Increased frequency of interleukin-4 and reduced frequency of interferon-γ and IL-17-producing CD4+ and CD8+ cells in scleromyxedema.

BACKGROUND: Little is known about the pathogenesis of scleromyxedema, a life-threatening fibromucinosis disease with immunological dysregulation. OBJECTIVES: To investigate on T-cell phenotype, function and cytokine biology in search of new insights supporting the immunopathogenesis of the disease. METHODS: We analysed the frequency of circulating lymphocyte subsets, the T-cell maturation stage, the generation of antigen-specific T-cell lines and T-cell cytokine secretion. RESULTS: The analysis of T-cell maturation stage and the TCR spectratyping findings revealed that scleromyxedema patients showed clear immunological signs of long-lasting immune system activation and stimulation leading to a skewed T-cell repertoire. Moreover, these analyses showed that both CD4+ and CD8+ T cells from scleromyxedema patients have a profound deficiency (even after stimulation) relatively to the production of IFN-γ and IL17 with respect to healthy donor control cells, while they are massively skewed towards IL4 secretion after stimulation. CONCLUSIONS: Our data indicate that a chronic Th2-skewed T-cell response against an unknown target antigen leading to abnormally high IL4 secretion, a pro-fibrotic cytokine, is a main immunological hallmark of scleromyxedema patients. These results, never reported before, may have a translational therapeutic value due to the availability of anti-IL4 agents such as dupilumab.

Kidney Intragraft Homing of De Novo Donor-Specific HLA Antibodies Is an Essential Step of Antibody-Mediated Damage but Not Per Se Predictive of Graft Loss.

Donor-specific HLA antibody (DSA)-mediated graft injury is the major cause of kidney loss. Among DSA characteristics, graft homing has been suggested as an indicator of severe tissue damage. We analyzed the role of de novo DSA (dnDSA) graft homing on kidney transplantation outcome. Graft biopsy specimens and parallel sera from 48 nonsensitized pediatric kidney recipients were analyzed. Serum samples and eluates from graft biopsy specimens were tested for the presence of dnDSAs with flow bead technology. Intragraft dnDSAs (gDSAs) were never detected in the absence of serum dnDSAs (sDSAs), whereas in the presence of sDSAs, gDSAs were demonstrated in 72% of biopsy specimens. A significantly higher homing capability was expressed by class II sDSAs endowed with high mean fluorescence intensity and C3d- and/or C1q-fixing properties. In patients with available sequential biopsy specimens, we detected gDSAs before the appearance of antibody-mediated rejection. In sDSA-positive patients, gDSA positivity did not allow stratification for antibody-mediated graft lesions and graft loss. However, a consistent detection of skewed unique DSA specificities was observed over time within the graft, likely responsible for the damage. Our results indicate that gDSAs could represent an instrumental tool to identify, among sDSAs, clinically relevant antibody specificities requiring monitoring and possibly guiding patient management.

High-dose intravenous immunoglobulin therapy for scleromyxoedema: a prospective open-label clinical trial using an objective score of clinical evaluation system.

BACKGROUND: Scleromyxoedema is a primary fibro-mucinosis whose therapy is still challenging. OBJECTIVE: To evaluate the safety and efficacy of high-dose intravenous immunoglobulin (IVIg) for the management of scleromyxoedema prospectively using an objective score. METHODS: In a prospective open-label study, IVIg was administered to eight patients with scleromyxoedema in a dose of 2 g/kg per month. The patients were followed-up to a minimum of 6 months, and their disease activity and response to treatment were assessed using the Physician's Global Assessment of disease severity (PGA) and a modified objective skin scoring system for patients with scleroderma (modified Rodnan score system for scleromyxoedema or mRSSS). We used a stringent statistical nonparametric test, the Mann-Whitney U-test, to assess the changes in the mRSSS following therapy with IVIg. RESULTS: Eight patients were included (five males) with a mean age of 59 years. Mean duration of scleromyxoedema was 19 months (6-37 months). The mean duration of treatment was 36.5 months (range 7-74 months).The patients were followed-up for a minimum of 15 months to a maximum of 87 months (mean 44 months). The mean baseline mRSSS of our cohort was 82.38 (37-145, SD 40.763) at the start of treatment, and this significantly decreased to 14.88 (0-37, SD 12.988) (P = 0.012) at the last clinical evaluation with a decrease in mRSSS of 81.6%. No considerable side effects were noted. Paraproteinemia remained substantially unchanged. In six cases, maintenance infusions were required to preserve disease control, while in two patients, therapy was stopped after 7 and 11 months. Relapses, however, occurred, respectively, after 6 and 25 months. CONCLUSIONS: Our study is the first to demonstrate a statistically clinical objective improvement of clinical symptoms of scleromyxoedema with IVIg.

Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses.

Uncontrolled BK polyomavirus (BKPyV) replication in kidney transplant recipients (KTRs) causes polyomavirus-associated nephropathy and allograft loss. Reducing immunosuppression is associated with clearing viremia and nephropathy and increasing BKPyV-specific T cell responses in most patients; however, current immunoassays have limited sensitivity, target mostly CD4(+) T cells, and largely fail to predict onset and clearance of BKPyV replication. To characterize BKPyV-specific CD8(+) T cells, bioinformatics were used to predict 9mer epitopes in the early viral gene region (EVGR) presented by 14 common HLAs in Europe and North America. Thirty-nine EVGR epitopes were experimentally confirmed by interferon-γ enzyme-linked immunospot assays in at least 30% of BKPyV IgG-seropositive healthy participants. Most 9mers clustered in domains, and some were presented by more than one HLA class I, as typically seen for immunodominant epitopes. Specific T cell binding using MHC class I streptamers was demonstrated for 21 of 39 (54%) epitopes. In a prospective cohort of 118 pediatric KTRs, 19 patients protected or recovering from BKPyV viremia were experimentally tested, and 13 epitopes were validated. Single HLA mismatches were not associated with viremia, suggesting that failing immune control likely involves multiple factors including maintenance immunosuppression. Combining BKPyV load and T cell assays using immunodominant epitopes may help in evaluating risk and reducing immunosuppression and may lead to safe adoptive T cell transfer.

Acquisition of C3d-Binding Activity by De Novo Donor-Specific HLA Antibodies Correlates With Graft Loss in Nonsensitized Pediatric Kidney Recipients.

Alloantibody-mediated graft injury is a major cause of kidney dysfunction and loss. The complement-binding ability of de novo donor-specific antibodies (dnDSAs) has been suggested as a prognostic tool to stratify patients for clinical risk. In this study, we analyzed posttransplant kinetics of complement-fixing dnDSAs and their role in antibody-mediated rejection development and graft loss. A total of 114 pediatric nonsensitized recipients of first kidney allograft were periodically monitored for dnDSAs using flow bead assays, followed by C3d and C1q assay in case of positivity. Overall, 39 patients developed dnDSAs, which were C1q(+) and C3d(+) in 25 and nine patients, respectively. At follow-up, progressive acquisition over time of dnDSA C1q and C3d binding ability, within the same antigenic specificity, was observed, paralleled by an increase in mean fluorescence intensity that correlated with clinical outcome. C3d-fixing dnDSAs were better fit to stratify graft loss risk when the different dnDSA categories were evaluated in combined models because the 10-year graft survival probability was lower in patients with C3d-binding dnDSA than in those without dnDSAs or with C1q(+) /C3d(-) or non-complement-binding dnDSAs (40% vs. 94%, 100%, and 100%, respectively). Based on the kinetics profile, we favor dnDSA removal or modulation at first confirmed positivity, with treatment intensification guided by dnDSA biological characteristics.

Regulatory T cells and minimal change nephropathy: in the midst of a complex network.

