Breast density in NF1 women: a retrospective study.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by neurofibromin haploinsufficiency due to pathogenic variants in the NF1 gene. Tumor predisposition has long been associated with NF1, and an increased breast cancer (BC) incidence and reduced survival have been reported in recent years for women with NF1. As breast density is another known independent risk factor for BC, this study aims to evaluate the variability of breast density in patients with NF1 compared to the general population. Mammograms from 98 NF1 women affected by NF1, and enrolled onto our monocentric BC screening program, were compared with those from 300 healthy subjects to verify differences in breast density. Mammograms were independently reviewed and scored by a radiologist and using a Computer-Aided Detection (CAD) software. The comparison of breast density between NF1 patients and controls was performed through Chi-squared test and with multivariable ordinal logistic models adjusted for age, body mass index (BMI), number of pregnancies, and menopausal status.breast density was influenced by BMI and menopausal status in both NF1 patients and healthy subjects. No difference in breast density was observed between NF1 patients and the healthy female population, even after considering the potential confounding factors.Although NF1 and a highly fibroglandular breast are known risk factors of BC, in this study, NF1 patients were shown to have comparable breast density to healthy subjects. The presence of pathogenic variants in the NF1 gene does not influence the breast density value.

Core stabilisation exercises reduce chronic low back pain in Air Force fighter pilots: a randomised controlled trial.

BACKGROUND: There is evidence that core stabilisation, strength and endurance training contribute to reduce low back pain in the general population. However, we are not aware of the effect of these exercises on fighter aviation pilots. Therefore, the present study aims to investigate the effects of an exercise protocol on chronic low back pain in Brazilian Air Force fighter pilots. Changes in neck pain, lumbar disability, range of motion, strength and resistance were also investigated. METHODS: Fourteen participants with chronic low back pain were randomised into two groups: stabilisation exercise group (SEG-n=7), exercise protocol twice a week for 12 weeks) and the regular exercise group (REG-n=7), which performed their own usual exercise routine. The evaluations were carried out before and after the training period. The primary outcome was the intensity of low back pain and the secondary outcomes were cervical pain, functional disability, range of motion, maximum isometric strength and trunk muscle resistance. RESULTS: The SEG had a significant reduction in low back pain compared with the REG (difference of 2.3 points, p=0.04) and a lower rate of cervical pain (difference of 2.5 points, p=0.01) at the end of the protocol. Maintenance of trunk muscle strength was also observed in the SEG over the period, while the REG presented a decrease in flexural strength to the right side (difference between groups: -3.7%, p=0.04). There were no differences in the rates of disability, range of motion or resistance to fatigue between groups. CONCLUSIONS: The stabilisation exercise programme focused on the core muscles was successful in decreasing the fighter pilots' chronic lumbar pain. Pilots are normally active; however, our results indicate that specific trunk training programmes should be offered considering the work needs of these subjects. CLINICAL TRIALS: 'Exercise protocol for pilots with back pain' (registered: 09 October 2018)-NCT03713814 (https://clinicaltrials.gov/ct2/show/NCT03713814).

The diagnostic performance of PIVKA-II in metabolic and viral hepatocellular carcinoma: a pilot study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a primary liver tumor derived from metabolic or viral chronic hepatitis, with few treatment options in advanced cases. New biomarkers that allow improving diagnosis and staging are widely desired. Here, we aim to evaluate the performance of Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) in combination with α-fetoprotein (AFP), in the diagnosis of HCC in patients with metabolic or viral hepatitis. PATIENTS AND METHODS: We enrolled 60 HCC patients (20 metabolic and 40 viral) and 20 healthy subjects (HS) as negative controls. PIVKA-II, AFP, Matrix metalloproteinase-9 (MMP-9) and Fibroblast growth factor (FGF) serum levels were assessed by immunoassays. RESULTS: AFP and PIVKA-II levels were obviously higher in patients than in HS. AFP displayed a better diagnostic performance than PIVKA-II for viral HCC while PIVKA-II was better for metabolic HCC. The combination of the two biomarkers did not improve the discriminating ability. CONCLUSIONS: PIVKA-II may be considered an independent predictor of macrovascular invasion from HCC cells and it can be used to better stratify HCC patients and should be evaluated in prospective studies for early detection of advanced HCC in metabolic subjects.

