An AI-based approach driven by genotypes and phenotypes to uplift the diagnostic yield of genetic diseases.

Identifying disease-causing variants in Rare Disease patients' genome is a challenging problem. To accomplish this task, we describe a machine learning framework, that we called "Suggested Diagnosis", whose aim is to prioritize genetic variants in an exome/genome based on the probability of being disease-causing. To do so, our method leverages standard guidelines for germline variant interpretation as defined by the American College of Human Genomics (ACMG) and the Association for Molecular Pathology (AMP), inheritance information, phenotypic similarity, and variant quality. Starting from (1) the VCF file containing proband's variants, (2) the list of proband's phenotypes encoded in Human Phenotype Ontology terms, and optionally (3) the information about family members (if available), the "Suggested Diagnosis" ranks all the variants according to their machine learning prediction. This method significantly reduces the number of variants that need to be evaluated by geneticists by pinpointing causative variants in the very first positions of the prioritized list. Most importantly, our approach proved to be among the top performers within the CAGI6 Rare Genome Project Challenge, where it was able to rank the true causative variant among the first positions and, uniquely among all the challenge participants, increased the diagnostic yield of 12.5% by solving 2 undiagnosed cases.

Go beyond the limits of genetic algorithm in daily covariate selection practice.

Covariate identification is an important step in the development of a population pharmacokinetic/pharmacodynamic model. Among the different available approaches, the stepwise covariate model (SCM) is the most used. However, SCM is based on a local search strategy, in which the model-building process iteratively tests the addition or elimination of a single covariate at a time given all the others. This introduces a heuristic to limit the searching space and then the computational complexity, but, at the same time, can lead to a suboptimal solution. The application of genetic algorithms (GAs) for covariate selection has been proposed as a possible solution to overcome these limitations. However, their actual use during model building is limited by the extremely high computational costs and convergence issues, both related to the number of models being tested. In this paper, we proposed a new GA for covariate selection to address these challenges. The GA was first developed on a simulated case study where the heuristics introduced to overcome the limitations affecting currently available GA approaches resulted able to limit the selection of redundant covariates, increase replicability of results and reduce convergence times. Then, we tested the proposed GA on a real-world problem related to remifentanil. It obtained good results both in terms of selected covariates and fitness optimization, outperforming the SCM.

Osteocalcin-expressing endothelial progenitor cells and serum osteocalcin forms are independent biomarkers of coronary atherosclerotic disease severity in male and female patients.

PURPOSE: Osteocalcin (OC), an osteoblast-derived regulator of metabolic processes, and circulating early endothelial progenitor cells (EPC, CD34 - /CD133 + /KDR +) expressing OC (OC +) are potential candidates linking bone metabolism and the vasculature and might be involved in vascular atherosclerotic calcification. This study aimed at assessing the association of circulating levels of different OC forms and of EPCs count with disease severity in patients with documented coronary atherosclerosis (CAD). METHODS: Patients (n = 59) undergoing coronary angiography were divided, according to stenosis severity, into (1) early coronary atherosclerosis (ECA) (n = 22), and (2) late coronary atherosclerosis (LCA) (n = 37). Total OC (TOC), carboxylated OC (cOC), undercarboxylated OC (unOC) were quantified by ELISA. EPC OC + count was assessed by flow cytometry. RESULTS: EPC OC + counts showed significant differences between ECA and LCA groups. unOC and unOC/TOC ratio were inversely correlated with EPC OC + count. A significant decrease in TOC and unOC plasma levels was associated with higher cardiovascular risk factors (CVRFs) number. EPC OC + count was correlated with LDL-C, total cholesterol, and triglycerides, with a greater significance in the LCA group. No association between the different forms of circulating OC (TOC, ucOC, cOC) and severity of CAD was found. CONCLUSION: This study showed a significant association between EPCs (CD34 - /CD133 + /KDR + /OC +), CAD severity and CVRFs, suggesting an active role for EPC OC + in the development of CAD. An inverse correlation between TOC, ucOC, and number of CVRFs was observed, suggesting that OC, regardless of its carboxylation status, may be developed as a further cardiovascular risk biomarker.

