Chronic MPTP in Mice Damage-specific Neuronal Phenotypes within Dorsal Laminae of the Spinal Cord

The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism. Such a disease is characterized by neuronal damage in multiple regions beyond the nigrostriatal pathway including the spinal cord. The neurotoxin MPTP damages spinal motor neurons. So far, in Parkinson’s disease (PD) patients alpha-synuclein aggregates are described in the dorsal horn of the spinal cord. Nonetheless, no experimental investigation was carried out to document whether MPTP affects the sensory compartment of the spinal cord. Thus, in the present study, we investigated whether chronic exposure to small doses of MPTP (5 mg/kg/X2, daily, for 21 days) produces any pathological effect within dorsal spinal cord. This mild neurotoxic protocol produces a damage only to nigrostriatal dopamine (DA) axon terminals with no decrease in DA nigral neurons assessed by quantitative stereology. In these experimental conditions we documented a decrease in enkephalin-, calretinin-, calbindin D28K-, and parvalbumin-positive neurons within lamina I and II and the outer lamina III. Met-Enkephalin and substance P positive fibers are reduced in laminae I and II of chronically MPTP-treated mice. In contrast, as reported in PD patients, alpha-synuclein is markedly increased within spared neurons and fibers of lamina I and II after MPTP exposure. This is the first evidence that experimental parkinsonism produces the loss of specific neurons of the dorsal spinal cord, which are likely to be involved in sensory transmission and in pain modulation providing an experimental correlate for sensory and pain alterations in PD

Efecto ecotoxicologico de tres metales pesados sobre el crecimiento radicular de cuatro plantas vasculares

Environmental risk assessment (ERA) of terrestrial environments polluted by heavy metals in Peru requires standardized biological organisms, the use of which is simple, practical, sensitive and repeatable, such as seeds of higher plants used in eco-toxicological bioassays. The aim of this research was to evaluate the phytotoxic effects of Cr6+, Hg2+ and Pb2+ as potassium dichromate (K2Cr207), mercury chloride (Cl2Hg) and lead acetate ((CH3C00)2Pb), respectively, on growing roots of four species of higher terrestrial plants: onions ( Allium cepa L., Liliaceae), red beets ( Beta vulgaris L., Chenopodiaceae), rice ( Oriza sativa L., Poaceae) and radishes (Raphanus sativus L., Brassicaceae) at 192 h (8 days) exposure. Bioassays of static sub-lethal toxicity for each metal and for each species of plant were performed, using a randomized complete block design: six concentrations and eight replicates with 240 seeds for each bioassay. The sequence in ascending order for mean inhibition concentration (IC50 in mg L-1) on root growth at 192 h exposure in the majority of cases was: Hg2+ > Cr6+> Pb2+. The perspectives of use for evaluation of soils contaminated by heavy metals in Peru are analyzed.La evaluaci\uf3n del riesgo ambiental (ERA) de los ambientes terrestres contaminados por metales pesados en el Per\ufa requiere del empleo de organismos biol\uf3gicos estandarizados, que sean sencillos, pr\ue1cticos, sensibles y repetibles, como las semillas de plantas superiores empleadas en bioensayos ecotoxicol\uf3gicos. Por ello, el objetivo de este trabajo fue evaluar el efecto fitot\uf3xico del Cr6+, Hg2+ y Pb2+ en forma de dicromato de potasio (K2Cr207), cloruro de mercurio (Cl2Hg) y acetato de plomo ((CH3C00)2Pb), respectivamente, sobre el crecimiento radicular de cuatro especies de plantas superiores terrestres: cebolla ( Allium cepa L., Liliaceae), betarraga ( Beta vulgaris L., Chenopodiaceae), arroz ( Oriza sativa L., Poaceae) y rabanito ( Raphanus sativus L., Brassicaceae) a 192 h (8 d\uedas) de exposici\uf3n. Se realizaron bioensayos de toxicidad subagudos est\ue1ticos para cada metal y para cada especie de planta, usando un dise\uf1o experimental en bloques completos al azar: seis concentraciones, ocho repeticiones, con un total de 240 semillas por bioensayo. La secuencia en orden ascendente para la concentraci\uf3n de inhibici\uf3n media (CI50 en mg L-1) del crecimiento radicular de las semillas a 192 h fue en la mayor\ueda de los casos: Hg2+ > Cr6+ > Pb2+. Se analizan las perspectivas de uso para la evaluaci\uf3n de suelos contaminados por metales pesados en el Per\ufa

Imaging technologies in the differential diagnosis and follow-up of brown tumor in primary hyperparathyroidism: case report and review of the literature

Brown tumors are osteolytic lesions associated with hyperparathyroidism (HPT). They may involve various skeletal segments, but rarely the cranio-facial bones. We report a case of a young boy with a swelling of the jaw secondary to a brown tumor presenting as the first manifestation of primary HPT (PHPT). He was found to have brown tumor located in the skull, as well. Different imaging technologies were employed for the diagnosis and follow-up after parathyroidectomy. We enclose a review of the literature on the employment of such imaging technologies in the differential diagnosis of osteolytic lesions. A multidisciplinary approach comprising clinical, laboratory and imaging findings is essential for the differential diagnosis of brown tumor in PHPT

Activity and safety of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II ITMO study.

