Occurrence of Taeniidae in a Middle Pleistocene speleothem of the Bàsura cave (Toirano, Liguria, Italy).

OBJECTIVE: This study aims to (i) analyse whether speleothems may contain fossil parasitic worm eggs and, if so, (ii) identify the pathogens involved, and (iii) place them in geological, palaeontological, and chronological contexts to know the zoonoses that could affect human and animal populations during the Middle Pleistocene. MATERIALS: A sample of calcite dated to the beginning of MIS 9 and MIS 8 from the Bàsura cave (Liguria, Italy) was analysed. METHODS: The chemical protocol applied is characterised using hydrochloric acid, the reduction of hydrofluoric acid application time, and by the absence of the use of base, dense liquor or acetolysis. RESULTS: An embryophore of a taeniid was recovered. CONCLUSIONS: Endoparasitic worm eggs can be found in speleothems. A taeniid embryophore was found in a calcite level dated to MIS 9. Zoonoses related to the Taeniidae family existed 300,000 years ago in the northern Mediterranean region and may have affected Middle Pleistocene predators, carnivores, or humans. Speleothems are good tools for paleoparasitological studies. SIGNIFICANCE: This is the oldest taeniid recovered and identified. LIMITATIONS: A more precise determination of the genus of this taeniid is not possible in the absence of more precise palaeontological data. SUGGESTIONS FOR FURTHER RESEARCH: An application of this approach to other Pleistocene speleothems could broaden the spectrum of parasites and their zoonoses over remote Pleistocene periods.

[Should you operate on a uterine septum ?] / Faut-il opérer un septum utérin ?

Uterine septum is the most common congenital uterine malformation and may cause obstetric problems such as repeated miscarriages, premature deliveries or dystocial presentations. It also appears to be associated with infertility. The uterine septum can be demonstrated by ultrasound, MRI and hysteroscopy. The benefit of hysteroscopic septoplasty remains controversial although most studies agree on the benefits of this treatment. It improves the fertility and obstetrical future of women by increasing the rate of pregnancies and live births and reducing the rate of miscarriages. Resection of the uterine septum is therefore encouraged in symptomatic patients but also in prophylaxis, in asymptomatic patients in order to increase the chances of carrying their pregnancy to term.

Le septum utérin est la malformation utérine congénitale la plus fréquente et peut être à l'origine de problèmes obstétricaux tels que des fausses couches à répétition, des accouchements prématurés ou des présentations dystociques. Par ailleurs, il semble également associé à une infertilité. Le septum utérin peut être mis en évidence à l'aide de l'échographie, de l'IRM et de l'hystéroscopie. Le bénéfice d'une septoplastie hystéroscopique reste controversé bien que la plupart des études s'accordent sur les bienfaits de ce traitement. En effet, il permet d'améliorer la fertilité et l'avenir obstétrical des patientes en augmentant le taux de grossesses et de naissances d'enfants vivants et en réduisant le taux de fausses couches. La résection du septum utérin est donc encouragée chez les patientes symptomatiques, mais également, en prophylaxie, chez des patientes asymptomatiques afin d'augmenter les chances de mener leur grossesse à terme.

Daily practice management of septate uterus: reproductive outcome after septoplasty.

Background: Septate uterus is the most common uterine malformation found in women presenting poor reproductive history. Hysteroscopic septoplasty (HS) restores the uterine anatomy in a safe procedure. Objectives: The goal of our study is to determine the reproductive outcomes after HS of symptomatic septate uterus. Materials and Methods: In a retrospective observational single centre study the reproductive outcomes and complications after HS were evaluated in 31 women with symptomatic septate uterus. The patients were separated into two groups according to the symptoms - infertility or recurrent pregnancy loss (RPL). Main outcome measures: were the pregnancy and live birth rate and secondarily the complication rate. Furthermore, the results were analysed depending on the need of assisted reproductive techniques (ART). Results: The treatment has resulted in an overall pregnancy rate of 71% for both groups. The spontaneous pregnancy rate is 45% and 8 pregnancies resulted from ART (26%). The overall first live birth rate is 51.6%. A decrease has been noticed in the miscarriage rate from 95.24% to 24% (p<0.001) in the overall population. Conclusions: In patients with a symptomatic septate uterus hysteroscopic septoplasty is a safe and effective procedure. The favourable results pointing out the benefits of surgery on the reproductive outcomes as well as the relatively simple and safe technique of HS make the intervention attractive.

Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG).

Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.

New research directions in medulloblastoma.

INTRODUCTION: Medulloblastoma is the most common type of pediatric malignant brain tumor where the most important amount of clinical and radiological data has been accumulated in recent years. This has led to its sophistication in the management of these patients with a clear benefit for the patients. Long-term outcome and sequelae have been described and their causes well understood such as preventive measures which can now be implemented. MATERIAL AND METHODS: This review paper does not attempt to make a systematic review of the literature in the field of research regarding medulloblastoma. It rather reflects more the opinion of a pediatric oncological team involved for a long time in this type of research. Therefore, a relevant literature review was carried out and selected by the senior author. RESULTS: Medulloblastoma is no longer a single entity but a group of at least 4 different diseases with a specific oncogenesis. In addition, biomarkers for prognosis have emerged to complement the known clinico-radiological risk factors. If this biological classification has allowed to modulate the therapeutic strategies, it has not yet brought many new drugs (except for the Sonic Hedgehog inhibitors) in the armamentarium against medulloblastomas. Consequently, some high-risk tumors remain difficult to cure. Combining data on oncogenesis and prognostic biomarkers will allow to define risk groups more specifically. New targeted therapies that are more effective and less toxic are desperately needed. Alternatively, it is also justified to study preventive measures to decrease the sequelae of the tumor and its treatments. From the therapeutic point of view, we scarcely know the biological determinants of chemosensitivity and radiosensitivity, as well as those associated with metastases which are indeed invaluable for tailored therapeutic strategies. CONCLUSION: If some genetic causes of medulloblastoma are known, the occurrence of the disease is largely unexplained for the others, justifying more research in this area. If genomics (and to a lesser extent epigenomics) of these neoplasms has been well studied, little is known on their proteomics and on the regulatory networks involved in the biological behavior of these tumor cells. New models are developed to test these aspects.

Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. METHODS: Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. RESULTS: 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). CONCLUSIONS: In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.

Boron doped diamond biotechnology: from sensors to neurointerfaces.

Boron doped nanocrystalline diamond is known as a remarkable material for the fabrication of sensors, taking advantage of its biocompatibility, electrochemical properties, and stability. Sensors can be fabricated to directly probe physiological species from biofluids (e.g. blood or urine), as will be presented. In collaboration with electrophysiologists and biologists, the technology was adapted to enable structured diamond devices such as microelectrode arrays (MEAs), i.e. common electrophysiology tools, to probe neuronal activity distributed over large populations of neurons or embryonic organs. Specific MEAs can also be used to build neural prostheses or implants to compensate function losses due to lesions or degeneration of parts of the central nervous system, such as retinal implants, which exhibit real promise as biocompatible neuroprostheses for in vivo neuronal stimulations. New electrode geometries enable high performance electrodes to surpass more conventional materials for such applications.

Grafting odorant binding proteins on diamond bio-MEMS.

Odorant binding proteins (OBPs) are small soluble proteins found in olfactory systems that are capable of binding several types of odorant molecules. Cantilevers based on polycrystalline diamond surfaces are very promising as chemical transducers. Here two methods were investigated for chemically grafting porcine OBPs on polycrystalline diamond surfaces for biosensor development. The first approach resulted in random orientation of the immobilized proteins over the surface. The second approach based on complexing a histidine-tag located on the protein with nickel allowed control of the proteins' orientation. Evidence confirming protein grafting was obtained using electrochemical impedance spectroscopy, fluorescence imaging and X-ray photoelectron spectroscopy. The chemical sensing performances of these OBP modified transducers were assessed. The second grafting method led to typically 20% more sensitive sensors, as a result of better access of ligands to the proteins active sites and also perhaps a better yield of protein immobilization. This new grafting method appears to be highly promising for further investigation of the ligand binding properties of OBPs in general and for the development of arrays of non-specific biosensors for artificial olfaction applications.

