Metabotropic glutamate receptors are associated with non-synaptic appendages of unipolar brush cells in rat cerebellar cortex and cochlear nuclear complex

Unipolar brush cells (UBCs) are a class of small neurons that are densely concentrated in the granular layers of the vestibulocerebellar cortex and dorsal cochlear nucleus. The UBCs form giant synapses with individual mossy fibre rosettes on the dendrioles which make up their brush formations and are provided with numerous, unusual non-synaptic appendages. In accord with the glutamatergic nature of mossy fibres, our previous post-embedding immunocytochemical studies indicated that various ionotropic glutamate receptor subunits are localized at the post-synaptic densities of the giant synapses, whereas the non-synaptic appendages are immunonegative. On the contrary, the metabotropic glutamate receptors mGluR1 and mGluR2/3 are situated at the non-synaptic appendages and are lacking at the post-synaptic densities. Other authors, however, have shown that antibodies to these metabotropic receptors stain both appendages and post-synaptic densities. In the present study, we have re-evaluated the distribution of metabotropic glutamate receptors in the UBCs of the cerebellum and the cochlear nuclear complex by light and electron microscopic pre-embedding immunocytochemistry with subtype-specific antibodies. We confirm that UBCs dendritic brushes are densely immunostained by antibody to mGluR1 particularly in the cerebellum and that antibody to mGluR2/3 labels at least a percentage of the UBC brushes in both the cerebellum and cochlear nuclei. At the ultrastructural level, it appears that mGluR1 and mGluR2/3 immunoreactivities are not associated with the post-synaptic densities of the giant mossy fibre–UBC synapses, but instead are concentrated on the non-synaptic appendages of the cerebellar UBCs. The non-synaptic appendages, therefore, may be an important avenue for regulating the excitability of UBCs and mediating glutamate effects on their still unknown intracellular signal transduction cascades. We also show that the pre-synaptic densities of UBC dendrodendritic junctions are mGluR2/3 positive. As previously demonstrated, antibodies to mGluR1 and mGluR2/3 label subsets of Golgi cells. Antibody to mGluR5 does not stain UBCs in the cerebellum and cochlear nucleus and reveals the somatodendritic compartment of Golgi cells situated in the core of the cerebellar granular layer, whilst cochlear nucleus Golgi cells are mGluR5 negative.     

9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene

Tuberous sclerosis is an autosomal dominant disease whose characteristicfeature is the development of multiple hamartomas in a varietyof organs and tissues. Two major loci have been identified sofar: TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3.Loss of heterozygosity at 16p13.3-associated markers has beenrecently observed in hamartomatous lesions of some tuberoussclerosis patients. Here we report the first evidence of lossof heterozygosity at the TSC1 critical region in a giant cellastrocytoma of a familial tuberous sclerosis case. Segregationanalysis showed that the 9q34 haplotype lost carried the putativenormal TSC1 gene. These data support the hypothesis of botha germline and somatic loss-of-function mutation for the developmentof tuberous sclerosis hamartomas and suggest a tumor-suppressor-likeactivity also for the TSC1 gene product. Finally, the possiblesignificance of a second small region of loss of heterozygosityat 9p21, found in the same astrocytoma, is discussed.     

The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.     

Normal sperm parameters per se do not reliably account for fertility: A case–control study in the real-life setting

A proportion of men are infertile despite having normal medical history/physical examination and normal semen analysis. We aimed to assess whether normal sperm parameters per se account for male factor fertility. 1,957 infertile men were compared with 103 age-comparable fertile controls. Semen analysis was based on 2010 World Health Organization reference criteria. Of all, 12.1% of infertile men and 40.8% of fertile men presented with normal sperm parameters. Among fertile men, 36.9% had isolated sperm abnormalities and 22.3% men showed two or more concomitant sperm abnormalities. Serum total testosterone was higher in infertile men with normal sperm parameters compared to those with ≥2 sperm abnormalities or azoospermia, but similar to those with isolated sperm abnormalities (p ≤ .001). Circulating hormones were similar among sperm parameters groups in fertile men. At multivariable analyses, testicular volume (OR 1.12, p ≤ .001) and FSH (OR 0.8, p ≤ .001) were associated with normal sperm parameters. Overall, the longer the infertility period, the greater the number of sperm parameters abnormalities (p < .01). In conclusion, we found that 12% of infertile men and only 41% of fertile men present with normal sperm parameters. Normal sperm parameters per se do not reliably account for fertility in the real-life setting.     