Mediterranean diet and the prevention of non-alcoholic fatty liver disease: results from a case-control study.

OBJECTIVE: Few studies report that Mediterranean dietary (MD) pattern has a beneficial role in the progression of non-alcoholic fatty liver disease (NAFLD). Evidence on its potential effect on the onset of disease are, however, scanty. With our study, we evaluated whether MD affects the risk of NAFLD with a large case-control study performed in Italy. PATIENTS AND METHODS: Three hundred and seventy-one cases of NAFLD and 444 controls were questioned on the demographic data and their dietary habits before diagnosis. Additionally, information about lifestyles and other related diseases, such as hypertension and diabetes mellitus were collected. The MD adherence was assessed using a pre-defined Mediterranean Diet Score (MDS). Odds ratios (OR) and 95% confidence intervals (CI) were obtained using a multiple logistic regression model. RESULTS: A high adherence to the MD is significantly associated with decreased risk of NAFLD (OR: 0.83 95% CI: 0.71-0.98). When the different MD components were examined separately, higher legumes consumption (OR: 0.62 95% CI: 0.38-0.99) and high fish consumption (OR 0.38 95% CI: 0.17-0.85) were reported to be protective against NAFLD. CONCLUSIONS: Our study shows that a high adherence to the MD decreases the risk of NAFLD.

Molecular evaluation of tissue proteins in vivo during controlled orthodontic movement.

Orthodontic tooth movement determines a biological response of all the tissues surrounding the teeth to which force is applied. The aim of this study is to evaluate which ideal orthodontic force, at the biological level, arouses an acute inflammatory response on periodontal tissues, and the duration of the force in order to establish an ideal experimental model of dental movement. The periodontal ligament and the alveolar bone change abruptly due to the biochemical adaptive response, resulting in a re-organization of the intracellular and the extracellular matrix. There is a modification of the local vascularization which stimulates a cascade production, synthesis and the release of arachidonic acid, metabolites, proteins, such as cytokines, and growth factors. Every dentist can control and should know the above-mentioned mechanism. Moreover, the production of proteins by modulating the direction and the intensity of the force can be changed but, above all, the duration.

Acute HEV hepatitis: clinical and laboratory diagnosis.

OBJECTIVE: Hepatitis E Virus (HEV) is probably the most common cause of acute hepatitis worldwide. It has been regarded for a long time as a disease limited to developing countries. Recently, the refinement of diagnostic techniques, on the one hand, and migratory flows, on the other hand, have also led to the identification of an increased number of HEV infections in industrialized countries. Four HEV genotypes have been identified across the world, with different epidemiological burdens and a wide range of clinical presentations. Here, we report a case series of acute HEV hepatitis observed in the last three years in our hospital. PATIENTS AND METHODS: We performed a search for HEV IgM and IgG in all subjects admitted for acute hepatitis without evidence of other possible infectious, toxic or metabolic causes of liver damage. In subjects with HEV IgM positivity, the search for HEV-RNA was performed. RESULTS: We diagnosed eight acute HEV infections: 2 epidemic and 6 sporadic forms. HEV-RNA was detected in serum in 2 cases. CONCLUSIONS: HEV infection appears to be a cause of acute hepatitis that we must keep in mind even in developed countries.

International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

BACKGROUND: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. METHODS: A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. RESULTS: Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients' age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: <1y, 36% (n = 46); 1-10y, 59% (n = 74); 11-16y, 3% (n = 4); and >16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. CONCLUSIONS: Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

Drug-induced liver injury 2017: the diagnosis is not easy but always to keep in mind.

A drug-induced liver injury (DILI) is defined as a liver injury caused by exposure to a drug or a non-infectious toxic agent with a variable degree of organ dysfunction. A better understanding of DILI epidemiology has been obtained in recent years with the institution of international registries in the United States and Europe. Despite the advances in the understanding and characterization of the phenomenon, DILI remains an exclusion diagnosis so, probability scores and the analysis of literature reports are useful tools in dealing with a suspected DILI. Idiosyncratic DILI can be considered a relatively rare event but it is one of the leading causes of acute liver failure. Thus, proper management is essential to avoid serious consequences. Here, we present an updated review of diagnostic and classification criteria of DILI. Prognostic tools, and principles of management and therapy have also been briefly discussed.

