Whole-Exome and Transcriptome Sequencing Expands the Genotype of Majewski Osteodysplastic Primordial Dwarfism Type II

Microcephalic Osteodysplastic Primordial Dwarfism type II (MOPDII) represents the most common form of primordial dwarfism. MOPD clinical features include severe prenatal and postnatal growth retardation, postnatal severe microcephaly, hypotonia, and an increased risk for cerebrovascular disease and insulin resistance. Autosomal recessive biallelic loss-of-function genomic variants in the centrosomal pericentrin (PCNT) gene on chromosome 21q22 cause MOPDII. Over the past decade, exome sequencing (ES) and massive RNA sequencing have been effectively employed for both the discovery of novel disease genes and to expand the genotypes of well-known diseases. In this paper we report the results both the RNA sequencing and ES of three patients affected by MOPDII with the aim of exploring whether differentially expressed genes and previously uncharacterized gene variants, in addition to PCNT pathogenic variants, could be associated with the complex phenotype of this disease. We discovered a downregulation of key factors involved in growth, such as IGF1R, IGF2R, and RAF1, in all three investigated patients. Moreover, ES identified a shortlist of genes associated with deleterious, rare variants in MOPDII patients. Our results suggest that Next Generation Sequencing (NGS) technologies can be successfully applied for the molecular characterization of the complex genotypic background of MOPDII

Unstable Maternal Environment, Separation Anxiety, and Heightened CO2 Sensitivity Induced by Gene-by-Environment Interplay

Background: In man, many different events implying childhood separation from caregivers/unstable parental environment are associated with heightened risk for panic disorder in adulthood. Twin data show that the occurrence of such events in childhood contributes to explaining the covariation between separation anxiety disorder, panic, and the related psychobiological trait of CO2 hypersensitivity. We hypothesized that early interference with infant-mother interaction could moderate the interspecific trait of response to CO2 through genetic control of sensitivity to the environment. Methodology: Having spent the first 24 hours after birth with their biological mother, outbred NMRI mice were crossfostered to adoptive mothers for the following 4 post-natal days. They were successively compared to normally-reared individuals for: number of ultrasonic vocalizations during isolation, respiratory physiology responses to normal air (20%O2), CO2-enriched air (6% CO2), hypoxic air (10%O2), and avoidance of CO2-enriched environments. Results: Cross-fostered pups showed significantly more ultrasonic vocalizations, more pronounced hyperventilatory responses (larger tidal volume and minute volume increments) to CO2-enriched air and heightened aversion towards CO2- enriched environments, than normally-reared individuals. Enhanced tidal volume increment response to 6%CO2 was present at 16–20, and 75–90 postnatal days, implying the trait’s stability. Quantitative genetic analyses of unrelated individuals, sibs and half-sibs, showed that the genetic variance for tidal volume increment during 6%CO2 breathing was significantly higher (Bartlett x = 8.3, p = 0.004) among the cross-fostered than the normally-reared individuals, yielding heritability of 0.37 and 0.21 respectively. These results support a stress-diathesis model whereby the genetic influences underlying the response to 6%CO2 increase their contribution in the presence of an environmental adversity. Maternal grooming/licking behaviour, and corticosterone basal levels were similar among cross-fostered and normally-reared individuals. Conclusions: A mechanism of gene-by-environment interplay connects this form of early perturbation of infant-mother interaction, heightened CO2 sensitivity and anxiety. Some no

[Carcinoma of the pancreatic remnant developing after pancreaticoduodenectomy for adenocarcinoma of the head of pancreas].

In November 1996 a 44-year-old man with an adenocarcinoma of the pancreatic head (T2 N1 Mx- UICC 1998 Stage III) underwent a Traverso-Longmire pancreaticoduodenectomy. Early reoperation was required owing to postoperative acute pancreatitis and haemorrhage of the pancreatic remnant, after which he received chemo- and radiotherapy. Twenty-nine months later, an increase in the level of CA19.9 was observed with neither clinical nor radiological evidence of cancer recurrence. Forty months later, there was evidence of a new neoplasia of the pancreatic remnant. Since the recurrence involved only the pancreatic remnant with no evidence of metastases and the patient was in good condition and enough time had elapsed since surgical eradication of the primary cancer, we decided to perform an en bloc resection of the pancreatic body and tail and the spleen. Histologically, the tumour proved to be a pancreatic adenocarcinoma (T2). It is difficult to assess whether this cancer of the pancreatic remnant was a recurrence or a second primary cancer because of the long recurrence-free survival period, the absence of neoplastic invasion of the resection margins of the two surgical specimens and the absence of multicentricity both of the portion of the gland removed by the first operation and that removed by the second

End to side mucomucosal Wirsung jejunostomy after pancreaticoduodenectomy: Immediate results and long term follow-up

