A role for autophagy in long‐term spatial memory formation in male rodents

A hallmark of long‐term memory formation is the requirement for protein synthesis. Administration of protein synthesis inhibitors impairs long‐term memory formation without influencing short‐term memory. Rapamycin is a specific inhibitor of target of rapamycin complex 1 (TORC1) that has been shown to block protein synthesis and impair long‐term memory. In addition to regulating protein synthesis, TORC1 also phosphorylates Unc‐51‐like autophagy activating kinase‐1 (Ulk‐1) to suppress autophagy. As autophagy can be activated by rapamycin (and rapamycin inhibits long‐term memory), our aim was to test the hypothesis that autophagy inhibitors would enhance long‐term memory. To examine if learning alters autophagosome number, we used male reporter mice carrying the GFP‐LC3 transgene. Using these mice, we observed that training in the Morris water maze task increases the number of autophagosomes, a finding contrary to our expectations. For learning and memory studies, male Long Evans rats were used due to their relatively larger size (compared to mice), making it easier to perform intrahippocampal infusions in awake, moving animals. When the autophagy inhibitors 3‐methyladenine (3‐MA) or Spautin‐1 were administered bilaterally into the hippocampii prior to training in the Morris water maze task, the drugs did not alter learning. In contrast, when memory was tested 24 hours later by a probe trial, significant impairments were observed. In addition, intrahippocampal infusion of an autophagy activator peptide (TAT‐Beclin‐1) improved long‐term memory. These results indicate that autophagy is not necessary for learning, but is required for long‐term memory formation.     

Characterization of D-3,4-cyclopropylglutamates as N-methyl-D-aspartate receptor agonists

The 4 configurational isomers of D-3,4-cyclopropylglutamate (D-CGA) have been synthesized and analyzed for their interactions as excitatory amino acid recognition sites. Additionally, functional assessment of the action of these compounds at the N-methyl-D-aspartate (NMDA) receptor was performed. All 4 analogs function as agonists at the NMDA receptor as evidenced by their ability to stimulate [3H]MK-801 binding to the coupled PCP recognition site. Furthermore, the rank order of potency of these compounds in stimulating [3H]MK-801 binding corresponds with their Ki values for the displacement of NMDA-selective L-[3H]glutamate and [3H]CGS-19755 binding (D-CGA-C greater than D-CGA-B greater than D-CGA-D greater than D-CGA-A). The D-CGA-C isomer has affinity and potency at the NMDA receptor similar to the endogenous agonist, L-glutamate. This high potency coupled with greater specificity than L-glutamate, makes D-CGA-C a potentially useful pharmacological tool for the study of this receptor.     

On the role of the transmembrane anchor sequence of influenza hemagglutinin in target cell recognition by class I MHC-restricted, hemagglutinin-specific cytolytic T lymphocytes

We have examined the requirement for the transmembrane hydrophobic anchor sequence of the influenza hemagglutinin (HA) in the formation of the antigenic moiety on the surface of target cells recognized by class I MHC-restricted murine CTL. For this analysis we have used a line of CV-1 monkey epithelial cells that express the transfected murine H-2Kd gene product as target cells and have used recombinant SV40-based late replacement vectors to achieve expression of genes encoding wild-type and mutant forms of HA. We have found that the majority of Kd-restricted HA-specific CTL clones recognize target cells that express a secreted HA molecule that lacks the transmembrane and cytoplasmic domains of the parent glycoprotein. Several Kd-restricted CTL clones that recognize subtype-specific and crossreactive epitopes on HA fail to recognize the anchor-negative, secreted HA or chimeric HA molecules containing the transmembrane and cytoplasmic domains of unrelated glycoproteins. These CTL clones appear to be directed to antigenic epitopes located within the transmembrane domain of HA, as defined by their capacity to recognize target cells sensitized with a synthetic 23-amino-acid peptide corresponding to sequences within this domain. The implications of these results for class I MHC-restricted CTL recognition are discussed.     

A new torque guide wire

A new guide wire that provides markedly improved torque control is described. It was compared with a conventional guide wire in two models, one simulating a drainage tube with numerous side holes and one, the biliary tree. The new wire was much more easily controlled than the conventional guide wire and passed through both models significantly faster (P less than .01 and P less than .005). Although some deterioration in control was noted when it was inserted through a catheter in vivo, the new torque-control wire still exhibited a definite improvement over conventional wires in directional control.     

