Acute Severe Isovolemic Anemia Impairs Cognitive Function and Memory in Humans

Background: Erythrocytes are transfused to prevent or treat inadequate oxygen delivery resulting from insufficient hemoglobin concentration. Previous studies failed to find evidence of inadequate systemic oxygen delivery at a hemoglobin concentration of 5 g/dl. However, in those studies, sensitive, specific measures of critical organ function were not used. This study tested the hypothesis that acute severe decreases of hemoglobin concentration alters human cognitive function.

Methods: Nine healthy volunteers, age 29 +/- 5 yr (mean +/- SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and after acute isovolemic reduction of their hemoglobin to 7, 6, and 5 g/dl and again after transfusion of their autologous erythrocytes to return their hemoglobin concentration to 7 g/dl. To control for duration of the experiment, each volunteer also completed the same tests on a separate day, without alteration of hemoglobin, at times of the day approximately equivalent to those on the experimental day.

Results: No test showed any change in reaction time or error rate at hemoglobin concentration of 7 g/dl compared with the data at the baseline hemoglobin concentration of 14 g/dl. Reaction time, but not error rate, for horizontal addition and digit-symbol substitution test (DSST) increased at hemoglobin 6 g/dl (mean horizontal addition, 19%; 95% confidence interval [CI], 4-34%; mean DSST, 10%; 95% CI, 4-17%) and further at 5 g/dl (mean horizontal addition, 43%; 95% CI, 6-79%; mean DSST, 18%; 95% CI, 4-31%). Immediate and delayed memory was degraded at hemoglobin 5 g/dl but not at 6 g/dl. Return of hemoglobin to 7 g/dl returned all tests to baseline, except for the DSST, which significantly improved, and returned to baseline the following morning after transfusion of all autologous erythrocytes.     

缩宫素引产中胎心率观察方法探讨

目的 探讨产妇静脉滴注缩宫素引产过程中优势胎心率观察法,以降低新生儿窒息率.方法 将788例静脉滴注缩宫素引产的产妇分为两组,观察组408例用胎心监护仪监测胎心率,对照组380例用传统的多普勒仪监测胎心率.结果 观察组胎儿宫内窘迫诊断率(28.9%)显著高于对照组(11.8%,P＜0.01);新生儿窒息率(3.2%)、阴道手术助产率(2.5%)显著低于对照组(8.2%、7.1%,均P＜0.05);剖宫产率比较,两组差异无显著性意义(P＞0.05).结论 行静脉滴注缩宫素引产的产妇采用胎心监护仪监测胎心率效果优于多普勒仪,有利于提高新生儿的出生质量.     

Recurrent Moderate Hypoglycemia Ameliorates Brain Damage and Cognitive Dysfunction Induced by Severe Hypoglycemia

OBJECTIVE

Although intensive glycemic control achieved with insulin therapy increases the incidence of both moderate and severe hypoglycemia, clinical reports of cognitive impairment due to severe hypoglycemia have been highly variable. It was hypothesized that recurrent moderate hypoglycemia preconditions the brain and protects against damage caused by severe hypoglycemia.

RESEARCH DESIGN AND METHODS

Nine-week-old male Sprague-Dawley rats were subjected to either 3 consecutive days of recurrent moderate (25–40 mg/dl) hypoglycemia (RH) or saline injections. On the fourth day, rats were subjected to a hyperinsulinemic (0.2 units · kg⁻¹ · min⁻¹) severe hypoglycemic (∼11 mg/dl) clamp for 60 or 90 min. Neuronal damage was subsequently assessed by hematoxylin-eosin and Fluoro-Jade B staining. The functional significance of severe hypoglycemia–induced brain damage was evaluated by motor and cognitive testing.

RESULTS

Severe hypoglycemia induced brain damage and striking deficits in spatial learning and memory. Rats subjected to recurrent moderate hypoglycemia had 62–74% less brain cell death and were protected from most of these cognitive disturbances.