BACKGROUND/AIMS: Pancreatico-duodenectomy (PD) is nowadays a widely performed operation which still carries a risk of some morbidity and mortality due to leakage of the Pancreatico-jejunostomy. The aim of the present paper is to describe critically the experience of a surgical team with a large number of consecutive non-selective PDs, where the same surgical procedure was adopted in all cases to manage the pancreatic stump. METHODOLOGY: Sixty six Whipple/Child PDs and 4 Traverso-Longmire (Duodenum Preserving PD) were performed between 1974 and 1993, by the same surgical team in our surgical department. The management of the pancreatic stump was always the same: a hand-made end-to-side mucomucosa Wirsung-jejunostomy, completed by a second layer between pancreatic capsula and jejunal seromuscular wall. RESULTS: The overall mortality was 7.1% (5 cases). Only one death could be ascribed to pancreaticojejunostomy related complications (post-operative acute pancreatitis). Specific morbidity was 12.6% (9 cases). Only one complication was related to the Wirsung-jejunostomy (leakage of the anastomosis, treated by a "sleeve" end-to-end pancreato-jejunostomy). Long-term patency of the anastomosis was shown by ERCP. CONCLUSIONS: Even if this anastomotic technique requires a little more time and attention by the surgeon, we think that the low incidence of pancreatico-jejunal anastomosis related complications represents a validation of the method, and a motivation to adopt this anastomotic technique. The long-term patency of the muco-mucosal Wirsung-jejunostomy is another valid argument that supports this kind of management of the pancreatic stump after PD

Gastointestinal stromal tumors: a series of 23 surgically treared cases

AIM OF THE STUDY: The recently introduced new nosological category, Gastro Intestinal Stromal Tumors, brought the Authors to a revision of their series and to a critical analysis of surgical behaviour for the treatment of that pathology. MATERIAL AND METHOD: A series of 23 cases of GIST, observed between 1977 and 1999 has been taken into account. In the earlier cases, histopathological classification has been reviewed according to the most used criterions in international scientific literature. RESULTS: 17 of 23 observed tumors were located on the stomach, 4 on the duodenum and 2 on the jejunum. 20 of these cases derived from muscular tissue and 3 cases derived both from muscular and neural tissues. In 7 cases (30%) tumors were accidentally discovered during surgical intervention or diagnostic procedures for other causes. Surgical treatment was performed in all cases and consisted in 6 gastric resections, 14 gastric free-margin excisions, 2 duodenal resections and 1 jejunal resection. The follow-up (performed on 18 patients, with a minimum of 1 year, a maximum of 17 years and a median of 6 years) showed 2 deaths (11%) due to oncological causes, while 2 of the patients (11%) died for other causes. CONCLUSIONS: The only treatment for that group of tumors is, at the moment, surgery. Although that kind of neoplasms has mainly non-aggressive biological behaviour, a radical resection must be performed, due to the absence of macroscopic criterions to help distinguishing, during surgical intervention, aggressive tumors from non-aggressive ones

Trattamento chirurgico del cancro del retto con conservazione dello sfintere: risultati funzionali in rapporto alla sede dell'anastomosi.

Background. Unsatisfactory functional results are reported not only after coloanal anastomosis but also after anterior rectal resection with colorectal anastomosis. The aim of this study is to establish functional outcome predictive factors related to surgical technique and in particular the real influence of residual rectum length to identify which patients could take advantage of a colonic pouch reconstruction. Methods. In 214 of 327 patients who underwent surgery for rectal cancer sphincter preservation was achieved. These patients have been subdivided relating to the level of the anastomosis measured from the anal verge with a rigid proctoscope. In 93 patients functional results have been evaluated through clinical control and anorectal manometry. Results. In patients who underwent to anterior resection with anastomosis between 4 and 6 cm from the anal verge functional alterations appeared, such as leakage (13%), incontinence (5%), urgency (5%) and evacuation difficulty (10%). Nevertheless, comparing the anterior resections with anastomosis between 6 and 8 cm and those with anastomosis between 4 and 6 cm, the only parameter in which the difference resulted statistically significant was the rectal compliance. Conclusions. This result allows to consider that patients who undergo anterior resection with no more than 2-3 cm of residual rectum could take advantage by a colonic pouch reconstruction

Solid cystic tumor of the head of the pancreas in a young woman

This a case report of a solid papillary tumor of the pancreas in a young woman of 18 years, who was referred to after having suffered for a period of 8 months with a rather vague symptomatology, characterized by dyspepsia, fatigue and, towards the end of the 8 month period, weight loss (approximately 2 kg). In the last week, as a consequence of a modest abdominal trauma, the patient was submitted to abdominal CT that showed a burden at the head of the pancreas, demonstrating a round neoformation about 6 cm in diameter with solid echogenicity slightly hypodense. Subsequentlly, she underwent an operation with the diagnosis of pseudocystis of the pancreas. During surgery, a big cystic formation of the head of the pancreas, into which a drain was introduced, was revealed. The histological postoperative examination was compatible with pancreatic tumor with a low grade of malignancy, cystic papillary or solid papillary type. Therefore, the patient came under our observation and underwent an operation of pancreatoduodenectomy. Two years after the operation, the patient had completely recovered. In this case, we discussed the problem of performing certain preoperative diagnoses despite the aid of modern diagnostic imaging, this being a very rare illness that almost exclusively plagues young women (median age 19 years). This diagnosis has an uncertain histologicalal origin and is generally accompanied by a modest and vague symptomatology. The surgical procedure, given the low grade of malignancy of the neoplasm and the excellent long-term prognosis, must be, with respect to the oncological radicality, as conservative as possible