IFITM3 Interacts with the HBV/HDV Receptor NTCP and Modulates Virus Entry and Infection

The Na⁺/taurocholate co-transporting polypeptide (NTCP, gene symbol SLC10A1) is both a physiological bile acid transporter and the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Virus entry via endocytosis of the virus/NTCP complex involves co-factors, but this process is not fully understood. As part of the innate immunity, interferon-induced transmembrane proteins (IFITM) 1–3 have been characterized as virus entry-restricting factors for many viruses. The present study identified IFITM3 as a novel protein–protein interaction (PPI) partner of NTCP based on membrane yeast-two hybrid and co-immunoprecipitation experiments. Surprisingly, IFITM3 knockdown significantly reduced in vitro HBV infection rates of NTCP-expressing HuH7 cells and primary human hepatocytes (PHHs). In addition, HuH7-NTCP cells showed significantly lower HDV infection rates, whereas infection with influenza A virus was increased. HBV-derived myr-preS1 peptide binding to HuH7-NTCP cells was intact even under IFITM3 knockdown, suggesting that IFITM3-mediated HBV/HDV infection enhancement occurs in a step subsequent to the viral attachment to NTCP. In conclusion, IFITM3 was identified as a novel NTCP co-factor that significantly affects in vitro infection with HBV and HDV in NTCP-expressing hepatoma cells and PHHs. While there is clear evidence for a direct PPI between IFITM3 and NTCP, the specific mechanism by which this PPI facilitates the infection process remains to be identified in future studies.     

Nonsentinel node metastases in breast cancer patients with isolated tumor cells in the sentinel node: implications for completion axillary node dissection

BACKGROUND: Controversy exists regarding axillary dissection (ALND) for sentinel node (SLN) metastases detected as isolated tumor cells (ITC). We hypothesized that the number of positive non-SLNs is low and ALND is unnecessary for most patients with ITC. METHODS: From 1995 to 1999, 634 breast cancer patients underwent SLND. SLNs were examined using immunohistochemistry if hematoxylin and eosin was negative. ALND was recommended for ITC-positive SLNs. RESULTS: Seventy-eight patients (12.3%) with ITC-positive SLNs were offered ALND. Sixty-one consented, whereas 17 refused. Fifty-eight (95.1%) had negative non-SLNs. Three (4.9%) had non-SLN metastases. One patient (1.6%) had macrometastatic disease, whereas 2 (3.3%) had micrometastases. No ITC-only-positive SLN patient experienced axillary recurrence. CONCLUSIONS: When ALND was performed for ITC, 1.6% of non-SLNs harbored macrometastases and 3.3% had micrometastases. When ALND was not performed, axillary recurrence was not seen. The low risk of non-SLN disease in this study fails to support the routine use of ALND for ITC-positive SLNs.     

Laparoscopic cholecystectomy in Child-Pugh class C cirrhotic patients.

OBJECTIVES: This study aimed to determine whether laparoscopic cholecystectomy is a safe and advisable procedure in Child-Pugh C cirrhotic patients with symptomatic cholelithiasis. METHODS: The records of 42 laparoscopic cholecystectomies performed between January 1995 and February 2004 in patients with Child-Pugh A, B, and C cirrhosis were retrospectively reviewed, focusing on the 4 patients with Child-Pugh C cirrhosis. RESULTS: Among the 38 Child-Pugh A and B patients, no deaths occurred. In this group, only 1 Child-Pugh B cirrhotic patient required blood transfusion, and postoperative morbidity occurred in 10 patients including hemorrhage, wound infection, intraabdominal collection, and cardiopulmonary complications (morbidity rate 26%). The mean postoperative stay was 5 days (range, 3 to 13). The indication for surgery in the 4 Child-Pugh C patients was acute cholecystitis. In this group, 2 deaths occurred for severe liver failure in 1 case and for sepsis in the other. One patient developed heavy gallbladder bed bleeding, and a second operation was necessary to control the hemorrhage. The morbidity rate was 75%. Only 1 patient had no complications. The mean postoperative stay was 10 days (range, 4 to 17). CONCLUSIONS: Laparoscopic cholecystectomy is a safe procedure in well-selected Child-Pugh A and B cirrhotic patients indicated for surgery, but it is a very high-risk procedure in Child-Pugh C patients. Indications for surgery in Child-Pugh C patients should be evaluated very carefully and surgery should be avoided unless the patient needs an emergency cholecystectomy for acute cholecystitis. Child-Pugh C cirrhotic patients might better benefit from percutaneous drainage of the gallbladder.     

Evoluzione della chirurgia sostitutiva di ginocchio

LO SCALPELLO-OTODI Educational - The advent of knee arthroplasty is one of the most significant advances in surgery. Engineering and biomechanical innovations have shown a fast and effective...     

Distribution of exogenous [125I]-3-iodothyronamine in mouse in vivo: relationship with trace amine-associated receptors

3-Iodothyronamine (T1AM) is a novel chemical messenger, structurally related to thyroid hormone, able to interact with G protein-coupled receptors known as trace amine-associated receptors (TAARs). Little is known about the physiological role of T1AM. In this prospective, we synthesized [125I]-T1AM and explored its distribution in mouse after injecting in the tail vein at a physiological concentration (0.3?nM). The expression of the nine TAAR subtypes was evaluated by quantitative real-time PCR. [125I]-T1AM was taken up by each organ. A significant increase in tissue vs blood concentration occurred in gallbladder, stomach, intestine, liver, and kidney. Tissue radioactivity decreased exponentially over time, consistent with biliary and urinary excretion, and after 24?h, 75% of the residual radioactivity was detected in liver, muscle, and adipose tissue. TAARs were expressed only at trace amounts in most of the tissues, the exceptions being TAAR1 in stomach and testis and TAAR8 in intestine, spleen, and testis. Thus, while T1AM has a systemic distribution, TAARs are only expressed in certain tissues suggesting that other high-affinity molecular targets besides TAARs exist.     

Family-directed cognitive adaptation pilot: Teaching cognitive adaptation to families of individuals with schizophrenia

ABSTRACT

Cognitive deficits are a major determinant of functional outcome in schizophrenia. A promising treatment involves teaching individuals to use cognitive adaptation strategies to minimize the functional impact of cognitive difficulties. We developed Family-Directed Cognitive Adaptation (FCA) to train caregivers to help their relatives with schizophrenia use cognitive adaptations to improve living skills. The goal of this open pilot trial was to examine the feasibility of FCA. Ten adults with schizophrenia, each with at least one relative, participated in FCA and were evaluated at baseline, posttreatment, and 6-month follow-up. Domains assessed included adaptive functioning, psychiatric symptoms, school/work involvement, hospitalizations, family burden, and treatment satisfaction. Participants reported high levels of satisfaction with FCA, and all families completed the 16-session intervention. Relatives reported reduced burden at termination and follow-up. No participants were hospitalized during the treatment or follow-up period, and rates of work/school involvement increased from 30% at baseline to 50% at the end of treatment and follow-up. Individuals improved in negative symptoms and adaptive functioning over the course of treatment, but these gains were not maintained. This pilot provides preliminary support for the acceptability and feasibility of FCA and points to the need to address the maintenance of treatment gains after termination.