Psychological stress-induced cerebrovascular dysfunction: the role of metabolic syndrome and exercise.

NEW FINDINGS: What is the central question of this study? How does chronic stress impact cerebrovascular function and does metabolic syndrome accelerate the cerebrovascular adaptations to stress? What role does exercise training have in preventing cerebrovascular changes to stress and metabolic syndrome? What is the main finding and its importance? Stressful conditions lead to pathological adaptations of the cerebrovasculature via an oxidative nitric oxide pathway, and the presence of metabolic syndrome produces a greater susceptibility to stress-induced cerebrovascular dysfunction. The results also provide insight into the mechanisms that may contribute to the influence of stress and the role of exercise in preventing the negative actions of stress on cerebrovascular function and structure. ABSTRACT: Chronic unresolvable stress leads to the development of depression and cardiovascular disease. There is a high prevalence of depression with the metabolic syndrome (MetS), but to what extent the MetS concurrent with psychological stress affects cerebrovascular function is unknown. We investigated the differential effect of MetS on cerebrovascular structure/function in rats (16-17 weeks old) following 8 weeks of unpredictable chronic mild stress (UCMS) and whether exercise training could limit any cerebrovascular dysfunction. In healthy lean Zucker rats (LZR), UCMS decreased (28%, P < 0.05) ex vivo middle cerebral artery (MCA) endothelium-dependent dilatation (EDD), but changes in MCA remodelling and stiffness were not evident, though cerebral microvessel density (MVD) decreased (30%, P < 0.05). The presence of UCMS and MetS (obese Zucker rats; OZR) decreased MCA EDD (35%, P < 0.05) and dilatation to sodium nitroprusside (20%, P < 0.05), while MCA stiffness increased and cerebral MVD decreased (31%, P < 0.05), which were linked to reduced nitric oxide and increased oxidative levels. Aerobic exercise prevented UCMS impairments in MCA function and MVD in LZR, and partly restored MCA function, stiffness and MVD in OZR. Our data suggest that the benefits of exercise with UCMS were due to a reduction in oxidative stress and increased production of nitric oxide in the cerebral vessels. In conclusion, UCMS significantly impaired MCA structure and function, but the effects of UCMS were more substantial in OZR vs. LZR. Importantly, aerobic exercise when combined with UCMS prevented the MCA dysfunction through subtle shifts in nitric oxide and oxidative stress in the cerebral microvasculature.

Corneal endothelium damage with intraocular lenses: contact adhesion between surgical materials and tissue.

Intraocular lenses destroy corneal endothelial cells by contact adhesion between the acrylic lens and endothelial surfaces during cataract surgery. Glass and rubber surgical glove surfaces produce similar cell damage. This phenomenon may be important in many surgical procedures and appears to be preventable if a hydrophilic polymer interface is interposed between contacting tissue and the surfaces of materials used.

Successful bilateral lung transplantation for lymphangiomatosis.

Lymphangiomatosis is a rare disease of lymphatic proliferation for which no adequate treatment is known. We report the first successful case of bilateral lung transplantation for the treatment of end-stage pulmonary lymphangiomatosis. A successful outcome was achieved with continued survival beyond 4 years posttransplant and stable lung function. The primary obstacles to significant gains in pulmonary function were thoracic, skeletal and abdominal lymphangiomatosis, which led to pulmonary restriction. Our report demonstrates that pulmonary lymphangiomatosis should be included among those diseases for which lung transplantation is considered potentially beneficial treatment but also emphasizes the importance of screening patients carefully for chest wall and abdominal lymphangiomas that may impede recovery.

SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance.

The cause of death among the majority of epithelial ovarian cancer (EOC) patients involves passive dissemination of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into adjacent organs. Thus, it is important to identify the factors that mediate EOC metastasis and implantation, including clearance of the mesothelium. Sushi domain containing 2 (SUSD2) encodes a type I transmembrane protein containing several functional domains inherent to adhesion molecules. Immunohistochemical analysis determined the presence of SUSD2 in several subtypes of EOC, with the strongest staining observed in high-grade serous ovarian carcinomas (HGSOCs). A high-density, clinically annotated HGSOC tissue microarray was stained with an anti-SUSD2 antibody. Patients with tumors that had a low percentage of SUSD2 staining cells had a shorter median survival (31.7 months) compared with patients who had tumors with extensive SUSD2 staining (49.1 months; P-value=0.0083). To investigate the role of SUSD2 in HGSOCs, stable OVCAR3, OVSAHO and KURAMOCHI cell lines were established with knockdown (KD) or non-targeting (NT) of SUSD2. Boyden chamber and wound-healing assays demonstrated that OVCAR3, OVSAHO and KURAMOCHI SUSD2-KD cells migrated at significantly higher rates compared with their SUSD2 NT counterpart cell lines. Quantitative reverse transcription-PCR and western immunoblot analysis indicated an inverse relationship between SUSD2 and well-characterized mesenchymal proteins, including Twist-1, Zeb-1, N-cadherin, STEAP1, AHNAK, Snail-1, COL5A2 and Snail-3 in OVCAR3, OVSAHO and KURAMOCHI cell line models. In addition, OVCAR3 and KURAMOCHI SUSD2-KD spheroids displayed increased mesothelial clearance ability compared with cells that express endogenous levels of SUSD2. These data suggest that SUSD2 has a role in the inhibition of mesothelial clearance, which is required for metastasis. Altogether, our findings indicate that SUSD2 impedes migration, epithelial-to-mesenchymal transitional and mesothelial clearance of HGSOC cells, consistent with prolonged survival of patients with SUSD2-expressing tumors.

