A decade of system- and population-based osteoporosis care improvement.

The results of a 9-year osteoporosis clinical improvement project are reviewed, and the implications for secondary fracture prevention are discussed.

Cytoplasmic particles and aminoacyl transferase I activity.

It has been possible to show by electron microscopy of samples selected from sucrose gradients that particles of specific size and shape are present in supernatant fluids derived from nucleated animal and plant cells, but not in extracts from Escherichia coli. Aminoacyl transferase I activity in these same gradients sediments in two peaks representing material of approximately 5-7S and 18-20S. A rectangular particle, 100 x 145 A in size, sediments at 19S and coincides with the second peak of transferase I activity. The possibility that the rectangular particle may be a "carrier" particle associated with transferase I is discussed.

Renal regulation of acid-base equilibrium during chronic administration of mineral acid.

Previous studies in metabolic alkalosis have demonstrated that two factors are the prime determinants of acid excretion and bicarbonate reabsorption; first, the diversion to distal exchange sites of sodium previously reabsorbed in the proximal tubule and loop of Henle; and, second, a stimulus to sodium-cation exchange greater than that produced by a low-salt diet alone. In the present study we have examined the hypothesis that these two factors are also the prime determinants of acid excretion during the administration of mineral acid loads. To test this hypothesis, we have administered to dogs ingesting a low NaCl diet a daily dose of 7 meq/kg of H+ with anions (chloride, sulfate, or nitrate) whose differing degrees of reabsorbability influence the speed and completeness with which each is delivered to the distal nephron with its accompanying Na+. After 2-3 wk of acid administration, and after an initial urinary loss of Na+ and K+, the steady-state value for plasma [HCO3-] was 8.6 meq/liter below control in the HCl group, 3.7 meq/liter below control in the H2SO4 group, and unchanged from control in the HNO3 group; all of these values were significantly different from each other. We would propose the following explanation for our findings: when HCl is administered chronically, marked acidosis occurs because distal delivery of Cl- is restricted by the ease with which the Cl- can be reabsorbed in the proximal portions of the nephron. Only when Cl- retention produces sufficient hyperchloremia to insure delivery of Na+ (previously reabsorbed in proximal tubule and loop of Henle) to the distal nephron in quantities equal to ingested Cl is this primary constraint removed. In the case of sulfuric and nitric acids, there is no constraint on distal delivery, the nonreabsorbability of the administered anion causing prompt, total delivery of Na+ to exchange sites in quantities equal to administered hydrogen. Thus, with H2SO4 and HNO3 the sole constraint on removal of the acid load is the inability of the distal exchange mechanism to conserve the Na+ increment fully by means of H+ exchange. Escape of Na+ and K+ into the urine and the resulting stimulus to Na(+)-H+ exchange remove this constraint and are responsible for establishment of a new steady-state of acid-base equilibrium at plasma [HCO3-] levels significantly higher than those seen with HCl. The feeding of HCl in the presence of a normal salt intake led to a degree of metabolic acidosis not significantly different from that seen in dogs ingesting a low-salt diet. We suggest that the presence of dietary sodium at distal exchange sites did not enhance acid excretion because it is only after a loss of body sodium stores that sodium avidity is increased sufficiently to allow full removal of the acid load. The present findings indicate that the fundamental factors controlling acid excretion and bicarbonate reabsorption in metabolic acidosis are closely similar to those operative in metabolic alkalosis.

Redesigning the care of rheumatic diseases at the practice and system levels. Part 1: practice level process improvement (Redesign 101).

Redesigning the delivery-of-care processes for rheumatic diseases within rheumatology practices and health systems is critical to improving the outcomes and costs of care for the patients we serve. This work is best accomplished using Continuous Quality Improvement Methods, also known as Plan-Do-Study-Act (PDSA) cycles that are widely utilized in many other industries, but not often in health care or among physicians. This first of two companion articles provides background on health care redesign, understanding of PDSA methods, and examples of successful rheumatology practice process redesigns based on PDSA. It is offered as a starting point for rheumatologists preparing for this necessary work.

Redesigning the care of rheumatic diseases at the practice and system levels. Part 2: system level process improvement (Redesign 201).

