A different perspective on sofosbuvir-ledipasvir treatment of patients with HCV genotype 1b cirrhosis: The ital-c network study.

The effectiveness of a 12-week course of sofosbuvir-ledipasvir in treatment-experienced HCV genotype 1b-infected patients with cirrhosis is still under debate. Our primary endpoint was to compare the sustained virological response at post-treatment week 12 (SVR12) of sofosbuvir-ledipasvir in combination with ribavirin for 12 weeks, and sofosbuvir-ledipasvir alone for 24 weeks. This was a prospective observational study that enrolled 424 (195 naive, 229 experienced; 164 treated for 12 weeks with Ribavirin and 260 with sofosbuvir-ledipasvir alone for 24 weeks) consecutive HCV genotype 1b-infected patients with cirrhosis. The SVR12 rates were 93.9% and 99.2% in patients treated for 12 and 24 weeks, respectively (P = .002). The baseline characteristics of patients treated for 12 weeks were significantly different from those treated for 24 weeks as regards their younger age (P = .002), prevalence of Child-Pugh class A (P = .002), lower MELD scores (P = .001) and smaller number of nonresponders (P = .04). The shorter treatment was significantly associated with a lower SVR12 in univariate and multivariate analyses (P = .007 and P = .008, respectively). The SVR rate was unaffected by age, gender, BMI, Child-Pugh class, MELD score or previous antiviral treatment. Patients receiving ribavirin experienced more episodes of ascites and headache but less recurrence of hepatocellular carcinoma (HCC), and were prescribed more diuretics and cardiopulmonary drugs. No patient discontinued treatment. The therapeutic regimen of sofosbuvir-ledipasvir plus ribavirin administered for 12 weeks was less effective than sofosbuvir-ledipasvir alone given for 24 weeks. At odds with European guidelines, the recommended 12-week treatment with sofosbuvir-ledipasvir alone might be suboptimal for this setting of patients.

Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network.

BACKGROUND: IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES). METHODS: Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variants in linked regions were identified and validated using Sanger sequencing. Custom TaqMan assays were designed and carried out in the 16 kindreds and an independent cohort of 240 IgAN patients and 113 control subjects. RESULTS: We found suggestive linkage signals in 12 loci. After sequential filtering and validation of WES data, we identified 24 private or extremely rare (MAF <0.0003) linked variants segregating with IgAN status. These were present within coding or regulatory regions of 23 genes that merged into a common functional network. The genes were interconnected by AKT, CTNNB1, NFKB, MYC and UBC, key modulators of WNT/ß-catenin and PI3K/Akt pathways, which are implicated in IgAN pathogenesis. Overlaying publicly available expression data, genes/proteins with expression notably altered in IgAN were included in this immune-related network. In particular, the network included the glucocorticoid receptor gene, NR3C1, which is the target of corticosteroid therapy routinely used in the treatment of IgAN. CONCLUSION: Our findings suggest that disease susceptibility could be influenced by multiple rare variants acting in a common network that could provide the starting point for the identification of potential drug targets for personalized therapy.

Patient classification and outcome prediction in IgA nephropathy.

OBJECTIVE: IgA Nephropathy (IgAN) is a common kidney disease which may entail renal failure, known as End Stage Kidney Disease (ESKD). One of the major difficulties dealing with this disease is to predict the time of the long-term prognosis for a patient at the time of diagnosis. In fact, the progression of IgAN to ESKD depends on an intricate interrelationship between clinical and laboratory findings. Therefore, the objective of this work has been the selection of the best data mining tool to build a model able to predict (I) if a patient with a biopsy proven IgAN will reach ESKD and (II) if a patient will reach the ESKD before or after 5 years. MATERIAL AND METHODS: The largest available cohort study worldwide on IgAN has been used to design and compare several data-driven models. The complete dataset was composed of 1174 records collected from Italian, Norwegian, and Japanese IgAN patients, in the last 30 years. The data mining tools considered in this work were artificial neural networks (ANNs), neuro fuzzy systems (NFSs), support vector machines (SVMs), and decision trees (DTs). A 10-fold cross validation was used to evaluate unbiased performances for all the models. RESULTS: An extensive model comparison based on accuracy, precision, recall, and f-measure was provided. Overall, the results indicate that ANNs can provide superior performance compared to the other models. The ANN for time-to-ESKD prediction is characterized by accuracy, precision, recall, and f-measure greater than 90%. The ANN for ESKD prediction has accuracy greater than 90% as well as precision, recall, and f-measure for the class of patients not reaching ESKD, while precision, recall, and f-measure for the class of patients reaching ESKD are slightly lower. The obtained model has been implemented in a Web-based decision support system (DSS). CONCLUSIONS: The extraction of novel knowledge from clinical data and the definition of predictive models to support diagnosis, prognosis, and therapy is becoming an essential tool for researchers and clinical practitioners in medicine. The proposed comparative study of several data mining models for the outcome prediction in IgAN patients, using a large dataset of clinical records from three different countries, provides an insight into the relative prediction ability of the considered methods applied to such a disease.