CONCLUSIONS

Antecedent recurrent moderate hypoglycemia preconditioned the brain and markedly limited both the extent of severe hypoglycemia–induced neuronal damage and associated cognitive impairment. In conclusion, changes brought about by recurrent moderate hypoglycemia can be viewed, paradoxically, as providing a beneficial adaptive response in that there is mitigation against severe hypoglycemia–induced brain damage and cognitive dysfunction.Hypoglycemia is the major obstacle in achieving tight glycemic control in people with diabetes (1). Intensive insulin therapy increases the risk of iatrogenic hypoglycemia (2). Episodes of both moderate and severe hypoglycemia have long-term clinical consequences. Recurrent moderate hypoglycemia induces a maladaptive response that limits symptoms of hypoglycemia (hypoglycemia unawareness), limits the counterregulatory response to subsequent hypoglycemia (hypoglycemia-associated autonomic failure), and thus jeopardizes patient safety (1). By depriving the brain of glucose, more severe hypoglycemia causes brain damage in animal studies and leads to long-term impairments in learning and memory (3,4). However, studies examining the effect of severe hypoglycemia in humans are conflicting. Severe hypoglycemia has been shown to alter brain structure (5–7) and cause significant cognitive damage in many (5,7–12) but not all (13–16) studies. Reasons for the discrepancy between human and animal studies are unknown, but a major contributing factor may be the extent of glycemia control (including recurrent hypoglycemia) prior to the episode of severe hypoglycemia.In other models of brain damage, such as ischemic stroke, brief, mild episodes of antecedent brain ischemia has been shown to cause a beneficial adaptation that protects the brain against a subsequent episode of more severe ischemia (a phenomena known as ischemic preconditioning) (17). In a similar fashion, antecedent, recurrent episodes of moderate hypoglycemia were hypothesized to protect the brain against damage caused by a subsequent episode of more severe hypoglycemia.To investigate this hypothesis, recurrent moderately hypoglycemic (25–40 mg/dl) rats (RH rats) and control saline-injected rats (CON rats) were subjected to hyperinsulinemic, severe hypoglycemic clamps (10–15 mg/dl). One group of rats was killed 1 week after severe hypoglycemia to quantify brain damage, while a second group of rats was evaluated by behavioral and cognitive tests 6–8 weeks after the severe hypoglycemia. The results demonstrated that recurrent antecedent moderate hypoglycemia preconditioned the brain and protected it against neurological damage and cognitive defects induced by an episode of severe hypoglycemia.     

COX-2在重症急性胰腺炎所致肝脏损伤中的作用

目的研究环氧合酶-2(COX-2)在重症急性胰腺炎(SAP)大鼠肝组织中的表达,探讨COX-2在SAP肝脏损伤中的作用。方法以3.5%牛磺胆酸钠胰胆管逆行注射诱导大鼠SAP模型。随机分为对照组和SAP组,术后4、8、16及24h测定血清淀粉酶(AMY)、丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、肿瘤坏死因子(TNF)-α水平和腹水AMY;光镜下观察胰腺和肝组织损伤情况;免疫组化方法检测COX-2在肝组织中的表达。结果SAP组各时间点血清AMY、ALT、AST、TNF-α及腹水AMY水平均较对照组明显升高,差异均有统计学意义(P0.05),与胰腺和肝脏组织的病理学改变相一致。术后不同时相COX-2在肝组织中的表达阳性率明显高于对照组,差异均有统计学意义(P0.05),COX-2表达与ALT(rs=0.949,P=0.039)、AST(rs=0.972,P=0.016)及血清AMY(rs=0.944,P=0.041)呈正相关。结论SAP时COX-2表达上调可能在SAP合并肝脏损伤中发挥重要作用。     

攻下药物对重型急性胰腺炎急性肺损伤模型大鼠的治疗作用观察

目的:观察急性重型胰腺炎急性肺损伤动物模型肺泡巨噬细胞计数、活性、分泌炎性细胞因子功能变化及药物对其影响。方法:制备大鼠重型胰腺炎模型,采取肺泡巨噬细胞做各项指标检测及病理学检查。结果:模型组病理表现为明显的肺损伤,大承气汤治疗效果最显著。模型组肺泡巨噬细胞计数、活性、分泌炎性细胞因子显著高于对照组(P<0-01) ,各治疗组显著低于模型组( P< 0-01) ,善得定抑制巨噬细胞分泌炎性细胞因子作用最强,大承气汤抑制巨噬细胞数量较显著。结论:肺泡巨噬细胞过度活化,过度分泌炎性细胞因子是重型急性胰腺炎急性肺损伤发病的重要原因之一。中药能控制过度的炎性反应状态,对受损伤的肺组织细胞具有保护作用     

