UPDATED AGE-SPECIFIC EXTERNAL DOSE AND EXPOSURE RATE COEFFICIENTS FOR 131I PATIENT RELEASE.

Updated effective dose rate and exposure rate coefficients for age-specific receptors representing members of the public were computed for external exposures from age-specific patients administered 131I to treat thyroid dysfunction for patient release evaluation. Coefficients were compared to the simplified point source method described by United States Nuclear Regulatory Commission Regulatory Guide (RG) 8.39, which does not consider age-specific parameters, morphometry or time-dependent 131I biodistribution. Monte Carlo age-specific phantom simulations were correlated with modified continuous voiding patient biokinetic models approximating age-specific dose and exposure rates as a function of time postadministration. Dose rates resulted in an overapproximation by a factor of ~3 from differentiated thyroid cancer patients (5% uptake) and by ~2 from hyperthyroid patients (80%) at 8 h postadministration compared to RG8.39. This study provides a paradigm where age-specific morphometry and biokinetic integration must be jointly considered when developing patient release guidelines for 131I and future radionuclide therapies.

Co-option of Plasmodium falciparum PP1 for egress from host erythrocytes.

Asexual proliferation of the Plasmodium parasites that cause malaria follows a developmental program that alternates non-canonical intraerythrocytic replication with dissemination to new host cells. We carried out a functional analysis of the Plasmodium falciparum homolog of Protein Phosphatase 1 (PfPP1), a universally conserved cell cycle factor in eukaryotes, to investigate regulation of parasite proliferation. PfPP1 is indeed required for efficient replication, but is absolutely essential for egress of parasites from host red blood cells. By phosphoproteomic and chemical-genetic analysis, we isolate two functional targets of PfPP1 for egress: a HECT E3 protein-ubiquitin ligase; and GCα, a fusion protein composed of a guanylyl cyclase and a phospholipid transporter domain. We hypothesize that PfPP1 regulates lipid sensing by GCα and find that phosphatidylcholine stimulates PfPP1-dependent egress. PfPP1 acts as a key regulator that integrates multiple cell-intrinsic pathways with external signals to direct parasite egress from host cells.

Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans.

Apicomplexans invade a variety of metazoan host cells through mechanisms involving host cell receptor engagement and secretion of parasite factors to facilitate cellular attachment. We find that the parasite homolog of calcineurin, a calcium-regulated phosphatase complex central to signal transduction in eukaryotes, also contributes to host cell invasion by the malaria parasite Plasmodium falciparum and related Toxoplasma gondii. Using reverse-genetic and chemical-genetic approaches, we determine that calcineurin critically regulates and stabilizes attachment of extracellular P. falciparum to host erythrocytes before intracellular entry and has similar functions in host cell engagement by T. gondii. Calcineurin-mediated Plasmodium invasion is strongly associated with host receptors required for host cell recognition, and calcineurin function distinguishes this form of receptor-mediated attachment from a second mode of host-parasite adhesion independent of host receptors. This specific role of calcineurin in coordinating physical interactions with host cells highlights an ancestral mechanism for parasitism used by apicomplexans.

Release of vasopressin in response to hypoxia and the effect of aminergic and opioid antagonists.

Plasma vasopressin, arterial blood gas tensions, pH, arterial blood pressure, heart rate and respiration were monitored in conscious rats breathing room air or exposed to varying degrees of hypoxia. A similar series of observations was made in a group of anaesthetized rats and in rats treated with alpha- and beta-adrenergic and dopaminergic blocking agents. The effect of two opioid antagonists on the vasopressin response was also noted. Hypoxia produced an increase in circulating vasopressin concentrations in both conscious and anaesthetized rats. In the conscious animals the increase reached statistical significance when the animals were exposed to 12% oxygen in nitrogen, which produced a fall in arterial PaO2 of 44.7 +/- 5.0%. Guanethidine, phentolamine and propranolol all produced a significant fall in the basal concentrations of vasopressin, while guanethidine, phenoxybenzamine and propranolol blocked the increase seen on breathing 12% oxygen in nitrogen. Naloxone and levallorphan also reduced the vasopressin response to hypoxia. Thus it appears that aminergic pathways play a role in the maintenance of circulating concentrations of vasopressin and in the response to hypoxia. Endogenous opioids also appear to be involved in the hypoxic response.

A comparison of the vasopressin response of rats to intraperitoneal and intravenous administration of hypertonic saline, and the effect of opioid and aminergic antagonists.

