Successful redo open thoracoabdominal aortic aneurysm surgery in a patient with vascular Ehlers-Danlos syndrome: A case report.

We report a case of a 63-year-old woman diagnosed with vascular Ehlers-Danlos syndrome (vEDS) who survived two prophylactic surgeries for the dilatation of a thoracoabdominal aortic aneurysm. She initially developed acute type B aortic dissection at the age of 44 years. Five years later, her dissected descending aorta was enlarged to 54 mm; thus, the descending aorta was replaced as the first surgery. Fortunately, the intra- and post-operative courses were uneventful. Fourteen years post her first surgery, the dissected thoracoabdominal aorta distal to the graft expanded to 53 mm; however, no anastomotic leakage was observed. Genetic testing revealed a COL3A1 abnormality, confirming the diagnosis of vEDS. Thoracoabdominal aorta replacement using deep hypothermia circulatory arrest was performed because of the high risk of aortic aneurysm rupture. The second surgery was performed without complications, and no complications were observed 13 months post-surgery. The major reason for a successful surgery in this patient was the relatively low vascular fragility associated with vEDS. This case demonstrates that there may be considerable individual differences in vascular fragility in patients with vEDS. Thus, surgical repair, along with endovascular therapy, might still be a beneficial option for patients with vEDS having large aortic aneurysms and a high risk of rupture. Learning objective: Prophylactic surgery for vascular lesions in Ehlers-Danlos syndrome (vEDS) is generally not recommended because of its high vascular fragility. However, if a patient with vEDS has an aortic aneurysm that is at a very high risk of rupture, aggressive treatment is a plausible option as there may be considerable individual differences in vascular fragility among patients with vEDS.

Prevalence of Human Adenovirus Type 3 Associated with Pharyngoconjunctival Fever in Children in Osaka, Japan during and after the COVID-19 Pandemic.

The incidence and type distribution of human adenovirus (HAdV) infections among children with pharyngoconjunctival fever (PCF) in Osaka, Japan between 2019 and 2023 were analyzed to assess the effect of the coronavirus disease 2019 (COVID-19) pandemic. The number of reported PCF cases in Osaka decreased from 2020 to 2022, followed by an unprecedented increase in 2023. HAdV-C strains, including types C1, C2, and C5, were detected in throughout the study period. Conversely, HAdV-B3 was not detected for 2 years and 9 months from March 2020 to December 2022, but the number of detections increased from July 2023. Overall, HAdV-B3 was the most frequently detected type (27 of 52 strains), and genetic analysis of its hexon hypervariable regions showed that, except for one strain, the HAdV-B3 strains identified after 2022 had different amino acid substitutions to those identified in 2019 and 2020. These results suggest that the PCF epidemic in 2023 was predominantly caused by variant strains of HAdV-B3, and that children were susceptible owing to a lack of exposure to HAdV-B3 between 2020 and 2022. Ongoing surveillance is needed to evaluate the impact of COVID-19 on the prevalence of HAdV infection.

Robot-assisted thoracic surgery versus video-assisted thoracic surgery for mediastinal lesions.

