Effects of peripheral FAAH blockade on NTG-induced hyperalgesia--evaluation of URB937 in an animal model of migraine.

BACKGROUND: Systemic nitroglycerin (NTG) activates brain nuclei involved in nociceptive transmission as well as in neuroendocrine and autonomic functions in rats. These changes are considered relevant for migraine because NTG consistently provokes spontaneous-like migraine attacks in migraineurs. Several studies have suggested a relationship between the endocannabinoid levels and pain mediation in migraine. URB937, a peripheral inhibitor of fatty acid amide hydrolase (FAAH)-the enzyme that degrades anandamide, produces analgesia in animal models of pain, but there is no information on its effects in migraine. AIM: We evaluated whether URB937 alters nociceptive responses in the animal model of migraine based on NTG administration in male rats, using the tail flick test and the plantar and orofacial formalin tests, under baseline conditions and after NTG administration. Furthermore, we investigated whether URB937 affects NTG-induced c-Fos expression in the brain. RESULTS: During the tail flick test, URB937 showed an antinociceptive effect in baseline conditions and it blocked NTG-induced hyperalgesia. URB937 also proved effective in counteracting NTG-induced hyperalgesia during both the plantar and orofacial formalin tests. Mapping of brain nuclei activated by NTG indicates that URB937 significantly reduces c-Fos expression in the nucleus trigeminalis caudalis and the locus coeruleus. CONCLUSIONS: The data suggest that URB937 is capable of changing, probably via indirect mechanisms, the functional status of central structures that are important for pain transmission in an animal model of migraine.

Effects of CGRP receptor antagonism in nitroglycerin-induced hyperalgesia.

BACKGROUND: The release of calcitonin gene-related peptide (CGRP) from trigeminal nerves plays a central role in the pathophysiology of migraine and clinical evidence shows an antimigraine effect for CGRP receptor antagonists. Systemic administration of nitroglycerin (NTG), a nitrovasodilator, consistently provokes spontaneous-like migraine attacks in migraine sufferers; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission. AIM: The aim of this article is to test the analgesic effect of the CGRP receptor antagonist MK-8825 in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia. RESULTS: MK-8825 showed analgesic activity when administered alone at both the tail flick test and the formalin test. Furthermore, the CGRP antagonist proved effective in counteracting NTG-induced hyperalgesia in both tests. MK-8825 indeed reduced the nociceptive behavior when administered either simultaneously or prior to (30-60 minutes before) NTG. CONCLUSION: These data suggest that MK-8825 may represent a potential therapeutic tool for the treatment of migraine.

Activating two-dimensional semiconductors for photocatalysis: a cross-dimensional strategy.

The emerging two-dimensional (2D) semiconductors substantially extend materials bases for versatile applications such as semiconductor photocatalysis demanding semiconductive matrices and large surface areas. The dimensionality, while endowing 2D semiconductors the unique properties to host photocatalytic functionality of pollutant removal and hydrogen evolution, hurdles the activation paths to form heterogenous photocatalysts where the photochemical processes are normally superior over these on the mono-compositional counterparts. In this perspective, we present a cross-dimensional strategy to employ thenD (n= 0-2) clusters or nanomaterials as activation partners to boost the photocatalytic activities of the 2D semiconductors. The formation principles of heterogenous photocatalysts are illustrated specifically for the 2D matrices, followed by selection criteria of them among the vast 2D database. The computer investigations are illustrated in the density functional theory route and machine learning benefitted from the vast samples in the 2D library. Synthetic realizations and characterizations of the 2D heterogenous systems are introduced with an emphasis on chemical methods and advanced techniques to understand materials and mechanistic studies. The perspective outlooks cross-dimensional activation strategies of the 2D materials for other applications such as CO2removal, and materials matrices in other dimensions which may inspire incoming research within these fields.

Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE.

Variability on the energy properties of charcoal and charcoal briquettes for barbecue.

