Laparoscopic removal of mullerian duct remnants in boys

Abstract: Purpose: Mullerian duct remnants (MDRs) are present in a male pseudohermaphroditic form characterized by failure of the mullerian duct to regress due to insufficient production or peripheral action of mullerian inhibiting substance. The MDR can be asymptomatic but it often results in infections, stones and voiding troubles. Furthermore, it may develop into a neoplasm. Therefore, surgery is mandatory for large MDRs and symptomatic patients. Laparoscopic removal is described. Materials and Methods: Six males were treated from February 1998 to February 2003. Age at surgery was between 3 and 18 years (mean 8.6). All patients showed severe hypospadias and 2 had mixed gonadal dysgenesis with ambiguous genitalia. Three patients presented with urogenital infections and all had a large MDR. Laparoscopic procedures, which were preceded by cystoscopy, were performed using a 10 mm umbilical trocar for the camera and 3, 5 mm trocars for instruments placed in the suprapubic region and iliac fossa bilaterally. The remnants were ligated with endoscopic loops or an endoscopic GIA stapler and cut. Results: Mean operative time was 2 hours. We noted no complications. In 2 cases there was deferential ectopia and in another of mixed gonadal dysgenesis bilateral gonadectomy was performed because of the risk of degeneration. Feeding started on postoperative day I and the patients were discharged home on day 5. After a followup of 8 months to 4 years all boys were healthy. Conclusions: Multiple approaches are used in traditional surgery, often leading to complications. Laparoscopy improves the view, decreases surgical risk and operative time, avoids large scars and allows more rapid hospital discharge

Hepatic epidermoid cyst

open6noWe describe the extraordinary finding of a hepatic epidermoid cyst in a 5-year-old patient, treated successfully with laparoscopic deroofing and mucosal stripping. The pathologic examination revealed a cyst with the same features of a true epithelial splenic cyst whose origin is still controversial, even though a coelomic derivation is the most accredited hypothesis. A cyst in this anatomic district with such characteristics has never been described in existent literature.openDi Salvo, N.*; Libri, M.; Gargano, T.; Salfi N; Ruggeri, G.; Lima, M.Di Salvo, N.*; Libri, M.; Gargano, T.; Salfi N; Ruggeri, G.; Lima, M

Amniotic fluid absorption and growth functions in humans: what can we indirectly learn from congenital digestive atresias?

Background: Amniotic fluid (AF) was thought of just as a mechanical cushioning to the foetus. Nowadays, its role during pregnancy is getting more attention, suggesting hitherto unknown aspects. The aim of the study is to speculate on AF nutritional functions and its clinical repercussions based on what digestive tract (DT) atresias seem to suggest. Methods: A retrospective analysis of the patients admitted to our department for DT atresias between 2000 and 2020 was conducted. Patients’ birth weight (BW), gestational age (GA) at birth and diagnosis were recorded. The following were excluded from the study: oesophageal atresias (OA) with tracheoesophageal fistula (TOF), colonic and anal atresias and patients with associated major comorbidities. A control group was made of patients admitted to our ward in the same period for congenital pulmonary airway malformations (CPAM). To standardize the BW, it was coupled with birth GA calculating the newborn percentiles. The mean newborn percentiles of OAs, duodenal atresias (DAs), jejunal atresias (JAs), and ileal atresias (IAs) were independently compared with the control group using Student’s t-test. Lastly, the significance of the frequencies’ distribution of newborns born small for gestational age (SGA) between the DT atresias and the control group was evaluated with the χ2 test, and the OR were calculated. A p-value < 0.05 was considered statistically significant. Results: A total of 231 patients were eligible for the study: 36 OAs without TOF, mean BW 2488.8 ± 491 g (range 1630–3750 g), mean GA 36.8 ± 2.1 weeks (31–40 weeks), mean newborn percentile 18 ± 22 (1–75); 20 DAs, mean BW 2586.8 ± 577.9 g (1250–3462 g), mean GA 36.2 ± 2.5 weeks (31–40 weeks), mean newborn percentile 31 ± 23 (3–79); 17 JAs, mean BW 2483.5 ± 621.7 g (900–3205 g), mean GA 34.8 ± 2.1 weeks (30–38 weeks), mean newborn percentile 44 ± 28 (4–96); 17 IAs, mean BW 2646.1 ± 769.8 g (1162.0–3888 g), mean GA 35.9 ± 3.2 weeks (30–41 weeks), mean newborn percentile 44 ± 26 (1–82); and 141 CPAMs with mean BW 3287.4 ± 492.0 g (980–4580 g), mean GA 38.7 ± 1.8 weeks (26–41 weeks), mean newborn percentile 43 ± 26 (1–99). The number of SGA neonates was 18 between OA patients (50%), 4 between DAs (20%), 1 between JAs (6%), 2 between IAs (12%) and 11 between CPAMs (8%). The mean percentile of the OAs and DAs was lower than the control group with a p of < .01 and .03 while no statistical significance was found in the comparison between DAs, JAs, IAs and CPAMs with a p of .06, .86 and .59. The incidence of SGA in the control group resulted lower than the one in the DT atresias where it becomes higher the more proximal the atresia is (p < .05). The OR of SGA newborn in the OA group was 11.8, in DA 3.0, in JA 0.7 and in IA 1.6. Conclusion: AF showed to have a great impact on foetal growth, and its preferred site of absorption seemed to be the stomach and duodenum. Its nutritional role could have an important predictive value in diagnosing DT atresia both prenatally and postnatally

