Developing and implementing a multi-modality imaging optimization study in paediatric radiology: Experience and recommendations from an IAEA coordinated research project.

Optimization of imaging examinations is a key requirement of both the International and European Basic Safety Standards, and the focus of much international activity. Although methodologies are well established in principle, there continues to be a variety of practical issues both in collecting and interpreting dose and image quality data and in making successful interventions to optimize exposures. A Coordinated Research Project, involving institutes from ten different countries, was established by the IAEA to assess the efficacy of recommended optimization methodologies in the field of paediatric radiology and to derive practical guidance on their implementation. The steps followed in this process were identification of the imaging process to be investigated (abdomen and chest x-rays, micturating cysto-urethrograms, and brain & thorax CT scans); collection of dose and image quality data; evaluation and comparison of the data between institutes and to standards; identification and implementation of interventions for optimization; and re-evaluation of dose and image quality parameters. The project succeeded both in achieving effective interventions for optimization of specific imaging tasks in individual institutes and in identifying key issues with potential to handicap this process. The main area in which problems were encountered was in the collation of reliable dose and image quality data. The reasons for this were explored and a series of recommendations have been made, summarized into 'ten practical tips' for optimization to assist institutes, particularly those in the early stages of addressing optimization issues.

Effect of industrial processing and storage procedures on oxysterols in milk and milk products.

Oxysterols are products of enzymatic and/or chemical cholesterol oxidation. While some of the former possess broad antiviral activities, the latter mostly originate from the deterioration of the nutritional value of foodstuff after exposure to heat, light, radiation and oxygen, raising questions about their potential health risks. We evaluated the presence of selected oxysterols in bovine colostrum and monitored the evolution of their cholesterol ratio throughout an entire industrial-scale milk production chain and after industrially employed storage procedures of milk powders. We report here for the first time the presence of high levels of the enzymatic oxysterol 27-hydroxycholesterol (27OHC) in concentrations of antiviral interest in bovine colostrum (87.04 ng mL-1) that decreased during the first postpartum days (56.35 ng mL-1). Of note, this oxysterol is also observed in milk and milk products and is not negatively affected by industrial processing or storage. We further highlight an exponential increase of the non-enzymatic oxysterols 7ß-hydroxycholesterol (7ßOHC) and 7-ketocholesterol (7KC) in both whole (WMPs) and skimmed milk powders (SMPs) during prolonged storage, confirming their role as reliable biomarkers of cholesterol oxidation over time: after 12 months, 7ßOHC reached in both SMPs and WMPs amounts that have been found to be potentially toxic in vitro (265.46 ng g-1 and 569.83 ng g-1, respectively). Interestingly, industrial processes appeared to affect the generation of 7ßOHC and 7KC differently, depending on the presence of fat in the product: while their ratios increased significantly after skimming and processing of skimmed milk and milk products, this was not observed after processing whole milk and milk cream.

Paediatric nuclear medicine practice: an international survey by the IAEA.

PURPOSE: The International Atomic Energy Agency (IAEA) decided to initiate a survey to evaluate the current status of the practice of paediatric nuclear medicine worldwide, with the focus mainly on low and middle-income countries specifically in Latin America, Eastern Europe, Africa and Asia. This investigation sought to determine if the practice in paediatric nuclear medicine in these countries differed from that indicated by the survey of the Nuclear Medicine Global Initiative (NMGI) and if nuclear medicine practitioners were following established paediatric nuclear medicine guidelines. METHODS: A total of 133 institutes took part in the survey from 62 different IAEA member states within Africa (29), Asia (39), Europe (29) and Latin America (36). The four most frequent conventional (single-photon) nuclear medicine procedures were 99mTc labelled MDP, DSMA, MAG3 and pertechnetate thyroid scans. In addition, 46 centres provided data on FDG PET/CT, including exposure data for the CT component. Nearly half of the sites (48%) perform less than 200 paediatric nuclear medicine studies per year, while 11% perform more than 1000 such studies per year. RESULTS: Administered activities largely exceeded the recommendations for most of the sites for DMSA, MAG3 and pertechnetate, while compliance with international standards was somehow better for MDP studies. For FDG PET, the results were more uniform than for conventional nuclear medicine procedures. However, the use of CT in PET/CT for paediatric nuclear medicine revealed a high variability and, in some cases, high, dose-length product (DLP) values. This observation indicates that further attention is warranted for optimizing clinical practice in FDG PET/CT. CONCLUSIONS: Overall, in most parts of the world, efforts have been undertaken to comply either with the EANM dosage card or with the North American Consensus Guidelines. However, variability in the practice of paediatric nuclear medicine still exists. The results of this survey provide valuable recommendations for a path towards global standardization of determining the amount of activity to be administered to children undergoing nuclear medicine procedures.