Three-dimensional electrode arrays for retinal prostheses: modeling, geometry optimization and experimental validation.

Three-dimensional electrode geometries were proposed to increase the spatial resolution in retinal prostheses aiming at restoring vision in blind patients. We report here the results from a study in which finite-element modeling was used to design and optimize three-dimensional electrode geometries. Proposed implants exhibit an array of well-like shapes containing stimulating electrodes at their bottom, while the common return grid electrode surrounds each well on the implant top surface. Extending stimulating electrodes and/or the grid return electrode on the walls of the cavities was also considered. The goal of the optimization was to find model parameters that maximize the focalization of electrical stimulation, and therefore the spatial resolution of the electrode array. The results showed that electrode geometries with a well depth of 30 µm yield a tenfold increase in selectivity compared to the planar structures of similar electrode dimensions. Electrode array prototypes were microfabricated and implanted in dystrophic rats to determine if the tissue would behave as hypothesized in the model. Histological examination showed that retinal bipolar cells integrate the electrode well, creating isolated cell clusters. The modeling analysis showed that the stimulation current is confounded within the electrode well, leading to selective electrical stimulation of the individual bipolar cell clusters and thereby to electrode arrays with higher spatial resolution.

Staphylococcus aureus on Computer Mice and Keyboards in Intensive Care Units of the Universitas Academic Hospital; Bloemfontein; and ICU staff's Knowledge of its Hazards and Cleaning Practices

Nosocomial infections result in severe health and financial difficulties for patients and healthcare facilities. The objective of the study was to determine the presence of Staphylococcus aureus on computer mice and keyboards in the intensive care units (ICUs) of Universitas Academic Hospital; Bloemfontein; and ICU staff's knowledge regarding cleaning of computer mice and keyboards and their potential hazard as reservoirs for pathogens. Swab specimens from computer mice and keyboards (14 each) were investigated for S. aureus. Swabbing was repeated six months later. Standard microbiology laboratory methods were used to culture and identify organisms. An anonymous questionnaire completed by the ICU staff determined their awareness of computer mice and keyboards as potential sources of nosocomial infections. In addition to various environmental microorganisms and normal human flora; S. aureus was initially isolated from one computer mouse; and from two keyboards and five mice six months later. The questionnaire response rate was 85.6. Seventy-one percent of respondents stated that they regarded keyboards and mice as an important source of nosocomial infections. Nevertheless; 62of doctors and 40.3of nurses indicated that they never washed their hands before or after using the computer. Ninety-seven percent of respondents were not aware of an official cleaning policy for computer equipment. In order to prevent nosocomial infections resulting from microbial transmission between equipment; staff and patients; proper cleaning policies should be implemented

BioMEA: a 256-channel MEA system with integrated electronics.

In order to understand the dynamics of large neural networks, where information is widely distributed over thousands of cells, one of today's challenges is to successfully record the simultaneous activities of as many neurons as possible. This is made possible by using microelectrodes arrays (MEAs) positioned in contact with the neural tissue. Thanks to microelectronics' microfabrication technologies, it now becomes possible to build high density MEAs containing several hundreds of microelectrodes. However, increasing the number of electrodes using conventional electronics is difficult to achieve. Moreover, high density devices addressing all channels independently for simultaneous recording and stimulation are not readily available. Here, we present a 256-channel in vitro MEA system with integrated electronics allowing simultaneous recording and stimulation of neural networks. Both actions are performed independently on all channels.

Parathyroid hormone fragments inhibit active hormone and hypocalcemia-induced 1,25(OH)2D synthesis.