In recent years there has been a strong increase in interest in the world of barbecues and outdoor cooking in high-income countries. Referring to FAO data, an exponential growth in imports of charcoal was observed in Europe and North America. Italy is one of the major European consumers and importers. On the market it is possible to find material with different characteristics and origins. However, analysis aimed at ascertaining the quality of the material are poorly performed. This research aimed to analyze the energy properties of charcoal commonly available on the Italian market. Twenty-four bags of charcoal and charcoal briquettes were analyzed. Eighteen samples represent the products most easily found on the market, in stores and on websites. In addition, six samples were supplied directly by the producer/importing company. The samples were grouped according to the continent of origin of the material (Europe, North-Central America and South America). Charcoal briquette samples were included together in a group. Referring to the ISO 17225-1 standard, the moisture content, ash content, heating value, volatile matter and fixed carbon were determined. Except for the moisture content, the results of the tests performed on all parameters show a strong variability both between different groups and within the same group. In detail, the European charcoal samples show characteristics more suitable for their use in barbecues. These have the highest values of fixed carbon and heating value and, at the same time, low values of ash and volatile matter. On the contrary, charcoal briquettes have less suitable characteristics for barbecue. The work also highlighted some gaps in the reference standard relating to laboratory analyses. To ensure careful control of the qualitative characteristics of the products on the market, it is necessary to promote the creation of a quality brand.

Case Report: Invasive Fungal Infection and Daratumumab: A Case Series and Review of Literature.

Life expectancy of multiple myeloma (MM) patients has improved in last years due to the advent of anti-CD38 monoclonal antibodies in combination with immunomodulators and proteasome inhibitors. However, morbidity and mortality related to infections remain high and represent a major concern. This paper describes the "real life" risk of invasive fungal infections (IFI) in patients treated with daratumumab-based therapy and reviews the relevant literature. In a series of 75 patients we only observed three cases of fungal pneumonia. Unfortunately, the early signs and symptoms were not specific for fungal infection. Diagnostic imaging, microbiology and patient history, especially previous therapies, are critical in the decision to start antifungal treatment. Recognising the subgroup of MM patients with high risk of IFI can increase the rate of diagnosis, adequate treatment and MM-treatment recovery.

Targeted association analysis identified japonica rice varieties achieving Na(+)/K (+) homeostasis without the allelic make-up of the salt tolerant indica variety Nona Bokra.

During the last decade, a large number of QTLs and candidate genes for rice tolerance to salinity have been reported. Using 124 SNP and 52 SSR markers, we targeted 14 QTLs and 65 candidate genes for association mapping within the European Rice Core collection (ERCC) comprising 180 japonica accessions. Significant differences in phenotypic response to salinity were observed. Nineteen distinct loci significantly associated with one or more phenotypic response traits were detected. Linkage disequilibrium between these loci was extremely low, indicating a random distribution of favourable alleles in the ERCC. Analysis of the function of these loci indicated that all major tolerance mechanisms were present in the ERCC although the useful level of expression of the different mechanisms was scattered among different accessions. Under moderate salinity stress some accessions achieved the same level of control of Na(+) concentration and Na(+)/K(+) equilibrium as the indica reference variety for salinity tolerance Nona Bokra, although without sharing the same alleles at several loci associated with Na(+) concentration. This suggests (a) differences between indica and japonica subspecies in the effect of QTLs and genes involved in salinity tolerance and (b) further potential for the improvement of tolerance to salinity above the tolerance level of Nona Bokra, provided the underlying mechanisms are complementary at the whole plant level. No accession carried all favourable alleles, or showed the best phenotypic responses for all traits measured. At least nine accessions were needed to assemble the favourable alleles and all the best phenotypic responses. An effective strategy for the accumulation of the favourable alleles would be marker-assisted population improvement.

Constraining the evolution of the fundamental constants with a solid-state optical frequency reference based on the 229Th nucleus.