褪黑素在活性氧致精子线粒体功能损伤中的保护作用

目的 :探讨活性氧 (ROS)对精子线粒体功能的损伤以及褪黑素 (MLT)的保护作用。　方法 :采用Percoll梯度离心法选择具有正常生理功能的精子 ,作为本实验的正常精子模型。应用次黄嘌呤—黄嘌呤氧化酶体系产生ROS ,在MLT存在与不存在情况下 ,与精子模型分别孵育 30和 6 0min后 ,采用酶组织化学方法分析精子线粒体部位的琥珀酸脱氢酶 (SDH)活性 ,采用Rhodamine 1 2 3(Rh1 2 3)荧光探针标记精子 ,通过流式细胞仪检测线粒体膜电位。　结果 :正常精子与ROS孵育后 ,精子线粒体膜电位明显降低 ,线粒体SDH活力降低极为显著 ;而MLT则减轻了ROS对精子线粒体功能的损伤。　结论 :ROS可通过对精子线粒体膜电位和SDH活力的影响 ,而导致精子线粒体功能损伤 ;MLT可通过其有效的抗氧化能力 ,保护精子对抗ROS对其线粒体功能的损伤     

咪唑安定复合异丙酚镇静时的心率变异性变化

目的：观察心率变异性（ＨＲＶ）在咪唑安定、异丙酚及其复合镇静时的变化。方法：选择ＡＳＡⅠ－Ⅱ级,在下胸腰段硬膜外阻滞下择期手术的成同人６０例,随机分为四组,每组１５例,Ⅰ组为咪唑安定组,Ⅱ组为咪唑安定０．０２５ｍｇ／ｋｇ加异丙酚组,Ⅲ组为咪唑安定０．０５ｍｇ／ｋｇ加异丙酚组,Ⅳ组为异丙酚组Ⅰ组,Ⅳ组每间隔２－３分钟静注咪唑安定１．５ｍｇ或 丙酚２０ｍｇ;Ⅱ组,Ⅲ组先静注咪唑安定０．０２５ｍｇ／ｋｇ     

活性氧致人精子运动功能和存活力变化的分析

目的 :对活性氧 (ROS)作用后精子的运动参数和存活率的变化进行分析 ,以证实ROS是否为引起精子运动功能障碍的病因之一。　方法 :采用Percoll梯度离心法选择具有正常生理功能的人精子作为正常精子模型 ,应用次黄嘌呤 黄嘌呤氧化酶体系产生ROS ,在有氧环境下与精子模型孵育后 ,运用计算机辅助精液分析 (CASA)系统 ,分析ROS攻击后精子运动参数的改变。　结果 :与对照组相比 ,正常精子模型与ROS孵育 30min后 ,精子活动率、曲线速度 (VCL)、直线速度 (VSL)、平均路径速度 (VAP)均明显下降 (P <0 .0 0 1) ,头侧摆幅度 (ALH)尚无明显改变 (P >0 .0 5 ) ,而与ROS孵育 6 0min后 ,精子运动功能近乎丧失 ,精子主要运动参数趋向于零。　结论 :ROS与正常精子作用后 ,可导致精子运动功能下降 ,从而证实ROS为精子运动功能障碍的病因之一。     

Effects of Precurarization on the Blood Pressure and Heart Rate Changes Induced by Suxamethonium Facilitated Laryngoscopy and Intubation

The effects of precurarization on blood pressure and heart rate increases during laryngoscopy and intubation were studied in 60 surgical patients, who were randomly allocated to four groups, receiving as a pretreatment d-tubocurarine (0.05 mg/kg), alcuronium (0.03 mg/kg), pancuronium (0.008 mg/kg) or saline in a double-blind fashion. d-Tubocurarine and alcuronium pretreatments seemed to attenuate the blood pressure increase during laryngoscopy and intubation under suxamethonium. Moreover, d-tubocurarine pretreatment protected effectively against high blood-pressure increases. Heart-rate increases were of the same magnitude in all the pretrealed groups. d-Tubocurarine pretreat ment abolished suxamethonium-induced fasciculations completely, whereas alcuronium pretreatment gave protection in 93% and pancuronium pretreatment in 43% of patients.     

