Venus water loss is dominated by HCO+ dissociative recombination.

Despite its Earth-like size and source material1,2, Venus is extremely dry3,4, indicating near-total water loss to space by means of hydrogen outflow from an ancient, steam-dominated atmosphere5,6. Such hydrodynamic escape likely removed most of an initial Earth-like 3-km global equivalent layer (GEL) of water but cannot deplete the atmosphere to the observed 3-cm GEL because it shuts down below about 10-100 m GEL5,7. To complete Venus water loss, and to produce the observed bulk atmospheric enrichment in deuterium of about 120 times Earth8,9, nonthermal H escape mechanisms still operating today are required10,11. Early studies identified these as resonant charge exchange12-14, hot oxygen impact15,16 and ion outflow17,18, establishing a consensus view of H escape10,19 that has since received only minimal updates20. Here we show that this consensus omits the most important present-day H loss process, HCO+ dissociative recombination. This process nearly doubles the Venus H escape rate and, consequently, doubles the amount of present-day volcanic water outgassing and/or impactor infall required to maintain a steady-state atmospheric water abundance. These higher loss rates resolve long-standing difficulties in simultaneously explaining the measured abundance and isotope ratio of Venusian water21,22 and would enable faster desiccation in the wake of speculative late ocean scenarios23. Design limitations prevented past Venus missions from measuring both HCO+ and the escaping hydrogen produced by its recombination; future spacecraft measurements are imperative.

Evaluation of the carbon dioxide laser on vital human primary pulp tissue.

PURPOSE: The purpose of this study was to evaluate the response of the human primary pulp to the carbon dioxide laser and formocresol for vital pulp therapy. METHODS: Fifteen healthy children with intact, caries-and-restoration-free, contralateral primary cuspids with at least two-thirds of the roots remaining who were scheduled for orthodontic extraction were randomly assigned to pulpotomy treatment with a carbon dioxide laser or formocresol. The treated teeth were clinically and radiographically evaluated at 28 and 90 days post-treatment prior to extraction. The extracted teeth were evaluated histologically for pulpal response. RESULTS: All teeth were asymptomatic and clinically normal at both observation periods. Internal root resorption was observed in one formocresol and two laser treated teeth. There was a significant inverse correlation between the laser energy applied to the pulp and the degree of inflammation at 28 days (P = .01) but not at 90 days (P = .27). CONCLUSION: Carbon dioxide laser treatment compared favorably to formocresol for pulpotomy in primary teeth.

Neonatal resuscitation: the NRP guidelines.

The Neonatal Resuscitation Programme, sponsored by the Canadian Heart and Stroke Foundation and by the American Heart Association, is a structured learning package and workshop for all individuals who provide resuscitation for newborns. The emphasis is on rapid, decisive action using algorithms based on clearly stated criteria. This CME article serves as an introduction to the NRP and discusses some of the new guidelines regarding concurrent ventilation and chest compressions, tracheal suction for meconium and the use of medications. The author encourages readers who find this article helpful to register in an accredited NRP course to receive the extensive illustrated textbook and to benefit from the "hands-on" nature of the workshop.

Structure-based design of inhibitors of purine nucleoside phosphorylase. 4. A study of phosphate mimics.

9-(3,3-Dimethyl-5-phosphonopentyl)guanine was synthesized and found to be a potent inhibitor of purine nucleoside phosphorylase (PNP) (IC50 = 44 nM). A number of other functional end groups were investigated as phosphate mimics attached to the 9-position of guanine by this same alkyl side chain, which provided a sensitive method for the detection of any interaction of these groups with the phosphate binding site of PNP. Both the sulfonic acid (compound 13) and the carboxylic acid (compound 15) end groups interact significantly with the phosphate binding site, but in different ways, as determined by X-ray crystallographic analysis of the complexes. The sulfonic acid of 13, which binds about one-fourth as tightly as the phosphonate 12, binds in the phosphate subsite much like the phosphonic acid. The carboxylic acid, the interaction of which is much weaker, turns away from the center of the phosphate binding site to form hydrogen bonds with Ser 200 and Met 219. Thus, the only phosphate mimics that bind like phosphate itself are themselves highly ionic, probably with limited ability to penetrate cell membranes.