BACKGROUND: Biliary tract cancer (BTC) is a highly lethal disease for which the best available therapy remains undetermined. The mammalian target of rapamycin (mTOR) pathway is up-regulated in several cancers, including BTC, and preclinical evidence indicates that mTOR inhibition may be effective in the treatment of BTC. We sought to evaluate the activity and tolerability of the mTOR inhibitor RAD001-everolimus-in patients with BTC progressing after prior chemotherapy. PATIENTS AND METHODS: This was an open-label, single-arm, phase II study (EUDRACT 2008-007152-94) conducted in eight sites in Italy. Patients with locally advanced, metastatic or recurrent BTC progressing despite previous chemotherapy received a daily oral dose of everolimus 10 mg administered continuously in 28-day cycles. The two primary end points were disease control rate (DCR) and objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS) and time-to-progression (TTP). RESULTS: Thirty-nine patients were enrolled. The DCR was 44.7%, and the ORR was 5.1%. One patient showed a partial response at 2 months and one patient showed a complete response sustained up to 8 months. The median (95% confidence interval) PFS was 3.2 (1.8-4.0) months, and the median OS was 7.7 (5.5-13.2) months. The median TTP was 2.0 (1.7-3.7) months. Most common toxicities were asthenia (43.6%), thrombocytopenia (35.9%), pyrexia (30.8%) and erythema, mainly of mild-to-moderate severity. Two patients required dose reduction due to adverse events. CONCLUSION: Everolimus demonstrated a favourable toxicity profile and encouraging anti-tumour activity. Further trials are needed to establish the role of everolimus in the treatment of BTC. EUDRACT 2008-007152-94

CXCR3 identifies human naive CD8+ T cells with enhanced effector differentiation potential

In mice, the ability of naive T (TN) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8+ TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3+ TN cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags.Moreover, CXCR3+ TN cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3+ TN cells were transcriptionally equivalent to murine CXCR3+ TN cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8+ T cells

Evaluaci\uf3n del riesgo ambiental del insecticida metamidofos en bioensayos con cuatro organismos acu\ue1ticos no destinatarios

The aim of this research was to evaluate the ecotoxicological effect of methamidophos using two formulations of different toxicological class [Monofos\uae, class Ia (extremely dangerous) and Tamaron\uae, class Ib (highly dangerous)] on four non-target aquatic organisms: bloodworm Chironomus calligraphus (Goeldi, 1905) (Diptera: Chironomidae), black sea urchin Tetrapygus niger Molina, 1782(Echinodermata: Arbaciidae), neon tetra Paracheirodon innesi (Rabout, 1940) (Osteichthyes: Characidae); and rainbow trout Oncorhynchus mykiss (Walbaum, 1792) (Osteichthyes: Salmonidae). Both methamidophos formulations evidenced a high risk effect on the aquatic environment, finding effects on larvae of C. calligraphus (Class Ia, LC50 at 48 h = 1.32 mg a.i. L-1 and Class Ib, LC50 at 48 h = 4.5 mg a.i. L-1), on fertilization of T. niger (Class Ia, IC50 at 1 h = 1423 mg a.i. L-1 and Class Ib, IC50 at 1 h = 608 mg a.i. L-1), on P. innesi (Class Ia, LC50 at 96 h = 20.56 mg a.i. L-1 and Class Ib, LC50 at 96 h = 10.13 mg a.i. L-1) and O. mykiss (Class Ib, LC50 at 96 h = 19.12 mg a.i. L-1). The sequence of sensibility to methamidophos in both formulations was: C. calligraphus > O. mykiss 48 P. innesi > T. niger.In addition, two sublethal effects were evaluated on P. innesi, immobilization and strange swimming, and finally an increment of opercular movement in O. mykiss. Risk quotients (RQ) indicated in all cases a high risk of methamidophos towards the aquatic environments.El objetivo de este trabajo fue evaluar el efecto ecotoxicol\uf3gico del metamidofos, en dos formulaciones de diferente categor\ueda toxicol\uf3gica [Monofos\uae, categor\ueda Ia (extremadamente peligroso) y Tamaron\uae, categor\ueda Ib (altamente peligroso)] sobre cuatro organismos acu\ue1ticos no destinatarios: la lombriz roja Chironomus calligraphus (Goeldi, 1905) (Diptera:Chironomidae), el erizo negro Tetrapygus niger Molina, 1782(Echinodermata: Arbaciidae), el ne\uf3n tetra Paracheirodon innesi (Rabout, 1940) (Osteichthyes: Characidae) y la trucha Oncorhynchus mykiss (Walbaum, 1792) (Osteichthyes: Salmonidae). Ambas formulaciones del metamidofos provocaron un alto riesgo sobre el ambiente acu\ue1tico, al encontrarse efectos sobre las larvas de C. calligraphus (Clase Ia, CL50 a 48 h = 1,32 mg i.a. L-1 y Clase Ib, CL50 a 48 h = 4,5 mg i.a. L-1), sobre la fertilizaci\uf3n de T. niger (Class Ia, CI50 a 1 h = 1423 mg i.a. L-1 y Clase Ib, CI50 a 1 h = 608 mg i.a. L-1),en P. innesi (Clase Ia, CL50 a 96 h = 20,56 mg i.a. L-1 y Clase Ib, CL50 a 96 h = 10,13 mg i.a. L-1) y en O. mykiss (Clase Ib, CL50 a 96 h = 19,12 mg i.a. L-1). La secuencia de sensibilidad al metamidofos en ambas formulaciones fue: C. calligraphus > O. mykiss 48 P. innesi > T. niger.En adici\uf3n, se evaluaron dos efectos subletales en P. innesi, inmovilizaci\uf3n y nado extra\uf1o, y finalmente, incremento de movimiento opercular en O. mykiss. Los cuocientes de riesgo (CR) indicaron en todos los casos un alto riesgo del metamidofos en el ambiente acu\ue1tico

