Fibronectin and vitronectin promote human fetal osteoblast cell attachment and proliferation on nanoporous titanium surfaces.

Improvements in osteoconduction of implant biomaterials require focusing on the bone-implant interface, which is a complex multifactorial system. Surface topography of implants plays a crucial role at this interface. Nanostructured surfaces have been shown to promote serum protein adsorption and osteoblast adhesion when compared to micro-structured surfaces for bone-implant materials. We studied the influence of the serum proteins fibronectin and vitronectin on the attachment and proliferation of osteoblasts onto nanostructured titania surfaces. Human fetal osteoblastic cells hFOB 1.19 were used as model osteoblasts and were grown on nanoporous TiO2 templates, using Ti6AI4V and commercially pure Ti substrates as controls. Results show a significant increase in cell proliferation'on nanoporous TiO2 over flat substrates. Initial cell attachment data exhibited a significant effect by either fibronectin or vitronectin on cell adhesion at the surface of any of the tested materials. In addition, the extent of cell adhesion was significantly different between the nanoporous TiO2 and both Ti6AI4V and commercially pure Ti substrates, with the first showing the highest surface coverage. There was no significant difference on osteoblast attachment or proliferation between the presence of fibronectin or vitronectin using any of the material substrates. Taken together, these results suggest that the increase in osteoblast attachment and proliferation shown on the nanoporous TiO2 is due to an increase in the adsorption of fibronectin and vitronectin because of the higher surface area and to an enhanced protein unfolding, which allows access to osteoblast binding motifs within these proteins.

ATP excites mouse vomeronasal sensory neurons through activation of P2X receptors.

Purinergic signaling through activation of P2X and P2Y receptors is critically important in the chemical senses. In the mouse main olfactory epithelium (MOE), adenosine 5'-triphosphate (ATP) elicits an increase in intracellular calcium ([Ca(2+)](I)) and reduces the responsiveness of olfactory sensory neurons to odorants through activation of P2X and P2Y receptors. We investigated the role of purinergic signaling in vomeronasal sensory neuron (VSN)s from the mouse vomeronasal organ (VNO), an olfactory organ distinct from the MOE that responds to many conspecific chemical cues. Using a combination of calcium imaging and patch-clamp electrophysiology with isolated VSNs, we demonstrated that ATP elicits an increase in [Ca(2+)](I) and an inward current with similar EC(50)s. Neither adenosine nor the P2Y receptor ligands adenosine 5'-diphosphate, uridine 5'-triphosphate, and uridine-5'-disphosphate could mimic either effect of ATP. Moreover, the increase in [Ca(2+)](I) required the presence of extracellular calcium and the inward current elicited by ATP was partially blocked by the P2X receptor antagonists pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate and 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate. Consistent with the activation of P2X receptors, we detected gene expression of the P2X1 and 3 receptors in the VNO by Reverse transcription polymerase chain reaction (RT-PCR). When co-delivered with dilute urine, a natural stimulus, ATP significantly increased the inward current above that elicited by dilute urine or ATP alone. Mechanical stimulation of the VNO induced the release of ATP, detected by luciferin-luciferase luminometry, and this release of ATP was completely abolished in the presence of the connexin/pannexin hemichannel blocker, carbenoxolone. We conclude that the release of ATP could occur during the activity of the vasomotor pump that facilitates the movement of chemicals into the VNO for detection by VSNs. This mechanism could lead to a global increase in excitability and the chemosensory response in VSNs through activation of P2X receptors.

Cardiovascular effects of buccal exposure to dermal nicotine patches in the dog: a comparative evaluation.