Epidural sufentanil does not attenuate the central haemodynamic effects of caesarean section performed under epidural anaesthesia.

The effect of sufentanil 30 micrograms added to the epidural local anaesthetic solutions used for anaesthesia during elective Caesarean section on central haemodynamic variables was studied. Haemodynamic measurements made by thoracic electrical bioimpedance (TEB) monitoring were compared in 21 healthy parturients undergoing Caesarean section under epidural anaesthesia with and without the addition of epidural sufentanil. The patients were randomized to control (Group C) and study (Group S) groups. Following iv prehydration, an epidural catheter was placed at the L2-3 or L3-4 interspace. After a negative test dose, in a double-blinded protocol, patients in Group S received sufentanil 30 micrograms (0.6 ml) in 4.4 ml lidocaine carbonate 2% with 5 micrograms.ml-1 epinephrine and those in Group C received 5 ml lidocaine carbonate 2% with epinephrine. Lidocaine carbonate 2% with 5 micrograms.ml-1 epinephrine was then titrated to establish an anaesthetic level of T4. Haemodynamic variables (heart rate, mean arterial blood pressure, cardiac index, ejection fraction and end-diastolic index) were measured non-invasively, continuously throughout the perioperative period. There were no differences noted in haemodynamic measurements between the groups at any time perioperatively. However, differences occurred within the groups when compared with baseline values. Heart rate was increased in both groups intraoperatively. Cardiac index was increased throughout the intraoperative period in Group S but was less frequently elevated in Group C. Ejection fraction was increased throughout the perioperative period in Group S but not in Group C. End-diastolic index increased following iv preloading in both groups and returned to baseline with induction of epidural block.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphonate analogs of carbocyclic nucleotides.

Cyclopentadiene was converted in six steps to the key intermediate (+/-)-(1 alpha,2 beta,4 alpha)-4-amino-2-(benzyloxy)cyclopentanol (10), which in turn was converted to the carbocyclic nucleoside analogs 14 and 19 by standard procedures developed in these laboratories. Compounds 14 and 19 were then further converted to the target phosphonates 1b and 2b by modification of literature procedures. The phosphonate 1b was 40-fold more cytotoxic to HEp-2 cells than its parent, CDG, presumably after conversion to the diphosphoryl phosphonate.

Maternal positioning affects fetal heart rate changes after epidural analgesia for labour.

Adverse fetal heart rate (FHR) changes suggestive of fetal hypoxia are seen in patients with normal term pregnancies after initiation of epidural block for labour analgesia. It was our hypothesis that, in some parturients, these changes were a consequence of concealed aortocaval compression resulting in decreased uterine blood flow. We expected that the full lateral position compared with the wedged supine position would provide more effective prophylaxis against aortocaval compression. To test our hypothesis we studied the role of maternal positioning on FHR changes during onset of epidural analgesia for labour. Eighty-eight ASA Class I or II term parturients were randomized into two groups: those to be nursed in the wedged supine position and those to be nursed in the full lateral position during induction of an epidural block. External FHR monitoring was employed to assess the fetal response to initiation of labour epidural analgesia. Epidural catheters were sited with the parturients in the sitting position and the patients then assumed the study position. After a negative test dose, a standardized regimen of bupivacaine 0.25% was employed to provide labour analgesia. The quality and efficacy of the block were assessed using VAS pain scores, motor block scores and sensory levels. The results demonstrated that there was no difference in the quality of analgesia provided nor in the incidence of asymmetric blocks. There was no difference in the observed incidence of FHR changes occurring during the initiation of the epidural block.(ABSTRACT TRUNCATED AT 250 WORDS)

Obstetrical anaesthesia and analgesia in chronic spinal cord-injured women.