The vasopressin response of rats to i.p. injection of hypertonic sodium chloride (1.5 mol/l) was compared with that following i.v. infusion of 1.05 mol sodium chloride/l. The two regimes produced a similar vasopressin response in terms of the osmotic threshold, although the slopes of the plot of plasma vasopressin levels against plasma osmolality were not identical. Pretreatment with naloxone and levallorphan increased the resting vasopressin levels and effectively potentiated vasopressin release in response to hypertonic saline by reducing the osmotic threshold for hormone release. Thus, opioid peptides appear to exert an inhibitory effect on vasopressin release under resting and stimulated conditions. The adrenoreceptor antagonists propranolol, phenyoxybenzamine and phentolamine produced a fall in resting vasopressin concentrations while propranolol and phenoxybenzamine potentiated the osmotic release of vasopressin in association with a fall in the osmotic threshold. This would suggest that noradrenergic pathways are excitatory at rest while having an inhibitory effect on the osmotic response. Metoclopramide also produced a fall in resting plasma vasopressin concentrations while increasing the osmotic response. In contrast haloperidol did not affect the vasopressin response.

Conversion of triglycylvasopressin to lysine-vasopressin in man.

The concentrations in plasma of triglycl-8-lysine-vasopressin (TGLVP), determined by radioimmunoassay, and lysine-vasopressin, determined by bioassay, have been monitored in five subjects after intravenous (7.5 micron/kg) or intranasal (5 mg) administration of TGLVP. The level of excretion in urine was also measured. The TGLVP concentration in plasma fell rapidly after the intravenous injection, the mean half-time of disappearance being 24.2 +/- 1.9 (S.E.M.) min (d.f. 4). Biologically active lysine-vasopressin reached a peak between 60 and 120 min. A similar pattern was seen following intranasal instillation but only a small proportion of the administered dose appeared in the plasma and the concentration of lysine-vasopressin was relatively higher. Less than 1% of the TGLVP injected appeared in the urine. Intravenous TGLVP had no effect on systolic blood pressure but produced an increase in diastolic blood pressure of 1.7 +/- 0.19 kPa (d.f. 4) and a fall in heart rate of 9 +/- 2.3 beats/min. Creatinine clearance and sodium excretion remained relatively constant in all subjects throughout the study but intravenous injection of TGLVP resulted in an antidiuresis which was evident within the first hour of observation and was maintained for a further 4 h. It was concluded that TGLVP is converted to lysine-vasopressin in man and after an intravenous injection of 7.5 micron/kg sufficiently high concentrations of lysine-vasopressin may be maintained for 2 h to produce sustained vasoconstriction. Tryglycylvasopressin may therefore be of value in controlling haemorrhage.

The detection of Plasmodium falciparum and P. vivax in DNA-extracted blood samples using polymerase chain reaction.

Seventeen pairs of published primer sets were compared for their relative sensitivity to detect malaria DNA extracted from blood samples, which were obtained from Pakistani patients suffering from malaria. The primer sets investigated consisted of: (i) 9 pairs of direct primers and 3 sets of nested primers for detecting Plasmodium falciparum, (ii) 2 pairs of direct primers and 2 sets of nested primers for detecting P. vivax, and (iii) 1 set of multiplex primers for detecting both P. falciparum and P. vivax, simultaneously. After a miniscreen of 9 DNA-extracted blood samples using the 17 primer sets stated above, 5 primer sets were short-listed (based on their superior sensitivity) and used for a maxi-screen of DNA extracted from 126 microscopy-positive blood samples from Pakistan, with the following results. (i) For the detection of P. falciparum, the direct primer pair 'PF1 + PF2' gave a sensitivity of 95% and the nested primer set 'RIT405 + RIT406/RIT371 + RIT372' gave a sensitivity of 97%. (ii) For the detection of P. vivax, the direct primer pair 'Forward + Reverse' and the nested primer set 'PLF + UNR/PLF + VIR' both gave a sensitivity of 94%. (iii) The nested multiplex primer set 'rPLU5 + rPLU6/rFAL1 + rFAL2 + rVIV1 + rVIV2' gave a sensitivity of 97% and 96% for P. falciparum and P. vivax, respectively. It was concluded that the nested multiplex primer set was the most optimal primer set to use for the detection of malaria DNA extracted from blood samples. Furthermore, the nested multiplex primer set has the advantage of simultaneously detecting and differentiating between P. vivax and P. falciparum.

Ketamine infusion for postoperative analgesia: a prospective cohort study in asthmatics.

