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The purpose of this study is to investigate if an orally administered combination of aspirin and ketamine will provide better analgesia than a ketamine alone in adult patients presenting to the Emergency Department (ED) with acute musculoskeletal pain.We conducted a prospective, randomized, open-label trial of ED patients aged 18 and older presenting with moderate to severe acute musculoskeletal pain as defined by an 11-point numeric rating scale (NRS) with an initial score of ≥5. Patients were randomized to receive either 324 mg of VTS-Aspirin™ and 0.5 mg/kg of oral ketamine (AOK) that is directly swallowed or 0.5 mg/kg of oral ketamine (OK) alone that is swished first and then swallowed. Patients were assessed at baseline, 30, 60, 90, and 120 min. The primary outcome was a difference in pain scores between the two groups at 60 min post-administration. Secondary outcomes included adverse events and the need for rescue analgesia.We enrolled 60 patients in the study (30 per group). The difference in mean pain scores at 60 min between the AOK and OK groups was 2.6 [95% CI: 1.38-3.77] showing a lower mean pain score in the OK group. At 60 min, the AOK group had a change in mean pain score from 8.4 to 6.3 (difference 2.1; 95% CI: 1.35-3.00). The OK group had a change in mean pain score from 7.8 to 3.7 (difference 4.1, 95% CI: 3.25-4.90). No clinically concerning changes in vital signs were observed. No serious adverse events occurred in either group. The most commonly reported adverse effects were dizziness and fatigue. None of the participants required rescue analgesia at 60 min post-medications administration.The administration of an oral combination of VTS-Aspirin ™ and ketamine resulted in less analgesia compared to oral ketamine alone, for the short-term treatment of moderate to severe acute musculoskeletal pain in the ED.govRegistration: NCT04860804.

Gulf War Illness (GWI), a disorder suffered by approximately 200,000 veterans of the first Gulf War, was caused by exposure to low-level organophosphate pesticides and nerve agents in combination with battlefield stress. To elucidate the mechanistic basis of the brain-related symptoms of GWI, human-induced pluripotent stem cells (hiPSCs) derived from veterans with or without GWI were differentiated into forebrain glutamatergic neurons and then exposed to a Gulf War (GW) relevant toxicant regimen consisting of a sarin analog and cortisol, a human stress hormone. Elevated levels of total and phosphorylated tau, reduced microtubule acetylation, altered mitochondrial dynamics/transport, and decreased neuronal activity were observed in neurons exposed to the toxicant regimen. Some of the data are consistent with the possibility that some veterans may have been predisposed to acquire GWI. Wistar rats exposed to a similar toxicant regimen showed a mild learning and memory deficit, as well as cell loss and tau pathology selectively in the CA3 region of the hippocampus. These cellular responses offer a mechanistic explanation for the memory loss suffered by veterans with GWI and provide a cell-based model for screening drugs and developing personalized therapies for these veterans.

Induced pluripotent stem cells (iPSCs) hold great promise for developing personalized regenerative medicine, however characterization of their biological features is still incomplete. Moreover, changes occurring in long-term cultured iPSCs have been reported, suggesting these as a model of cellular aging. For this reason, we addressed the ultrastructural characterization of iPSCs, with a focus on possible time-dependent changes, involving specific cell compartments. To this aim, we comparatively analysed cultures at different timepoints, by an innovative electron microscopic technology (FIB/SEM). We observed progressive loss of cell-to-cell contacts, associated with increased occurrence of exosomes. Mitochondria gradually increased, while acquiring an elongated shape, with well-developed cristae. Such mitochondrial maturation was accompanied by their turnover, as assessed by the presence of autophagomes (undetectable in young iPSCs), some containing recognizable mitochondria. This finding was especially frequent in middle-aged iPSCs, while being occasional in aged cells, suggesting early autophagic activation followed by a decreased efficiency of the process with culturing time. Accordingly, confocal microscopy showed age-dependent alterations to the expression and distribution of autophagic markers. Interestingly, responsivity to rapamycin, highest in young iPSCs, was almost lost in aged cells. Overall, our results strongly support long-term cultured iPSCs as a model for studying relevant aspects of cellular senescence, involving intercellular communication, energy metabolism, and autophagy.