Scanning electron microscopy study of small bowel biopsies in chronic diarrhoea in childhood.

In this study we have compared the results of Scanning Electron Microscopy (SEM) with Light- and Stereomicroscopy in a series of small bowel biopsies in children. In 9 cases displaying features of partial or subtotal atrophy, Light and Dissecting-Microscopy yielded similar results. The distinction between coeliac and non-coeliac chronic diarrhoea was only possible on clinical grounds, and by the immunological detection of specific antibodies. On SEM however coeliac patients showed characteristic alterations consisting of: absence of villi; prominent crypt outlets resulting in a mosaic appearance; concentric furrows running all around the openings; and downy brush feature at high power. The microvilli were loosely distributed and had an irregular pleomorphic outline; they often displayed a drumstick swelling of the tip and were bent. In contrast, non-coeliac chronic diarrhoea cases were characterized by a thick mucous layer on the mucosal surface, that made it impossible to visualize further changes. Peculiar vascular changes in lymphangiectasia and in sickle beta thalassemia could be detected only by Light Microscopy. In addition, in the lymphangiectasia case SEM allowed the detection of enteroadherent bacteria; and in the lambliasis case, of pseudomembranes. Absence of glycocalyx was noted both in controls and in patients. The results of this study point to a diagnostic utility of SEM particularly in the differential diagnosis of chronic diarrhoea; moreover they suggest that enteroadherent bacteria may not be pathogenic and that the absence of glycocalyx is not specific for allergic enteropathy as previously claimed.

Endoscopic ballistic lithotripsy in the treatment of bladder calculi in patients with neurogenic voiding dysfunction.

Bladder stones represent a troublesome complication in patients suffering from neurogenic voiding dysfunction, in whom prompt and effective therapy is required. A variety of endoscopic lithotripsy methods are available; however, current devices can be tedious to use. We have treated 17 patients affected by bladder calculi and spinal cord injury or multiple sclerosis by means of the ballistic lithotripter EMS Swiss Lithoclast. The mean diameter of the stones was 2.7 cm. The mean operative time was 27 minutes. There were five intraoperative complications, including crises of autonomic dysreflexia (three patients) and light hematuria (two patients). There was no malfunction of the lithotripter and no long-term complications. All the patients were stone free at 6 months postoperatively. In conclusion, endoscopic lithotripsy with the ballistic lithotripter proved to be a very effective, rapid, and safe method for treating bladder calculi in patients with neurogenic bladders.

Pancreatitis caused by duodenal duplication.

The authors present the investigations and surgical treatment of two cases of duodenal cystic duplication. Abdominal pain and gastroesophageal reflux were the most important symptoms and signs associated with an history of recurrent acute pancreatitis. Computed tomography scan, ultrasound examination, and cholangiography confirmed preoperatively the diagnosis, and a transduodenal surgical approach was carried out in both children. A simple marsupialization of the cyst was performed in the former, and a sphincterotomy with papillosphincteroplasty was associated in the latter. The diagnosis was confirmed by microscopy, and both the children are asymptomatic after a 14 and 18 months of follow-up. This report focuses on the importance of the cholangiopancreatography for every child presenting with recurrent, unexplained bouts of acute pancreatitis, and underlines the technical surgical aspects on the basis of the anatomic identification of the malformation.

Continuous (6 hour) urodynamic monitoring in children with neuropathic bladder.

