Copper and zinc as a window to past agricultural land-use.

Intensive agricultural management significantly affects soil chemical properties. Such impacts, depending on the intensity of agronomic practices, might persist for several decades. We tested how current soil properties, especially heavy metal concentrations, reflect the land-use history over a 24,000 ha area dominated by intensive apple orchards and viticulture (South Tyrol, ITA). We combined georeferenced soil analyses with land-use maps from 1850 to 2010 in a space-for-time approach to detect the accumulation rates of copper and zinc and understand how present-day soil heavy metal concentrations reflect land-use history. Soils under vineyards since the 1850s showed the highest available copper concentration (median of 314.0 mg kg-1, accumulation rate between 19.4 and 41.3 mg kg-1·10 y-1). Zinc reached the highest concentration in the same land-use type (median of 32.5 mg kg-1, accumulation rate between 1.8 and 4.4 mg kg-1·10 y-1). Using a random forest approach on 44,132 soil samples, we extrapolated land-use history on the permanent crop area of the region, reaching an accuracy of 0.72. This suggests that combining current soil analysis, historical management information, and machine learning models provides a valuable tool to predict land-use history and understand management legacies.

Use of Eribulin mesylate as second-line therapy in elderly patients with HER/2 negative metastatic breast cancer (MBC): efficacy, tolerability and Quality of Life.

OBJECTIVE: Eribulin mesylate (Halaven®) is a non-taxane inhibitor of microtubule indicated as monotherapy in patients with metastatic breast cancer (MBC), which progresses after anthracycline and taxanes therapy. In this retrospective observational study, we want to evaluate the efficacy of Eribulin in elderly women with MBC pretreated with anthracyclines and taxanes. PATIENTS AND METHODS: 40 elderly patients > 70 years of age were enrolled, and the median age was 76 years (range 70-82). Overall survival (OS), Progression Free Survival (PFS), Objective Response Rate (ORR) were primary endpoints, tolerability, carcinoembryonic antigen levels 15.3 (Ca 15.3), before and after treatment, and Quality of Life (QoL) were secondary endpoints. RESULTS: Eribulin treatment was well tolerated, produced a good level of disease control, a manageable toxicity profile and a significant impact on QoL. Median OS was 12.8 months and median PFS was 3.2 months. A significant correlation was observed between reduction of Ca 15.3 and PFS with a value of 0.59 (p = 0.002). CONCLUSIONS: Despite a limited number of patients and a modest manageable toxicity, Eribulin is a chemotherapy treatment that has showed to be an effective and well-tolerated therapeutic option in elderly patients with MBC. Further analysis should focus on the elderly patients in our setting of study.

Echo-guided injection of botulinum toxin versus blind endoscopic injection in patients with achalasia: final report.

AIM: Achalasia, also known as Esophageal achalasia, is an esophageal motility disorder involving the smooth muscle layer of the esophagus and the lower esophageal sphincter (LES). It is characterized by incomplete LES relaxation, increased LES tone, and lack of peristalsis of the esophagus (inability of smooth muscle to move food down the esophagus) in the absence of other explanations like cancer or fibrosis. In our experience, the echo-guided injection technique is the first procedure to implement to cure patients. After endoscopic-echo-guided injection technique, in patients presenting with refractory symptoms, the authors believe in surgical technique (extramucosal myotomy) as a good alternative technique to be implemented. METHODS: From 1999 to 2010, the authors have treated 36 patients (Group A), 24 male and 12 female (age 26-78) with diagnosis of esophageal achalasia. Patients underwent botulinum toxin injection during echo-guided identification of the lower esophageal sphincter. Results were compared with 32 patients (Group B) (age 36-78) who underwent blind treatment. RESULTS: Patients of Group A presented complete relief of obstruction, patients of Group B had an obstruction remission in the 86% of the cases. Results were confirmed by manometric assessments in the early months after endoscopic treatment. CONCLUSION: The authors emphasize the importance of the injection of botulinum toxin into the thicker area of the muscle layer of the lower esophageal sphincter. Patients undergoing echo-guided injection technique presented complete relief of obstruction, confirmed by manometric assessments in the early months after treatment.