OBJECTIVE: Safety concerns have been raised over the possible effects of inappropriate exposure to transdermal nicotine patches. This study was initiated to determine whether placement of these products into the mouth could affect cardiovascular function. METHODS: In a series of 10 anesthetized beagle dogs, Nicoderm, Habitrol, ProStep I (Intact), ProStep D (Damaged) transdermal nicotine products or the Skoal Bandit smokeless tobacco plug were placed in the buccal cavity for 5 minutes. Systemic arterial blood pressure and the electrocardiogram were monitored for up to 90 minutes after exposure with blood samples at intervals during the first 10 minutes for plasma nicotine concentration. RESULTS: The systolic and diastolic arterial blood pressures and heart rate increased within 2 minutes of buccal exposure to either the intact or the damaged ProStep nicotine product. Ventricular arrhythmias were observed in 6 of 10 dogs exposed to the intact patch and 7 of 10 dogs exposed to the damaged patch during the period of maximal cardiovascular response. Modest increases in systemic blood pressure and heart rate were seen with the Nicoderm and Habitrol products but not with the Skoal Bandit. The increases in systemic arterial pressure and heart rate occurring after exposure to ProStep were significantly more severe than those observed after Nicoderm and Habitrol. Mean peak nicotine levels of 9.8 microg/mL (ProStep 1), 5.4 microg/mL (ProStep D), 3.4 microg/mL (Habitrol), 2.5 microg/mL (Nicoderm), and 0.12 microg/mL (Skoal Bandit) were detected within 2 to 10 minutes after buccal placement of the product. CONCLUSIONS: Certain transdermal nicotine patches, when applied to a nondermal site such as the buccal cavity for a short period (5 minutes) can rapidly provoke significant cardiovascular alterations (hypertension, tachycardia, and ventricular arrhythmias). The magnitude of the cardiovascular responses occurring after buccal exposure to a product such as ProStep could pose a risk to susceptible individuals.

The effects of changes in hearing status in cochlear implant users on the acoustic vowel space and CV coarticulation.

In order to examine the role of hearing status in controlling coarticulation, eight English vowels in /bVt/ and /dVt/ syllables, embedded in a carrier phrase, were elicited from 7 postlingually deafened adults and 2 speakers with normal hearing. The deaf adults served in repeated recording sessions both before and up to a year after they received cochlear implants and their speech processors were turned on. Each of the two hearing control speakers served in two recording sessions, separated by about 3 months. Measures were made of second formant frequency at obstruent release and at 25 ms intervals until the final obstruent. An index of coarticulation, based on the ratio of F2 at vowel onset to F2 at midvowel target, was computed. Changes in the amount of coarticulation after the change in hearing status were small and nonsystematic for the /bVt/ syllables; those for the /dVt/ syllables averaged a 3% increase--within the range of reliability measures for the 2 hearing control speakers. Locus equations (F2 at vowel onset vs. F2 at vowel midpoint) and ratios of F2 onsets in point vowels were also calculated. Like the index of coarticulation, these measures tended to confirm that hearing status had little if any effect on coarticulation in the deaf speakers, consistent with the hypothesis that hearing does not play a direct role in regulating anticipatory coarticulation in adulthood. With the restoration of some hearing, 2 implant users significantly increased the average spacing between vowels in the formant plane, whereas the remaining 5 decreased that measure. All speakers but one also reduced vowel duration significantly. Four of the speakers reduced dispersion of vowel formant values around vowel midpoint means, but the other 3 did not show this effect.

Covariation of cochlear implant users' perception and production of vowel contrasts and their identification by listeners with normal hearing.

This study investigates covariation of perception and production of vowel contrasts in speakers who use cochlear implants and identification of those contrasts by listeners with normal hearing. Formant measures were made of seven vowel pairs whose members are neighboring in acoustic space. The vowels were produced in carrier phrases by 8 postlingually deafened adults, before and after they received their cochlear implants (CI). Improvements in a speaker's production and perception of a given vowel contrast and normally hearing listeners' identification of that contrast in masking noise tended to occur together. Specifically, speakers who produced vowel pairs with reduced contrast in the pre-CI condition (measured by separation in the acoustic vowel space) and who showed improvement in their perception of these contrasts post-CI (measured with a phoneme identification test) were found to have enhanced production contrasts post-CI in many cases. These enhanced production contrasts were associated, in turn, with enhanced masked word recognition, as measured from responses of a group of 10 normally hearing listeners. The results support the view that restoring self-hearing allows a speaker to adjust articulatory routines to ensure sufficient perceptual contrast for listeners.

Language-specific, hearing-related changes in vowel spaces: a preliminary study of English- and Spanish-speaking cochlear implant users.

