Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease.

Telomerase reverse transcriptase (TERT) (catalytic subunit of telomerase) is linked to the development of coronary artery disease (CAD); however, whether the role of nuclear vs. mitchondrial actions of TERT is involved is not determined. Dominant-negative TERT splice variants contribute to decreased mitochondrial integrity and promote elevated reactive oxygen species production. We hypothesize that a decrease in mitochondrial TERT would increase mtDNA damage, promoting a pro-oxidative redox environment. The goal of this study is to define whether mitochondrial TERT is sufficient to maintain nitric oxide as the underlying mechanism of flow-mediated dilation by preserving mtDNA integrity.Immunoblots and quantitative polymerase chain reaction were used to show elevated levels of splice variants α- and ß-deletion TERT tissue from subjects with and without CAD. Genetic, pharmacological, and molecular tools were used to manipulate TERT localization. Isolated vessel preparations and fluorescence-based quantification of mtH2O2 and NO showed that reduction of TERT in the nucleus increased flow induced NO and decreased mtH2O2 levels, while prevention of mitochondrial import of TERT augmented pathological effects. Further elevated mtDNA damage was observed in tissue from subjects with CAD and initiation of mtDNA repair mechanisms was sufficient to restore NO-mediated dilation in vessels from patients with CAD. The work presented is the first evidence that catalytically active mitochondrial TERT, independent of its nuclear functions, plays a critical physiological role in preserving NO-mediated vasodilation and the balance of mitochondrial to nuclear TERT is fundamentally altered in states of human disease that are driven by increased expression of dominant negative splice variants.

Quantum Critical Point in the Itinerant Ferromagnet Ni_{1-x}Rh_{x}.

We report a chemical substitution-induced ferromagnetic quantum critical point in polycrystalline Ni_{1-x}Rh_{x} alloys. Through magnetization and muon spin relaxation measurements, we show that the ferromagnetic ordering temperature is suppressed continuously to zero at x_{crit}=0.375 while the magnetic volume fraction remains 100% up to x_{crit}, pointing to a second order transition. Non-Fermi liquid behavior is observed close to x_{crit}, where the electronic specific heat C_{el}/T diverges logarithmically, while immediately above x_{crit} the volume thermal expansion coefficient α_{V}/T and the Grüneisen ratio Γ=α_{V}/C_{el} both diverge logarithmically in the low temperature limit, further indication of a ferromagnetic quantum critical point in Ni_{1-x}Rh_{x}.

Quantum Spin Ice Dynamics in the Dipole-Octupole Pyrochlore Magnet Ce_{2}Zr_{2}O_{7}.

Neutron scattering measurements on the pyrochlore magnet Ce_{2}Zr_{2}O_{7} reveal an unusual crystal field splitting of its lowest J=5/2 multiplet, such that its ground-state doublet is composed of m_{J}=±3/2, giving these doublets a dipole-octupole (DO) character with local Ising anisotropy. Its magnetic susceptibility shows weak antiferromagnetic correlations with θ_{CW}=-0.4(2) K, leading to a naive expectation of an all-in, all-out ordered state at low temperatures. Instead, our low-energy inelastic neutron scattering measurements show a dynamic quantum spin ice state, with suppressed scattering near |Q|=0, and no long-range order at low temperatures. This is consistent with recent theory predicting symmetry-enriched U(1) quantum spin liquids for such DO doublets decorating the pyrochlore lattice. Finally, we show that disorder, especially oxidation of powder samples, is important in Ce_{2}Zr_{2}O_{7} and could play an important role in the low-temperature behavior of this material.

Detailed examination of fenfluramine-phentermine users with valve abnormalities identified in Fargo, North Dakota.

Although several studies have reported on valve abnormalities among users of fenfluramine or dexfenfluramine, detailed information on these subjects has not been provided, limiting the ability to understand who may be at risk for valve abnormalities and to generate hypotheses about the etiology and pathogenesis of these abnormalities. This study was a detailed medical record review of 18 previously reported users of fenfluramine and phentermine, all with valve abnormalities on echocardiogram and 2 with surgical pathology. Both clinical characteristics and medication use were recorded by trained abstracters using a standardized data collection form. Two subjects (11%) had other possible etiologies of valve disease: a history of rheumatic fever and prescribed ergotamine. Three subjects (17%) had a history of migraine headaches and 4 (22%) had murmurs noted before using fenfluramine. Use of medications that may affect serotonin receptors was common: ergotamine (1 subject, 5%), selective serotonin reuptake inhibitors (6, 33%), sumatriptan (2, 11%), and mirtazapine (1, 5%). Prior medication and nonmedication allergies were recorded in 6 (33%) and 3 (17%) subjects, respectively. All subjects had symptoms possibly due to fenfluramine or phentermine side effects. This study raises the hypotheses that valvular heart disease among fenfluramine users may be less common than previously estimated, that serotonin excess may play a role in valve pathology, and that a patient's response to anorexigens and other medications may serve as a marker for increased risk. Further study is needed to test these hypotheses.

