Acid, protons and Helicobacter pylori

The anti-ulcer drugs that act as covalent inhibitors of the gastric acid pump are targeted to the gastric H+/K+ ATPase by virtue of accumulation in acid and conversion to the active sulfenamide. This results in extremely effective inhibition of acid secretion. Appropriate dosage is able to optimize acid control therapy for reflux and peptic ulcer disease as compared to H2 receptor antagonists. However, clinical data on recurrence show that Helicobacter pylori eradication should accompany treatment of the lesion. These drugs have been found to synergize with many antibiotics for eradication. The survival of aerobes depends on their ability to maintain a driving force for protons across their inner membrane, the sum of a pH and potential difference gradient, the protonmotive force (pmf). The transmembrane flux of protons across the F1F0 ATPase, driven by the pmf, is coupled to the synthesis of ATP. The internal pH of H. pylori was measured using the fluorescent dye probe, BCECF, and the membrane potential defined by the uptake of the carbocyanine dye, DiSC3 [5] at different pHs to mimic the gastric environment. The protonmotive force at pH 7.0 was composed of a delta pH of 1.4 (-84mV) and a delta potential difference of -131mV, to give a pmf of -215 mV. The effect of variations in external pH on survival of the bacteria in the absence of urea correlated with the effect of external pH on the ability of the bacteria to maintain a pmf. The effect of the addition of 5 mM urea on the pmf was measured at different medium pH values. Urea restored the pmf at pH 3.0 or 3.5, but abolished the pmf at pH 7.0 or higher, due the production of the alkalinizing cation, NH3. Hence H. pylori is an acid-tolerant neutrophile due to urease activity, but urease activity also limits its survival to an acidic environment. These data help explain the occupation of the stomach by the organism and its distribution between fundus and antrum. This distribution and its alteration by proton pump inhibitors also explains the synergism of proton pump inhibition and antibiotics such as amoxicillin and clarithromycin in H. pylori eradication.     

The effect of simulated cataract on the glaucomatous visual field

PURPOSE: The current study is designed to determine the effect of light scattering (simulated cataract) on glaucomatous visual fields. METHODS: Twelve patients with relative scotomas caused by glaucoma underwent the 30-2 threshold test with the Humphrey Visual Field Analyzer twice: once with and once without having a light-diffusing piece of ground glass in front of the eye, which, in previous experiments, has been shown to decrease perimetric threshold by 4.4 decibels (dB) in normal eyes. As controls, 12 patients underwent the same examination with and without a piece of clear glass in front of the eye. In each pair of fields, five points were analyzed within the relative scotoma and compared with five points in a normal area of the opposite hemifield. RESULTS: The diffusing ground glass produced a mean decrease of perimetric threshold of 5.7 dB (standard deviation [SD] = 3.3 dB) within the area of relative scotoma compared with 6.1 dB (SD = 2.4 dB) within the normal area and 4.4 dB (SD = 2.25 dB) at the fovea. The differences between means were not statistically significant. In addition, the diffusing glass did not affect the corrected pattern SD (CPSD) index (6.5 dB with the diffuser and 6.5 dB without). CONCLUSION: Light scattering depresses the glaucomatous visual field diffusely. Relative glaucomatous scotomas and normal areas are depressed equally, expressed as change in decibel of sensitivity. Therefore, in following patients with cataracts and glaucoma, depression of threshold sensitivity in glaucomatous areas out of proportion to normal areas should not be attributed to the light-scattering effect of the cataract, but rather to possible worsening of glaucomatous damage.     

Bizarre parosteal osteochondromatous proliferation. An unusual bone tumor

Bizarre parosteal osteochondromatous proliferation of bone is a rare, benign bone tumor. The authors discuss two cases involving the bones of the feet, and review clinical, radiographic, and histopathologic characteristics. Awareness of this lesion is essential as bizarre parosteal osteochondromatous proliferation of bone can be mistaken for a malignancy.     

Inflammatory bowel disease and refractory anaemia (myelodysplasia)

Two patients with colitis and refractory anaemia requiring multiple transfusions are described. In one the anaemia was detected at the onset of colitis before drug treatment; in the other it started after 21 years of treatment with sulphasalazine and during an exacerbation of colitis with perianal abscess for which he had just been started receiving prednisolone, cofluampicil and metronidazole. Glomerulonephritis developed two weeks after the onset of anaemia. These findings together with a recent report of four patients with Crohn's disease and refractory anaemia suggests that the association may be more than coincidental and may be immune mediated.     

