BedMachine v3: Complete Bed Topography and Ocean Bathymetry Mapping of Greenland From Multibeam Echo Sounding Combined With Mass Conservation.

Greenland's bed topography is a primary control on ice flow, grounding line migration, calving dynamics, and subglacial drainage. Moreover, fjord bathymetry regulates the penetration of warm Atlantic water (AW) that rapidly melts and undercuts Greenland's marine-terminating glaciers. Here we present a new compilation of Greenland bed topography that assimilates seafloor bathymetry and ice thickness data through a mass conservation approach. A new 150 m horizontal resolution bed topography/bathymetric map of Greenland is constructed with seamless transitions at the ice/ocean interface, yielding major improvements over previous data sets, particularly in the marine-terminating sectors of northwest and southeast Greenland. Our map reveals that the total sea level potential of the Greenland ice sheet is 7.42 ± 0.05 m, which is 7 cm greater than previous estimates. Furthermore, it explains recent calving front response of numerous outlet glaciers and reveals new pathways by which AW can access glaciers with marine-based basins, thereby highlighting sectors of Greenland that are most vulnerable to future oceanic forcing.

Gender differences in the effects of cardiovascular drugs.

Although sex-specific differences in cardiovascular medicine are well known, the exact influences of sex on the effect of cardiovascular drugs remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics, so that is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-based drugs thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than men, and remain underrepresented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardiovascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these sex-related differences is fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strategies both in men and women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovascular drugs and provides recommendations to close the gaps in our understanding of sex-specific differences in drug efficacy and safety.

Description of Tessaracoccus profundi sp.nov., a deep-subsurface actinobacterium isolated from a Chesapeake impact crater drill core (940 m depth).

A novel actinobacterium, designated CB31(T), was isolated from a 940 m depth sample of a drilling core obtained from the Chesapeake meteor impact crater. The strain was isolated aerobically on R2A medium agar plates supplemented with NaCl (20 g l(-1)) and MgCl2 x 6 H2O (3 g l(-1)). The colonies were circular, convex, smooth and orange. Cells were slightly curved, rod-shaped in young cultures and often appeared in pairs. In older cultures cells were coccoid. Cells stained Gram-positive, were non-motile and did not form endospores. The diagnostic diamino acid of the peptidoglycan was LL: -diaminopimelic acid. The polar lipids included phosphatidylglycerol, diphosphatidglycerol, four different glycolipids, two further phospholipids and one unidentified lipid. The dominant menaquinone was MK-9(H(4)) (70%). The major cellular fatty acid was anteiso C15:0 (83%). The DNA G + C content was 68 mol%. The strain grew anaerobically by reducing nitrate to nitrite or by fermenting glucose. It was catalase positive and oxidase negative. It grew between 10 and 45 degrees C, with an optimum between 35 and 40 degrees C. The pH range for growth was 5.7-9.3, with an optimum at pH 7.5. The closest phylogenetic neighbors based on 16S rRNA gene sequence identity were members of the genus Tessaracoccus (95-96% identity). On the basis of phenotypic and phylogenetic distinctiveness, strain CB31(T) is considered to represent a novel species of the genus Tessaracoccus, for which we propose the name Tessaracoccus profundi sp. nov.. It is the first member of this genus that has been isolated from a deep subsurface environment. The type strain is CB31(T) (=NCIMB 14440(T) = DSM 21240(T)).

Biocorrosion and biofilm formation in a nutrient limited heating system subjected to alternating microaerophilic conditions.

Severe biofilm formation and biocorrosion have been observed in heating systems even when the water quality complied with existing standards. The coupling between water chemistry, biofilm formation, species composition, and biocorrosion in a heating system was investigated by adding low concentrations of nutrients and oxygen under continuous and alternating dosing regimes. Molecular analysis of 16S rRNA gene fragments demonstrated that the amendments did not cause changes in the overall bacterial community composition. The combined alternating dosing of nutrients and oxygen caused increased rates of pitting (bio-) corrosion. Detection of bacteria involved in sulfide production and oxidation by retrieval of the functional dsrAB and apsA genes revealed the presence of Gram-positive sulfate- and sulfite-reducers and an unknown sulfur-oxidizer. Therefore, to control biocorrosion, sources of oxygen and nutrients must be limited, since the effect of the alternating operational conditions apparently is more important than the presence of potentially corrosive biofilm bacteria.