Fatty liver and drugs: the two sides of the same coin.

Drug-induced liver injury (DILI) is a common and underestimated cause of liver disease. Several drugs and other xenobiotics can be the cause of different clinicopathologic patterns of liver disease. Steatosis and steatohepatitis are rare but well-documented types of DILI. Over the past decades commonly used drugs like amiodarone, tamoxifen, irinotecan, methotrexate, valproic acid and glucocorticoids have been recognized to be associated with steatosis. Even though the pathophysiological pathways are still only partially understood, inhibition of mitochondrial beta-oxidation, reduced very low-density lipoprotein secretion, insulin resistance induction and increased de novo synthesis or increased liver uptake of fatty acids are considered the main pathogenic mechanisms through which drugs can lead to hepatic steatosis. On the other hand, fatty liver itself is a very common clinical condition, and there is a growing awareness of the potential risk factors for DILI due to the underlying metabolic condition itself.

Liver transplantation for drug-induced acute liver failure.

OBJECTIVES: To summarize the different clinical features of drug-induced acute liver failure, the diagnostic work-up, conservative management and the prognostic scores currently used to list patients for liver transplantation. EVIDENCE AND INFORMATION SOURCES: The current review is based on an analysis of the current literature and the caseload experience of the Authors on this topic. STATE OF THE ART: Drug-induced liver injury is the leading cause of acute liver failure in the adult population in Western countries, with a transplant-free survival rate of less than 50%. Main subtypes include paracetamol and idiosyncratic drug-induced injury, which differ in epidemiology, clinical course, prognosis and conservative management. In cases of a high likelihood of death, urgent hepatic transplantation is indicated, but the decision whether and when to put a patient with drug-induced acute liver failure on the list for urgent liver transplant is extremely difficult and requires constant interdisciplinary exchange and continuous updating of the clinical picture. CONCLUSIONS: Intensive management should be done in a clinical tertiary referral center which has a specialized team of hepatologists and a liver transplant center.

Identification of A3 adenosine receptor agonists as novel non-narcotic analgesics.

Chronic pain negatively impacts the quality of life in a variety of patient populations. The current therapeutic repertoire is inadequate in managing patient pain and warrants the development of new therapeutics. Adenosine and its four cognate receptors (A1 , A2A , A2B and A3 ) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A1 and A2A receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A3 receptor is only in its infancy, but exciting preclinical observations of A3 receptor antinociception, which have been bolstered by clinical trials of A3 receptor agonists in other disease states, suggest pain relief without cardiovascular side effects and with sufficient tolerability. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and to consider the current data regarding A3 receptor-mediated antinociception. We will highlight recent findings regarding the impact of the A3 receptor on pain pathways and examine the current state of selective A3 receptor agonists used for these studies. The adenosine-to-A3 receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain.

Abdominal acupuncture reduces laser-evoked potentials in healthy subjects.

OBJECTIVE: Acupuncture is known to reduce clinical pain, although the exact mechanism is unknown. The aim of the current study was to investigate the effect of acupuncture on laser-evoked potential amplitudes and laser pain perception. METHODS: In order to evaluate whether abdominal acupuncture is able to modify pain perception, 10 healthy subjects underwent a protocol in which laser-evoked potentials (LEPs) and laser pain perception were collected before the test (baseline), during abdominal acupuncture, and 15 min after needle removal. The same subjects also underwent a similar protocol in which, however, sham acupuncture without any needle penetration was used. RESULTS: During real acupuncture, both N1 and N2/P2 amplitudes were reduced, as compared to baseline (p<0.01). The reduction lasted up to 15 min after needle removal. Furthermore, laser pain perception was reduced during real acupuncture, although the difference was marginally significant (p=0.06). CONCLUSIONS: Our results show that abdominal acupuncture reduces LEP amplitude in healthy subjects. SIGNIFICANCE: Our results provide a theoretical background for the use of abdominal acupuncture as a therapeutic approach in the treatment of pain conditions. Future studies will have to be conducted in clinical painful syndromes, in order to confirm the analgesic effect of acupuncture in patients suffering from pain.