Inhibition of steroidogenesis in cultured Leydig tumor cells by 22-amino-23,24-bisnor-5-cholen-3 beta-O1 and (20R) 20-phenyl-5-pregnene-3 beta,20-diol.

Using the cholesterol side-chain cleavage enzyme purified from bovine adrenals, we have previously shown that 22-amino-23,24-bisnor-5-cholen-3-beta-ol (22-ABC) and (20R) 20-phenyl-5-pregnene-3 beta, 20 diol (20-PPD) are potent competitive inhibitors of this enzyme. The studies presented herein were designed to characterize the effects of these new inhibitors on steroid production by intact cells. Using cultured Leydig tumor cells, we compared the effects of 22-ABC, 20-PPD, and aminoglutethimide (a well-known inhibitor of the cholesterol side-chain cleavage enzyme) on hormone-stimulated steroidogenesis. Our results show that these compounds inhibit steroid production in a dose-dependent manner and that 20-PPD and 22-ABC are about 100 and 4 times more active, respectively, than aminoglutethimide. In these cells, the inhibitory effects of the new compounds seem to be localized exclusively at the conversion of cholesterol to pregnenolone.

Imidazole antimycotics: inhibitors of steroid aromatase.

Miconazole and clotrimazole, members of a class of imidazole agents which have broad spectrum antimycotic activity, were shown to be potent inhibitors of steroid aromatase activity of human placental microsomes. The I50 values for the inhibition of aromatase activity by miconazole, clotrimazole, ketoconazole, and aminoglutethimide were 0.6, 1.8, 60 and 44 microM respectively. The most effective compound, miconazole, exhibited competitive kinetics with respect to androstenedione, the aromatase substrate. The apparent inhibitory constant (Ki) was 55 nM, under assay conditions where the apparent Km for androstenedione was 220 nM. The inhibition of aromatase activity by miconazole was shown to be reversible by dilution. Miconazole was a relatively poor inhibitor of the cholesterol side chain cleavage activity of a placental mitochondria-enriched fraction, while both clotrimazole and ketoconazole markedly inhibited this mitochondrial monooxygenase activity. Spectrophotometric studies revealed that miconazole bound to the cytochrome P-450 component of the placental microsomal aromatase complex and had negligible effect on NADPH-cytochrome c (P-450) reductase activity. These results strongly support direct interaction of miconazole with microsomal cytochrome P-450 in human placental microsomes with high affinity resulting in the inhibition of aromatase activity.

Inhibition of rat liver microsomal cytochrome P-450 steroid hydroxylase reactions by imidazole antimycotic agents.

The imidazole antimycotic agents ketoconazole, miconazole and clotrimazole were tested for their abilities to inhibit the reactions involved in the oxidative metabolism of androst-4-ene-3,17-dione by rat liver microsomal cytochromes P-450. All three compounds were found to function as potent inhibitors of steroid hydroxylase reactions, producing 50% inhibition of 6 beta-, 16 beta-, and 16 alpha-hydroxylase activities at concentrations between 10(-7) and 10(-5) M. The antimycotic agents, when added to liver microsomes, bound to cytochrome P-450 with high affinity to produce a "type II" spectral complex. These agents showed differential inhibition of the various steroid hydroxylases and were found not to affect the activities of the liver microsomal steroid 5 alpha-reductase or the androst-4-ene-3,17-dione 17-oxidoreductase. The results presented demonstrate an interaction of these imidazole antimycotic agents with the various cytochromes P-450 of liver microsomes, resulting in selective inhibition of monooxygenase activity.

Lens glide in implant surgery.

The lens glide is a disposable, sterile piece of Silastic that is designed to make insertion of intraocular lenses safer and simpler. Since the use of the lens glide has become part of our routine surgical procedure in implant surgery, there has been a notable reduction in vitreous loss and in postoperative corneal problems.