Minimal change nephrosis (MCN) is an important cause of morbidity in children. In spite of successful therapies having been developed in the last three decades, most aspects related to pathogenesis still remain poorly defined. Evolution in basic immunology and results deriving from animal models of the disease suggest a complex interaction of factors and cells starting from activation of innate immunity and continuing with antigen presentation. Oxidants, CD80 and CD40/CD40L have probably a relevant role at the start. Studies in animal models and in human beings also suggest the possibility that the same molecules (i.e. CD80, CD40) are expressed by podocytes under inflammatory stimuli, representing a direct potential mechanism for proteinuria. B and T cells could play a relevant role this contest. Implication of B cells is suggested indirectly by studies utilizing anti-CD20 monoclonal antibodies as the main therapy. The role of regulatory T cells (Tregs ) is supported mainly by results in animal models of nephrotic syndrome (i.e. adriamycin, puromycin, lipopolysaccharide), showing a protective effect of direct Treg infusion or stimulation by interleukin 2 (IL-2). Limited studies have also shown reduced amounts of circulating Tregs in patients with active MCN cells. The route from bench to bedside would be reduced if results from animal models were confirmed in human pathology. The expansion of Tregs with recombinant IL-2 and new anti-CD20 monoclonal antibodies is the beginning. Blocking antigen-presenting cells with cytotoxic T lymphocyte antigen (CTLA-4)-Ig fusion molecules inhibiting CD80 and/or with blockers of CD40-CD40 ligand interaction represent potential new approaches. The hope is that evolution in therapies of MCN could fill a gap lasting 30 years.

Posttransplant de novo donor-specific hla antibodies identify pediatric kidney recipients at risk for late antibody-mediated rejection.

The emerging role of humoral immunity in the pathogenesis of chronic allograft damage has prompted research aimed at assessing the role of anti-HLA antibody (Ab) monitoring as a tool to predict allograft outcome. Data on the natural history of allografts in children developing de novo Ab after transplantation are limited. Utilizing sera collected pretransplant, and serially posttransplant, we retrospectively evaluated 82 consecutive primary pediatric kidney recipients, without pretransplant donor-specific antibodies (DSA), for de novo Ab occurrence, and compared results with clinical-pathologic data. At 4.3-year follow up, 19 patients (23%) developed de novo DSA whereas 24 had de novo non-DSA (NDSA, 29%). DSA appeared at a median time of 24 months after transplantation and were mostly directed to HLA-DQ antigens. Among the 82 patients, eight developed late/chronic active C4d+ antibody-mediated rejection (AMR), and four C4d-negative AMR. Late AMR correlated with DSA (p < 0.01), whose development preceded AMR by 1-year median time. Patients with DSA had a median serum creatinine of 1.44 mg/dL at follow up, significantly higher than NDSA and Ab-negative patients (p < 0.005). In our pediatric cohort, DSA identify patients at risk of renal dysfunction, AMR and graft loss; treatment started at Ab emergence might prevent AMR occurrence and/or progression to graft failure.

Review of the MitraClip clinical evidence.

MitraClip system is the only catheter-based device for percutaneous mitral valve repair available for clinical use, after receipt of the CE Mark in 2008, while it is currently under review for FDA approval in the US. To date, over 3500 MitraClip implants have been performed worldwide, mainly in high risk surgical patients. The aim of this review is to review all the current evidences of the MitraClip therapy in an aim to define its clinical role in the treatment of mitral regurgitation (MR).

Failure of regulation results in an amplified oxidation burst by neutrophils in children with primary nephrotic syndrome.