Technology Penetration of Endovascular Aortic Aneurysm Repair in Southern California

Our objective was to investigate the penetration of endovascular abdominal aortic aneurysm repair (EVAR) in the large, diverse health-care market of southern California over 3 years and to study variability in the pattern of distribution of EVAR in southern California counties by analyzing available demographic, geographic, and socioeconomic data from California state health-care databases. Information abstracted from the inpatient hospital discharge data for patients undergoing AAA repair for the years 2001, 2002, and 2003, derived from the Office of Statewide Health Planning and Development, included age, gender, race, hospitals performing EVAR, and payors for the service. Per-capita income (PCI) for the year 1999 and the population size of each county for the respective years were obtained from the U.S. Census Bureau. Data pertaining to members of the Southern California Vascular Surgical Society (SCVSS) serving the southern California region were obtained from the SCVSS membership directory. Data were categorized based on 10 counties in southern California. All the above variables were analyzed using the chi-squared test, with p < 0.05 considered significant. The proportions of EVAR for the years 2001, 2002, and 2003 were 15.4% (n = 409), 20.2% (n = 492), and 25.9% (n = 566), respectively. This is a 67.8% (p < 0.0001) increase in EVAR application in southern California since 2001. However, the proportion of EVAR varied among counties (p < 0.0001), with 457 EVARs performed in Los Angeles County and eight in Imperial County during the study period. EVAR proportion was higher in patients aged ≥65 years (p < 0.0001) and male patients (p < 0.0001). The proportion of EVAR was significantly higher in counties with more than 20 vascular surgeons available (p < 0.0001) and PCI >$21,000 (p < 0.0001) and in Medicare, health maintenance organization, preferred provider organization, and private insurance holders (p < 0.0001). There was a trend toward increased EVARs in counties with more than eight hospitals that performed EVAR (p = 0.0545). However, no significant difference in EVAR proportion was observed among subgroups based on race (p = 0.535) and population size (p = 0.84). Although the number and proportion of EVAR increased significantly in southern California over 3 years, the penetration of the procedure varied among counties. County affluence, payor mix, and the number of vascular surgeons/county influenced the variability. These observations suggest that economic barriers may limit access to new biomedical technology. This has implications for health-care public policy directed toward providing equal access to medical care without regard to economic status. Presented at the Twenty-third Annual Meeting of the Southern California Vascular Surgical Society, La Quinta, CA, May 13-15, 2005.     

Renal revascularization in Takayasu arteritis-induced renal artery stenosis

PURPOSE: This study was undertaken to define the long-term effects of renal revascularization on blood pressure, and renal and cardiac function in patients with Takayasu arteritis-induced renal artery stenosis (TARAS). METHODS: Twenty-seven patients (25 women; mean age, 27 years) with TARAS underwent intervention. Primary, primary assisted, and secondary patency rates were determined, and the late effects on blood pressure, renal and cardiac function, and survival were analyzed. RESULTS: All patients had hypertension (mean blood pressure, 167/99 mm Hg; 2.5 antihypertensive medications per patient). Mean estimated glomerular filtration rate in patients not receiving hemodialysis was 76 mL/min, and in five patients serum creatinine concentration was greater than 1.5 mg/dL. Three patients were hemodialysis-dependent, and two had intractable congestive heart failure. Forty interventions were performed, including 32 aortorenal bypass procedures, two repeat implantations, four nephrectomies, and two transluminal angioplasty procedures. Postoperative morbidity was 19%. There were no deaths. During follow-up (mean, 68 months), three graft stenoses, all due to intimal hyperplasia, and three graft occlusions occurred. Two of three graft stenoses were successfully revised. At 1, 3, and 5 years of follow-up, primary patency was 87%, 79%, and 79%, respectively; primary assisted patency was 93%, 89%, 89%, respectively; and secondary patency was 93%, 89%, and 89%, respectively. Intervention resulted in a decrease in blood pressure to a mean of 132/79 mm Hg (P<.0001), and the need for antihypertensive medications was reduced to one per patient (P<.01). Mean glomerular filtration rate increased to 88 mL/min (P<.005), and two patients no longer required hemodialysis. Congestive heart failure resolved in both patients, and did not recur. There were three deaths during follow-up, with 5-year and 10-year actuarial survival of 96% and 80%, respectively. CONCLUSIONS: Renal revascularization to treat TARAS is durable, has a salutary effect on blood pressure, and enhances long-term renal and cardiac function. This response establishes renal revascularization as a successful and durable intervention for TARAS, and a benchmark to which other therapies should be compared.     