We describe a novel approach to directly measure the energy of the narrow, low-lying isomeric state in 229Th. Since nuclear transitions are far less sensitive to environmental conditions than atomic transitions, we argue that the 229Th optical nuclear transition may be driven inside a host crystal with a high transition Q. This technique might also allow for the construction of a solid-state optical frequency reference that surpasses the short-term stability of current optical clocks, as well as improved limits on the variability of fundamental constants. Based on analysis of the crystal lattice environment, we argue that a precision (short-term stability) of 3×10(-17)<Δf/f<1×10(-15) after 1 s of photon collection may be achieved with a systematic-limited accuracy (long-term stability) of Δf/f∼2×10(-16). Improvement by 10(2)-10(3) of the constraints on the variability of several important fundamental constants also appears possible.

Alterations of the endocannabinoid system in an animal model of migraine: evaluation in cerebral areas of rat.

Endocannabinoids are involved in the modulation of pain and hyperalgesia. In this study we investigated the role of the endocannabinoid system in the migraine model based on nitroglycerin-induced hyperalgesia in the rat. Male rats were injected with nitroglycerin (10 mg/kg, i.p.) or vehicle and sacrificed 4 h later. The medulla, the mesencephalon and the hypothalamus were dissected out and utilized for the evaluation of activity of fatty acid amide hydrolase (that degrades the endocannabinoid anandamide), monoacylglycerol lipase (that degrades the endocannabinoid 2-arachidonoylglycerol), and binding sites specific for cannabinoid (CB) receptors. The findings obtained show that nitroglycerin-induced hyperalgesia is associated with increased activity of both hydrolases and increased density of CB binding sites in the mesencephalon. In the hypothalamus we observed an increase in the activity of fatty acid amide hydrolase associated with an increase in density of CB binding sites, while in the medulla only the activity of fatty acid amide hydrolase was increased. Anandamide also proved effective in preventing nitroglycerin-induced activation (c-Fos) of neurons in the nucleus trigeminalis caudalis. These data strongly support the involvement of the endocannabinoid system in the modulation of nitroglycerin-induced hyperalgesia, and, possibly, in the pathophysiological mechanisms of migraine.

[Case-mix index and length of hospitalization]. / L'indice di case-mix e la durata della degenza.

The ACG (Adjusted Clinical Groups) case-mix system is a classification method of diseases of patients, focused on the person. Depending on the pattern of these morbid conditions, the ACG system assigns each patient to a single group (an ACG group), which allows to capture the effects of a group of diseases in estimates of resource use. Diseases are classified into a diagnostic group (ADG) according to 5 clinical dimensions: duration (acute, recurrent or chronic), severity (minor/major vs stable/unstable), diagnostic assessment (symptoms vs diseases), etiology (infectious, traumatic or other), specialty (medical, surgical, obstetric, ...). All diseases can be classified into these dimensions and into one of 32 groups. The ACG case-mix system uses an algorithm to classify each patient into one of 93 ACG categories. Each person is assigned to an ACG according to his ADG combination, his age and his gender. With the repayment system "case-mix", surgery has become central for all great hospitals in virtue of its great productive potential. The case-mix index is one of the factors which influence the duration of hospitalization. The case-mix system has emphasized the importance of the duration of hospitalization, encouraging the planning of programs in order to discharge patients early after surgical operations. It has also stimulated the surgical activity in operating units with "budget" forecasts in which resources are provided according to an expected level of specialist surgery.

Angiomegaly and arterial aneurysms.

Angiomegaly is characterized by an alteration in the elastic component of arterial and venous vessels determining their elongation and tortuousness. This involves an increased risk of thromboembolism and aneurysmal degeneration in affected subjects, even if they have been asymptomatic for a long time. The aim of this study is to demonstrate the correlation between angiomegaly and aneurysmal disease. A total of 163 patients suffering from a peripheral arterial aneurysm were included, 74 of these with an iliac aneurysm, 41 with a femoral aneurysm and 48 suffering from popliteal aneurysm. All patients were examined by color Doppler ultrasonography (CDU) and angio-CT with contrast medium. Eighteen cases of arteriomegaly were diagnosed, and the prevalence in the examined population was 11%. This study demonstrates the close association existing between aneurysms in peripheral arteries and arteriomegaly. Peripheral arterial aneurysms in association with arteriomegaly involve an increased risk of complications like thrombosis, embolism and rupture. The showed familiarity in the arteriomegaly incidence leads to predisposition of screening programs, using CDU, among relatives of patients affected by arteriomegaly and/or peripheral arterial aneurysms.