The mechanism responsible for proteinuria in non-genetic idiopathic nephrotic syndrome (iNS) is unknown. Animal models suggest an effect of free radicals on podocytes, and indirect evidence in humans confirm this implication. We determined the oxidative burst by blood CD15+ polymorphonucleates (PMN) utilizing the 5-(and-6)-carboxy-2',7'-dichlorofluorescin diacetate (DCF-DA) fluorescence assay in 38 children with iNS. Results were compared with PMN from normal subjects and patients with renal pathologies considered traditionally to be models of oxidative stress [six anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, seven post-infectious glomerulonephritis]. Radicals of oxygen (ROS) production was finally determined in a patient with immunodeficiency, polyendocrinopathy, enteropathy X-linked (IPEX) and in seven iNS children after treatment with Rituximab. Results demonstrated a 10-fold increase of ROS production by resting PMN in iNS compared to normal PMN. When PMN were separated from other cells, ROS increased significantly in all conditions while a near-normal production was restored by adding autologous cells and/or supernatants in controls, vasculitis and post-infectious glomerulonephritis but not in iNS. Results indicated that the oxidative burst was regulated by soluble factors and that this regulatory circuit was altered in iNS. PMN obtained from a child with IPEX produced 100 times more ROS during exacerbation of clinical symptoms and restored to a near normal-level in remission. Rituximab decreased ROS production by 60%. In conclusion, our study shows that oxidant production is increased in iNS for an imbalance between PMN and other blood cells. Regulatory T cells (Tregs) and CD20 are probably involved in this regulation. Overall, our observations reinforce the concept that oxidants deriving from PMN are implicated in iNS.

Quality of life in parents of children with cerebral palsy: is it influenced by the child's behaviour?

The aims of the present study were: to examine the quality of life (QOL) of parents of children with cerebral palsy (CP) and to establish the possible effect of behaviour problems on their QOL. One-hundred children with CP, aged between 4 and 10 years, and both their parents were included in the study. Both parents completed the WHOQOL-BREF, to assess their QOL. A sample of 60 parents of healthy children was used as control group. The primary caregiver also completed the CHILD BEHAVIOUR CHECKLIST (CBCL). Parents of children with CP showed lower scores on physical and psychological domains than the control group on QOL. In the psychological domain the mothers of children with hemiplegia had the lowest scores. The mothers reported lower scores than the fathers for the physical domain in the group of children with diplegia and quadriplegia and for the psychological domain in the group of children with hemiplegia. Children with hemiplegia showed externalizing scores at CBCL higher than the other groups, that could explain the poorer QOL scores of their mothers. In conclusions our results provide useful information on the QOL in families with different forms of CP, useful in planning interventions for the family of children with CP.

Infant neurological examination from 3 to 12 months: predictive value of the single items.

The prognostic value of the single items of a standardised neurological examination, the Hammersmith Infant Neurologic Examination (HINE), was explored longitudinally in 658 infants at 3, 6, 9 and 12 months post-term age. ROC curves were built based on the presence/absence of cerebral palsy at 2 years of age. Global HINE scores showed very high prediction (ROC curve areas above 0.9) at all ages. The items with the highest predictive value were always movement quality and quantity. In the first semester, among the most predictive items were those assessing tone, while beyond that time they were reflexes and reactions. Our results show that the high predictive value of the HINE across the first year of life is granted by the successful combination of different groups of items for each age-period. This should be recognised in clinical practice when assessing the significance of individual neurological profiles.

Spinal Cord Stimulation in Failed Back Surgery Syndrome: Effects on Posture and Gait-A Preliminary 3D Biomechanical Study.

We studied 8 patients with spinal cord stimulation (SCS) devices which had been previously implanted to treat neuropathic chronic pain secondary to Failed Back Surgery Syndrome. The aim of our study was to investigate the effects of SCS on posture and gait by means of clinical scales (Short Form Health Survey-36, Visual Analogue Scale for pain, and Hamilton Depression Rating Scale) and instrumented evaluation with 3D Gait Analysis using a stereophotogrammetric system. The latter was performed with the SCS device turned both OFF and ON. We recorded gait and posture using the Davis protocol and also trunk movement during flexion-extension on the sagittal plane, lateral bending on the frontal plane, and rotation on the transversal plane. During and 30 minutes after the stimulation, not only the clinical scales but also spatial-temporal gait parameters and trunk movements improved significantly. Improvement was not shown under stimulation-OFF conditions. Our preliminary data suggest that SCS has the potential to improve posture and gait and to provide a window of pain-free opportunity to optimize rehabilitation interventions.

Basal insulin therapy is associated with beneficial effects on postoperative infective complications, independently from circulating glucose levels in patients admitted for cardiac surgery.

