Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of ...movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies.
Background
Since May 2022, a new outbreak of monkeypox has been reported in several countries, including Spain. The clinical and epidemiological characteristics of the cases in this outbreak may ...differ from those in earlier reports.
Objectives
To document the clinical and epidemiological characteristics of cases of monkeypox in the current outbreak.
Methods
We conducted a prospective cross‐sectional study in multiple medical facilities in Spain to describe the cases of monkeypox in the 2022 outbreak.
Results
In total, 185 patients were included. Most cases started with primarily localized homogeneous papules, not pustules, in the probable area of inoculation, which could be cutaneous or mucous, including single lesions. Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms. Less common lesions included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Four patients were hospitalized, none died. Smallpox vaccination and well‐controlled HIV disease were not associated with markers of severity. Contact during sex is the most likely mechanism of transmission. In this outbreak, cases have been described in men who have sex with men and are strongly associated with high‐risk sexual behaviours. Seventy‐six per cent of the patients had other sexually transmitted diseases upon screening.
Conclusions
The clinical findings in this outbreak differ from previous findings and highly suggest contact transmission and initiation at the entry site. The characterization of the epidemiology of this outbreak has implications for control.
What is already known about this topic?
Monkeypox eruption is described as consisting of pustules.
The roles of HIV and previous smallpox vaccination in the prognosis are unknown.
The transmission route was initially described as respiratory droplets and was later suggested to be via sexual contact.
What does this study add?
Initial lesions at the probable inoculation area were homogeneous and papular (pseudopustules). Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms.
Less common signs included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Well‐controlled HIV and previous smallpox vaccination were not associated with severity. No patient died.
The data support the hypothesis of transmission via contact during sex. Although this might change, the outbreak is currently limited mostly to men who have sex with men, with high‐risk factors for sexually transmitted diseases.
Monkeypox eruption starts as pseudopustules at the inoculation site and can be followed by distant pustular lesions. It is transmitted by contact and, although it can be very uncomfortable, no patient in our series died.
Linked Comment: R.E. Watchorn and C.B. Bunker. Br J Dermatol 2022; 187:636–637.
Plain language summary available online
Abstract Striatal neurons forming the indirect pathway (iSPNs) are particularly vulnerable in Huntington's disease (HD). In this study we set out to investigate morphological and physiological ...alterations of iSPNs in two mouse models of HD with relatively slow disease progression (long CAG repeat R6/2 and zQ175-KI). Both were crossed with a transgenic mouse line expressing eGFP in iSPNs. Using the open-field and rotarod tests, we first defined two time points in relation to the occurrence of motor deficits in each model. Then, we investigated electrophysiological and morphological properties of iSPNs at both ages. Both HD models exhibited increased iSPN excitability already before the onset of motor deficits, associated with a reduced number of primary dendrites and decreased function of Kir- and voltage-gated potassium channels. Alterations that specifically occurred at symptomatic ages included increased calcium release by back-propagating action potentials in proximal dendrites, due to enhanced engagement of intracellular calcium stores. Moreover, motorically impaired mice of both HD models showed a reduction in iSPN spine density and progressive formation of huntingtin (Htt) aggregates in the striatum. Our study therefore reports iSPN-specific alterations relative to the development of a motor phenotype in two different mouse models of HD. While some alterations occur early and are partly non-progressive, others potentially provide a pathophysiological marker of an overt disease state.
Purpose
To investigate the impact of preoperative nutritional factors body mass index (BMI), hypoalbuminemia (< 3.5 g/dL, sarcopenia) on complication and mortality rates after radical cystectomy (RC) ...for bladder cancer.
Methods
The PubMed database was systematically searched for studies investigating the effect of nutritional status on postoperative outcomes after RC. English-language articles published between March 2010 and March 2020 were reviewed. For statistical analyses odds ratios (ORs) and hazard ratios (HRs) weighted mean was applied.
Results
Overall, 81 studies were included. Twenty-nine studies were enrolled in the final analyses. Patients with a 25–29.9 kg/m
2
BMI (OR 1.55, 95% confidence interval CI 1.14–2.07) and those with a BMI ≥ 30 kg/m
2
(OR 1.73, 95% CI 1.29–2.40) had a significantly increased risk of 30 day complications after RC. Preoperative hypoalbuminemia increased the risk of 30 day complications (OR 1.56, 95% CI 1.07–2.35); it was a predictor of worse 3 year overall survival (OS) (HR 1.86, 95% CI 1.32–2.66). Sarcopenic patients had a higher risk of 90 day complications than non-sarcopenic ones (OR 2.49, 95% CI 1.22–5.04). Sarcopenia was significantly associated with unfavorable 5 year cancer-specific survival (CSS) (HR 1.73, 95% CI 1.07–2.80), and OS (HR 1.60, 95% CI 1.13–2.25).