Verbal and Cross-Modal Ratings of Music: Validation and Application of an Icon-Based Rating Scale.

Can music be rated consistently using nonverbal descriptors such as colours and temperatures? 144 participants rated 6 experimenter-selected and 2 self-selected pieces of music along 15 bipolar icon (graphic) scales intended to portray emotions, and sensory experiences consisting of colour, temperature, shape, speed, texture, and weight. Participants also rated the same pieces using bipolar verbal scales which aimed to encompass the concepts represented by the icons (e.g., the word "red" for the colour red). Furthermore, the icons themselves were subjected to open-ended verbal labelling to validate the icon scale. Colour icons spontaneously evoked a cross-modal association on 67% of occasions: blue being cool, and red/orange being warm or hot, and the icon scale had overall good face validity. Music regularly and consistently evoked multisensory associations (using the icon scale) including shapes, colours, weight, and temperatures, in addition to emotions. Cross-modal perception is indicative of music's character rather than the enjoyment of the music. The icon scale provides new insights into music perception and for applications where language skill may limit participant expression.

Guidance on prevention of unintended and accidental radiation exposures in nuclear medicine.

Nuclear medicine (NM) procedures for diagnosis and treatment of disease are performed routinely in hospitals throughout the world. These involve preparation and administration to patients of pharmaceuticals labelled with radioactive material. The International Atomic Energy Agency (IAEA) and the World Health Organisation highlighted the need for improvement in prevention of medical radiation incidents and accidents in the Bonn Call-for-Action in 2012. An IAEA Technical Meeting was held on prevention of unintended exposures and accidents in NM in 2018 to address the issue. Exposures can take place at any time when radioactive material is being produced and used, and the risk continues after procedures have been completed. Thus there is potential for staff or members of the general public to be exposed, as well as patients. This paper sets out guidelines for incident prevention based on presentations and discussions at the meeting, and review of reports from the literature. It deals with potential incidents in in-house radionuclide production, radiopharmaceutical preparation, administration to patients, and following a procedure, as well as aspects in management of radioactive materials. Special attention has been paid to therapeutic procedures, as these have the potential to cause more harm to patients from erroneous administrations, including tissue reactions from extravasation of radiopharmaceutical, and could lead to significant contamination events. Administration of NM therapy is generally contraindicated in pregnancy. Identification of any patient who may be pregnant is crucial and it might be necessary to verify this with a pregnancy test for patients within the age band considered to be fertile. Inclusion of NM therapy incidents in the IAEA automated reporting system SAFRON is recommended. In summary, the paper aims to highlight errors that could occur during different phases of NM procedures in order to aid prevention of incidents. The value of periodic audit in evaluating systems in place on a regular basis is emphasised. Approaches to incident investigation and follow-up are described, and the need to ensure corrective action is taken to address any deficiencies stressed.

A short-term study of the effects of ozone irrigation in an orthodontic population with fixed appliances.

