Neuroprotective effects of tramadol on cerebral injuries caused by hind limb ischaemia/reperfusion in rats

Skeletal muscle ischaemia–reperfusion-induced acute remote injury is mediated by activated neutrophils and formation of free radicals. Several investigators have demonstrated that the opioid pathway is involved in tissue preservation during hypoxia or ischaemia. Tramadol hydrochloride is an effective analgesic used for severe acute and chronic pain conditions. The present study was designed to investigate the potential protective effects of tramadol hydrochloride on cerebral oxidative stress and damage as well as lipid peroxidation, brain oedema and histological changes induced by hind limb ischaemia and reperfusion injury in rats. Thirty-six male Wistar rats were randomly allocated into two experimental groups: ischaemia–reperfusion (group I) and ischaemia–reperfusion + tramadol hydrochloride (group II). Hind limb ischaemia was induced by clamping the femoral artery. After 2-h ischaemia, the clamp from the femoral vessels was removed and the animal underwent 24-h reperfusion. Tramadol hydrochloride was given intravenously at a dose of 20 mg/kg, immediately before reperfusion. After reperfusion, animals were euthanized and the cerebral structure, lipid peroxidation and brain oedema in the cerebral tissue were assessed. Histopathological assessment of cerebral injury was split into four grades. The extent of lipid peroxidation was measured by estimating the amount of malondialdehyde. Brain oedema was calculated as the percentage water content of the brain. Brain oxidative stress and damage were significantly attenuated by treatment with tramadol hydrochloride. Compared with the ischaemia–reperfusion group, histological changes in brain tissues (p?p?P?相似文献   

A biallelic frameshift indel in PPP1R35 as a cause of primary microcephaly

Protein phosphatase 1 regulatory subunit 35 (PPP1R35) encodes a centrosomal protein required for recruiting microtubule-binding elongation machinery. Several proteins in this centriole biogenesis pathway correspond to established primary microcephaly (MCPH) genes, and multiple model organism studies hypothesize PPP1R35 as a candidate MCPH gene. Here, using exome sequencing (ES) and family-based rare variant analyses, we report a homozygous, frameshifting indel deleting the canonical stop codon in the last exon of PPP1R35 [Chr7: c.753_*3delGGAAGCGTAGACCinsCG (p.Trp251Cysfs*22)]; the variant allele maps in a 3.7 Mb block of absence of heterozygosity (AOH) in a proband with severe MCPH (−4.3 SD at birth, −6.1 SD by 42 months), pachygyria, and global developmental delay from a consanguineous Turkish kindred. Droplet digital PCR (ddPCR) confirmed mutant mRNA expression in fibroblasts. In silico prediction of the translation of mutant PPP1R35 is expected to be elongated by 18 amino acids before encountering a downstream stop codon. This complex indel allele is absent in public databases (ClinVar, gnomAD, ARIC, 1000 genomes) and our in-house database of 14,000+ exomes including 1800+ Turkish exomes supporting predicted pathogenicity. Comprehensive literature searches for PPP1R35 variants yielded two probands affected with severe microcephaly (−15 SD and −12 SD) with the same homozygous indel from a single, consanguineous, Iranian family from a cohort of 404 predominantly Iranian families. The lack of heterozygous cases in two large cohorts representative of the genetic background of these two families decreased our suspicion of a founder allele and supports the contention of a recurrent mutation. We propose two potential secondary structure mutagenesis models for the origin of this variant allele mediated by hairpin formation between complementary GC rich segments flanking the stop codon via secondary structure mutagenesis.     