新型主动脉旁与主动脉内球囊反搏对羊重度急性心力衰竭辅助的实验研究

目的比较新型主动脉旁反搏装置（paraaortic counterpulsation device,PACD）与主动脉内球囊反搏（intraaortic balloon pump,IABP）装置对羊重度急性心力衰竭的辅助效果。方法选成年小尾寒羊8只,将自制PACD（每搏量为55 ml）的无瓣人工血管吻合于降主动脉,同时于降主动脉内植入IABP（每搏量为40 ml）进行反搏辅助。结扎冠状动脉分支建立重度急性心力衰竭动物模型,观察PACD和IABP辅助对重度急性心力衰竭辅助后的血流动力学变化;实验结束后观察PACD辅助和羊主要器官的变化。结果成功建立了8只羊心力衰竭模型,心力衰竭后心排血量（CO）、肺毛细血管楔压（PCWP）、平均动脉压（MAP）和左心室舒张期末压（LVEDP）与基础值比较差异均有统计学意义（t=-8.466,34.083,25.767,-5.219,P=0.000）。应用IABP和PACD辅助后,平均动脉舒张压（MADP）较辅助前不明显或明显增高（38.34±7.13 mm Hg vs.38.42±6.81 mm Hg,P=0.418;38.34±7.13 mmHg vs.54.14±10.13 mm Hg,P=0.001）,IABP与PACD比较差异有统计学意义（P=0.010）;而LVEDP较辅助前无明显降低（7.43±2.54 mm Hg vs.7.32±2.14 mm Hg,P=0.498;7.43±2.54 mm Hg vs.6.53±1.91 mm Hg,P=0.821）,IABP与PACD比较差异无统计学意义（P=0.651）;冠状窦血流量（CSF）较辅助前不明显或明显增加（86.63±7.71 ml/min vs.87.04±6.53 ml/min,P=0.981;86.63±7.71 ml/min vs.110.52±11.03 ml/min,P=0.000）,IABP与PACD比较差异有统计学意义（P=0.000）;IABP辅助后,左侧颈动脉流量（LCAF）较辅助前无明显降低（131.07±21.26 ml/min vs.128.36±20.38 ml/min,P=0.689）,而PACD辅助后较辅助前增加（131.07±21.26 ml/min vs.151.29±18.37 ml/min,P=0.008）,IABP与PACD比较差异有统计学意义（P=0.002）。PACD后血囊、人工血管内及动物心脏、肝、肾、肺等器官未见血栓、栓塞和缺血坏死;病理切片在光学显微镜下观察未见明显异常。结论 IABP对羊重度急性心力衰竭无辅助作用,而PACD辅助明显提高了MADP,增加了冠状窦血流量,改善了脑灌注流量,对重度心力衰竭具有良好的循环辅助效果。     

Metabolism and Function of the Heart During Acute Asphyxia and in Postasphyxial Recovery

In asphyxia, the energy production by anaerobic glycolysis does not suffice to meet the energy demand of the heart. This energy deficit results in a rapid and complete depletion of creatine phosphate, and in a continuous decrease in ATP and the sum of adenine nucleotides. Upon restoration of the oxygen supply, the creatine phosphate returns to normal within 1-2 minutes. Restoration of ATP and the sum of adenine nucleotides may require many hours and is determined by the depletion of the degradation products of the nucleotides which takes place during the anaerobic period. In the anaesthetised rabbits subjected to asphyxia myocardial power is rapidly and profoundly depressed, but returns to normal within 1-2 minutes if artificial ventilation is applied, and asphyxia has not exceeded 5 minutes. The impaired cardiac performance during asphyxia and its postasphyxial restoration changes with the myocardial creatine phosphate and a small portion of the cellular ATP which is thought to be associated with the contraction process.     

