The higher lectin binding of glomerular compared with serum IgA1 suggests that O-glycosylated IgA1 molecules abnormally and selectively deposit in the kidney. These results provide the first evidence that mesangial IgA1 is abnormally O-glycosylated, and support a direct role for abnormal IgA1 O-glycosylation in the mechanism of mesangial IgA deposition in IgAN.

New ventures often do not correctly foresee real market opportunities or the best way to address them. How to cope with unforeseen, unpredictable factors, also referred to as unknown unknowns, is critical for new ventures. Findings in the fields of innovation and project management have shown that dealing with the unpredictable requires management approaches different from those used for classical plan-andachieve-the-target projects. Management approaches for novel initiatives include a combination of trial-and-error learning (i.e., flexible redefinition of the new venture business model as new information emerges) and selectionism (i.e., running multiple parallel trials and choosing the best performing approach ex post). The management approach must be chosen when the venture is set up. This requires a venture management team to diagnose at the outset whether unknown unknowns are present (or possible), although unknown unknowns cannot be identified initially by definition because they emerge over time. Anecdotal testimony from experienced venture managers and project managers suggests they have a feeling for where their knowledge is limited. However, such a claim is controversial. Some researchers think the concept of diagnosing unforeseeable influence factors is an oxymoron. Thus, the research question in this article is this: How can unforeseeable influence factors in a new venture be diagnosed at the outset? Research to date has insufficiently addressed the a priori identification of the type of uncertainty faced by a new venture. Based on models from decision theory, this article suggests dividing the overall problem of structuring the venture into subproblems for which the management team can identify knowledge gaps. Using a case study, the article describes how knowledge gaps were identified for the subareas of a new venture in a real situation and how this diagnosis was used to correctly identify the areas where unknown unknowns lurk. These areas were managed in a different way (i.e., with learning and experimentation) than the other subproblems (i.e., with targets and deadlines). As a result, the venture could successfully respond to unforeseeable events. The results of this study suggest that a decomposition of the overall venture management problem into subproblems is feasible and natural to managers, that a qualitative assessment of knowledge gaps and vulnerability to unknown unknowns is possible, and that a structured, process-like approach can be used to identify subproblems, to determine their uncertainty profiles, and to update the uncertainty profiles. These results are immediately useful to venture management and venture capitalists in setting up the venture's structure for effective response to uncertainty. The results advance research about uncertainty management by offering a systematic set of

Protein-overload proteinuria in rats induces tubular cell apoptosis. This effect is only partially balanced by proliferation and potentially provides a direct mechanism whereby heavy proteinuria can induce tubular atrophy and progressive renal failure.

Neurotoxicity and renotoxicity were compared in rats given by gastric gavage five daily doses of 8.0 mg Hg/kg methyl- or ethylmercuric chloride or 9.6 mg Hg/kg ethylmercuric chloride. Three or 10 days after the last treatment day rats treated with either 8.0 or 9.6 mg Hg/kg ethylmercury had higher total or organic mercury concentrations in blood and lower concentrations in kidneys and brain than methylmercury-treated rats. In each of these tissues the inorganic mercury concentration was higher after ethyl- than after methylmercury. Weight loss relative to the expected body weight and renal damage was higher in ethylmercury-treated rats than in rats given equimolar doses of methylmercury. These effects became more severe when the dose of ethylmercury was increased by 20%. Thus in renotoxicity the renal concentration of inorganic mercury seems to be more important than the concentration of organic or total mercury. In methylmercury-treated rats damage and inorganic mercury deposits were restricted to the P2 region of the proximal tubules, while in ethylmercury-treated rats the distribution of mercury and damage was more widespread. There was little difference in the neurotoxicities of methylmercury and ethylmercury when effects on the dorsal root ganglia or coordination disorders were compared. Based on both criteria, an equimolar dose of ethylmercury was less neurotoxic than methylmercury, but a 20% increase in the dose of ethylmercury was enough to raise the sum of coordination disorder scores slightly and ganglion damage significantly above those in methylmercury-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical trials with daptomycin were halted in December 1990 because of treatment failures including two resistant Staphylococcus aureus strains. High protein binding of daptomycin (>90,%) and the lower-thanexpected concentrations in serum with the dosage regimen of 3 mg/kg of body weight every 12 h may have contributed to these failures. To evaluate the effect that higher concentrations would have on bactericidal activity measured by time-kill curves, peak and trough concentrations were estimated for dosage regimens of 3, 5, and 10 mg/kg every 12 h. MICs, MBCs, and killing curves for daptomycin and vancomycin were performed by using the estimated concentrations with four S. aureus strains obtained from patients who failed daptomycin therapy for endocarditis. MICs and MBCs of daptomycin demonstrated a greater inoculum effect than those of vancomycin; MICs and MBCs of daptomycin increased three-to fourfold, but those of vanconmycin increased only one-to twofold when the inoculum was increased from 5 x IV0 to 5 x 107 CFLJ/ml.No pH-dependent effect on MICs or MBCs was seen. Strenuous experimental conditions were chosen: high inoculums (5 x 107 CFU/ml), extremes of pH (6.4, 7.4, and 8), and stationary and exponentially growing organisms; and all experiments completed in the presence of pooled human serum. Daptomycin exhibited concentration-dependent killing and statistically faster kill rates than vancomycin against stationary-or exponential-growth-phase organisms. A pH-dependent decrease in activity with daptomycin was also demonstrated. Daptomycin and vancomycin produced higher kill rates against exponentially growing organisms. The results indicate that the use of higher dosage regimens with compounds similar to daptomycin may be capable of overcoming the effects of pH, high inoculum, and protein binding.Daptomycin is derived from Streptomyces roseosporus and represents a new class of antimicrobial agents known as peptolides (acidic lipopeptide antibiotics) (3). Daptomycin has an antimicrobial spectrum similar to that of vancomycin and teicoplanin, with activity against gram-positive aerobic and anaerobic bacteria, including methicillin-resistant staphylococci (6, 7, 14, 16-19). Daptomycin also maintains activity against vancomycin-resistant gram-positive bacteria which are being recognized increasingly as pathogens (6). The mechanism of action appears to differ from that of vancomycin and was previously thought to be due to the inhibition of precursors to peptidoglycan synthesis, but new information indicates that membrane disruption and the inhibition of amino acid transport are the sole mechanisms of action (1-3). Daptomycin, like aminoglycosides and quinolones, exhibits concentration-dependent bacterial killing, a characteristic not demonstrated by the glycopeptides (4, 12).Daptomycin was studied in early clinical trials with a dosage of 2 mg/kg of body weight per day. These trials were terminated because of failures despite seemingly adequate levels in serum. The most recent clinical trials with daptomycin w...