Changing delivery-of-care processes for rheumatic diseases to improve outcomes and costs will require redesign not only within rheumatology practices but also within health systems. Preventive services, acute care, management of chronic co-morbidities, and rheumatology care for rheumatic disease patients can only be accomplished through the close integration of multiple practices and other health system resources. Rheumatologists can play an important role in system-level process improvement without which our own patient care will be compromised. Continuous Quality Improvement methods, also known as Plan-Do-Study-Act (PDSA) cycles, are ideally suited for system-level process redesign. This second of two companion articles describes the properties of systems and explores the redesign of interdisciplinary rheumatic disease care.

Quantitative measurement of patient status in the regular care of patients with rheumatic diseases over 25 years as a continuous quality improvement activity, rather than traditional research.

Patient assessment in rheumatology is characterized by an important paradox: many extensively-characterized quantitative measures and indices have been developed for rheumatoid arthritis (RA), psoriatic arthritis, systemic lupus erythematosus (SLE), ankylosing spondylitis, vasculitis, osteoarthritis, fibromyalgia, and other rheumatic diseases. However, most regular rheumatology care is guided largely by qualitative clinical impressions, without such measures or indices or any quantitative data other than laboratory tests to assess patient status and/or quality of care. This paradox may be explained in part by regarding the development of measures primarily as clinical research activities, while viewing the application of measurements in regular clinical care as continuous quality improvement (CQI) activities. The development of measures has emphasized validity and reliability, but generally ignored feasibility and acceptability to patients and health professionals, both of which are needed for application in regular clinical care. A summary of the application of clinical measurement in patients with RA over 25 years between 1982 and 2007 at a weekly academic rheumatology clinic conducted by the senior author is presented as 20 often contemporaneous CQI cycles. These cycles include development of a user-friendly modified health assessment questionnaire (MHAQ); assessment of psychological status; monitoring of mortality outcomes; comparisons of joint counts, radiographic scores, and laboratory tests to the MHAQ; a 28-joint count; prospective study of the MHAQ to predict mortality when joint counts, radiographic scores, and laboratory tests are available; development of a multidimensional HAQ (MDHAQ) with complex activities; a fatigue scale; a self-report joint count; scoring templates; a computerized data management system; flow sheets to monitor MDHAQ status; visual analog scales as 21 circles rather than 10 cm lines; composite RAPID3 (rheumatology assessment patient index data) scores for 3 patient measures; and defining RAPID categories for high, moderate and low severity, and near remission. The latter cycles remain under study as ongoing CQI activities.

Leukocyte migration inhibition in vitro in bladder carcinoma.

The leukocyte migration inhibition response in vitro of peripheral blood leukocytes from patients with transitional cell carcinoma of the urinary bladder, other genitourinary diseases, and normal controls was studied. The agarose droplet migration inhibition method was used to determine the cell-mediated immune reactivity of bladder tumor patients to antigens derived from allogeneic bladder tumor cell lines by hypertonic potassium chloride extraction. Sixty-nine bladder tumor patients were tested 131 times and included 68 positive and 63 negative results. A positive assay was shown to correlate strongly with the presence of tumor at the time of testing (p less than 0.001). Five of 24 patients with other genitourinary diseases had positive inhibition assays, but none of the 26 normal controls were positive. These results suggest that this in vitro assay method may prove valuable in monitoring bladder tumor patients for completeness of initial tumor resection and for clinical recurrence as well as for further studies of the tumor-specific immune response in this disease.

The diagnosis of glomerular diseases: acute glomerulonephritis and the nephrotic syndrome.

Rapid and efficient diagnosis of diseases presenting as acute glomerulonephritis and/or nephrotic syndrome is critical for early and appropriate therapy aimed at preservation of renal function. Although there may be overlap in clinical presentation, and some patients present with clinical features of both syndromes, this analysis serves as an initial framework to proceed with serologic testing and/or pathologic confirmation en route to final diagnosis. Efficient and timely diagnosis is essential in these situations because progression to end-stage renal disease may result if the underlying disease is not promptly treated.

Amoxapine-associated acute renal failure.

Acute renal failure, a brief seizure, and mild rhabdomyolysis developed in a 27-year-old man following overdosage with the tricyclic antidepressant, amoxapine. Renal function returned to normal approximately ten days following drug ingestion. Strikingly, of 111 cases of amoxapine overdosage reported to the manufacturer, acute renal failure has occurred in 12. Of these 12 patients, seizures were documented in seven, and presumptive or definitive evidence of rhabdomyolysis or myoglobinuria was documented in eight. Three possible mechanisms of the renal failure are (1) acute tubular necrosis secondary to nontraumatic rhabdomyolysis; (2) hypotension-induced acute tubular necrosis; and (3) direct nephrotoxic reaction from amoxapine. Rapid hydration with intravenously administered saline is proposed as a means of reducing the substantial incidence of acute renal failure following amoxapine overdosage.