The effect of pulpal fluid flow on tensile bond strength of a glass-ionomer cement: an in vivo and in vitro comparison

Previous studies of the bonding capabilities of glass-ionomer cements have concentrated on the use of in vitro testing conditions. Since early moisture contamination appears to have adverse effects on the physical properties of glass-ionomer cements, and with the probability of pulpally derived dentinal fluid being present under in vivo conditions, the objective of this study was to compare in vivo tensile bond strength with in vitro tensile bond strength of a glass-ionomer cement to dentin utilizing the same teeth under similar test conditions. A glass-ionomer lining cement was placed on freshly exposed labial dentin of the maxillary incisor on 10 Rhesus monkeys. Immediately following placement, an orthodontic button was placed over the cement and left undisturbed for 1 hour. The teeth were then extracted and stored in 100% relative humidity for 23 hours. An Instron testing machine was used to register in kilograms the force required to cause tensile bond failure of the cement. Identical methodology was then used on the same teeth for in vitro testing. The concluding results indicate that a statistically significant difference (P < or = 0.05) exists between in vivo and in vitro tensile bond strengths of the glass-ionomer lining cement and that the bond failure was cohesive in character for all cases both in vivo and in vitro. These findings suggest that clinically, tensile bond strengths of glass-ionomer cements to cut dentin can be expected to be weaker in vital teeth than in devital teeth.     

Consensus Conference on Platelet Transfusion, Royal College of Physicians of Edinburgh, 27-28 November 1997. Synopsis of background papers

The effects of 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxypheneth yl)-N-methylamino] ethane hydrochloride (KCB-328), in comparison with those of dofetilide, were studied on the action potentials (APs) of isolated guinea pig papillary muscles. KCB-328 (0.003-3 microM) concentration-dependently prolonged the AP duration at 90% repolarization (APD90) at 1- and 3-Hz pacing, and the concentration-response relations at 1 and 3 Hz resemble each other. Dofetilide (0.001-1 microM) also produced the concentration-dependent prolongation of APD90 but more pronouncedly at 1 than at 3 Hz, demonstrating the reverse frequency-dependent effect. KCB-328 at 0.03, 0.1, 0.3, and 1 microM increased APD90 by 11 +/- 1, 19 +/- 1, 25 +/- 1, and 29 +/- 1% at 3 Hz and by 9 +/- 1, 19 +/- 2, 27 +/- 2, and 33 +/- 2% at 1 Hz, respectively. Prolongation of the effective refractory period (ERP) by each drug is parallel to those of APD90 at each pacing frequency. KCB-328 modified neither the maximal velocity of depolarization, amplitude of AP, and resting membrane potential in the fast APs, nor any parameters of the slow APs. In a separate experiment, the effects of KCB-328 on the ERP of contractile response (ERPc) of excised guinea-pig papillary muscles also were studied at 1 and 3 Hz. KCB-328 (0.01-10 microM) lengthened the ERPc in a concentration-dependent and frequency-independent manner as in the electrophysiologic results. This frequency-independent ERPc prolongation by KCB-328 was not influenced by increased extracellular K+ concentration from 4 to 10 mM. These results suggest that KCB-328 might be a selective class III agent with effects that are relatively frequency independent.     

Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors

Previous studies indicate that the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR141716A), inhibits the anandamide- and delta9-tetrahydrocannabinol- (THC) induced hypotension and bradycardia in anesthetized rats with a potency similar to that observed for SR141716A antagonism of THC-induced neurobehavioral effects. To further test the role of CB1 receptors in the cardiovascular effects of cannabinoids, we examined two additional criteria for receptor-specific interactions: the rank order of potency of agonists and stereoselectivity. A series of cannabinoid analogs including the enantiomeric pair (-)-11-OH-delta9-THC dimethylheptyl (+)-11-OH-delta9-THC dimethylheptyl were evaluated for their effects on arterial blood pressure and heart rate in urethane anesthetized rats. Six analogs elicited pronounced and long lasting hypotension and bradycardia that were blocked by 3 mg/kg of SR141716A. The rank order of potency was (-)-11-OH-delta9-THC dimethylheptyl > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > THC > anandamide > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol, which correlated well with CB1 receptor affinity or analgesic potency (r = 0.96-0.99). There was no hypotension or bradycardia after palmitoylethanolamine or (+)-11-OH-delta9-THC dimethylheptyl. An initial pressor response was also observed with THC and anandamide, which was not antagonized by SR141716A. We conclude that the similar rank orders of potency, stereoselectivity and sensitivity to blockade by SR141716A indicate the involvement of CB1-like receptors in the hypotensive and bradycardic actions of cannabinoids, whereas the mechanism of the pressor effect of THC and anandamide remains unclear.     