OBJECTIVE: This study investigates the role of hearing in vowel productions of postlingually deafened cochlear implant users. Two hypotheses are tested that derive from the view that vowel production is influenced by competing demands of intelligibility for the listener and least effort in the speaker: 1) Hearing enables a cochlear implant user to produce vowels distinctly from one another; without hearing, the speaker may give more weight to economy of effort, leading to reduced vowel separation. 2) Speakers may need to produce vowels more distinctly from one another in a language with a relatively "crowded" vowel space, such as American English, than in a language with relatively few vowels, such as Spanish. Thus, when switching between hearing and non-hearing states, English speakers may show a tradeoff between vowel distinctiveness and least effort, whereas Spanish speakers may not. DESIGN: To test the prediction that there will be a reduction of average vowel spacing (AVS) (average intervowel distance in the F1-F2 plane) with interrupted hearing for English-speaking cochlear implant users, but no systematic change in AVS for Spanish cochlear implant users, vowel productions of seven English-speaking and seven Spanish-speaking cochlear implant users, who had been using their implants for at least 1 yr, were recorded when their implant speech processors were turned off and on several times in two sessions. RESULTS: AVS was consistently larger for the English speakers with hearing than without hearing. The magnitude and direction of AVS change was more variable for the Spanish speakers, both within and between subjects. CONCLUSION: Vowel distinctiveness was enhanced with the provision of some hearing in the language group with a more crowded vowel space but not in the language group with fewer vowels. The view that speakers seek to minimize effort while maintaining the distinctiveness of acoustic goals receives some support.

Changes in speech intelligibility of postlingually deaf adults after cochlear implantation.

OBJECTIVE: This study examines changes in the intelligibility of CVC words spoken by postlingually deafened adults after they have had 6 to 12 mo of experience with a cochlear implant. The hypothesis guiding the research is that the intelligibility of these speakers will improve after extended use of a cochlear implant. The paper also describes changes in CVC word intelligibility analyzed by phoneme class and by features. DESIGN: The speech of eight postlingually deaf adults was recorded before activation of the speech processors of their cochlear implants and at 6 mo and 1 yr after activation. Seventeen listeners with no known impairment of hearing completed a word identification task while listening to each implant user's speech in noise. The percent information transmitted by the speakers in their pre- and postactivation recordings was measured for 11 English consonants and eight vowels separately. RESULTS: An overall improvement in word intelligibility was observed: seven of the eight speakers showed improvement in vowel intelligibility and six speakers showed improvement in consonant intelligibility. However, the intelligibility of specific consonant and vowel features varied greatly across speakers. CONCLUSIONS: Extended use of a cochlear implant by postlingually deafened adults tends to enhance their intelligibility.

A reproducible nonlethal animal model for studying cyanide poisoning.

Previous studies using bolus intravenous injections of sodium cyanide have been used to model the sudden exposure to high concentrations of cyanide that could occur on the battlefield. This study was designed to develop a model that would simulate the type of exposure to cyanide gas that could happen during actual low-level continuous types of exposure and then compare it with the bolus model. Cardiovascular and respiratory recordings taken from anesthetized dogs have been used previously to characterize the lethal effects of cyanide. The intravenous, bolus injection of 2.5 mg/kg sodium cyanide provides a model in which a greater than lethal concentration is attained. In contrast, our model uses a slow, intravenous infusion of cyanide to titrate each animal to its own inherent end point, which coincides with the amount of cyanide needed to induce death through respiratory arrest. In this model, therapeutic intervention can be used to restore respiration and allow for the complete recovery of the animals. After recovery, the same animal can be given a second infusion of cyanide, followed again by treatment and recovery, providing a reproducible end point. This end point can then be expressed as the total amount of cyanide per body weight (mg/kg) required to kill. In this study, the average dose of sodium cyanide among 12 animals was 1.21 mg/kg, which is approximately half the cyanide used in the bolus model. Thus, titration to respiratory arrest followed by resuscitation provides a repetitive-use animal model that can be used to test the efficacy of various forms of pretreatment and/or therapy without the loss of a single animal.

