Infrared spectroscopy and density functional theory investigation of calcite, chalk, and coccoliths--do we observe the mineral surface?

We have measured infrared spectra from several types of calcite: chalk, freshly cultured coccoliths produced by three species of algae, natural calcite (Iceland Spar), and two types of synthetic calcite. The most intense infrared band, the asymmetric carbonate stretch vibration, is clearly asymmetric for the coccoliths and the synthetic calcite prepared using the carbonation method. It can be very well fitted by two peaks: a narrow Lorenzian at lower frequency and a broader Gaussian at higher frequency. These two samples both have a high specific surface area. Density functional theory for bulk calcite and several calcite surface systems allows for assignment of the infrared bands. The two peaks that make up the asymmetric carbonate stretch band come from the bulk (narrow Lorenzian) and from a combination of two effects (broad Gaussian): the surface or near surface of calcite and line broadening from macroscopic dielectric effects. We detect water adsorbed on the high surface area synthetic calcite, which permits observation of the chemistry of thin liquid films on calcite using transmission infrared spectroscopy. The combination of infrared spectroscopy and density functional theory also allowed us to quantify the amount of polysaccharides associated with the coccoliths. The amount of polysaccharides left in chalk, demonstrated to be present in other work, is below the IR detection limit, which is 0.5% by mass.

Identification of novel potent hydroxamic acid inhibitors of peptidyl deformylase and the importance of the hydroxamic acid functionality on inhibition.

Peptidyl deformylase (PDF) is a metallo protease that catalyzes the removal of a formyl group from the N-termini of prokaryotic prepared polypeptides, an essential step in bacterial protein synthesis. Screening of our compound collection using Staphylococcus aureus PDF afforded a very potent inhibitor with an IC(50) in the low nanomolar range. Unfortunately, the compound that contains a hydroxamic acid did not exhibit antibacterial activity (MIC). In order to address the lack of activity in the MIC assay and to determine what portion of the molecule was responsible for binding to PDF, we prepared several analogues. This paper describes our findings that the hydroxamic acid functionality found in 1 is mainly responsible for the high affinity to PDF. In addition, we identified an alternative class of PDF inhibitors, the N-hydroxy urea 18, which has both PDF and antibacterial activity.

Optimal antidepressant dosing. Practical framework for selection, titration, and duration of therapy.

Appropriate antidepressant dosing and trial duration are crucial for successful treatment of depression. Before prescribing an antidepressant, primary care physicians should take into account each patient's history, responses to previous antidepressants, depressive symptoms, coexisting illnesses, and current prescriptions. Physicians must be able to help patients manage side effects and know when to discontinue treatment, switch antidepressants, or refer patients to a psychiatrist.

White coat hypertension and target organ involvement: the impact of different cut-off levels on albuminuria and left ventricular mass and geometry.

The aim of this cross-sectional study which took place in a hypertension clinic at a district general hospital in Denmark was to make a pragmatic definition of white coat hypertension. A total of 420 patients were referred consecutively from general practice with newly diagnosed untreated essential hypertension and 146 normal subjects were drawn at random from the Danish national register. The following measurements were taken: office blood pressure; 24-h ambulatory blood pressure (BP) monitoring; echocardiography with determination of left ventricular mass index and relative wall thickness; and early morning urine albumin/creatinine ratios. Four different cut-off levels were studied. An ambulatory daytime BP of 135.6/90.4 mm Hg was found to correspond to an office BP of 140/90 mm Hg in normal controls; used as a cut-off level in patients with newly diagnosed hypertension it separated 19% as white coat hypertensives. The end-organ involvement of these white coat hypertensives differed significantly from those with established hypertension but not from the normal controls. Lower cut-off levels were less efficient in this respect, as was the case when the systolic BP was not taken into account. In conclusion a pragmatic definition of white coat hypertension should--apart from well-established hypertensive office measurements--include a cut-off level close to 135/90 mm Hg ambulatory daytime BP.

Cancer risk in fathers and brothers of testicular cancer patients in Denmark. A population-based study.