AIM: The aim of the present study was to compare the clinical efficacy of chlorhexidine and ozonised water in the oral hygiene maintenance of orthodontic patients. MATERIALS AND METHODS: Study design: This is a prospective clinical study. Thirty patients with orthodontic brackets were selected at the Versilia General Hospital (Lido di Camaiore, Italy). Patients were randomly allocated to one of two groups: standard oral hygiene session followed by prescription of either chlorhexidine mouth-rinse or ozonated water. At each moment of the follow-up, the following parameters were recorded: pocket probing depth (PPD), full-mouth plaque index (FMPI), and full mouth bleeding score (FMBS). STATISTICS: Sample size was computed according to previously published data. Significance level was set at 0.05 for all analyses, and non-parametric Wilcoxon signed rank test was used for comparisons. RESULTS: At baseline, mean PPD was 1.89 ± 0.13 mm for the control group and 1.95 ± 0.10 mm for the test group. Mean FMPI was 63.9 ± 16.5% and 68.7 ± 10.33% respectively. Mean FMBS was 31.5 ± 15.6% and 32.8 ± 8.85 respectively. One month after treatment (T2), both groups showed a significant improvement of FMPI and FMBS. Mean FMPI was 42.8 ± 14.3% and 24.3 ± 6.41% respectively. Mean FMBS was 19.5 ±12.6% and 4.70 ± 3.56% respectively. The test group treated with ozone exhibited a greater improvement of FMPI and FMBS. CONCLUSIONS: Ozone yielded better outcomes than chlorhexidine in the management of gingivitis in orthodontic patients. Ozone should be further investigated in longitudinal studies with larger samples.

Increased production of 27-hydroxycholesterol in human colorectal cancer advanced stage: Possible contribution to cancer cell survival and infiltration.

So far, the investigation in cancer cell lines of the modulation of cancer growth and progression by oxysterols, in particular 27-hydroxycholesterol (27HC), has yielded controversial results. The primary aim of this study was the quantitative evaluation of possible changes in 27HC levels during the different steps of colorectal cancer (CRC) progression in humans. A consistent increase in this oxysterol in CRC mass compared to the tumor-adjacent tissue was indeed observed, but only in advanced stages of progression (TNM stage III), a phase in which cancer has spread to nearby sites. To investigate possible pro-tumor properties of 27HC, its effects were studied in vitro in differentiated CaCo-2 cells. Relatively high concentrations of this oxysterol markedly increased the release of pro-inflammatory interleukins 6 and 8, monocyte chemoattractant protein-1, vascular endothelial growth factor, as well as matrix metalloproteinases 2 and 9. The up-regulation of all these molecules, which are potentially able to favor cancer progression, appeared to be dependent upon a net stimulation of Akt signaling exerted by supra-physiological amounts of 27HC.

Adrenocortical carcinoma: the dawn of a new era of genomic and molecular biology analysis.

Over the last decade, the development of novel and high penetrance genomic approaches to analyze biological samples has provided very new insights in the comprehension of the molecular biology and genetics of tumors. The use of these techniques, consisting of exome sequencing, transcriptome, miRNome, chromosome alteration, genome, and epigenome analysis, has also been successfully applied to adrenocortical carcinoma (ACC). In fact, the analysis of large cohorts of patients allowed the stratification of ACC with different patterns of molecular alterations, associated with different outcomes, thus providing a novel molecular classification of the malignancy to be associated with the classical pathological analysis. Improving our knowledge about ACC molecular features will result not only in a better diagnostic and prognostic accuracy, but also in the identification of more specific therapeutic targets for the development of more effective pharmacological anti-cancer approaches. In particular, the specific molecular alteration profiles identified in ACC may represent targetable events by the use of already developed or newly designed drugs enabling a better and more efficacious management of the ACC patient in the context of new frontiers of personalized precision medicine.

Moving beyond quality control in diagnostic radiology and the role of the clinically qualified medical physicist.