A Population Dynamic Energy Budget-Based Tumor Growth Inhibition Model for Etoposide Effects on Wistar Rats.

PURPOSE: This work aimed to develop a population PK/PD tumor-in-host model able to describe etoposide effects on both tumor cells and host in Walker-256 tumor-bearing rats. METHODS: Etoposide was investigated on thirty-eight Wistar rats randomized in five arms: two groups of tumor-free animals receiving either placebo or etoposide (10 mg/kg bolus for 4 days) and three groups of tumor-bearing animals receiving either placebo or etoposide (5 or 10 mg/kg bolus for 8 or 4 days, respectively). To analyze experimental data, a tumor-in-host growth inhibition (TGI) model, based on the Dynamic Energy Budget (DEB) theory, was developed. Total plasma and free-interstitial tumor etoposide concentrations were assessed as driver of tumor kinetics. RESULTS: The model simultaneously describes tumor and host growths, etoposide antitumor effect as well as cachexia phenomena related to both the tumor and the drug treatment. The schedule-dependent inhibitory effect of etoposide is also well captured when the intratumoral drug concentration is considered as the driver of the tumor kinetics. CONCLUSIONS: The DEB-based TGI model capabilities, up to now assessed only in mice, are fully confirmed in this study involving rats. Results suggest that well designed experiments combined with a mechanistic modeling approach could be extremely useful to understand drug effects and to describe all the dynamics characterizing in vivo tumor growth studies.

Modeling tumor growth inhibition and toxicity outcome after administration of anticancer agents in xenograft mice: A Dynamic Energy Budget (DEB) approach.

Host features, such as cell proliferation rates, caloric intake, metabolism and energetic conditions, significantly influence tumor growth; at the same time, tumor growth may have a dramatic impact on the host conditions. For example, in clinics, at certain stages of the tumor growth, cachexia (body weight reduction) may become so relevant to be considered as responsible for around 20% of cancer deaths. Unfortunately, anticancer therapies may also contribute to the development of cachexia due to reduced food intake (anorexia), commonly observed during the treatment periods. For this reason, cachexia is considered one of the major toxicity findings to be evaluated also in preclinical studies. However, although various pharmacokinetic-pharmacodynamic (PK-PD) tumor growth inhibition (TGI) models are currently available, the mathematical modeling of cachexia onset and TGI after an anticancer administration in preclinical experiments is still an open issue. To cope with this, a new PK-PD model, based on a set of tumor-host interaction rules taken from Dynamic Energy Budget (DEB) theory and a set of drug tumor inhibition equations taken from the well-known Simeoni TGI model, was developed. The model is able to describe the body weight reduction, splitting the cachexia directly induced by tumor and that caused by the drug treatment under study. It was tested in typical preclinical studies, essentially designed for efficacy evaluation and routinely performed as a part of the industrial drug development plans. For the first time, both the dynamics of tumor and host growth could be predicted in xenograft mice untreated or treated with different anticancer agents and following different schedules. The model code is freely available for downloading at http://repository.ddmore.eu (model number DDMODEL00000274).

Body composition and metabolic changes during a 520-day mission simulation to Mars.

PURPOSE: The "Mars-500 project" allowed to evaluate the changes in psychological/physiological adaptation over a prolonged confinement, in order to gather information for future missions. Here, we evaluated the impact of confinement and isolation on body composition, glucose metabolism/insulin resistance and adipokine levels. METHODS: The "Mars-500 project" consisted of 520 consecutive days of confinement from June 3, 2010 to Nov 4, 2011. The crew was composed of six male subjects (three Russians, two Europeans, and one Chinese) with a median age of 31 years (range 27-38 years). RESULTS: During the 520-day confinement, total body mass and BMI progressively decreased, reaching a significant difference at the end (417 days) of the observation period (- 9.2 and - 5.5%, respectively). Fat mass remained unchanged. A progressive and significant increase of fasting plasma glucose was observed between 249 and 417 days (+ 10/+ 17% vs baseline), with a further increase at the end of confinement (up to + 30%). Median plasma insulin showed a non-significant early increment (60 days; + 86%). Total adiponectin halved (- 47%) 60 days after hatch closure, remaining at this nadir (- 51%) level for a further 60 days. High molecular weight adiponectin remained significantly lower from 60 to 168 days. CONCLUSIONS: Based on these data, countermeasures may be envisioned to balance the potentially harmful effects of prolonged confinement, including a better exercise program, with accurate monitoring of (1) the individual activity and (2) the relationship between body composition and metabolic derangement.

