The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans.

The dopamine D2 and D3 receptors are implicated in schizophrenia and its pharmacological treatments. These receptors undergo intracellular trafficking processes that are modulated by dysbindin-1 (Dys). Indeed, Dys variants alter cognitive responses to antipsychotic drugs through D2-mediated mechanisms. However, the mechanism by which Dys might selectively interfere with the D3 receptor subtype is unknown. Here, we revealed an interaction between functional genetic variants altering Dys and D3. Specifically, both in patients with schizophrenia and in genetically modified mice, concomitant reduction in D3 and Dys functionality was associated with improved executive and working memory abilities. This D3/Dys interaction produced a D2/D3 imbalance favoring increased D2 signaling in the prefrontal cortex (PFC) but not in the striatum. No epistatic effects on the clinical positive and negative syndrome scale (PANSS) scores were evident, while only marginal effects on sensorimotor gating, locomotor functions, and social behavior were observed in mice. This genetic interaction between D3 and Dys suggests the D2/D3 imbalance in the PFC as a target for patient stratification and procognitive treatments in schizophrenia.

Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex.

The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (<24 h). COMT selectively and reversibly modulated the recall of remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC.

Adolescence is the starting point of sex-dichotomous COMT genetic effects.

The catechol-o-methyltransferase (COMT) genetic variations produce pleiotropic behavioral/neuroanatomical effects. Some of these effects may vary among sexes. However, the developmental trajectories of COMT-by-sex interactions are unclear. Here we found that extreme COMT reduction, in both humans (22q11.2 deletion syndrome COMT Met) and mice (COMT-/-), was associated to cortical thinning only after puberty and only in females. Molecular biomarkers, such as tyrosine hydroxylase, Akt and neuronal/cellular counting, confirmed that COMT-by-sex divergent effects started to appear at the cortical level during puberty. These biochemical differences were absent in infancy. Finally, developmental cognitive assessment in 22q11DS and COMT knockout mice established that COMT-by-sex-dichotomous effects in executive functions were already apparent in adolescence. These findings uncover that genetic variations severely reducing COMT result in detrimental cortical and cognitive development selectively in females after their sexual maturity. This highlights the importance of taking into account the combined effect of genetics, sex and developmental stage.

Dopamine transporter (DAT) genetic hypofunction in mice produces alterations consistent with ADHD but not schizophrenia or bipolar disorder.

ADHD, schizophrenia and bipolar disorder are psychiatric diseases with a strong genetic component which share dopaminergic alterations. Dopamine transporter (DAT) genetics might be potentially implicated in all these disorders. However, in contrast to DAT absence, the effects of DAT hypofunction especially in developmental trajectories have been scarcely addressed. Thus, we comprehensively studied DAT hypofunctional mice (DAT+/-) from adolescence to adulthood to disentangle DAT-dependent alterations in the development of psychiatric-relevant phenotypes. From pre-adolescence onward, DAT+/- displayed a hyperactive phenotype, while responses to external stimuli and sensorimotor gating abilities were unaltered. General cognitive impairments in adolescent DAT+/- were partially ameliorated during adulthood in males but not in females. Despite this, attentional and impulsivity deficits were evident in DAT+/- adult males. At the molecular level, DAT+/- mice showed a reduced expression of Homer1a in the prefrontal cortex, while other brain regions as well as Arc and Homer1b expression were mostly unaffected. Amphetamine treatments reverted DAT+/- hyperactivity and rescued cognitive deficits. Moreover, amphetamine shifted DAT-dependent Homer1a altered expression from prefrontal cortex to striatal regions. These behavioral and molecular phenotypes indicate that a genetic-driven DAT hypofunction alters neurodevelopmental trajectories consistent with ADHD, but not with schizophrenia and bipolar disorders.

Simultaneous infection by four feline lungworm species and implications for the diagnosis.