Prognosis in steroid-treated idiopathic nephrotic syndrome in adults. Analysis of major predictive factors after ten-year follow-up.

This long-term study analyzes the prognostic value of the quantitative urinary protein excretion during and following steroid administration, the renal functional status three years after the onset of disease, and the degree of histologic damage in adult patients with steroid-treated idiopathic nephrotic syndrome (INS). No patient who had a complete (proteinuria less than 0.1 gm/day) or partial (proteinuria less than 2.0 gm/day) remission during steroid administration progressed to renal failure. Furthermore, no patient in whom urinary protein excretion subsequently fell to below 2.0 gm/day ever progressed to renal failure. Only 3 of 49 patients in whom renal function was normal three years after the onset of INS developed renal failure. Finally, renal failure occurred in only 2 of 28 patients with mild abnormalities by light microscopy, compared with 12 of 21 patients with more advanced glomerular abnormalities. Thus, a partial, as well as a complete remission during steroid administration, subsequent reduction in proteinuria to below 2 gm/day, persistence of normal renal function beyond three years, or the presence of mild histologic abnormalities auger a favorable long-term prognosis in patients with INS.

Serum electrolyte and acid base composition. The influence of graded degrees of chronic renal failure.

Data from 41 ambulatory patients with graded degrees of uncomplicated, chronic renal failure were used to define the quantitative relationship between serum acid-base and electrolyte composition and the serum creatinine level. Even in patients with only moderate renal insufficiency, serum total carbon dioxide (tCO2) content was reduced significantly. This early fall in tCO2 was offset by an increase in serum chloride (Cl-), serum undetermined anton concentration (A-) remaining normal. In patients with more severe degrees of renal insufficiency, further decrements in tCO2 occurred that were proportional to the increment in serum creatinine. These latter decrements in tCO2 were associated with equivalent increments in A-, serum Cl- remaining unchanged at the elevated level observed during moderate renal insufficiency. Confidence limits of 95% for tCO2 and A- were calculated from the data.

Drug-induced hyperkalemia.

After reviewing the available data on drug-induced hyperkalemia, we conclude that the situation has not improved since Lawson quantitatively documented the substantial risks of potassium chloride over a decade ago (90). As discussed, the risk of developing hyperkalemia in hospital remains at least at the range of 1 to 2% and can reach 10%, depending on the definition used (Table 2). Potassium chloride supplements and potassium-sparing diuretics remain the major culprits but they have been joined by a host of new actors, e.g., salt substitutes, beta-blockers, converting enzyme inhibitors, nonsteroidal antiinflammatory agents, and heparin, among others. Readily identifiable risk factors (other than drugs) for developing hyperkalemia are well-known but seem to be consistently ignored, even in teaching hospitals. The presence of diabetes mellitus, renal insufficiency, hypoaldosteronism, and age greater than 60 years results in a substantial increase in the risk of hyperkalemia from the use of any of the drugs we have reviewed. If prevention of hyperkalemia is the goal, as it should be, the current widespread and indiscriminate use of potassium supplements and potassium-sparing diuretics will need to end. We remain intrigued by Burchell's prescient pronouncement of over a decade ago that "more lives have been lost than saved by potassium therapy" (28).

In vitro assessment of delayed hypersensitivity in the human. Inhibition of cell migration from agarose microdroplets.

The in vitro migration inhibition responses of peripheral blood leukocytes from tuberculin skin test positive and negative donors were tested to validate and determine optimal conditions for the agarose droplet method in the human. In vitro migration inhibition was observed in skin test positive donors in the presence of 25 microgram PPD/ml of medium using both unfractionated leukocytes and a mixture of immune lymphocytes with allogeneic polymorphonuclear leukocyte indicators. The supernatants of tuberculin positive lymphocytes cultured with PPD also inhibited the migration of human polymorphonuclear leukocytes and guinea pig peritoneal exudate cells but did not alter that of murine peritoneal exudate cells. These studies establish that the agarose droplet method is an efficient approach to the in vitro assessment of cell-mediated immunity in the human and define suitable indicator cell populations for assay of human lymphokines.