Quality control (QC), according to ISO definitions, represents the most basic level of quality. It is considered to be the snapshot of the performance or the characteristics of a product or service, in order to verify that it complies with the requirements. Although it is usually believed that "the role of medical physicists in Diagnostic Radiology is QC", this, not only limits the contribution of medical physicists, but is also no longer adequate to meet the needs of Diagnostic Radiology in terms of Quality. In order to assure quality practices more organized activities and efforts are required in the modern era of diagnostic radiology. The complete system of QC is just one element of a comprehensive quality assurance (QA) program that aims at ensuring that the requirements of quality of a product or service will consistently be fulfilled. A comprehensive Quality system, starts even before the procurement of any equipment, as the need analysis and the development of specifications are important components under the QA framework. Further expanding this framework of QA, a comprehensive Quality Management System can provide additional benefits to a Diagnostic Radiology service. Harmonized policies and procedures and elements such as mission statement or job descriptions can provide clarity and consistency in the services provided, enhancing the outcome and representing a solid platform for quality improvement. The International Atomic Energy Agency (IAEA) promotes this comprehensive quality approach in diagnostic imaging and especially supports the field of comprehensive clinical audits as a tool for quality improvement.

Identification of the putative binding pocket of valerenic acid on GABAA receptors using docking studies and site-directed mutagenesis.

BACKGROUND AND PURPOSE: ß2/3-subunit-selective modulation of GABAA receptors by valerenic acid (VA) is determined by the presence of transmembrane residue ß2/3N265. Currently, it is not known whether ß2/3N265 is part of VA's binding pocket or is involved in the transduction pathway of VA's action. The aim of this study was to clarify the localization of VA's binding pocket on GABAA receptors. EXPERIMENTAL APPROACH: Docking and a structure-based three-dimensional pharmacophore were employed to identify candidate amino acid residues that are likely to interact with VA. Selected amino acid residues were mutated, and VA-induced modulation of the resulting GABAA receptors expressed in Xenopus oocytes was analysed. KEY RESULTS: A binding pocket for VA at the ß(+) /α(-) interface encompassing amino acid ß3N265 was predicted. Mutational analysis of suggested amino acid residues revealed a complete loss of VA's activity on ß3M286W channels as well as significantly decreased efficacy and potency of VA on ß3N265S and ß3F289S receptors. In addition, reduced efficacy of VA-induced IGABA enhancement was also observed for α1M235W, ß3R269A and ß3M286A constructs. CONCLUSIONS AND IMPLICATIONS: Our data suggest that amino acid residues ß3N265, ß3F289, ß3M286, ß3R269 in the ß3 subunit, at or near the etomidate/propofol binding site(s), form part of a VA binding pocket. The identification of the binding pocket for VA is essential for elucidating its pharmacological effects and might also help to develop new selective GABAA receptor ligands.

Gas chromatography-mass spectrometry microanalysis of alpha- and gamma-tocopherol in plasma and whole blood.

BACKGROUND: Assessing vitamin E status in humans is critical for nutritional evaluation and verification of clinical and biological compliance of supplemented subjects. An accurate analytical method for measuring the two main vitamin E isoforms, i.e. α- and γ-tocopherol (α- and γ-TOH) in small volumes of plasma can facilitate the application of this analysis to clinical trials and in situations where a limited amount of sample is available. METHODS: We have developed a micro method, which uses only 5 µL plasma, based on isotope dilution, trimethylsilation and GC-MS. The method was validated according to the guidelines of the International Conference on Harmonization of analytical procedures. The method was also applied to 5 µL of whole blood for the potential use in conditions were the availability of specimens is limited. RESULTS: Accurate quantitation of α-TOH and γ-TOH was achieved at levels ≥ 0.417 µM and ≥ 0.007 µM, respectively. Within-day coefficient of variation was 1.31% and 4.70% for α-TOH and γ-TOH, respectively. Between-day coefficient of variation was 1.32% and 2.88% for α-TOH and γ-TOH, respectively. Recovery, assessed at three concentration levels, ranged 98-103% and 100-102% for α-TOH and γ-TOH, respectively. The method allowed the detection of α-TOH and γ-TOH in 5 µL whole blood and in membranes of red blood cells washed from 5 µL of blood as well. The analytical performance was assessed in plasma from a cohort of Italian healthy subjects (n = 205). The mean plasma concentrations were 28.01 ± 6.31 and 0.68 ± 0.48 µM (mean ± SD) for α-TOH and γ-TOH, respectively. Alpha-TOH correlated with total cholesterol (r = 0.617, p < 0.0001) and triglycerides (r = 0.420, p < 0.0001) while γ-TOH correlated modestly with total cholesterol (r = 0.213, p < 0.0001) but not with triglycerides. γ-TOH, but not α-TOH, was significantly lower in smokers than in non-smokers (0.72 ± 0.50 vs. 0.56 ± 0.37, µM, mean ± SD, p = 0.017). Given the high sensitivity, the method allowed to be applied to 5 µM whole blood without specific modification. CONCLUSIONS: This micro-method represents an analytical advancement in α- and γ-TOH assay that is available to accurately verify the nutritional status and compliance after supplementation in large-scale settings, and to measure the two vitamers in conditions where sample availability is limited.