Developmental regulation of cryptdin, a corticostatin/defensin precursor mRNA in mouse small intestinal crypt epithelium.

Cryptdin mRNA codes for the apparent precursor to a corticostatin/defensin-related peptide that accumulates to high levels in mouse intestinal crypt epithelium during postnatal development. The primary structure, intestinal cell distribution, and developmental appearance of cryptdin mRNA have been determined. Cryptdin mRNA is 450-480 nucleotides long. Translation of the partial cryptdin cDNA sequence reveals a 70-amino acid open reading frame that includes 32 carboxy-terminal residues that align with those in the consensus sequence, C.CR...C....ER..G.C....CCR, which is a common feature of leukocyte defensins and lung corticostatins (Selsted, M. E., D. M. Brown, R. J. DeLange, S. S. L. Harwig, and R. I. Lehrer. 1985. J. Biol. Chem. 260:4579-4584; Zhu, Q., J. Hu, S. Mulay, F. Esch, S. Shimasaki, and S. Solomon. 1988. Proc. Natl. Acad. Sci. USA. 85:592-596). In situ hybridization of cryptdin cDNA to paraformaldehyde-fixed, frozen sections of adult jejunum and ileum showed intense and specific labeling of epithelial cells in the base of all crypts. Analysis of sections from suckling mice showed that cryptdin mRNA is detectable in 10-20% of crypts in 10-d-old mice, in approximately 80% of crypts in 16-d-old mice, and in all crypts of mice 20 d and older. During the fourth week, the sequence accumulates in crypts to the maximal adult level. Cryptdin mRNA content in adult small intestine is independent both of T cell involvement and luminal bacteria. The role of cryptdin in small bowel physiology remains to be determined: cryptdin may inhibit bacterial translocation, modulate intestinal hormone synthesis, influence hormonal sensitivity of the intestinal epithelium, or exhibit a multiplicity of related activities.

Thyroid tissue remnants after "total thyroidectomy".

Total Thyroidectomy (TT) is a gold standard for benign bilateral pathologies and malignant pathologies of the thyroid. TT has numerous advantages over less radical approaches, such as the resolution of the thyroid pathology, avoidance of recurrences, and improved response to life-long substitutive organotherapy. TT has a negligible rate of recurrence. Near Total Thyroidectomy (NTT) is associated with a low rate of recurrence. Subtotal Thyroidectomy (ST), in which a portion of the thyroid gland is deliberately left in the thyroid lodge, has a considerably higher rate of recurrence. The incidence of complications with TT is similar to that with other techniques of thyroid exeresis. However, despite the radical intent of surgeons, a real TT is not always carried out. The complete removal of all the thyroid tissue employing TT is not the norm and micro/macroscopic remnants almost always remain. The literature on these tissue remnants is often based on techniques that are not very accurate in terms of determining the diameters of the tissue remaining. In our study, conducted by colour echo-doppler of the thyroid lodge in 102 patients who had undergone TT for benign thyroid pathologies, we demonstrated significant thyroid tissue remnants after TT in 34 cases of 102 (33,3%). Therefore, out of a total of 102 so-called "total thyroidectomies", only 68 (66,7%) were really total, whereas 12 patients (11,76%) had near total thyroidectomy, leaving tissue remnants < 1 cm, and 22 patients (21,57%) had subtotal thyroidectomy, with tissue remnants > or = 1 cm.

Role of calcitonin gene-related peptide and substance P in different models of pain.

