Ventriculo-gallbladder shunt: case series and literature review.

BACKGROUND: The ventriculoperitoneal shunt (VPS) is the gold-standard surgical technique to treat hypertensive hydrocephalus; however, it may fail in 20 to 70% of cases. The present study shows an alternative for patients with contraindications to VPS. METHODS: A case series of nine patients. The medical records of all patients under 17 years of age who underwent ventriculo-gallbladder (VGB) shunt at a pediatric hospital from January 2014 to October 2022 were reviewed. RESULTS: There were 6 (66.7%) males and 3 (33.3%) females. The average age of 73.6 months or 6.1 years at the time of surgery. They had undergone, on average, 5.1 VPS reviews before the VGB shunt. Five (55.5%) had complications of VGB shunt: infection (11.1%), atony (11.1%), hypodrainage (11.1%), and ventriculoenteric fistula (22.2%); all these patients got better at surgical reapproach, and in two of them, the VGB shunt was re-implanted. CONCLUSION: This case series shows a lower risk of death and a similar risk of complications compared to other alternative shunts. This article spotlighted VGB as a viable alternative when VPS fails or has contraindications.

WISP1/CCN4 aggravates cartilage degeneration in experimental osteoarthritis.

OBJECTIVE: Increased Wisp1 expression was previously reported in experimental and human osteoarthritis (OA). Moreover, adenoviral overexpression of Wisp1 in naïve mouse knee joints resulted in early OA-like cartilage lesions. Here, we determined how the matricellular protein WISP1 is involved in the pathology that occurs in the complex osteoarthritic environment with aging and experimental OA in wild type (WT) and Wisp1-/- mice. METHODS: WT and Wisp1-/- mice were aged or experimental OA was induced with intraarticular collagenase injection, destabilization of the medial meniscus (DMM) or anterior cruciate ligament transection (ACLT). Joint pathology was assessed using histology and microCT. Protease expression was evaluated with qRT-PCR and activity was determined by immunohistochemical staining of the aggrecan neoepitope NITEGE. Protease expression in human end-stage OA synovial tissue was determined with qRT-PCR after stimulation with WISP1. RESULTS: With aging, spontaneous cartilage degeneration in Wisp1-/- was not decreased compared to their WT controls. However, we observed significantly decreased cartilage degeneration in Wisp1-/- mice after induction of three independent experimental OA models. While the degree of osteophyte formation was comparable between WT and Wisp1-/- mice, increased cortical thickness and reduced trabecular spacing was observed in Wisp1-/- mice. In addition, we observed decreased MMP3/9 and ADAMTS4/5 expression in Wisp1-/- mice, which was accompanied by decreased levels of NITEGE. In line with this, stimulation of human OA synovium with WISP1 increased the expression of various proteases. CONCLUSIONS: WISP1 plays an aggravating role in the development of post-traumatic experimental OA.

Combination treatment with statins and bezafibrate induces myotoxicity via inhibition of geranylgeranyl pyrophosphate biosynthesis and Rho activation in L6 myoblasts and myotube cells.

Statins and fibrates are frequently used to treat hyperlipidemia; however, these drugs may have adverse effects such as rhabdomyolysis. The incidence of rhabdomyolysis due to fibrates and statins is low (0.0028-0.0096%) when administered as monotherapy, however it increases to 0.015-0.021% when the drugs are used in combination. The mechanism underlying myotoxicity induced by the combination of statins and fibrates is yet unclear. Here, we investigated the mechanisms underlying induced myotoxicity in rat myoblasts L6 and differentiated L6 cells (myotubes) using a combination of statins and fibrates. We found that cell death induced by a combination of fluvastatin or simvastatin with bezafibrate or fenofibrate in L6 myoblasts and myotubes was mediated by inhibition of geranylgeranyl pyrophosphate (GGPP) production. Additionally, the drug combination inhibited Rho activation in L6 myoblasts and myotube cells. In L6 myoblasts, the combination of statins and bezafibrate enhanced p27 expression and induced G1 arrest and apoptosis. Furthermore, combined treatment suppressed Akt activation and enhanced Bim expression in L6 myotubes but did not affect extracellular regulated protein kinase 1/2 activation. These results suggested that combined administration of statins and fibrates induced death of L6 myoblasts and myotube cells by inhibiting GGPP biosynthesis and Rho pathway activation. Supplementation with GGPP may be therapeutically beneficial for preventing myotoxicity associated with combined statin and fibrates treatment.