Mannan-binding lectin is a determinant of survival in infective endocarditis.

Mannan-binding lectin (MBL) is a collectin plasma protein activating the lectin pathway of the complement system, enhancing opsonophagocytosis and modulating the cytokine response to inflammation. Deficiency of MBL, caused by structural mutations or promoter polymorphisms in the MBL2 gene, has been associated with increased susceptibility to infection and autoimmune disease. Thus, as infective endocarditis remains a severe disease requiring intensive and long-term treatment with antibiotics, we examined whether there was an association between MBL and clinical outcome in 39 well-characterized patients with infective endocarditis. Five patients (13%) had MBL concentrations < 100 microg/l and were considered MBL-deficient. This proportion was similar to that in a healthy control group of blood donors. Mortality 3 months after diagnosis was 20% in patients with MBL-deficiency and 9% in patients with normal MBL. The 5-year mortality was 80% and 25%, respectively. MBL-deficiency was on univariate survival statistics associated with significantly higher mortality on follow-up (P=0 x 03). In conclusion, this is the first report of an association between MBL-deficiency and survival in infective endocarditis. The present observation is important, as replacement therapy in MBL-deficient patients is possible. For certain high-risk subgroups, it opens new perspectives for improvement of treatment and outcome in infective endocarditis.

Severe intracellular magnesium and potassium depletion in patients after treatment with cisplatin.

The purpose of this study is (1) to evaluate skeletal muscle magnesium (Mg) and potassium (K) during treatment with cisplatin; (2) to evaluate the predictive value of plasma (P)-Mg for intracellular Mg during cisplatin treatment; and (3) to evaluate whether changes in intracellular K influence skeletal muscle Na,K-ATPase. In all, 65 patients had a needle muscle biopsy obtained before and 26 patients both before and after cisplatin treatment. Biopsies were analysed for Mg, K, and Na,K-ATPase concentrations, and P-Mg and P-K determined. Treatment with a total dose of approximately 500 mg (270 mg m(-2) surface area) cisplatin over 80 days was associated with reductions in muscle [Mg] (95% CI) (8.95 (8.23-9.63) to 7.76 (7.34-8.18) mumol g(-1) wet wt. (P<0.01), and muscle [K] (90.81 (83.29-98.34) to 82.87 (78.74-87.00) mumol g(-1) wet wt. (P<0.05), as well as in P-Mg 0.82 (0.80-0.85) to 0.68 (0.64-0.73) mmol l(-1) (P<0.01 but not in P-K (4.0 (3.8-4.1) vs 3.8 (3.7-4.0) mmol l(-1)). No simple correlations were observed between P-Mg and muscle [Mg], or between P-K and muscle [K], either before (n=65) or after (n=26) treatment with cisplatin. The changes in [Mg] and [K] were not associated with changes in the muscle Na,K-ATPase concentration. Following treatment with cisplatin, an approximately 15% decline in P-Mg was accompanied by an approximately 15% loss of muscle [Mg], as well as an approximately 10% reduction of muscle [K] and fatigue and muscle weakness previously ascribed to hypomagnesaemia may therefore also be well explained by muscle K depletion observed despite normal levels of P-K. There was no correlation between P-Mg and SM-Mg or between P-K and SM-K. Thus, P-Mg and P-K are not reliable indicators for Mg and K depletion during treatment with cisplatin. However, the majority of patients will present Mg and K depletion after cisplatin therapy and of these only very few patients will present a low P-Mg or P-K. Therefore, routine supplementation should be considered in all patients receiving cisplatin.

Diabetes- and semi-starvation-induced changes in metabolism and regulation of Na,K-ATPase in rat heart.

