Direct ink writing of catalytically active UiO-66 polymer composites.

Metal-organic frameworks (MOFs) hold significant potential for use in gas storage, sensing and catalysis. To uncover this potential, MOF processing must develop in line with MOF materials. Here, direct ink writing-based 3D printing of UiO-66 MOF composites and their thermal treatment give mechanically stable yet highly porous composites effective for the catalytic breakdown of methyl-paraoxon, a simulant of highly toxic organophosphate nerve agents.

Declining cardiovascular disease incidence and environmental components.

After rising for many years in the mid-to-late 1930s the mortality from ischaemic heart disease (IHD) began to decline in many countries. This represents a decline in both out-of-hospital (community) and hospital deaths. Non-fatal myocardial infarction (MI) has also declined. A literature review was conducted to examine lifestyle and environmental factors contributing to the decline. Half of the decline is attributable to changes in lifestyle and in the known major risk factors. Changes in nutrition appear relevant to the decline, in particular an increased ratio of polyunsaturated to saturated fat intake and a reduced saturated fat intake overall. There is little evidence to support a role of changing alcohol consumption, changing coffee consumption, changing exercise levels or reduction in excess weight in the declining incidence of IHD. While the benefit of smoking cessation is a clear one, its impact on the differing trends in various countries is not clear. Socio-economic factors appear to influence the rate and extent of decline in IHD in different groups and may help explain some of the regional differences in IHD incidence. Reductions in blood pressure within the 'normal range' which may occur with lifestyle changes may also be an important contributor.

A general-practice study of the efficacy and tolerability of metoprolol in mild essential hypertension.

The efficacy and tolerability of metoprolol (100 mg once a day) were assessed in general practice in 6713 newly-diagnosed or previously-treated hypertensive patients in an open study of eight weeks' duration. In 3534 mildly-hypertensive patients who were eligible for the efficacy analysis, the mean blood pressure level was reduced by 19/10 mmHg; 68% of the patients achieved diastolic blood pressures below 90 mmHg by the end of the assessment period. Of 6557 patients who were eligible for the tolerability analysis, only 5.6% of patients withdrew because of adverse events. The incidence of adverse events diminished considerably from the clinic assessment at four weeks (20%) to that at eight weeks (11%). At the completion of the study, 92% of the mildly-hypertensive patients were to continue with metoprolol, either as monotherapy (including 64% of patients who were receiving 100 mg once a day and 6% of patients who were receiving 50 mg once a day), or as combination therapy. Analysis of the large subgroup of mildly-hypertensive elderly patients (n = 1214) and of moderately-hypertensive patients, whose diastolic pressures exceeded the set upper limits (n = 2505), showed similar efficacy and tolerability results. Sixty-eight per cent of the former and 47% of the latter demonstrated satisfactory control of blood pressure. These results show that the majority of mildly-hypertensive patients can be controlled with 50-100 mg of metoprolol once a day.

Differences in left ventricular function between anterior and inferior myocardial infarction of equivalent enzymatic size.