Epstein-Barr virus load for early detection of lymphoproliferative disorder in pediatric renal transplant recipients.

AIM: The aims of this study were to establish a protocol for monitoring Epstein-Barr virus (EBV) infection for identification of pediatric renal transplant recipients with a high risk of developing posttransplant lymphoproliferative disorder (PTLD) and to predict the development of PTLD. SUBJECTS AND METHODS: Peripheral blood mononuclear cells (PBMCs) and plasma EBV loads were measured by nested PCR (n-PCR) and real-time PCR (r-PCR) every 1 - 3 months after grafting in 17 pediatric recipients who were seronegative for EBV before grafting (4 with EBV-associated symptoms, including 2 with PTLD (Group A); 6 with asymptomatic persistent high EBV loads in PBMCs of > 1,000 copies/µgDNA for over 6 months (Group B); and 7 with neither EBV-associated symptoms nor persistent high EBV loads in PBMCs (Group C)). RESULTS: n-PCR revealed EBV-DNA in PBMCs from all patients. The EBV genome was present in plasma in 3 (75%), 1 (17%), and 0 (0%) in Groups A, B and C (p < 0.01 for A vs. B and A vs. C). EBV loads detected by r-PCR in PBMCs were significantly higher in Groups A (p < 0.05) and B (p < 0.01) compared to Group C. EBV genomes in plasma were detected by n- and r-PCR in only the 2 cases with PTLD. One patient with lymphadenitis in Group A and 1 patient in Group B had EBV-DNA in plasma based on n-PCR, but the viral loads using r-PCR were < 250 copies/ml. CONCLUSION: EBV loads in PBMCs alone are insufficient for predicting EBV-associated symptoms including PTLD. Plasma EBV loads (over 250 copies/ml) estimated by r-PCR may be useful to distinguish PTLD from other EBV-associated diseases or asymptomatic viremia.

Three-dimensional conformal radiation therapy for canine aortic body tumour: 6 cases (2014-2019).

OBJECTIVE: To determine the feasibility of three-dimensional conformal radiation therapy for canine aortic body tumours. MATERIALS AND METHODS: Medical records of dogs that had undergone three-dimensional conformal radiation therapy with presumptive diagnosis of aortic body tumour were reviewed for clinical characteristics, treatment modality and outcomes. RESULTS: Eight dogs were diagnosed with aortic body tumour and were treated with three-dimensional conformal radiation therapy. One dog had proliferation of a mass in the right atrium during treatment and died of respiratory distress. Another dog did not undergo follow-up CT to evaluate the treatment response due to the increased blood urea nitrogen values. The remaining 6 dogs were included in the case series. Radiotherapy was performed using a median dose per fraction of 7 Gy (3.3-7.14 Gy), a median of seven divided doses (7-15) and a total median dose of 49 Gy (45-50 Gy). The median number of CT scans during the follow-up period was 5 (range: 3-8 times). CT revealed acute side effects in four dogs-grade 1 effects related to the lung (n = 4) and skin (n = 2). Self-limiting or asymptomatic late side effects (grade 1 lung-related effect) were observed in three dogs. After therapy, one dog demonstrated a complete response, another demonstrated a partial response and the disease remained stable in four animals. The median follow-up period was 514.5 (235-1219) days. After three-dimensional conformal radiation therapy, the aortic body tumour reduced gradually over time without regrowth in all these 6 dogs. CLINICAL SIGNIFICANCE: In this small case series, aortic body tumours responded to three-dimensional conformal radiation therapy. Transient and self-limiting side effects of the treatments were common. Further controlled studies are required to prove the effectiveness and the safety of this intervention.

Tumor PD-L1 and VEGF Expression, and CD8 T Cell Infiltration Predict Clinical Response to Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer.

