The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis.

Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases.

Diffuse large B-cell lymphoma of the colon with synchronous liver metastasis: a rare case report mimicking metastatic colorectal adenocarcinoma.

BACKGROUND: Primary colorectal lymphoma represents a rare minority among the colonic neoplasms. Early diagnosis is often difficult because of unspecific symptoms, with subsequent delays in diagnosis and management. We describe a rare case of colonic lymphoma presenting with synchronous liver metastasis. CASE PRESENTATION: A 70-year-old male with a 6-mo history of vague abdominal pain, constipation and melena was referred to our hospital. Computed tomography scan of abdomen revealed the presence of a mass along the proximal ascending colon. Colonoscopy biopsy showed external compression of the cecum with two ulcerations of mucosa, but it was not consistent for a definitive diagnosis. Because the difficulties in the preoperative pathological diagnosis, the high risk of bowel obstruction and the correlated hemorrhagic risk, the patient underwent a right hemicolectomy associated with locoregional lymphadenectomy and liver resection.The surgically resected right colon and liver tumors were all immunohistochemically diagnosed as diffuse large B-cell lymphomas (DLBCL). The patient refused any other antineoplastic treatment; he is alive and free of disease at 3 years after initial diagnosis. CONCLUSIONS: Primary colonic lymphomas represent a rare minority among the colonic neoplasms. Their correct pre-operative identification is crucial for the design of treatment. This case highlights the difficulty in diagnosing of primary colonic lymphoma. To our knowledge, this is the first report of a colonic lymphoma presenting with a colonic mass and a synchronous liver metastasis.

Intravenous pyogenic granuloma of the right adrenal gland: report of a case.

Pyogenic granuloma (PG) is a tumor-like lesion that typically arises on human skin. Intravenous pyogenic granuloma (IVPG) is the vascular counterpart, mostly observed in the venous structures of the neck and upper extremities. Chronic irritation of the skin, traumatic injury, and hormonal alterations seem to be implicated in the pathogenesis of PG. The incidence of PG, and IVPG, is very low in the reported scientific literature, and this underlines the need for understanding unresolved questions concerning the uncommon presentation, and correct diagnosis before surgical intervention. This report describes a case of IVPG diagnosed in a 55-year-old female that presented for observation of chronic abdominal pain associated with nausea and anorexia. A well-defined mass located in the right adrenal gland was documented by ultrasonography and finally confirmed by contrast enhanced CT of the abdomen. There were no radiological signs of liver, kidney, or vascular infiltration. The 35 × 22 mm adrenal gland lesion, suspected to be an adrenal gland tumor, was resected using a minimally invasive approach. Laparoscopic right adrenalectomy was successfully performed. The histology documented the typical morphological features of IVPG in the context of a normal right adrenal gland. This report describes and discusses the unusual presentation of intraabdominal IVPG located in the adrenal gland region together with a review of the current literature.

Risk factors for conversion of laparoscopic cholecystectomy.

BACKGROUND: Conversion during laparoscopic cholecystectomy has adverse effects on operating time, postoperative morbidity and hospital costs. Identifying risk factors for conversion is thus important to help surgeons to plan and counsel the patient and arranging operating schedules accordingly. This study evaluated retrospectively preoperative and intraoperative risk factors for conversion in 906 laparoscopic cholecystectomies for gallbladder calculosis. METHODS: Examined preoperative variables were: age, sex, obesity, arterial hypertension, diabetes, previous acute myocardial infarction, chronic obstructive pulmonary disease, non-ischemic heart disease, chronic hepatitis, hepatic cirrhosis, previous pancreatitis, biliary colics, endoscopic retrograde cholangiopancreatography (ERCP) and abdominal or cardiac surgery,as well as pain, fever, a high white blood cell count, ultrasound signs of cholecystitis at hospitalization. Intraoperative variables were: adhesiolysis, associated hepatic biopsy. RESULTS: Twenty-five operations were converted (conversion rate: 2.76%). Factors significantly associated with conversion were: age over 60 years, diabetes, previous supramesocolic abdominal surgery, ultrasound signs of cholecystitis, white cell count over 9x10(3)/dl, previous acute myocardial infarction and preoperative ERCP, intraoperative adhesiolysis (0.001

Portal vein gas due to gangrenous cholecystitis treated by a laparoscopic procedure: report of a case.

Portal pneumatosis is a rare diagnostic factor, which is often associated with ischemic intestinal accidents. It has been associated with a negative prognosis for a very long time, and the presence of portal pneumatosis is usually an indication for the need to perform a laparotomy. A 68-year-old male patient with diabetes, obstructive lung disease, and a previous cerebral stroke associated with left hemiplegia presented with abdominal pain, fever and neutrophil leukocytosis. Computed tomography (CT) scan showed the presence of portal pneumatosis with signs of acute cholecystitis and remarkable gastrectasia. In consideration of the serious clinical picture, the patient first underwent esophagogastroduodenal endoscopy (EGDS), which showed ulcerative hemorrhagic gastritis. He then underwent a laparoscopic cholecystectomy. The histology results confirmed the intraoperative diagnosis of gangrenous cholecystitis. The patient was discharged on the 7th postoperative day. With the use of new diagnostic techniques, especially CT, the incidence of portal pneumatosis has increased and consequently the clinical approach of surgeons to this pathology is also changing. Indeed, when portal pneumatosis is not associated with intestinal ischemia, the therapeutic approach must be guided by the clinical condition of the patient and by the investigation of the causes of this pathology. The laparoscopic approach can be extremely useful either in the diagnosis (if this has not been achieved by noninvasive means) or in treatment, if possible, of the causes implicated by the portal pneumatosis.