The reasons for the poorer prognosis of anterior versus inferior myocardial infarction of equivalent enzymatic size remain uncertain. We investigated whether there are differences in left ventricular function between patients with anterior and inferior infarctions of equivalent enzymatic size to account for their differing outcomes. Clinical, serum enzyme, and electrocardiographic data were prospectively recorded in a consecutive series of patients less than 70 years of age with their first myocardial infarction. At 29 +/- 6 days following infarction, ejection fraction and left ventricular wall motion were assessed by gated heart scintigraphy and functional capacity by treadmill exercise testing in 19 patients with anterior and in 23 patients with inferior myocardial infarction. Peak creatine kinase and QRS scores were used to estimate total infarct size and left ventricular infarct size respectively. The anterior infarcts were of similar size to the inferior infarcts as determined by peak creatine kinase (1444 [mean] +/- 1161 [SD] U/L versus 1484 [mean] +/- 1182 [SD] U/L, respectively, P = 0.91) and peak aspartate transaminases (174 +/- 112 U/L versus 164 +/- 102 U/L, P = 0.78). The anterior myocardial infarct group had a greater percentage of the left ventricle infarcted on QRS scoring than the inferior infarct group (25.9 +/- 14.4% versus 11.1 +/- 6.0% respectively, P = 0.0004), lower global left ventricular ejection fraction (45.8 +/- 16% versus 54.6 +/- 9.2%, P = 0.04) and greater left ventricular regional wall abnormality. A significant negative correlation existed between left ventricular ejection fraction and peak creatine kinase for both groups, but was more marked with anterior infarction (r = -0.78, P less than 0.01) compared with inferior infarction (r = -0.49, P less than 0.05). Exercise-induced ST segment elevation was more frequent in the anterior than the inferior infarct group (59% versus 18%, P less than 0.02). However, both infarct locations had similar exercise tolerance, exercise-induced angina and ST segment depression. Despite equivalence of infarct size of the two infarct locations on enzyme testing, anterior infarction was associated with greater abnormality of left ventricular function with lower resting global left ventricular ejection fraction; greater resting left ventricular regional wall abnormality and greater exercise-induced ST segment elevation. These differences probably contribute to the poorer prognosis of patients with anterior infarction compared to those with inferior infarction of equivalent enzymatic size, given the previously well-documented prognostic importance of left ventricular function.

Anterior ST segment depression in inferior myocardial infarction: effect on complications and long-term survival.

The effect of anterior ST segment depression in inferior myocardial infarction on early complications and long-term prognosis was studied. A modification of the Minnesota Code was used for grading the extent of ST segment depression in leads V2 to V4 on the first hospital electrocardiogram. In 267 patients with acute inferior myocardial infarction, 107 had isoelectric anterior ST segments, 84 had minor (less than or equal to 0.5 mm) depression, and 76 had major (greater than 0.5 mm) depression. Patients with anterior ST segment depression had higher serum enzyme levels, higher Norris coronary prognostic indices, and more frequent cardiac failure during the acute stages, but similar 28 day case fatality rate (11.1%) compared with patients without anterior ST segment depression (12.6%). In the subsequent four years total cardiac death rates were not significantly different and the pattern of survival was not influenced, but there was a higher fatal re-infarction rate in patients with major anterior ST segment depression. Thus, anterior ST segment depression in inferior myocardial infarction was associated with more severe infarction in the early phase but was not a reliable marker of high risk after recovery. Selection of patients for further investigation should not be based on this observation alone.

Prognostic significance of electrocardiographic site of infarction after correction for enzymatic size of infarction.

To assess whether the site of myocardial infarction is an independent prognostic indicator, the outcome of patients with anterior myocardial infarction was compared with that of patients with inferior infarction. A consecutive series of patients who had suffered their first myocardial infarction was analyzed (398 with anterior and 391 with inferior infarction). Patients with anterior myocardial infarction had a higher 1 year mortality than those with inferior infarction (18.3% vs 10.5%, p = .002). When patients were matched for infarct size determined by peak creatine kinase (CK) level expressed as a multiple of the upper limit of normal, those with anterior myocardial infarction tended to have a higher 1 year mortality than those with inferior infarction for all subgroups of peak CK. Early mortality (day 1 to 28 after myocardial infarction) was greater in the anterior than in the inferior myocardial infarction group (10% vs 6.4%, p = .03); this was most significant when peak CK was greater than four times normal (12.4% vs 7.0%, p = .04). Late mortality was also higher in the anterior (8.4% vs 4.1%, p = .04) than the inferior infarction group and this was most significant when peak CK was less than two times normal (15.2% vs 0%, p = .02) or greater than eight times normal (10.6% vs 4.1%, p = .04). Multivariate analysis with proportional-hazards regression confirmed the prognostic significance of location of infarction independent of peak CK level. Thus, infarct location was found to be a predictor of prognosis that is independent of infarct size based on peak CK levels.

Carcinoma of uterine cervix with myocardial metastases associated with chest pain and asystolic arrest.

