Modulatory effects of phosphatidylserine on the binding of muscarinic cholinergic receptor ligands

The modulation of the binding of muscarinic cholinergic receptor ligands by phosphatidylserine purified from bovine cerebral cortex (BC-PS) was examined in vitro and in vivo. The enrichment of bovine cerebral cortical synaptosomal membranes with BC-PS, using a fusion technique, produced a concentration-dependent decrease in the affinity (increase in K _d ) of [³H]quinuclidinyl benzylate (³H-QNB) specific binding to muscarinic acetylcholine receptors (mAChR), without changes in their maximal number (Bmax). Similar results were observed when [³H]oxotremorine (³H-OXO) was used to label a high affinity subpopulation of mAChR. On the other hand, preincubation of BC-PS liposomes with synaptosomal membranes in a nonoptimum fusion condition (at pH 7.4) did not alter the binding properties of both radioligands. Fusion experiments using a pure phosphatidylserine preparation from spinal cord revealed a similar decrement in the affinity of³H-QNB specific binding. Five day’s intraperitoneal (i.p.) administration of 15 mg/kg of BC-PS liposomes in rats increased the maximal number of cerebral cortical binding sites for³H-OXO. Scatchard analysis revealed no changes in the apparent dissociation constant. This modification is selective in relation to the neural structure studied. Thus, BC-PS treatment did not modify³H-OXO binding in the hippocampal formation and cerebellum. In contrast, parallel experiments using the muscarinic antagonist³H-QNB showed no alteration in the binding properties of mAChR. Five day’s i.p. administration of 15 mg/kg/d of phosphatidylcholine from bovine cerebral cortex (BC-PC) liposomes produced quite similar results to those obtained with BC-PS. These results indicate that mAChR are under the modulatory action of phosphatidylserine (PS) and phosphatidylcholine (PC), and suggest that this endogenous phospholipids may play a regulatory role on the mAChR. The possible implications of these findings on the effects of PC or PS treatment in neurological disorders involving a decrease in central cholinergic functions are discussed.     

Cross neutralization of SARS-CoV-2 omicron subvariants after repeated doses of COVID-19 mRNA vaccines

We have measured the humoral response to messenger RNA (mRNA) vaccines in COVID-19 naïve and convalescent individuals. Third doses of mRNA COVID-19 vaccines induced a significant increase in potency and breadth of neutralization against SARS-CoV-2 variants of concern (VoC) including Omicron subvariants BA.1, BA.2, and BA.2.12.1, that were cross-neutralized at comparable levels and less for BA.4/5. This booster effect was especially important in naïve individuals that only after the third dose achieved a level that was comparable with that of vaccinated COVID-19 convalescents except for BA.4/5. Avidity of RBD-binding antibodies was also significantly increased in naïve individuals after the third dose, indicating an association between affinity maturation and cross neutralization of VoC. These results suggest that at least three antigenic stimuli by infection or vaccination with ancestral SARS-CoV-2 sequences are required to induce high avidity cross-neutralizing antibodies. Nevertheless, the circulation of new subvariants such as BA.4/5 with partial resistance to neutralization will have to be closely monitored and eventually consider for future vaccine developments.     

Pancreas-kidney transplantation for intensivists: perioperative care and complications

Simultaneous pancreas-kidney transplantation is a therapeutic option for type I diabetics with end-stage renal disease. It aims to correct the uremic state, to normalize glucose hemeostasis, and to ameliorate diabetic complications. Careful donor-recipient selection and meticulous intra-operative and postoperative care will substantially impact recipient morbidity. An understanding of the technical aspects of the surgical procedure and its metabolic and immunological consequences is necessary to successfully manage a pancreas-kidney transplant recipient, many of whom are nursed in intensive care units. A successful outcome is predicted in early recognition of technical complications and aggressive management of rejection to achieve the current 1-year graft survival rates of 75% for pancreas transplants and 84% for kidney transplants.     

Surgical Findings in Idiopathic Trigeminal Neuropathy Mimicking a Trigeminal Neurinoma

Summary  Idiopathic trigeminal neuropathy is a benign disorder where the main clinical feature is facial numbness limited to the territory of one or more divisions of the trigeminal nerve, persisting for a few weeks to several years and in which no underlying disease can be identified. The case of a 37-year-old man with a brief history of sensory and motor trigeminal symptoms who showed magnetic resonance imaging (MRI) findings consistent with a small trigeminal neurinoma is reported. The patient was operated on but no tumour could be found during surgery and a biopsy was taken from the portio major. Pathological diagnosis was chronic non granulomatous inflammatory reaction with areas of coagulation necrosis. Control MRI showed complete resolution of the trigeminal abnormalities. It is concluded that in patients with MRI findings suggestive of a small trigeminal schwannoma, benign idiopathic trigeminal neuropathy should also be considered in the differential diagnosis. A conservative approach with sequential MRI studies may avoid an unnecessary surgical exploration.     

Morphological changes in ocular surface in dry eyes and other disorders by impression cytology

A study was conducted on 107 eyes of 70 patients with dry eye disorders and mechanical and chemical extrinsic alterations and 64 eyes of 32 control subjects in order to describe a possible specific response of the conjunctival and corneal surface. We found the presence of snakelike chromatin cells and other nuclear changes, squamous metaplasia, and inflammatory cells in the conjunctiva in all groups. A decrease in goblet cell densities was also found in all groups, except for patients with blepharoconjunctivitis. The corneal cells were slightly larger in patients with keratoconjunctivitis sicca.Correspondence to: L. Rivas     

Immunohistochemical expression of DNA repair proteins in familial breast cancer differentiate BRCA2-associated tumors.

PURPOSE: Morphologic and immunohistochemical studies of familial breast cancers have identified specific characteristics associated with BRCA1 mutation-associated tumors when compared with BRCA2 and non-BRCA1/2 tumors, but have not identified differences between BRCA2 and non-BRCA1/2 tumors. Because BRCA1 and BRCA2 genes participate in the DNA repair pathway, we have performed an immunohistochemical study with markers related to this pathway to establish the profile of the three groups. MATERIALS AND METHODS: We have studied two tissue microarrays that include 103 familial and 104 sporadic breast tumors, with a panel of DNA repair markers including ATM, CHEK2, RAD51, RAD50, XRCC3, and proliferating cell nuclear antigen. RESULTS: We found more frequent expression of CHEK2 in BRCA1 and BRCA2 tumors than in non-BRCA1/2 and sporadic tumors. We found absence of nuclear expression and presence of cytoplasmic expression of RAD51 in BRCA2 tumors that differentiate them from other familial tumors. We validated these results with a new series of patient cases. The final study with 253 familial patient cases (74 BRCA1, 71 BRCA2, 108 non-BRCA1/2), and 288 sporadic patient cases, has allowed us to confirm our preliminary results. Because BRCA2 tumors present a specific immunohistochemical profile for RAD51 and CHEK2 markers that is different from non-BRCA1/2 tumors, we have built a multivariate model with these markers that distinguish both tumors with an estimated probability of at least 76%. CONCLUSION: Our results suggest that BRCA2 tumors demonstrate more cytoplasmic and less nuclear RAD51 staining, and increased CHEK2 staining. This pattern may distinguish BRCA2 from familial non-BRCA1/2 tumors.