The effect of protein binding on the activity of teicoplanin against Staphylococcus aureus was evaluated. Bactericidal rates of teicoplanin in cation-supplemented Mueller-Hinton broth (SMHB) and in a 1:1 mixture of pooled human serum and cation-supplemented Mueller-Hinton broth (PHS-SMHB) were compared with those of vancomycin. Eight concentrations of each drug ranging from 15 to 150 ,ug/ml were studied in two series which correspond to the concentrations in serum achieved with low-(6 mg/kg of body weight once daily) and high-dose (30 mg/kg once daily) teicoplanin. Overall, the bactericidal rate of teicoplanin was lower than that of vancomycin. In the presence of serum, the bactericidal rate of teicoplanin in PHS-SMHB was lower than that in SMHB, often resulting in only one log10 drop in CFU over a 24-h period. There was no statistical difference in the bactericidal rates of high-and low-concentration teicoplanin in either medium. Additionally, concentration-dependent killing in SMHB was not evident with either agent. The bactericidal rates of teicoplanin and vancomycin in a 1:1 mixture of serum ultrafiltrate and SMHB at 60 ,g/ml were also studied. It was noted that the bactericidal rate of neither agent was affected by the presence of serum ultrafiltrate. This finding is consistent with teicoplanin's high degree of protein binding (reported to be >90% in undiluted serum) and further substantiates the hypothesis that only the free drug is active against microorganisms. These data support protein binding as being a factor in teicoplanin activity against S. aureus.

Aim-To investigate vascular endothelial growth factor (VEGF) mRNA expression in glomerular disease in the context of heavy proteinuria. Methods-Non-radioisotopic in situ hybridisation was performed using a cocktail of 12 deoxyoligonucleotides complementary to VEGF mRNA labelled during solid phase synthesis with 2,4-dinitrophenyl. Archival renal biopsies were studied from cases of minimal change nephropathy, membranous nephropathy, diabetic nephropathy, and controls, matched for age, sex, race, and storage time. Hybrid detection used NBT/ BCIP colorimetric development. Conclusions-Using non-radioisotopic in situ hybridisation, VEGF mRNA is almost exclusively expressed by visceral glomerular epithelial cells. Abnormal numbers of cells are seen in both minimal change and diabetic nephropathy. As VEGF exists in a number of functionally distinct isoforms, further study of qualitative VEGF isoform expression in diagnostic groups is indicated. (J Clin Pathol 1999;52:735-738)

The pharmacokinetics and bactericidal killing rates (BR) of daptomycin (D) and vancomycin (V) in 12 intravenous drug abusers (6 treated with daptomycin and 6 treated with vancomycin) were evaluated. Pharmacokinetic ,.irameters were determined from multiple serum samples drawn at steady state over a 12-h dosing interval ak -. intravenous infusions of 3 mg of D per kg of body weight and 1,000 mg of V. The BRs were determined from the 1-and 6-h serum samples by using four isolates of Staphylos' xus aureus (three methicillin susceptible and one methicillin resistant) obtained from the patients enroll.-in the study. Peak serum daptomycin concentrations were lower and volumes of distribution were hig. !r than reported in healthy volunteers. Although not statistically different, D clearance was 22% highur than reported in healthy volunteers. V pharmacokinetics were similar to those reported in previous studies. Daptomycin's BRs, although comparable to those of V in patients' serum, were significantly decreased compared with those found in broth. This may be related to the high degree of protein binding of D (93% versus 50%o for V). Conversely, the BRs of V in serum were significantly greater than those in broth. The BRs of D and V in broth were greater when killing curves were performed with test strains in logarithmic versus stationary-phase growth. The ability to kill organisms in stationary phase may be an important factor in determining the performance of an antibiotic in deep-seated infections such as endocarditis. The high degree of protein binding may have contributed to the clinical failure rate found with D, and it is plausible that higher-dosage regimens of D would overcome these problems with efficacy.