Riboflavin is essential in numerous cellular oxidation/reduction reactions but is not synthesized by mammalian cells. Riboflavin absorption occurs through the human riboflavin transporters RFVT1 and RFVT3 in the intestine and RFVT2 in the brain. Mutations in these genes are causative for the Brown–Vialetto–Van Laere (BVVL), childhood-onset syndrome characterized by a variety of cranial nerve palsies as well as by spinal cord motor neuron (MN) degeneration. Why mutations in RFVTs result in a neural cell–selective disorder is unclear. As a novel tool to gain insights into the pathomechanisms underlying the disease, we generated MNs from induced pluripotent stem cells (iPSCs) derived from BVVL patients as an in vitro disease model. BVVL-MNs explained a reduction in axon elongation, partially improved by riboflavin supplementation. RNA sequencing profiles and protein studies of the cytoskeletal structures showed a perturbation in the neurofilament composition in BVVL-MNs. Furthermore, exploring the autophagy–lysosome pathway, we observed a reduced autophagic/mitophagic flux in patient MNs. These features represent emerging pathogenetic mechanisms in BVVL-associated neurodegeneration, partially rescued by riboflavin supplementation. Our data showed that this therapeutic strategy could have some limits in rescuing all of the disease features, suggesting the need to develop complementary novel therapeutic strategies.

Patient-derived induced pluripotent stem cells (iPSCs) provide a novel tool to investigate the pathophysiology of poorly known diseases, in particular those affecting the nervous system, which has been difficult to study for its lack of accessibility. In this emerging and promising field, recent iPSCs studies are mostly used as "proof-of-principle" experiments that are confirmatory of previous findings obtained from animal models and postmortem human studies; its promise as a discovery tool is just beginning to be realized. A recent number of studies point to the functional similarities between in vitro neurogenesis and in vivo neuronal development, suggesting that similar morphogenetic and patterning events direct neuronal differentiation. In this context, neuronal adhesion, cytoskeletal organization and cell metabolism emerge as an integrated and unexplored processes of human neurogenesis, mediated by the lack of data due to the difficult accessibility of the human neural tissue. These observations raise the necessity to understand which are the players controlling cytoskeletal reorganization and remodeling. In particular, we investigated human in vitro neurogenesis using iPSCs of healthy subjects to unveil the underpinnings of the cytoskeletal dynamics with the aim to shed light on the physiologic events controlling the development and the functionality of neuronal cells. We validate the iPSCs system to better understand the development of the human nervous system in order to set the bases for the future understanding of pathologies including developmental disorders (i.e. intellectual disability), epilepsy but also neurodegenerative disorders (i.e. Friedreich's Ataxia). We investigate the changes of the cytoskeletal components during the 30days of neuronal differentiation and we demonstrate that human neuronal differentiation requires a (time-dependent) reorganization of actin filaments, intermediate filaments and microtubules; and that immature neurons present a finely regulated localization of Glu-, Tyr- and Acet-TUBULINS. This study advances our understanding on cytoskeletal dynamics with the hope to pave the way for future therapies that could be potentially able to target cytoskeletal based neurodevelopmental and neurodegenerative diseases.

Our aims were to develop a noninvasive predictive tool to identify cirrhotic patients with esophageal varices and to evaluate whether portal Doppler ultrasonographic parameters may improve the value of other predictors. One hundred forty-three consecutive compensated cirrhotic patients underwent upper gastrointestinal endoscopy. Fourteen clinical, biochemical, ultrasonographic, and Doppler ultrasonographic parameters of each patient were also recorded. Esophageal varices were detected in 63 of the 143 patients examined (44%; 95% confidence interval [CI] 36.2-52.6). Medium and large esophageal varices were observed in 28 subjects (44%; 95% CI 31.4-58.4). Using stepwise logistic regression, presence of esophageal varices was independently predicted by prothrombin activity less than 70% (odds ratio [OR]: 5.83; 95% CI: 2.6-12.8), ultrasonographic portal vein diameter greater than 13 mm (OR: 2.92; 95% CI: 1.3-6.4), and platelet count less than 100 x 10(9)/L (OR: 2.83; 95% CI: 1.27-6.28). Variables included in the model were used to generate a simple incremental rule to evaluate each individual patient. The discriminating ability of the prediction rule was relevant (area under the curve: 0.80) and did not change by replacing ultrasonographic portal vein diameter with congestion index of portal vein. We concluded that compensated cirrhotic patients should be screened by upper gastrointestinal endoscopy when prothrombin activity less than 70%, platelet count less than 100 x 10(9)/L, and ultrasonographic portal vein diameter greater than 13 mm are observed, whereas those without any of these predictors should not undergo endoscopy. The contribution provided by portal Doppler ultrasonographic parameters does not appear of practical utility.