Immunosuppressive monoclonal antibody to CD64 from patients with long-term stable multiple sclerosis.

High intrathecal levels of anti-myelin basic protein (MBP) IgM were previously found to be significantly associated with early favorable course in a cohort of patients with multiple sclerosis (MS). A mAb to MBP 105-120 recognizing the 222-228 epitope of the extracellular domain of high affinity immunoglobulin gamma Fc-receptor I (CD64) was isolated from EBV(+) B cell clones of long-term stable RRMS patients. This mAb exerted immunosuppressive activity on MS-derived T cell lines through induction and release of high amounts of interleukin-10 and decreased levels of interleukin-12 from activated monocytes providing the biological basis for a potential new treatment for MS and other immune-mediated neurological disorders.

Defining origins of malignant B cells: a new circulating normal human IgM(+)D(+) B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population.

In probing the cell of origin in malignant B cells, an imprint of somatic hypermutation (SHM) in immunoglobulin (Ig) variable (V) region genes delineates antigen encounter, and identifying the precise pathway generating SHM in the normal B-cell counterpart becomes relevant. SHM remains the definitive memory imprint in normal human B cells, but CD27 expression also delineates memory. Recently, dye extrusion adenosine triphosphate-binding transporter assays identified circulating isotype-switched memory B cells that lacked CD27, yet exhibited low levels of SHM. To extend findings, we report a pre-switched CD27(-ve) circulating memory B-cell population in normal blood using comparable assays, and isolated CD19(+)IgM(+)D(+)CD27(-ve) cells (>99% purity) for the analysis of IGHV5/IGHV3-IGHM transcripts. Of these (n=334), approximately 78% were germ line and naive B cell derived. Strikingly, 21.9% of the transcripts were mutated. They showed 3-5 mutations (13.5% of sequences) and >5 mutations (8.4% of sequences) per transcript. Accrual of mutations in a subset of CD19(+)IgM(+)D(+)CD27(-ve) cells define a new circulating pre-switched memory B-cell pool, present in substantial numbers in the population harboring naive B cells. These CD19(+)IgM(+)D(+)CD27(-ve) memory B cells may have a distinct lineage and function, and seem relevant to understanding origins of malignant B cells, in particular those of hairy cell leukemia cells, which display mutated V genes yet lack CD27 expression.

Humoral immunity to respiratory syncytial virus in young and elderly adults.

Respiratory syncytial virus (RSV) has been demonstrated to cause substantial disease in elderly and immunocompromised subjects. The relationship of serum antibody to RSV infection and the risk of infection in elderly subjects is controversial, thus we evaluated the presence of neutralizing antibodies to RSV in healthy people of different age groups and the correlation with viral protection. Baseline blood samples from 197 subjects aged 20-80 years were analysed for the presence of anti-RSV antibodies either by indirect immunofluorescence and microneutralization test. The percentage of people who had neutralizing antibodies to RSV was significantly higher (P=0.001) in the youngest group (92.51%) compared to the frail group (36.21%). The RSV antibody level tends to wane in some older people; this factor could determine proneness to RSV re-infections in the elderly who are at a greater risk of developing severe respiratory disease.

[Spontaneous pneumoperitoneum: a case secondary to thoracic trauma]. / Pneumoperitoneo spontaneo: presentazione di un caso secondario a trauma toracico.

Spontaneous pneumoperitoneum is the radiographic manifestation of free air in the peritoneal cavity without visceral perforations and peritoneal signs, and it occurs in about 10% of the cases of pneumoperitoneum. The etiology can be postoperative, thoracic, abdominal, gynecologic, idiopathic; it generally introduces a benign evolution and does not require surgical treatment but just a conservative approach. The authors describe here a case of spontaneous pneumoperitoneum secondary to thoracic trauma. This case is interesting for the occurrence of pneumoperitoneum without clinical peritoneal signs such as fever and leucocytosis, after closed thoracic trauma in absence of pneumothoracic and pneumomediastinum. Correct clinical approach has allowed a conservative treatment avoiding an useless laparotomy.