Conclusion
High BMI, hypoalbuminemia, and sarcopenia significantly increased the complication rate after RC. Hypoalbuminemia predicted worse 3 year OS and sarcopenia predicted unfavorable 5 year CSS and OS. Preoperative assessment of RC patients’ nutritional status is a useful tool to predict perioperative and survival outcomes.
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•The highly suitable areas are those along the coasts of Gargano and Manfredonia.•The existing fish farms are located in suitable areas.•The existing shellfish farms are often in ...areas resulted unsuitable.•Spatial integration of different data has supported the MSP framework.•MSP allows a balance between conservation and sustainable use of marine habitat.
An efficient and adaptive strategy within the EU Marine Spatial Planning Directive has to manage the existing and increasing conflicts between human uses and habitat conservation in coastal-marine areas. Among the different human activities developed along the coasts, aquaculture occupies a primary role. In this context, the aims of this research have been: (1) to propose a conceptual model suitable for aquaculture marine spatial planning; (2) to collect and integrate indicators useful for the characterization of the study area in terms of socio-ecological-economic sensitivities and pressures; and (3) to identify and map the most suitable areas for the development of new fish and shellfish farms. The study area is the Apulia Region (Southern Italy) with a coastline of about 1,000 km, in the Adriatic and Ionian Seas, and characterized by several economic activities within a high value natural context. The evaluation of area’s suitability for fish and shellfish farms have been carried out through the ecological characterization of the coastal areas, the identification of the socio-economic, ecological, cultural, and legal-military constraints and the estimate of the “Suitability Index” that, through a Weighted Linear Combination, integrates environmental variables and allows to classify areas as “Highly Suitable”, “Suitable” or “Unsuitable”. The “highly suitable areas” for new fish and shellfish farms are mainly located in northernmost of the Southern Adriatic Sea along the Gargano coast and in the Gulf of Manfredonia, whilst concerning the Northern Ionian Sea they are at a mean distance of 5 Km from the shoreline. The suitability maps have shown that existing fish farms are in line with their suitable areas but, surprisingly, this has seemed not to be true for shellfish farms. This can be explained by the fact that these aquaculture activities have traditionally been present in some areas (e.g., Taranto Seas), currently strongly impacted by human activities. This research has highlighted that despite aquaculture is generally conceived as an environmental impacting activity, it could be also impacted by other environmental and/or anthropic stressors (i.e., industrial ports, sewage discharges). Considering all these elements, the present research addresses decision-makers, providing information and tools necessary to plan in a more aware way, and also stakeholders interested in investing in the aquaculture sector, who could benefit from the proposed suitability maps for fish and shellfish farms for a sustainable development of this sector.
Background. Cow’s milk allergy (CMA) is the most common food allergy in early childhood. Children with CMA require a precise and punctual diagnosis. Oral food challenge (OFC) is the gold-standard ...procedure for diagnosing allergies, but it is laborious and requires a particular setting. The aim of the study was to identify the cutoff value of serum allergen-specific IgE values able to predict a positive response to OFC. Methods. Children with suspected CMA performed OFC with cow’s milk (CM) or derivatives. Total IgE and specific IgE to raw CM, α-lactalbumin, β-lactoglobulin, and casein were measured. Results. Seventy-two children performed OFC, and 30 (41.6%) had a positive response. The significant predictive factors were sensitization to raw CM extract (p=0.03), α-lactalbumin (p=0.013), β-lactoglobulin (p=0.09), and casein (p=0.019). The cutoff was, respectively: 5.13 kUA/L for raw CM, 1.47 for α-lactalbumin, 1.35 for β-lactoglobulin, and 4.87 for casein. Conclusions. This study allowed us to define a set of cutoff values for CM protein-specific IgE. However, these cutoffs should be interpreted not as a diagnostic tool for CMA but only predictive of response to OFC in a specific territory. Thus, the practical message may be that a value above the cutoff allows a good approximation to identify children to be started on OFC.
To construct monochorionic (MC) twin-specific longitudinal Doppler references for umbilical artery pulsatility index (UA-PI), middle cerebral artery (MCA) PI and peak systolic velocity (PSV) and ...ductus venosus (DV) PI derived from a strictly selected cohort of uncomplicated MC twins. The secondary aim of the study was to compare our findings with singleton reference charts.
A retrospective evaluation was made of all consecutive uncomplicated MC twin pregnancies referred to our Unit from 2010 to 2018. Fortnightly serial examinations were performed of UA-PI, MCA-PI, MCA-PSV and DV-PI, according with the clinical protocol, from 20 to 37 weeks of gestation. We included cases with at least four ultrasound examinations, delivery at our hospital and complete neonatal follow up. A two-step method was used to trace the estimated centile curves: estimation of the median was performed with appropriate fractional polynomials by a multilevel model and estimation of the external centiles through the residuals (quantile regression). The comparison with singletons was made by plotting the references derived from the present study on the referred charts commonly used for singletons.