Mathematical modeling of growth and death dynamics of mouse embryonic stem cells irradiated with γ-rays.

Following ionizing radiation, mouse embryonic stem cells (mESCs) undergo both apoptosis and block at G2/M phase of the cell cycle. The dynamics of cell growth and the transition through the apoptotic phases cannot be directly inferred from experimental data, limiting the understanding of the biological response to the treatment. Here, we propose a semi-mechanistic mathematical model, defined by five compartments, able to describe the time curves of untreated and γ-rays irradiated mESCs and to extract the information therein embedded. To this end, mESCs were irradiated with 2 or 5 Gy γ-rays, collected over a period of 48 h and, at each time point, analyzed for apoptosis by using the Annexin V assay. When compared to unirradiated mESCs, the model estimates an additional 0.2 probability to undergo apoptosis for the 5 Gy-treated cells, and only a 0.07 (not statistically significantly different from zero) when a 2 Gy-irradiation dose is administered. Moreover, the model allows us to estimate the duration of the overall apoptotic process and also the time length of its early, intermediate, and late apoptotic phase.

Traumatic sheep myiasis: A review of the current understanding.

Myiasis, or the infestation of live humans and vertebrate animals by dipterous larvae, is a health issue worldwide. The economic impact and potential threat to animal health and wellbeing of this disease under the animal husbandry sector is considerable. Sheep are a highly vulnerable livestock category exposed to myiasis (sheep strike), due to several unique predisposing factors that attract flies. The successful mitigation of this disease relies on a thorough understanding of fly population dynamics associated with the change in weather patterns and the evaluation of this disease through different branches of science such as chemistry, molecular biology, and microbiology. The present review provides a summary of the existing knowledge of strike in sheep, discussed in relation to the application of volatile organic compounds, metagenomics, and molecular biology, and their use regarding implementing fly control strategies such as traps, and to increase the resilience of sheep to this disease through improving their health and wellbeing.

Space Flight-Promoted Insulin Resistance as a Possible Disruptor of Wound Healing.

During space flight, especially when prolonged, exposure to microgravity results in a number of pathophysiological changes such as bone loss, muscle atrophy, cardiovascular and metabolic changes and impaired wound healing, among others. Interestingly, chronic low-grade inflammation and insulin resistance appear to be pivotal events linking many of them. Interestingly, real and experimental microgravity is also associated to altered wound repair, a process that is becoming increasingly important in view of prolonged space flights. The association of insulin resistance and wound healing impairment may be hypothesized from some dysmetabolic conditions, like the metabolic syndrome, type 2 diabetes mellitus and abdominal/visceral obesity, where derangement of glucose and lipid metabolism, greater low-grade inflammation, altered adipokine secretion and adipocyte dysfunction converge to produce systemic effects that also negatively involve wound healing. Indeed, wound healing impairment after traumatic events and surgery in space remains a relevant concern for space agencies. Further studies are required to clarify the molecular connection between insulin resistance and wound healing during space flight, addressing the ability of physical, endocrine/metabolic, and pharmacological countermeasures, as well as nutritional strategies to prevent long-term detrimental effects on tissue repair linked to insulin resistance. Based on these considerations, this paper discusses the pathophysiological links between microgravity-associated insulin resistance and impaired wound healing.

A translational model-based approach to inform the choice of the dose in phase 1 oncology trials: the case study of erdafitinib.

