The inflammasome is hypothesized to be a key mediator of the response to physiological and psychological stressors, and its dysregulation may be implicated in major depressive disorder. Inflammasome ...activation causes the maturation of caspase-1 and activation of interleukin (IL)-1β and IL-18, two proinflammatory cytokines involved in neuroimmunomodulation, neuroinflammation and neurodegeneration. In this study, C57BL/6 mice with genetic deficiency or pharmacological inhibition of caspase-1 were screened for anxiety- and depressive-like behaviors, and locomotion at baseline and after chronic stress. We found that genetic deficiency of caspase-1 decreased depressive- and anxiety-like behaviors, and conversely increased locomotor activity and skills. Caspase-1 deficiency also prevented the exacerbation of depressive-like behaviors following chronic stress. Furthermore, pharmacological caspase-1 antagonism with minocycline ameliorated stress-induced depressive-like behavior in wild-type mice. Interestingly, chronic stress or pharmacological inhibition of caspase-1 per se altered the fecal microbiome in a very similar manner. When stressed mice were treated with minocycline, the observed gut microbiota changes included increase in relative abundance of Akkermansia spp. and Blautia spp., which are compatible with beneficial effects of attenuated inflammation and rebalance of gut microbiota, respectively, and the increment in Lachnospiracea abundance was consistent with microbiota changes of caspase-1 deficiency. Our results suggest that the protective effect of caspase-1 inhibition involves the modulation of the relationship between stress and gut microbiota composition, and establishes the basis for a gut microbiota-inflammasome-brain axis, whereby the gut microbiota via inflammasome signaling modulate pathways that will alter brain function, and affect depressive- and anxiety-like behaviors. Our data also suggest that further elucidation of the gut microbiota-inflammasome-brain axis may offer novel therapeutic targets for psychiatric disorders.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IntroductionAutism Spectrum Disorder and Social Anxiety Disorder are mental illnesses characterized by a dysfunction in social behavior (SB); a phenomenon largely mediated by the medial prefrontal ...cortex (mPFC). Clinical studies have demonstrated that lysergic acid diethylamide (LSD), a partial agonist of the 5-HT2A receptor, can promote SB. However, its mechanism of action on SB is unknown.ObjectivesTo assess the effects of repeated LSD administration on social behavior in mice and to identify which mPFC receptors mediate LSD’s behavioral effects.MethodsEight-week-old C57BL/6J male mice received vehicle or repeated LSD (30 μg/kg/day i.p. for 7 days) as well the selective 5-HT2A receptor antagonist MDL, or the AMPA receptor antagonist NBQX. Twenty-four hours following the last injection, mice underwent the Direct Social Interaction Test and the Three-Chamber Test (TCT) to assess sociability and preference for social novelty. in vivo electrophysiological recordings were performed in mice treated with vehicle or LSD using multi-barrelled electrodes for microiontophoretic ejections of the selective 5-HT2A receptor agonist DOI or the selective AMPA receptor agonist quisqualate on mPFC pyramidal neurons.ResultsRepeated treatment with low doses of LSD increased the interaction time in the DSI as well as sociability and social novelty indices in the TCT. These pro-social effects were blocked by the intra-PFC administration of both 5-HT2A and AMPA antagonists. LSD also potentiated, in a current-dependent manner, the excitatory response of mPFC neurons to 5-HT2Aand AMPA agonists.ConclusionsRepeated, low doses of LSD increases social behavior via a mechanism of action that is mediated by 5-HT2A and AMPA in the mPFC.
