An experimental approach to spinal fusion using sintered bovine bone in a pig model

Sintered bovine bone is a biomaterial based on calcium phosphate, an organized crystal of bone mineral that possesses a natural trabecular structure. The authors considered whether sintered bovine bone can integrate with recipient bone and adjust to the strength of recipient bone for anterior spinal fusion in an animal model. Either autologous iliac bone or sintered bovine bone was implanted for a spinal body fusion. Some pigs underwent exposure of the spinal bodies without implantation. Based on radiographic evaluation, manual palpation, biomechanical testing, and histologic examination, spinal fusion with sintered bovine bone resulted in a composition and structure similar to that of the autograft (or of no implantation). The sintered bovine bone with its moderate strength tended to adjust to the bone stiffness of the host bone in the specimens as new bone grew.     

Soluble thrombomodulin and antibodies to bovine glomerular endothelial cells in patients with Henoch-Sch?nlein purpura

AIM—To evaluate the clinical significance of soluble thrombomodulin and antiendothelial cell antibodies (AECA) in children with Henoch-Schönlein purpura.METHODS—Binding of serum AECA to bovine glomerular endothelial cells was evaluated by enzyme linked immunosorbent assay, cytotoxicity against glomerular endothelial cells by spectrophotometric assay, and soluble thrombomodulin concentrations by sandwich enzyme immunoassay.RESULTS—IgA AECA were detected in seven of 15 patients with Henoch-Schönlein purpura and nephritis, but were not detected in patients without nephritis or in controls. Patients with Henoch-Schönlein nephritis had raised titres of IgA AECA and serum thrombomodulin; severe proteinuria and renal histological changes were associated with raised titres of IgA AECA and raised serum thrombomodulin. No subjects had complement dependent cytotoxicity against glomerular endothelial cells.CONCLUSIONS—High titres of IgA AECA and raised serum thrombomodulin may be clinically useful markers of renal involvement in patients with Henoch-Schönlein purpura.     

Cerulenin, an inhibitor of protein acylation, selectively attenuates nutrient stimulation of insulin release: a study in rat pancreatic islets

Nutrients such as glucose stimulate insulin release from pancreatic beta-cells through both ATP-sensitive K+ channel-independent and -dependent mechanisms, which are most likely interrelated. Although little is known of the molecular basis of ATP-sensitive K+ channel-independent insulinotropic nutrient actions, mediation by cytosolic long-chain acyl-CoA has been implicated. Because protein acylation might be a sequel of cytosolic long-chain acyl-CoA accumulation, we examined if this reaction is engaged in nutrient stimulation of insulin release, using cerulenin, an inhibitor of protein acylation. In isolated rat pancreatic islets, cerulenin inhibited the glucose augmentation of Ca2+-stimulated insulin release evoked by a depolarizing concentration of K+ in the presence of diazoxide and Ca2+-independent insulin release triggered by a combination of forskolin and phorbol ester under stringent Ca2+-free conditions. Cerulenin inhibition of glucose effects was concentration dependent, with a 50% inhibitory concentration (IC50) of 5 microg/ml and complete inhibition at 100 microg/ml. Cerulenin also inhibited augmentation of insulin release by alpha-ketoisocaproate, a mitochondrial fuel. Furthermore, cerulenin abolished augmentation of both Ca2+-stimulated and Ca2+-independent insulin release by 10 micromol/l palmitate, which causes palmitoylation of cellular proteins. In contrast, cerulenin did not attenuate insulin release elicited by nonnutrient secretagogues, such as a depolarizing concentration of K+, activators of protein kinases A and C, and mastoparan. Glucose oxidation, ATP content in islets, and palmitate oxidation were not affected by cerulenin. In conclusion, cerulenin inhibits nutrient augmentation of insulin release with a high selectivity. The finding is consistent with a prominent role of protein acylation in the process of beta-cell nutrient sensing.     