Cancer-induced bone pain: Mechanisms and models.

Cancerous cells can originate in a number of different tissues such as prostate, breast and lung, but often go undetected and are non-painful. Many types of cancers have a propensity to metastasize to the bone microenvironment first. Tumor burden within the bone causes excruciating breakthrough pain with properties of ongoing pain that is inadequately managed with current analgesics. Part of this failure is due to the poor understanding of the etiology of cancer pain. Animal models of cancer-induced bone pain (CIBP) have revealed that the neurochemistry of cancer has features distinctive from other chronic pain states. For example, preclinical models of metastatic cancer often result in the positive modulation of neurotrophins, such as NGF and BDNF, that can lead to nociceptive sensitization. Preclinical cancer models also demonstrate nociceptive neuronal expression of acid-sensing receptors, such as ASIC1 and TRPV1, which respond to cancer-induced acidity within the bone. CIBP is correlated with a significant increase in pro-inflammatory mediators acting peripherally and centrally, contributing to neuronal hypersensitive states. Finally, cancer cells generate high levels of oxidative molecules that are thought to increase extracellular glutamate concentrations, thus activating primary afferent neurons. Knowledge of the unique neuro-molecular profile of cancer pain will ultimately lead to the development of novel and superior therapeutics for CIBP.

Acupuncture versus valproic acid in the prophylaxis of migraine without aura: a prospective controlled study.

BACKGROUND: The pharmacologic treatment of migraine still remains below the expectations. The aim of this study is to compare the effectiveness of traditional acupuncture and valproic acid in migraine prophylaxis. METHODS: A prospective, controlled study was performed in 100 patients affected by migraine without aura lasting for over one year. The patients were stratified for sex and randomly divided into two groups of 50 patients each. Patients belonging to Group A (acupuncture) were submitted to 20 sessions of acupuncture, while patients belonging to Group V valproate) were administered Valproic acid (Depakin Chrono®) at a dose of 600 mg/day; 10 mg Rizatriptan wafers were allowed as needed to treat the attacks. The Midas Index (MI) and pain intensity (PI, by VAS) were recorded before treatment (T0), at three (T1) and six (T2) months; a six-point scale Pain Relief score (PRS), the Rizatriptan intake and adverse events were recorded at T1 and T2. RESULTS: Eighty-two out of 100 patients completed the study (9 dropouts in each group). In both groups the MI improved at T1 and T2 (P<0.0001). Pain intensity was better at T1 in group V (P<0.0001), but PI and PRS (P=0.02) as well as rizatriptan intake (P=0.001) were better in group A at T2. The rate of adverse events was 47.8% in group V and 0% in group A. CONCLUSION: Our data show a lower pain intensity and lower Rizatriptan intake at six-months follow-up with no adverse events in acupuncture patients compared to those treated with valproic acid.

Recurrent respiratory infections: why not talking about it any more?

Recurrent respiratory infections (RRIs) are a common and benign condition affecting about 6% of schoolchildren. Only mild, likely postinfective, modifications of the immune system have been proven, and parents should be reassured that the condition is self-limited. Nevertheless, if not correctly diagnosed, children may undergo several unnecessary investigations and multiple antibiotic courses. On the other hand, in some cases, efforts should be made to identify promptly possible underlying disease, including congenital or acquired immunodeficiency, vascular or airways malformation, tuberculosis, cystic fibrosis, or immotile-cilia syndrome. Careful medical history and clinical examination are usually sufficient to distinguish RRIs and no further research is generally needed. In uncertain cases a complete blood count with differential and the evaluation of total immunoglobulin serum levels are sufficient to exclude neutropenia, T- or B-lymphocyte defects, and selective IgA deficiency. It is essential to observe environmental risk factors: reducing environmental tobacco smoke at home is a fundamental goal and the postponed enrolment of children at day-care centres reduces the risk of RRIs. Antibiotic treatment are not justified since they do not shorten the course of the condition or prevent complications. Use of anti-cough syrups should be avoided. Nasal lavage with saline serum and the blowing are the only justified interventions. Adenoidectomy and tonsillectomy should be planned only in conditions included in validated guidelines.

