Pharmacokinetically guided dosing of carboplatin and etoposide during peritoneal dialysis and haemodialysis

The delineation of T helper cell subsets into T helper type 1 (Th1) and T helper type 2 (Th2) populations based on the production of specific cytokines has been useful in understanding the regulation and progression of immune-based pathologies. In order to test the relevance of this concept to human solid organ transplantation, in situ and system Th1 and Th2 cytokine profiles were characterized in liver allograft recipients. Bile and serum samples obtained posttransplant were analyzed for the cytokines IL-2, IFN-gamma, IL-4, and IL-10. Significant elevations of IL-4 and IL-10 were measured at the site of graft rejection. In contrast, IL-2, IFN-gamma, and IL-4 were markedly elevated in the circulation during rejection. Analyses of sequential bile samples revealed that Th1 and Th2 cytokines showed similar kinetics of production in response to alloantigen. Taken together, these results indicate that acute rejection of human allografts can proceed [correction of procede] in the presence of minimal levels of the Th1 cytokines IL-2 and IFN-gamma and high levels of IL-4 and IL-10.     

Does antithrombotic therapy influence residual thrombus after thrombolysis of platelet-rich thrombus? Effects of recombinant hirudin, heparin, or aspirin

BACKGROUND: Thrombolysis to normal flow in patients with acute myocardial infarction preserves left ventricular function and decreases mortality. Failure of early reperfusion, reocclusion, or residual thrombus may be due to concurrent activation of the platelet-coagulation system. Thus, we hypothesized that the best concomitant antithrombotic therapy (recombinant [r]-hirudin, heparin, or aspirin) will maximally accelerate thrombolysis by r-tissue-type plasminogen activator (rTPA) and reduce residual thrombus. METHODS AND RESULTS: Occlusive thrombi were formed in the carotid arteries of 29 pigs (by balloon dilatation followed by endarterectomy at the site of injury-induced vasospasm) and matured for 30 minutes before rTPA was started, with or without antithrombotic therapy. Thrombolysis was assessed with the use of angiography and measurement of residual thrombus. Pigs were allocated to one of five treatments: placebo, rTPA, rTPA plus r-hirudin, rTPA plus heparin, or rTPA plus intravenous aspirin. No placebo-treated pig reperfused. Two of six animals treated with rTPA alone reperfused compared with seven of seven animals treated with rTPA plus r-hirudin (reperfusion time, 33 +/- 10 minutes), six of seven animals treated with rTPA plus heparin (reperfusion time, 110 +/- 31 minutes), and two of six animals with rTPA plus aspirin. The activated partial thromboplastin time was prolonged in only the rTPA plus r-hirudin group (25 +/- 0.1 times baseline) and the rTPA plus heparin group (5.3 +/- 0.2 times baseline). Residual 111In-platelet and 125I-fibrin(ogen) depositions were lower in the heparin-treated group and lowest in the r-hirudin-treated group (heparin versus hirudin, respectively; incidence of residual macroscopic thrombus was six of six animals versus two of seven [P = .01]; 125I-fibrin(ogen), 170 +/- 76 versus 48 +/- 6 x 10(6) molecules/cm2 [P = .02]; 111In-platelets, 47 +/- 15 versus 13 +/- 2 x 10(6)/cm2, P = .10). No pigs developed spontaneous bleeding. CONCLUSIONS: Thrombin inhibition with heparin or r-hirudin significantly accelerated thrombolysis of occlusive platelet-rich thrombosis, but only the best antithrombotic therapy (r-hirudin) eliminated or nearly eliminated residual thrombus.     

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.