Background: Robot-assisted thoracic surgery (RATS) has become widely used for mediastinal procedures since 2018 when it was included in insurance coverage in Japan. Few studies have compared the surgical outcomes of RATS with the more established video-assisted thoracic surgery (VATS) approach to mediastinal surgery. We aimed to compare the perioperative outcomes of VATS and RATS to examine the advantages of the RATS approach in a single institutional cohort. Methods: A total of 144 patients who underwent VATS and 46 who underwent RATS mediastinal surgery between 2014 and 2022 were enrolled. We compared clinicopathological features such as age, sex, smoking history, respiratory function, surgical field, laterality, surgical procedure, board certification of the surgeon, and histology between the two groups. Perioperative outcomes including operation time, volume of blood lost, number of conversion cases to open surgery, duration of chest drainage, postoperative hospital stay, and postoperative complications were also reviewed. Results: The comparison of patient characteristics between the groups showed significant differences in median age (VATS, 52.5 years; RATS, 67.0 years; P=0.001), combined resection of surrounding tissues of the tumor (VATS, 2.1%; RATS, 10.9%; P=0.02), board certification of the surgeon (VATS, 53.5%; RATS, 100.0%; P<0.001), and histology (RATS group had a higher percentage of thymic epithelial tumors, P=0.01). Regarding perioperative outcomes, the median operation time was 120 min in the VATS group and 88 min in the RATS group, showing a significant difference (P=0.03). There were no significant differences in the volume of blood lost, incidence of conversion to open chest surgery, duration of chest drainage, postoperative length of stay in hospital, and incidence of perioperative complications. In the perioperative outcomes of cases operated on by board-certified surgeons, the median operation time (VATS, 117 min; RATS, 88 min; P=0.02) and median postoperative length of stay in hospital (VATS, 7 days; RATS, 6 days; P=0.001) showed significant differences, while other postoperative outcomes were not significantly different. Conclusions: RATS for mediastinal surgery is as safe as the VATS approach and may result in a shorter operative time and postoperative hospital stay. Further analysis of RATS for mediastinal surgery in a larger cohort is warranted.

[Robot-assisted Thoracic Surgery for Mediastinal Tumor].

In Japan, robot-assisted thoracic surgery (RATS) was introduced in thoracic surgery in 2001, but it did not become widespread. However, surgery for mediastinal tumors and lobectomy for lung cancer with RATS were covered by insurance in 2018 and are currently becoming popular as a general practice, following video-assisted thoracic surgery(VATS). Forty-six patients with mediastinal tumors were treated by RATS from February 2014 to November 2022 in our institution. Theoretically, the RATS approach is performed from one side in a semi-supine position under CO2 insufflation as with the VATS approach of our institution. In the case of extended thymectomy, a bilateral approach is performed by changing the patient's position. The median surgery time was 88 min, and the median surgery time in unilateral and bilateral approaches were 79 and 208 min, respectively. Blood loss during surgery was quite minimum, and no patients required conversion to VATS or thoracotomy. Regarding adverse events, postoperative bleeding was observed in one patient (2.2%). RATS has been successfully introduced and expanded safely for mediastinal tumors. Considering further expansion of RATS indications while conducting verification by comparison with VATS in the future is necessary.

Macrophage Depletion Reactivates Fecal Virus Shedding following Resolution of Acute Hepatitis A in Ifnar1-/- Mice.

Although hepatitis A virus (HAV) is associated only with acute hepatitis in humans, HAV RNA persists within the liver for months following resolution of liver inflammation and cessation of fecal virus shedding in chimpanzees and murine models of hepatitis A. Here, we confirm striking differences in the kinetics of HAV RNA clearance from liver versus serum and feces in infected Ifnar1-/- mice and investigate the nature of viral RNA persisting in the liver following normalization of serum alanine aminotransferase (ALT) levels. Fecal shedding of virus produced in hepatocytes declined >3,000-fold between its peak at day 14 and day 126, whereas intrahepatic HAV RNA declined only 32-fold by day 154. Viral RNA was identified within hepatocytes 3 to 4 months after inoculation and was associated with membranes, banding between 1.07 and 1.14 g/cm3 in isopycnic iodixanol gradients. Gradient fractions containing HAV RNA demonstrated no infectivity when inoculated into naive mice but contained neutralizing anti-HAV antibody. Depleting CD4+ or CD8+ T cells at this late point in infection had no effect on viral RNA abundance in the liver, whereas clodronate-liposome depletion of macrophages between days 110 and 120 postinoculation resulted in a striking recrudescence of fecal virus shedding and the reappearance of viral RNA in serum coupled with reductions in intra-hepatic Ifnγ, Tnfα, Ccl5, and other chemokine transcripts. Our data suggest that replication-competent HAV RNA persists for months within the liver in the presence of neutralizing antibody following resolution of acute hepatitis in Ifnar1-/- mice and that macrophages play a key role in viral control late in infection. IMPORTANCE HAV RNA persists in the liver of infected chimpanzees and interferon receptor-deficient Ifnar1-/- mice for many months after neutralizing antibodies appear, virus has been cleared from the blood, and fecal virus shedding has terminated. Here, we show this viral RNA is located within hepatocytes and that the depletion of macrophages months after the resolution of hepatic inflammation restores fecal virus shedding and circulating viral RNA. Our study identifies an important role for macrophages in virus control following resolution of acute hepatitis A in Ifnar1-/- mice and may have relevance to relapsing hepatitis A in humans.