Calpain inhibitor inhibits secretory granule maturation and secretion of GH

Clathrin- and AP-1-coated buds are present on immature secretory granules of endocrine cells that mature into clathrin-uncoated granules. The mechanism of clathrin and adaptor protein uncoating has remained obscure. Benzyloxycarbonyl-L-leucyl-L-leucinal (ZLLal), a calpain inhibitor, reduced growth hormone (GH) secretion with intracellular accumulation, in a GH-secreting rat pituitary tumor cell. Pulse and chase demonstrated that ZLLal retarded the turnover of clathrin (Clt.H) and adaptins. ZLLal-treatment co-immunoprecipitated the increased amounts of GH with Clt.H and adaptins compared to control cells, suggesting the intracellular accumulation of immature secretory granules. Clt.H and adaptins were limited-proteolyzed by m-calpain in vitro, indicating that calpain may be involved partly in the maturation of secretory granules in endocrine cells via the process of clathrin uncoating.     

Long-lasting renal dysfunction following tacrolimus induction therapy in ulcerative colitis patients

Although tacrolimus (TAC) has remarkable effects in ulcerative colitis (UC) patients when given as remission induction therapy, some can develop renal dysfunction during TAC administration, resulting in withdrawal, though related details remain poorly understood. This study was conducted to determine the impact of oral TAC on renal function for remission induction therapy in UC patients. Fifty-five patients (10 elderly, 45 non-elderly) with UC and treated with oral TAC at our hospital were retrospectively evaluated. Renal function was assessed using estimated glomerular filtration rate (eGFR). Although a high clinical response to TAC was seen in both elderly and non-elderly, a decline in eGFR was noted in nearly all patients regardless of age, with a maximum change of −34.4% from the baseline value at week 11. Furthermore, eGFR decline recovered quickly after TAC discontinuation, though did not return to the baseline at two years following cessation. The rate of eGFR change at week 12 was significantly associated with patient age (β = −0.3242, p = 0.0103) and peak serum trough level during TAC treatment (β = 0.3563, p = 0.0051). Furthermore, the rate of decline in eGFR was significantly greater during treatment with TAC in the elderly as compared to non-elderly, with a large difference in eGFR decline rate between those groups also noted at two years after withdrawal of treatment. Careful attention to renal function when administering oral TAC for UC is important and changes in eGFR should be monitored closely in elderly patients even after treatment cessation.     

Obstetric outcomes in nulliparous women aged 35 and over with singleton pregnancies conceived by in vitro fertilization

Objective To investigate obstetric outcomes in singleton pregnancies conceived by in vitro fertilization (IVF) to nulliparous women older than 35 compared to those of their younger counterparts. Methods Nulliparous women 35 years and older at delivery conceived by IVF (n = 89) were compared with nulliparous women 34 years and younger at delivery conceived by IVF (n = 48). Data included antenatal data, gestational age at delivery, maternal and neonatal complications and mode of delivery. Results The incidence of pregnancy-induced hypertension in the younger group was significantly higher than that in the elderly group (13 vs. 3.4%, P = 0.043). There were no measurable differences in other obstetric outcomes such as placental abnormality, premature delivery or neonatal asphyxia between the two groups. Conclusion The current results suggest that obstetric complications in pregnancies conceived IVF are attributed to mechanisms other than those depend on advanced maternal age.     

The Simultaneous Onset of Pancreatitis and Colitis as Immune-related Adverse Events in a Patient Receiving Nivolumab Treatment for Renal Cell Carcinoma

Immune checkpoint inhibitors (ICIs), which have anti-tumor effects, are currently approved for treatment of several kinds of advanced malignancies. However, with their increasing use, a variety of immune-related adverse events (irAEs) in administered patients have been reported. We herein report a rare case of the simultaneous onset of acute pancreatitis and colitis as irAEs during nivolumab treatment given to a patient with renal cell carcinoma, who then shown marked improvement with corticosteroid therapy.