PURPOSE: Erdafitinib (JNJ-42756493, BALVERSA) is a tyrosine kinase inhibitor indicated for the treatment of advanced urothelial carcinoma. In this work, a translational model-based approach to inform the choice of the doses in phase 1 trials is illustrated. METHODS: A pharmacokinetic (PK) model was developed to describe the time course of erdafitinib plasma concentrations in mice and rats. Data from multiple xenograft studies in mice and rats were analyzed using the Simeoni tumor growth inhibition (TGI) model. The model parameters were used to derive a range of erdafitinib exposures that might inform the choice of the doses in oncology phase 1 trials. Conversion of exposures to doses was based on preliminary PK assessments from the first-in human (FIH) study. RESULTS: A one-compartment PK disposition model, with linear absorption and dose-dependent clearance, adequately described the PK data in both mice and rats via an allometric scaling approach. The TGI model was able to describe tumor growth dynamics, providing quantitative measurements of erdafitinib antitumor potency in mice and rats. Based on these estimates, ranges of efficacious unbound concentration were identified for erdafitinib in mice (0.642-5.364 µg/L) and rats (0.782-2.565 µg/L). Based on the FIH data, it was possible to transpose exposures into doses and doses of above 4 mg/day provided erdafitinib exposures associated with significant TGI in animals. The findings were in agreement with the results of the FIH trial, in which the first hints of clinical activities were observed at 6 mg. CONCLUSION: The successful modeling exercise of erdafitinib preclinical data showed how translational PK-PD modeling might be a tool to help to inform the choice of the doses in FIH studies.

Role of the energy sensor adenosine monophosphate-activated protein kinase in the regulation of immature gonadotropin-releasing hormone neuron migration.

BACKGROUND: The 5'-AMP-activated protein kinase (AMPK) plays a fundamental role in regulating energy homeostasis as well as feeding and metabolism, through central and peripheral actions. AMPK is activated by conditions causing ATP depletion and by different metabolic molecules, such as adiponectin and AMPK agonist, such as 5-aminoimidazole- 4-carboxamide-1-ß-D-ribofuranoside (AICAR). AMPK activation has also been shown to affect the migration of different cell types and to participate in the central control of reproductive function, although information concerning AMPK and the development of the hypothalamic reproductive compartment is lacking. AIM: To explore whether AMPK activation by globular adiponectin (gAdipo) and AICAR may affect the migratory ability of GnRH neurons. MATERIALS AND METHODS: We used GN11 immature GnRH neurons (in vitro model system), RT-PCR and Western blot analysis, and Boyden's chamber assay. RESULTS: gAdipo did not affect FBS-stimulated migration of GN11 cells and activated AMPK through the mandatory phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Akt, which also interact one to each other. AICAR treatment inhibited FBS-stimulated GN11 cell migration, through a long-lasting activation of AMPK. A downstream activation of ERK1/2 by AICAR was also observed and inhibition of ERK1/2 amplified AICAR-induced inhibition of migration. CONCLUSIONS: The direct, but not the indirect, activation of AMPK appears to negatively affect FBSinduced GN11 cell migration, suggesting that the final balance between pro-migratory and anti-migratory actions may also depend upon the specific sequence of intracellular signals activated by one agent.

Sex hormones and adipokines in healthy pre-menopausal, post-menopausal and elderly women, and in age-matched men: data from the Brisighella Heart study.