BACKGROUND/AIM: We evaluated the efficacy of "the tumor immune microenvironment (TIME) classification" for predicting clinical response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). In addition, we aimed to evaluate the "modified TIME classification", which adds the vascular endothelial growth factor (VEGF) status to TIME. MATERIALS AND METHODS: Programmed cell death receptor ligand-1 (PD-L1), CD8 T cell tumor-infiltrating lymphocytes (CD8+TILs) count and VEGF expression analyses were performed using immuno - histochemistry in 44 patients who had undergone ICI monotherapy. RESULTS: Regarding TIME classification, type-I (PD-L1 high and CD8+TILs high) had a significantly higher response than the other types. Using the modified TIME classification, type-IA (PD-L1 high, CD8+TILs high, and VEGF low) had a significantly higher response than the other types. CONCLUSION: The modified TIME classification, which adds tumor VEGF expression to "the TIME classification", could be useful in predicting clinical response to ICI monotherapy.

S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial.

BACKGROUND: The ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy. PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients' data were updated in February 2020. RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31). CONCLUSION: Our final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups.

Paired immunoglobulin-like receptor (PIR)-A is involved in activating mast cells through its association with Fc receptor gamma chain.

Paired immunoglobulin-like receptor (PIR)-A and PIR-B possess similar ectodomains with six immunoglobulin-like loops, but have distinct transmembrane and cytoplasmic domains. PIR-B bears immunoreceptor tyrosine-based inhibitory motif (ITIM) sequences in its cytoplasmic domain that recruit Src homology (SH)2 domain-containing tyrosine phosphatases SHP-1 and SHP-2, leading to inhibition of B and mast cell activation. In contrast, the PIR-A protein has a charged Arg residue in its transmembrane region and a short cytoplasmic domain that lacks ITIM sequences. Here we show that Fc receptor gamma chain, containing an immunoreceptor tyrosine-based activation motif (ITAM), associates with PIR-A. Cross-linking of this PIR-A complex results in mast cell activation such as calcium mobilization in an ITAM-dependent manner. Thus, our data provide evidence for the existence of two opposite signaling pathways upon PIR aggregation. PIR-A induces the stimulatory signal by using ITAM in the associated gamma chain, whereas PIR-B mediates the inhibitory signal through its ITIMs.

Requirement of SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 for paired immunoglobulin-like receptor B (PIR-B)-mediated inhibitory signal.

Paired immunoglobulin-like receptor B (PIR-B) (p91) molecule has been proposed to function as an inhibitory receptor in B cells and myeloid lineage cells. We demonstrate here that the cytoplasmic region of PIR-B is capable of inhibiting B cell activation. Mutational analysis of five cytoplasmic tyrosines indicate that tyrosine 771 in the motif VxYxxL plays the most crucial role in mediating the inhibitory signal. PIR-B-mediated inhibition was markedly reduced in the SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 double-deficient DT40 B cells, whereas this inhibition was unaffected in the inositol polyphosphate 5'-phosphatase SHIP-deficient cells. These data demonstrate that PIR-B can negatively regulate B cell receptor activation and that this PIR-B-mediated inhibition requires redundant functions of SHP-1 and SHP-2.

Cbl suppresses B cell receptor-mediated phospholipase C (PLC)-gamma2 activation by regulating B cell linker protein-PLC-gamma2 binding.

Accumulating evidence indicates that the Cbl protein plays a negative role in immune receptor signaling; however, the mode of Cbl action in B cell receptor (BCR) signaling still remains unclear. DT40 B cells deficient in Cbl showed enhanced BCR-mediated phospholipase C (PLC)-gamma2 activation, thereby leading to increased apoptosis. A possible explanation for the involvement of Cbl in PLC-gamma2 activation was provided by findings that Cbl interacts via its Src homology 2 (SH2) domain with B cell linker protein (BLNK) after BCR ligation. BLNK is a critical adaptor molecule for PLC-gamma2 tyrosine phosphorylation through its binding to the PLC-gamma2 SH2 domains. As a consequence of the interaction between Cbl and BLNK, the BCR-induced recruitment of PLC-gamma2 to BLNK and the subsequent PLC-gamma2 tyrosine phosphorylation were inhibited. Thus, our data suggest that Cbl negatively regulates the PLC-gamma2 pathway by inhibiting the association of PLC-gamma2 with BLNK.

Four cases of postrenal renal failure induced by renal stone associated with rotavirus infection.