Reversal of propranolol blockade of adrenergic receptors and related toxicity with drugs that increase cyclic AMP.

An overdose of propranolol, a widely used nonselective beta-adrenergic receptor blocking agent, can result in hypotension and bradycardia leading to irreversible shock and death. In addition, the blockade of adrenergic receptors can lead to alterations in neurotransmitter receptors resulting in the interruption of the activity of other second messengers and the ultimate cellular responses. In the present experiment, three agents, aminophylline, amrinone, and forskolin were tested in an attempt to reverse the potential lethal effects of a propranolol overdose in dogs. Twenty-two anesthetized beagle dogs were given a 10-min infusion of propranolol at a dose of 1 mg/kg/min. Six of the dogs, treated only with intravenous saline, served as controls. Within 15-30 min all six control dogs exhibited profound hypotension and severe bradycardia that led to cardiogenic shock and death. Seven dogs were treated with intravenous aminophylline 20 mg/kg 5 min after the end of the propranolol infusion. Within 10-15 min heart rate and systemic arterial blood pressure returned to near control levels, and all seven dogs survived. Intravenous amrinone (2-3 mg/kg) given to five dogs, and forskolin (1-2 mg/kg) given to four dogs, also increased heart rate and systemic arterial blood pressure but the recovery of these parameters was appreciably slower than that seen with aminophylline. All of these animals also survived with no apparent adverse effects. Histopathologic evaluation of the hearts of the dogs treated with aminophylline showed less damage (vacuolization, inflammation, hemorrhage) than the hearts from animals given propranolol alone. Results of this study showed that these three drugs, all of which increase cyclic AMP, are capable of reversing the otherwise lethal effects of a propranolol overdose in dogs.

The effect of changes in hearing status on speech sound level and speech breathing: a study conducted with cochlear implant users and NF-2 patients.

According to a dual-process theory of the role of hearing in speech production, hearing helps maintain an internal model used by the speech control mechanism to achieve phonemic goals. It also monitors the acoustic environment and guides relatively rapid adjustments in postural parameters, such as those underlying average speech sound level and rate, in order to achieve suprasegmental goals that are a compromise between intelligibility and economy of effort. In order to obtain evidence bearing on this theory, acoustic and aerodynamic measures were collected from seven adventitiously deaf speakers who received cochlear implants, three speakers who had severe reduction in hearing following surgery for Neurofibromatosis-2, and one hard of hearing speaker. These speakers made recordings of the Rainbow Passage and an English vowel inventory before and after intervention. All but one of the postlingually deaf speakers who received prosthetic hearing reduced speech sound level, SPL. Three of these significantly increased a measure of inferred glottal aperture, H1-H2, and their session means for these two parameters were inversely correlated longitudinally. All but one of the speakers terminated respiratory limbs closer to functional residual capacity (FRC) once prosthetic hearing was supplied. Finally, the implant users' average values of air expenditure moved toward normative values with prosthetic hearing. These results are attributed to the mediation of changes in respiratory and glottal posture aimed at reducing speech sound level and economizing effort.

Recovery of an oligonucleotide using silver ions immobilized onto paramagnetic particles.

A 3'-GCCCCTTTTTAAAAACCCCG-5' oligonucleotide can be recovered from aqueous solution using paramagnetic particles containing immobilized silver ions. Binding and elution experiments were conducted by attaching either fluorescein isothiocyanate (FITC) to the 3'-end or Texas Red or fluorescein phosphoramidite (FAM) to the 5'-end of the oligonucleotide. For the 5'-end FAM labeled oligonucleotide, a binding constant of 4.2 x 10(7) was measured at pH 7 using phosphate buffer. The percent of bound FAM labeled oligonucleotide eluted from the paramagnetic particles were found to be 97% using an aqueous solution of thiodiglycol. While the FAM molecule by itself does not bind to the silver activated paramagnetic particles, the choice of fluorescent label affects binding affinities and elution recoveries.

Effectiveness of intramuscularly administered cyanide antidotes on methemoglobin formation and survival.