Besides Aelurostrongylus abstrusus, other parasites belonging to the superfamily Metastrongyloidea, namely Oslerus rostratus, Troglostrongylus brevior and to the family Trichuridae, i.e. Eucoleus aerophilus (syn. Capillaria aerophila), have also been reported as agents of respiratory infection in domestic cats. A case of simultaneous infection by four feline lungworm species in Sardinia is herein described. An adult female cat (Felis silvestris catus), road-killed in the southeast part of Sardinia (municipality of Villacidro, province of Cagliari), Italy, was referred to the Laboratory of Parasitology of the Veterinary Teaching Hospital in Sassari. At necropsy, the lungs were examined and dissected under a stereomicroscope for the presence of parasites, and first-stage larvae (L1) of broncho-pulmonary nematodes were searched for in a faecal sample using the Baermann method. Parasites collected in the lungs were morphologically identified as A. abstrusus, E. aerophilus, and O. rostratus. In addition to the above species, L1s of Troglostrongylus spp. were detected at coproscopy but no adult specimen was found in the lungs. The morphological identification was confirmed by the molecular amplification and sequencing of cox1 mitochondrial gene, 18S and ITS2 ribosomal DNA. This finding stands as the first simultaneous infection by four feline lungworm species in the same animal, and as the first report of O. rostratus and E. aerophilus in Sardinia.

What can we learn from a statistically inconclusive trial? Consensus conference on the EVOLVE study results.

The link between serum parathyroid hormone (iPTH) and cardiovascular (CVS) mortality has not been fully elucidated. The EVOLVE Study was designed to test whether a drug such as cinacalcet, aimed at lowering iPTH, could reduce the astonishingly high cardiovascular risk in patients on maintenance dialysis (CKD-5D). Accordingly, the primary outcome of the study was the combined endpoint of time to death or hospitalization due to CVS factors or from any cause. Time to bone fracture and parathyroidectomy were regarded as secondary endpoints. At study completion, the Intention-To-Treat analysis documented a non- significant 7% (Hazard Ratio: 0.93; 95% Confidence interval: 0.85-1.02; P = 0.11) reduction of the primary composite endpoint. However, the intention to treat analysis does not take into account adherence to drug regimens or control for factors that may potentially jeopardize the conduction of the study. In particular, in spite of a careful pre-planned study sample calculation, the final power of the EVOLVE study was 54% instead of the assumed 90%, greatly reducing the reliability of study results. Furthermore, the pre-planned multivariable adjustment of the primary endpoint suggests a nominally significant reduction of the risk of the primary composite endpoint when age is entered into the statistical model. The sensitivity analysis further corroborates this result. The Lag Time Censoring Analysis (LTCA) evidenced a nominally significant 15% risk reduction of the composite endpoint among patients allocated to cinacalcet if the patients follow-up was terminated 6 months after the study drug discontinuation, as pre-planned in the protocol. It is interesting that the LTCA suggests that the effect of cinacalcet weakened over time and became insignificant after about 1 year from drug discontinuation. Although authors could not detect any effect of cinacalcet on bone fracture associated with cinacalcet use, the secondary analyses of the EVOLVE trial suggest a nominally significant 60-70% risk reduction of parathyroidectomy and a reassuring safety profile of prolonged exposure to cinacalcet. In summary, the EVOLVE study adds to the list of inconclusive randomized clinical trials in Nephrology. However, the preplanned exploratory and sensitivity analyses suggest that when imbalances of patients characteristics at study entry (i.e. age) or study drug discontinuation are considered, a 'nominally' significant risk reduction in CVS and parathyroidectomy associated with cinacalcet treatment is noted.

Gadolinium-associated nephrogenic systemic fibrosis: the need for nephrologists' awareness.

Nephrogenic systemic fibrosis (NSF) / nephrogenic fibrosing dermopathy (NFD) is a recently described disease, occurring only in patients with variable degrees of renal failure (RF) previously exposed to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. Public advisories are consistent on some key points including that no cases of NSF/NFD have been reported in patients with normal renal function, and GBCAs may be toxic in patients with RF due to the prolongation of the half-time allowing dissociation and extravasation of highly toxic gadolinium-free ions, potentially linked to the scleroderma-like NSF/NFD, a systemic disabling disease with a mortality rate of up to 30%. The most intriguing feature remains which cofactor might be at play to explain why the disease occurs only in a minority of exposed patients. Therefore, renal dysfunction (substrate) and gadolinium chelates (trigger agent) are necessary but not sufficient. The challenge for nephrologists includes (a) evidence of transmetallation, such as gadolinium deposits in bone, increased urinary zinc excretion, iron-transferrin dissociation or "spurious hypocalcemia" in exposed people; (b) research for uremic cofactors such as increased serum calcium/phosphate, acidosis, use of phosphate-chelating agents able to act as efficient competitor ligands or other drugs; and (c) identification of at-risk patients (with moderate to severe renal dysfunction) and definition of the role of dialysis in removing gadolinium chelates, if any. Nephrologists are called to action to collect and organize information to identify cofactors for NSF/NFD, and therefore they must be aware of this new pathology, as the eye sees only what the mind knows.

