Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide

SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the "synthetic pentasaccharide" (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 +/- 0.3 v 48 +/- 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 +/- 15 anti-factor Xa U/mg v 850 +/- 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti-factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti-factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50 values = 40.0 +/- 3.4 and 105.0 +/- 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti-factor Xa activity. SANORG 34006 enhanced rt-PA-induced thrombolysis and inhibited accretion of 125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.     

Anterior cervical corpectomy for cervical spondylotic myelopathy

OBJECTIVE: To evaluate the efficacy of anterior surgery for the treatment of cervical spondylotic myelopathy, we have reviewed our experience with anterior cervical corpectomy (ACC) at the University of Florida, specifically analyzing neurological outcomes and complications. These results have been compared with historical control subjects receiving laminectomy or "no treatment." METHODS: Between 1982 and 1992, 93 ACC operations were performed for the primary diagnosis of cervical spondylotic myelopathy. This consecutive series of patients was reviewed retrospectively. Age, gender, pre- and postoperative myelopathy severity, number of levels decompressed, and neurological complications were assessed. Myelopathy severity was graded using the Nurick myelopathy grading system. The average follow-up period was 39 months (range, 2-137 mo). RESULTS: Symptomatic improvement was achieved for 92% of patients (F = 28.9, df = 2172, P < 0.001). Nurick scores reflected improvement for 86% of patients, with the conditions of 13% remaining unchanged and only one patient showing worsening. Preoperative myelopathy severity was weakly correlated with age (P < 0.05) but was not correlated with gender or number of levels decompressed. Similarly, postoperative myelopathy severity was not significantly correlated with age, gender, preoperative myelopathy severity, or number of levels decompressed. ACC-treated patients showed an average improvement of 1.24 points on the Nurick scale, compared with an improvement of 0.07 points for patients treated with laminectomy (P < 0.001) and a deterioration of 0.23 points for patients undergoing conservative treatment (P < 0.001). Complications were slightly more likely to occur in older patients (P < 0.05). The number of levels decompressed was not significantly correlated with complications. Only one permanent neurological complication was seen in this series of patients. CONCLUSION: We conclude that ACC is a safe and effective treatment for cervical spondylotic myelopathy. In an average of 39 months, ACC showed improved results in terms of myelopathy scores, compared with historical control subjects receiving either no treatment or laminectomy. Age, gender, preoperative myelopathy severity, and extent of disease were not negative predictors of clinical outcomes.     

Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation

Normal human diploid fibroblasts have a finite replicative lifespan in vitro, which has been postulated to be a cellular manifestation of aging in vivo. Several studies have shown an inverse relationship between donor age and fibroblast culture replicative lifespan; however, in all cases, the correlation was weak, and, with few exceptions, the health status of the donors was unknown. We have determined the replicative lifespans of 124 skin fibroblast cell lines established from donors of different ages as part of the Baltimore Longitudinal Study of Aging. All of the donors were medically examined and were declared "healthy," according to Baltimore Longitudinal Study of Aging protocols, at the time the biopsies were taken. Both long- and short-lived cell lines were observed in all age groups, but no significant correlation between the proliferative potential of the cell lines and donor age was found. A comparison of multiple cell lines established from the same donors at different ages also failed to reveal any significant trends between proliferative potential and donor age. The rate of [3H]thymidine incorporation and the initial rates of growth during the first few subcultivations were examined in a subset of cell lines and were found to be significantly greater in fetal lines than in postnatal lines. Cell lines established from adults did not vary significantly either in initial growth rate or in [3H]thymidine incorporation. These results clearly indicate that, if health status and biopsy conditions are controlled, the replicative lifespan of fibroblasts in culture does not correlate with donor age.     

Evolution of carbohydrate metabolic pathways

Current studies of hyperthermophilic archaea and bacteria, the phylogenetically deepest-rooted and slowest-evolving extant organisms known, are allowing new insights into the nature of presumably ancient metabolic pathways. The apparent common occurrence of modified non-phosphorylated Entner-Doudoroff (ED) pathways among saccharolytic archaea and the absence of the conventional Embden-Meyerhof-Parnas (EMP) mode of glycolysis indicate that the ED pathway is the older route of carbohydrate dissimilation. However, gluconeogenesis via the "reversed" EMP route has been found in archaea. Thus, the EMP pathway was probably an anabolic pathway to begin with; its catabolic role came later, with the evolution of fructose phosphate kinases, using ATP, ADP or pyrophosphate as phosphate donors. Similarly, the presence of reductive reactions of the citric acid cycle in anaerobic archaea and the most deeply rooted bacteria, including autotrophs, indicates that the citric acid cycle was originally a reductive biosynthetic pathway.     

Modeling of interfacial intermetallic compounds in the application of very fine lead-free solder interconnections

Intermetallic compounds (IMCs) are formed between lead-free solders and base metals during soldering processes. The morphology as well as the amount of the IMCs, in particular the interfacial IMCs, are important to mechanical performance of the solder joints in their service environment. This is especially the case in state-of-art ultrafine-pitch wafer-level packaging, in which solder joints could become as small as 50 μm in diameter or even less. However, research addressing growth kinetics of the IMCs in the existing literature has concentrated on fitting experimental data onto a simple parabolic growth equation, which cannot account for all the complicated physics involved in the process of IMC formation. There are a few models based on Fick’s diffusion equations in the literature, which assume the growing IMC interface is planar. A combined thermodynamic–kinetic model has been derived from the relationships amongst some thermodynamic parameters; however, this model is only one dimension (1-D) in nature. 2-D models have also been proposed, e.g. an implicit boundary tracking method, and a phase field model. This paper reviews the modeling techniques in the literature for both the growth kinetics and morphology of the interfacial IMCs, under the context of lead-free soldering in very fine interconnections. The advantages and disadvantages of each method are discussed. Possible solutions to include the geometrical features of micro solder joints in the modeling of growth kinetics of interfacial IMC are presented.     