BACKGROUND: Although hyperglycemia is a strong predictor of postoperative infective complications (PIC), little is known about the effect of basal insulin therapy (BIT) per se on PIC. AIM: To evaluate if there is an association between BIT, independent of glucose levels, and a possible improvement of PIC during the perioperative cardiosurgery period (PCP). METHODS: In 812 patients admitted for cardiac intervention and treated with a continuous intravenous insulin infusion (CIII) for hyperglycemic levels (>130 mg/dl), a retrospective analysis was performed during the PCP (January 2009-December 2011). Upon transfer to the cardiac surgery division, if fasting glucose was ≥130 mg/dl, a basal + premeal insulin therapy was initiated (121 patients, group 1); for <130 mg/dl, a premeal insulin alone was initiated (691 patients, group 2). FINDINGS: Compared with group 2, group 1 showed reductions in PIC (2.48% vs 7.96%, p < 0.049; odds ratio: 0.294; 95% CI: 0.110-0.780), C-Reactive Protein (p < 0.05) and white blood cell (p < 0.05) levels despite glucose levels and CIII that were higher during the first two days after surgery (179.8 ± 25.3 vs 169.5 ± 10.6 mg/dl, p < 0.01; 0.046 ± 0.008 vs 0.037 ± 0.015 U/kg/h, p < 0.05, respectively). Normal glucose levels were achieved in both groups from day 3 before the discharge. The mean length of hospital duration was 18% lower in group 1 than in group 2 (7.21 ± 05.08 vs 8.76 ± 9.08 days, p < 0.007), providing a significant impact on public health costs. CONCLUSIONS: Basal + preprandial insulin therapy was associated with a lower frequency of PIC than preprandial insulin therapy alone, suggesting a beneficial effect of basal insulin therapy on post-surgery outcome.

Efficacy and safety of topiramate in infants according to epilepsy syndromes.

Studies of the efficacy of topiramate (TPM) in infants and young children are few. Here we report an open, prospective, and pragmatic study of effectiveness of TPM in terms of epilepsy syndromes, in children aged less than 2 years. The median follow-up period was 11 months. We enrolled 59 children in the study: 22 affected by localization-related epilepsy (LRE), 23 by generalized epilepsy, six by Dravet's syndrome, and eight with unclassifiable epilepsy. TPM was effective (responders showed a decrease of more than 50% in seizure frequency) in 47% of patients, including 13% who were seizure-free at the last visit. TPM was more effective in localization-related epilepsy (48% of responders) than in generalized epilepsy (32% of responders). In the latter group, 19 patients suffered from infantile spasms. Four of six patients with cryptogenic infantile spasms became seizure-free. Of the 13 patients with symptomatic infantile spasms, only one was seizure-free. Results were poor for patients with Dravet's syndrome. In general, TPM was well tolerated. The most frequently reported adverse effects were drowsiness, irritability, hyperthermia, and anorexia. The present study concludes that TPM is effective for a broad range of seizures in infants and young children and represents a valid therapeutic option in this population.

Ovarian adrenergic nerves directly participate in the control of luteinizing hormone-releasing hormone and beta-adrenergic receptors during puberty: a biochemical and autoradiographic study.