Vitreous wick syndrome following discission of the posterior capsule.

Discission of the posterior capsule frequently is performed by surgeons doing extracapsular cataract extraction and phacoemulsification. Two cases of the vitreous wick syndrome were noted six days and two weeks, respectively, after discission of the posterior capsule, and immediate surgical repair was done. It is important to be aware of the vitreous wick syndrome as a complication of posterior capsule discission because prompt diagnosis and surgical repair may prevent the development of bacterial endophthalmitis or epithelial downgrowth.

Peritoneal adhesions: prevention with the use of hydrophilic polymer coatings.

Postoperative adhesions, especially peritoneal adhesions, pose an increasingly serious surgical problem. Modern surgical studies have generally attempted to deal with the problem after extensive surgical tissue damage has already occurred. This report focuses on our preliminary findings from exploratory laparotomies with canine and rat animal models, which suggest (1) that inadvertent and generally unappreciated serosal trauma may occur by contact adhesion as well as abrasion and drying mechanisms and (2) that hydrophilic polymer coatings, such as providone (polyvinylpyrrolidone), may be effective in protecting the peritoneal surface from damage. This opens up an important new approach to dealing with the problem: application of adhesive and lubricating tissue and surgical material coatings prior to surgical manipulations to limit tissue damage and thereby minimize postoperative complications. The implications of this study to many other surgical procedures may also be of considerable consequence.

Effects of aminoglutethiumide and its metabolite, N-acetylaminoglutethimide, on bovine adrenocortical and human placental cytochromes P-450scc.

The ability of aminoglutethimide to inhibit cholesterol conversion to pregnenolone was lost upon acetylation of the arylamine nitrogen. This appears to be due to failure of N-acetyl-d-aminoglutethimide to bind to cytochrome P-450scc, since it does not produce the altered low spin form of the enzyme formed upon binding of d-aminoglutethimide. These findings provide further evidence for a role of the free arenamine function in aminoglutethimide and related inhibitors.

Retrobulbar block using pentothal as a sedative for ambulatory cataract surgery.

Cataract surgery comprises 80% to 85% of the surgical procedures performed at our ambulatory surgical center. We have developed a safe and effective method of sedation and amnesia for performing a retrobulbar block. We use sodium thiopental, administered intravenously, just prior to the block. We encourage the anesthesia departments of other facilities to consider this relatively simple blocking procedure for the comfort and safety of the patient.

Polycarbonate intraocular lenses.

Bisphenol-A polycarbonate has been investigated as an improved polymer for ocular implants, especially for intraocular lenses (IOLs). Polycarbonate properties afford special opportunities for development of tougher, stronger, one-piece IOLs. Autoclave or gamma sterilizability and a higher refractive index may provide additional IOL advantages over polymethylmethacrylate. Implant studies in rabbits have shown polycarbonate IOLs to be well tolerated in the anterior chamber for 2.5 years. Polycarbonate appears promising for new IOLs and other ocular implant applications.

Modified electrodes with synthetic biocatalytic membranes.

A biocatalytic membrane based on an immobilized enzyme molecule has been prepared. Oxidative electropolymerization of 8-hydroxyquinaldine (8-OHQ) monomers in 0.2 M, pH 7 phosphate buffer containing glucose oxidase (GOx) has been carried out to modify the surfaces of GC, Au, and Pt rotating disk electrodes. The biocatalytic properties of the synthesized membrane were characterized by studying the catalytic activities of the immobilized GOx. Signals obtained from modified GC electrodes with this biomembrane were mainly attributed to the immobilized GOx. Signals obtained from modified Pt or Au electrodes were due to the combined contribution of the enzyme and the native electrode's material. The potential analytical applications of these modified electrodes as bioelectrochemical sensors were also investigated.

Ileorectal anastomosis for ulcerative and Crohn's colitis.

Except in the presence of severe perineal suppuration or sphincter damage by previous surgery for fistulas, the rectum was preserved in all patients considered candidates for surgery for inflammatory disease of the bowel. A primary anastomosis with a single-layer 5-0 monofilament stainless steel wire was carried out when a relatively healthy rectum with erythema and granularity presented. For patients with more severe disease of the rectum, a two-stage operation with intensive interval treatment of the rectum stump with topical corticosteroids was carried out. Of a total of eighty-six patients with involvement of the colon and rectum with either Crohn's disease or chronic ulcerative colitis, fifty-six patients were treated by local abdominal colectomy and ileorectal anastomosis. Twenty-four had primary anastomosis and thiry-two had a two-stage operation. One anastomotic dehiscence developed. A mean follow-up of 8.4 years (6 months to 20 years) has been satisfactory. Only three anastomoses have been taken down for unsatisfactory results. With the proper selection of patients and with appropriate treatment of the diseased rectal segment, a large majority of patients with inflammatory disease of the bowel can have long-term salutory results after colectomy and ileorectal anastomosis.