Improved acute and rehabilitative care and emphasis on integrating patients into society after spinal cord injury is likely to result in increasing numbers of cord-injured women presenting for obstetrical care. Anaesthetists providing care to these women should be familiar with the complications resulting from chronic cord injury and aware that many may be aggravated by the physiological changes of normal pregnancy. These complications include reduced respiratory volumes and reserve, decreased blood pressure and an increased incidence of thromboembolic phenomena, anaemia and recurrent urinary tract infections. Patients with cord lesions above the T5 spinal level are at risk for the life-threatening complication of autonomic hyperreflexia (AH) which results from the loss of central regulation of the sympathetic nervous system below the level of the lesion. Sympathetic hyperactivity and hypertension result in response to noxious stimuli entering the cord below the level of the lesion. Labour appears to be a particularly noxious stimulus and patients with injuries above T5 are at risk for AH during labour even if they have not had previous AH episodes. Morbidity is related to the degree of hypertension and intracranial haemorrhage has been reported during labour and attributed to AH. We report our experience in providing care to three parturients with spinal cord injuries. Two patients had high cervical lesions, one of whom experienced AH during labour and was treated with an epidural block. The second was at risk for AH having had episodes in the past and received an epidural block to provide prophylaxis for AH. In both cases epidural blockade provided effective treatment and prophylaxis for AH.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of dexamethasone on the inhibition of pseudophakic bacterial endophthalmitis.

We investigated the effect of dexamethasone on gentamicin prophylaxis of pseudophakic bacterial endophthalmitis in a rabbit model. In 20 eyes treated with gentamicin and either dexamethasone or dexamethasone vehicle, there were no cases of either clinical or culture-positive endophthalmitis.

Continuous infusion epidural analgesia for obstetrics: bupivacaine versus bupivacaine-fentanyl mixture.

Continuous infusion epidural analgesia (CIEA) using a mixture of bupivacaine and fentanyl was evaluated in this randomized, double-blind study involving 75 nulliparous women by comparing the mixture (Group I, Bupivacaine 0.125% and fentanyl 4 micrograms.ml-1 -24 patients) with two concentrations of bupivacaine alone (Group II, bupivacaine 0.25% - 24 patients; and Group III, bupivacaine 0.125% - 27 patients). Epidural anaesthesia was established in Group I with 6 ml 0.125% bupivacaine with fentanyl 50 micrograms and in both Groups II and III with 6 ml 0.25% bupivacaine. In the women whose pain score (Visual Analogue Scale) decreased by at least 50% within 15 min, CIEA was given until delivery. The initial infusion rate in all three groups was set at 7 ml.hr-1, but was decreased in the event of motor block or excessive sensory level. For inadequate analgesia, bupivacaine 0.25% in 3 ml supplements was given every 30 min, as required. During the first stage of labour, 88% of women in Group I reported excellent or good analgesia compared with 92% of women in Group II (NS) and with 59% in Group III (P less than 0.05). The proportion of women reporting excellent/good analgesia during the second stage was approximately 65% in all three groups. The total cumulative dose of bupivacaine in Group I was 54 +/- 36 mg, compared with 107 +/- 47 mg for Group II (P = 0.001), and 71 +/- 41 mg for Group III (NS). Group I patients required less supplementation with bupivacaine than either Group II or III patients during the first stage but only with Group III patients during the second stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombocytopenia and hemorrhages in veal calves infected with bovine viral diarrhea virus.

The relationship between bovine viral diarrhea virus (BVDV) infection and thrombocytopenia was studied in 18 veal calves experimentally infected with BVDV. All calves were free of BVDV, and 13 calves were free of serum neutralizing antibodies to BVDV before virus inoculation. Calves were inoculated at approximately 10 days of age, and platelet counts were monitored over a period of several weeks. Ten additional calves housed in close proximity were kept as uninoculated controls. A profound decrease in platelet counts by 3 to 11 days after inoculation was seen in all calves that had neutralizing antibody titers less than 1:32 before infection. Severe thrombocytopenia (less than 5,000 platelets/microliter) was seen in 12 calves, 11 of which also developed hemorrhages. Necropsy findings in 3 severely thrombocytopenic calves that died included multiple hemorrhages throughout the body. Calves that recovered had increased platelet counts, and in most instances, a corresponding increase in neutralizing antibody titers to BVDV. At 11 days after inoculation, BVDV was detected on platelets by use of immunofluorescence, but evidence of surface-bound immunoglobulin was not found. The results suggest that a nonimmunoglobulin-mediated method of platelet destruction or sequestration develops as a sequela to BVDV infection.

Anaesthesia for caesarean section in a parturient with quintuplet gestation, pulmonary oedema and thrombocytopaenia.