Systemic exposure to inhaled beclometasone/formoterol DPI is age and body size dependent.

AIM: Prescription of inhaled corticosteroids to children with asthma is recommended at half the nominal dose of adults in order to reduce the risk of systemic side effects. However, there is a lack of pharmacokinetic trials supporting such dose reduction regimens. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed dose combination of beclometasone-dipropionate (BDP) and formoterol after dry powder inhaler (DPI) administration in children, adolescents and adults. METHODS: The pharmacokinetic profiles of formoterol and beclometasone-17-monopropionate (B17MP; active metabolite of BDP) were evaluated over 8 h from two independent studies comprising children (6-11yrs, n = 27), adolescents (12-17 yrs, n = 28) and adults (≥18 yrs, n = 30) receiving a single, fixed dose of BDP/formoterol (children: 200 µg/24 µg, adolescents and adults: 400 µg/24 µg) via DPI. RESULTS: The systemic exposure (AUC) for children versus adults was almost doubled for formoterol and similar for B17MP despite the halved BDP dose administered in children. In adolescents the AUC for formoterol and B17MP were approximately one third higher than in adults for both compounds. Upon normalization for the BDP/formoterol dose in the three populations the AUC and peak concentration (C(max)) correlated inversely with age and body surface area of the patients (r ≤ -0.53; p < 0.0001). CONCLUSION: The systemic exposure to the active ingredients of BDP/formoterol administered as DPI correlates inversely with age and body size suggesting that dry powder dosage regimens should be adjusted for age and body size to avoid high systemic drug levels in children.

Computational approaches for the identification and optimization of Src family kinases inhibitors.

Src family kinases (SFKs) are a group of non-receptor tyrosine kinases whose activity is involved in the regulation of cellular morphology, motility, proliferation and survival. An aberrant activation and expression of these kinases contribute to the pathogenesis and progression of a broad range of diseases, such as a large number of solid tumors, various hematological malignancies and some neuronal pathologies. The search for SFK inhibitors is therefore a promising research topic in medicinal chemistry. Computational studies such as receptor-based and/or ligand-based virtual screening, docking, and molecular modeling proved to be a powerful tool for identifying new SFKs inhibitors. In this review we report and analyze the main examples of computational approaches that allowed the identification of new SFKs ligands and the optimization of either activity and pharmacokinetic profile of lead compounds.

Osteocalcin increase after bariatric surgery predicts androgen recovery in hypogonadal obese males.