清胰汤对大鼠急性胰腺炎肺损伤中水通道蛋白-1(AQP-1)表达的影响

目的:探讨清胰汤对大鼠急性胰腺炎肺损伤时水通道蛋白-1(AQP-1)表达的影响。方法:将Wistar大鼠分为假手术组(SHAM)、肺损伤组(ALI)、地塞米松组(DEX)与清胰汤组(QYT)。采用逆行胰胆管注射去氧胆酸诱发大鼠急性胰腺炎肺损伤模型,SHAM组仅翻动胰腺,DEX组于造模后立即于股静脉注射地塞米松,QYT组于造模后立即予清胰汤灌胃治疗。各组于造模后8h取血及肺组织。检测血淀粉酶、血气、肺干/湿比值和肺组织病理切片,放免法测血清TNF-α水平,RT-PCR检测肺组织AQP-1 mRNA的表达,免疫组化法检测肺组织AQP-1的表达。结果:胰腺炎ALI组血清淀粉酶、TNF-α明显升高,DEX组与QYT组则明显下降。ALI组AQP-1mRNA和AQP-1的蛋白表达显著下调,DEX组与QYT组较肺损伤组呈显著上调。DEX组与QYT组低氧血症、肺干/湿比值、肺组织病理损害程度较ALI组明显减轻。AQP-1mRNA和AQP-1的蛋白表达与TNF-α的水平呈负相关性。结论:清胰汤通过抑制TNF-α的释放,上调水通道蛋白-1表达,从而减轻急性胰腺炎的肺损伤。     

高压氧对兔油酸性急性呼吸窘迫综合征酏保护作用

目的：研究高压氧（HB0）是否对油酸（0A）诱导免急性呼吸窘迫综合征（ARDS）有肺保护作用。方法：成年健康新西兰大白兔36只,随机分为正常对照组（N）、ARDS组（A）、ARDs常规治疗60分钟组（M60）、ARDS常规治疗120分钟组（M120）、ARDs高压氧治疗60分钟组（O60）和ARDS高压氧治疗120分钟组（O120）。M60组和M120组为兔制备ARDs模型后接氧气吸入治疗60min和120min.     

Effect of Interpersonal and Cognitive Stressors on Habituation and the Utility of Heart Rate Variability to Measure Habituation

Habituation is a decrease in responding to a repeated stimulus. Operant responding and salivation measure habituation in eating behaviour research. Stress may increase eating by acting as a distractor, yielding spontaneous recovery and prolonging responding for food. Our research tested differences in the ability of cognitive and interpersonal stressors to recover responding for food. We also tested heart rate variability (HRV) as a measure of habituation. Twenty women worked for portions of macaroni and cheese for 15 trials on three separate laboratory visits. Between the 12th and 13th trial, one of three different stressor types (speech, stroop and subtraction) was presented during each visit. HRV was measured continuously throughout the laboratory visits. Responding for food declined across the 12 trials with no difference in rate of habituation by visit (p > 0.8) There was no difference between stressor type in the magnitude of spontaneous recovery after each stressor (p > 0.8). Rates of habituation of HRV variables correlated (p < 0.02) with the rate of operant responding habituation. Cognitive and interpersonal stressors do not differ in their ability to recover reduced responding for food. HRV variables may measure habituation to food similar to operant responding. Copyright © 2014 John Wiley & Sons, Ltd.     

液电、电磁冲击波源碎石治疗引起急性肾功能损害的比较

目的：研究比较液电和电磁波源碎石机两种碎石治疗方式对肾功能的损害,对此两种碎石机碎石治疗可能存在的不同程度的肾功能损害进行评估.方法：对两组条件相近的肾结石患者分别进行液电、电磁波源碎石机碎行治疗,检测治疗前后尿酶（NAG、γ-GT）和尿β2-MG的排泄.并运用one-way analysis of variance utili-zing the Student-Newman-Keuls test进行统计分析.结果：两组患者ESWL后尿NAG、γ-GT均显著升高,7天左右恢复至治疗前水平;两组患者碎石后尿β2-MG显著升高,在第7天时有轻度升高,第15天降至正常,两种碎石机间所引起的尿酶、β2-MG升高的程度没有统计学筹异.结论：液电、电磁波源碎石机碎石治疗均能引起暂时性的急性肾功能损害,两者对肾功能的损害从尿酶的角度来看无显著的差异.     