BACKGROUND: Sex hormones and adipokines seem to differently interact in both genders at different ages. AIM: To comparatively evaluate the serum level of adipokines and sex hormones in healthy non-pharmacologically treated premenopausal women, post-menopausal women, and elderly women, and in age-matched men. SUBJECTS: From the historical cohort of the Brisighella Heart Study we selected 199 adult healthy subjects (males: 89; females: 110), aged 62.5±12.4 yr. Men and women included in the age-class subgroups were matched for body mass index (BMI), waist circumference, blood pressure, heart rate, fasting plasma glucose, plasma lipids. RESULTS: Leptin did not differ among various age classes in men, while pre-menopausal women displayed significantly lower serum leptin than post-menopausal women (-6.7 ± 2.2 pg/ml, p=0.036). Post-menopausal women had significantly greater serum leptin when compared with age-matched men (+13.1 ± 2.0 pg/ml, p<0.001); the same was observed for elderly women when compared with elderly men (+11.2 ± 2.3 pg/ml, p<0.001). At any age, women had significantly lower serum testosterone/estrone ratio than age-matched men (p<0.01). Serum DHEAS was inversely proportional to age in both genders. The main predictors of adiponectin level are age in men (p=0.027) and BMI in women (p=0.003). The main predictors of leptin level are BMI and the testosterone/estrone ratio in both sexes (p<0.05). The testosterone/estrone ratio is also the main predictor of ghrelin levels in women (p=0.006). CONCLUSION: Sex hormones and adipokines show specific interactions in the two genders and in different age-classes in a representative sample of adult healthy subjects.

Effect of Type of Tissue on the Development of Chrysomya rufifacies (Diptera: Calliphoridae) in Sri Lanka.

Chrysomya rufifacies (Macquart), the hairy maggot blow fly, is of great importance for the field of forensic entomology due to its habit as an early colonizer of decomposing vertebrate remains and myiasis producer. Development studies on this species have been conducted in scattered regions of the world, using types of tissue from several species of animals as a rearing medium. Despite the commonality of C. rufifacies in Sri Lanka, developmental studies have never been performed in this region. As well, the effects of diet on development have not been tested. In the current study, C. rufifacies immatures were reared on skeletal muscle, liver, and heart from domestic swine, with flies from colonies maintained at 25 and 28°C. The minimum time needed to complete each stage at 25°C on liver (224.14 h) was fastest followed by skeletal muscle (249.33 h) and heart (251.64 h) respectively, whereas at 28°C, fly development was quickest on heart muscle (178.27 h) followed by liver (178.50 h) and skeletal muscle (186.17 h) respectively. A significant difference in total development time was determined for temperature, while the rearing medium was not significant. Temperature also showed a significant effect on the length and the width of the larvae, while the type of tissue statistically impacted only the width.

Feasibility study of hospital antimicrobial stewardship analytics using electronic health records.

BACKGROUND: Hospital antimicrobial stewardship (AMS) programmes are multidisciplinary initiatives to optimize antimicrobial use. Most hospitals depend on time-consuming manual audits to monitor clinicians' prescribing. But much of the information needed could be sourced from electronic health records (EHRs). OBJECTIVES: To develop an informatics methodology to analyse characteristics of hospital AMS practice using routine electronic prescribing and laboratory records. METHODS: Feasibility study using electronic prescribing, laboratory and clinical coding records from adult patients admitted to six specialities at Queen Elizabeth Hospital, Birmingham, UK (September 2017-August 2018). The study involved: (i) a review of AMS standards of care; (ii) their translation into concepts measurable from commonly available EHRs; and (iii) a pilot application in an EHR cohort study (n = 61679 admissions). RESULTS: We developed data modelling methods to characterize antimicrobial use (antimicrobial therapy episode linkage methods, therapy table, therapy changes). Prescriptions were linked into antimicrobial therapy episodes (mean 2.4 prescriptions/episode; mean length of therapy 5.8 days), enabling several actionable findings. For example, 22% of therapy episodes for low-severity community-acquired pneumonia were congruent with prescribing guidelines, with a tendency to use broader-spectrum antibiotics. Analysis of therapy changes revealed IV to oral therapy switching was delayed by an average 3.6 days (95% CI: 3.4-3.7). Microbial cultures were performed prior to treatment initiation in just 22% of antibacterial prescriptions. The proposed methods enabled fine-grained monitoring of AMS practice down to specialities, wards and individual clinical teams by case mix, enabling more meaningful peer comparison. CONCLUSIONS: It is feasible to use hospital EHRs to construct rapid, meaningful measures of prescribing quality with potential to support quality improvement interventions (audit/feedback to prescribers), engagement with front-line clinicians on optimizing prescribing, and AMS impact evaluation studies.

Free insulin-like growth factor (IGF)-1 and IGF-binding proteins-2 and -3 in serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients.