We report a case of secondary deposition of carcinoma of the uterine cervix in the myocardium with development of ischaemic cardiac pain, ST segment elevation and asystolic cardiac arrest. The coronary arteries were free of obstruction. To the best of our knowledge, this is a unique presentation of a rare myocardial metastasis.

Metastatic uterine cervical cell carcinoma to myocardium.

Metastatic involvement of the myocardium is a rare premorbid diagnosis. Multiple examinations were performed on a 43-year-old woman who presented with ischemic chest pain, palpitations, and nausea. Twelve months previously, a poorly differentiated squamous cell carcinoma of the uterine cervix was removed with no evidence of metastases or residual tumor. Following numerous investigations, a provisional diagnosis of cardiac tumor was made. At operation, involvement of the septum, inferior wall, and apex with some extension into the distal anterior wall was noted. Histology confirmed nonkeratinizing cell carcinoma in keeping with metastases from the uterine cervix.

Cross-sectional echocardiographic diagnosis of unruptured right sinus of Valsalva aneurysm dissecting into the interventricular septum.

We present a case of an unruptured right coronary sinus of Valsalva aneurysm with dissection into the interventricular septum diagnosed pre-operatively by cross-sectional echocardiography. The unique echocardiographic features of this rare, although potentially fatal congenital lesion, are described.

Toxic shock syndrome -- some new features.

A thirty-year-old female presented with a high fever, conjunctivitis, confusion, vomiting, watery diarrhoea, diffuse erythroderma, shock and oliguric renal failure. Staphylococcus aureus phage 29/52 (Group 1) was isolated from a high vaginal swab. In addition to all the previously reported features which defined toxic shock syndrome, there were pustular skin vesicles, altered red cell morphology, and severe myocardial involvement. Treatment with fluid replacement, cloxacillin, haemodialysis, positive inotropic agents, and supportive measures resulted in a full recovery.

The influence of heart rate on digoxin-induced inhibition of myocardial Na+-K+-ATPase activity in the dog.

1. Groups of sedated dogs were studied at spontaneous heart rates (HR), 55-100/min, or at paced HR 200/min, with or without intravenous digoxin administration. After 60 min, active rubidium uptake (86 Rb+) of ventricular samples was determined in vitro. 2. Untreated fast and slow HR groups had similar uptakes. Following digoxin, 0.08 mg/kg, uptake was less at fast than slow HR (63.8, s.e.m. = 4.5 v. 87.5, s.e.m. = 5.0 pmol/mg LV/15 min, P less than 0.01). After 0.125 mg/kg, values were again lower in the fast HR group in which five of seven developed ventricular tachycardia. 3. Heart rate does not alter in vitro activity of myocardial Na+-K+-ATPase but does influence inhibition of the enzyme resulting from digoxin administration.

Cardiac beta-adrenoreceptors in the thyroxine-treated dog.

1. Myocardial beta-adrenoreceptors, assessed in membrane preparations of left ventricle by 3H-dihydroalprenolol binding, were compared in dogs following thyroxine administration (n = 6), aorto-caval fistula (n = 12), and in normal dogs (n = 7). 2. Left ventricular hypertrophy occurred in response to both aorto-caval fistula and thyroxine treatment. Yield of myocardial membrane between the different groups was not significantly different. 3. Binding site concentration (pmol/mg membrane protein) in dogs with aorto-caval fistulae was similar to that in normal dogs and was not significantly influenced by the presence or absence of cardiac failure, degree of hypertrophy or duration of fistula. 4. Thyroxine-treated dogs had an increased concentration of binding sites (c. 1.8-fold) compared with both fistula and normal groups, while binding affinities were similar in all groups. 5. The data suggest that beta-adrenoreceptor concentrations in myocardium increase as a direct result of thyroid hormone action rather than as a result of secondary haemodynamic changes or ventricular hypertrophy.

Age dependence of myocardial Na+-K+-ATPase activity and digitalis intoxication in the dog and guinea pig.