Calcitonin gene-related peptide (CGRP) and substance P (SP) play an important role in the development of pain and hyperalgesia. Experimental models have demonstrated that nitroglycerin (NTG)--a nitric oxide donor--provokes a hyperalgesic state, probably via the activation of second-order neurons in the nucleus trigeminalis caudalis. In order to gain further insight into the role of CGRP and SP in different types of experimental pain, we evaluated and compared changes in immunoreactivity (-ir) for these two neuropeptides at different levels of the central nervous system [nucleus trigeminalis caudalis (NTC) and dorsal horns of the lumbar spinal cord] in two animal models of hyperalgesia: systemic NTG administration and formalin test. Following NTG administration, CGRP-ir decreased steadily in the NTC, whereas SP-ir increased transiently. In the lumbar dorsal horns, NTG induced a decrease in SP-ir 1 h after its administration. Formalin injection induced an ipsilateral increase in both CGRP and SP immunostaining at 1 and 2 h in the lumbar dorsal horns. In the NTC, a significant decrease in CGRP-ir was observed at 1 h. The changes in the staining intensities were paralleled by changes in the numbers of CGRP and of SP varicosities in both the NTC and the lumbar dorsal horns. These findings show specific changes in CGRP and SP at different levels of the central nervous system in the different models of pain. In the case of the formalin test, the changes involve both neuropeptides synchronously and to the same extent, whereas in the case of NTG administration, CGRP seems to play a more prevalent and long-lasting role, particularly at the NTC level.

Groundwater protection from cadmium contamination by permeable reactive barriers.

This work studies the reliability of an activated carbon permeable reactive barrier in removing cadmium from a contaminated shallow aquifer. Laboratory tests have been performed to characterize the equilibrium and kinetic adsorption properties of the activated carbon in cadmium-containing aqueous solutions. A 2D numerical model has been used to describe pollutant transport within a groundwater and the pollutant adsorption on the permeable adsorbing barrier (PRB). In particular, it has been considered the case of a permeable adsorbing barrier (PAB) used to protect a river from a Cd(II) contaminated groundwater. Numerical results show that the PAB can achieve a long-term efficiency by preventing river pollution for several months.

CD3+ graft cell count influence on chronic GVHD in haploidentical allogeneic transplantation using post-transplant cyclophosphamide.

The effects of graft or donor characteristics in haploidentical hematopoietic cell transplantation (HCT) using post-transplant cyclophosphamide (PT-Cy) are largely unknown. In this multicenter retrospective study we analyzed the correlations between graft cell composition (CD34+, CD3+) and donor features on transplant outcomes in 234 patients who underwent HCT between 2010 and 2016. On multivariate analysis, the use of peripheral blood stem cells (PBSC) was associated with an increased incidence of grade 2-4 acute GVHD [HR 1.94, 95% confidence Interval (CI) = 1.01-3.98, p = 0.05]. An elevated CD3+ graft content was associated with an increased incidence of all-grade chronic GVHD [HR 1.36 (95% CI = 1.06-1.74), p = 0.01]. This effect was confirmed only for the PBSC graft group. A higher CD34+ graft content had a protective role on non-relapse mortality [HR 0.78 (95% CI = 0.62-0.96), p = 0.02] but this was confirmed only for the bone marrow (BM)-derived graft cohort. Donor characteristics did not influence any outcomes. GVHD prophylaxis should be modulated accordingly to CD3+ graft content, especially when a PBSC graft is used. These results need further validation in prospective trials.

Fetal bile salt metabolism. II. Hepatic excretion of endogenous bile salt and of a taurocholate load.