Inhibition of VEGFR-2 Reverses Type 1 Diabetes in NOD Mice by Abrogating Insulitis and Restoring Islet Function

The dysregulation of receptor tyrosine kinases (RTKs) in multiple cell types during chronic inflammation is indicative of their pathogenic role in autoimmune diseases. Among the many RTKs, vascular endothelial growth factor receptor (VEGFR) stands out for its multiple effects on immunity, vascularization, and cell migration. Herein, we examined whether VEGFR participated in the pathogenesis of type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. We found that RTK inhibitors (RTKIs) and VEGF or VEGFR-2 antibodies reversed diabetes when administered at the onset of hyperglycemia. Increased VEGF expression promoted islet vascular remodeling in NOD mice, and inhibition of VEGFR activity with RTKIs abrogated the increase in islet vascularity, impairing T-cell migration into the islet and improving glucose control. Metabolic studies confirmed that RTKIs worked by preserving islet function, as treated mice had improved glucose tolerance without affecting insulin sensitivity. Finally, examination of human pancreata from patients with T1D revealed that VEGFR-2 was confined to the islet vascularity, which was increased in inflamed islets. Collectively, this work reveals a previously unappreciated role for VEGFR-2 signaling in the pathogenesis of T1D by controlling T-cell accessibility to the pancreatic islets and highlights a novel application of VEGFR-2 antagonists for the therapeutic treatment of T1D.In type 1 diabetes (T1D), genetic and environmental risk factors lead to immune dysregulation, provoking an autoimmune response directed toward insulin-producing β-cells of the islets of Langerhans. Previous investigations have estimated that β-cells or islets in nonobese diabetic (NOD) mice and humans are diminished to 10–30% of their initial mass (1,2), and the residual islets are largely dysfunctional when hyperglycemia is first detected (1,2). However, low levels of C-peptide can be detected in T1D patients as far out as 1–2 years postdiagnosis, indicating a window of opportunity for therapies that can restore or preserve islet mass and function (3).Multitarget receptor tyrosine kinase inhibitors (RTKIs), such as sunitinib, were originally designed to target malignant tumors that express dysregulated tyrosine kinases, including platelet-derived growth factor (PDGF)-R, c-FMS, or c-Kit. However, these inhibitors also target vascular endothelial growth factor (VEGF) receptors (VEGFRs), which are elevated in the parenchyma and tissue vasculature in many tumor microenvironments and during chronic inflammation. VEGF regulates vasculogenesis and angiogenesis largely through activation of VEGFR-2 (4). In addition to stimulating endothelial cell mitogenesis and cell migration, VEGF also has effects on a limited number of other cell types, including stimulation of monocyte/macrophage migration. Studies of transgenic mice lacking VEGFR-1 (5) or that express VEGFR-1 with a “dead” kinase domain (6) reveal that VEGFR-1 functions as a negative regulator of vasculogenesis and angiogenesis. Similarly, VEGFR-2 deficiency is embryonically lethal in mice but is attributed to a nonfunctional and underdeveloped vascular system (7). The phenotypes of VEGFR-1 and VEGFR-2–null mice indicate that, although VEGF-A has limited function through VEGFR-1, the vascular remodeling functions of VEGF-A are largely mediated through the activation of VEGFR-2.Tyrosine kinase inhibitors (TKIs) have shown efficacy in mouse models of muscular dystrophy (8), multiple sclerosis (9), rheumatoid arthritis (10–12), and psoriasis (13). TKI can prevent and reverse diabetes in NOD mice (14–16). Imatinib, which predominantly targets c-abl and PDGF, reversed diabetes in NOD mice (14), but other RTKIs with distinct inhibitory profiles (e.g., sunitinib) were even more effective, suggesting that the precise constellations of TK targets were critical for maximum efficacy. In this regard, the VEGF-A/VEGFR-2 pathway, a key target of sunitinib, stands out as a key kinase regulating the pathogenesis of several of these inflammatory disorders (17–19). Intriguingly, VEGF serum levels are elevated in T1D patients compared with healthy controls and positively correlate with increased HbA_1c levels (20).In this study, we determined whether VEGFR-2 might be involved in the pathogenesis of T1D and tested the therapeutic efficacy of VEGFR-2 inhibition in the NOD mouse model of T1D. We report that inhibition of VEGFR-2 by RTKIs or blocking antibodies rapidly reversed diabetes and maintains euglycemia with continued drug administration. Reversal of diabetes was attributed to an abrogation of vascular remodeling in the pancreatic islets, which impairs T-cell trafficking and the severity of insulitis, ultimately improving glucose tolerance. Histological analysis of human and mouse pancreata revealed a positive correlation between the severity of insulitis and islet vascularity, implicating inflammation as a major driving force in the vascular remodeling observed in the islets. Collectively, our findings suggest that VEGF/VEGFR-2 signaling serves a critical gatekeeper function by controlling essential remodeling of the vasculature that is necessary for T cells to gain access to tissues.