Infants and young animals tolerate higher doses of digitalis glycosides, relative to body weight, than adults. One possible explanation for this could be an age-dependent difference in the myocardial digitalis receptor, the Na+-K+-ATPase. Two functions of this enzyme were studied in adult, 1- and 6-week-old dogs and guinea pigs: in vitro myocardial uptake of rubidium (86Rb) and binding of ouabain. In guinea pigs, rubidium uptake (pmol Rb/mg LV per 15 min) was: 1 week old: 100.9 +/- 7.1 (mean +/- SE); 6 week: 79.8 +/- 6.7 adult: 55.2 +/- 7.9; (1 week: 6 week: P less than 0.025; 1 week: adult, P less than 0.001; 6 week: adult, P less than 0.025). Similarly in dogs, rubidium uptake was significantly greater at 1 week than at 6 weeks (208 +/- 13 vs. 144 +/- 9; P less than 0.001) and the latter greater than in adults (111 +/- 4) (P less than 0.005). Other groups of anesthetized adult and 6-week-old dogs were given digoxin, 0.3 mg/kg, iv. The young dogs took significantly longer to become cardiotoxic (17.3 +/- 3.4 min vs. 9.3 +/- 1.4 min; P less than 0.025), while their myocardial digoxin uptake was at least as great. Rubidium uptake showed an average decrease of 56% after digoxin but residual uptakes were not different in the two groups. Data for ouabain binding showed similar differences between the various groups of dogs studied. Increased myocardial Na+-K+-ATPase activity, reflected in greater active cation transport and specific enzyme binding, has been demonstrated in young animals and may be partly responsible for their greater tolerance to digitalis glycosides.

Entry of quinidine into cerebrospinal fluid.

Some of the unwanted effects of quinidine commonly occurring in clinical practice involve the central nervous system. We therefore assessed the rate and extent of quinidine passage into cerebrospinal fluid (CSF) in humans and dogs. In eight human subjects receiving oral quinidine therapy, lumbar CSF quinidine concentrations averaged 16% of unbound serum concentrations (range: 4% to 37%). The findings were confirmed when simultaneous serum (total and unbound) and CSF quinidine concentrations were followed for up to 8 hours after a single intravenous dose of quinidine in anesthetized dogs. Quinidine appeared promptly in CSF of all animals, but CSF concentrations averaged only 37% to 46% of unbound serum levels. The in vitro octanol:water partition coefficient for quinidine at physiologic pH was greater than 100, indicating that unbound quinidine should readily traverse the blood-brain barrier. Thus, passage of quinidine into CSF appears not to be governed by passive diffusion alone. Quinidine may participate in an active transport system such as that which removes certain other basic substances from CSF.

Entry of diazepam and its major matabolite into cerebrospinal fluid.

Five dogs received a single 1.0 mg/kg dose of diazepam (DZ) IV. Concentrations of DZ and its major metabolite desmethyldiazepam (DMDZ) were simultaneously measured in plasma and cisternal cerebrospinal fluid (CSF) for up to 8 h after the dose by electron-capture gas-liquid chromatography. DZ was rapidly eliminated from plasma (half-life 0.3--1.3 h); DZ disappearance was mirrored by formation of DMDZ, which in turn was eliminated slowly, Both DZ and DMDZ rapidly penetrated CSF and concentrations in CSF declined parallel with those in plasma. Despite rapid uptake, the extent of CSF transfer of DZ and DMDZ was limited by plasma protein binding. Mean CSF:plasma concentrtion ratios for DZ (range 0.023--0.137) and DMDZ (range 0.047--0.119) were highly correlated with the unbound fraction in plasma (r = 0.95 and 0.80, respectively). Thus DZ and DMDZ concentrations in CSF, presumed to reflect concentrations at the site of action, are determined by unbound plasma concentrations. The intensity of pharmacologic action is more likely to correlate with unbound than with total plasma concentrations.

Immunogenicity and kinetics of distribution and elimination of sheep digoxin-specific IgG and Fab fragments in the rabbit and baboon.