OBJECTIVE: Bone modulates testis function through osteocalcin (OCN) production. This paper assesses the association between serum OCN and androgen production recovery in morbidly obese males at 9 months after bariatric surgery. SUBJECTS: A cohort of n=103 obese males with mean±s.d. body mass index (BMI) 47.7±8.2 kg m(-2), age 42±11 years, consisting of n=76 patients undergoing gastric bypass and n=27 in the waiting list for surgery. RESULTS: At 9 months from surgery, a significant increase was observed in mean±s.d. total OCN (tOCN=10.4±10.3 ng ml(-1), P<0.001) and undercarboxylated OCN (ucOCN=5.4±3.7 ng ml(-1), P<0.001), total testosterone (TT, 5.6±6.5 nM, P<0.001) and calculated free testosterone (cFT, 0.035±0.133 nM, P<0.006), sex hormone binding globulin (SHBG, 21.2±16.7 nM, P<0.001) and decrease in estradiol (E2, -30.1±51.9 pM, P<0.001) levels only in operated patients, with a significant reduction in BMI (24%) and waist (20%). A positive correlation existed between tOCN and ucOCN (age-adjustment (age-adj.): ß=0.692, P<0.001) and their variations (age-adj.: ß=0.629, P<0.001) after surgery. Multivariate analysis in operated patients showed a significant positive association between variations in tOCN and TT (age-adj.: ß=0.289, P=0.012), SHBG (age-adj.: ß=0.326, P=0.005) but not with cFT variation. tOCN, but not luteinizing hormone (LH) variation was the only significant predictive factor of cFT recovery in the hypogonadal (TT<12 nM) operated subjects even after age- and BMI-adjustment (adj.: ß=0.582, P<0.05). cFT improvement was significantly higher when considering operated patients with tOCN increase (0.045±0.123 vs -0.02±0.118 nM, P=0.015), hypogonadism (0.059±0.111 vs -0.059±0.138 nM, P=0.002) and younger than 35 years (0.102±0.108 vs -0.019±0.123 nM, P=0.009). CONCLUSION: OCN recovery observed after bariatric surgery is significantly associated with cFT improvement independently of BMI variation and age in hypogonadal morbidly obese males.

Use of the BasGan algorithm for [123I]FP-CIT SPECT quantification: a phantom study.

AIM: The BasGan algorithm has been specifically developed for semi-automatic quantification of [123I]FP-CIT SPECT studies. The aim of this work was to evaluate the software linearity and its dependence on the main acquisition parameters of the SPECT study. METHODS: The anthropomorphic Striatal Phantom filled with different striatal to background activity concentration ratios was used to verify software linearity. The software response was studied with different acquisition parameters and system configurations. For this purpose, phantom studies were performed with varying radius of rotation, pixel size, number of projections and with different collimator types. For each configuration the tomographic spatial resolution was also determined using the Triple Line Source Phantom. The reconstructed SPECT images were corrected for attenuation and scatter. RESULTS: The BasGan outcome highly correlates with the real Specific Binding Ratio when fixed gamma camera configuration and reconstruction method are used. However, the software quantification depends on system configuration and decreases with increasing partial volume effect. A comparison of the BasGan output with tomographic spatial resolution data for each configuration shows that the software response highly correlates with this quantity. CONCLUSION: The BasGan algorithm is a free, easy-to-use and solid tool for quantification of [123I]FP-CIT images. The software outcome depends on system configuration, but highly correlates with tomographic spatial resolution. Then, the measurement of this quantity turns out to be a simple method to normalize the BasGan quantification for different imaging devices, making it possible the use of available reference values for normal subjects and multicentre studies.

Brand of dipotassium EDTA vacuum tube as a new source of pre-analytical variability in routine haematology testing.

This study assesses the use of different dry K2 (dipotassium) EDTA vacuum tubes and whether or not they might represent a bias in haematological testing. Blood was collected in three dipotassium EDTA vacuum tubes from different manufacturers: Venosafe, Vacuette and Vacutainer. Samples were analysed on an Advia 2120i analyser. Significant differences among results and biases were compared with current quality specifications. Significant differences were found for haematocrit (HCT), mean corpuscular volume (MCV), white blood cell count (WBC) and platelet distribution width (PDW) when comparing Venosafe vs. Vacuette; for MCV, WBC and PDW when comparing Venosafe vs. Vacutainer; and for HCT and MCV when comparing Vacuette vs. Vacutainer. Clinically significant variations were observed for HCT and PDW in Venosafe vs. Vacuette; PDW in Venosafe vs. Vacutainer; and HCT and MCV in Vacuette vs. Vacutainer. The use of dipotassium EDTA vacuum tubes from different manufacturers represent a clinically relevant source of variation for HCT, MCV and PDW.

Productive HIV-1 infection of human cervical tissue ex vivo is associated with the secretory phase of the menstrual cycle.