AIMS/HYPOTHESIS: In comparison with healthy controls, rats with streptozotocin-induced diabetes exhibit retarded gain in body weight. This is generally attributed to lowered protein synthesis resulting from abnormal metabolism. Furthermore, decreased abundance and activity of Na,K-ATPase in heart and skeletal muscle has been described. However, decreased gain in body weight per se is accompanied by a down-regulation of skeletal muscle Na,K-ATPase. Thus, the aim of the present study was to evaluate cardiac Na,K-ATPase in semi-starvation and diabetes. METHODS: Diabetes was induced in male Wistar rats with streptozotocin. In healthy parallel running control rats body weight gain was kept reduced by limited food intake. RESULTS: Semi-starved and diabetic rats demonstrated 18 and 16% (p < 0.05) retarded gain in body weight after 63 days. As compared to semi-starved rats, diabetic animals exhibited a 59-273% (p < 0.05) increase in glucose, glycohaemoglobin, triglyceride and cholesterol plasma levels. Activity of heart K-pNPPase, reflecting Na,K-ATPase, in crude membrane homogenates was reduced by 29 and 10% (p < 0.05) by diabetes and semi-starvation. The age-dependent reduction in heart K-pNPPase in normal controls was 6%. After subtracting the age-dependent change, the reductions were 25 and 4% in diabetes and semi-starvation, respectively. After subtracting the semi-starvation-associated change, the diabetes-induced reduction was 22-27%. The reduction was in accord with measurements of Na,K-ATPase activities in partially purified membranes, Na,K-ATPase isoforms and cytochemical evaluations. Expressed per heart, the reduction in Na,K-ATPase was 30%. CONCLUSIONS/INTERPRETATION: Streptozotocin-induced diabetes selectively reduces heart Na,K-ATPase concentration by around 1/4, which reduces the capacity of the heart for maintaining K- and Ca-homeostasis. This may pose a risk of arrhythmias and may be associated with heart failure in diabetic cardiomyopathy.

Myocardial Na,K-ATPase: the molecular basis for the hemodynamic effect of digoxin therapy in congestive heart failure.

Congestive heart failure may be deemed the epidemic of cardiology in the 21st century in the industrialized part of the world. Although new therapies improving morbidity and mortality from chronic heart failure have emerged it is likely that there is a growing role for digoxin. Thus, digoxin treatment is known to control symptoms of congestive heart failure when added to standard therapy. In this setting, we review the prevailing knowledge of the Na,K-ATPase, the cellular receptor for the inotropic action of digitalis glycosides, in relation to the hemodynamic effect of digoxin. It is concluded that if improvement of hemodynamics is needed in congestive heart failure, this knowledge should be taken into account and in many cases digoxin should be added to standard therapy. Digoxin is still the only safe inotropic drug for oral use that improves hemodynamics. Digoxin should be used to heart failure patients in sinus rhythm when they after institution of mortality reducing treatment still have heart failure symptoms, and to patients intolerant to heart failure mortality reducing drugs. Digoxin should probably in heart failure patients with sinus rhythm be given in the lowest possible dose that relieves symptoms sufficiently.

Receptor occupancy with digoxin vs receptor occupancy with a putative endogenous digitalislike factor.

The possibility that an endogenous ligand for the digitalis receptor might exist has been a source of speculation resulting in efforts over the past decades to identify such a hormone. In the current context it is of interest that prolonged wash of myocardial and skeletal muscular samples from subjects who were not in digoxin treatment generally resulted in small tendencies to increase 3H-ouabain binding ranging from 2 to 9% and from -2 to 7%, respectively. It may be appreciated that neither wet weight nor water content of left ventricular or skeletal muscular samples have been found to change as a result of the prolonged wash. Although these tendencies most likely are a mere play of chance, it may be argued that the studies did not entirely rule out the possibility of the existence of a quantitatively small amount of endogenous digitalislike factor. However, based on the evaluations of receptor occupancy with digoxin during treatment of 24-34% in the left ventricle and 9-13% in skeletal muscle, it would seem reasonable to expect that a comparatively larger fraction of digitalis receptors should be occupied by a putative endogenous digitalislike factor, if such a factor were to be of any physiological significance.