Tandem application with transvaginal ultrasound guidance

PURPOSE: Intrauterine tandem placement can be difficult in brachytherapy for cervical cancer. A prospective study was planned to investigate transvaginal ultrasound (TVU) guidance for intrauterine tandem insertions in the treatment of cervix cancer. METHODS AND MATERIALS: Between January 1997 and January 2002, TVU was used after pelvic external beam radiotherapy in 48 cervical cancer patients with a high complication risk because the cervical canal orifice could not be identified and/or the patients could not undergo hysterometry. The TVU findings were graded as 1-4, with a higher number indicating greater difficulty in implantation. The tandem was inserted using the guidance of the TVU findings. Tandem application difficulties were graded in accordance with the number of implantation trials. The relations between tandem applicability and possible factors were analyzed. RESULTS: By TVU, the difficulties in tandem insertion were graded as Grade 1 in 5 cases, Grade 2 in 23 cases, Grade 3 in 17 cases, and Grade 4 in 3 cases. The tandem was inserted in 19 patients on the first try, 12 patients on the second try, 12 patients on the third try, and 2 patients on the fourth try. However, the cervical canal could not be opened in 3 patients. Factors such as median age, stage, chemotherapy, diameter of the tandem applicators, time between external beam radiotherapy and brachytherapy, and the rate of tumor regression were not statistically significant. The ultrasound grade (p = 0.02) and diameter of the tandem applicator (p = 0.007) were statistically significant. Perforation and sepsis were not observed. CONCLUSION: TVU guidance before brachytherapy has a positive contributory effect in reducing the morbidity rate of patients considered high risk.     

Rectus Muscle Resection for Vertical Strabismus in Thyroid Eye Disease

Purpose: Rectus muscle resection in thyroid eye disease (TED) is generally avoided due to the risk of worsening restriction or reactivating inflammation. However, for some patients with large-angle strabismus or diplopia in primary gaze despite maximum recession surgery, rectus muscle resection may be beneficial. We report our surgical experience with rectus muscle resection in the management of vertical strabismus associated with TED.

Methods: Retrospective review of eight patients with TED and vertical diplopia who underwent vertical rectus muscle resection by a single surgeon (IBM) at a tertiary referral centre in Liverpool, UK, from 2001 to 2013. The goal of surgery was elimination of diplopia in primary and reading position. Vertical deviations were measured in prism dioptres (^?) before and after surgery at one month, four months and final visit by prism alternate cover testing at ? m and 6 m.

Results: The mean ± standard deviation vertical deviation for near and distance reduced significantly from 14.2^? ± 8.4^? and 15.8^? ± 8.8^? pre-operatively to 5.7^? ± 4.9^? and 6.7^? ± 7^? at the four-month visit, respectively (p< 0.05). At the four-month follow-up, five (62.5%) patients achieved binocular single vision in primary and reading position with either no prisms or prisms less than 5^?. Further recession surgery, Harada-Ito procedure, or lateral rectus resection were necessary in four (50%) patients with persistent diplopia. No patient developed recurrence of inflammation or increased muscle restriction.

Conclusions: Vertical rectus resection could be considered as an additional surgical strategy in the management of TED patients with vertical strabismus without adverse sequelae.     

COVID-19 Mortality and Social Inequalities: Epidemiological analysis of the emergence and disappearance of the SARS-CoV-2 Kappa variant within a region of British Columbia,Canada

BackgroundThe Kappa variant is designated as a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of interest (VOI). We identified 195 Kappa variant cases in a region of British Columbia, Canada—the largest published cluster in North America.ObjectivesTo describe the epidemiology of the Kappa variant in relation to other circulating SARS-CoV-2 variants of concern (VOC) in the region to determine if the epidemiology of the Kappa variant supports a VOI or VOC status.MethodsClinical specimens testing positive for SARS-CoV-2 collected between March 10 and May 2, 2021, were screened for the detection of known circulating VOCs; approximately 50% of specimens were subsequently selected for whole genome sequencing (WGS). Epidemiological analysis was performed comparing the characteristics of Kappa cases to the main circulating variants in the region (Alpha and Gamma) and to non-VOC/VOI cases.ResultsA total of 2,079 coronavirus disease 2019 (COVID-19) cases were reported in the region during the study period, of which 54% were selected for WGS. The 1,131 sequenced cases were categorized into Kappa, Alpha, Gamma and non-VOC/VOI. While Alpha and Gamma cases were found to have a significantly higher attack rate among household contacts compared to non-VOI/VOC cases, Kappa was not.ConclusionEpidemiological analysis supports the designation of Kappa as a VOI and not a VOC. The Alpha and Gamma variants were found to be more transmissible, explaining their subsequent dominance in the region and the rapid disappearance of the Kappa variant. Variant surveillance strategies should focus on both detection of established VOCs and detection of potential new VOCs.