孔边裂纹J积分失效评定曲线

计算了单边椭圆缺口试件（ＳＥＮＣＰ）高应变区裂纹的Ｊ积分失效评定曲线（ＦＡＣ），考察了影响ＦＡＣ的几种因素。结果表明：在外加载荷与塑性屈服载荷之比（Ｌｒ）１．０时，用Ｒ６通用失效评定曲线进行结构高应变区裂纹断裂评定与疲劳剩余寿命估算是安全的。     

应用联合减压术治疗中晚期脑疝疗效观察

目的　观察联合减压术治疗特重型颅脑损伤合并嵌顿性脑疝的效果。方法　将 97例格拉斯哥昏迷评分 (GCS) 3～ 5分的特重型颅脑损伤合并嵌顿性脑疝患者随机分为两组 ,分别采用联合减压术 (46例 )与常规骨瓣开颅术 (5 1例 )治疗 ,术后两组均经常规治疗。随访 1～ 32个月 ,平均 7个月。比较两组患者临床疗效、颅内压变化及并发症发生率。结果　联合减压治疗组有效率为 80 .4 % (37/ 4 6例 ) ,其中恢复良好、中残2 7例 (占 5 8.7% ) ,重残 10例 (占 2 1.7% ) ,死亡 9例 (占 19.6 % ) ;常规骨瓣开颅术对照组有效率为 33.4 %(17/ 5 1例 ) ,其中恢复良好、中残 6例 (占 11.8% ) ,重残 11例 (占 2 1.6 % ) ,死亡 34例 (占 6 6 .6 % ) ,两组有效率和病死率比较差异均有显著性 (P均 <0 .0 1)。联合减压治疗组患者颅内压下降速度和程度优于常规骨瓣开颅术对照组 (P<0 .0 5 )。联合减压治疗组患者的急性脑膨出、切口疝、切口脑脊液漏、外伤性癫疒间及术后枕叶脑梗死发生率均明显低于常规骨瓣开颅术对照组 (P<0 .0 5或 P<0 .0 1) ,但两组术后颅内感染发生率差异无显著性 (P>0 .0 5 )。结论　联合减压术治疗特重脑损伤合并嵌顿性脑疝患者的疗效优于常规骨瓣开颅术。     

A method for shape optimization of a hip prosthesis to maximize the fatigue life of the cement

The long term success of total joint replacement can be limited by fatigue failure of the acrylic cement and the resulting disruption of the bone-cement interface. The incidence of such problems may be diminished by reduction of the fatigue notch factor in the cement, so that stress concentrations are avoided and the fatigue crack initiation time maximized. This study describes a method for numerical shape optimization whereby the finite element method is used to determine an optimal shape for the femoral stem of a hip prosthesis in order to minimize the fatigue notch factor in the cement layer and at interfaces with the bone and stem.

A two-dimensional model of the proximal end of a femur fitted with a total hip prosthesis was used which was equivalent to a simplified three-dimensional axisymmetric model. Software was developed to calculate the fatigue notch factor in the cement along the cement/stem and cement/bone interfaces and in the proximal bone. The fatigue notch factor in the cement at the cement/stem interface was then minimized using the ANSYS finite element program while constraining the fatigue notch factor at the cement/bone interface at or below its initial level and maintaining levels of stress in the proximal bone to prevent stress shielding. The results were compared with those from other optimization studies.     

脑疝复位天幕切开与常规手术治疗重型脑外伤脑疝的临床对照研究

目的　比较脑疝复位天幕裂孔切开与常规去骨瓣手术治疗重型脑外伤引起脑挫裂伤脑水肿、颅内血肿出现脑疝晚期患者的手术效果。方法　共收治重型脑外伤脑疝晚期患者5 6例,分为2组:脑疝复位组31例;常规手术组2 5例。患者术前GCS计分均为3～5分、双瞳孔散大或有不同程度散大,所有患者都经头颅CT扫描确定脑损伤情况。结果　患者术后存活者随访1a ,脑疝复位组:恢复良好/中残1 0例、重残/长期昏迷7例、死亡1 4例(45 %) ;常规手术组:恢复良好/中残1例、重残/长期昏迷3例、死亡2 1例(84 %) (P <0 .0 5 )。脑疝复位组术后大脑后动脉梗死、应激性溃疡、脑积水发生率明显低于常规手术组(P均<0 .0 5 )。结论　脑疝复位天幕裂孔切开治疗重型脑外伤引起脑挫裂伤脑水肿、颅内血肿出现脑疝晚期患者疗效明显优于常规去骨瓣手术。     

