Combining olfactory test and motion analysis sensors in Parkinson's disease preclinical diagnosis: A pilot study

Objectives: Preclinical diagnosis of Parkinson's disease (PD) is nowadays a topic of interest as the neuropathological process could begin years before the appearance of motor symptoms. Several symptoms, among them hyposmia, could precede motor features in PD. In the preclinical phase of PD, a subclinical reduction in motor skills is highly likely. In this pilot study, we investigate a step-by-step method to achieve preclinical PD diagnosis. Material and methods: We used the IOIT (Italian Olfactory Identification Test) to screen a population of healthy subjects. We identified 20 subjects with idiopathic hyposmia. Hyposmic subjects underwent an evaluation of motor skills, at baseline and after 1 year, using motion analysis sensors previously created by us. Results: One subject showed significant worsening in motor measurements. In this subject, we further conducted a dopaminergic challenge test monitored with the same sensors and, finally, he underwent [123I]-FP/CIT (DaTscan) SPECT brain imaging. The results show that he is probably affected by preclinical PD. Conclusions: Our pilot study suggests that the combined use of an olfactory test and motor sensors for motion analysis could be useful for a screening of healthy subjects to identify those at a high risk of developing PD

Efficacy and safety of dalbavancin in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and other infections in a real-life setting: data from an Italian observational multicentric study (DALBITA study)

Objectives: We evaluated the efficacy and safety of dalbavancin in ABSSSI and ‘other sites’ infections’ (OTA). Methods: Observational study involving 11 Italian hospitals including patients that received ≥1 dose of dalbavancin in 2016–2019. The outcome was end-of-treatment efficacy and safety in ABSSSI and OTA in a real-life setting. Results: 206 patients enrolled (males 50%, median age 62 [IQR 50–76] years), 60.2% ABSSSI, 39.8% OTA. 69.7% ABSSSI vs 90.7% OTA (p = 0.003) and 46.3% ABSSSI vs 37.2% OTA (p = 0.786) received previous and concomitant antibiotics, respectively. 82.5% reached clinical cure. Eleven (5.4%) patients had non-serious adverse events (AE). OTA patients showed longer hospitalization (13.5 days, 5.5–22 vs 3, 0–11.7; p<0.0001) and received longer previous (18 days, 9–30 vs 11, 7–19; p = 0.007)/concomitant antibiotic treatments (21 days, 14–52 vs 11, 8–14; p < 0.0001), compared to ABSSSI. ABSSSI and OTA showed similar efficacy (85.5% vs 75%, p = 0.459) and safety (no AE: 81.5% vs 64.3%, p = 0.258); efficacy was independent of previous/concomitant therapies. Conclusions: Dalbavancin demonstrated a success rate of >80%, with similar efficacy/safety in ABSSSI and off-label indications. The preferential use of dalbavancin as second-line or combination therapy would seem to suggest the need for in-depth studies focused on its off-label use

Sea level changes during the last and present interglacials in Sal Island (Cape Verde archipelago)

Last interglacial and Holocene deposits are particularly well developed in the southern parts of Sal Island (Cape Verde Archipelago). They primarily consist of low-elevation (≤2 m above sea level [a.s.l.]) marine deposits made of a basal conglomerate embedded in carbonate mud, passing upwards to calcarenites. All deposits contain an abundant fauna with corals, algae and molluscs with Strombus latus Gmelin and accompanying warm water species of the “Senegalese” fauna. Small scale geomorphological mapping with detailed morphosedimentary analysis revealed lateral facies changes and imbricate (offlapping) structures that suggest small-scale oscillations of paleo-sealevels during high sea stand intervals. U-series measurements (in coral fragments) allowed unequivocal identification of Marine Isotope Substage (MIS) 5.5 units, but were not precise enough to date the sea level oscillations of the interval. However, geomorphological data and sedimentary facies analysis suggest a double sea level highstand during the peak of the last interglacial. MIS 5.5 age deposits occur at Sal and the Canary Islands at low topographic elevations, between 1 and 2 masl. However, these values are lower than the elevations measured for the correlative terraces outcropping at the western tropical Atlantic islands, widely considered to be tectonically stable. Combining the results in this paper with earlier investigations of the “Senegalese” fauna distribution as far north as the Mediterranean basin, it is suggested that the last-interglacial oceanic temperatures in this basin, as well as the temperatures in other islands of the Eastern Atlantic and the coasts of Morocco, were warmer than modern temperatures

The Salt Sensitivity Induced by Disruption of Cell Wall-Associated Kinase 1 (SlWAK1) Tomato Gene Is Linked to Altered Osmotic and Metabolic Homeostasis

omato cell wall-associated kinase 1 (SlWAK1) has only been studied in biotic stress response and hence its function in abiotic stress remains unknown. In a screening under salinity of an insertional mutant collection of tomato (Solanum lycopersicum L.), a mutant exhibiting lower degree of leaf chlorosis than wild type (WT) together with reduced leaf Na+ accumulation was selected. Genetic analysis of the mutation revealed that a single T-DNA insertion in the SlWAK1 gene was responsible of the mutant phenotype. Slwak1 null mutant reduced its shoot growth compared with WT, despite its improved Na+ homeostasis. SlWAK1 disruption affected osmotic homeostasis, as leaf water content was lower in mutant than in WT under salt stress. In addition, Slwak1 altered the source-sink balance under salinity, by increasing sucrose content in roots. Finally, a significant fruit yield reduction was found in Slwak1 vs. WT under long-term salt stress, mainly due to lower fruit weight. Our results show that disruption of SlWAK1 induces a higher sucrose transport from source leaf to sink root, negatively affecting fruit, the main sink at adult stage

