A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome.

Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-old Wfs1∆exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

A comparative analysis of healing of surgical cleft lip corrected in utero and neonates.

We studied the healing process in surgically created cleft lips in fetal mice and compared it with that in newborn mice with cleft lips. Our purpose was to determine the time for optimal healing, defined as minimal scarring, for a repaired cleft lip. Full-thickness paramedian lip incisions were made in NMRI mice in utero, in 2- and 4-day-old neonates, and in adults (n = 10 in each experimental and control group). The healing process was studied by biochemical analysis of hyaluronic acid and hydroxyproline content in the repaired cleft tissue. We found that the production of hyaluronic acid remained stable during the healing period and was similar in all experimental groups. However, there was an unexplained but consistent depression in the hyaluronic acid content of fetal tissue 2 days after repair. Hydroxyproline was present in the fetal healing tissue, but in a low concentration, starting 4 days after surgical incision of the lip. The production of hydroxyproline in 2-day-old neonates was similar to that in the fetuses throughout the healing period (p less than 0.0005). However, the production of hydroxyproline increased in 4-day-old neonatal and adult tissues. In conclusion, we found an optimal healing period for mice with minimal collagen production in the late fetal stage, and this lasted 2 days after birth.

[The surgical treatment of obstructive cancers of the left colon. Apropos of a series of 66 cases]. / Le traitement chirurgical des cancers occlusifs du côlon gauche. A propos d'une série de 66 cas.

From 1977 to 1989, 66 patients were operated on in emergency, without any bowel preparation, for acutely obstructing left-sided colon cancer. Two synchronous cancers were diagnosed and the 68 tumours were located as follows: 13 on the left transverse colon or at the splenic flexure, 7 on the descending colon, 37 on the sigmoid, and 11 at the rectosigmoid junction or below. According to Astler-Coller staging, 15 patients were classified as B, 17 as C and 25 as D. Initial treatment was a colostomy in 58 patients (88%), or a resection with or without anastomosis in 2 and 6 cases respectively. Most patients underwent a two- or more rarely a three-stage resection and 44 patients left the hospital without either tumour or stomy. Cumulative operative mortality was 12%. Five-year survival rates were 21% for the patients with a minimal potential follow-up of 5 years, and 39% for curative resections (disease-free survival of 33%). From these results, we think that two-staged resection, with close proximal colostomy followed by resection and anastomosis, remains an appropriate approach for most obstructing left-sided colon cancers; more tempting procedures such as resection with primary anastomosis or subtotal colectomy are probably indicated in selected patients.