The rat ovary receives sympathetic innervation from the superior ovarian nerve (SON) and the plexus nerve (OP). To examine the possibility of a direct adrenergic mechanism controlling ovarian receptor distribution during the onset of puberty, we have studied the acute (48-h) effect of unilateral nervotomy (combined section of SON and OP nerves) on ovarian LHRH and beta-adrenergic receptor concentrations and distribution using both radioreceptor assays and in vitro autoradiography. Ovarian LHRH receptor concentration increased sharply between 12 and 20 days of age. At this time receptors were mostly associated with follicles and interstitial cells, whereas at 37 days of age, when a measurable loss in the receptor concentration was observed, light and diffuse autoradiographic labeling of receptors was also found in the corpora lutea. Complete removal of adrenergic input to the gland produced a sharp decrease in LHRH-binding activity within the denervated ovary at each time interval studied, with no effect in the innervated contralateral gland. Autoradiographic data also revealed a decrease in both the number of labeled follicles and the intensity of the labeling. beta-Adrenergic receptor concentration increased progressively between days 12 and 27, reaching a peak value at 37 days of age. Labeling was very weak at 12 days of age and increased progressively at 20 and 27 days of age. At this time, receptors were mostly localized by autoradiography in the interstitial cells, while at 37 days of age corpora lutea were strongly labeled. Ovarian beta-adrenergic receptors showed a marked drop when acutely deprived of their neural tone, as illustrated by the 2- to 3-fold decrease in receptor-binding capacity within the denervated gland. The autoradiographic data also showed marked changes in beta-adrenergic receptor distribution, specially at 37 days of age. At this time, the labeling of corpora lutea was markedly decreased in denervated ovaries. The present results clearly demonstrate that complete removal of ovarian adrenergic tone produces a profound decrease in the concentrations of LHRH and beta-adrenergic receptors within the ovary, although it cannot be excluded that peptidergic factors also arriving via the SON and OP could have some influence on the regulation of these receptors. The results support the concept of a direct involvement of the central nervous system in ovarian function. They also suggest that during ovarian development a neural efferent system might be involved in the adjustment of ovarian responsiveness to stimulation by the gonadotropins via changes in receptor content and/or distribution in the different ovarian compartments.

Upregulation of lymphocyte beta-adrenergic receptor in Down's syndrome: a biological marker of a neuroimmune deficit.

To test the hypothesis of an altered central nervous system influence upon the immune system of Down's syndrome (DS) patients and in order to establish a peripheral biological marker of neuroimmune deficit, we have studied the characteristics of the beta 2-adrenergic receptor (B2AR) system in peripheral blood monocytes (PBMC) of 12 pre-pubertal (six boys and six girls) individuals and correlated alterations in binding with changes in distribution of lymphocyte subsets. Using the very potent beta-adrenergic antagonist, iodocyanopindolol ([125I]CYP), as a ligand, the present study shows that a typical BAR population of the beta 2-subtype is present in PBMC from DS children, with binding kinetics and structural specificity similar to those measured in PBMC from patients with other (non-genetic) forms of mental retardation, or in PBMC from age-matched healthy subjects. On the other hand, this study revealed a significant increase in B2AR binding capacity of PBMC from DS subjects (Bmax = 5258 +/- 470 sites/cell) compared to the values measured in the control population of retarded children (Bmax = 1965 +/- 280 sites/cell), characterized by an approximately three-fold increase in the Bmax, without changes in binding affinity (KD = 40.5 +/- 2.0 and 36.6 +/- 2.5 pM in DS and retarded patients, respectively). The flowcytometric analysis of lymphocyte subsets using a panel of monoclonal antibodies against a series of lymphocyte markers revealed a profound alteration in the distribution of lymphocyte subtypes with an almost 50% decrease in B cell and T-helper populations, a three-fold increase in T-cytotoxic suppressor, a seven-fold increase in lymphocyte-activated killer cells (LAK) and 30% increase in natural killer (NK) subpopulations. When fluorescence-labelled lymphocytes were visualized in the cytofluorograph and sorted for their use in the radioreceptor assay, B cells had approximately twice the number of B2AR when compared to T cells; and cytotoxic/suppressor showed a higher binding capacity compared to T-helper cells. On the other hand, labelled lymphocytes from DS patients showed a specific increase in receptor number in B cells, T-cytotoxic suppressor and NK subpopulations. It is concluded that a profound catecholaminergic dysfunction not previously appreciated in DS is reflected by a significant alteration in lymphocyte subset distribution and by a specific up-regulation of lymphocyte B2AR in phenotypically and functionally distinct T and B cells as well NK subpopulations, suggesting a possible denervation supersensitivity phenomenon.(ABSTRACT TRUNCATED AT 400 WORDS)

Functional organization of thalamic projections to the motor cortex. An anatomical and electrophysiological study in the rat.

