Dynamic motility of microglia:Purinergic modulation of microglial movement in the normal and pathological brain

小神经胶质细胞具有高分支且可以动态移动的细胞突起,在生理条件下监控脑的活动。在病理刺激下,小神经胶质细胞表现出形态学变化,向损伤部位迁移,并在此处的炎性反应和神经元损伤中发挥重要作用。在脑损伤发生的数分钟内,小神经胶质细胞突起很快延伸至损伤部位。这种趋化作用为损伤部位的ATP释放和随之发生的小神经胶质细胞嘌呤能受体-P2Y12R活化所触发。除嘌呤能信号之外,大量神经元信号分子正向或负向调控小神经胶质细胞的移动,这对调节病理条件下的小神经胶质细胞功能性活化起重要作用。本综述重点讨论小神经胶质细胞的动态移动过程,并描述几种在正常和病理脑组织中调节小神经胶质细胞移动的重要信号分子及其作用。     

Urinary control after the definitive reconstruction of cloacal anomaly

PURPOSE: Urinary control after definitive repair of a cloacal anomaly is difficult to achieve. The present report aims to describe the clinical course of urinary control, and the need for the management of bladder dysfunction after reconstruction. METHODS: The present consecutive series consisted of 11 girls who underwent definitive repair of cloacal anomalies over a period of 11 years. Eight patients were associated with hydrocolpos. Radiological examination included a plain X-ray radiograph of the lumbosacral spine and a voiding cystourethrography with or without a urodynamic study. RESULTS: Reconstruction of the cloaca was performed on patients aged between 1 and 3 years using a posterior sagittal approach. Vaginal reconstruction was carried out 13 times in 11 patients using tubularized vaginal flap, distal rectal segment, perineal skin flap, or total urogenital sinus mobilization. Cystostomy or vesicostomy was carried out in four newborns/infants. Another seven patients could void spontaneously but incompletely with residual urine. Occult spinal dysraphism was found in five patients and hemisacrum in two patients. After definitive reconstruction, most patients acquired an adequate to normal bladder volume for 1-year-olds. Normal detrusor-sphincter function was seen in three patients. Detrusor areflexia was seen in two patients who underwent in utero vesico-amniotic shunt. Detrusor underactivity was observed in six patients. Bladder compliance was good in all patients except for one. No patients in the present series showed persistent urinary incontinence from the bladder neck or urethral dysfunction. CONCLUSION: It is postulated that wetting after definitive repair may be the result of overflow incontinence and poor bladder contractility rather than sphincter injury. The main clinical characteristic of bladder dysfunction was a failure to empty. We could not define the exact etiology, but iatrogenic injury from extensive dissection can lead to the higher risks of peripheral nerve damage. Accomplishment of definitive repair involves not only anatomical reconstruction, but also postoperative urinary control, including the initiation of clean intermittent catheterizations under repeated urodynamic evaluations.     

Invasive micropapillary carcinoma of the urinary bladder: An immunohistochemical study of neoplastic and stromal cells

A 66-year-old man complained of hematuria. A cystoscopy revealed a non-papillary tumor and radical cystectomy was performed. Macroscopically, an ulcerative lesion was observed. Microscopically, the neoplasm showed a mixture of urothelial carcinoma, squamous cell carcinoma and micropapillary carcinoma. Immunohistochemically, micropapillary carcinoma cells were positive for cytokeratins 7 and 20, carcinoembryonic antigen and CA125. Additionally, myofibroblasts were distributed in a chicken-wire pattern in the stroma of micropapillary carcinoma. Subsequently, the patient died of carcinoma 1 year after the onset of symptoms. Our results support the previous hypothesis that bladder micropapillary carcinoma runs an aggressive clinical course and suggest that micropapillary carcinoma may show the glandular differentiation of urothelial carcinoma and show the stromal reaction by myofibroblasts resembling that of carcinoma in other anatomic sites.     