Kinetics of uptake, clearance, transfer, and metabolism of hexaflumuron by eastern subterranean termites (Isoptera: Rhinotermitidae).

The rates of uptake, clearance, insect-to-insect transfer, and metabolism of [14C] hexaflumuron [N-(((3,5-dichloro-4-(1,1,2,2-tetrafluroethoxy)phenyl)- amino)carbonyl)-2,6-diflurobenzamide] were measured in eastern subterranean termite workers, Reticulitermes flavipes (Kollar), fed cellulose diets containing either 0.1 or 0.5% (wt:wt) hexaflumuron. The rate of uptake, level of maximum uptake, and amount of insect-to-insect transfer were concentration dependent. The clearance rate constant for hexaflumuron was independent of concentration, with a mean value of 3.2 x 10(-3)/h. This corresponds to a mean half-life for hexaflumuron inside termites of 9 d. No evidence of metabolism of hexaflumuron to additional products was detected when extracting and examining the radioactivity contained in the fecal and regurgitated material within the termite holding apparatus 40 d after exposure to the chemical. Hexaflumuron was efficiently transferred from treated to untreated termites, through trophallaxis, resulting in spread of the toxicant throughout the insect population. The combination of uptake and efficient transfer of hexaflumuron between treated and untreated termites ensures broad distribution of the material even to insects not directly exposed to the toxicant. The distribution of hexaflumuron by termite workers, along with their minimal ability to metabolize the compound to other metabolites, and their slow ability to clear the material from the termite population results in death of the entire group of termites contained within the holding apparatus.

Evaluation of a commercial enzyme-linked immunosorbent assay for detection of Borrelia burgdorferi exposure in dogs.

OBJECTIVE: To evaluate the effectiveness of a commercially available ELISA kit for detecting antibodies against Borrelia burgdorferi in dogs. SAMPLE POPULATION: Banked sera from 440 military working dogs were used for serologic analyses. PROCEDURE: Serum samples were analyzed for antibodies against B burgdorferi by use of a commercially available ELISA and subsequently by western blot analysis as a confirmatory test. RESULTS: Results from the ELISA indicated that 89 (20%) samples were positive for exposure to B burgdorferi or canine Lyme disease vaccine, and 351 (80%) were negative. Follow-up testing by western blot analysis indicated that results for 109 (25%) samples were positive and 331 (75%) were negative for exposure. All samples that had positive results on the ELISA also had positive results on western blot analysis (true positives). Of the 351 samples that had negative results on the ELISA, only 331 had negative results on western blot analysis (true negatives). The remaining 20 samples had positive results on western blot analysis. By use of a standard 2 x 2 table, it was determined that the ELISA had a sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 94%. CONCLUSIONS AND CLINICAL RELEVANCE: The commercial ELISA kit evaluated in this study appeared to lack adequate sensitivity for detecting all potential cases of borreliosis in dogs. The ELISA was also unable to discriminate natural exposure from exposure attributable to vaccination, which could complicate interpretation of positive results and treatment of dogs with clinical signs.

Leaching potential of pervious concrete and immobilization of Cu, Pb and Zn using pervious concrete.

This paper investigates the leaching potential of pervious concrete and its capacity for immobilizing Cu, Pb and Zn, which are common contaminants in urban runoff. Batch experiments showed that the leachability of Cu, Pb and Zn increased when pH<8. According to PHREEQC equilibrium modeling, the leaching of major ions and trace metals was mainly controlled by the dissolution/precipitation and surface complexation reactions, respectively. A 1-D reactive transport experiment was undertaken to better understand how pervious concrete might function to attenuate contaminant migration. A porous concrete block was sprayed with low pH water (pH=4.3±0.1) for 190 h. The effluent was highly alkaline (pH~10 to 12). In the first 50 h, specific conductance and trace-metal were high but declined towards steady state values. PHREEQC modeling showed that mixing of interstitial alkaline matrix waters with capillary pore water was required in order to produce the observed water chemistry. The interstitial pore solutions seem responsible for the high pH values and relatively high concentrations of trace metals and major cations in the early stages of the experiment. Finally, pervious concrete was sprayed with a synthetic contaminated urban runoff (10 ppb Cu, Pb and Zn) with a pH of 4.3±0.1 for 135 h. It was found that Pb immobilization was greater than either Cu or Zn. Zn is the most mobile among three and also has the highest variation in the observed degree of immobilization.