To evaluate the relative merits of purified IgG and Fab preparations of defined specificity for potential clinical use, immunogenicity studies were carried out in baboon and rabbit experimental models. Distribution and elimination kinetics of purified sheep digoxin-specific IgG and Fab fragments were also studied following intravenous administration to baboons. Serial plasma and urine Fab concentrations were determined from trichloroacetic acid-precipitable 125I counts from pre-labelled preparations and also by measurement of the antibody's functional 3H-digoxin binding capacity. Results were compared with data obtained from IgG by 3H-digoxin binding. Kinetic data analysed by computer-fitted functions demonstrated that plasma Fab disappearance was best described by a tri-exponential function, whereas a bi-exponential function best described the IgG data. Initial distribution half-life (t 1/2) of Fab (0.28-0.32 hr) was considerably shorter than that of IgG (4.0 hr) and contributed a greater proportion of the total fall in plasma level over 24 hr. Fab elimination t 1/2 (9-13 hr) was also shorter than IgG (61 hr), but appreciably longer than earlier estimates in rabbits, guinea-pigs, rats and mice. The total volume of distribution of Fab was 8.7 times greater than that of IgG measured by the same method. Over the first 24 hr after administration 30-45% of administered Fab was recoverable in active form in urine, while 93% of total administered 125I counts from 125I-Fab preparations (bound and free) could be recovered. Less than 1% of administered IgG binding activity was recovered in urine during the initial 24 hr. The relative immunogenicities of sheep digoxin-specific IgG and Fab fragments were studied in six baboons. Both IgG and Fab elicited prompt immune responses when injected intramuscularly with Freund's complete adjuvant. Intravenous injection of soluble sheep IgG resulted in a prompt immune response in one baboon while repeated injections caused only a late, weak response in a second animal. Soluble sheep Fab fragments elicited only delayed and weak responses in the two baboons thus challenged. Further immunogenicity studies in ninteen rabbits showed significantly earlier and greater antibody responses to intravenously administered sheep IgG antigen than to Fab fragments derived from the same IgG population. These studies demonstrate that digoxin-specific Fab fragments undergo more rapid and extensive distribution to the extra vascular compartment and also more rapid renal excretion than IgG. Furthermore, Fab fragments are significantly less immunogenic than the parent IgG population. These data indicate potentially important therapeutic advantages for digoxin-specific Fab compared with IgG when administered for the reversal of life-threatening digitlis toxicity.

Effects of inotropic and arrhythmogenic digoxin doses and of digoxin-specific antibody on myocardial monovalent cation transport in the dog.

The effects of digoxin on monovalent cation active transport were determined in cardiac tissue obtained from dogs given inotropic, toxic, or lethal doses of digoxin. In hemodynamically monitored dogs, active uptake of the K+ analogue Rb+ was determined in vitro in a control myocardial biopsy, and then in serial biopsies from the same dog after the infusion of [3H]digoxin in doses sufficient to cause a sustained positive inotropic effect in the absence of toxicity, and finally after additional doses to induce overt toxicity. Nontoxic digoxin doses producing a mean increase of 20% in left ventricular (LV) dP/dt significantly reduced Rb+ active transport by 25% below control values. At the onset of digoxin-induced arrhythmias, maximal LV dP/dt was 53% above control whereas active Rb+ transport was reduced by 60% below baseline values (P less than 0.001). Control dogs given vehicle alone showed no significant change in contractility or in monovalent cation active transport. In another group of dogs given a lethal dose of digoxin, Rb+ active transport was reduced 59% below control levels at the onset of overt toxicity and was further reduced 80% below control at the time of onset of a fatal rhythm disturbance. When dogs were given high affinity digoxin-specific IgG or Fab fragments at the onset of overt toxicity, toxicity was rapidly reversed, and monovalent cation active transport increased to 51% of control at the time of restoration of sinus rhythm. Twenty-four hours after antibody reversal of arrhythmias, monovalent cation transport values approximated normal control levels. These data provide quantitative estimates of the extent of inhibition of monovalent cation transport by digoxin at inotropic, toxic, and lethal endpoints. Similar degrees of transport inhibition were present at the time of onset of digoxin-induced arrhythmias and at the time or arrhythmia reversal by digoxin-specific antibodies.