Portal hypertensive gastropathy (PHG) is frequently found among patients with hepatic cirrhosis and at present the only way to detect and follow PHG is via endoscopy.To assess gastric and intestinal permeability and investigate its relationship to endoscopic findings and indices of portal hypertension and hepatic function.Thirty-one non-diabetic patients with hepatic cirrhosis and PHG (PHG+) were studied and compared with 17 cirrhotic patients without PHG (PHG-). All patients underwent endoscopy for the assessment of PHG and Helicobacter pylori status, ultrasound determination of the diameters of spleen and portal vein, and, subsequently, an oral load of sucrose, lactulose, and mannitol. Sugar concentrations were determined in 6-h urine specimens and expressed as a percentage of the orally administered dose or as lactulose/mannitol ratio.The urinary sucrose excretion was significantly elevated in patients with PHG compared to those without (PHG+, 0.20% +/- 0.03; PHG-, 0.07% +/- 0.01; P0.001). No difference was found for the small intestinal probes lactulose and mannitol. Gastric sucrose permeability correlated positively with the endoscopic lesion score (P0.001), but not with other parameters of portal hypertension or hepatic function. H. pylori status did not influence gastric permeability. The sensitivity of this test reached 100% for PHG scores2.Gastric permeability to sucrose is increased in patients with PHG, independently of the presence of H. pylori. Sucrose permeability may be useful for the follow-up of patients with PHG.

Lateral meniscal cysts are usually small asymptomatic lesions, and to find a large cyst with extensive bony changes arising from this cyst is exceedingly rare. These changes are usually erosive defects of the tibia. Dull pain with an associated mass are classical findings. A 47-year-old man developed a symptomatic lateral meniscal cyst that eroded a large part of the lateral tibial plateau. Arthroscopy and arthrotomy with cyst excision was required in this case and led to the amelioration of his symptoms.

A retrospective study of imaging-directed percutaneous fine-needle aspiration cytology of focal renal lesions was performed. The objectives were to determine the efficacy and safety of renal aspiration biopsy in establishing the diagnosis of renal cell carcinoma and avoiding nephrectomy in patients with a renal mass and disseminated metastases or with a renal mass and relative contraindications to nephrectomy.Between September 1987 and September 1991, 55 consecutive patients had 57 imaging-directed renal aspiration biopsies at our institution. We examined the medical records, pathology reports, imaging studies, and follow-up information of the 23 patients who had the procedure because of disseminated metastases (10 patients) or relative contraindications to nephrectomy (13 patients). Preliminary diagnoses were based on the cytopathology, and final diagnoses were based on the surgical pathology (six patients) or clinical course over more than 6 months (17 patients).Cytopathologic findings were true-positive in 12 patients, true-negative in eight, false-negative in three, and false-positive in none. The sensitivity was 80%, the specificity was 100%, and the accuracy was 87%. Of the 10 patients with a renal mass and disseminated metastases, aspiration cytology failed to show malignancy in only one. None of these patients had surgery, and all died within 1 year. Of the 13 patients with relative contraindications to surgery, seven were treated without surgery. The cytologic diagnosis was renal cell carcinoma in two of the seven, and these two patients have since died. Cytopathology was negative for renal cell carcinoma in five of the seven, and subsequent imaging studies in these patients have shown no renal mass enlargement or metastases 2-3 years after biopsy (three patients) or the patients have died of severe heart disease (two patients). Nephrectomy was performed in the remaining six patients, and no evidence of disease had been found 2-4 years after removal of two oncocytomas and four renal cell carcinomas. There were no significant complications.Percutaneous renal aspiration biopsy cytology is accurate, safe, and useful in establishing the diagnosis of renal cell carcinoma in patients with disseminated metastases or relative contraindications to surgery.

The authors report their experience in the reconstruction of the anterior cruciate ligament using the Leeds-Keio ligament in 12 patients, 7 by open arthrotomy and 5 by an arthroscopic technique. The biological evolution of the new ligament was studied macroscopically and histologically in the first 6 cases treated by open arthrotomy. Arthroscopic monitoring and biopsy was carried out 4 to 10 months after operation. In 5 cases the new ligament appeared to be intact and histologically vital, with proliferation of new tissue along the new ligament. There were broken filaments of dacron hanging from the intercondylar cavity in only one case. The first macroscopic, histological and ultrastructural results show that despite a few limitations the Leeds-Keio ligament has the features required for replacement of the anterior cruciate ligament, although it will be necessary to wait 4 or 5 years before fully evaluating the durability and function of the ligament and the best operative method.