Descending thoracic aortic repair outcomes for chronic aortic dissection: a single-centre experience.

OBJECTIVES: Thoracic endovascular aortic repair is a widely accepted treatment for chronic aortic dissection because of good early results compared to open surgical repair. We provide early and long-term results of descending thoracic aortic repair for chronic aortic dissection. METHODS: Patients who underwent descending thoracic aortic repair for chronic aortic dissection between January 2012 and December 2020 at Kawasaki Aortic Centre were included in this analysis. RESULTS: Four hundred ninety-two patients (median age, 64 years; interquartile range, 52-75 years) were included. The median duration of follow-up was 3.2 years (interquartile range, 1.5-5.2 years). The early mortality rate was 2.0% (n = 10); strokes occurred in 17 patients (3.5%); and spinal cord injuries occurred in 30 patients (6.1%). Early major adverse events including early death, stroke, spinal cord injury, tracheostomy and haemodialysis at the time of discharge occurred in 62 patients. Multivariable analysis indicated that age > 70 years and non-elective surgery were predictors of early major adverse events. Among patients without both risk factors (i.e. low-risk patients), 1 early death (0.4%), 3 strokes (1.5%) and 1 spinal cord injury (0.4%) were observed, 2 tracheostomies were performed (0.8%) and no patients required haemodialysis at the time of hospital discharge. The 5-year survival rate was 87.2%. The cumulative incidence of chronic aortic dissection-related aortic reintervention at 5 years was 7.9%. CONCLUSIONS: Descending thoracic aortic repair for chronic aortic dissection resulted in good early and long-term results, and it can serve as the gold standard for low-risk patients.

Evaluation of overall and disease-free survival in patients with free flaps for oral cancer resection.

PURPOSE: Sarcopenia is characterized by depletion of skeletal muscle mass (SMM) and can cause increased postoperative complication in free flap procedure. One of the most important considerations while deciding the indication of the procedure is patients' survival. This study aimed to verify the relationship between low SMM and survival in patients who undergo oral cancer resection using free flap. METHODS: SMM was evaluated using the skeletal muscle index (SMI cm2 /m2 ), which was defined using cross-sectional areas of skeletal muscles on computed tomography at the level of the third lumbar vertebrae normalized for height. Overall, 111 patients who underwent primary oral cancer resection and free flaps were included. Multivariate Cox regression analyses were used to evaluate the prognostic factors for survival. RESULTS: A total of 25 patients (22.5%) were diagnosed with low SMM. The mean SMI was 42.2 cm2 /m2 . Multivariable analyses showed that increased age (hazard ratio [HR]; 4.98, p = .004), infiltrative growth pattern INF-c (HR; 3.83, p = .037), and low SMM (HR; 2.59, p = .034) were significant negative prognostic factors for overall survival. Increased age (HR; 3.18, p = .005), extra-nodal extension (HR; 3.30, p = .001), and low SMM (HR; 2.42, p = .017) were significant negative prognostic factors for disease-free survival. CONCLUSIONS: Low SMM is a significant negative prognostic factor for overall and disease-free survival in oral cancer patients undergoing free flap. Future prospective studies are warranted to identify effective preoperative exercise and nutrition programs to improve low skeletal muscle and survival rate in patients undergoing free flap procedures.

[Surgical Resection of a Solitary Pulmonary Nodule in a Patient with Breast Cancer-A Case Report].

