The "point of no return" and the rate of progression in the natural history of IgA nephritis

BACKGROUND: Based on the observation of 7 patients with chronic IgA nephritis and on a course to end-stage renal failure after several years, D'Amico et al. [1993] reported on a "point of no return" at 2.5 to 3 mg/dl serum creatinine. After exceeding this limit all 7 patients exhibited an irreversible progressive renal failure. PATIENTS AND METHODS: Therefore, 115 patients with IgA nephritis from the "German Glomerulonephritis Therapy Study" were examined in order to look for the existence of such a "point of no return". RESULTS: Three different courses could be distinguished: a stable chronic course with constantly normal or only minor elevated serum creatinine lasting for years (91 patients), a progressive course with continuously increasing serum creatinine (22 patients), and a rare (only 2 patients) early acute course with a short-term increase of serum creatinine followed by a rapid return to the normal range. After exceeding 3 mg/dl serum creatinine no remissions were observed in the progressive cases. Sixteen patients showed a rapid, continuously progressive course until end-stage renal failure with exactly the same progression as the 7 patients of D'Amico et al. Six patients of the 22 progressors were not observed long enough. The serum creatinine level doubled on average from 3 to 6 mg/dl within 10 months. CONCLUSION: Our study confirmed the existence of a "point of no return" at 3 mg/dl (265 micromol/l) during the natural course of chronic IgA nephritis.     

Definition of ocular antigens in ciliary body and retinal ganglion cells by the marker antibody pANCA

PURPOSE: A subset of patients with anterior uveitis express the marker, perinuclear anti-neutrophil cytoplasmic antibody (pANCA). In this study, recombinantly isolated pANCA monoclonal antibodies were used to search for ocular cells expressing the pANCA antigen. METHODS: Paraffin sections of human ocular tissues obtained after death were analyzed by immunohistochemistry to identify cell types expressing pANCA antigen. Microdissected eye-bank ocular tissue was characterized by western blot analysis to confirm antigen expression and identify candidate protein species. RESULTS: Immunohistochemical analysis with pANCA monoclonal antibodies revealed cytoplasmic antigen expression in retinal ganglion cells and ciliary body epithelium. pANCA antigen expression was restricted to tissues bearing these cell types by western blot analysis. A common set of epitope-positive protein species was shared by the two tissues (28 kDa, 80 kDa, and 90 kDa). Comparison of ocular tissues from seven subjects revealed no heterogeneity in antigen expression. CONCLUSIONS: In this study, novel cytoplasmic antigens of the pANCA marker antibody expressed in ciliary body and retinal tissue were identified. Validation of these antigens as targets of inflammation in pANCA+ uveitis requires further biochemical and immunologic analysis.     

Retinal pigment epithelial cells from Royal College of Surgeons dystrophic rats can take up melanin granules

· Background: Many successful pigment epithelium transplantation studies involving pink-eyed Royal College of Surgeons (RCS) dystrophic rats showed highly pigmented transplanted cells forming a double layer with slightly pigmented cells, attached to Bruch’s membrane. Since it is not clear whether transplanted pigmented cells can displace retinal pigment epithelial (RPE) host cells from Bruch’s membrane, we suggested that RPE cells of RCS dystrophic rats can phagocytize melanin granules, possibly derived from perished transplanted cells. · Methods: In a series of three experiments, RPE cells of nine pink-eyed, 2-month-old RCS dystrophic rats were isolated by trypsinization and mechanical dissection and cultivated in Dulbecco’s modified Eagles’ medium. These cells were then fed with melanin granules, isolated from bovine RPE cells, double-trypsinized after phagocytosis and viewed by light and electron microscopy. We also transplanted iris pigment epithelial (IPE) cells of 20-day-old Long-Evans rats into the subretinal space of pink-eyed RCS dystrophic rats of the same age, shown in light-microscopic photography after 42 days. · Results: Living RPE cells were heavily pigmented after feeding with isolated melanin granules in all three experiments as viewed by light microscopy. In addition, we identified melanin granules phagocytized by dystrophic RPE cells in electron microscopy. After transplantation of pigmented IPE cells into the subretinal space of pink-eyed RCS dystrophic rats’ eyes, a layer of slightly pigmented cells was seen on Bruch’s membrane below the transplanted IPE cells, shown in light microscopy. · Conclusion: We have shown by phagocytosis assay that dystrophic RPE cells can take up melanin granules in vitro. Our results assume that pigmented cells in transplantation studies, found as a monolayer, attached to Bruch’s membrane, cannot automatically be identified as transplanted cells. Instead, the possibility of perished transplanted cells serving as melanin donors for RPE host cells must be taken into consideration. Received: 11 March 1998 Revised version received: 5 May 1998 Accepted: 26 May 1998     

Reduced haloperidol does not interfere with the antipsychotic activity of haloperidol in the treatment of acute schizophrenia.