There are several reports of familial testicular cancer in the literature but few systematic attempts have been made to estimate the risk of testicular cancer in first-degree relatives of patients with this neoplasm, and the risk remains to be fully assessed in population-based studies. By means of data from the Danish Cancer Registry, we identified all testicular cancer patients (index cases) born and diagnosed during 1950-1993 in Denmark. Their fathers were identified from national registries, as were the brothers of a subcohort of these patients. Familial cancer occurrence was determined through linkage with the cancer registry and compared with the cancer incidence in the general male population in Denmark. The ratio of observed to expected cancers generated the measure used for the relative risk. Fathers of 2,113 index cases with testicular cancer experienced an almost 2-fold risk of developing testicular cancer themselves (RR = 1.96; 95% CI: 1.01-3.43). Overall, the fathers had a decreased relative cancer risk (RR = 0.84; 95% CI: 0.74-0.95) with a significantly decreased risk of cancers of the lung and digestive organs. Brothers of a subcohort of 702 index cases showed a markedly increased risk of testicular cancer (RR = 12.3; 95% CI: 3.3-3 1.5). In conclusion, we documented a significantly increased familial risk of testicular cancer which was relatively more pronounced between brothers than between fathers and sons. These findings support the possible involvement of a genetic component in the aetiology of testicular cancer, but also leave room for a hypothesized influence of in-utero exposures, such as specific maternal hormone levels, that might be shared by brothers.

[Albuminuria in persons with real hypertension, white coat hypertension and normotension]. / Albuminuri hos personer med reel hypertension, konsultationshypertension og normotension.

A prospective comparison of office blood pressure, daytime ambulatory blood pressure and urinary albumin excretion was performed in 284 consecutive patients from general practice with newly diagnosed, untreated mild to moderate hypertension. Based on daytime ambulatory blood pressure 173 were classified as established hypertensives and 111 as white coat hypertensives. A sample of 127 subjects drawn from the Danish national register served as a normotensive control group. It was found that urinary albumin/creatinine ratio differed significantly between the three groups; the difference remained significant after correction for covariables. Early morning urine albumin/creatinine ratio was weakly but significantly correlated to blood pressure. Early morning urine albumin/creatinine ratio was as reproducible a measure as 24-hour albumin excretion. It is concluded that white coat hypertensive patients have less renal involvement than patients with established hypertension, but more than a normotensive control group.

Microalbuminuria in 411 untreated individuals with established hypertension, white coat hypertension, and normotension.

We compared urinary albumin excretion in normotensive subjects and patients with white coat and established hypertension. The study involved prospective comparison of office blood pressure, daytime ambulatory blood pressure, and urinary albumin excretion in consecutive patients (n = 284) who were selected from general practice with newly diagnosed mild to moderate hypertension before the institution of pharmacologic antihypertensive therapy. All patients had a diastolic office blood pressure above 90 mm Hg; 173 had a consistently elevated diastolic blood pressure (established hypertension), and 111 had an average daytime ambulatory blood pressure below 90 mm Hg (white coat hypertension). A sample of 127 subjects drawn from the Danish national register served as a normotensive control group. The main outcome measure was the ratio of early morning urinary albumin to creatinine. This ratio differed significantly among the three groups, being (on a molar basis) 21 +/- 69 x 10(-6) in the normotensive subjects, 22 +/- 39 x 10(-6) in the white coat hypertensive patients, and 51 +/- 177 x 10(-6) in patients with established hypertension. The difference remained significant after correction for covariables. The ratio of early morning urinary albumin to creatinine was weakly but significantly correlated to blood pressure, was more pronounced for ambulatory than for office measurements, was more pronounced for systolic than for diastolic pressure, and was more pronounced for hypertensive than for normotensive individuals. The ratio was as reproducible a measure as 24-hour albumin excretion. We conclude that white coat hypertensive patients have less renal involvement than patients with established hypertension but more than a normotensive control group.

Left ventricular mass and geometry in patients with established hypertension and white coat hypertension.