Solitary lung tumors after radical surgery for breast cancer often present difficulty in diagnosis and treatment. This report describes the case of a patient with a previous history of radicalsurgery for breast cancer who underwent lung surgery. Solitary pulmonary nodules should be diagnosed in patients with breast cancer, because treatments and prognoses differ between metastatic and primary tumors. At the age of 43 years, this patient underwent surgicaltreatment for breast cancer. Eighteen years later, a solitary mass was observed in the middle lobe of the right lung. Right middle lobectomy was performed using video-assisted thoracic surgery. The diagnosis was primary lung carcinoma. In case of primary lung carcinoma, radical treatment is possible through surgical resection. On the contrary, breast cancer metastasis has been known to have subtypes with characteristics that may often be different from those of the originall esions; therefore, surgicalresection helps in the reevaluation of receptor expression. Thus, early pathological diagnosis using surgical resection is useful for early diagnosis and treatment.

Open Thoracoabdominal Aortic Aneurysm Repair: Contemporary Outcomes for 393 Elective Cases.

BACKGROUND: The purpose of this study was to reveal the midterm and long-term mortality rates among patients with thoracoabdominal aortic aneurysm (TAAA) after open TAAA repair and to clarify the effect of aneurysm type on mortality. METHODS: We retrospectively analyzed data for 393 patients (290 men; age, 63.2 ± 12.7 years) who underwent open TAAA repair of elective Crawford extent I, II, or III TAAAs (62, 197, and 134 patients, respectively) between June 2003 and December 2015. The overall survival probability and differences according to aneurysm type were assessed using the Kaplan-Meier product limit method. Also, the effect of aneurysm type on mortality was assessed using the hazard ratio and Cox proportional hazards regression. RESULTS: The overall survival probabilities at 3 months, 1 year, 5 years, and 10 years were 90%, 84%, 78%, and 75%, respectively. The age-adjusted relative mortality rate was significantly higher for patients with dissecting aneurysms than for those with nondissecting aneurysms (relative risk, 1.62; 95% confidence interval, 1.03 to 2.55). In the multivariate Cox proportional hazard regression model, the hazard ratio for all-cause mortality did not differ between patients with dissecting and those with nondissecting aneurysms. However, those with dissecting aneurysms had increased mortality rates as their percentage vital capacity decreased (hazard ratio, 0.7; 95% confidence interval, 0.5 to 1.0); a similar trend was not observed for those with nondissecting aneurysms. CONCLUSIONS: Open TAAA repair can be safely performed with acceptable midterm and long-term results. Poor pulmonary function can impair the survival outcome of patients with dissecting aneurysms.

Surgical outcomes of aortic repair via transapical cannulation and the adventitial inversion technique for acute Type A aortic dissection.

OBJECTIVES: To evaluate the surgical outcomes of aortic repair via transapical cannulation and the adventitial inversion technique for acute Type A aortic dissection. METHODS: Between 2008 and 2015, a total of 300 patients with acute Type A aortic dissection underwent emergency surgery, consisting of 271 hemiarch repairs and 29 total aortic arch replacements, using transapical cannulation and the adventitial inversion technique at a distal anastomosis. The mean follow-up periods were 31.7 ± 25.2 months. Overall, 18% (54/300) of the patients were octogenarians, and 21.7% (65/300) had cardiac tamponade; 25% (75/300) had preoperative malperfusion. RESULTS: The in-hospital and 30-day mortality rates were 8.3% (25/300) and 6.7% (20/300), respectively. The 30-day mortality rate was 2.7% (6/225) among patients without preoperative malperfusion and 18.7% (14/75) among patients with malperfusion (P < 0.0001), 7.4% (4/54) among octogenarians and 6.5% (16/246) among patients aged less than 80 years (P = 0.81), and 6.3% (17/271) among patients treated with hemiarch repair and 10.3% (3/29) among patients treated with total aortic arch replacement (P = 0.403). Preoperative malperfusion was an independent predictor of perioperative mortality in a multivariable analysis. During the follow-up period, distal reintervention was performed in 11% (33/300) of the patients. The rates of freedom from reintervention at 1, 3 and 5 years were 95.9%, 88.9% and 80.0%, respectively. The overall survival rates at 1, 3 and 5 years were 88.7%, 86.7% and 82.0%, respectively. The in-hospital mortality rate for elective reintervention was 3.0% (1/33). CONCLUSIONS: Aortic repair via transapical cannulation and the adventitial inversion technique for acute Type A aortic dissection provides good early and mid-term results. The safety of elective distal reintervention can be guaranteed. To obtain better operative outcomes, effective treatment for cases with malperfusion is mandatory.