A within-subject comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and both substances.

A cannabis withdrawal syndrome has been characterized, but its clinical significance remains uncertain. One method of assessing the significance of cannabis withdrawal is to compare it directly to an established withdrawal syndrome. The present study was a within-subject comparison of cannabis, tobacco, and combined cannabis and tobacco withdrawal among users of both substances. Participants (N=12) completed three 5-day periods of abstinence in a randomized order, separated by 9-day periods of usual substance use. Overall withdrawal severity associated with cannabis alone and tobacco alone was of a similar magnitude. Withdrawal during simultaneous cessation of both substances was more severe than for each substance alone, but these differences were of short duration and substantial individual differences were noted. These results are consistent with other evidence suggesting cannabis withdrawal is clinically important and warrants detailed description in the DSM-V and ICD-11. Additional research is needed to replicate these findings and to further investigate the effects of abstaining from multiple drugs simultaneously.

Effect of gestational hypercholesterolaemia on omental vasoreactivity, placental enzyme activity and transplacental passage of normal and oxidised fatty acids.

OBJECTIVE: Maternal hypercholesterolaemia during pregnancy increases lipid peroxidation in mothers and fetuses and programs increased susceptibility to atherosclerosis later in life. The objective of this study was to elucidate the role of the placenta in mediating oxidative stress from mother to offspring. DESIGN: Comparison between normo- and hypercholesterolaemic mothers (n = 36 each) and their children. SETTING: Obstetric wards, hospitals of the University of Naples and Regione Campania. POPULATION: Healthy primiparas delivering by caesarean section. METHODS: Biochemical measurements of oxidative stress and serum leptin in cord plasma and placenta, immunochemistry of placenta microvessels, and vasoreactivity studies were performed. MAIN OUTCOME MEASURES: Oxidative status (i.e. lipid composition and content of oxidised fatty acids, activity of pro- and antioxidant enzymes, immunohistochemical presence of oxidation-specific epitopes) in maternal and cord blood and in placental tissue, as well as vascular reactivity in omental arteries. RESULTS: Hypercholesterolaemia during pregnancy was associated with extensive changes in fatty acid composition of both maternal and cord blood lipids, sufficient to alter vasoreactivity of omental vessels. Results also indicated that the placenta is not only subject to substantial oxidative stress, but that it may further increase fetal oxidative stress through changes of pro- and antioxidant enzyme activities. CONCLUSIONS: The placenta plays an important role in both transmitting and enhancing pathogenic effects of gestational hypercholesterolaemia.

A convenient method for the stereoselective conversion of aryl peptidyl ketones into the corresponding aryl aminomethin derivatives, a novel class of modified peptides.

In this paper we describe a reductive amination procedure that can be employed in the preparation of a novel class of pseudopeptides in which a specific amide bond is replaced by a CH(Ar)NH group. The developed methodology, performed using NaBH(3)CN and TiCl(4), is characterized by the formation of diastereomeric intermediates in a relative 1:1 ratio. It provides aryl aminomethin pseudopeptides in moderate but satisfactory yields and with definite stereochemistry on the asymmetric centres next to the modified peptide bond.

IGF-I and IGFBP-3 assessment in the management of childhood onset growth hormone deficiency.

The diagnosis of growth hormone (GH) deficiency (GHD) in childhood is not straightforward, being still based on a comprehensive clinical, anthropometric, endocrine and neuroradiological assessment. Due to their GH dependency and relative stability in circulation, IGF-I and IGFBP-3 serum concentrations were proposed as reliable indicators of daily GH secretion. However, the sensitivity of assays for both IGF-I and IGFBP-3 is inadequate to exclude the diagnosis of GHD merely on the basis of a normal value of the two parameters, although it seems likely that IGF-I values higher than -1 SD reflect a normal GH secretion. On the other hand, as the specificity of both measurements is over 90%, subnormal concentrations strongly support the diagnosis of GHD. Finally, combining the evaluation of growth velocity with IGF-I measurement, sensitivity and specificity reach a value > or =95%, implying that two subnormal values strongly suggest and two normal values strongly oppose the diagnosis of GHD.