This study was designed to compare the cardiac mass and geometry in white coat hypertensive patients and established hypertensive patients through the prospective comparison of office blood pressure, daytime ambulatory blood pressure, and echocardiographically determined left ventricular mass and cardiac geometry in consecutive patients. We studied 143 patients from general practice in an outpatient hypertension unit. The patients had newly diagnosed mild-to-moderate hypertension prior to the institution of pharmacological anti-hypertensive therapy. All patients had a diastolic office blood pressure above 90 mm Hg; 90 had a consistently elevated diastolic blood pressure (established hypertension), whereas 53 had an average daytime ambulatory blood pressure below 90 mm Hg (white coat hypertension). Left ventricular mass index was significantly higher in the group with established hypertension, 102.4 +/- 26.6 g/m2 (mean +/- SD) v 93.6 +/- 23.5 (P = .045). Relative wall thickness was likewise significantly higher, 0.36 +/- 0.07 v 0.33 +/- 0.06 (P = .004). There was no significant difference in left atrial dimension. In a multiple regression model the ambulatory measurements and not the office measurements were statistically significantly associated with the extent of cardiac hypertrophy. Further, 44/53 (83%) of the patients with white coat hypertension had normal left ventricular dimensions, versus only 55/90 (61%) of the patients with established hypertension (P = .033). Thus, white coat hypertensive patients display less cardiac involvement than patients with established hypertension, indicating that they should rather be treated as normotensives than as hypertensives, ie, not with pharmacological antihypertensive therapy.

Two metabolites of anticonvulsant U-54494A: their anticonvulsant activity and interaction with sodium channel.

U-54494A, 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzamide, has been shown to be a potent and long-acting anticonvulsant without analgesic or sedative effects on intact animals. The persistence of anticonvulsant activity after a decline in its concentration in the brain implies the conversion of the parent drug into active metabolites. In this study, two major metabolites of U-54494A, U-83892E [cis-N-(2-aminocyclohexyl)-3,4-dichlorobenzamide] and U-83894A [cis-N-(2-methylaminocyclohexyl)-3,4-dichlorobenzamide], were identified. The synthetic metabolites displayed anticonvulsant activity against electric shock in experimental animals and blocked voltage-gated sodium channel in N1E-115 neuroblastoma cells in voltage- and use-dependent manner by interacting with the inactivated channels as well as with the channels in the resting state (like the parent compound). These observations may provide one explanation for the long duration of the anticonvulsant activity of the parent compound U-54494A and further underscore the importance of voltage-dependent sodium channels in neuronal excitability, especially during seizures.

Echinostoma caproni in rats: worm population dynamics and host blood eosinophilia during primary infections with 6, 25 and 50 metacercariae and resistance to secondary and superimposed infections.

Hooded-Lister rats were inoculated with 6, 25, 50 or 100 metacercariae of the intestinal trematode Echinostoma caproni. Worm establishment and the pattern of egg excretion were followed during the course of primary infections with 6, 25 and 50 metacercariae. Peripheral blood eosinophilia was followed at all infection levels. After 1 month, worm recovery and faecal egg output showed a gradual decline with increasing duration of infection. High worm burdens were expelled later than smaller worm burdens, and egg output persisted longer in animals exhibiting a high initial egg output. The level of blood eosinophilia increased with increasing degree of infection and with the level of egg output. A marked concomitant resistance to superimposed infection was observed on the challenge of rats harbouring 21- and 49-day-old infections with 50 metacercariae. In addition, rats were partially resistant to secondary infection at challenge day 14 following anthelmintic removal of primary 7-day-old infections with 50 metacercariae and were completely resistant at challenge day 7 following elimination of a primary 14-day-old primary infection.

Use of a bacteriocin produced by Pediococcus acidilactici to inhibit Listeria monocytogenes associated with fresh meat.

A bacteriocin produced by Pediococcus acidilactici had an inhibitory and bactericidal effect on Listeria monocytogenes associated with fresh meat. MICs were significantly lower than minimum killing concentrations. When meat was inoculated with L. monocytogenes, the bacteriocin reduced the number of attached bacteria in 2 min by 0.5 to 2.2 log cycles depending upon bacteriocin concentration. Meat treated initially with the bacteriocin resulted in attachment of 1.0 to 2.5 log cycles fewer bacteria than that attained with the control. The bacteriocin, after 28 days of refrigerated storage on meat surfaces, was stable and exhibited an inhibitory effect on L. monocytogenes.

Pregnanolone emulsion. A preliminary pharmacokinetic and pharmacodynamic study of a new intravenous anaesthetic agent.