Distinct genetic clades of enterovirus D68 detected in 2010, 2013, and 2015 in Osaka City, Japan.

The first upsurge of enterovirus D68 (EV-D68), a causative agent of acute respiratory infections (ARIs), in Japan was reported in Osaka City in 2010. In this study, which began in 2010, we surveyed EV-D68 in children with ARIs and analyzed sequences of EV-D68 strains detected. Real-time PCR of 19 respiratory viruses or subtypes of viruses, including enterovirus, was performed on 2,215 specimens from ARI patients (<10 years of age) collected between November 2010 and December 2015 in Osaka City, Japan. EV-D68 was identified in 18 enterovirus-positive specimens (n = 4 in 2013, n = 1 in 2014, and n = 13 in 2015) by analysis of viral protein 1 (VP1) or VP4 sequences, followed by a BLAST search for similar sequences. All EV-D68 strains were detected between June and October (summer to autumn), except for one strain detected in 2014. A phylogenetic analysis of available VP1 sequences revealed that the Osaka strains detected in 2010, 2013, and 2015 belonged to distinct clusters (Clades C, A, and B [Subclade B3], respectively). Comparison of the 5' untranslated regions of these viruses showed that Osaka strains in Clades A, B (Subclade B3), and C commonly had deletions at nucleotide positions 681-703 corresponding to the prototype Fermon strain. Clades B and C had deletions from nucleotide positions 713-724. Since the EV-D68 epidemic in 2010, EV-D68 re-emerged in Osaka City, Japan, in 2013 and 2015. Results of this study indicate that distinct clades of EV-D68 contributed to re-emergences of this virus in 2010, 2013, and 2015 in this limited region.

TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions.

Receptor molecules play key roles in the cellular entry of picornaviruses, and TIM1 (HAVCR1) is widely accepted to be the receptor for hepatitis A virus (HAV), an unusual, hepatotropic human picornavirus. However, its identification as the hepatovirus receptor predated the discovery that hepatoviruses undergo nonlytic release from infected cells as membrane-cloaked, quasi-enveloped HAV (eHAV) virions that enter cells via a pathway distinct from naked, nonenveloped virions. We thus revisited the role of TIM1 in hepatovirus entry, examining both adherence and infection/replication in cells with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-engineered TIM1 knockout. Cell culture-derived, gradient-purified eHAV bound Huh-7.5 human hepatoma cells less efficiently than naked HAV at 4°C, but eliminating TIM1 expression caused no difference in adherence of either form of HAV, nor any impact on infection and replication in these cells. In contrast, TIM1-deficient Vero cells showed a modest reduction in quasi-enveloped eHAV (but not naked HAV) attachment and replication. Thus, TIM1 facilitates quasi-enveloped eHAV entry in Vero cells, most likely by binding phosphatidylserine (PtdSer) residues on the eHAV membrane. Both Tim1-/-Ifnar1-/- and Tim4-/-Ifnar1-/- double-knockout mice were susceptible to infection upon intravenous challenge with infected liver homogenate, with fecal HAV shedding and serum alanine aminotransferase (ALT) elevations similar to those in Ifnar1-/- mice. However, intrahepatic HAV RNA and ALT elevations were modestly reduced in Tim1-/-Ifnar1-/- mice compared to Ifnar1-/- mice challenged with a lower titer of gradient-purified HAV or eHAV. We conclude that TIM1 is not an essential hepatovirus entry factor, although its PtdSer-binding activity may contribute to the spread of quasi-enveloped virus and liver injury in mice.IMPORTANCE T cell immunoglobulin and mucin-containing domain protein 1 (TIM1) was reported more than 2 decades ago to be an essential cellular receptor for hepatitis A virus (HAV), a picornavirus in the Hepatovirus genus, resulting in its designation as "hepatitis A virus cellular receptor 1" (HAVCR1) by the Human Genome Organization Gene Nomenclature Committee. However, recent studies have shown that HAV exists in nature as both naked, nonenveloped (HAV) virions and membrane-cloaked, quasi-enveloped infectious virus (eHAV), prompting us to revisit the role of TIM1 in viral entry. We show here that TIM1 (HAVCR1) is not an essential cellular receptor for HAV entry into cultured cells or required for viral replication and pathogenesis in permissive strains of mice, although it may facilitate early stages of infection by binding phosphatidylserine on the eHAV surface. This work thus corrects the published record and sets the stage for future efforts to identify specific hepatovirus entry factors.