Figure1 Computed tomography shows a giant cystic lesion in the abdomen Figure2 Laparoscopic view of the giant ovarian right cyst after decompression Figure3 An intraumbilical incision is used to ...exteriorise and decompress the cyst Figure4 One 10-mm trocar (camera port) is placed through the umbilicus. Figure5 The ‘spaghetti manoeuvre’ is used to roll the cyst around a grasper Discussion Other authors have claimed that a minimally invasive approach is impractical for giant ovarian cysts because of the restricted operating field, the possibility of malignancy and the tendency of cysts to rupture, but we believe that pure laparoscopic evaluation and excision is a safe and feasible treatment if performed by experienced surgeons. The laparoscopic approach may reduce postoperative adhesions that can be associated with significant benefits, including improved fertility, reduction in pelvic pain and improved quality of life.
The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein ...Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
The extent of surgery for pediatric papillary thyroid carcinoma is debatable. The aim of this study was to evaluate the feasibility of offering pediatric patients a tailored surgical approach ...based on certain clinical features.
Methods
A national multicenter retrospective review of 250 pediatric patients treated for papillary thyroid carcinoma in a 14-year period was performed. Outcomes of interest included tumor-related features, type of surgery, surgical morbidity, disease-free and overall survival rates. Recurrence was thoroughly analyzed with particular focus on how it correlated with certain patient- and tumor-related features.
Results
The majority of patients (58.8 %) had tumors >2 cm in size. Nodal involvement occurred in 115/250 (46 %) patients and distant metastasis in 4 % (10/250). Total thyroidectomy and lobectomy were performed in 90.4 % (226/250) and 9.6 % (24/250) of patients, respectively. The overall rate of surgical complications was 20.8 % (52/250). These included transient and permanent hypoparathyroidism (13.6 and 4.4 %, respectively), and vocal fold palsy (2.8 %). All surgical complications occurred exclusively in the total thyroidectomy group. The rate of recurrent disease was 12 % (30/250) with the vast majority of recurrences (96.6 %) occurring in the total thyroidectomy group. The risk of recurrence correlated significantly with certain tumor-related features (size > 2 cm, multifocality, extrathyroidal invasion, nodal positivity, and distant metastasis). However, it did not correlate with the patient’s age or sex. Overall survival was 100 %.
Conclusion
Pediatric patients are likely to benefit from a tailored surgical strategy. Uniformly offering patients total thyroidectomy seems to be an overly radical approach.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Male patients treated for anorectal malformations (ARM) and recto-urethral fistula (RUF) tend to develop recurrent epididymo-orchitis (EO) which occurs approximately in 20% of all them.
The optimal ...management of this condition is unclear because of the extreme its rarity and the unavailability of detailed analysis in literature. To date the majority of this patients benefits from medical treatment and symptoms reduce over time but few data have been published in literature about management of patients with intractable EO.
To describe the efficacy of unilateral vasectomy in patients operated on for anorectal malformations with RUF and affected by intractable EO.
We present five patients who met the criteria for intractable EO, and followed at our centre four of whom have undergone unilateral vasectomy.
The first episode of EO presented at 42,00 mos ±29.39. Initially, patients were all managed with analgesics and antibiotics. For the failure of therapy, five patients were all offered unilateral vasectomy but only four families accepted procedure. Surgical treatment was performed as a day case without complications. Postoperative follow up was 88,50 mos ±68.36. Prompt and durable resolution of symptoms was observed.
The long-term effects of recurrent EO in ARM are often underestimated. Prompt and appropriate intervention should prevent this undesirable sequela. Unfortunately, the optimal management of this complication is unclear, partly because of its extreme rarity. The established management needs to follow the route of correcting underlying anomalies and providing long-term analgesic and antibiotics but this may have undesired side effects. We therefore offered families vasectomy for complete symptom resolution and/or drug withdrawal. Vasectomy, as a form of treatment for, can be justified if it can prevent pain, infection and destruction of the testes. Early vasectomy may save enough functional testis tissue.