Ketamine, most often used as an anaesthetic agent can provide adequate post operative analgesia when delivered in the form of infusion, replacing narcotics, which can cause bronchospasm in susceptible individuals. This cohort study was undertaken to assess the feasibility of providing complete post operative analgesia in asthmatics with ketamine delivered in sub-anaesthetic doses (6.10-6.41 ugm./kg.-1/min-1). Diazepam (0.97-1.02 ugm./kg.-1/min-1) was delivered from the same infusion to eliminate the unwanted effects of ketamine. Ketamine induced little alteration in blood pressure while tachycardia was significant (P < 0.05). Respiratory functions observed, were favourable for asthmatics. Diazepam helped in reducing ketamine induced side effects, but after infusion over long periods tendency of cumulation was observed. Complications encountered were minimum with more than 93% patient acceptability for this method of analgesia.

Non typical presentation of systemic lupus erythematosis.

A case of systemic lupus erythematosis (SLE) affecting the heart, joints, skin and kidneys is reported. Antinuclear antibodies were insignificant at presentation. Diagnosis was only possible with passage of time and renal biopsy.

[Acid base changes and muscle relaxants].

Previous publications have provided conflicting results concerning the effects of respiratory and metabolic acid base changes on the neuromuscular effects of nondepolarizing muscle relaxants. The varying results can be attributed not only to experimental design or species difference, but also to the accompanying changes in the pharmacokinetics in vivo. Using the phrenic nerve-hemidiaphragm preparation of rats, in which many variables of in vivo studies can be eliminated, respiratory and metabolic acid-base changes were induced by varying carbon dioxide (PCO2) and bicarbonate (HCO3) concentrations in the Krebs' solution and their effects on the potencies of muscle relaxants were compared. Decreasing pH by increasing Pco2 or by decreasing HCO3 increased the potencies of the monoquaternary relaxants (d-tubocurarine, vecuronium and rocuronium), while pH changes did not affect the potencies of the bisquaternary relaxants (metocurine, pancuronium and pipecuronium). Above difference between mono- and bisquaternary relaxants may reflect pH-induced changes in the ionization of the tertiary ammonium and resulting in changes in the sensitivity to the anionic nicotinic receptors. Neostigmine-induced antagonism was not affected by acid-base changes. These results in vitro were compared and correlated with the previous results in vivo.

A study into loss of consciousness.

The case notes of patients admitted with loss of consciousness (LOC) to BMH Rinteln over 18 months were retrospectively studied. Forty percent of those diagnosed as epileptic were heavy goods vehicle (HGV) drivers. This paper audits the criteria for diagnosis and discusses its implications on the soldier's career.

Ibuprofen sodium is absorbed faster than standard Ibuprofen tablets: results of two open-label, randomized, crossover pharmacokinetic studies.

BACKGROUND: A novel ibuprofen (IBU) formulation, Advil(®) Film-Coated Tablets (IBUNa), was developed. OBJECTIVE: Pharmacokinetic comparison of IBUNa versus other IBU formulations. STUDY DESIGN: Two randomized, single-dose, open-label, five-way crossover pharmacokinetic studies. SETTING: Inpatient research clinic. SUBJECTS: Seventy-one healthy adult volunteers. INTERVENTION: Study 1: In three periods, fasted subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg, Advil(®) Liqui-Gels(®) (IBULG) 2 × 200 mg, and Motrin(®) IB (IBUMot) 2 × 200 mg tablets. In two periods following a high-fat breakfast, subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg and IBULG 2 × 200 mg. Study 2: In five study periods, fasted subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg, Advil(®) FastGel(®) (IBUFG) 2 × 200 mg, Nurofen(®) (IBUNur) 2 × 200 mg, Advil(®) (IBUAdv) 2 × 200 mg, and Nurofen(®) Express containing IBU lysinate (IBULys) 2 × 342 mg. MAIN OUTCOME MEASURE: Log-transformed area under the plasma concentration versus time curve to last observable concentration (AUCL) and maximum plasma concentration (C max) were the primary pharmacokinetic parameters; time to maximum measured plasma concentration (T max) was analyzed post hoc. RESULTS: IBUNa was bioequivalent to IBULG (fasted and fed) and IBUFG and IBULys (fasted) for rate (C max) and extent (AUCL) of IBU absorption. After fasting, AUCL was bioequivalent for IBUNa and IBUMot, IBUAdv, and IBUNur, but C max occurred significantly earlier with IBUNa. After fasting, median IBUNa T max was comparable to that for IBULG, IBUFG, and IBULys, but was much shorter than that for IBUMot, IBUNur, and IBUAdv. Food slowed absorption of IBUNa and IBULG similarly. All treatments were tolerated similarly. CONCLUSION: IBUNa is absorbed faster but to a similar extent as standard IBU formulations.