Eye injuries from assault with chemicals.

Sixty four patients with eye injuries resulting from assault with chemicals were reviewed. In 17 eyes of 16 patients there was total corneal epithelial loss with varying degrees of limbal ischaemia. Nine eyes were effectively blinded and two eyes suffered less severe but permanent impairment of vision.

Avoiding coagulopathy in vascular surgery.

The possibility of coagulopathy can be minimized by attending to certain general perioperative details to avoid hypothermia, hypotension-shock, and multiple transfusions. In this paper, we present our protocol for avoiding coagulopathy in vascular surgery. In the past 1 1/2 years, we have used perioperative plasmapheresis in 204 patients undergoing cardiac or aortic peripheral vascular surgery. Autologous platelet-rich plasma is transfused at the completion of the operation after heparin reversal. Our data show an approximate 50% reduction in homologous blood product requirement. Seventy-five percent of patients having aortic surgery received no homologous blood products during their hospital stay. For those undergoing cardiac surgery, there has been about a 45% reduction in the use of homologous blood products. In our experience, autologous platelet-rich plasma not only decreases the risk of transmittable disease, but promotes hemostasis.

The plasma collection system: a new concept in autotransfusion.

We have used the Haemonetics Cell-Saver autotransfusion technique in over 6,500 cases since 1979, salvaging more than 11,000 units of packed red blood cells. Major utilization has been in cardiac, vascular, and orthopedic cases. Coagulopathy associated with hypothermia, shock, multiple transfusions, and the autotransfusion technique, which removes clotting factors and platelets, often necessitated use of fresh-frozen plasma and platelet packs postoperatively to control bleeding and clotting problems. However, this defeats the prevention of disease transmission, transfusion reaction, and autoimmunization. Haemonetics has recently developed a plasma collection system which salvages up to 1,000 cc of platelet-rich plasma. Early experience suggests this technique will not only decrease the incidence of postoperative bleeding but further decrease the use of homologous (bank) blood and components. A step-by-step guide to the plasma collection system is discussed. The plasma collection system augments the present autotransfusion technique that conserves red blood cells, thus making complete autologous blood transfusion a reality.

The cell-saver and autologous transfusion: an underutilized resource in vascular surgery.

The vascular surgeon's best resource for blood transfusion is the patient's own blood. It is readily available for recycling, already precisely typed and crossmatched, and without the risk of transfusion-related diseases such as hepatitis and AIDS. The relative ease, safety, and cost-effectiveness of autologous blood transfusions, intraoperative autotransfusions, and postoperative autotransfusions has been shown in our hospital experience with 320 cases and in the literature. We predict that autologous donor blood and autotransfusion will soon be widely accepted and utilized as the best and safest method of blood replacement.

Arterial thromboembolism. A 20-year perspective.

Our experience with 739 patients with lower extremity thromboembolism since the advent of the balloon catheter has led us to several important observations: As the etiology has shifted from rheumatic to atherosclerotic, we treat a more complex group of patients, one fourth of whom have severe, preexisting peripheral occlusive disease. Early diagnosis and treatment is essential to decrease the mortality and morbidity, which has ranged about 25% +/- 10%. Anticoagulation must be continued in the postoperative period, accepting wound hematomas as a fair "trade-off" to prevent recurrent embolus and distal thrombosis in areas inaccessible to the catheter. Postoperative use of heparin "buys time" to further assess marginal results of embolectomy allowing arteriography and careful planning of secondary operations to assure not only a viable but a functional limb. There is little mention in the literature to emphasize this approach, which we think is essential for long-term salvage. Early in the series, patients were treated with heparin or embolectomy alone. There were 161 secondary operations in 135 patients following embolectomy consisting of repeated thromboembolectomy, popliteal exploration, sympathectomy, bypass graft(s), angioplasty, and endarterectomy. Additionally, 44 patients had a direct attack correcting the cardiac source of their embolism. Our overall mortality (12%) and limb salvage (95%) shows marked improvement compared with earlier reports. Therefore, we recommend combined embolectomy and heparin as the primary choice of therapy.