HMG CoA reductase inhibition reduces sarcolemmal Na(+)-K(+) pump density.

OBJECTIVES: HMG CoA reductase inhibitors reduce cellular availability of mevalonate, a precursor in cholesterol synthesis. Since the cholesterol content of cell membranes is an important determinant of Na(+)-K(+) pump function we speculated that treatment with HMG CoA reductase inhibitors affects Na(+)-K(+) pump activity. METHODS: We treated rabbits and rats for 2 weeks with the HMG CoA reductase inhibitor lovastatin and measured Na(+)-K(+) pump current (I(p)) in isolated rabbit cardiac myocytes using the whole cell patch-clamp technique, K-dependent p-nitrophenyl phosphatase (p-NPPase) activity in crude myocardial and skeletal muscle homogenates, and vanadate-facilitated 3H-ouabain binding in intact skeletal muscle samples from rats. RESULTS: Treatment with lovastatin caused statistically significant reductions in I(p), myocardial and skeletal muscle K-dependent p-NPPase activity and 3H-ouabain binding in the myocardium and skeletal muscle. The lovastatin-induced decrease in I(p) was eliminated by parenteral co-administration of mevalonate. However, this was not related to cardiac cholesterol content. CONCLUSIONS: Treatment with lovastatin reduces Na(+)-K(+) pump activity and abundance in rabbit and rat sarcolemma.

Na,K-ATPase in the myocardium: molecular principles, functional and clinical aspects.

The role that Na,K-ATPase plays in Na+ and K+ antiport through the sarcolemma, in cation-homeostasis in cardiomyocytes as well as in excitation-contraction coupling and cell signalling in the myocardium is now widely recognized. It was its key importance for the cell membrane function that kept this enzyme intensively studied during the last three decades and finally brought to its discoverer the deserved Nobel Prize. Almost weekly are appearing new data concerning structure, function, regulation and role of the Na,K-ATPase in different physiological and pathological conditions. The special importance of the enzyme for heart function as well as the great amount of data that is concerned specifically with the heart Na,K-ATPase and accumulated since yet, started to call for setting them in order. The present paper updates basically important data on the cardiac Na,K-ATPase in relation to its specific properties, molecular mechanisms of function, mode of action, humoral and pharmacological modulation, adaptability, physiological role and clinical aspects.

Hyperaldosteronemia in rabbits inhibits the cardiac sarcolemmal Na(+)-K(+) pump.

Aldosterone upregulates the Na(+)-K(+) pump in kidney and colon, classical target organs for the hormone. An effect on pump function in the heart is not firmly established. Because the myocardium contains mineralocorticoid receptors, we examined whether aldosterone has an effect on Na(+)-K(+) pump function in cardiac myocytes. Myocytes were isolated from rabbits given aldosterone via osmotic minipumps and from controls. Electrogenic Na(+)-K(+) pump current, arising from the 3:2 Na(+):K(+) exchange ratio, was measured in single myocytes using the whole-cell patch clamp technique. Treatment with aldosterone induced a decrease in pump current measured when myocytes were dialyzed with patch pipette solution containing Na(+) in a concentration of 10 mmol/L, whereas there was no effect measured when the solution contained 80 mmol/L Na(+). Aldosterone had no effect on myocardial Na(+)-K(+) pump concentration evaluated by vanadate-facilitated [(3)H]ouabain binding or by K(+)-dependent paranitrophenylphosphatase activity in crude homogenates. Aldosterone induced an increase in intracellular Na(+) activity. The aldosterone-induced decrease in pump current and increased intracellular Na(+) were prevented by cotreatment with the mineralocorticoid receptor antagonist spironolactone. Our results indicate that hyperaldosteronemia decreases the apparent Na(+) affinity of the Na(+)-K(+) pump, whereas it has no effect on maximal pump capacity.