SmarTEG: An autonomous wireless sensor node for high accuracy accelerometer-based monitoring

We report on a self-sustainable, wireless accelerometer-based system for wear detection in a band saw blade. Due to the combination of low power hardware design, thermal energy harvesting with a small thermoelectric generator (TEG), an ultra-low power wake-up radio, power management and the low complexity algorithm implemented, our solution works perpetually while also achieving high accuracy. The onboard algorithm processes sensor data, extracts features, performs the classification needed for the blade’s wear detection, and sends the report wirelessly. Experimental results in a real-world deployment scenario demonstrate that its accuracy is comparable to state-of-the-art algorithms executed on a PC and show the energy-neutrality of the solution using a small thermoelectric generator to harvest energy. The impact of various low-power techniques implemented on the node is analyzed, highlighting the benefits of onboard processing, the nano-power wake-up radio, and the combination of harvesting and low power design. Finally, accurate in-field energy intake measurements, coupled with simulations, demonstrate that the proposed approach is energy autonomous and can work perpetually

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network

Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt–Jakob disease: evaluation of a first-in-human treatment programme

Background: Human prion diseases, including Creutzfeldt–Jakob disease (CJD), are rapidly progressive, invariably fatal neurodegenerative conditions with no effective therapies. Their pathogenesis involves the obligate recruitment of cellular prion protein (PrPC) into self-propagating multimeric assemblies or prions. Preclinical studies have firmly validated the targeting of PrPC as a therapeutic strategy. We aimed to evaluate a first-in-human treatment programme using an anti-PrPC monoclonal antibody under a Specials Licence. Methods: We generated a fully humanised anti-PrPC monoclonal antibody (an IgG4κ isotype; PRN100) for human use. We offered treatment with PRN100 to six patients with a clinical diagnosis of probable CJD who were not in the terminal disease stages at the point of first assessment and who were able to readily travel to the University College London Hospital (UCLH) Clinical Research Facility, London, UK, for treatment. After titration (1 mg/kg and 10 mg/kg at 48-h intervals), patients were treated with 80–120 mg/kg of intravenous PRN100 every 2 weeks until death or withdrawal from the programme, or until the supply of PRN100 was exhausted, and closely monitored for evidence of adverse effects. Disease progression was assessed by use of the Medical Research Council (MRC) Prion Disease Rating Scale, Motor Scale, and Cognitive Scale, and compared with that of untreated natural history controls (matched for disease severity, subtype, and PRNP codon 129 genotype) recruited between Oct 1, 2008, and July 31, 2018, from the National Prion Monitoring Cohort study. Autopsies were done in two patients and findings were compared with those from untreated natural history controls. Findings: We treated six patients (two men; four women) with CJD for 7–260 days at UCLH between Oct 9, 2018, and July 31, 2019. Repeated intravenous dosing of PRN100 was well tolerated and reached the target CSF drug concentration (50 nM) in four patients after 22–70 days; no clinically significant adverse reactions were seen. All patients showed progressive neurological decline on serial assessments with the MRC Scales. Neuropathological examination was done in two patients (patients 2 and 3) and showed no evidence of cytotoxicity. Patient 2, who was treated for 140 days, had the longest clinical duration we have yet documented