Cervical tissue explants (CTEs) from 22 HIV-1 seronegative women were exposed to R5 HIV-1 ex vivo. Eight CTEs were productively infected in terms of HIV-1 p24Gag release in culture supernatants, whereas 14 were not. Nonetheless, both accumulation of HIV-1gag DNA and of p24Gag(+) CD4(+) T cells and macrophages occurred in both productive and, at lower levels, in nonproductive CTEs. Nonproductive CTEs differed from productive CTEs for higher secretion of C-C motif chemokine ligand 3 (CCL3) and CCL5. A post-hoc analysis revealed that all productive CTEs were established from women in their secretory phase of the menstrual cycle, whereas nonproductive CTEs were derived from women either in their secretory (28%) or proliferative (36%) menstrual cycle phases or with an atrophic endometrium (36%). Thus, our results support the epidemiological observation that sexual HIV-1 transmission from males to women as well as from women to men is more efficient during their secretory phase of the menstrual cycle.

Novel factors interfering with human immunodeficiency virus-type 1 replication in vivo and in vitro.

The strategy of all retroviral infections is based on establishing an equilibrium between virus replication and proviral latency in the infected host. The human immunodeficiency virus-type 1 (HIV-1), belonging to the subfamily of lentiviridae, adds an additional level of sophistication to this general rule by encoding two regulatory genes (tat and rev) and four accessory genes (nef, vif, vpr and vpu); HIV-2, structurally similar to HIV-1 but characterized by lower pathogenicity in vivo, encodes another accessory gene, vpx. The function of these accessory genes has become clear in recent years: they serve as countermeasures to host-cell restriction factors that prevent or curtail the capacity of HIV to productively infect its target cells (typically, CD4+ T lymphocytes, macrophages and dendritic cells). Some of the best characterized restriction factors for HIV-1 are Tripartite Motif-5α (TRIM5α), preventing infection of nonhuman primates, although not being effective in humans, and apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC 3G), counteracted by the viral accessory protein Vif. In addition, several other molecules are under scrutiny for their mechanism of action and potential exploitation as novel anti-HIV agents. This review will summarize the recently emerging knowledge on these novel factors and their potential relevance for the discovery of new anti-HIV agents targeting not only the replicative, but also the latent state of HIV infection.

Single-nucleotide polymorphism-defined class I and class III major histocompatibility complex genetic subregions contribute to natural long-term nonprogression in HIV infection.

We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in ≥4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype.

A standardized protocol for the perioperative management of myasthenia gravis patients. Experience with 110 patients.

BACKGROUND: Video-assisted thoracoscopic extended thymectomy (VATET) is well established in the treatment of myasthenia gravis; however, patient selection remains controversial. Perioperative management protocol is lacking, and concerns regarding post-operative myasthenic crisis still remain. We performed a retrospective observational study evaluating the impact of the introduction of a protocol in the perioperative management of patients with myasthenia gravis who underwent VATET. METHODS: The perioperative management protocol was developed by a team of neurologists and anesthesiologists who reviewed the literature and their previous experience on myasthenia gravis patients. Respiratory, clinical, and neurological patient features were included in the protocol evaluation. A retrospective review of patients who underwent VATET before and after introduction to the protocol was finally performed. RESULTS: The medical records of 66 patients (pre-protocol group) and 44 patients (protocol group) were available for the study. In the pre-protocol group, 17 patients (26%) were admitted to intensive care unit (ICU) during the post-operative period, while three patients (6.8%) of the protocol group met the criteria for ICU post-operative admission. This resulted in a reduction of 73.5% of patients admitted to ICU (P = 0.023) and in an 80% (P = 0.002) reduction of the use neuromuscular blocking agents. Two post-operative myasthenic crises preceded by bulbar symptoms (1.8%) were identified in the pre-protocol group patients. CONCLUSIONS: Although the application of our protocol results in a substantial reduction in the recovery of patients in the ICU and in hospital costs, there was no substantial difference in mortality and morbidity between patients admitted to the surgical ward or to ICU.