In adults the development of modern equipment for ambulatory monitoring permits long-term evaluation of the lower urinary tract which is more accurate than standard urodynamics (SUD). In children continuous urodynamic monitoring (CUM) has been used infrequently and therefore standardisation of the method has not been previously achieved, nor have the techniques and difficulties of performing 24-hour monitoring been solved. The aim of this study was to identify a technical method of CUM in children which was feasible and to verify its usefulness. For this purpose, we reviewed our preliminary experiences of CUM in children with neuropathic bladder. From March to November 1995 we made an outpatient study of the neuropathic bladders of 11 myelodysplastic children aged 1 to 18 years (average age 10.2 years). 7 of them were males and 4 females. All underwent SUD. With the children resting in bed, a 6-hour CUM (Lectromed MPR-2) was performed using a 4 Fr. microtip intravesical catheter (suprapubic in 3 infants and transurethral in 8 children) and an intrarectal catheter. The parents and/or a nurse monitored the fluid intake and micturition events and recorded the data in a diary. Based on the CUM experience in infants with non-neurogenic bladder dysfunction, the 3 suprapubic studies were done after 12 hours of urethral drainage in order to prevent leakage of urine. In all of the patients we were able to study 2 to 4 bladder fillings during a period of 6 to 8 hours (average 6.5 hours) observation. In 9 of the 11 children the CUM pattern was comparable to the SUD one but in the 2 remaining patients CUM showed uninhibited contractions. Higher uninhibited voiding contraction pressures were recorded in hyper-reflexic bladders. Our preliminary results show that it is feasible to perform CUM in children and that it has advantages over standard cystometry in the investigation of children with neuropathic bladder even if it is carried out for short term (6 hours).

Multisystem evaluation in one case of pure autonomic failure.

Pure autonomic failure (PAF) is a rare syndrome characterized by a primitive failure of the autonomic nervous system (ANS). We have studied a 53-year old woman suffering from PAF by using ANS provocative tests investigating the cardiovascular system (standing up test, controlled ventilation, Valsalva manoeuvre, handgrip test, cold pressor test, mental stress test, plasma catecholamine levels), tests investigating the intrinsic ocular innervation (pupil reactivity), and the bladder function (urodynamic tests). Our results have shown abnormalities of all the studied parameters and they have also confirmed that these patients need a multidisciplinary autonomic evaluation to correctly identify the syndrome.

[Miction disorders symptomatic of neurologic disease]. / Disfunzioni minzionali sintomatiche di malattie neurologiche.

Urodynamic test has a main role in: 1) making a precise diagnosis in presence of urinary symptoms not clearly interpretable by other means; 2) assessing the characteristics of neurogenic bladder for a correct treatment; 3) detecting an underlying, previously not diagnosed neurologic disease in patients with voiding abnormalities. This report concerns 10 patients with urinary symptoms in whom the urodynamic tests allowed to suspect a neurogenic problem. Seven pts. showed an areflexic bladder with positive betanechol supersensitive test, 3 pts. had detrusor hyperreflexia, while in 2 cases there was a low compliant bladder. All the patients with detrusor hyperreflexia had also detrusor sphincter dyssynergia, while 5 out of 7 pts. with detrusor areflexia showed a denervated perineal floor. The final neurologic diagnoses were 4 protruded discs, 2 multiple scleroses, 1 cerebral tumor, 2 spinal tumors, 1 cervical spondylosis.

Transient neonatal hyperinsulinemic hypoglycemia and neurological outcome: a case report.

Transient neonatal hyperinsulinemic hypoglycemia (TNHI) is a form of neonatal-onset hyperinsulinism which usually resolves completely in a few days or months. It is secondary to conditions such as maternal diabetes mellitus or intra-uterine growth retardation. Other rare causes of TNHI are perinatal asphyxia and gestational diabetes. Hyperinsulinemic hypoglycemia (HI) is also observed in association with rare metabolic or genetic conditions. It can also occur in newborns without risk factors. TNHI is usually a transient phenomenon. However, some newborns can have prolonged HI that requires treatment with diazoxide, persists for several months and then resolves spontaneously. Neonatal hyperinsulinemic hypoglycemia must be promptly and correctly diagnosed and treated in order to avoid neurological consequences. We describe a case of transient neonatal hyperinsulinemic hypoglycemia in a full-term born without perinatal complications and appropriate for gestational age with an unfavourable neurological outcome.