for iatrogenic CJD and showed patterns of disease-associated PrP that differed from untreated patients with CJD, consistent with drug effects. Patient 3, who had sporadic CJD and only received one therapeutic dose of 80 mg/kg, had weak PrP synaptic labelling in the periventricular regions, which was not a feature of untreated patients with sporadic CJD. Brain tissue-bound drug concentrations across multiple regions in patient 2 ranged from 9·9 μg per g of tissue (SD 0·3) in the thalamus to 27·4 μg per g of tissue (1·5) in the basal ganglia (equivalent to 66–182 nM). Interpretation: Our academic-led programme delivered what is, to our knowledge, the first rationally designed experimental treatment for human prion disease to a small number of patients with CJD. The treatment appeared to be safe and reached encouraging CSF and brain tissue concentrations. These findings justify the need for formal efficacy trials in patients with CJD at the earliest possible clinical stages and as prophylaxis in those at risk of prion disease due to PRNP mutations or prion exposure. Funding: The Cure CJD Campaign, the National Institute for Health Research UCLH Biomedical Research Centre, the Jon Moulton Charitable Trust, and the UK MRC

Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial

Importance: Mutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD. Objective: To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations. / Interventions: An escalating dose of oral ambroxol to 1.26 g per day. Design, Setting, and Participants: This single-center open-label noncontrolled clinical trial was conducted between January 11, 2017, and April 25, 2018, at the Leonard Wolfson Experimental Neuroscience Centre, a dedicated clinical research facility and part of the University College London Queen Square Institute of Neurology in London, United Kingdom. Participants were recruited from established databases at the Royal Free London Hospital and National Hospital for Neurology and Neurosurgery in London. Twenty-four patients with moderate PD were evaluated for eligibility, and 23 entered the study. Of those, 18 patients completed the study; 1 patient was excluded (failed lumbar puncture), and 4 patients withdrew (predominantly lumbar puncture-related complications). All data analyses were performed from November 1 to December 14, 2018. / Main Outcomes and Measures: Primary outcomes at 186 days were the detection of ambroxol in the CSF and a change in CSF GCase activity. / Results: Of the 18 participants (15 men [83.3%]; mean [SD] age, 60.2 [9.7] years) who completed the study, 17 (8 with GBA1 mutations and 9 without GBA1 mutations) were included in the primary analysis. Between days 0 and 186, a 156-ng/mL increase in the level of ambroxol in CSF (lower 95% confidence limit, 129 ng/mL; P < .001) was observed. The CSF GCase activity decreased by 19% (0.059 nmol/mL per hour; 95% CI, -0.115 to -0.002; P = .04). The ambroxol therapy was well tolerated, with no serious adverse events. An increase of 50 pg/mL (13%) in the CSF α-synuclein concentration (95% CI, 14-87; P = .01) and an increase of 88 ng/mol (35%) in the CSF GCase protein levels (95% CI, 40-137; P = .002) were observed. Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, -10.4 to -3.1; P = .001). These changes were observed in patients with and without GBA1 mutations. / Conclusions and Relevance: The study results suggest that ambroxol therapy was safe and well tolerated; CSF penetration and target engagement of ambroxol were achieved, and CSF α-synuclein levels were increased. Placebo-controlled clinical trials are needed to examine whether ambroxol therapy is associated with changes in the natural progression of PD. Trial Registration: ClinicalTrials.gov identifier: NCT02941822; EudraCT identifier: 2015-002571-24