BACKGROUND: The insulin-like growth factor-1 (IGF-1) signaling system is regulated by many factors which interact in regulating the bioavailability of IGF-I. In this context, little information is available on free IGF-1, the bioactive form of IGF-1, in amyotrophic lateral sclerosis (ALS). METHODS: We investigated the endogenous expression of IGF-1, and two related binding proteins (IGF-binding proteins, IGFBP-2 and BP-3) in serum and cerebrospinal fluid (CSF) of 54 sporadic ALS (sALS) patients. Twenty-five healthy individuals and 25 with other neurological diseases (OND) were used as controls. Total and free IGF-1, and IGFBP-3 levels were detected by immunoradiometric assay (IRMA); IGFBP-2 levels were determined by radioimmunoassay (RIA). RESULTS: Total and free IGF-1, IGFBP-2 and BP-3 serum levels were not significantly different between patients and controls, although in sALS patients free IGF-1 was negatively correlated with ALS-Functional Rating Scale-revised (ALS-FRS-R) score (r = -0.4; P = 0.046) and forced vital capacity (FVC) (r = -0.55; P < 0.04). In CSF, free IGF-1 was significantly increased in sALS patients compared with OND (P < 0.0001). CONCLUSIONS: Though in the serum we did not find significant differences amongst the three groups, IGF-1 bioavailability, represented by the free IGF-1 levels, correlated with disease severity. In the CSF, the significant increment of the free fraction of IGF-1 suggests an up-regulation of the IGF-1 system in the intrathecal compartment of sALS patients. Since IGF-1 is a trophic factor for different tissues, we speculate that high levels of the free IGF-1 in sALS might reflect a physiological defensive mechanism promoted in response to neural degeneration and/or muscle atrophy.

Plasma adiponectin and leptin concentrations in professional rugby players.

Adipose tissue synthesizes and secretes a number of cytokine hormones, defined adipokines, which have emerged as critical regulators of several metabolic functions, including energy homeostasis, insulin action and lipid metabolism. The present study is aimed at assessing the relationship between plasma concentrations of leptin and adiponectin and body composition in a cohort of 38 male professional rugby players (age: 22-35 years). Anthropometric evaluation included body mass index (BMI, range: 23.4-35.1 kg/m2) and whole body bioelectric impedance to determine absolute fat-free mass (FFM), absolute fat mass (FAT), relative percentage of fat mass (FAT percent) and fat-free mass (FFM percent). FAT percent ranged from 15 to 34 percent, corresponding to a FAT of 11.5-38.7 kg, whereas FFM range was 62.1-83.5 kg. Plasma leptin range was 1.2-4.3 ng/mL and adiponectin range was 2.0-16.6 microg/mL. Plasma leptin and adiponectin concentrations and their ratio did not correlate with BMI, nor with FAT, FAT percent, FFM and FFM percent, even after correction for BMI. The findings of this study suggest that in professional rugby players some additional factors, like neuroendocrine adaptations, other than adipose mass play a relevant role in the determination of adipokine levels, which in this group appear to be rather independent of body composition.

Spatial distribution of trace metals (Cd, Pb, Hg, Cu, Zn, Fe and Mn) and oligo-elements (Mg, Ca, Na and K) in surface sediments of the Gulf of Tunis (Northern Tunisia).

The purpose of this paper is to evaluate the levels and spatial distribution of trace metals (Cd, Pb, Cu, Hg, Zn, Fe, and Mn), oligo-elements (Mg, Ca, Na and K), total organic carbon (TOC), and total nitrogen (TN) in the fine fraction of surface sediments collected from 38 stations in Gulf of Tunis (Mediterranean Sea, Northern Tunisia) between 2004 and 2005. The results showed that metals, oligo-elements, TOC, and TN concentrations in the sediments of the Gulf of Tunis are generally low compared to those found in other similar coastal marine areas. The spatial distribution of metals showed areas of major accumulation of Pb, Cd, Cu, Fe, and Zn in the central area of the Gulf and near the Mejerda River. The marine currents are influencing factors on metal accumulation in sediments. The principal component analysis applied to our elemental analytical results showed that there is a positive correlation between Fe, Zn, Cu, and Pb. These metals have a stronger affinity with site connection in the sediments than Ca and Mn.