Gallbladder carcinoma late metastases and incisional hernia at umbilical port site after laparoscopic cholecystectomy.

A potentially serious complication of laparoscopic cholecystectomy is the inadvertent dissemination of unsuspected gallbladder carcinoma. There are increasing reports of seeding of tumor at the trocar sites following laparoscopic cholecystectomy in patients with unexpected or inapparent gallbladder carcinoma. Although the mechanism of the abdominal wall recurrence is still unclear, laparoscopic handling of the tumor, perforation of the gallbladder, and extraction of the specimen without an endobag may be risk factors for the spreading of malignant cells. The Authors report the case of late development of umbilical metastasis after laparoscopic cholecystectomy; the presence of an incisional hernia and the finding of a stone in subcutaneous tissue demonstrate the diffusion of tumor cells into subcutaneous tissue during the extraction of gallbladder. The patient underwent an excision of the metastases. She is disease free two years after surgical treatment.

Molecular analysis of the Drosophila miniature-dusky ( m-dy) gene complex: m-dy mRNAs encode transmembrane proteins with similarity to C. elegans cuticulin.

Mutations in the Drosophila miniature-dusky ( m-dy) gene complex were first reported by Morgan and Bridges about 90 years ago. m-dy mutants have abnormally small wings, a phenotype attributed to a cell-autonomous reduction in the size of the epidermal cells comprising the differentiated wing. Using a molecular genetic approach, we have characterized the m-dy chromosomal interval and identified a pair of adjacent transcription units corresponding to m and dy. A dy mutant known as dy (And) has a single base substitution within the protein-coding region that is predicted to result in an amber stop codon and premature translational termination. We show that dy mRNA is expressed at two discrete periods during the life cycle--one during embryonic development and early larval instars, the second during adult development, coincident with wing differentiation. In agreement with the phenotypic similarity of m and dy mutants, sequence comparisons reveal a similarity between the predicted MINIATURE and DUSKY proteins, and indicate that the m and dy genes are members of a larger Drosophila gene family. Both m and dy, as well as other members of this superfamily, are predicted to encode transmembrane proteins with similarity to C. elegans cuticle proteins known as cuticulins. We postulate that m, dy and other members of this protein superfamily function as structural components of the Drosophila cuticulin layer. Such a role for m and dy products in wing differentiation is sufficient to explain the morphological phenotypes associated with m-dy mutants.

Assessing resting heart rate in adolescents: determinants and correlates.

The aim of this study was to evaluate the distribution of resting heart rate and its biological and environmental determinants in adolescents. The study was cross- sectional and the population consisted of 2230 children and adolescents, age range 12-18 years, enrolled randomly from state schools in Turin, Italy. In all participants the following parameters were evaluated: heart rate, blood pressure (BP), weight, height, degree of sexual development, physical activity, parental socio-cultural level. Heart rate and BP were measured after 5, 10 and 15 min in a sitting position. Furthermore, to obtain regression equations to define heart rate as a function of the other variables available, a multiple regression analysis was performed. In both sexes BP, but not heart rate, declined significantly from the first to the last determination. Heart rate was positively and significantly correlated to BP level in both sexes; heart rate was higher in girls (3 bpm) and followed a progressive decreasing trend with age in both sexes, that was opposite to BP values. Age, sexual maturation, height, physical activity and parental socio-cultural level were independent determinants of resting heart rate. In conclusion, resting heart rate in adolescents is related to several methodological, constitutional and environmental factors that have to be taken into account when assessing heart rate values and constructing tables of normal values.

Haplotype tagging for the identification of common disease genes.

Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated, even the most recent studies have not placed significant emphasis on the most informative and cost-effective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.

Ambulatory blood pressure monitoring and clinical characteristics of the true and white-coat resistant hypertension.

The resistant hypertension has been differentiated in true resistant hypertension and white-coat resistant hypertension by using ambulatory blood pressure monitoring. White-coat resistant hypertension was defined as high clinic blood pressure, despite triple treatment for at least 3 months, but day-time blood pressure values < 135/85 mmHg. The aim of this study was to evaluate the presence of different clinical characteristics between two types of resistant hypertension. The study group consisted of 49 patients with essential hypertension, resistant to an adequate and appropriate triple-drug therapy, that included a diuretic, with all 3 drugs prescribed in near maximal doses and that had persistently elevated clinic blood pressure (> 140/90 mm Hg), for at least 3 months. They represented the 2% of 2500 hypertensive outpatients that referred at our Hypertension Unit. Patients with white-coat resistant hypertension (n=19) were older (p<0.05) than those with true resistant hypertension (n=30). The sodium intake (p<0.05) and alcohol intake (p<0.05) were significantly higher in patients with true resistant hypertension than in those with white-coat resistant hypertension. The renin plasma activity and plasma aldosterone were higher (p<0.05) in patients with true resistant hypertension than in those with white-coat resistant hypertension with normal plasma electrolyte balance. There were no significant differences in mean values of office systolic and diastolic blood pressures between white coat resistant hypertensives and true resistant hypertensives (165+17 vs 172+28 and 98+12 vs 102+14 mmHg). Day-time and night-time ambulatory 24-h-systolic and diastolic blood pressures were significantly higher in the true resistant hypertensive patients when compared with white-coat resistant hypertensives (153+15 vs 124+10 mmHg and 97+9 vs 76+6 mmHg all p<0.001). Day-time and night-time ambulatory 24-h-heart rate were significantly higher in the true resistant hypertensive patients when compared with white-coat resistant hypertensives (79+11 vs 71+9 beats/min; p<0.01; 68+9 vs 60+6 beats/min, p<0.001). The ABP readings were analysed by a Fourier series with 4 harmonics. According to the runs test both two groups of patients showed a circadian rhythm for both systolic and diastolic blood pressure. The nocturnal fall in SBP, DBP and HR was not different in both groups of patients. In conclusion, our findings showed that true resistant hypertensive patients were characterized both by higher heart rate and higher plasma renin activity values as an expression of a possible increased sympathetic activity. Thus, the combination of ABPM with the assessment of the clinical characteristics allow to differentiate better the true drug-resistant hypertension from the white coat resistant hypertension.

Antihypertensive drugs and sympathetic nervous system.

Several studies have demonstrated that essential hypertension is accompanied by sympathetic activation, which contributes to blood pressure elevation. Sympathetic activation also has adverse consequences in hypertensive patients beyond initiating blood pressure elevation. There is evidence that neural vasoconstriction has metabolic effects in skeletal muscle, impairing glucose delivery to muscles. In the liver, retarding of post prandial clearance of lipids contributes to hyperlipidemia. Cardiac sympathetic activation is a probable cause of sudden death in hearth failure. A trophic effect of sympathetic activation on cardiovascular growth is also likely, contributing to the development of left ventricular hypertrophy. Consequently, one of the major aims of antihypertensive therapy should be to attenuate sympathetic tone. It is possible that, among the antihypertensive drugs available, those inhibiting the sympathetic nervous system might best reduce cardiovascular risk.

Baroreflex sensitivity in secondary hypertension.