Rotavirus (RV) is a common pathogen that causes acute gastroenteritis in childhood. Some cases with RV infection also have prerenal renal failure induced by dehydration associated with vomiting and diarrhea. Here, we report 4 patients with RV infection who developed postrenal renal failure induced by urinary tract obstruction with uroammoniac calculi or crystals. The patients did not have metabolic disorders or abnormalities of the urinary tract, and increased urinary excretion of uric acid was not recognized at discharge. In addition, no abnormalities in the uric acid transporter (URAT1) were found in any of the patients. Uric acid stone formation was considered to have originated from the low pH caused by dehydration and the increase of urinary uric acid excretion from damaged cells.

Epithelioid sarcoma on the foot masquerading as an intractable wound for > 18 years.

Slow-growing sarcomas may give rise to intractable wounds, which may be attributed to commoner causes. A 57-year-old man with diabetes mellitus presented with a 24-year history of a chronic wound that originated on his left great toe. Because of the long history, the nonspecific histological findings and the complication of ulcerative colitis, we misdiagnosed his ulcer as pyoderma gangrenosum. The wound was eventually diagnosed correctly by histological examination of a skin biopsy and the use of immunohistochemistry to detect cytokeratin, epithelial membrane antigen and vimentin. Specimens obtained 16 years earlier showed the same staining pattern. Radiological examinations revealed no metastasis. The patient received a below-knee amputation without further chemotherapy or radiotherapy. When patients have intractable ulcers, appropriate biopsies and immunohistochemical examinations are sometimes necessary to exclude a malignancy even if the history and symptoms do not suggest a diagnosis of sarcoma.

Growth site localization of Rho1 small GTP-binding protein and its involvement in bud formation in Saccharomyces cerevisiae.

The Rho small GTP-binding protein family regulates various actomyosin-dependent cell functions, such as cell morphology, locomotion, cytokinesis, membrane ruffling, and smooth muscle contraction. In the yeast Saccharomyces cerevisiae, there is a homologue of mammalian RhoA, RHO1, which is essential for vegetative growth of yeast cells. To explore the function of the RHO1 gene, we isolated a recessive temperature-sensitive mutation of RHO1, rho1-104. The rho1-104 mutation caused amino acid substitutions of Asp 72 to Asn and Cys 164 to Tyr of Rho1p. Strains bearing the rho1-104 mutation accumulated tiny- or small-budded cells in which cortical actin patches were clustered to buds at the restrictive temperature. Cell lysis and cell death were also seen with the rho1-104 mutant. Indirect immunofluorescence microscopic study demonstrated that Rho1p was concentrated to the periphery of the cells where cortical actin patches were clustered, including the site of bud emergence, the tip of the growing buds, and the mother-bud neck region of cells prior to cytokinesis. Indirect immunofluorescence study with cells overexpressing RHO1 suggested that the Rho1p-binding site was saturable. A mutant Rho1p with an amino acid substitution at the lipid modification site remained in the cytoplasm. These results suggest that Rho1 small GTP-binding protein binds to a specific site at the growth region of cells, where Rho1p exerts its function in controlling cell growth.

Conversion of bacteriorhodopsin into a chloride ion pump.

In the light-driven proton pump bacteriorhodopsin, proton transfer from the retinal Schiff base to aspartate-85 is the crucial reaction of the transport cycle. In halorhodopsin, a light-driven chloride ion pump, the equivalent of residue 85 is threonine. When aspartate-85 was replaced with threonine, the mutated bacteriorhodopsin became a chloride ion pump when expressed in Halobacterium salinarium and, like halorhodopsin, actively transported chloride ions in the direction opposite from the proton pump. Chloride was bound to it, as revealed by large shifts of the absorption maximum of the chromophore, and its photointermediates included a red-shifted state in the millisecond time domain, with its amplitude and decay rate dependent on chloride concentration. Bacteriorhodopsin and halorhodopsin thus share a common transport mechanism, and the interaction of residue 85 with the retinal Schiff base determines the ionic specificity.

Nephrogenic systemic fibrosis in a patient on long-term hemodialysis.