Bile salt metabolism was studied in fetal dogs 1 wk before term. The size and distribution of the fetal bile salt pool were measured, and individual bile salts were identified. The hepatic excretion of endogenous bile salts was studied in bile fistula fetuses, and the capacity of this excretory mechanism was investigated by the i.v. infusion of a load of sodium taurocholate-(14)C up to 20 times the endogenous pool size. The total fetal bile salt pool was 30.9+/-2.7 mumoles, of which two-thirds was in the fetal gallbladder. Expressed on a body weight basis, this was equal to approximately one-half the estimated pool size in the adult dog (119.2+/-11.3 vs. 247.5+/-33.1 mumoles/kg body wt). Measurable quantities of bile salt were found in small bowel (6.0+/-1.8 mumoles), large bowel (1.1+/-0.3 mumoles), liver (1.2+/-0.5 mumoles), and plasma (0.1+/-0.03 mumoles). Plasma bile salt levels were significantly greater in fetal than in maternal plasma (1.01+/-0.24 mug/ml vs. 0.36+/-0.06 mug/ml; P < 0.05). Fetal hepatic bile salt excretion showed a fall over the period of study from 2.04+/-0.34 to 0.30+/-0.07 mumoles/hr. The maximal endogenous bile salt concentration in fetal hepatic bile was 18.7+/-1.5 mumoles/ml. The concentration in fetal gallbladder bile was 73.9+/-8.6 mumoles/ml; and, in those studies in which hepatic and gallbladder bile could be compared directly, the gallbladder appeared to concentrate bile four- to fivefold.Taurocholate, taurochenodeoxycholate, and taurodeoxycholate were present in fetal bile, but no free bile salts were identified. The presence of deoxycholate was confirmed by thin-layer chromatography and gas liquid chromatography, and the absence of microorganisms in fetal gut suggests that it was probably transferred from the maternal circulation. After infusion of a taurocholate load, fetal hepatic bile salt excretion increased 30-fold, so that 85-95% of the dose was excreted by the fetal liver during the period of observation. Placental transfer accounted for less than 5% of the dose. Fetal bile volume increased 15-fold on average, while bile salt concentrations increased two- to threefold. It is concluded that bile salt is taken up, conjugated, and excreted by the fetal liver with remarkable efficiency. The excreted material is either stored and concentrated in the fetal gallbladder or released into the intestine and reabsorbed to be reexcreted in bile.

[Acute renal failure in granulomatous interstitial nephritis]. / Insufficienza renale acuta secondaria a nefrite granulomatosa interstiziale.

Sarcoidosis is a granulomatous disorder with multiorgan involvement which may appear in an isolated form but more often as a systemic disease. We report the case of a 53-year-old woman presenting with acute renal failure, hypercalcemia, elevated 1.25 dihydroxycholecalciferol, and a history of fatigue, weight loss and arthralgia of several months. Kidney biopsy had revealed interstitial noncaseating granulomas, so sarcoidosis was considered as a potential diagnosis after exclusion of other granulomatous disorders. Granulomatous tubulo-interstitial nephritis (GIN) is an uncommon disease with a low, but perhaps underestimated incidence: only about 100 cases have been described in the literature. In these cases it was found that the disease may lead to deterioration of renal function and irreversible progress to end-stage renal disease. The treatment of choice is the administration of steroids.

Control of infectious mortality due to carbapenemase-producing Klebsiella pneumoniae in hematopoietic stem cell transplantation.

Carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infections are an emerging cause of death after hematopoietic stem cell transplantation (HSCT). In allogeneic transplants, mortality rate may rise up to 60%. We retrospectively evaluated 540 patients receiving a transplant from an auto- or an allogeneic source between January 2011 and October 2015. After an Institutional increase in the prevalence of KPC-Kp bloodstream infections (BSI) in June 2012, from July 2012, 366 consecutive patients received the following preventive measures: (i) weekly rectal swabs for surveillance; (ii) contact precautions in carriers (iii) early-targeted therapy in neutropenic febrile carriers. Molecular typing identified KPC-Kp clone ST512 as the main clone responsible for colonization, BSI and outbreaks. After the introduction of these preventive measures, the cumulative incidence of KPC-Kp BSI (P=0.01) and septic shocks (P=0.01) at 1 year after HSCT was significantly reduced. KPC-Kp infection-mortality dropped from 62.5% (pre-intervention) to 16.6% (post-intervention). Day 100 transplant-related mortality and KPC-Kp infection-related mortality after allogeneic HSCT were reduced from 22% to 10% (P=0.001) and from 4% to 1% (P=0.04), respectively. None of the pre-HSCT carriers was excluded from transplant. These results suggest that active surveillance, contact precautions and early-targeted therapies, may efficiently control KPC-Kp spread and related mortality even after allogeneic HSCT.