Sediment features, macrozoobenthic assemblages and trophic relationships (delta13C and delta15N analysis) following a dystrophic event with anoxia and sulphide development in the Santa Giusta lagoon (western Sardinia, Italy).

Macrozoobenthic assemblages and stable carbon (delta(13)C) and nitrogen (delta(15)N) isotope values of various primary producers (macroalgae and angiosperms) and consumers (macroinvertebrate filter/suspension feeders, deposit feeders, detritivores/omnivores and carnivores and fishes) were studied in the Santa Giusta lagoon (Sardinia, Italy) before (spring) and after (autumn) a dystrophic event which occurred in the summer of 2004. A few days after the dystrophy, the physico-chemical characteristics of sediments and macrozoobenthic assemblages were also investigated. In the latter occasion, high total organic carbon (3.9%) and organic matter (15.9%) contents of surface sediments went together with peaks in acid-volatile sulphide concentrations. Certain immediate effects were quite extreme, such as the drastic reduction in macrozoobenthos and the massive fish kill in August 2004. Among the macrozoobenthos, there were few individuals of chironomid larvae and Capitella cf. capitata left. However, by October, chironomid larvae were numerous, indicating a lack of predators (e.g. fish) and competitors. In addition, some bivalve species and polychaetes which were absent, or present in small numbers before the event, became relatively numerous. The results are discussed based on a knowledge of the sulphide tolerance of these species. Stable isotope analysis clearly showed that the basal level of the food web for most consumers consisted mainly of macroalgae and sedimentary organic matter, and that the values before and after the dystrophic event were not significantly different from one another. This indicates that the relations among different trophic levels were quickly restored following the dystrophic event.

Distribution and ecological relevance of fine sediments in organic-enriched lagoons: the case study of the Cabras lagoon (Sardinia, Italy).

In organic-enriched sedimentary systems, like many Mediterranean coastal lagoons, a detailed analysis of sediment grain size composition and partitioning within the muds is crucial to investigate sedimentological trends related to both hydrodynamic energy and basin morphology. In these systems, sediment dynamics are particularly important because the partitioning and transport of fine sediments can strongly influence the redistribution and accumulation of large amounts of organic matter, and consequently the distribution of benthic assemblages and the trophic status and functioning of a lagoon. Nevertheless, studies on benthic-sediment relationships have been based mainly on a rather coarse analysis of sediment grain size features. In muddy systems, however, this approach may impede a proper evaluation of the relationships and effects of the distribution of fine sediment and organic matter on the biotic benthic components. Here we show that the distribution of sedimentary organic matter (OM) and total organic carbon (TOC) in the Cabras lagoon (Sardinia, Italy) can be explained (i.e., predicted) as a function of a nonlinear increase in the amount of the cohesive fraction of sediments (< or = 8 microm grain size particles) and that this fraction strongly influences the structure, composition and distribution of macrobenthic assemblages. Even in such a homogeneously muddy system, characterized by "naturally" occurring impoverished communities, impaired benthic assemblages were found at < or = 8 microm, OM, TOC contents of about 77%, 11% and 3.5%, respectively. A review of studies conducted in Mediterranean coastal lagoons highlighted a lack of direct integrated analysis of sediment features and the biotic components. We suggest that, especially in organic-enriched coastal lagoons, monitoring programs should primarily investigate and consider the cohesive fraction of sediments in order to allow a better assessment of benthic-sediment relationships and ecological quality of the system.

Hypothalamic neuropeptide systems as targets for potential anti-obesity drugs.

Food intake and energy homeostasis are controlled by peripheral humoral signals, afferent neuronal pathways to the brain and central signals, represented, in particular, by neuropeptides. This review reports the status of development of novel compounds targeting some hypothalamic neuropeptide systems which are currently viewed as potential targets to treat obesity.