Inotropic and toxic effects of a polar cardiac glycoside derivative in the dog.

It has been suggested that central nervous system (CNS) neuroexcitation plays an important role in digitalis-induced cardiac arrhythmias. To elucidate further the role of the CNS in digitalis-induced arrhythmias, the inotropic and toxic effects of a highly polar semisynthetic cardiac glycoside, 3beta-O-(4 amino-4,6 dideoxy-beta-D-galactopyranosyl)-digitoxigenin (ASI-222) were compared to those of digoxin and correlated with plasma and cerebrospinal fluid (CSF) concentrations of each drug. Thirteen dogs anesthetized with sodium pentobarbital were given repeated intravenous doses of digoxin or ASI-222. Ventricular tachycardia was elicited at a mean dose of digoxin of 0.12 mg/kg, compared with 0.09 mg/kg for ASI-222 (not significant). Terminal ventricular fibrillation occurred after 0.18 mg/kg of digoxin, a value significantly larger than the ASI-222 dose (0.14 mg/kg, P less than 0.05) required to produce lethal arrhythmias. Digoxin produced a 21% increase in LV dP/dt at a plasma digoxin concentration of 20.0 +/- 2 ng/ml (mean +/- SEM) 30 minutes after 0.05 mg/kg; the CSF digoxin concentration at this time averaged 0.7 +/- 0.1 ng/ml. At death, the plasma digoxin concentration was 88 +/- 16 ng/ml and CSF digoxin concentration was 5.7 +/- 1.6 ng/ml. ASI-222 produced a similar 25% increase in LV dP/dt 30 minutes after administration of 0.05 mg/kg, with a plasma concentration of 18 +/- 2 ng/ml as determined by a newly developed radioimmunoassay. The plasma ASI-222 concentration at death, 95 +/- 18 ng/ml, was similar to that of digoxin. However, CSF samples at 30 minutes and at death showed no detectable levels of ASI-222. Thus, despite similar inotropic and toxic responses and similar plasma drug concentrations compared to digoxin, ASI-222 was demonstrated to have limited if any access to the CNS as judged by CSF concentrations. These findings suggest that direct CNS stimulation does not play a primary part in the genesis of digitalis-induced cardiac arrhythmias in this experimental model, or that CNS effects are mediated by an area or areas lacking an effective blood-brain barrier.

Contrasting rates of reversal of digoxin toxicity by digoxin-specific IgG and Fab fragments.

Both heterologous IgG and Fab fragments of appropriate affinity and specificity have been shown capable of reversing advanced cardiac glycoside toxicity. Fab fragments are more rapidly excreted and theoretically have a smaller risk of unwanted immunologic effects, but relative rates of toxicity reversal have not been established. Rates of reversal of advanced digoxin toxicity by digoxin-specific IgG and Fab fragments were therefore compared in a dog model of advanced digoxin intoxication. Initial studies confirmed more rapid distribution of sheep Fab fragments (M.W. 50,000) than of the parent IgG molecule (M.W. 150,000) after intravenous injection. Twenty-five pentobarbital-anesthetized dogs were given 0.3 mg/kg digoxin intravenously, resulting in rapid onset of ventricular tachycardia in all animals. Eight dogs subsequently given nonspecific IgG or Fab died in asystole or ventricular fibrillation an average of 55 minutes after digoxin administration. Ten of 11 dogs given 1.33 moles of binding sites per mole of digoxin as intact IgG returned to sinus rhythm at a mean time of 85 minutes after antibody infusion. In contrast, six of six dogs given an equivalent dose of specific Fab fragments returned to sinus rhythm in a significantly shorter mean time of 36 minutes (P less than 0.01). Variability of time to arrhythmia reversion was less in Fab-treated dogs. These data demonstrate a decisive advantage of specific Fab fragments over intact IgG for potential clinical use in advanced, life-threatening digoxin intoxication.