Outpatient diabetes clinical decision support: current status and future directions.

Outpatient clinical decision support systems have had an inconsistent impact on key aspects of diabetes care. A principal barrier to success has been low use rates in many settings. Here, we identify key aspects of clinical decision support system design, content and implementation that are related to sustained high use rates and positive impacts on glucose, blood pressure and lipid management. Current diabetes clinical decision support systems may be improved by prioritizing care recommendations, improving communication of treatment-relevant information to patients, using such systems for care coordination and case management and integrating patient-reported information and data from remote devices into clinical decision algorithms and interfaces.

Kinetic Studies on the Xanthophyll Cycle in Barley Leaves (Influence of Antenna Size and Relations to Nonphotochemical Chlorophyll Fluorescence Quenching).

Xanthophyll-cycle kinetics as well as the relationship between the xanthophyll de-epoxidation state and Stern-Volmer type nonphotochemical chlorophyll (Chl) fluorescence quenching (qN) were investigated in barley (Hordeum vulgare L.) leaves comprising a stepwise reduced antenna system. For this purpose plants of the wild type (WT) and the Chl b-less mutant chlorina 3613 were cultivated under either continuous (CL) or intermittent light (IML). Violaxanthin (V) availability varied from about 70% in the WT up to 97 to 98% in the mutant and IML-grown plants. In CL-grown mutant leaves, de-epoxidation rates were strongly accelerated compared to the WT. This is ascribed to a different accessibility of V to the de-epoxidase due to the existence of two V pools: one bound to light-harvesting Chl a/b-binding complexes (LHC) and the other one not bound. Epoxidation rates (k) were decreased with reduction in LHC protein contents: kWT > kmutant >> kIML plants. This supports the idea that the epoxidase activity resides on certain LHC proteins. Irrespective of huge zeaxanthin and antheraxanthin accumulation, the capacity to develop qN was reduced stepwise with antenna size. The qN level obtained in dithiothreitol-treated CL- and IML-grown plants was almost identical with that in untreated IML-grown plants. The findings provide evidence that structural changes within the LHC proteins, mediated by xanthophyll-cycle operation, render the basis for the development of a major proportion of qN.

Epoetin enhances erythropoiesis in normal men undergoing repeated phlebotomies.

Epoetin may enhance autologous blood donation, but efficacy and dose response have not been established. This multicenter, double-blind trial compared intravenous placebo (n = 23) with epoetin beta, 250 U/kg (n = 23), 500 U/kg (n = 19), and 1000 U/kg (n = 22), administered three times weekly for 26 days. Normal men (age, 28 +/- 7 years; mean +/- SD) received phlebotomies up to three times weekly as long as the hemoglobin remained greater than or equal to 12 gm/dl. Subjects treated with epoetin donated 32% more units of blood (p less than 0.05) compared with placebo. A dose response was not observed. Platelet counts increased with epoetin compared with placebo, but platelet function and bleeding time did not change. Prothrombin times increased and partial thromboplastin times decreased with both epoetin and placebo. The supernatant of packed red blood cells collected after multiple phlebotomies and stored 42 days had slightly lower glucose concentrations and pH after therapy with epoetin. Blood pressure did not change with epoetin or placebo. These findings support the efficacy and safety of epoetin for enhancing the erythropoietic response of normal subjects during intensive phlebotomy.

How do house officers spend their nights? A time study of internal medicine house staff on call.

Recommendations to limit the working hours of house staff are forcing directors of training programs to reevaluate how house officers spend their time. We studied how 35 house officers in internal medicine spent their on-call time in three teaching hospitals: an urban county hospital, a university hospital, and a regional Veterans Administration medical center. Trained observers accompanied each member of different on-call teams for five nights and quantified how their time was spent. Teams consisting of residents and interns admitted three new patients per night at the Veterans Administration hospital, six at the university hospital, and eight at the county hospital. Each house officer received 16 to 25 calls per night. Up to 12 percent of their time was spent doing procedures (such as inserting intravenous catheters or drawing blood specimens) most of which could have been done by nonphysicians. From 87 to 175 minutes of on-call time was spent in direct patient evaluation, and the mean time spent on each new-patient evaluation ranged from 17 to 31 minutes. The mean time before the evaluation was interrupted ranged from 7 to 11 minutes. In contrast, 66 to 197 minutes per night was spent documenting new-patient evaluations in the hospital record. The average sleep time ranged from 122 to 273 minutes; however, the mean time before sleep was interrupted ranged from 40 to 86 minutes. We conclude that while on call, house officers spend relatively little time in direct patient contact, but they spend considerable time charting. They are frequently interrupted while working and trying to sleep. These data may be useful in finding administrative ways to improve patient care and the experience of the house staff while on call and in evaluating the effect of reforms.

Reticulocytosis: defective reticulin degradation, a case report.