Hypoxic ventilatory responsiveness in Tibetan compared with Han residents of 3,658 m

Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations.     

Evaluation of two commercial kits for serum gastrin assay, and comparison with a conventional radioimmunoassay procedure

We compared two gastrin radioimmunoassay kits ("Immutope" kit, Squibb & Co.; "Gastrin R.I.A." kit, Schwarz/Mann) to the conventional gastrin radioimmunoassay of Yalow and Berson [Gastroenterology 58, 1 (1970)] as run by us and by a second reference laboratory. Although both kits were found to effectively discriminate above-normal and normal values for serum gastrin, they significantly underestimated very high values (greater than 1500 ng/liter). The Schwarz/Mann kit clearly had a superior quality label (lower nonspecific binding and higher specific activity) and a shorter incubation time. However, the 90-min incubation period cited for their kit caused overestimation of gastrin values in the lower range (5-300 ng/liter), which could be corrected by prolonging the incubation to 24 h. The Squibb antibody had fairly good cross reactivity to all gastrin species tested; the Schwarz/Mann antibody had poor affinity for natural human gastrin G34-II. Good correspondence was found for sera run by both reference laboratories (y = 0.96x + 10, r = 0.997), and values obtained with the Schwarz/Mann kit correlated best (+ 0.815) with those from the conventional radioimmunoassay procedure.     

Inhibition of feline collateral vessel development following experimental thrombolic occlusion

We compared development of feline hindlimb collateral circulation after acute occlusion of the terminal aorta by ligation, thrombus formation, and formation of a "closed" aortic loop containing thromboplastin. Collateral circulation development was assessed by aortograms, scintillation scans, neurological signs following occlusion, measurement of hindlimb muscle blood flow, and forelimb and hindlimb temperature. In cats in which aortic occlusion was the result of ligation or thromboplastin in the aortic loop, paralysis was not evident. Aortograms and scintillation scans indicated hindlimb blood flow. Both muscle temperature and blood flow data indicated that the return of blood flow was rapid. The 5th lumbar artery appears to be the origin of the collateral vessels. The mid-zone component is a dorsal and ventral vertebral route and an epaxial muscle route. The reentry components are the 6th or 7th lumbar arteries. The collateral vessels arise from preexisting collateral vessels. Of those cats in which aortic occlusion was the result of a thrombus, all exhibited paralysis. Aortograms, scintillation scans, muscle temperature, and hindlimb blood flow data indicated reduced hindlimb blood flow. The results suggest that the thrombus has an inhibitory effect on the development of collateral circulation.     

Bypass surgery for vascular disease of the carotid system

A series of 58 operations on 56 patients, in whom a branch of the superficial temporal artery was anastomosed to a branch of the middle cerebral artery (STA-MCA bypass or Yasargil procedure), is reviewed. These operations were performed chiefly for occlussions or for inaccessible stenotic lesions of the internal carotid or middle cerebral arteries. Patency in eight patients operated on from April 1971 through November 1973 was low (25%). Patency in patients operated on since July 1974 has been high (95%). There have been no deaths and no major ischemic strokes attributable to the surgery. The rationale for this procedure is considered in relationship to the anatomy and physiology of the cerebral circulation and the pathogenesis of syndromes of cerebral ischemia. The operation appears to have a low morbidity in good-risk patients. The role of this operation in managing common manifestations of cerebral vascular disease such as focal transient cerebral ischemic attacks (TIAs) and amaurosis fugax, although not fully established, appears encouraging. The procedure seems useful for orthostatic cerebral ischemia caused by multiple occlusions of major extracranial (and intracranial) vessels and, occasionally, for progressing strokes related to internal carotid artery occlusion, both of which are relatively uncommon manifestations of cerebral vascular occlusive disease. It may have application in the rare "slow stroke." The procedure is probably of limited value, if any, in the management of large completed infarcts but may be indicated in selected patients with small infarctions who have preserved most of their cerebral function and who have had evidence of subsequent focal ischemic events. The procedure is useful for bypassing giant aneurysms or basofrontal tumors invading major vessels. It may have a role in the management of fibromuscular disease of the internal carotid artery.     

Trigonometric Integrals for the magnetic field of the coil of rectangular cross section

Formulas are derived giving the vector potential and the magnetic field components of a general coil of rectangular cross section and constant winding density. The solution is given in a cylindrical coordinate system in terms of trigonometric integrals. The formulas presented have been cross-checked and validated against alternative expressions giving the various field components as integrals of expressions containing Bessel and Struve functions. The trigonometric integrals for the fields can be evaluated easily to several hundred significant figures using mathematical packages such as Maple or Mathematica. Alternatively, they can be evaluated with a small FORTRAN program. Sample results and field line plots obtained with the method are given, and the field of a coil of rectangular cross section is examined in some detail. A comparison with the results of a finite-element method is also given.