Biliary Secretion of Quasi-Enveloped Human Hepatitis A Virus.

Hepatitis A virus (HAV) is an unusual picornavirus that is released from cells cloaked in host-derived membranes. These quasi-enveloped virions (eHAV) are the only particle type circulating in blood during infection, whereas only nonenveloped virions are shed in feces. The reason for this is uncertain. Hepatocytes, the only cell type known to support HAV replication in vivo, are highly polarized epithelial cells with basolateral membranes facing onto hepatic (blood) sinusoids and apical membranes abutting biliary canaliculi from which bile is secreted to the gut. To assess whether eHAV and nonenveloped virus egress from cells via vectorially distinct pathways, we studied infected polarized cultures of Caco-2 and HepG2-N6 cells. Most (>99%) progeny virions were released apically from Caco-2 cells, whereas basolateral (64%) versus apical (36%) release was more balanced with HepG2-N6 cells. Both apically and basolaterally released virions were predominantly enveloped, with no suggestion of differential vectorial release of eHAV versus naked virions. Basolateral to apical transcytosis of either particle type was minimal (<0.02%/h) in HepG2-N6 cells, arguing against this as a mechanism for differences in membrane envelopment of serum versus fecal virus. High concentrations of human bile acids converted eHAV to nonenveloped virions, whereas virus present in bile from HAV-infected Ifnar1-/- Ifngr1-/- and Mavs-/- mice banded over a range of densities extending from that of eHAV to that of nonenveloped virions. We conclude that nonenveloped virions shed in feces are derived from eHAV released across the canalicular membrane and stripped of membranes by the detergent action of bile acids within the proximal biliary canaliculus. IMPORTANCE: HAV is a hepatotropic, fecally/orally transmitted picornavirus that can cause severe hepatitis in humans. Recent work reveals that it has an unusual life cycle. Virus is found in cell culture supernatant fluids in two mature, infectious forms: one wrapped in membranes (quasi-enveloped) and another that is nonenveloped. Membrane-wrapped virions circulate in blood during acute infection and are resistant to neutralizing antibodies, likely facilitating HAV dissemination within the liver. On the other hand, virus shed in feces is nonenveloped and highly stable, facilitating epidemic spread and transmission to naive hosts. Factors controlling the biogenesis of these two distinct forms of the virus in infected humans are not understood. Here we characterize vectorial release of quasi-enveloped virions from polarized epithelial cell cultures and provide evidence that bile acids strip membranes from eHAV following its secretion into the biliary tract. These results enhance our understanding of the life cycle of this unusual picornavirus.

Feasibility of magnetic resonance elastography for the pancreas at 3T.