Successful first aid therapy for cyanide intoxication is dependent upon immediate administration of antidotes which directly or indirectly interact with the cyanide ion to remove it from circulation. Owing to the severe respiratory, cardiovascular and convulsive episodes following acute cyanide intoxication, the most practical approach is to administer antidotes by intramuscular injection. Exceptionally rapid methemoglobin formers-hydroxylamine hydrochloride (HH) and dimethylaminophenol (DMAP)-are usually able to prevent the lethal effect of cyanide following intramuscular injections in doses sufficient to induce 20% methemoglobin (HH = 20 mg kg-1 and DMAP = 2 mg kg-1). Sodium nitrite, the methemoglobin inducer approved for military use, must be administered by intravenous infusion because it is not an effective cyanide antidote by the intramuscular route. In the normal unintoxicated animal an intramuscular injection of 20 mg kg-1 sodium nitrite will form 20% methemoglobin; however, in acute cyanide intoxication the associated severe bradycardia appears to limit the rate of absorption and thus the rapid formation of methemoglobin. If the bradycardia is prevented or reversed by atropine, the rate of absorption of sodium nitrite and the formation of methemoglobin is able to reverse the otherwise lethal effects of cyanide. Thus, an intramuscularly administered combination of 20 mg kg-1 sodium nitrite and 1 mg kg-1 atropine sulfate, rapidly absorbed from the intramuscular site, appears to achieve the same degree of effectiveness against acute cyanide intoxication as intramuscularly administered HH or DMAP. It would appear from these studies that HH, DMAP and sodium nitrite with atropine are all potentially effective intramuscular antidotes for acute cyanide poisoning.

Reversal of acute theophylline toxicity by calcium channel blockers in dogs and rats.

Theophylline, widely used in the treatment of pulmonary diseases, has a narrow therapeutic index; the recommended plasma levels being 10-20 micrograms/ml in humans. The misuse or abuse of theophylline can cause life-threatening central nervous system and cardiovascular effects. Increased intracellular Ca2+ levels are thought to play an important role in theophylline toxicity and death. The objective of this study was to determine whether Ca2+ channel blockers, e.g. verapamil, nifedipine, or diltiazem, prevent sudden death caused by theophylline treatment in rats and dogs. Groups of Sprague-Dawley rats were treated with theophylline alone (150 mg/kg i.p.) or with theophylline pretreatment followed by administration of verapamil (0.25 to 0.5 mg/kg i.p.), nifedipine (0.25 to 1.0 mg/kg i.p.), or diltiazem (0.5 to 1.0 mg/kg i.p.), 2.5 to 15 min later. The rats were observed for toxic signs and survival over a period of 15 days. All three calcium channel blockers significantly reduced the theophylline-induced sudden death in rats. In a separate study, neither verapamil (0.5 mg/kg i.p.) nor nifedipine (1.0 mg/kg i.p.) prevented the theophylline-induced myocardial necrosis in the rat. In beagle dogs, verapamil (0.5 mg/kg i.v.) prevented theophylline (15 mg/kg/min i.v. for 10 min)-induced hypotension, arrhythmias, and sudden death. Our results support previously reported findings that calcium plays a major role in theophylline-induced toxicity and death.

Medical studies of poisonous land and sea snakes.

The comparative toxicity and pathophysiology of thirteen (13) of poisonous snakes indigenous to the area in and around Saudi Arabia were determined. Four snakes from the Viperidae family, six from the Elapidae family, and three representative sea snakes from the family Hydrophiodae were included. Anesthetized adult Beagle dogs and anesthetized monkeys were used in the study. Vital physiologic functions were recorded continuously as were changes in the blood coagulation system and any tissue damage produced by the venom at the site of envenomation. Venom was administered intravenously or by an actual bite. Venom from the snakes of the family Viperidae produced death in an average of 3 hours. The average lethal dose was 1.13 mg/kg. Depression of 1st and 2nd stage clotting factors and a decrease in fibrinogen levels and in platelet counts were observed with these venoms. Findings suggestive of intravascular coagulation also were observed with moderate hemolysis of the formed elements. Some local hemorrhage was seen at the site of envenomation. Venom from the Elapidae family of snakes produced death at an average of 1.7 hours. The average lethal dose was 0.70 mg/kg. Death appeared to be primarily due to respiratory paralysis after blockade at the neuromuscular junction. Only moderate hemolysis was seen with these venoms. No intravascular coagulation or tissue damage was seen. The venom of the family Hydrophiodae consistently produced death in less than 30 minutes at an average dose of 0.06 mg/kg. Tissue damage was not observed, and changes were not observed in the hematologic parameters monitored.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular studies of phenylpropanolamine.