To date, the only available treatment to achieve definitive resolution of symptoms in intractable unilateral EO is vasectomy. Long-term effects of such procedure on fertility are unknown. The treatment of recurrent EO in cases without site predilection remains a matter of contention.Summary TableMain features of case patients.Summary TableAge at recruitment (mos)Age at first EO (mos)Medical ManagementUEDR at VCUGUnilateral VasectomySide of VasectomyAge at UV (mos)Δ first EO-UVSymtoms ResolutionPO FU (mos)A242412 mos “on demand” AB and AGYesYesLeft3612Yes63B84726 mos AB prophylaxisNoYesLeft9220Yes60C37212 mos “on demand” AB and AGYesYesRight8412Yes190D3612 mos “on demand” AB and AGNoYesLeft2014Yes41E33612 mos “on demand"AB and AG + 4mosAB prophylaxisNoNo∖∖∖No∖Abbreviations: AB: antibiotics AG: analgesics; UEDR urethra-ejaculatory duct reflux; VCUG: voiding cystourethrography; UV unilateral vasectomy; Δ interval of time; PO postoperative; FU follow up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
Malignant ovarian germ cell tumors (MOGCT) carry an excellent prognosis, and the treatment aims to achieve results with the least possible treatment‐related morbidity. The aim of this study ...was to assess the outcomes of pediatric patients with MOGCT.
Methods
Patients were treated according to their stage: surgery and surveillance for stage I; a modified bleomycin–etoposide–cisplatin (BEP) regimen for stages II (three cycles), III, and IV (three cycles) with surgery on residual disease.
Results
Seventy‐seven patients were enrolled (median age 11.8 years), 26 with dysgerminoma (Dysg), 13 with immature teratoma and elevated serum alpha‐fetoprotein levels (IT + AFP), and 38 with nondysgeminoma (Non‐Dysg) staged as follows: 27 stage I, 13 stage II, 32 stage III, 5 stage IV. Among evaluable patients in stage I (5‐year event‐free survival EFS 72.1% 95% CI: 56.4–92.1%; 5‐year overall survival OS 100%), seven relapsed (three patients with Dysg and four patients with Non‐Dysg) and were rescued with chemotherapy (plus surgery in three patients). Among the evaluable patients with stages II–IV, 48 (98%) achieved complete remission after chemotherapy ± surgery, one (IT + AFP, stage IV) had progressive disease. In the whole series (median follow‐up 80 months), the 5‐year OS and EFS were 98.5% (95% CI: 95.6–100%) and 84.5% (95% CI: 76.5–93.5%).
Conclusions
We confirm the excellent outcome for MOGCT. Robust data are lacking on surgical staging, surveillance for Non‐Dysg with stage I, the management of IT + AFP, and the most appropriate BEP regimen. As pediatric oncologists, we support the role of surveillance after proper surgical staging providing cases are managed by experts at specialized pediatric centers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Among hospitalized adults and children pain is undertreated. This study wants to assess the effectiveness of pain therapy in two departments of a large children's hospital.
During a single day work ...three committees, administering a questionnaire to patients or parents, have evaluated the adherence to international recommendations (JCI and WHO) in the management of analgesic therapy. Patient demographics, prevalence and intensity (moderate and/or severe) of pain (during hospitalization, 24 hours before and at the time of the interview), analgesia (type, route, duration and frequency of administration) and Pain Management Index (=analgesic score-pain score) were recorded.
75 patients participated in the study (age: 2 months up to 24 years, mean 7.8 ± 6). During hospitalization 43 children (57%) had no pain while 32 (43%) have experienced pain. 22 children (29 %) had pain 24 hours before and 12 (16%) at the time of the interview. The average value of the PMI was -0.8±1.3 with a minimum of -3 and a maximum of +2: 60% (19) of the children had a PMI less than 0 (undertreated pain) while 40% (13) had a value=or>0. Out of 32 patients who needed an analgesic therapy 14 (44%) received an around-the-clock dosing, 8 (25%) an intermittent therapy and 10 (31%) no treatment.17 (77 %) were the single drug therapy and 5 (23%) the multimodal ones.
The prevalence of pain in the two departments is high. The main cause is that knowledge is not still well translated into clinical practice.
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