The aim of this study was to investigate the effect of reduced haloperidol, the main metabolite of the antipsychotic drug haloperidol, on psychopathology improvement and extrapyramidal adverse effects in acute schizophrenia. The steady-state pharmacokinetics of reduced haloperidol was studied. Serum concentrations of reduced haloperidol (C(RH)) and haloperidol (C(H)) were measured in an open clinical trial over 6 weeks of treatment in 57 acutely schizophrenic patients. Psychopathology was measured by the Brief Psychiatric Rating Scale and several subscales. The assay of extrapyramidal adverse effects was conducted by means of the Extrapyramidal Symptom Rating Scale. A significant serum concentration-therapeutic effect relationship (SCTER) of haloperidol of the same data has been demonstrated. In our study, the influence of the metabolite reduced haloperidol on the antipsychotic activity of haloperidol was analysed by means of regression analysis of the residuals of the SCTER of haloperidol with C(RH). In addition, the steady-state pharmacokinetics of reduced haloperidol and direct relationships between C(RH) and the metabolite ratio C(RH)/C(H) with psychopathology improvement and extrapyramidal adverse effects were investigated. Reduced haloperidol was not found to interfere with the antipsychotic action of the parent drug. Patients with elevated C(RH) or elevated metabolite ratio C(RH)/C(H) did not show consistently lower clinical improvements compared with the fitting curve of the SCTER of haloperidol and therefore no significant relationship between C(RH) and the residuals of the SCTER of haloperidol was detected. Furthermore, no significant result was found in the analysis of the direct relationships of C(RH) and C(RH)/C(H) with clinical variables which, for example, indicate decreased outcome with increased C(RH). In contrast, because of the pharmacokinetic dependence of C(RH) and C(H), a trend for a bisigmoidal relationship with C(RH) emerged for some outcome variables which was traced as an epiphenomenon from the bisigmoidal SCTER of the parent drug (e.g. change of hostility after 3 weeks). No relationship of reduced haloperidol with extrapyramidal adverse effects could be detected. It is concluded that serum concentrations of reduced haloperidol are of minor value for the interpretation of data of therapeutic drug monitoring of haloperidol in patients with acute schizophrenia. Reduced haloperidol does not act as a 'false neuroleptic'.     

Age-Specific Native Hawaiian Mortality: A Comparison of Full, Part, and Non-Hawaiians

PURPOSE OF THE PAPER: The purpose of this paper is to test if the previously identified disparity in mortality rates among full Hawaiians, part Hawaiians, and non­Hawaiians in the state of Hawaii has continued into the 1990s. SUMMARY OF METHODS UTILIZED: Based on Hawaii vital records and population data, standardized age­specific mortality rates by cause and 95% confidence intervals were estimated. PRINCIPAL FINDINGS: The most striking finding was the significant differences in mortality rates in four age strata ­­ 45­54, 55­64, 65­74, and 75­84 ­­ with mortality rates highest for full Hawaiians, lowest for non­Hawaiians, and intermediate for part Hawaiians. CONCLUSIONS: Findings suggest that Native Hawaiians continue to be at greater risk of death compared with non­Hawaiians, with full Hawaiians at greatest risk. RELEVANCE TO ASIAN PACIFIC ISLANDER AMERICAN POPULATIONS: Asian and Pacific Islander Americans have been called the model minority. These data provide evidence that Native Hawaiians, especially full Hawaiians, have dramatically higher mortality rates than non­Hawaiians and merit special attention.     

Radiation doses of yttrium-90 citrate and yttrium-90 EDTMP as determined via analogous yttrium-86 complexes and positron emission tomography

Yttrium-90 is used for palliative therapy for the treatment of skeletal metastases, but because it is a pure - emitter, data on the pharmacokinetics and radiation doses to metastases and unaffected organs are lacking. To obtain such data, the present study employed yttrium-86 as a substitute for⁹⁰Y, with detection by positron emission tomography (PET). The study compared the properties of two different⁸⁶Y complexes —⁸⁶y-citrate and⁸⁶Y -ethylene diamine tetramethylene phosphonate (EDTMP) — in ten patients with prostatic cancer who had developed multiple bone metastases (the ten patients being divided into two groups of five). Early dynamics were measured up to 1 h post injection (p.i.) over the liver region, followed by subsequent whole-body PET scans up to 3 days p.i. Absolute uptake data were determined for normal bone, bone metastases, liver and kidney. Radiation doses were calculated according to the MIRD recommendations. Based on the pharmacokinetic measurements of the distribution of the⁸⁶Y complexes, it was possible to calculate radiation doses for the bone metastases and the red bone marrow delivered by complexes containing⁹⁰Y. In 1 cm³ of bone metastasis, doses of 26±11 mGy/MBq and 18±2 mGy/MBq were determined per MBq of injected⁹⁰Y- citrate and⁹⁰Y- EDTMP, respectively. The doses to the bone marrow were 2.5±0.4 mGy/MBq for⁹⁰Y- citrate and 1.8±0.6 mGy/MBq for⁹⁰Y-EDTMP.⁸⁶Y and PET provide quantitative information applicable to the clinical use of⁹⁰Y. This method may also be useful for the design of other⁹⁰Y radiopharmaceuticals and for planning radiotherapy dosages.     

Ketamine for analgosedative therapy in intensive care treatment of head-injured patients

Summary Ketamine was supposed to be contra-indicated in head injured patients although it possesses numerous advantages over other commonly used analgosedative drugs. Referring to these potential advantages and the lack of definitive data about its effect upon ICP, CPP or neurological development, we conducted a prospective study in which moderate or severely head injured patients (n=35) were prospectively allocated to receive treatment either with a combination of ketamine and midazolam or fentanyl and midazolam. The initial dose was 6.5 mg/kg/day midazolam, 65 mg/kg/day ketamine or 65 g/kg/day fentanyl and was later adjusted due to clinical requirements for a period of 3 to 14 days. Comparably high dosages of detamine have been found necessary (104 mg/kg/day).Four patients from the ketamine group (n=17) and 5 from the control group (n=18) were withdrawn during treatment due to persistent ICP above 25 mm Hg, countermeasured by barbiturate coma. Two more patients were withdrawn due to development of cardiovascular arrest (ketamine group) and multi organ failure. A comparison of the remaining patients revealed a lower requirement of catecholamines (significant on first day, p<0.05), an on average 8 mm Hg higher cerebral perfusion pressure and a 2 mm Hg higher intracranial pressure in the fentanyl group. Enterai food intake was better in the study group. The outcome was comparable in both groups with or without inclusion of withdrawn patients.