Phenylpropanolamine is found in a number of over-the-counter preparations commonly used for appetite control or as a cold remedy. Even though widely used, some questions still exist as to its effect on the cardiovascular system of man. Both anesthetized and unanesthetized adult beagle dogs were used in this study. In the unanesthetized conditioned dog, blood pressure and heart rate were measured using an inflatable tail cuff. In the first group, consisting of 12 dogs, phenylpropanolamine was given (0.0, 3.1, 6.25 and 12.5 mg/kg) via a stomach tube and the animals were followed for 300 minutes. Each dose of phenylpropanolamine was given to 4 groups made up of 3 dogs each. It produced dose-dependent increases in blood pressure and decreases of heart rate. Maximum changes were noted at 30 to 60 minutes, lasting for 3 to 5 hours. A second group of 9 unanesthetized dogs was given repeated oral doses of phenylpropanolamine (3 groups of 3 animals each). Doses of 3 mg/kg and 6 mg/kg, given orally, produced approximately the same increase in blood pressure and decrease of heart rate as previously observed. At 6 hours, these same doses of phenylpropanolamine produced little or no change in either parameter. At 24 hours after the first dose, however, the dogs responded in much the same manner as with the first administration of phenylpropanolamine. Control dogs given water did not exhibit any degree of tachyphylaxis. Dogs anesthetized with Na pentobarbital were given oral and intravenous doses of phenylpropanolamine (0.0-25 mg/kg). The overall response was like that observed in the unanesthetized preparation with the important exception that low doses (0.1-3 mg/kg) produced significant increases in both heart rate and blood pressure, while higher doses (6-25 mg/kg) resulted in a lesser overall effect. Six anesthetized animals were used to study the effects of phenylpropanolamine and norepinephrine on the cardiovascular function. Both the increase in blood pressure and left ventricular force of contraction, produced by the first dose of phenylpropanolamine, were markedly reduced or absent with the second administration of the drug. In addition, the classic blood pressure response to norepinephrine was likewise increased by prior administration of phenylpropanolamine.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhancement of acute myocardial lesions by asthma drugs in rats.

Asthma morbidity and mortality have risen significantly in the last 10 years. The reasons for the increase are multifactorial. One proposed explanation is possible myocardial toxicity arising from the use of beta-agonists alone or in combination with methylxanthines. Previous studies have shown that beta-agonists given alone and beta-agonist/methylxanthine combinations given at higher than recommended clinical doses induced dose-related cardiotoxicity and sudden death in rats. The objective of the present study was to determine whether or not beta-agonists given alone and in combination with methylxanthines at recommended clinical doses also induce cardiotoxicity and sudden death in rats. The beta-agonists, isoproterenol hydrochloride (15 micrograms/kg), fenoterol hydrobromide (40 micrograms/kg), and terbutaline hemisulfate (0.4 mg/kg) were given in single sc doses separately and concurrently with the methylxanthines aminophylline hydrate (20 mg/kg) and caffeine (40 mg/kg), which were given up to a susceptible animal model, the heavy Sprague-Dawley rat. beta-agonist-induced myocardial toxicity (necrosis) was observed. The toxicity was enhanced by aminophylline resulting in the sudden death (most likely due to ventricular fibrillation) of some animals. A decrease in serum iron levels was observed in rats of all beta-agonist and/or methylxanthine-treated groups.

Albumin modulation of paracellular permeability of pig vena caval endothelium shows specificity for pig albumin.