Inflammatory bowel disease in children and adolescents in Italy: data from the pediatric national IBD register (1996-2003).

BACKGROUND: The purpose was to assess in Italy the clinical features at diagnosis of inflammatory bowel disease (IBD) in children. METHODS: In 1996 an IBD register of disease onset was established on a national scale. RESULTS: Up to the end of 2003, 1576 cases of pediatric IBD were recorded: 810 (52%) ulcerative colitis (UC), 635 (40%) Crohn's disease (CD), and 131 (8%) indeterminate colitis (IC). In the period 1996-2003 an increase of IBD incidence from 0.89 to 1.39/10(5) inhabitants aged <18 years was observed. IBD was more frequent among children aged between 6 and 12 years (57%) but 20% of patients had onset of the disease under 6 years of age; 28 patients were <1 year of age. Overall, 11% had 1 or more family members with IBD. The mean interval between onset of symptoms and diagnosis was higher in CD (10.1 months) and IC (9 months) versus UC (5.8 months). Extended colitis was the most frequent form in UC and ileocolic involvement the most frequent in CD. Upper intestinal tract involvement was present in 11% of CD patients. IC locations were similar to those of UC. Bloody diarrhea and abdominal pain were the most frequent symptoms in UC and IC, and abdominal pain and diarrhea in CD. Extraintestinal symptoms were more frequent in CD than in UC. CONCLUSIONS: The IBD incidence in children and adolescents in Italy shows an increasing trend for all 3 pathologies. UC diagnoses exceeded CD.

Impact of the endorectal ultrasound probe on uroflow parameters in males.

OBJECTIVES: The aim of this study was to test the null hypothesis that the presence in the rectum of an endorectal ultrasound probe during transrectal voiding ultrasonography (TRVUS) would have no significant effect on uroflowmetry parameters. PATIENTS AND METHODS: We studied 43 randomly selected men undergoing TRVUS of the prostate for non-neurogenic lower urinary tract symptoms. Uroflowmetry was performed immediately before and during the TRVUS. Results were compared with a paired Student's t test; the null hypothesis was confirmed by p values >0.05. RESULTS: Forty patients were able to void with the endorectal probe inserted, and 95% described this micturition as representative of their usual voiding behavior. No significant statistical difference was found between uroflowmetry parameters before and during TRVUS, confirming our null hypothesis. CONCLUSION: Our data suggest that uroflowmetry in combination with TRVUS can be a reliable tool for evaluating disorders of micturition in males, at least in selected cases.

Non-neurogenic neurogenic bladder.

A case report of a 10 year old boy, presenting with a non-neurogenic neurogenic bladder is described and taken into account to discuss the most common etiologies of voiding dysfunction in children. Focus is placed on spinal dysraphism as a cause of a neurogenic bladder in opposition to non-neurogenic neurogenic bladders, to stress the differences in etiology, pathology and treatment.

[The effects of lactitol in the treatment of intestinal stasis in childhood]. / Effetti del lattitolo nel trattamento della stasi intestinale in età pediatrica.

Thirty-nine children (18 males, 21 females) suffering from intestinal stasis were treated with lactitol or a reference drug (lactulose in crystalline form), according to a balanced randomization, for 15 days. The first group of children included 19 subjects treated with lactitol, the second group included 20 subjects treated with lactulose. The dosages of lactitol and lactulose were, respectively, of 150-350 mg/kg and of 150-300 mg/kg daily per os with a single administration in the morning. During the trial, the children did not take any concomitant drug. For each patient the tested parameters were: number of intestinal evacuations, consistency of stool and adverse reactions (abdominal swelling, abdominal pain, nausea, vomiting, meteorism) daily; routine laboratory tests at the beginning and at the end of the trials. The results showed that the subjects treated with lactitol have manifested, besides a proved therapeutic efficacy, a better tolerability and compliance than the subjects treated with lactulose.

Neurophysiological evaluation of central-peripheral sensory and motor pudendal fibres.