A novel missense mutation, Leu390Val, in the cardiac beta-myosin heavy chain associated with pronounced septal hypertrophy in two families with hypertrophic cardiomyopathy.

OBJECTIVE: An examination of the genetic background and phenotypic presentation of familial hypertrophic cardiomyopathy (FHC) with respect to specific mutations in the MYH7-gene encoding the cardiac beta-myosin heavy chain. SETTINGS: Two families (n = 22) from a cohort of 67 families with FHC were studied at the National University Hospital, Rigshospitalet, Copenhagen. METHODS: Clinical, non-invasive examinations of all included family members followed by molecular genetic analysis including PCR-single strand conformation polymorphism/heteroduplex (SSCP/HD) analysis and sequencing of exon 3-23 of the MYH7-gene. RESULTS: We found FHC associated with a missense mutation in two families, i.e. a C > G transversion at position g10124 and a G > T transversion at position g10126 causing the change of a leucine residue at codon 390 to a valine residue. The mutation is located in the actin-binding region of the beta-myosin heavy chain. The leucine residue is evolutionarily conserved in vertebrate myosins. In the two families, the phenotypic presentations in the clinically affected were characterized by asymmetric septal hypertrophy (septum diameter 18.8 (5.0) mm (mean (SD)) with only minor involvement of the left ventricular free wall (posterior wall diameter 11.0 (2.2) mm). Furthermore, the left ventricular systolic and diastolic functions were well preserved, even at a high age. The symptomatic status of the clinically affected patients depended on the presence or absence of a concomitant left ventricular outflow tract gradient. CONCLUSIONS: We report a novel missense mutation associated with FHC caused by a double nucleotide transversion. The penetrance of the mutation was not complete, but in clinically affected patients the mutation gives rise to an echocardiographic phenotype, predominantly characterized by pronounced septal hypertrophy.

Outcome of septal myectomy in patients with hypertrophic obstructive cardiomyopathy.

OBJECTIVES: To study the outcome of septal myectomy in patients with hypertrophic obstructive cardiomyopathy. DESIGN: Septal myectomy in patients with hypertrophic cardiomyopathy with obstruction of the left ventricular outflow tract (HOCM) is symptomatically effective, and complication rates have been found to be low in large centres performing the procedure routinely. Representing a small centre we studied the outcome after septal myectomy in 11 consecutive patients, aged 44 +/- 21 (mean +/- SD) years with HOCM myectomized at our institution from 1991 to 1998. The patients were evaluated preoperatively using echocardiography and left-sided heart catheterization. RESULTS: Eight patients were operated on after medical treatment had failed and three after sudden deterioration of cardiac function. A Morrow myectomy was performed in 10 patients and a modified Konno procedure in one. Significant reductions were observed in left ventricular outflow tract gradients (77 +/- 29 to 10 +/- 7 mmHg, p < 0.01; n = 11), the degree of mitral valve regurgitation (grades 0-3) (1.7 +/- 1.0 to 0.8 +/- 0.7, p < 0.01; n = 11), NYHA functional classification score (2.4 +/- 1.0 to 1.5 +/- 0.7, p < 0.01; n = 11) and all five patients with angina preoperatively had an improved CCS angina classification score. There were no operative or early postoperative (30 days) deaths. One patient operated on with the modified Konno procedure was reoperated for a septal patch suture leak. During follow-up (43 +/- 24 months, range 11-83), the linearized mortality rate was 3.6% per year. One patient died from a pancreas cancer, one probably from coronary artery disease and one suddenly of unknown cause. CONCLUSION: We conclude that septal myectomy efficiently relieves symptoms in HOCM patients, possibly reflecting the direct as well as secondary effects of left ventricular outflow tract gradient reduction. The present results, obtained at a smaller centre for this procedure, should be considered when choosing from available therapeutic alternatives when medical therapy fails: dual chamber pacemaker implantation, percutaneous transluminal septal myocardial ablation or myectomy.