We measured endothelial hydraulic conductivity (Lp,e) and endothelial electrical resistance (Re) of pig vena cava in pig serum albumin (PSA) and bovine serum albumin (BSA) to determine whether specificity for the autologous albumin found in dog vena cava is a general property of mammalian endothelium. Pigs were anesthetized with pentobarbital sodium for surgical removal of the thoracic inferior vena cava. A vessel segment was placed as a membrane separating two compartments in a chamber. Vessels kept in 30 mg/ml BSA had Lp,e values of 1.30 +/- 0.81 x 10(-7) cm.s-1.cmH2O-1 (n = 9) and Re values of 13.8 +/- 2.6 omega.cm2 (n = 3). Vessels kept in PSA had Lp,e values of 0.257 +/- 0.125 x 10(-7) cm.s-1.cmH2O-1 (n = 5) and Re values of 21 +/- 6.3 omega.cm2 (n = 4). The differences between Lp,e and Re in BSA and PSA were statistically significant (P < 0.05). In vessels kept in PSA, switching to BSA caused a doubling of Lp,e. Lower Lp,e and higher Re in PSA as compared with those in BSA suggest that specificity for the autologous albumin is a general phenomenon in mammalian endothelium and that albumin binding to specific sites is associated with its permeability effect.

Synergism between dipyridamole and cisplatin in human ovarian carcinoma cells in vitro.

Dipyridamole (DPM), a nucleoside membrane transport inhibitor, enhanced the cytotoxicity of cisplatin (DDP) for human ovarian carcinoma 2008 cells by a factor of 4.7 +/- 0.4-fold (mean +/- SD) and for the 10-fold DDP-resistant 2008/C13*5.25 subline by a factor of 5.8 +/- 2.7-fold. This interaction was shown to be truly synergistic by isobologram and median effect analysis. DPM enhancement of DDP cytotoxicity was schedule dependent; it was greatest when cells were exposed to DPM continuously during and following a 1-h exposure to DDP and less pronounced when DPM exposure was limited to pretreatment or concurrent treatment only. DPM increased DDP uptake in a concentration-dependent manner as measured with both [195mPt]-DDP and the DDP analogue [3H]-cis-dichloro(ethylenediamine) platinum. Nitrobenzylthioinosine, another nucleoside membrane transport inhibitor, did not enhance DDP cytotoxicity or uptake at concentrations that produced equivalent degrees of inhibition of [3H]uridine uptake. DPM did not interact synergistically through an increase in cellular cyclic AMP levels. DPM did not increase trypan blue or propidium iodide uptake, or change cell size, indicating that it did not nonspecifically increase membrane permeability. We conclude that DPM interacts synergistically with DDP and that, while an increase in DDP uptake is one component of the mechanism of this interaction, there are additional components since maximal effect was observed only with prolonged DDP exposure.

1991 Sir Henry Wellcome Medal and Prize recipient. Medical studies of the poisonous land and sea snakes found in and around Saudi Arabia.

Studies were carried out to determine the comparative toxicity and pathophysiology of 13 of the more poisonous snakes indigenous to Saudi Arabia. Included were four snakes from the Viperidae family, six from the Elapidae family, and three representative sea snakes from the family Hydrophidae. Anesthetized adult beagle dogs and anesthetized monkeys were used in the study. Vital physiological functions were continuously recorded as were changes in the blood coagulation system and any tissue damage produced by the venom at the site of envenomation. For the intravenous administration of the venom, lyophilized venom was obtained by "milking" each of the live specimens used in the study. Actual envenomation was accomplished by grasping the poisonous reptile and allowing the snake to strike the shaved exposed gluteal muscle of the anesthetized animal. Venom from the snakes of the family Viperidae produced death in an average of 3 hours. The average lethal dose was 1.13 mg/kg. Depression of first and second stage clotting factors was observed with these venoms as well as a decrease in fibrinogen levels and in platelet counts. Findings suggestive of intravascular coagulation were also observed with moderate hemolysis of the formed elements. Some local hemorrhage was seen at the site of envenomation. Venom from the Elapidae family of snakes produced death at an average of 1.7 hours. The average lethal dose was 0.70 mg/kg. Death appeared to be primarily due to respiratory paralysis following blockade at the neuromuscular junction. Only moderate hemolysis was seen with these venoms. No intravascular coagulation or tissue damage was seen. The venom of the family Hydrophidae consistently produced death in less than 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)