Patients with renal failure sometimes develop nephrogenic systemic fibrosis (NSF) following administration of gadolinium, and a few cases have been reported in Japan. There is no definitive cure; the disease is progressive and can be fulminant. We report a case of a 54-year-old woman with multiple pathologies, including lupus nephritis at 23 years, peritoneal dialysis at 34 years, hepatocellular carcinoma at 47 years, a switch to hemodialysis, partial hepatectomy and axillo-femoral bypass grafting for severe aortic stenosis at 52 years, as well as multiple MRI exposures. One month after the last MRI including an intravenous gadolinium contrast agent (Magnevist), she developed thickening of the skin with brownish hyperpigmentation on the lower legs spreading later to all extremities, which limited joint movement and resulted in contractures. She was treated with low-dose prednisolone and cyclosporine, however, she remains at present unable to walk or extend the joints of the upper and lower extremities and needs analgesia for sharp pain in the thickened skin. Various factors including multiple exposures to gadolinium-containing MRI contrast agents, inflammatory burden, and hepatic disease might have played a role in the development of NSF. This is the case of a Japanese patient with gadopenate-dimeglumine (Magnevist) related NSF. Regardless of ethnicity and the type of contrast agent, we should be aware of the potential development of NSF in patients with renal failure.

Salting-out taste-masking system generates lag time with subsequent immediate release.

Salting-out effects were utilized for developing a multiparticulate system balancing numbness masking and high bioavailability. A "salting-out taste-masking system" consisting of a drug core containing acetaminophen as a model drug, a salting-out layer containing sodium carbonate (Na(2)CO(3)) and hydroxypropylmethylcellulose (HPMC), and a water-penetration-control layer consisting of cetanol was designed and prepared. The system successfully generated a long lag time while achieving immediate drug release. In the system, the Na(2)CO(3) release rate was slower and the lag time was longer than when the water-penetration-control layer was not present. During the release of Na(2)CO(3) from the system, the release of HPMC and drug was suppressed. These results indicated that the water-penetration-control layer maintained a high concentration of Na(2)CO(3), prevented HPMC's dissolution, and generated a long lag time of drug release. The system generated longer lag time and released drug more immediately than formulation containing the water-penetration-control layer of same thickness without the salting-out layers. These results indicated the salting-out layers were necessary for obtain a long lag time and subsequent immediate drug release. This novel taste-masking system has the potential to be a useful multiparticulate dosage form for effective, safe, and user-friendly drug therapy.

[Large cell neuroendocrine carcinoma of the lung].

Large cell neuroendocrine carcinoma (LCNEC) is a neuroendocrine tumor comprising a subgroup of large cell carcinoma and is a type of lung cancer showing a neuroendocrine characteristic similar to that of small cell lung carcinoma In our institution, we started to diagnose LCNEC by immunostaining in 2002, and we herein report 9 patients diagnosed with LCNEC from January 2002 to May 2008. The average patient age was 74.9, male/female ratio was 8/1, and all 9 patients had a smoking history. Pathological stages IA/IB/IIB/IIIA comprised 4/1/2/2, respectively. Peripherally located and lobulated tumors were noted on preoperative computed tomography (CT), and moderate uptake of fluoro-2-deoxy-D-glucose (FDG), which balanced with the size, was recognized on positron emission tomography (PET). All 9 patients underwent surgery and 7 underwent radical surgery. Postoperative adjuvant chemotherapy was performed for 4 patients. Three showed recurrence, and 2 of these 3 died of the primary disease. The remaining 7 patients have survived to date. The possibility of LCNEC must be considered when peripherally located lung cancer with lobulation is noted on CT and shows moderate uptake of FDG for its size on PET, and multimodal treatment is needed if the diagnosis is determined postoperatively.

Molecular design of new inhibitors of peroxidase activity of cytochrome c/cardiolipin complexes: fluorescent oxadiazole-derivatized cardiolipin.