The treatment of the expectant mother with deep venous thrombosis.

Experience with 12 expectant mothers with DVT from 1978 to 1983 supports heparin therapy. After early experience with four patients with various doses of intravenous and subcutaneous mini-heparin both in and out of the hospital, we have selected a program of outpatient, self-administered adjusted subcutaneous heparin. There has been no maternal or fetal mortality. There have been no serious bleeding or post-phlebitic complications, although two patients have had flare-ups of superficial phlebitis during the follow-up over the last four-and-a-half years. There have been three subsequent pregnancies, two of which were first trimester miscarriages and one uneventful term delivery of a normal infant.

Polytetrafluoroethylene vein composite grafts across the knee.

Fifteen Gore-tex vein composite femoral-popliteal artery bypass procedures were performed during the four year period of December 1975 to December 1979. Nine were performed for salvage of the limb and six, for incapacitating claudication. Preoperatively, all patients had an arteriographic evaluation of the outflow tract. CPR by the life-table method was 63 per cent at six years. Early failures were three occlusions within two months in patients with poor outflow. One late occlusion occurred at 16 months, and the limb was salvaged with a femoral tibial bypass graft. Another late occlusion was treated by thrombectomy at 24 months with continued patency. Late revision was carried out in one patient at seven months. This consisted of repair of a stenosis of the distal popliteal artery with salvage of the graft. Only two of ten grafts available for evaluation beyond one year have become occluded. All patients operated upon for claudication or with good runoff have patent grafts. On the contrary, none of the grafts to an isolated popliteal segment remained patent. When there is not sufficient autogenous saphenous vein available for femoral-popliteal bypass, the ready availability of a synthetic graft makes it an attractive choice. Nevertheless, our 63 per cent CPR at six years strongly suggests that the composite graft is a durable option.

Value of postoperative heparin therapy in peripheral arterial thromboembolism.

The experience with 359 patients with arterial thromboembolism from 1963 to 1982 has been reported. Combined operative and anticoagulant therapy appears the most beneficial form of treatment. Treatment with heparin after catheter embolectomy was associated with a decrease in mortality (7.6 percent), number of amputations (5 percent), and recurrent emboli (6 percent). Serious wound complications occurred less frequently than anticipated (8 percent). We advocate prompt arteriography and revascularization procedures to ensure long-term limb function after initial embolectomy for salvage, if the result is less than optimal or expected. Postoperative heparin seems to buy time in marginal cases, enabling secondary operations to ensure a satisfactory outcome in most patients.

Management of deep venous thrombosis and pulmonary embolism during pregnancy.

Despite venous stasis and a hypercoagulable state during pregnancy, the reported incidences of deep venous thrombosis and pulmonary embolism are remarkably low, about 1 in 2,000 and 1 in 10,000 cases, respectively. Mortality from antepartum thromboembolism has been reported in about 15 percent of untreated patients and less than 1 percent of treated patients. Adequate anticoagulant therapy significantly reduces maternal mortality and decreases postpartum morbidity. The proper anticoagulant agent for use during pregnancy has been widely debated. Coumarin compounds pass through the placenta and into the fetus. Hemorrhagic complications in the fetus are uncommon if prothrombin times are carefully controlled and if the drug is discontinued before delivery. However, coumarin during the first trimester has the teratogenic hazard of producing chondrodysplasia punctata. Heparin, in contrast, does not cross the placental barrier and is considered more effective treatment for deep venous thrombosis; however, long-term intravenous administration during pregnancy has been considered both impractical and possibly hazardous due to the risk of osteoporosis after 6 months of therapy. In our study, a combined regimen of intravenous and subcutaneous heparin was used successfully in four women with deep venous thrombosis. One patient who had recurrent embolization while on adequate intravenous heparin underwent vena caval clipping and had an uneventful Cesarian section at term with a normal infant. Another patient also underwent Caesarian section with a normal infant, while the other two women had normal vaginal deliveries at term. Miniheparin therapy was continued for 3 months postpartum, followed by long-term aspirin and Ascriptin therapy. Carefully controlled heparin therapy in a pregnant woman with deep venous thrombosis both safe and beneficial for mother and fetus.