Tentorial Meningiomas. Report on Twenty-Seven Cases

Summary ? Objective. Report our experience with 27 tentorial meningiomas (TM) surgically treated between 1985 and 1998.  Methods. The records of 27 patients with TMs were retrospectively reviewed for clinical presentation, neuroradiological evaluation, surgical treatment and long-term outcome. The extent of tumor resection was scored according to the Simpson's grading for tumor removal. Long-term results were evaluated according to the Glasgow Outcome Score (GOS).  Results. The average age was 53 years. Female predominance was 74%. The most common complaints at presentation were headaches (51%), gait ataxia (33%), memory disturbances (30%) and hypo-acousia (30%). A classification of TMs into 5 subgroups according to tumor site is proposed on the basis of imaging studies. A cerebrospinal fluid shunt was established prior to direct approach in 7 patients and as the sole procedure in one inoperable patient. Twenty-seven direct approaches were undertaken in 26 patients, including 17 infratentorial and 10 supratentorial approaches. Total tumor removal was achieved in 20 patients (77%) and subtotal removal in 6 (23%). Fifteen patients (55%) experienced 22 postoperative complications. One patient died three months after a subtotal resection (mortality=3,7%). With a mean follow-up of 54 months, all 26 survivors are currently alive with 23 having resumed their normal activities and 3 needing assistance. Five of 6 patients with subtotal resection survived and were followed for a period ranging from 72 to 132 months: none showed residual tumor progression and no re-operation was considered. An additional patient experienced a ?true? recurrence 6 years after total removal, with no tumor progression 2 years after his recurrence was recognized.  Discussion. The best surgical approach to TMs is still a controversial matter. The advantages and drawbacks of conventional versus transbasal approaches are reviewed. Our experience suggests that subtotal removal can be associated with long recurrence-free intervals and preserved quality of life. TMs located at the tentorial edge carried a definitely worse prognosis than peripheral forms.     

The effect of notch filtering on the waveform of the newborn auditory brainstem response

Abstract

Objective: To identify whether the use of a notch filter significantly affects the morphology or characteristics of the newborn auditory brainstem response (ABR) waveform and so inform future guidance for clinical practice. Design: Waveforms with and without the application of a notch filter were recorded from babies undergoing routine ABR tests at 4000, 1000 and 500 Hz. Any change in response morphology was judged subjectively. Response latency, amplitude, and measurements of response quality and residual noise were noted. An ABR simulator was also used to assess the effect of notch filtering in conditions of low and high mains interference. Results: The use of a notch filter changed waveform morphology for 500 Hz stimuli only in 15% of tests in newborns. Residual noise was lower when 4000 Hz stimuli were used. Response latency, amplitude, and quality were unaffected regardless of stimulus frequency. Tests with the ABR stimulator suggest that these findings can be extended to conditions of high level mains interference. Conclusions: A notch filter should be avoided when testing at 500 Hz, but at higher frequencies appears to carry no penalty.     

Brief overview of selected approaches in targeting pancreatic adenocarcinoma

Introduction: Pancreatic adenocarcinoma (PDAC) has the worst prognosis of any major malignancy, with 5-year survival painfully inadequate at under 5%. Investigators have struggled to target and exploit PDAC unique biology, failing to bring meaningful results from bench to bedside. Nonetheless, in recent years, several promising targets have emerged.

Areas covered: This review will discuss novel drug approaches in development for use in PDAC. The authors examine the continued efforts to target Kirsten rat sarcoma viral oncogene homolog (KRas), which have recently been successfully abated using novel small interfering RNA (siRNA) eluting devices. The authors also discuss other targets relevant to PDAC including those downstream of mutated KRas, such as MAPK kinase and phosphatidylinositol 3-kinase.

Expert opinion: Although studies into novel biomarkers and advanced imaging have highlighted the potential new avenues toward discovering localized tumors earlier, the current therapeutic options highlight the fact that PDAC is a highly metastatic and chemoresistant cancer that often must be fought with virulent, systemic therapies. Several newer approaches, including siRNA targeting of mutated KRas and enzymatic depletion of hyaluronan with PEGylated hyaluronidase are particularly exciting given their early stage results. Further research should help in elucidating their potential impact as therapeutic options.     

From the Cover: PNAS Plus: Nicastrin functions to sterically hinder γ-secretase–substrate interactions driven by substrate transmembrane domain