Pregnanolone emulsion, a new steroid anaesthetic agent, was administered intravenously as bolus doses to six young healthy male volunteers in a preliminary pharmacokinetic and pharmacodynamic study. The plasma concentration-time curves fitted a two-compartment model. The elimination half-life was between 0.9 and 1.4 hours, volume of central compartment between 0.95 and 2.10 litres/kg, volume of distribution between 3.75 and 5.58 litres/kg and total body clearance between 1.80 and 3.07 (litres/hour)/kg. The excretion in urine of unchanged pregnanolone was less than 0.1%. The pharmacodynamic properties were found to be similar to those of Althesin, with immediate induction of anaesthesia of short duration. The anaesthetic affected haemodynamics only slightly; minor depression of ventilation, with an increase in PaCO2, occurred in several of the subjects. Excitation of short duration occurred in one subject during induction of sleep and slight involuntary muscle movements in another subject during sleep. It is impossible to draw any clear conclusions of the clinical efficacy and tolerance from this limited normal subject trial, but pregnanolone emulsion seems worthy of further clinical trial.

Electroacupuncture and postoperative pain.

We studied 20 otherwise healthy women undergoing lower abdominal surgery. Immediately after wound closure, while still anaesthetized, they received either electroacupuncture (EA) or no further treatment. They were allowed pethidine for postoperative analgesia by patient-controlled infusion pump. Signs of postoperative distress (pain, nausea, drowsiness) were evaluated after 2 and 6 h by visual analogue scale scores. The group receiving EA consumed half the quantity of pethidine as that used used by the no treatment group. Two patients in the EA group had no postoperative analgesia in the first 2 h. There was no difference in the assessments of postoperative distress between groups. No patient was aware of having received EA or not.

Infusion of vecuronium assessed by tactile evaluation of evoked thumb twitch.

In 15 patients (ASA I-II) undergoing intraabdominal gynaecological surgery, muscle paralysis for tracheal intubation and surgery was achieved by a combined bolus and demand infusion of vecuronium. The initial loading dose of 67 micrograms kg-1 and the rate of subsequent infusion were determined by evaluation of the tactile twitch response to train-of-four (TOF) stimulation of the ulnar nerve while the neuromuscular blockade obtained was recorded blindly for control on the contralateral arm. A maintenance dose of 4.9 mg h-1 (2.0-7.6 mg h-1) produced a smooth course of blockade with minimum and maximum values of twitch height during infusion of 2% and 12%, respectively. A period of 15.9 min elapsed from the end of infusion to a TOF-ratio of 0.7, when neostigmine 2.5 mg was administered at the point of two palpable twitches to TOF-stimulation. Simple tactile evaluation of peripheral nerve stimulation is sufficient to determine the infusion rate of vecuronium required to produce stable and appropriate neuromuscular blockade during intra-abdominal surgery.

Maintenance of constant 95% neuromuscular blockade by adjustable infusion rates of pancuronium and atracurium.

In a double-blind study, 39 patients (ASA groups I-II,) were given either pancuronium or atracurium as an infusion during surgery. The drugs were given as an initial loading dose of 0.064 mg kg-1 or 0.30 mg kg-1, respectively, followed by an infusion, the rate of which was regulated to produce a constant 95% depression of the evoked twitch response throughout surgery. No significant difference in the number of corrections of the infusion rate per hour was found (4.6 v. 4.9). Mean infusion maintenance doses were 35 and 356 micrograms kg-1 h-1, respectively. The inter-individual variability of maintenance doses for the two drugs did not differ, the coefficients of variation being 0.32 and 0.24. On stopping the infusion, the patients given atracurium recovered to a 15% twitch faster than those given pancuronium. In addition neostigmine produced a quicker recovery in this group. Thus atracurium may be a more satisfactory drug for use by infusion.

Pregnanolone emulsion. A new steroid preparation for intravenous anaesthesia: an experimental study in mice.

The anaesthetic activity of pregnanolone (a metabolite of progesterone) in emulsion formulation administered intravenously to male mice was compared with that of Althesin. The loss of righting reflex for 15 seconds was used to estimate the anaesthetic effect. The mean anaesthetic dose (AD50) for the pregnanolone emulsion was 5.25 mg/kg and for Althesin, 2.8 mg/kg. The mean lethal dose (LD50) was 44 mg/kg for pregnanolone and 54 mg/kg for Althesin. The sleeping time after pregnanolone was 2.5-3.5 times longer than after Althesin in dosages above 7.5 mg/kg. No signs of pain or local reaction from injection were observed for either of the drugs. The onset of action was fast for both drugs, with only minor signs of excitation, and recovery was rapid and without excitation. The results indicate that the anaesthetic properties of pregnanolone emulsion are very similar to those of Althesin. Further studies will show whether it can fill the major vacuum left in anaesthetic practice after the withdrawal of Althesin.