Cystic intestinal pneumatosis of the small gut: Etiopathogenesis and review of literature.

Cystic intestinal pneumatosis (CIP) is the presence of gas bubbles inside the wall of the intestine. In literature it has been reported to be associated with a variety of clinical conditions such as: superior mesenteric ischemia, intestinal perforation, bowel necrosis, infections which can cause mucosal alterations and therefore increasing its permeability, necrotizing enterocolitis in babies, trauma, intestinal obstruction, autoimmune and pulmonary pathologies. Its presence is usually documented by radiological techniques such as abdominal X-ray, CT scan and endoscopy and are usually characterized by the typical pattern of gas bubbles in the wall of the intestine. Majority of cases may be managed conservatively but intramural gas resulting from bowel necrosis represents a surgical emergency. We admitted an 86- year old man who presented with mild to moderate and persistent non-specific abdominal pain recurring for the last three weeks. No history of previous surgery was recorded. On examination, bowel sounds were dull and rare, general tenderness on the left of the abdomen but no particular resistance was noted, breath sounds were reduced and right hemi-thorax had reduced expansion as well. The patient was dehydrated and no central or peripheral neurological deficits were observed. Chest X-ray was performed and showed the presence of free air beneath the diaphragm. A complete abdominal CT scan was then done and documented the presence of pneumoperitoneum and multiple cystic like structures containing air in the right peri-splenic and para-renal regions. Laparotomy was then done for suspected perforation of the gut. The small gut was entangled with adhesions and presence of cystic structures with bubbles of air along the wall of the gut. The affected part of the small gut was then resected. The histology result confirms the presence of cystic pneumatosis of the small gut without any sign of intestinal wall perforation. KEY WORDS: Cystic pneumatosis, Pneumoperitoneum, Radiological investigations, Surgical approach.

Association between neuroendocrine tumor of the ileum and two colonic primary malignancies. A case report and review of literature.

BACKGROUND: A high rate of association between neuroendocrine tumors (NETs) and secondary primary malignancy (SPM) has been described in literature and this association can occur either in a synchronous or a metachronous presentation. A wide range of hypothesis has been postulated to explain the high rate of association between NETs and SPM, without definitive conclusions. CASE PRESENTATION: We report a case of an ileal neuroendocrine tumor found incidentally at the histologic examination of the surgical specimen in a 72 years old male underwent to right hemi colectomy for two colic adenomatous polips with high grade dysplasia. CONCLUSION: Large multicentric epidemiological studies should be considered to assess the association between NETs and SPM. KEY WORDS: Neuroendocrine tumors (NETs), Progression-Free Survival (PFS), Secondary primary malignancy (SPM).

Appendicitis by Enterobius vermicularis presenting with recurrent abdominal pain and eosinophilia A case report.

INTRODUCTION: Enterobius vermicularis (EV) is the most common parasitic infection in developed countries. Enterobius vermicularis infestation of the appendix can cause symptoms of appendiceal pain, independent of microscopic evidence of acute inflammation. The diagnosis of a parasitic infestation is generally achieved only after the pathologic examination of the resected appendices. CASE REPORT: We present a case of a 23 year old female with enterobiasis of appendix presented with clinical features of acute appendicitis. The appendix was surgically removed and the specimen was pathologically. CONCLUSION: We highlight that the symptoms of appendicitis can be due to Enterobius vermicularis infestation also without any histological evidence of acute inflammation. High index of suspicion and including parasitic origin in differential diagnosis of abdominal disturbances might hopefully KEY WORDS: Appencitis, Elminth, Enterobius vermicularis (EV).

Diaphragmatic hernia Report of two cases, classification, and review of literature.

Morgagni-Larrey hernia is uncommon congenital disease in the adults and presents with mild to severe clinical symptoms. In literature, about 80% of Morgagni -Larrey hernia are found on the right side of the chest cavity and have usually a peritoneal sack. Only 2-3% of patients at birth are symptomatic and therefore eligible for urgent surgery. Less severe forms of the disease are characterized by persistent epigastric and subcostal pains sometimes associated with vomiting and are frequently mistaken for dyspeptic disturbances. We present two case reports; the first one is a patient of 74 years who presented with persistent epigastric pain, vomiting, slight to moderate dyspnea on exertion associated with tachycardia, tachypnea and dyspeptic symptoms. Such symptoms have been going on for the last 6 months. The second patient is a 90 year old woman who was admitted in our ward for abdominal pain and distension associated with vomiting. In both cases a Morgagni-Larrey diaphragmatic hernia was discovered by using esophagogastroduodenoscopy, gastrographyn swallow and CT scan in the first case and only CT scan in the second one. KEY WORDS: Morgagni-Larrey hernia, Radiological investigations, Symptoms in adults, Surgical approach.