In rats, horseradish peroxidase crystals were injected in motor cortical foci functionally identified by means of the motor effects evoked by electrical stimulations. The location in the thalamus of the neurons linked to different motor cortical foci was studied. Thalamic neurons were retrogradely labeled in both "motor" (ventralis lateralis and ventralis medialis) and "non-motor" nuclei: centralis lateralis, lateralis posterior, mediodorsalis and posterior thalamic nuclear group, as well as the ventrobasal complex. The ventrobasal complex was labeled after horseradish peroxidase injections in hindlimb and trunk motor areas. The ascending projections toward the motor cortex from both "motor" and "non-motor" thalamic nuclei are organized more precisely and more elaborately than previously reported. The motor cortical afferents from the nucleus ventralis lateralis are organized in three planes, rostrocaudally, dorsoventrally and mediolaterally. An inverted relation exists in the rostrocaudal plane between the nucleus ventralis lateralis and the motor cortex: the caudal motor cortex region (hindlimb) receives fiber inputs from the rostral region of the nucleus ventralis lateralis, whereas the caudal zone of the nucleus ventralis lateralis projects to the rostral motor cortex region (forelimb and vibrissae). A dorsoventral organization has also been observed in the rostral region of the nucleus ventralis lateralis: the ventral aspect is the source of fibers directed to the distal hindlimb region, whereas fibers originating from the dorsal aspect are directed to the proximal hindlimb area. A mediolateral relationship exists between medial and lateral sides of the nucleus ventralis lateralis and, respectively, proximal and distal forelimb cortical areas. There is some overlap between the various nuclear regions thus delineated. Four functional zones were found in the lateral half of the nucleus ventralis medialis and were classified according to their projection to the motor cortex; these are involved in motor control of the proximal and distal forelimb, vibrissae and ocular movements. The projection is topographically organized according to both an inverted rostrocaudal and a direct dorsoventral-mediolateral arrangement. Caudally, dorsal and ventral nuclear parts project to rostromedial (vibrissae) and rostrolateral (distal forelimb) regions of the motor cortex, respectively. More rostral nuclear zones project to more caudal (proximal forelimb, eye) cortical regions. There is little overlap between these four nuclear subdivisions. The nucleus centralis lateralis projects to vibrissae and proximal, as well as distal, forelimb areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Pseudo-TORCH syndrome or Baraitser-Reardon syndrome: diagnostic criteria.

Intracranial calcification and microcephaly, which represent the main clinical features of the TORCH-syndrome, can also be determined by a rare autosomal recessive infection-like condition named pseudo-TORCH syndrome. This emerging entity has been registered in eight families so far. We report on five patients from three unrelated Italian families affected by pseudo-TORCH syndrome. Reevaluation of literature allowed us to draw a specific clinical profile of the syndrome. Indeed, congenital microcephaly, congenital cerebral calcification, spasticity and seizures are the main clinical features, and have been present in almost all patients reported so far. On the contrary, findings resembling congenital infectious diseases including neonatal icterus, hyperbilirubinemia, thrombocytopenia, and hepatomegaly, affect less than half of the patients. Considering the diagnosis of pseudo-TORCH syndrome in patients with neonatal microcephaly and cerebral calcification is necessary since an early diagnosis may allow adequate genetic counseling to the families.

Birth weight for gestational age centiles for Italian neonates.

OBJECTIVE: To provide centiles for birth weight (BW) according to gestational age (GA) and sex for infants born in Italy. METHODS: We used records of the whole neonatal population of Tuscany, a region in Italy, from July 1991 to June 2002 as resulting from the database of the cystic fibrosis neonatal screening program (n=290129). We excluded as unlikely for GA those BW that were more than two interquartile ranges above the 75th centile or below the 25th centile for each GA and gender group. RESULTS: We present the 3rd, 10th, 25th, 50th, 75th, 90th and 97th centiles of BW for GA from the 24th to 43rd week of gestation for male and female Italian neonates, as both tables and smoothed curves. CONCLUSIONS: The large size of the examined population allows us to provide up-to-date, reliable BW for GA centiles for Italian newborns, especially for lower GAs.