The study group comprised 150 uncomplicated MC twin pairs. Estimated centiles (3rd, 5th, 10th, 50th, 90th, 95th, 97th) of UA-PI, MCA-PI, MCA-PSV and DV-PI in function of the gestational age are presented. The comparison with singletons showed substantial differences, with higher UA-PI and lower MCA-PI and PSV median values in MC twins. Median DV PI values were similar to the values for singletons, while the upper centiles were higher in MC twins.
This study sets out MC twin-specific longitudinal references for UA-PI, MCA-PI, MCA-PSV and DV-PI derived from the largest series of uncomplicated MC twin pregnancies presently available. The comparison with singleton reference values underscores the deviation from physiology that is intrinsic to these unique pregnancies and supports the need for MC twin-specific charts.
Among the UNCCD SDGs 2030, there is the recognition that land consumption can strongly affect the provision of ecosystem services. From the perspective of land degradation neutrality, urban level is ...the right scale when planning actions against land consumption. The aims of this research are: (1) to assess land consumption at urban landscape scale and its effects on natural capital flow provision; and (2) to identify sustainable strategic planning choices for land consumption mitigation and natural capital enhancement. We propose and test an approach based on multi-temporal landscape spatial analysis (land use/land cover map, land consumption map, and landscape metrics) and ecosystem services’ flow assessment for the identification of areas at risk of loss of natural capital flow. The results have shown that from 2006 to 2019, land consumption has increased with a consequent decrease of natural capital flow. LULC dynamics has been analyzed in terms of landscape risk to lose natural capital flow, highlighting that the management of Galatone urban landscape is still far from land consumption neutrality. Landscape metrics have allowed the analysis of the aggregation among land consumption areas. The mitigation of land consumption should be based on the identification of suitable nature-based solutions towards the balance between past land consumption and future land recovery.
Immune checkpoint inhibitors (ICI) are an integral part of bladder cancer therapy, however, the relevance of ICI treatment for mixed and pure squamous cell carcinoma of the bladder remains poorly ...studied. Therefore, we analysed the expression of programmed death-ligand 1 (PD-L1) in urothelial carcinomas with squamous differentiation (UC/SCC) and pure squamous cell carcinoma (SCC) of the bladder and studied a UC/SCC patient with ICI therapy.
Tissue microarrays of 45 UC/SCC and 63 SCC samples were immunohistochemically stained with four anti-PD-L1 antibodies (28-8, 22C3, SP142 and SP263). PD-L1 expression was determined for tumour cells (TP-Score), immune cells (IC-Score) and combined (CPS, combined positive score). In addition, we present clinical and histological data of an UC/SCC patient with nivolumab therapy.
Overall, positive PD-L1 staining ranged between 4.8 and 61.9% for IC and 0 and 51.2% for TC depending on the used antibody. There were no significant differences between UC/SCC and SCC. According to current FDA guidelines for example for first line therapy of urothelial cancer with pembrolizumab (CPS ≥ 10), a subset of SCC patients up to 20% would be eligible. Finally, our UC/SCC index patient revealed excellent therapy response regarding his lung metastasis.
Our data reveal a PD-L1 expression in squamous differentiated carcinomas comparable with current data shown for urothelial tumours. In accordance with the encouraging clinical data of the index patient we suggest ICI treatment also for mixed and pure SCC of the urinary bladder.
The purpose of this study is to demonstrate that the most critically ill patients with COVID-19 have greater autonomic nervous system dysregulation and assessing the heart rate variability, allows us ...to predict severity and 30-day mortality. This was a multicentre, prospective, cohort study. Patients were divided into two groups depending on the 30-day mortality. The heart rate variability and more specifically the relative parasympathetic activity (ANIm), and the SDNN (Energy), were measured. To predict severity and mortality multivariate analyses of ANIm, Energy, SOFA score, and RASS scales were conducted. 112 patients were collected, the survival group (n = 55) and the deceased group (n = 57). The ANIm value was higher (p = 0.013) and the Energy was lower in the deceased group (p = 0.001); Higher Energy was correlated with higher survival days (p = 0.009), and a limit value of 0.31 s predicted mortalities with a sensitivity of 71.9% and a specificity of 74.5%. Autonomic nervous system and heart rate variability monitoring in critically ill patients with COVID-19 allows for predicting survival days and 30-day mortality through the Energy value. Those patients with greater severity and mortality showed higher sympathetic depletion with a predominance of relative parasympathetic activity.
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