PURPOSE: 1) To assess the usefulness of an elastic belt bracing the upper abdomen for reducing the miscalculated areas of the pancreas on 3.0T magnetic resonance elastography (MRE); 2) to test whether MRE can detect difference of stiffness between normal pancreas and the focal pancreatic diseases. MATERIALS AND METHODS: Using an initial eight normal volunteers, miscalculated areas were compared between MRE with the elastic belt and without the belt on 3.0T MRI. Then, using the belt, MRE of the normal pancreas was measured using 14 volunteers and 11 patients with focal pancreatic lesions. RESULTS: The median (95% confidence interval [CI]) percentages of correctly calculated areas were 57.4% (32.9-63.0) with the elastic belt and 35.3% (11.4-60.4) without the belt (P = 0.0078). The stiffness of each pancreatic segment of the normal volunteers (mean ± SE) was 2.37 ± 0.16 kPa for the head, 2.46 ± 0.17 kPa for the body, and 2.58 ± 0.26 kPa for the tail. The stiffness of seven pancreatic cancers was 6.06 ± 0.49 kPa, which was higher than the overall pancreatic stiffness of the normal volunteers (2.47 ± 0.11 kPa, P < 0.0001). Stiffness of the pancreatic lesions in the head of 6.03 ± 0.42 kPa, body of 5.57 ± 0.82 kPa, and tail of 5.9 ± 1.9 kPa were also higher than those of corresponding segments of the normal volunteers (P = 0.0011, 0.0029, and 0.029, respectively). CONCLUSION: With the elastic belt, miscalculation of the pancreatic stiffness was reduced. MRE showed differences of stiffness between normal pancreas and pancreatic lesions.

Minimally Invasive Transaortic Mitral Decalcification During Aortic Valve Replacement.

Mitral annular calcification accompanied by aortic stenosis is hazardous for both double-valve replacement and transcatheter aortic valve implantation. Less invasive mitral procedure is required in this condition, and minimally invasive approach may further reduce the operative risk in high-risk patients. Here, we report minimally invasive transaortic mitral decalcification during aortic valve replacement through minithoracotomy. We believe that this option is feasible in patients who are at prohibitive risk for double-valve replacement or transcatheter aortic valve implantation because of severe mitral annular calcification.

Epidermal growth factor receptor inhibition with erlotinib partially prevents cisplatin-induced nephrotoxicity in rats.

The effects of blocking the epidermal growth factor receptor (EGFR) in acute kidney injury (AKI) are controversial. Here we investigated the renoprotective effect of erlotinib, a selective tyrosine kinase inhibitor that can block EGFR activity, on cisplatin (CP)-induced AKI. Groups of animals were given either erlotinib or vehicle from one day before up to Day 3 following induction of CP-nephrotoxicity (CP-N). In addition, we analyzed the effects of erlotinib on signaling pathways involved in CP-N by using human renal proximal tubular cells (HK-2). Compared to controls, rats treated with erlotinib exhibited significant improvement of renal function and attenuation of tubulointerstitial injury, and reduced the number of apoptotic and proliferating cells. Erlotinib-treated rats had a significant reduction of renal cortical mRNA for profibrogenic genes. The Bax/Bcl-2 mRNA and protein ratios were significantly reduced by erlotinib treatment. In vitro, we observed that erlotinib significantly reduced the phosphorylation of MEK1 and Akt, processes that were induced by CP in HK-2. Taken together, these data indicate that erlotinib has renoprotective properties that are likely mediated through decreases in the apoptosis and proliferation of tubular cells, effects that reflect inhibition of downstream signaling pathways of EGFR. These results suggest that erlotinib may be useful for preventing AKI in patients receiving CP chemotherapy.

Therapeutic effects of human mesenchymal stem cells in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis.

INTRODUCTION: Multipotent mesenchymal stem cells (MSCs) have become a promising therapeutic approach in many clinical conditions. The hypothesis that MSCs can provide a potential therapy for human anti-glomerular basement membrane (GBM) glomerulonephritis (GN) was tested. METHODS: Nephrotoxic serum nephritis was induced in Wistar-Kyoto rats on day 0. Groups of animals were given either human MSCs (hMSCs, 3×10(6)) or vehicle by intravenous injection on day 4; all rats were sacrificed at either day 7 or day 13. RESULTS: Fluorescently labeled hMSCs were localized in glomeruli and tubulointerstitium 5 h after hMSC administration and persisted until 48 h, but hMSCs were barely detectable after 7 days. hMSC-treated rats had decreased kidney weight, proteinuria, and glomerular tuft area at each time point. The serum creatinine level and degree of glomerular crescent formation were decreased by hMSC treatment on day 13. ED1-positive macrophages, CD8-positive cells, and TUNEL-positive apoptotic cells in glomeruli were reduced by hMSC treatment on day 7, and this trend in apoptotic cells persisted to day 13. Renal cortical mRNA for TNF-α, IL-1ß, and IL-17, and the serum IL-17A level were decreased, whereas renal cortical mRNA for IL-4 and Foxp3 and the serum IL-10 level were increased in the MSC-treated group on day 7. Collagen types I and III and TGF-ß mRNA were decreased by hMSC treatment on day 13. CONCLUSION: The present results demonstrated that anti-inflammatory and immunomodulatory effects were involved in the mechanism of attenuating established experimental anti-GBM GN by hMSCs. These results suggest that hMSCs are a promising therapeutic candidate for the treatment of anti-GBM GN.