The case of a 32-year-old parturient with a quintuplet pregnancy is described. The pregnancy had been complicated by premature labour which was treated with ritodrine tocolysis. Betamethasone was administered to hasten fetal lung maturation. The ritodrine therapy was complicated with fluid overload and pulmonary oedema requiring intravenous diuretic treatment. The patient presented urgently for Caesarean section, with fluid overload and worsening thrombocytopaenia. Life-threatening pulmonary oedema was manifest in the immediate preinduction period, following insertion of a pulmonary artery catheter and surgery was delayed to improve the mother's condition with intravenous diuretic therapy. Induction was carried out with the patient in the sitting position, with cricoid pressure maintained to protect the airway as the patient was lowered to a wedged, supine position. Intravenous nitroglycerin was used to control blood pressure. Low pressure mask-bag ventilation was utilized to maintain oxygen saturation and the patient was intubated and ventilated with positive end-expiratory pressure. Positive pressure ventilation was continued for 24 hours postoperatively. The perioperative course is reviewed and followed by a discussion of the anaesthetic considerations for multiple gestation pregnancies.

Potential anticancer agents: 5-(N-substituted-aminocarbonyl)- and 5-(N-substituted-aminothiocarbonyl)-5,6,7,8-tetrahydrofolic acids.

5-[[N-[(Ethoxycarbonyl)alkyl]amino]carbonyl] (6-9) and the corresponding aminothiocarbonyl (12-15) derivatives of 5,6,7,8-tetrahydrofolic acid were prepared as multisubstrate analogues of the substrate--cofactor adduct in the reactions catalyzed by the folate-mediated one-carbon transfer reactions. Evaluation in vitro showed that 7 (alkyl = hexyl) was cytotoxic to H.Ep.-2 cells (ED50, 4 microM) but noncytotoxic to proliferating L1210 cells. No activity was observed for 7 against the P388 leukemia in mice.

Nitrosoureido nucleosides as potential inhibitors of nucleotide biosynthesis.

Several nitrosoureido nucleosides (3a, 3b, 5a, 7a, 7c, and 10a) designed as inhibitors of enzymes that metabolize pyrimidine nucleotides have been prepared and their chemical and biological properties studied. The methylnitrosoureas 3a and 3b were not significantly cytotoxic to H.Ep.-2 and L1210 cells in vitro but showed moderate activity in the P388 mouse leukemia screen (79% ILS for 3a and 56% ILS for 3b). The (chloroethyl)nitrosoureas 7a and 7c inhibited proliferation of L1210 cells, were cytotoxic to H.Ep.-2 cells, and demonstrated good activity against P388 in vivo (135% ILS with one 30-day survivor for 7a and 191% ILS with two 30-day survivors for 7c). Overnight exposure of L1210 cells to 7a and 7c resulted in cell enlargement accompanied by cell lysis. Macromolecular synthesis in enlarged cells, particularly RNA and protein synthesis, was markedly increased relative to that in untreated control cells. The half-lives of each of the nitrosoureas in pH 7 buffer was determined and compared with biological activity.

Inhibition of pseudophakic endophthalmitis in a rabbit model.

A clear lens extraction with insertion of a posterior chamber intraocular lens (PC-IOL) was performed in one eye of each of 20 rabbits. An intracameral injection of 50,000 organisms of gentamicin-sensitive Staphylococcus aureus was given before completion of the surgical procedure. At the completion of surgery, a subconjunctival injection of either gentamicin (20 mg) or gentamicin vehicle was administered randomly, in a masked fashion, to the operative eye. Rabbits were observed daily for signs of endophthalmitis. Vitreous taps were performed on all operative eyes. Ninety percent (p = .001) of control eyes became clinically infected and 80% (p = .007) of control eyes grew S. aureus from their vitreous aspirate. None of the gentamicin-treated eyes became clinically or microbiologically infected with S. aureus.

Reactive 5'-substituted 2',5'-dideoxyuridine derivatives as potential inhibitors of nucleotide biosynthesis.