Carboxyl (C)-terminal fragments of parathyroid hormone (PTH) oppose the calcemic, phosphaturic, and bone-resorbing effects of active hormone. To study the action of these fragments on 1,25(OH)(2)D (1,25-dihydroxyvitamin D) synthesis, we infused parathyroidectomized rats with human or rat active 1-34 or 1-84 PTH at doses selected to produce similar calcemic responses. Human active PTH influenced neither phosphate nor 1,25(OH)(2)D concentrations. However, active 1-34 rat PTH decreased phosphate to the same level as vehicle-treated rats and increased 1,25(OH)(2)D to very high levels, whereas active 1-84 PTH decreased phosphate but maintained 1,25(OH)(2)D. As the latter effect could have been due to C-terminal fragment generation during its metabolic breakdown, we infused a mixture of rat C-terminal fragments alone or with rat 1-34. The C-terminal fragments decreased 1,25(OH)(2)D and prevented hypocalcemic-induced 1,25(OH)(2)D synthesis. When infused with active rat 1-34, they lowered the 1,25(OH)(2)D level to that seen with intact rat 1-84. The C-terminal fragments did not influence either basal or rat 1-34- or 1-84-induced CYP27B1 mRNA levels, suggesting that their inhibitory effects on 1,25(OH)(2)D synthesis appears to be post-transcriptional.

High-sensitivity optical monitoring of a micromechanical resonator with a quantum-limited optomechanical sensor.

We experimentally demonstrate the high-sensitivity optical monitoring of a micromechanical resonator and its cooling by active control. Coating a low-loss mirror upon the resonator, we have built an optomechanical sensor based on a very high-finesse cavity (30 000). We have measured the thermal noise of the resonator with a quantum-limited sensitivity at the 10(-19) m/sqrt[Hz] level, and cooled the resonator down to 5 K by a cold-damping technique. Applications of our setup range from quantum optics experiments to the experimental demonstration of the quantum ground state of a macroscopic mechanical resonator.

Randomized trial of paroxetine in end-stage COPD.

BACKGROUND: Although the underlying pathology is initially confined to the lungs, the associated emotional responses to chronic obstructive pulmonary disease (COPD) contribute greatly to the resulting morbidity. The objective of this study was to examine the effect of an antidepressant drug on disease-specific quality of life in patients with end-stage COPD who present significant depressive symptoms. METHODS: We conducted a 12-week, randomized double-blind placebo-controlled trial of Paroxetine in which quality of life measured by the Chronic Respiratory Questionnaire (CRQ), an evaluative COPD-specific quality-of-life questionnaire, was the primary outcome. RESULTS: 23 patients were randomized and 15 completed the trial (8 on Paroxetine; 7 on placebo). In the per-protocol analysis, we observed statistically and clinically significant improvements favoring the active treatment in 2 of the 4 domains of the CRQ: emotional function (adjusted mean difference: 1.1; 95% confidence interval [CI]: 0.0 - 2.2) and mastery (difference: 1.1; CI: 0.4 - 1.8). Dyspnea and fatigue improved, but to an extent that did not reach statistical significance. In the intention-to-treat analysis, none of the differences in CRQ scores was significant. Paroxetine was not associated to any worsening of respiratory symptoms. CONCLUSIONS: The results of this small randomized trial indicated that patients with end-stage COPD may benefit from antidepressant drug therapy when significant depressive symptoms are present. This study underlined the difficulties in conducting experimental studies in frail and elderly patients with COPD.

Breathing frequency and use of expiratory muscles do influence the dynamic positive end-expiratory pressure.

End-expiratory air trapping due to obstructive airway disease can be estimated through the measurement of intrinsic positive end-expiratory pressure PEEPi. The influence of breathing-frequency and use of expiratory muscles on PEEPi were measured in 10 normal and 10 chronic bronchitic patients (COPD). Insignificant control values of PEEPi increased to measurable values at high breathing rate in normal subjects. Control values were higher in COPD patients and increased at fast breathing rate. When corrected for the use of expiratory muscles according to simultaneous gastric pressure drop, PEEPi decreased in COPD, but still increased at high rate. We conclude that modifying the respiratory rate can increase PEEPi values independently of the severity of airway obstruction and the use of expiratory muscles. Before estimating the pathological value of a PEEPi measurement or evaluating the effects of a treatment, we always need to know the simultaneous breathing frequency.