γ-Secretase is an intramembrane-cleaving protease that processes many type-I integral membrane proteins within the lipid bilayer, an event preceded by shedding of most of the substrate’s ectodomain by α- or β-secretases. The mechanism by which γ-secretase selectively recognizes and recruits ectodomain-shed substrates for catalysis remains unclear. In contrast to previous reports that substrate is actively recruited for catalysis when its remaining short ectodomain interacts with the nicastrin component of γ-secretase, we find that substrate ectodomain is entirely dispensable for cleavage. Instead, γ-secretase–substrate binding is driven by an apparent tight-binding interaction derived from substrate transmembrane domain, a mechanism in stark contrast to rhomboid—another family of intramembrane-cleaving proteases. Disruption of the nicastrin fold allows for more efficient cleavage of substrates retaining longer ectodomains, indicating that nicastrin actively excludes larger substrates through steric hindrance, thus serving as a molecular gatekeeper for substrate binding and catalysis.Regulated intramembrane proteolysis (RIP) involves the cleavage of a wide variety of integral membrane proteins within their transmembrane domains (TMDs) by a highly diverse family of intramembrane-cleaving proteases (I-CLiPs) (1). I-CLiPs are found in all forms of life and govern many important biological functions, including but not limited to organism development (2), lipid homeostasis (3), the unfolded protein response (4), and bacterial quorum sensing (5). As the name implies, RIP must be tightly regulated to ensure that the resultant signaling events occur only when prompted by the cell and to prevent cleavage of the many nonsubstrate “bystander” proteins present within cellular membranes. Despite this, very little is known about the molecular mechanisms by which I-CLiPs achieve their exquisite specificity. Although traditional soluble proteases maintain substrate specificity by recognizing distinct amino acid sequences flanking the scissile bond, substrates for intramembrane proteases have little to no sequence similarity.Recent work on rhomboid proteases has demonstrated that this family of I-CLiPs achieves substrate specificity via a mechanism that is dependent on the transmembrane dynamics of the substrate rather than its sequence of amino acids (6, 7). Here, rhomboid possesses a very weak binding affinity for substrate and, in a rate-driven reaction, only cleaves those substrates that have unstable TMD helices that have had time to unfold into the catalytic active site, where they are cleaved before they can dissociate from the enzyme–substrate complex. Although it may be tempting to speculate that this is a conserved mechanism for all I-CLiPs, rhomboid is the only family of I-CLiPs that does not require prior activation of substrate through an initial cleavage by another protease (8). Specifically, site-2 protease substrates must be first cleaved by site-1 protease (9), signal peptide peptidase substrates are first cleaved by signal peptidase (10), and ectodomain shedding by α- or β-secretase is required before γ-secretase cleavage of its substrates (11, 12). These facts suggest that the diverse families of I-CLiPs likely have evolved fundamentally different mechanisms by which they recognize and cleave their substrates.Presenilin/γ-secretase is the founding member of the aspartyl family of I-CLiPs. The importance of γ-secretase function in biology and medicine is highlighted by its cleavage of the notch family of receptors, which is required for cell fate determination in all metazoans (2, 13–16), and of the amyloid precursor protein (APP), which is centrally implicated in Alzheimer’s disease (AD) (14, 17). In addition to APP and notch, γ-secretase has over 90 other reported substrates, many of which are involved in important signaling events (12, 18). Despite this, little is known about the mechanism by which γ-secretase binds and cleaves its substrates. Currently, the only known prerequisite for a substrate to be bound and hydrolyzed by γ-secretase is that it be a type-I integral membrane protein that first has most of its ectodomain removed by a sheddase, either α- or β-secretases (11, 12, 19). How γ-secretase selectively recognizes ectodomain-shed substrates and recruits them for catalysis while at the same time preventing cleavage of nonsubstrates remains unsettled.γ-Secretase is a multimeric complex composed of four integral membrane proteins both necessary and sufficient for full activity: presenilin, nicastrin, Aph-1, and Pen-2 (20–24). Presenilin is the proteolytic component, housing catalytic aspartates on TMDs 6 and 7 of its nine TMDs (17, 25, 26). After initial complex formation, the mature proteolytically active complex is formed when presenilin undergoes auto-proteolysis, resulting in N- and C-terminal fragments (NTF and CTF, respectively) (17, 27, 28), a process thought to be stimulated by the three-TMD component Pen-2 (29). The seven-TMD protein Aph-1 is believed to play a scaffolding role in complex formation (30, 31). Nicastrin is a type-I integral membrane protein with a large, heavily glycosylated ectodomain (32–34) that contains multiple stabilizing disulfide bridges (24, 34).The ectodomain of nicastrin is structurally homologous to a bacterial amino peptidase (34). Although nicastrin lacks the specific amino acids required for peptidase activity, it has been proposed to bind the N terminus of ectodomain-shed substrate, thereby directing substrate TMD to the γ-secretase active site for cleavage (35, 36). This mechanism has been suggested to depend on a key binding interaction between the free amine at the N terminus of the shortened substrate ectodomain and E333 of the vestigial amino peptidase domain of nicastrin (35, 36). However, the importance of nicastrin in substrate recognition has been questioned (37, 38), and although an initial high-resolution structure of γ-secretase suggested a role for nicastrin in substrate recognition (24), the most recent structures of the γ-secretase complex and the nicastrin ectodomain reveal that E333 is actually buried within the interior of nicastrin and resides on the opposite side of the complex relative to the active site (39, 40). Although this makes it unlikely that nicastrin is involved in direct substrate binding barring a large, energy-intensive conformational change, the basic mechanism of substrate recognition by γ-secretase remains controversial and requires resolution.Here, we demonstrate that nicastrin functions to sterically exclude substrates based on ectodomain size rather than actively recruit them for catalysis. This blocking mechanism allows γ-secretase to distinguish substrate from nonsubstrate and explains why substrate ectodomain shedding by α- or β-secretases is a prerequisite for γ-secretase catalysis. In contrast to rhomboid, γ-secretase apparently binds substrate TMD tightly, making the nicastrin steric hindrance mechanism necessary to prevent cleavage of nonectodomain-shed substrates and nonsubstrates alike.