Automated volumetry of pulmonary nodules on multidetector CT: influence of slice thickness, reconstruction algorithm and tube current. Preliminary results.

PURPOSE: To evaluate the influence of slice thickness, reconstruction algorithm and tube current (mA) on the performance of a software package in determining the volume of solid pulmonary nodules on multidetector-row computed tomography (MDCT). MATERIALS AND METHODS: A chest phantom containing artificial solid nodules with known volume was imaged with two MDCT scans at 100 and 40 mAs (200 mA and 80 mA, 0.5-s rotation time), respectively. Data were reconstructed with slice thicknesses of 1.25 and 2.5 mm and five different algorithms. The volumes of three nodules (juxtavascular, intraparenchymal, juxtapleural) were calculated using three-dimensional (3D) volumetric software. Differences between estimated and real volume were reported for each nodule and reconstruction set. RESULTS: The software segmented all nodules on 1.25-mm-thick reconstructions, independently from the mAs. It did not segment the juxtapleural nodule on 2.5-mm-thick reconstructions at 40 mAs. Mean values of the differences, which better approximated the real volume of the nodules, were obtained with high-spatial-resolution algorithms on both 100 and 40 mAs images at 1.25-mm slice thickness. CONCLUSIONS: Slice thickness, reconstruction algorithm and tube current can affect the 3D volume measurement of solid nodules. The best performance of the software, on both 100 and 40 mAs images, was observed with a slice thickness of 1.25 mm and high-spatial-resolution algorithms.

Visual score and quantitative CT indices in pulmonary fibrosis: Relationship with physiologic impairment.

PURPOSE: The aim of this study was to assess the accuracy of some computed tomography (CT) quantitative indices (histogram features, ranges of density and one novel volumetric index) in the discrimination between normals and patients affected by lung fibrosis, and to compare their morphologic-functional relationship with the visual score one. MATERIALS AND METHODS: We analysed thin-section CTs and pulmonary function tests (PFTs) of six healthy subjects and 31 patients affected by lung fibrosis, including 17 with a usual interstitial pneumonia pattern (UIP group), and 14 with a predominant pattern of ground-glass opacities without honeycombing (non-UIP group). Presence and extent of various CT findings were assessed by the visual score as well as by CT computer indices. RESULTS: Together with the histogram features, fibrosis ratio (defined as the ratio of nonfibrotic CT lung volume divided by total CT lung volume) contributed to objectively differentiate fibrotic lungs from normal lungs. The range of density 700 to 400 HU showed the greatest degree of correlation with physiologic abnormality in the non-UIP group. In the UIP group, the lone visual score provided prediction of functional impairment. CONCLUSIONS: The visual score is still the main radiological method of quantifying the extent of abnormalities in patients with UIP, whilst the range of density 700 to 400 HU can be helpfully applied in a predominant pattern of ground-glass and reticular opacities without honeycombing.

[The treatment of osteodystrophy in dialyzed uremic patients: results of the first Sardinian audit]. / Il trattamento dell'osteodistrofia nei pazienti uremici in dialisi: risultati del primo Audit sardo.