Does inspiratory behaviour affect the efficiency of non-invasive ventilation in COPD patients?

Non-invasive ventilation (NIV) is more and more used. Some failures of the technique have been reported, and efforts are needed to understand them. Collaboration (inspiratory behaviour) of the patient during NIV could play a role in the success of this technique. We have studied the influence of this one on the efficiency of NIV. While ventilating 10 stable chronic obstructive pulmonary disease patients with a nasal pressure support ventilation (PSV), we measured their flow and volume with a pneumotachograph and oesophageal and gastric pressures during three different respiratory voluntary behaviours: relaxed inspiration, active inspiratory effort and resisted inspiration. We showed that when compared with the relaxed inspiration: (a) Active inspiratory effort increases slightly minute ventilation from 14.8 +/- 4.7 to 15.41 +/- 4.19 during PSV 10/0 without change of breathing frequency but with an important increase of inspiratory work (W(OB)) from 14.47 +/- 9.43 to 28.55 +/- 25.35 J/min (P=0.008). PEEPi increases with active behaviour during PSV but not during BiPAP. (b) A resisted inspiration decreases inspiratory work (to 7.53 +/- 8.6 J/min) at the price of a decrease of the minute ventilation to 11.47 +/- 4.20 l/min (P=0.06). Results of ventilation, PEEPi and work parameters were identical during the bilevel pressure support (15/5 cm H2O). The aims of NIV being to increase ventilation and unload the inspiratory muscles, our results suggest that during NIV, a relaxed spontaneous breathing is preferable. These differences between the inspiratory behaviours could affect the expected benefits of PSV in acutely ill patients.

Origin of parathyroid hormone (PTH) fragments detected by intact-PTH assays.

BACKGROUND: Intact parathyroid hormone (I-PTH) assays react with non-(1-84)PTH, large carboxyl-terminal (C) fragments with a partially preserved amino-terminal (N) structure. They account for up to 50% of I-PTH in renal failure and may be implicated in PTH resistance. We wanted to know if they were secreted by the parathyroid glands and generated by peripheral metabolism of PTH(1-84). METHODS: Anesthetized normal and nephrectomized (NPX) rats were injected i.v. with 1.5 microg human (h) PTH(1-84). Blood was obtained from 8 rats at 2, 4, 6, 8, 12, 24, 48 and 96 min. I-PTH (Allegro I-PTH) was measured in all samples. Pools of serum were fractionated by HPLC at each time point and the fractions assayed to quantitate hPTH(1-84) and non-(1-84)PTH. Secretion studies were performed with dispersed cells from 5 parathyroid adenomas. The serum of 10 patients with primary hyperparathyroidism and cell supernatants were fractionated by HPLC and were analyzed as described. RESULTS: hPTH(1-84) disappeared from serum biexponentially. The half-life of the first exponential was similar in normal (2.08 min) and NPX (1.94 min) rats, while that of the second was longer in NPX rats (32.4 vs 20.9 min). The residual quantity of hPTH(1-84) under the curve was greater in NPX (6964+/-2392 pmol) than in normal rats (3229+/-561 pmol; P<0.001). Non-(1-84)PTH concentration was maximal at 8 min in both groups and was higher in NPX (92.8+/-13.8 pmol/l) than in normal rats (38.8+/-7.2 pmol/l; P<0.01). The area under the curve of non-(1-84)PTH was also greater in NPX (1904+/-405 pmol) than in normal rats (664+/-168 pmol; P<0.001). All parathyroid adenomas secreted non-(1-84)PTH. It represented 21.1+/-3.9% of secreted and 32.5+/-1.3% of circulating I-PTH in primary hyperparathyroidism. CONCLUSIONS: Non-(1-84)PTH, like other C-PTH fragments, originates from both the peripheral metabolism of hPTH(1-84) and from parathyroid gland secretion. Renal failure influences its concentration by increasing the amount of substrate available and by reducing non-(1-84)PTH clearance. Its higher proportion in serum relative to cell supernatants in primary hyperparathyroidism reflects the added role of peripheral metabolism and the longer half-life of fragments.