Is Gd-DTPA required for routine cranial MR imaging?

Gadopentetate dimeglumine (gadolinium diethylenetriaminepentaacetic acid [DTPA]) was administered prospectively to 500 consecutive children and adults referred for routine cranial magnetic resonance (MR) imaging over a 4-month period. Pre- and postcontrast images were blindly and independently interpreted by two experienced neuroradiologists. Specific criteria were provided to the readers to define objectively when contrast material enhancement (or lack thereof) would be considered "radiologically helpful." Contrast-enhancing lesions were observed in 99 cases (20%). In only 15 cases (3%) did Gd-DTPA permit detection of lesions not also apparent on the precontrast studies. Contrast enhancement was considered radiologically helpful in 74 of the 99 cases. Lack of enhancement was considered helpful in 112 of the 500 cases (22%). Factors that may indicate increased usefulness of Gd-DTPA include increased patient age, definite lesion seen at computed tomography or precontrast MR imaging, prior craniotomy for tumor, and clinically documented systemic or central nervous system disease. Gd-DTPA should probably be used routinely for cranial MR imaging in most patients, except, perhaps, children and young adults with normal precontrast images.     

Hypoplasia of the descending thoracic and abdominal aorta: a report of two cases and review of the literature

Hypoplasia of the thoracic and abdominal aorta, referred to as atypical, elongated, or diffuse coarctation, is an exceedingly rare cardiovascular anomaly. Congenital, acquired, inflammatory, and infectious etiologies have been described. Symptoms typically occur within the first three decades of life and include hypertension, lower extremity claudication, and mesenteric ischemia. The condition is considered a life-threatening emergency as a result of the complications associated with severe hypertension. Diagnosis is best made with angiography. Surgical bypass grafting is the optimal method of treatment and must be tailored depending on the distribution of disease. We report two cases of diffuse hypoplasia involving the thoracic and abdominal aorta treated with thoracic aorta to abdominal aorta bypass.     

Dose Response of Intrathecal Adenosine in Experimental Pain and Allodynia

Background: Intrathecal adenosine reduces areas of mechanical hypersensitivity and provides analgesia in patients with neuropathic pain. Adenosine also causes side effects, yet its dose response for either efficacy or side effects has not been examined in double blind studies. We studied two doses of intrathecal adenosine in humans with experimental hypersensitivity and the ability of the adenosine receptor antagonist, aminophylline, to reverse adenosine's effects.

Methods: Following Internal Review Board approval and written informed consent, 35 volunteers were studied. Five volunteers were studied to confirm the stability of a new method of inducing hypersensitivity with capsaicin. The remaining 30 volunteers received, in a randomized, double-blind manner, saline, or adenosine, 0.5 or 2.0 mg, by intrathecal injection 40 min after areas of allodynia and hyperalgesia were established from capsaicin. Two hr later, volunteers were randomized to receive intravenous saline or aminophylline, 5 mg/kg.

Results: Topical capsaicin with intermittent heating resulted in stable areas of allodynia and hyperalgesia. Intrathecal adenosine, but not saline, reduced areas of allodynia and hyperalgesia from capsaicin, with no differences between doses. Side effects occurred in 1, 2, and 6 volunteers receiving saline, 0.5 mg and 2.0 mg adenosine, respectively. Aminophylline failed to reverse adenosine's effects.     

Haplotyping the human T-cell receptor beta-chain gene complex by use of restriction fragment length polymorphisms.

We have studied the genetic segregation of human T-cell receptor beta-chain (TCR beta) genes on chromosome 7q in 40 CEPH (Centre d'Etude du Polymorphisme Humain) families by using restriction fragment length polymorphisms (RFLPs). We constructed haplotypes from eight RFLPs by using variable- and constant-region cDNA probes, which detect polymorphisms that span more than 600 kilobases of the TCR beta gene complex. Analysis of allele distributions between TCR beta genes revealed significant linkage disequilibrium between only 6 of the 28 different pairs of RFLPs. This linkage disequillibrium strongly influences the most efficient order to proceed for typing of these RFLPs in order to achieve maximum genetic informativeness, which in this study revealed a 97.3% level of heterozygosity within the TCR beta gene complex. Our results should provide new insight into recent reports of disease associations with the TCR beta gene complex and should assist in designing future experiments to detect or confirm the existence of disease-susceptibility loci in this region of the human genome.