Quantification of nebivolol hydrochloride in human plasma by liquid chromatography using fluorescence detection: Use in pharmacokinetic study.

A simple, rapid, and sensitive method of reversed-phase high-performance liquid chromatography with fluorescence detection has been developed and validated for use in determining levels of nebivolol•HCl in human plasma. Sample preparation involves a simple single-step protein precipitation procedure and extraction of nebivolol in acetonitrile. The separation was performed on a Kromasil® RP-C18 column (Ф 4.6 mm × 250 mm, 5 µm) with a mobile phase consisting of 0.05 M potassium dihydrogen phosphate buffer/acetonitrile (40:60, v/v) adjusted to pH 3 using orthophosphoric acid. Analysis was carried out under isocratic conditions at a flow rate of 1.5 mL/min and at room temperature using a fluorescence detector with excitation at 288 nm and emission at 310 nm. The chromatographic run was 4 min. The calibration curve was linear over the concentration range 0.2-20 ng/mL. The method was validated in terms of its accuracy, precision, and specificity. The assay enabled the measurement of nebivolol with a minimum quantification limit of 0.16 ng/mL. The average recovery of nebivolol from spiked human plasma was 98.4 ± 3.3%. This method was successfully used in a pharmacokinetic study of oral administration of 5-mg tablets to healthy human volunteers.

Electrohydrothermoprobe--a simple alternative to laser therapy in the management of acute gastrointestinal haemorrhage.

One hundred and twenty six consecutive patients presenting with upper alimentary bleeding were endoscoped. Seventeen gastric and 11 duodenal lesions with visible blood vessels were identified and cauterised with the electrohydrothermoprobe. One gastric and four duodenal vessels rebled, necessitating surgery. For the gastric vessels this represents about one tenth of the expected rebleeding rate, and is a significant reduction. The technique appears to have no effect on the rebleeding rate in duodenal vessels.

Ketamine infusion for postoperative analgesia in asthmatics: a comparison with intermittent meperidine.

Narcotics commonly used for postoperative analgesia may release histamine and cause bronchospasm in asthmatics. Ketamine, on the other hand, provides analgesia and has the additional advantage of preventing and relieving bronchospasm. We therefore delivered subanesthetic doses of ketamine in combination with midazolam (5.88-6.42 micrograms.kg-1.min-1 and 1.17-1.28 micrograms.kg-1.min-1, respectively), via an infusion for postoperative analgesia after elective abdominal hysterectomy in patients with asthma. Data were compared with those from a similar group of patients receiving conventional intramuscular meperidine. A significant degree and earlier onset of analgesia (P < 0.05) was achieved in the ketamine group. For other variables no significant difference was observed between the groups (P > 0.05). Ketamine-midazolam infusion can thus provide a safe alternative to the usual parenteral narcotic therapy in asthmatics, in terms of analgesia and patient acceptability.

The effect of intracerebroventricular injections of morphine on vasopressin release in the rat.

1. An investigation was carried out to determine the effect of intracerebroventricular (I.C.V.) micro-injections of morphine on vasopressin (AVP) release in the urethane-anaesthetized rat. 2. Plasma AVP levels at different time intervals, following I.C.V. injection of 10-150 microgram morphine, were measured by radioimmunoassay. The effect of I.C.V. micro-injections of morphine on urine outflow was also studied in a group of water-loaded rats. 3. The vasopressin response to I.C.V. micro-injections of morphine was both dose- and time-dependent. High dose of 50 and 150 microgram morphine produced short latency stimulation of AVP release, followed by a fall. The low dose of 10 microgram morphine produced only a long latency inhibition. The most consistent response of I.C.V. injection of morphine was an inhibition of release. 4. Both stimulatory and inhibitory effects of morphine on vasopressin release were naloxone reversible and stereospecific. 5. I.C.V. micro-injections of morphine produced a dose-dependent rise in mean arterial blood pressure of short latency. Naloxone (0.5 mg/kg) completely abolished the rise seen with 10 microgram morphine and diminished the rise with 50 microgram. 6. Doses of 10 and 50 microgram morphine injected I.C.V. produced an immediate antidiuresis in water-loaded rats under urethane anaesthesia. 7. The vasopressin response to I.C.V. micro-injections of morphine is independent of the effects on the cardiovascular system and may involve different opiate receptor populations. The results also suggest the possibility that opiate receptors with different affinities for morphine may be responsible for the stimulatory and inhibitory effects of morphine on vasopressin release.