Liver transplantation versus liver resection for colorectal liver metastasis: a survival benefit analysis in patients stratified according to tumor burden score

Liver transplantation (LT) for colorectal liver metastasis (CRLM) may provide excellent survival rates in patients with unresectable disease. High tumor load is a risk factor for recurrence and low overall survival (OS) after liver resection (LR). We tested the hypothesis that LT could offer better survival than LR in patients with high tumor load. LR performed at Padua University Hospital for CRLM was compared with LT for unresectable CRLM performed both at Oslo and Padua. High tumor load was defined as tumor burden score (TBS) ≥ 9, and inclusion criteria were as in the SECA-I transplant study. 184 patients were eligible: 128 LRs and 56 LTs. 5-year OS after LR and LT was 40.5% and 54.7% (P = 0.102). In the high TBS cohort, 5-year OS after LR and LT was 22.7% and 52.2% (P = 0.055). In patients with Oslo score ≤ 2 and TBS ≥ 9 (13 LR; 24 LT) the 5-year OS after LR and LT was 14.6% and 69.1% (P = 0.002). The corresponding disease-free survival (DFS) was 0% and 22.9% (P = 0.005). Selected CRLM patients with low Oslo score and high TBS could benefit from LT with survival outcomes that are far better than what is achieved by LR.     

A capnography and transcutaneous CO2 profile of bariatric patients during early postoperative period after opioid-sparing anesthesia

BackgroundNoninvasive monitoring of partial pressure of carbon dioxide can be accomplished indirectly with capnography (P_ETCO₂) or with transcutaneous carbon dioxide monitoring (P_TCCO₂). The use of capnography has been shown to offer an advantage over pulse oximetry alone in the early detection of adverse respiratory events when supplemental oxygen is administered. Furthermore, capnography allows for the monitoring of various respiratory measures, including end-tidal carbon dioxide, respiratory rate, tidal volume, and changes in breathing patterns. Transcutaneous CO₂ also closely approximates arterial CO₂ values, but is not as easy to monitor for prolonged periods. The purpose of this study was to examine the usefulness of capnography and of transcutaneous carbon dioxide monitoring in patients recovering from obesity surgery at high risk of developing postoperative obstructive sleep apnea.MethodsIn a prospective observational study, 64 bariatric surgery patients at risk of developing obstructive sleep apnea were monitored in the postanesthesia care unit (PACU) with either capnography alone (31 patients) or capnography plus transcutaneous carbon dioxide monitoring (33 additional patients) every 3–5 minutes for the duration of their recovery. Primary endpoints included end-tidal and transcutaneous carbon dioxide, peripheral oxygen saturation, respiratory rate, pain scores, and incidence of adverse respiratory events.ResultsAlthough no adverse pulmonary events were observed, capnography detected several patients who experienced short periods of respiratory apnea while maintaining pulse oximetry readings within normal limits. Transcutaneous values were slow to change and averaged 4.5 ± 5.5 mm Hg (P < .05) higher than corresponding end-tidal measurements.ConclusionsThese results indicate the capabilities of both these noninvasive techniques for postoperative monitoring. Capnography acutely monitors changes in respiration, whereas transcutaneous monitoring more accurately reflects arterial CO₂ levels.     

Liver transplantation in a patient after COVID-19 – Rapid loss of antibodies and prolonged viral RNA shedding

To date, little is known about the duration and effectiveness of immunity as well as possible adverse late effects after an infection with SARS-CoV-2. Thus it is unclear, when and if liver transplantation can be safely offered to patients who suffered from COVID-19. Here, we report on a successful liver transplantation shortly after convalescence from COVID-19 with subsequent partial seroreversion as well as recurrence and prolonged shedding of viral RNA.