Pulse oximetric thresholds for tonsillectomy and adenotomy in children: significance of 1–2% decline in oxyhemoglobin saturation

Objectives:  We aimed to establish optimal overnight pulse oximetric thresholds for determining the indication of tonsillectomy and adenotomy (TA) in children by revising the definition of 'desaturation'.
Methods:  One hundred and thirty four children scheduled for TA (TA group, 5.3 ± 1.4 years old) and 112 otherwise healthy children scheduled for elective minor surgery (control group, 5.4 ± 1.5 years old) were enrolled into this prospective study. Data were recorded and stored every 10 s using Nellcor N-395. Desaturation/resaturation events were defined as x % change ( x  = 1–4) of SpO₂ (oxyhemoglobin saturation by pulse oximetry) in 10 s. The desaturation/resaturation indices were calculated as events per hour of total sleeping time. For each index, a wide range of temporary thresholds was set. The optimal thresholds for TA were the ones that maximized the weighted average for sensitivity, specificity (based on whether the index improved or not after TA), and the percentage of the control children whose indices were below the threshold.
Results:  For all the indices, the optimal thresholds that fulfilled the above condition were determined. Compared with the x  = 3–4% results, the application of x  = 1–2% approximately doubled the TA patients whose preoperative 'positive' indices improved after TA, with the weighted averages of 84.3–92.3% as described above.
Conclusions:  By defining desaturation/resaturation as a 1–2% change in SpO₂ from the preceding value, children with adenotonsillar hypertrophy whose pulse oximetric indices are expected to improve after TA can be detected by pulse oximetry with relatively high sensitivity and specificity.     

Saturable Function of P-Glycoprotein as a Drug-efflux Pump in Multidrug-resistant Tumour Cells

P-glycoprotein acts as an active drug-efflux pump in multidrug-resistant tumour cells. We studied the capacity of P-glycoprotein to extrude drugs from the cells. For nanomolar concentrations of vinblastine P388/ADR cells, which overexpress P-glycoprotein in the plasma membrane, accumulated vinblastine, at 37°C for 30 min, to a much lower extent than the sensitive cells (P388/S), while in the micromolar range the cellular concentration was similar for both types of cells. When cells were incubated with a low (10 nM) or high concentration (1 μM) of vinblastine while energy deprived, the vinblastine concentration increased only in the resistant cells incubated with the low concentration of vinblastine, and this increased level was lowered to the level under the normal conditions by addition of glucose. In contrast, the cellular concentrations in other cases were increased to the normal level by glucose. After cells were loaded with the low concentration of vinblastine, the cellular vinblastine was extruded more rapidly from the resistant cells than from the sensitive cells. The courses of vinblastine efflux from the cells loaded with the high concentration of vinblastine were similar in both types of cells. NA-382, a reported P-glycoprotein inhibitor, effectively increased the intracellular vinblastine and inhibited the drug efflux only from multidrug-resistant cells, P388/ADR and AH66 cells, which were incubated with the low concentration of vinblastine. Cellular uptake of NA-382 was also less in P388/ADR cells than in P388/S cells in culture with 10 nM but not 1 μM of the agent, and this low level was reversed to the level in the sensitive cells by 10 μM vinblastine. These results indicate that P-glycoprotein as a drug-efflux pump works effectively under low extracellular concentrations of substrates, but does not under the high concentrations.     

Antitumour Effects and Pharmacokinetics of Combination of Vinblastine with a Staurosporine Derivative,NA-382, in P388/ADR-bearing Mice

The effects of a staurosporine derivative, N-ethoxycarbonyl-7-oxostaurosporine (NA-382), on the pharmacokinetics of vinblastine were evaluated, compared with those of verapamil, in multidrug-resistant P388/ADR-bearing mice. At first, the in-vitro experiments indicated that NA-382 permeated into the cells better and were more effective in combined cytotoxicity with vinblastine and on accumulation of vinblastine than with verapamil in P388/ADR cells. In combined intraperitoneal injection with vinblastine (200 μ kg^?1) into P388/ADR-bearing mice, NA-382 in a suspension form (10 mg kg^?1) prolonged the life-span of the mice near to that of P388/S-bearing mice treated with vinblastine alone, but verapamil even at the maximum tolerated dosage (30 mg kg^?1) barely affected the in-vivo antitumour effect of vinblastine. When simultaneously administered with vinblastine to P388/ADR-bearing mice, NA-382 maintained significantly higher vinblastine levels in the tumour cells for 24 h and gave a larger area under the time-intracellular vinblastine concentration curve (0 to 24 h) than those receiving vinblastine alone, with long retention of the agent in ascitic fluid. Verapamil increased the cellular vinblastine content for only 6 h, accompanying a rapid elimination of the agent from the ascitic fluid. This study indicates that NA-382 is more effective against multidrug-resistance than verapamil, and its suspension is also advantageous for cancer chemotherapy of multidrug-resistant tumours.     