A deranged baroreceptor control of the cardiovascular functions has been reported in essential hypertension. Studies performed in experimental animals and in humans using different approaches have documented an impairment of both baroreflex heart rate modulation (resetting and loss of sensitivity) and baroreceptor control of peripheral vasomotor tone (only resetting). Baroreflex alterations have been reported also in secondary forms of hypertension, but data are controversial. This paper reviews recent works concerning baroreflex function in secondary hypertension. Either structural changes of arterial wall (decrease of vascular distensibility) or functional processes (involving angiotensin II, aldosterone, catecholamines, nitric oxide) have been proposed as potential mechanisms responsible for baroreflex readjustments in secondary hypertension. It remains unclear, and it is difficult to define exactly, if baroreflex changes associated with secondary form of hypertension are primarily due to factors specific for different hypertensive conditions, or merely follow blood pressure elevation.

Transcription of Dfos is stimulated by brain tumours of l(2)gl-deficient larvae of Drosophila melanogaster.

Mutations in the tumour suppressor gene l(2)gl cause formation of brain and imaginal disc tumours. The product of this gene was suggested to be a part of an intercellular communication system, regulating cell growth and differentiation. Oncogenic activation of many signalling pathways, involved in similar processes, result in increased activity of the AP-1 family of transcription factors. In this paper we explored the interaction between the cancer mutation l(2)gl and the level of transcription of the AP-1 proteins. We report that in brain tumours from l(2)gl-deficient larvae, transcription of the Drosophila melanogaster c-fos homologue was stimulated but that of the c-jun homologue was unchanged. Our results provide further evidence that the protein l(2)gl is a component of a signalling pathway, a nuclear target of which is the AP-1 family of transcription factors.

Baroreflex control of heart rate is impaired in pre-eclampsia.

Autonomic nervous dysfunction, such as parasympathetic and sympathetic impairment, has been suggested as possible cause of pre-eclampsia, but the studies are not conclusive. Our purpose was to assess non-invasively if pre-eclampsia is associated with a decreased baroreflex function. Nine women with pre-eclampsia (PE), eight normotensive pregnant women, and seven healthy normotensive non-pregnant women were studied. Continuous finger blood pressure was recorded by a Portapres device in the left lateral recumbent position and active standing. Baroreflex gain was evaluated by cross-spectral analysis of systolic blood pressure and pulse interval. The result was that baroreflex gain at rest was lower in pre-eclamptic women both compared to non-pregnant and healthy pregnant subjects (P<0.05). Moreover, a decrease of the baroreflex sensitivity was present in all pregnant women in the orthostatic position (P<0.05). In conclusion pregnancy per se is associated with a decrease in the baroreflex control of the heart, whereas in pre-eclampsia, the baroreflex sensitivity is impaired further.

Impaired baroreflex function and arterial compliance in primary aldosteronism.

The purpose of this study was to evaluate if changes in vascular properties were related to baroreflex function in patients with primary aldosteronism. Twenty-three patients with primary aldosteronism, 22 essential hypertensive patients and 16 normal controls were studied. Continuous finger blood pressure (BP) was recorded by Portapres device during supine rest and active stand up. Compliance was estimated from the time constant of pressure decay during diastole. Baroreflex sensitivity was calculated by autoregressive cross-spectral analysis of systolic BP and interbeat interval. The result was that baroreflex gain and compliance were lower in primary aldosteronism patients in the supine position (P = 0.002 and P < 0.05 respectively). Aldosterone plasma levels (R2 = 0.31, P = 0.01), age, systolic and diastolic BP, high and low frequency components of diastolic BP variability were independently related to compliance in primary aldosteronism. In conclusion primary aldosteronism is associated with an impaired baroreflex function related in part to a reduced arterial compliance. Despite a reduction of BP values and aldosterone levels, surgical or pharmacological treatment did not significantly change compliance values.

Lack of immunotoxicity of saquinavir (Ro 31-8959) used alone or in double or triple combination with AZT and ddC.