Interaction of a mitochondria-specific anionic phospholipid, cardiolipin (CL), with an intermembrane protein, cytochrome c (cyt c), yields a peroxidase complex. During apoptosis, the complex induces accumulation of CL oxidation products that are essential for detachment of cyt c from the mitochondrial membrane, induction of permeability transition, and release of proapoptotic factors into the cytosol. Therefore, suppression of the peroxidase activity and prevention of CL oxidation may lead to discovery of new antiapoptotic drugs. Here, we report a new approach to regulate the cyt c peroxidase activity by using modified CL with an oxidizable and fluorescent 7-nitro-2,1,3-benzoxadiazole (NBD) moiety (NBD-CL). We demonstrate that NBD-CL forms high-affinity complexes with cyt c and blocks cyt c-catalyzed oxidation of several peroxidase substrates, cyt c self-oxidation, and, most importantly, inhibits cyt c-dependent oxidation of polyunsaturated tetralinoleoyl CL (TLCL) and accumulation of TLCL hydroperoxides. Electrospray ionization mass spectrometry and fluorescence analysis revealed that oxidation and cleavage of the NBD moiety of NBD-CL underlie the inhibition mechanism. We conclude that modified CL combining a nonoxidizable monounsaturated trioleoyl CL with a C(12)-NBD fragment undergoes a regiospecific oxidation thereby representing a novel inhibitor of cyt c peroxidase activity.

Monitoring of Epstein-Barr virus load and killer T cells in pediatric renal transplant recipients.

AIM: The aim of this study is to establish a monitoring method to prevent Epstein-Barr virus (EBV)-associated symptoms including post-transplant lymphoproliferative disorder (PTLD) that occur after pediatric renal transplantation. SUBJECTS AND METHODS: Circulating EBV loads were quantified by real-time PCR every 1 - 3 months after grafting in 22 pediatric recipients (13 EBV-seronegative [R(-)] and 9 EBV-seropositive [R(+)] recipients before grafting). The peripheral blood cell populations of non-specific activated killer cells (CD8+HLA-DR+ phenotype) in 13 R(-) recipients and EBV-specific cytotoxic T cells (CTLs) reactive with a tetramer expressing HLA-A24-restricted EBV-specific antigens in 8 of 13 R(-) recipients were determined by flow cytometry. RESULTS: EBV-associated symptoms including PTLD (2 cases) were found in 4 R(-) and none of the R(+) recipients. The maximum of EBV load in the R(-) group was significantly higher that in the R(+) group. In R(-) recipients, 4 symptomatic cases had significantly more EBV genome than asymptomatic cases. EBV-specific CTLs were detected in 6 of the 8 R(-) recipients, but these CTLs could not be detected in 1 of the 2 cases at onset of PTLD. The percentage of CD8+HLA-DR+ cells was significantly higher in asymptomatic recipients than in recipients with EBV-associated symptoms whose EBV loads were over 400 copies/microg DNA. CONCLUSION: Monitoring of killer T cells and EBV loads may allow assessment of the risk of EBV-associated symptoms, and high EBV loads and low EBV-specific and/or non-specific CTL responses may be predictive for development of EBV-associated symptoms such as PTLD.

Role of cell death ligand and receptor system on regulation of follicular atresia in pig ovaries.

Several hundred thousand primordial follicles are present in the mammalian ovary, however, only a limited number develop to the pre-ovulatory stage, and then finally ovulate. The others, more than 99%, will be eliminated through a degenerative process called 'atresia'. The endocrinological regulatory mechanisms involved in follicular development and atresia have been characterized to a large extent, but the precise temporal and molecular mechanisms involved in the regulation of these events have remained unknown. From many recent studies, it is suggested that the apoptosis in ovarian granulosa cells plays a crucial role in follicular atresia. Notably, death ligand-receptor interaction and subsequent intracellular signalling have been demonstrated to be the key mechanisms regulating granulosa cell apoptosis. In this review, we provide an overview of granulosa cell apoptosis regulated by death ligand-receptor signalling. The roles of death ligands and receptors [Fas ligand (FasL)-Fas, tumour necrosis factor (TNF)alpha-TNF receptor (TNFR), and TNFalpha-related apoptosis-inducing ligand (TRAIL)-TRAIL receptor (TRAILR)] and intracellular death-signal mediators [Fas-associated death domain protein (FADD), TNF receptor 1-associated death domain protein (TRADD), caspases, apoptotic protease-activating factor 1 (Apaf1), TNFR-associated factor 2 (TRAF2), and cellular FLICE-like inhibitory protein (cFLIP), etc.] in granulosa cells will be discussed.