Mouse Hepatitis Virus Receptor as a Determinant of the Mouse Susceptibility to MHV Infection.

In this review, we report that the receptor of mouse hepatitis virus (MHV), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), is an important determinant of mouse susceptibility to MHV infection. This finding was revealed by using mouse strains with two different allelic forms of the MHV receptor, Ceacam1a and Ceacam1b. Although previous studies indicated that susceptibility is determined by a single gene, Ceacam1, our recent work in gene-replaced mice with chimeric Ceacam1 pointed toward the involvement of other host factors (genes) in the susceptibility. Studies on mouse susceptibility to MHV, as well as the factors involved in their susceptibility, are overviewed.

IL-17A stimulates granulocyte colony-stimulating factor production via ERK1/2 but not p38 or JNK in human renal proximal tubular epithelial cells.

We investigated the potential role of IL-17A in the induction of granulocyte colony-stimulating factor (G-CSF), a critical granulopoietic growth factor, in human renal proximal tubular epithelial cells. Human renal proximal tubular cells (HK-2, ATCC) were used to characterize the effects of IL-17A or IL-17F on G-CSF production, using ELISA, real-time RT-PCR, and immunoblotting. The cell surface expression of IL-17 receptors (IL-17Rs) was analyzed by flow cytometry. IL-17A stimulation of proximal tubular cells led to a dose- and time-dependent increase in secreted G-CSF. This effect was dependent on mRNA transcription and protein translation. Real-time RT-PCR demonstrated that G-CSF mRNA expression reached a maximum level at 6 h following IL-17A stimulation and that this increase was dose dependent. Both IL-17RA and IL-17RC were expressed on proximal tubular cells. IL-17A also enhanced TNF-α- or IL-1ß-mediated G-CSF secretion from cells. Additionally, IL-17A induced MAPK (ERK1/2 but not p38 MAPK or JNK) activation, and pharmacological inhibitors of MEK1/2 (U0126) but not of p38 MAPK (SB203580) or JNK (SP600125), significantly blocked the IL-17A-mediated G-CSF release. We demonstrated the potential ability of IL-17A to induce G-CSF in renal proximal tubular cells. It is proposed that IL-17A may play an important role in neutrophil transmigration and activation via stimulation of G-CSF in tubular injury.

A case of tuberculous peritonitis in a hemodialysis patient with high serum soluble interleukin-2 receptor and CA-125 levels.

A hemodialysis patient with tuberculous peritonitis with hypercalcemia and high serum soluble interleukin-2 receptor (sIL-2R) and CA-125 levels is reported. An 82-year-old woman who had been on hemodialysis therapy for 6 years was admitted to our hospital for evaluation and treatment of hypercalcemia. Laboratory examination and radiologic studies revealed markedly increased serum sIL-2R and CA-125 levels and exudative ascites, with high levels of adenosine deaminase (ADA) and CA-125, which was suggestive of malignancy or tuberculosis. She was finally diagnosed as having tuberculous peritonitis based on positivity for Mycobacterium tuberculosis in ascitic fluid. The ascites subsided with normalization of hypercalcemia and a marked decrease in serum sIL-2R and CA-125 levels in response to anti-tuberculosis treatment. This case indicates that serum sIL-2R and CA-125 levels can rise to levels suggestive of malignancy in tuberculous peritonitis, and that they can be used to monitor the response to anti-tuberculosis treatment.