Cost-effectiveness of chemoprophylaxis after occupational exposure to HIV

OBJECTIVES: To assess the economic efficiency of recent US Public Health Service recommendations for chemoprophylaxis with a combination of antiretroviral drugs following high-risk occupational exposure to human immunodeficiency virus (HIV). To provide a framework for evaluating the relative effectiveness and costs associated with candidate postexposure prophylaxis (PEP) regimens. METHODS: Standard techniques of cost-effectiveness and cost-utility analysis were used. The analysis compares the costs and consequences of a hypothetical, voluntary combination-drug PEP program consisting of counseling for all HIV-exposed health care workers, followed by chemoprophylaxis for those who elect it vs an alternative in which PEP is not offered. A societal perspective was adopted and a 5% discount rate was used. Hospital costs of recommended treatment regimens (zidovudine alone or in combination with lamivudine and indinavir) were used, following the dosing schedules recommended by the US Public Health Service. Estimates of lifetime treatment costs for HIV and acquired immunodeficiency syndrome were obtained from the literature. Because the effectiveness of combination PEP has not been established, the effectiveness of zidovudine PEP was used in the base-case analyses. MAIN OUTCOME MEASURES: Net PEP program costs, number of HIV infections averted, cost per HIV infection averted, and cost-utility ratio (net cost per discounted quality-adjusted life-year saved) for zidovudine, lamivudine, and indinavir combination PEP. Lower bounds on the effectiveness required for combination regimens to be considered incrementally cost saving, relative to zidovudine PEP alone, were calculated. Multiple sensitivity and threshold analyses were performed to assess the impact of uncertainty in key parameters. RESULTS: Under base-case assumptions, the net cost of a combination PEP program for a hypothetical cohort of 10,000 HIV-exposed health care workers is about $4.8 million. Nearly 18 HIV infections are prevented. The net cost per averted infection is just less than $400,000, which exceeds estimated lifetime HIV and acquired immunodeficiency syndrome treatment costs. Although combination PEP is not cost saving, the cost-utility ratio (about $37,000 per quality-adjusted life-year in the base case) is within the range conventionally considered cost-effective, provided that chemoprophylaxis is delivered in accordance with Public Health Service guidelines. Small incremental improvements in the effectiveness of PEP are associated with large overall societal savings. CONCLUSIONS: Under most reasonable assumptions, chemoprophylaxis with zidovudine, lamivudine, and indinavir following moderate- to high-risk occupational exposures is cost-effective for society. If combination PEP is minimally more effective than zidovudine PEP, then the added expense of including lamivudine and indinavir in the drug regimen is clearly justified.     

Synergistic neutralization of a chimeric SIV/HIV type 1 virus with combinations of human anti-HIV type 1 envelope monoclonal antibodies or hyperimmune globulins

A panel of 14 human IgG monoclonal antibodies (MAbs) specific for envelope antigens of the human immunodeficiency virus type 1 (HIV-1), 2 high-titer human anti-HIV-1 immunoglobulin (HIVIG) preparations, and 15 combinations of MAbs or MAb/HIVIG were tested for their ability to neutralize infection of cultured human T cells (MT-2) with a chimeric simian immunodeficiency virus (SHIV-vpu+), which expressed HIV-1 IIIB envelope antigens. Eleven MAbs and both HIVIGs were neutralizing. When used alone, the anti-CD4-binding site MAb b12, the anti-gp41 MAb 2F5, and the anti-gp120 MAb 2G12 were the most potent. When combination regimens involving two MAbs targeting different epitopes were tested, synergy was seen in all paired MAbs, except for one combination that revealed additive effects. The lowest effective antibody concentration for 50% viral neutralization (EC50) and EC90 were achieved with combinations of MAbs b12, 2F5, 2G12, and the anti-V3 MAb 694/98D. Depending on the combination regimen, the concentration of MAbs required to reach 90% virus neutralization was reduced approximately 2- to 25-fold as compared to the dose requirement of individual MAbs to produce the same effect. Synergy of the combination regimens implies that combinations of antibodies may have a role in passive immunoprophylaxis against HIV-1. The ability of SHIV to replicate in rhesus macaques will allow us to test such approaches in vivo.