epithelium that produce Lgr5-expressing cells, thereby establishing a lineage relationship between these two populations in vitro. Taken together, these data provide direct evidence that Bmi1 marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5(+) ISCs and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration.     

Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation

The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation.     

After treat-to-target: can a targeted ultrasound initiative improve RA outcomes?

For patients with rheumatoid arthritis (RA), remission can be achieved with tight control of inflammation and early use of disease modifying agents. The importance of remission as an outcome has been recently highlighted by European League Against Rheumatism recommendations. However, remission when defined by clinical remission criteria (disease activity score, simplified disease activity index, etc) does not always equate to the complete absence of inflammation as measured by new sensitive imaging techniques such as ultrasound (US) . There is evidence that imaging synovitis is frequently found in these patients and associated with adverse clinical and functional outcomes. This article reviews the data regarding remission, ultrasound imaging and outcomes in patients with RA to provide the background to a consensus statement from an international collaboration of ultrasonographers and rheumatologists who have recently formed a research network--the Targeted Ultrasound Initiative (TUI) group. The statement proposes that targeting therapy to PD activity provides superior outcomes compared with treating to clinical targets alone and introduces the rationale for a new randomised trial using targeted ultrasound in RA.     

A Double-Blind Randomized Controlled Trial (RCT) of Titanium-13Zirconium versus Titanium Grade IV Small-Diameter Bone Level Implants in Edentulous Mandibles - Results from a 1-Year Observation Period

Background: The use of endosseous dental implants has become common practice for the rehabilitation of edentulous patients, and a two‐implant overdenture has been recommended as the standard of care. The use of small‐diameter implants may extend treatment options and reduce the necessity for bone augmentation. However, the mechanical strength of titanium is limited, so titanium alloys with greater tensile and fatigue strength may be preferable. Purpose: This randomized, controlled, double‐blind, multicenter study investigated in a split‐mouth model whether small‐diameter implants made from Titanium‐13Zirconium alloy (TiZr, Roxolid?) perform at least as well as Titanium Grade IV implants. Methods and Materials: Patients with an edentulous mandible received one TiZr and one Ti Grade IV small‐diameter bone level implant (3.3 mm, SLActive®) in the interforaminal region. The site distribution was randomized and double‐blinded. Outcome measures included change in radiological peri‐implant bone level from surgery to 12 months post‐insertion (primary), implant survival, success, soft tissue conditions, and safety (secondary). Results: Of 91 treated patients, 87 were available for the 12‐month follow‐up. Peri‐implant bone level change (?0.3 ± 0.5 mm vs ?0.3 ± 0.6 mm), plaque, and sulcus bleeding indices were not significantly different between TiZr and Ti Grade IV implants. Implant survival rates were 98.9 percent and 97.8 percent, success rates were 96.6 percent and 94.4 percent, respectively. Nineteen minor and no serious adverse events were related to the study devices. Conclusion: This study confirms that TiZr small‐diameter bone level implants provide at least the same outcomes after 12 months as Ti Grade IV bone level implants. The improved mechanical properties of TiZr implants may extend implant therapy to more challenging clinical situations.     

Diagonal ear lobe crease and atherosclerosis: a review of the medical literature and dental implications

In Spain a significant number of individuals die from atherosclerotic disease of the coronary and carotid arteries without having classic risk factors and prodomal symptoms. The diagonal ear lobe crease (DELC) has been characterized in the medical literature as a surrogate marker which can identify high risk patients having occult atherosclerosis. This topic however has not been examined in either the medical or dental literature emanating from Spain. The majority of clinical, angiography and postmortem reports support the premise that DELC is a valuable extravascular physical sign able to distinguish some patients at risk of succumbing to atherosclerosis of the coronary arteries. A minority of studies have however failed to support this hypothesis. More recently reports using B mode ultrasound have also linked DELC to atherosclerosis of the carotid artery and another report has related DELC to the presence of calcified carotid artery atheromas on panoramic radiographs. DELC is readily visible during head and neck cancer screening examinations. In conjunction with the patient's medical history, vital signs, and panoramic radiograph, the DELC may assist in atherosclerotic risk.     

“Keep up the good work!”: A case study of the effects of a specific cognitive training in Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative condition characterized by significant impairment in multiple cognitive domains. In recent years, the development of cognitive trainings in AD has received significant attention. In the present case study we designed a cognitive training program (GEO, Geographical Exercises for cognitive Optimization) based on an errorless paradigm and tailored to the patient’s cultural interests. The aim of this training was to investigate the potential for acquiring and possibly retaining both procedural and verbal knowledge in early-stage AD. This study involved an 80-year-old female patient diagnosed with early-stage AD, and 10 matched healthy subjects. Participants were asked to perform the two GEO training tasks: a “puzzle-like” task for procedural memory, and an “association” task for verbal memory. Both the patient and the healthy controls were subsequently trained with GEO using the same two tasks for 2 months. Although the patient’s performance before training in both tasks was poor compared to healthy controls, after the training these differences disappeared. Our results showed that the patient was able to acquire new procedural abilities and verbal knowledge, and that her achievements were stable at the follow-up testing scheduled 3 months after the end of the intervention. This case study suggests a potentially useful strategy for cognitive training in AD.