Extensive neurophysiological investigations were carried out in 18 healthy volunteer subjects, and 6 patients with neurological disease. The tests consisted of spinal and scalp somatosensory evoked potentials (SEPs) to stimulation of the dorsal nerve of penis/clitoris, motor evoked potentials (MEPs) from the bulbocavernosus muscle (BC) and anal sphincter (AS) in response to scalp and sacral root stimulation, and measurement of sacral reflex latency (SRL) from BC and AS. In the control subjects, the mean sensory total conduction time (sensory TCT), as measured at the peak of the scalp P40 wave was 40.9 msec (range: 37.8-44.2). The mean sensory central conduction time (sensory CCT = spine-to-scalp conduction time) was 27.0 msec (range: 23.5-30.4). Transcranial brain stimulation was performed by using a magnetic stimulator both at rest and during voluntary contraction of the examined muscle. Sacral root stimulation was performed at rest. Motor total conduction times (motor TCT) to BC and AS muscles were respectively 28.8 and 30.0 msec at rest, and 22.5 and 22.8 msec during contraction. Motor central conduction times (motor CCT) to sacral cord segments controlling BC and AS muscles were respectively 22.4 and 21.2 msec at rest, and 15.1 and 12.4 msec during contraction. The mean latencies of SRL were respectively 31.4 msec in the bulbocavernosus muscle and 35.9 msec in the anal sphincter. Combined or isolated abnormalities of SEPs, MEPs and SRL were found in a small group of patients with neurological disorders primarily or secondarily affecting the genito-urinary tract.

Congenital bilateral juvenile granulosa cell tumor of the ovary in leprechaunism: a case report.

We report on a case of leprechaunism. In addition to the typical clinical and biochemical features, a bilateral juvenile granulosa cell tumor of the ovaries and cytomegalovirus hepatitis were found. The granulosa cell tumor may result from the mitogenic effect of insulin at high concentration, which acts via a mechanism mediated by insulin-like growth factor I receptors.

An atypical paediatric case of malignant atrophic papulosis (Köhlmeier-Degos disease).

A new case of malignant atrophic papulosis (Köhlmeier-Degos disease) is reported. Vascular symptoms began at 17 months of age with cerebral ischaemia and progressive involvement of fingers and toes with torpid ulcers and apical necrotic amputations. At 6 years of age he developed chronic intestinal ischaemia with malabsorption and a new cerebral attack; in spite of anti-aggregant therapy the disease progressed and he died 7 months after diagnosis from a third cerebral ictus. Since the typical skin lesions of the disease were absent, the diagnosis was made on the basis of a pathological pattern of an occluded biopsied artery. The elder brother presents clinical and instrumental vascular involvement without cutaneous lesions and could be slightly affected.

Hypertrophic gastropathy with transient sessile polyps.

We report an 8-year-old boy with hypertrophic gastropathy (HG) associated with duodenal Giardia lamblia infestation. The follow-up was complicated by the development of gastric polyps at the site of previous biopsies that spontaneously disappeared within 15 months. Despite the histological similarity, the different course between Ménétrier's disease (MD) in adults (chronic, with frequent development of sessile or pedunculate polyps) and HG (uncomplicated and usually spontaneously resolving) suggests a different pathogenesis. Viral (cytomegalovirus) and bacterial (Helicobacter pylori) infections have been described in association with HG and they could play an important pathogenetic role. The term HG better defines the childhood disease in which a conservative management is recommended.

[Ultrasonography in the follow-up of patients after extracorporeal shockwave lithotripsy]. / L'ecografia nel follow-up dei pazienti sottoposti a litotrissia extracorporea con onde d'urto.

Extracorporeal shock wave lithotripsy (ESWL) has revolutionized treatment of urinary stones, but created new clinical situations and problems in the interpretation of which x-rays and ultrasonography have proved invaluable. This paper defined the role of ultrasound in the follow-up of patients who had undergone ESWL and assessed its advantages and limitations in evaluating the efficacy of this form of therapy and in monitoring the elimination of stone fragments. The utility of ultrasound in the diagnosis and monitoring of the complications due to ESWL has been emphasized. Finally ultrasound is a valid tool when performing those echo-guided procedures which are essential for the treatment of obstructive complications secondary to ESWL.