The mechanisms of hepatic sinusoidal endothelial cell regeneration: A possible communication system associated with vascular endothelial growth factor in liver cells

Vascular endothelial growth factor (VEGF) has been shown to induce proliferation of sinusoidal endothelial cells in primary culture. To elucidate the mechanisms of sinusoidal endothelial cell regeneration in vivo, mRNA expression of VEGF and its receptors, flt-1 and KDR/flk-1, were studied in rat livers. Northern blot analysis revealed that VEGF-mRNA was expressed in hepatocytes immediately after isolation from normal rats. In contrast, non-parenchymal cells, including sinusoidal endothelial cells, expressed VEGF receptor-mRNA. Vascular endothelial growth factor-mRNA expression in hepatocytes was decreased during primary culture, but increased following a peak of DNA synthesis, induced by addition of epidermal growth factor or hepatocyte growth factor to the culture medium at 24 h of plating. In a 70% resected rat liver, VEGF-mRNA expression increased with a peak at 72 h after the operation, and mRNA expression of VEGF receptors between 72 and 168 h. In such a liver, mitosis was maximal in hepatocytes at 36 h and in sinusoidal endothelial cells at 96 h. Also, mRNA expression of both VEGF and its receptors was significantly increased in carbon tetrachloride-intoxicated rat liver compared with normal rat liver. Vascular endothelial growth factor expression was minimal in Kupffer cells isolated from normal rats, but marked in activated Kupffer cells and hepatic macrophages from the intoxicated rats. Vascular endothelial growth factor-mRNA expression was also increased in activated stellate cells from these rats and in the cells activated during primary culture compared with quiescent cells. We conclude that increased levels of VEGF expression in regenerating hepatocytes may contribute to the proliferation of sinusoidal endothelial cells in partially resected rat liver, probably through VEGF receptors up-regulated on the cells. Also, VEGF derived from activated Kupffer cells, hepatic macrophages and stellate cells may be involved in this proliferation in injured rat liver.     

Successful treatment of retinoic acid syndrome with high-dose dexamethasone pulse therapy in a child with acute promyelocytic leukemia treated with ATRA

A 5 year old female developed femoral pain, fever, and hemorrhagic tendency. She was diagnosed as having acute promyelocytic leukemia (APL). Approximately 2 weeks after the administration of all-trans retinoic acid (ATRA), she developed a high fever, edema, and respiratory distress which met the criteria for retinoic acid syndrome. At first, we tried to treat the patient with oral corticosteroid, however, this approach was unsuccessful. Considering the worsening of her condition, we then chose to administer a large dose of intravenous dexamethasone therapy for 3 days. Immediately after this therapy, she became afebrile, respiratory distress and edema disappeared, and there was a general improvement of the symptoms. All-trans retinoic acid at the reduced dose of 25 mg/m², was continued for an additional 6 weeks and then discontinued. Since the cessation of dexamethasone and ATRA, there has been no relapse of APL in this patient. Although based on only one case, we recommend the intravenous high-dose dexamethasone pulse therapy (13 mg/m² per day, for 3 days) for treating retinoic acid syndrome which develops in pediatric APL patients treated with ATRA.     

TREATMENT OF POLYCYSTIC OVARIAN DISEASE BY INDUCING OVULATION WITH PULSATILE SUBCUTANEOUS ADMINISTRATION OF HUMAN MENOPAUSAL GONADOTROPHIN ASSOCIATED WITH LUTEINIZING HORMONE-RELEASING HORMONE ANALOGUE

Treatment with a combination of luteinizing hormone-releasing analogue (GnRHa, Buserelin) and pulsatile administration of hMG (Group I) were used to induce ovulation in nine patients with polycystic ovary syndrome (PCO). The same patients were also treated with pulsatile hMG administration alone (Group II). Ovulation was observed in all twelve treatment cycles in Group I, and there were two pregnancies. In Group II, ovulation occurred in 22 of 26 treatment cycles. Ovarian hyperstimulation occurred in one cycle of Group I and in 5 of 26 cycles of Group II. The total dose per cycle of hMG to induce ovulation in Group I was significantly lower than that needed when only pulsatile hMG administration was used. In response to Buserelin administration, the concentrations of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) increased transiently and then declined to the normal range observed in the early follicular phase. The concentrations of FSH increased in response to hMG administration, resulting in a normal LH/FSH ratio. The present data demonstrated that pulsatile subcutaneous administration of hMG in addition to Buserelin was effective in inducing follicular maturation and ovulation in patients with PCO with a lower incidence of serious side-effects.