The Ground-Dwelling Arthropod Community of Península Valdés in Patagonia, Argentina

This is the first study based on a planned and intensive sampling effort that describes the community composition and structure of the ground-dwelling arthropod assemblage of Península Valdés (Patagonia). It was carried out using pitfall traps, opened for two weeks during the summers of 2005, 2006 and 2007. A total of 28, 111 individuals were caught. Ants (Hymenoptera: Formicidae) dominated this community, followed by beetles (Coleoptera) and spiders (Araneae). The most abundant species were Pheidole bergi Mayr (Hymenoptera: Formicidae) and Blapstinus punctulatus Solier (Coleoptera: Tenebrionidae). Two new species were very recently described as new based on specimens collected during this study: Valdesiana curiosa Carpintero, Dellapé & Cheli (Hemiptera, Miridae) and Anomaloptera patagonica Dellapé & Cheli (Hemiptera, Oxycarenidae). The order Coleoptera was the most diverse taxa. The distribution of abundance data was best described by the logarithmic series model both at the family and species levels, suggesting that ecological relationships in this community could be controlled by a few factors. The community was dominated by predators from a trophic perspective. This suggests that predation acts as an important factor driving the distribution and abundances of surface-dwelling arthropods in this habitat and as such serves as a key element in understanding desert, above-ground community structure. These findings may also be useful for management and conservation purposes in arid Patagonia

SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence

The Ground-Dwelling Arthropod Community of Península Valdés in Patagonia, Argentina

This is the first study based on a planned and intensive sampling effort that describes the community composition and structure of the ground-dwelling arthropod assemblage of Península Valdés (Patagonia). It was carried out using pitfall traps, opened for two weeks during the summers of 2005, 2006 and 2007. A total of 28, 111 individuals were caught. Ants (Hymenoptera: Formicidae) dominated this community, followed by beetles (Coleoptera) and spiders (Araneae). The most abundant species were Pheidole bergi Mayr (Hymenoptera: Formicidae) and Blapstinus punctulatus Solier (Coleoptera: Tenebrionidae). Two new species were very recently described as new based on specimens collected during this study: Valdesiana curiosa Carpintero, Dellapé & Cheli (Hemiptera, Miridae) and Anomaloptera patagonica Dellapé & Cheli (Hemiptera, Oxycarenidae). The order Coleoptera was the most diverse taxa. The distribution of abundance data was best described by the logarithmic series model both at the family and species levels, suggesting that ecological relationships in this community could be controlled by a few factors. The community was dominated by predators from a trophic perspective. This suggests that predation acts as an important factor driving the distribution and abundances of surface-dwelling arthropods in this habitat and as such serves as a key element in understanding desert, above-ground community structure. These findings may also be useful for management and conservation purposes in arid Patagonia