Saquinavir (Ro 31-8959; SQV) has been demonstrated to be a potent inhibitor of human immunodeficiency virus (HIV) proteinases and acts synergistically with dideoxynucleoside analogues. The aim of this study was to investigate the in vitro immunomodulatory effects of SQV on normal human peripheral blood mononuclear cells (PBMC) and on lamina propria mononuclear cells (LPMC). We used the drug either alone or in double and triple combination with AZT and ddC to assess whether SQV enhances the immunomodulatory effects induced by AZT and ddC that we previously observed. We demonstrated that SQV did not induce any modulation of the proliferative response either in PBMC or in LPMC. Similarly, NK cell-mediated cytotoxic activity and cytokine production were not modified by SQV. More importantly, SQV/AZT, SQV/ddC, and SQV/AZT/ddC combinations did not strengthen neither the inhibition of PBMC and LPMC proliferative response or the modulation of cytokine production induced by AZT, ddC, and AZT/ddC. On the other hand, the increased IL-2 production induced by AZT and ddC was not observed adding SQV to the dideoxynucleoside analogues. In conclusion, we demonstrated that SQV used in combination with AZT and ddC did not add any further immunotoxicity.

Blood pressure and heart rate in young thalassemia major patients.

The analysis of blood pressure (BP) and heart rate (HR) variability is currently used to investigate the mechanisms responsible for cardiovascular control; therefore, we assessed whether an impairment of 24-h BP and HR profiles and sympathovagal interaction modulating cardiovascular function was present in patients with thalassemia major (TM) in preclinical phase of heart disease. Nine beta-thalassemic patients 18 years old without clinical signs of cardiac failure and 9 age- and sex-matched controls were studied. Twenty-four-hour-ambulatory BP and HR were measured using the SpaceLabs 90207 device. A truncated Fourier series with four harmonics was used to describe the diurnal blood pressure profile. Mean 24-h ambulatory systolic BP, diastolic BP, and mean arterial pressure were significantly lower in TM patients than in normal subjects (P < .05). A significantly higher nighttime HR value was found in TM patients (P < .05). More than 40% of the TM patients did not show a significant diurnal BP and HR rhythm. In TM patients, the overall amplitude of systolic BP, diastolic BP, and HR was significantly lower than in controls (P < .01). The night/day differences of systolic BP, diastolic BP, and HR were significantly lower in TM patients than in normals (P < .01). Furthermore, we performed power spectral analysis on short-term continuous finger BP and HR data in supine position and during passive head-up tilt. Total spectral power of systolic BP was significantly lower in patients than controls (P < .05). Low-frequency (LF) power of systolic BP and diastolic BP and LF/high-frequency (HF) ratio of HR were significantly lower during tilt in TM patients compared to controls (P < .05). High-frequency power of HR was significantly higher in patients than controls (P < .05). The baroreflex gain assessed by alpha-index was the same in supine position but was higher in TM patients during passive tilt (P < .05). An inverse relationship between LF/HF ratio of HR and hemoglobin levels in TM patients was found. Finally, plasma norepinephrine levels were significantly lower in thalassemics (P < .005). In young TM patients in a preclinical stage of heart disease, these findings demonstrated abnormal 24-h BP and HR rhythms and a decreased short-term variability of BP and HR, in particular in the LF range, showing a diminished sympathetic activity.

A molecular rhythm mediating circadian clock output in Drosophila.

Analysis of the Drosophila lark gene indicates that it encodes an RNA-binding protein that functions as a regulatory element of the circadian clock output pathway controlling adult eclosion. We now demonstrate that the lark RNA-binding protein oscillates in abundance during the circadian cycle; importantly, the phasing of the lark rhythm is consistent with gene-dosage studies, which indicate that the protein behaves as a repressor molecule. The lark protein rhythm persists in constant conditions (continuous darkness and constant temperature) and is eliminated by period gene null mutations, confirming that it is under clock control and suggesting that it acts as an output mechanism that mediates the temporal regulation of adult eclosion. We also show that lark protein oscillates in abundance within a defined group of neuropeptide (CCAP) -containing neurons of the ventral nervous system (VNS), which in other insects are thought to comprise cellular elements of the clock output pathway regulating eclosion.