Dlk/ZIP kinase-induced apoptosis in human medulloblastoma cells: requirement of the mitochondrial apoptosis pathway

Dlk/ZIP kinase is a member of the Death Associated Protein (DAP) kinase family of pro-apoptotic serine/threonine kinases that have been implicated in regulation of apoptosis and tumour suppression. Expression of both Dlk/ZIP kinase and its interaction partner Par-4 is maintained in four medulloblastoma cell lines investigated, whereas three of seven neuroblastoma cell lines have lost expression of Par-4. Overexpression of a constitutively pro-apoptotic deletion mutant of Dlk/ZIP kinase induced significant apoptosis in D283 medulloblastoma cells. Cell death was characterized by apoptotic membrane blebbing, and a late stage during which the cells had ceased blebbing and were drastically shrunken or disrupted into apoptotic bodies. Over-expression of the anti-apoptotic Bcl-xL protein had no effect on Dlk/ZIP kinase-induced membrane blebbing, but potently inhibited Dlk/ZIP kinase-induced cytochrome c release and transition of cells to late stage apoptosis. Treatment with caspase inhibitors delayed, but did not prevent entry into late stage apoptosis. These results demonstrate that Dlk/ZIP kinase-triggered apoptosis involves the mitochondrial apoptosis pathway. However, cell death proceeded in the presence of caspase inhibitors, suggesting that Dlk/ZIP kinase is able to activate alternative cell death pathways. Alterations of signal transduction pathways leading to Dlk/ZIP kinase induced apoptosis or loss of expression of upstream activators could play important roles in tumour progression and metastasis of neural tumours. © 2001 Cancer Research Campaign http://www.bjcancer.co

Mutations targeting the coagulation pathway are enriched in brain metastases

Brain metastases (BMs) are the most common malignancy of the central nervous system. Recently it has been demonstrated that plasminogen activator inhibitor serpins promote brain metastatic colonization, suggesting that mutations in serpins or other members of the coagulation cascade can provide critical advantages during BM formation. We performed whole-exome sequencing on matched samples of breast cancer and BMs and found mutations in the coagulation pathway genes in 5 out of 10 BM samples. We then investigated the mutational status of 33 genes belonging to the coagulation cascade in a panel of 29 BMs and we identified 56 Single Nucleotide Variants (SNVs). The frequency of gene mutations of the pathway was significantly higher in BMs than in primary tumours, and SERPINI1 was the most frequently mutated gene in BMs. These findings provide direction in the development of new strategies for the treatment of BMs

Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6–12 months) subpopulation of OVA-301 phase III randomized trial

Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [6–12 months platinum-free interval (PFI)] is unclear

Radiating on Oceanic Islands: Patterns and Processes of Speciation in the Land Snail Genus Theba (Risso 1826)

Island radiations have played a major role in shaping our current understanding of allopatric, sympatric and parapatric speciation. However, the fact that species divergence correlates with island size emphasizes the importance of geographic isolation (allopatry) in speciation. Based on molecular and morphological data, we investigated the diversification of the land snail genus Theba on the two Canary Islands of Lanzarote and Fuerteventura. Due to the geological history of both islands, this study system provides ideal conditions to investigate the interplay of biogeography, dispersal ability and differentiation in generating species diversity. Our analyses demonstrated extensive cryptic diversification of Theba on these islands, probably driven mainly by non-adaptive allopatric differentiation and secondary gene flow. In a few cases, we observed a complete absence of gene flow among sympatrically distributed forms suggesting an advanced stage of speciation. On the Jandía peninsula genome scans suggested genotype-environment associations and potentially adaptive diversification of two closely related Theba species to different ecological environments. We found support for the idea that genetic differentiation was enhanced by divergent selection in different environments. The diversification of Theba on both islands is therefore best explained by a mixture of non-adaptive and adaptive speciation, promoted by ecological and geomorphological factors

Consensus criteria for chronic rhinosinusitis disease control:an international Delphi Study

Background: Chronic rhinosinusitis (CRS) disease control is a global metric of disease status for CRS. While there is broad acceptance that it is an important treatment goal, there has been inconsistency in the criteria used to define CRS control. The objective of this study was to identify and develop consensus around essential criteria for assessment of CRS disease control. Methods: Modified Delphi methodology consisting of three rounds to review a list of 24 possible CRS control criteria developed by a 12-person steering committee. The core authorship of the multidisciplinary EPOS 2020 guidelines was invited to participate. Results: Thirty-two individuals accepted the invitation to participate and there was no dropout of participants throughout the entire study (3 rounds). Consensus essential criteria for assessment of CRS control were: overall symptom severity, need for CRS-related systemic corticosteroids in the prior 6 months, severity of nasal obstruction, and patient-reported CRS control. Near-consensus items were: nasal endoscopy findings, severity of smell loss, overall quality of life, impairment of normal activities and severity of nasal discharge. Participants’ comments provided insights into caveats of, and disagreements related to, near-consensus items. Conclusions: Overall symptom severity, use of CRS-related systemic corticosteroids, severity of nasal obstruction, and patient-reported CRS control are widely agreed upon essential criteria for assessment of CRS disease control. Consideration of near-consensus items to assess CRS control should be implemented with their intrinsic caveats in mind. These identified consensus CRS control criteria, together with evidence-based support, will provide a foundation upon which CRS control criteria with wide-spread acceptance can be developed