BACKGROUND: Hyperphosphatemia in the uremic patient undergoing dialysis causes and makes the secondary hyperpharatyroidism progress. Nowadays it has a very important role in predicting mortality. The aim of the study was to assess by "Audit" to analyse adequacy of the Sardinian dialytic patients with reference to the optimal objective of the national and international guidelines. PATIENTS AND METHODS: The questionnaire of the audit was composed of 11 questions about the percentage distribution of: calcium in the dialysate, values of phosphoremia), Ca x P product, patients treated with vitamin D taking one or more phosphate binders, average dose, spKt/V > or = 1.2, serum aluminium, parathiroidectomy. RESULTS: We examined 1274 dialysis patients (93% on hemodialysis and 7% in CAPD) in 26 dialytic centers in our region (age 63.8 anni +/- 32.4; dialytic age 5.15 +/- 5.06. Phosphorus ranges (mg/dL) P < 5.5: 61.3 +/- 23%; between 5.5 e 6.5: 28.2 +/- 17.7%; and P > 6.5: 10.4 +/- 7.7%; Ca x P (<60): 77.8% +/- 16.6%; between 60-70: 16.8 +/- 13.4%; > 70: 4.99 +/- 4.7%. The more prescribed dialysate calcium was 1.5 mmol/L in HD (58.8%) HF (60.6%), HDF (51.6%) and CAPD (5.6%). PTH levels were: 31.1% (<120); 29.5% (120-250); 21.1% (250-450); 8% (450-600); 10.3% (>600). Patients on vitamin D: os daily 23.04 +/- 28%; post-dialysis boluses: os 32.6 +/- 28, i.v. 10.6 +/- 9%; no therapy 32.7 +/- 22.7%. The percentage use of phosphorus binders: 48.5% calcium carbonate (2.9 g/d); 7.12% calcium acetate (1.34 g/d); 13.5% sevelamer (2.79 g/d); 10% total aluminium based (0.62 g/d). The aluminium is dosed in 11/26 dialysis units (32.3% of the population); 2.3% +/- 0.9% of patients having Aluminium > 30 mcg/L. The dialytic patients have a Kt/V > or = 1.2: 80.1 +/- 19%. Parathyroidectomy incidences 1.8%. CONCLUSIONS: The data show good control of the average phosporous, there is a worrying percentage of patients with PTH values compatible with hypodynamic bone condition, lower and therefore safer calcium levels in the dialysate, poor aluminium control and low incidence of parathyroidectomy. In our experience the audit is a good way to verify and to correct the therapeutic choice in uremic osteodistrophy.

[Are convective treatments equivalent to the traditional ones? The Hemo Study and beyond (review)]. / Le terapie convettive equivalgono a quelle tradizionali? Lo studio Hemo ed oltre.

Dialysis treatments have allowed 'terminal patients' to live for years and years. However, life expectancy and quality are still consistently reduced in renal dialysis patients. Consequently, all efforts to device alternative treatments to the conventional ones are highly justified. Recently, the Hemo Study showed that neither the use of high flux membranes, nor the increase of the dialysis dose above the conventional, were capable to reduce significantly patient's mortality and morbidity, although 8% reduction of the risk of death was seen in patients treated with high flux vs. patients treated with low-flux dialysis. A relevant question is if convective treatments may offer an overprotection from morbidity and mortality, in comparison with low flux and high flux treatments. Data from the Registro Lombardo di Nefrologia e Trapianto published in 2000 showed a trend toward a better survival (RR= 90) and a significantly better protection from tunnel carpal syndrome (RR= 0.58; p= 0.03) in patients treated with convective treatments (hemofiltration and/or hemodiafiltration) vs. patients treated with diffusive dialysis. Except than a better cardiovascular stability observed on hemofiltration and an higher beta2-microglobuline clearance given by online hemofiltration and hemodiafiltration, evident clinical benefits of convective treatments, over the conventional high flux treatments, are not yet clearly demonstrated. Notwithstanding that, online convective treatments, that are performed with high flux compatible membranes and high technology machines, producing high quality water, offer at the moment the best bases for the improvement of clinical results of dialysis, especially in some category of patients.

Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity.

We describe two brothers, 11 and 13 years old, respectively, with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation. Electrophysiological studies showed marked reduction of motor and sensory conduction velocity and absence of sensory action potentials. Sural nerve biopsy, performed in both patients, showed absence of large myelinated fibers with normal density of small myelinated fibers without axonal degeneration. Signs of demyelination were found only in the younger patient. We suggest that motorsensory neuropathy associated with deafness and mental retardation with absence of large myelinated fibers on sural nerve biopsy represents a distinct clinicopathological entity, which is transmitted in families probably as an autosomal recessive trait.

Therapeutic process formalization in the treatment of respiratory failure in infants.

The model described formalizes the therapeutic process developed in the Pediatric Intensive Care Unit (PICU) of Merate's Hospital as a support of medical decisions and as a continuous control of the adequacy of the ventilatory therapy. Causal and temporal structure of the keypoints of the treatment are represented by Petri Nets. The model could be utilised in different pathologies and for different clinical approach giving a meaningful organizational impact.

[Hyperparathyroidism resulting from chronic renal insufficiency. Diagnosis and therapy]. / Iperparatiroidismo secondario ad insufficienza renale cronica. Diagnosi e terapia.