A solid phase radioimmunoassay for detection of serum autoantibodies in systemic lupus erythematosus.

Solid phase radioimmunoassay (RIA) methods for measuring autoantibodies in systemic lupus erythematosus (SLE) patients' serum were developed to improve the sensitivity and quantitative precision of these determinations. Two mechanical systems were studied: (1) acetone fixed cell monolayers in glass tubes and (2) antigen coated plastic beads. Both systems were sensitive and reproducible, giving serum dilution end-points between two and four orders of magnitude (100-10,000 times) greater than those obtained by fluorescence microscopy. The most sensitive, versatile system involves the coating of plastic beads with nuclear antigen(s), incubation overnight with sera and labelling with 125I conjugated antihuman globulin. Linear binding of this radioactive tag is obtained over a wide range of SLE serum dilutions and the slopes of the serum dilution titration curves are almost identical for all SLE patients' sera we have tested. Therefore, a standard titration curve can be constructed from the results with a positive serum, and end-point dilutions of unknown sera estimated from results obtained with a single serum dilution. Alternatively, binding ratios of unknown sera can be usefully compared at fixed dilutions with standard positive and negative sera. For example, high binding ratios (greater than 3.0) were obtained with 19/20 SLE sera and 0/20 control sera. Antigens used in these systems include crude, whole-cell lysates and lysates from purified nuclei. These RIA methods appear to provide certain advantages over existing autoantibody assay methods because they are relatively simple, sensitive, reproducible and potentially capable of measuring a variety of autoantibody specificities.

Platinum nephrotoxicity.

Platinum coordination complexes have recently been introduced in cancer chemotherapy with considerable success. However, significant nephrotoxicity has emerged as a factor that limits the therapeutic usefulness of these compounds. In this article we review the available knowledge on platinum nephrotoxicity and its prevention that has been derived from both toxicologic studies in animals and clinical trials in human subjects.

Hospital-acquired renal insufficiency: a prospective study.

Twenty-two hundred sixty-two consecutive medical and surgical admissions were evaluated prospectively to determine the contribution of iatrogenic factors to the development of renal insufficiency in hospital. Of 2,216 patients at risk, some degree of renal insufficiency developed in 4.9 percent. Decreased renal perfusion, postoperative renal insufficiency, radiographic contrast media, and aminoglycosides accounted for 79 percent of the episodes. Iatrogenic factors, broadly defined, accounted for 55 percent of all episodes. Poor prognostic indicators included oliguria, urine sediment abnormalities and, most importantly, severity of renal insufficiency; with an increase in serum creatinine of 3 mg/dl or greater, the mortality rate was 64 percent. Age, admission serum creatinine levels, and the number of episodes of renal insufficiency did not significantly affect outcome. We conclude that there is a substantial risk of the development of renal failure in hospital and that the mortality rate due to hospital-acquired renal insufficiency remains high.

Recurrent idiopathic membranous glomerulonephritis.

This study reports the clinical and pathological findings in a patient with recurrent membranous glomerulonephritis following transplantation of an HLA-identical kidney. Such a recurrence has been previously reported only once, although membranous glomerulonephritis is a common cause of nephrotic syndrome in adults. This case confirms that membranous glomerulonephritis may occasionally recur following renal transplantation and demonstrates that immunofluorescence and electron microscopic studies may be necessary to distinguish recurrent, membranous glomerulonephritis from the membranous changes frequently seen with chronic rejection. In light of the apparent low incidence of recurrent membranous glomerulonephritis, renal transplantation remains an excellent therapeutic option in this disease.

Transcatheter thromboembolectomy of acute renal artery occlusion.

Direct surgery of the renal artery has been performed for the relief of acute thrombotic or embolic occlusion of the renal artery to restore adequate renal perfusion and prevent irreversible renal failure. Occasionally, severe medical disease may increase surgical risk to a prohibitive level. An angiographic technique has been devised to provide an alternative approach and has been successfully used on five occluded renal arteries in four patients, with measurable benefit.

What a bank can do for the ophthalmologist.

The selection of a bank is the key to personal and professional finance. In this world of specialization, it is advisable to seek a banker who can assist one with not only the routine banking functions but also with credit accommodations and financial planning which will result in both the successful operation of a profession and the achieving of a sound estate plan.