5'-(Bromoacetamido)-2',5'-dideoxyuridine (3) and derivatives (8, 10, 12, and 14) substituted at the 5-position with bromo, iodo, fluoro, and ethyl groups have been synthesized as potential inhibitors of enzymes that metabolize pyrimidine nucleosides. Also prepared were 2',5'-dideoxyuridine derivatives (4-6) substituted at the 5'-position with 2-bromopropionamido, iodoacetamido, and 4-(fluorosulfonyl)benzamido groups. Compounds 3, 5, 8, 12, and 14 were examined for effect on macromolecular synthesis in L1210 leukemia cells in culture and compared with 5'-(bromoacetamido)-5'-deoxythymidine (1, BAT), a compound with demonstrated cytotoxicity and activity in vivo against P388 murine leukemia. Compounds 3, 8, 12, and 14 inhibited DNA synthesis without significant inhibition of RNA synthesis, and protein synthesis was affected less than DNA synthesis. Compounds 3, 5, 6, 8, 10, 12, and 14 were cytotoxic to H.Ep.-2 and L1210 cells in culture, and 3, 5, 8, and 12 showed activity in the P388 mouse leukemia screen.

Reactive 5'-substituted thymidine derivatives as potential inhibitors of nucleotide biosynthesis.

Fourteen derivatives of thymidine substituted at the 5'-position with haloacetamido (2-4), 2- and 3-bromopropionamido (5 and 6), bromoacetoxy (7), O-mesylglycolamido (8), bromo- and chloro-N-methylacetamido (10 and 11), bromomethanesulfonamido (12), ethyloxamido (13), 4- and 3-(fluorosulfonyl)benzamido (14 and 15), and (phenoxycarbonyl)amino (16) groups have been synthesized and evaluated as potential inhibitors of enzymes that metabolize purine and pyrimidine nucleosides. Rates of reaction of these nucleosides with mercaptoethanol at pH 7 were compared and related to biological activity. Compounds 2, 3, and 7 were cytotoxic to H.Ep.-2 and L1210 cells in culture and 5'-(bromo- and iodoacetamido)-5'-deoxythymidine (2 and 3) showed good activity against P388 leukemia in mice.

5'-Haloacetamido-5'-deoxythymidines: novel inhibitors of thymidylate synthase.

5'-Bromoacetamido-5'-deoxythymidine (BAT), 5'-iodoacetamido-5'-deoxythymidine (IAT), 5'-chloroacetamido-5'-deoxythymidine (CAT) and [14C]BAT were synthesized and their interactions with thymidylate synthase purified from L1210 cells were investigated. The inhibitory effects of these compounds on thymidylate synthase were in the order BAT greater than IAT greater than CAT, which is in agreement with their cytotoxic effects in L1210 cells. In the presence of substrate during preincubation, the concentration required for 50% inhibition of the enzyme activity by these inhibitors was 4-8-fold higher than it was in the absence of dUMP. The I50 values for BAT were 1 X 10(-5) M and 1.2 X 10(-6) M in the presence and absence, respectively, of dUMP during preincubation. These results were in agreement with the observed inhibition of thymidylate synthase by BAT in intact L1210 cells. A Lineweaver-Burk plot revealed that BAT behaved as a competitive inhibitor. The Km for the enzyme was 9.2 microM, and the Ki determined for competitive inhibition by BAT was 5.4 microM. Formation of a tight, irreversible complex is inferred from the finding that BAT-inactivation of thymidylate synthase was not reversible on prolonged dialysis and that the enzyme-BAT complex was nondissociable by gel filtration through a Sephadex G-25 column or by TSK-125 column chromatography. Incubation of thymidylate synthase with BAT resulted in time-dependent, irreversible loss of enzyme activity by first-order kinetics. The rate constant for inactivation was 0.4 min-1, and the steady-state constant of inactivation, Ki, was estimated to be 6.6 microM. The 5'-haloacetamido-5'-deoxythymidines provide specific inhibitors of thymidylate synthase that may also serve as reagents for studying the enzyme mechanism.

Potential inhibitors of nucleotide biosynthesis. 2. Halomethyl ketone derivatives of pyrimidine nucleosides.

Several halomethyl ketone derivatives of pyrimidine nucleosides have been prepared for evaluation as cytotoxic agents. The first series are 1-(8-halo-2,5,6,8- tetradeoxy -beta-D-erythro-oct-7 - ulofuranosyl )thymines (7-9), whereas the second type are halo derivatives of acetophenone (12-14 and 16). These compounds are cytotoxic, and one (13) showed activity against the P388 leukemia in vivo.