[Indications and efficacy of parathyroidectomy in the treatment of secondary hyperparathyroidism in patients with chronic renal failure: our experience]. / Indicazioni e validità della paratiroidectomia nel trattamento dell'iperparatiroidismo in corso di insufficienza renale cronica: nostra esperienza.

Although secondary hyperparathyroidism is improved by pharmacological therapy; 10-30% of patients with chronic renal failure undergo parathyroidectomy. The authors report on their experience with 66 cases of secondary hyperparathyroidism surgically treated over the period from January 1991 to December 2002. The surgical indications included: persistent hypercalcaemia, osteodystrophy with bone fractures, joint pain, itching and ectopic calcifications. The median preoperative parathyroid hormone level was 400 pg/ml. The operations performed were: subtotal parathyroidectomy (PTX 7/8) in 43 cases; total parathyroidectomy with autotransplantation (PTXt + At) in 13 cases; total parathyroidectomy (PTXt) alone in 6 cases and incomplete parathyroidectomy (PTXi) in 4 cases. The immediate results were satisfactory in each group. Calcium levels reverted to normal 24-48 hours postoperatively in 37 patients with PTX 7/8, in 11 patients with PTXt + At, in 5 patients with PTXt; 4 patients with PTXi showed a reduction, but no normalization, of calcium levels. Almost all patients, except those undergoing PTXi, showed an acceptable reduction in PTH levels in 25-35 days. Secondary hyperparathyroidism relapsed in 3 cases with PTXt + At and in 2 cases with PTX 7/8, while it proved persistent in 50% of patients with PTXi and in 7% of patients with PTX 7/8. Patients with PTXt mainly showed a substantial reduction of calcium levels. Parathyroidectomy is indispensable for the treatment of secondary hyper-parathyroidism. In our opinion, PTX 7/8 is the surgical treatment of choice because it is the easiest technique to perform and has the lowest relapse rate.

[Thyroid metastasis from renal carcinoma. Clinical case]. / Metastasi tiroidea da carcinoma renale. Caso clinico.

Metastatic thyroid tumours are uncommon among reported clinical cases, but are more frequent in autopsy series. The most common sites of the primary tumours are the breast (21%), kidney (12%) and lung (11%) and in some cases are detected only at autopsy. The clinical presence of thyroid tumefaction, whether associated or not with compressive symptoms, in a patient with a history of surgical treatment for renal cell carcinoma should lead to the suspicion of a metastatic nodule. The most important diagnostic technique is cytological examination after fine needle aspiration biopsy, combined with immunohistochemical staining. Total thyroidectomy, whether associated or not with radiation therapy, is the procedure of choice in these cases, when possible, above all in the presence of regional symptoms. In spite of treatment, however, the prognosis of metastatic disease is very poor. Therapeutic measures allow a mean survival of 34 months in the various reported series. The authors report the case of a 66-year-old female patient who had undergone left-side nephrectomy for a renal cell carcinoma 7 years earlier. The woman presented an increased thyroid volume mainly on the right side, with signs of tracheal compression. Ultrasonography of the thyroid gland and fine needle aspiration cytology showed malignant features. Scintigraphy strongly suggested the presence of a cold nodule in the right lobe. Subsequently, total thyroidectomy was performed and the histological examination revealed that the nodule was composed of tumour cells with abundant clear cytoplasm and round nuclei; with the characteristics of the renal cell carcinoma resected 7 years previously. Since computed tomography revealed secondaries in the lungs, the patient is still being managed with chemotherapy, with arrest of the metastatic progression, and is in a fairly good clinical condition.

The IL23R A/Gln381 allele promotes IL-23 unresponsiveness in human memory T-helper 17 cells and impairs Th17 responses in psoriasis patients.

We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers.

Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation.

Human skin immune homeostasis, and its regulation by specialized subsets of tissue-residing immune sentinels, is poorly understood. In this study, we identify an immunoregulatory tissue-resident dendritic cell (DC) in the dermis of human skin that is characterized by surface expression of CD141, CD14, and constitutive IL-10 secretion (CD141(+) DDCs). CD141(+) DDCs possess lymph node migratory capacity, induce T cell hyporesponsiveness, cross-present self-antigens to autoreactive T cells, and induce potent regulatory T cells that inhibit skin inflammation. Vitamin D(3) (VitD3) promotes certain phenotypic and functional properties of tissue-resident CD141(+) DDCs from human blood DCs. These CD141(+) DDC-like cells can be generated in vitro and, once transferred in vivo, have the capacity to inhibit xeno-graft versus host disease and tumor alloimmunity. These findings suggest that CD141(+) DDCs play an essential role in the maintenance of skin homeostasis and in the regulation of both systemic and tumor alloimmunity. Finally, VitD3-induced CD141(+) DDC-like cells have potential clinical use for their capacity to induce immune tolerance.

The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans.

IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.