Twenty-seven patients, eighteen females and nine males, with chronic renal failure and secondary hyperparathyroidism, were treated by subtotal parathyroidectomy. Bone pain, in 24 patients, hypercalcemia in 2 and severe pruritus in 1 were the main indications to surgery. Result evaluation was possible in twenty four patients. Bone pain disappeared or was reduced in 20/22 patients. Serum alkaline phosphatase and PTH returned to normal in 21/24 patients. There patients had persistent hyperparathyroidism because of inadequate surgical exploration. Another group of seven patients with secondary hyperparathyroidism recalcitant to medical therapy or relapsing after subtotal parathyroidectomy was treated with calcitriol ev. After nine months of follow-up PTH and alkaline phosphatase serum levels were reduced to normal value in all patients.

INFORM: European survey of computers in intensive care units.

The aims of this study were (a) to survey and evaluate the impact of information technology applications in High Dependency Environments (HDEs) on organizational, psychological and cost-effectiveness factors, (b) to contribute information and design requirements to the other workpackages in the INFORM Project, and (c) to develop useful evaluation methodologies. The evaluation methodologies used were: questionnaires, case studies, objective findings (keystroke) and literature search and review. Six questionnaires were devised covering organizational impact, cost-benefit impact and perceived advantages and disadvantages of computerized systems in HDE (psychological impact). The general conclusion was that while existing systems have been generally well received, they are not yet designed in such a developed and integrated way as to yield their full potential. Greater user involvement in design and implementation and more emphasis on training emerged as strong requirements. Lack of reliability leading to parallel charting was a major problem with the existing systems. It proved difficult to assess cost effectiveness due to a lack of detailed accounting costs; however, it appeared that in the short term, computerisation in HDEs tended to increase costs. It is felt that through a better stock control and better decision making, costs may be reduced in the longer run and effectiveness increased; more detailed longitudinal studies appear to be needed on this subject.

Inform: conceptual modelling of intensive care information systems.

Intensive care of a patient requires heavy monitoring and versatile therapeutic actions. These produce a huge amount of patient information. A problem exists in managing this data and other information from all supporting activities creating a need for an automated information management system. To have a sound basis for future automated information systems in intensive care unit (ICU), a conceptual model is created to cover both the clinical and other activities of the ICU. The conceptual model consists of data flow diagrams and entity-relationship diagrams with underlying common data dictionary. A modern CASE tool is utilized to build the model. The work forms a part of AIM-INFORM project, which has a purpose to develop information management and decision support systems for high dependency environment.

[Psoriatic arthritis: considerations on recent studies: serum beta 2 microglobulin and circulating T-gamma lymphocytes]. / Artrite psoriasica: considerazioni su recenti acquisizioni: la beta 2 microglobulina sierica e i linfociti T gamma circolanti.

The results of two recent studies of our group have been reported. They regard two immunological parameters of psoriatic arthritis: the proportions of T gamma lymphocytes in peripheral blood and the beta 2 microglobulin in the serum. The data obtained in psoriatic arthritis patients have been compared to those found in normal controls and in rheumatoid arthritis patients. T gamma mean values in psoriatic arthritis were significantly lower than those present in healthy subjects and in rheumatoid patients. These last patients showed beta 2 microglobulin mean values significantly higher than those observed in normal controls and in psoriatic arthritis patients. Conversely, the mean of beta 2 microglobulin levels in psoriatic arthritis has been found to be similar to that observed in normal controls, but a superimposition in the range of individual values of these two groups with the concentrations determined in rheumatoid subjects has been found. These results seem to be of interest in relation to the immunopathogenetic mechanism of psoriatic arthritis, but are of little help in the clinical differentiation of the two rheumatological affections considered.

Peripheral blood T lymphocyte subpopulations defined by monoclonal antibodies in rheumatoid arthritis: distribution in patients untreated and treated by oral gold therapy.

The distribution of T lymphocyte subsets was determined in peripheral blood (PB) of two groups of patients with rheumatoid arthritis by using monoclonal antibodies (OKT). In untreated patients the percentage of OKT4+ cells (helper/inducer) was found to be significantly increased as compared to healthy controls. In patients receiving oral gold therapy a similar increase in OKT4+ cells was confirmed; furthermore, these patients showed a significant decrease in OKT8+ cell population (cytotoxic/suppressor) compared to untreated patients and to normal controls. A small numerical superimposition of values of OKT4+ and OKT8+ lymphocytes was observed in untreated but not in treated patients.