In summary, this case illustrates a previously unrecognized syndrome of reticulocytosis secondary to a defect in reticulin degradation. We are aware of two other case reports in the literature which also describe patients with an elevated reticulocyte count who's red cells appeared to lack the ability to degrade reticulin (Lofters et. al.1978, Tulliez et. al. 1982). Both of these cases however, demonstrated only mild reticulocytosis and appeared to be related to preleukemic syndromes. Our patient had no evidence of preleukemia and indeed, has been followed for over four years without evidence of other hematologic abnormalities. The mild anemia that has persisted in this patient may suggest that although no evidence of hemolysis is obvious in this patient, some minor amount of hemolysis may be occurring. Due to the relative insensitivity of other measures of early red cell death (51Cr survival, bone marrow biopsy, etc...), and the loss of the the reticulocyte count as a sensitive index of hemolysis, a minor amount of hemolysis cannot be excluded. This does not decrease the validity of the observations noted above, since this massive reticulocytosis cannot be explained by minimal hemolysis. Whether this patient's reticulocytosis represents an acquired or congenital syndrome is unsettled at present. Although his brother is unaffected, and we have on record only a mildly elevated reticulocyte count from 1981, there remains a possibility that this syndrome is congenital. We are, at present, in the process of further characterizing the specific defect in these red cells. Further assays of Lipoxygenase and protease activity, the ability to ubiquitinate proteins, specific identification of the mitochondria-like structures, and protein synthesis assays are in progress or are planned. The inability to degrade reticulin in this patient's red cells and the impact of this upon other cellular physiologic processes afford an excellent opportunity to enhance our understanding of normal red cell physiology, particularly, we suspect in this patient, of Ubiquitin-ATP-dependent proteolysis.

Vesiculation of sickle erythrocytes during thermal stress.

Since it is not known why sickle RBCs tend to undergo microvesiculation, we have investigated their susceptibility to thermal stress. While normal RBCs start to vesiculate at 49.0 +/- 0 degrees C (n = 14), sickle RBCs begin to vesiculate at 47.9 +/- 0.5 degrees C, with a range of 46.5 to 48.5 degrees C (n = 14). This abnormality is reproduced by treating normal RBCs with phenazine methosulfate (PMS), which stimulates the excess intracellular generation of superoxide characteristic of sickle RBCs. For PMS-treated RBCs, there is a strong correlation between membrane protein thiol oxidation and vesiculation temperature (r = .977, P less than .001). The abnormal vesiculation temperature of both unmanipulated sickle RBCs and PMS-treated RBCs is significantly improved by treatment of the RBCs with dithiothreitol. The most dense sickle RBCs are most prone to vesiculation during thermal stress, and they are the subpopulation having the greatest amount of thiol oxidation. We conclude that the tendency of sickle RBCs to vesiculate during thermal stress is further evidence for functional abnormality of the RBC cytoskeleton due to thiol oxidation.

Excess heme in sickle erythrocyte inside-out membranes: possible role in thiol oxidation.

It has been suggested that the development of sickle RBC membrane defects might be related to abnormal amounts of membrane-associated heme (a term we use in its generic sense to include hemoglobins, hemichromes, and free heme). Techniques previously used to measure membrane heme, however, would not distinguish between what is truly membrane-associated and what is merely trapped in RBC ghost preparations. Consequently, we have examined extensively washed inside-out membranes (IOM) prepared from normal and sickle RBC. Approximately 25% of the sickle ghost heme is lost upon conversion to IOM, but sickle IOM still have a significant excess (1.6 +/- 0.3 nmol heme/mg membrane protein compared with 0.7 +/- 0.2 nmol/mg for normal IOM, P less than .001). Amounts of ghost heme are only poorly predictive of amounts of IOM heme (r = .664). Preparation of IOM by using isotonic lysis with saponin yields virtually identical amounts of IOM heme. Small amounts of heme (less than 15%) can be displaced from IOM by using manipulations that elute spectrin, displace electrostatically bound proteins, or cleave the cytoplasmic portion of band 3. Treatment of IOM with dithiothreitol (DTT), however, displaces the most heme (35%), and this is almost reproduced (25% displacement) by the treatment of intact RBC with DTT before IOM preparation. Sequential treatment with all manipulations still leaves about 40% of the heme in sickle IOM, which indicates a compartment more intimately associated with the membrane. At least part of this is free heme without globin, as evidenced by abnormal binding of radiochloroquine to sickle IOM. Conversely, some IOM-associated globin is globin without heme because the measurement of globin per se markedly overpredicts amount of IOM heme. There is a strong correlation between RBC density and amounts of either ghost or IOM heme. Finally, the amount of membrane thiol oxidation (as measured by thiol-disulfide-exchange chromatography) does not correlate at all with ghost heme (r = .105), but it correlates well with IOM heme (r = .877, P less than .001). These data demonstrate that there are abnormal amounts of heme truly associated with sickle RBC membranes, and they are consistent with the hypothesis that this membrane-associated heme participates in the pathobiology of the sickle RBC membrane, particularly those aspects perhaps related to thiol oxidation.

Inhibition of erythrocyte Ca2+-ATPase by activated oxygen through thiol- and lipid-dependent mechanisms.

We have studied erythrocyte Ca2+-ATPase as a model target for elucidating effects of activated oxygen on the erythrocyte membrane. Either intracellular or extracellular generation of activated oxygen causes parallel decrements in Ca2+-ATPase activity and cytoplasmic GSH, oxidation of membrane protein thiols, and lipid peroxidation. Subsequent incubation with either dithiothreitol or glucose allows only partial recovery of Ca2+-ATPase, indicating both reversible and irreversible components which are modeled herein using diamide and t-butyl hydroperoxide. The reversible component reflects thiol oxidation, and its recovery depends upon GSH restoration. The irreversible component is largely due to lipid peroxidation, which appears to act through mechanisms involving neither malondialdehyde nor secondary thiol oxidation. However, some portion of the irreversible component could also reflect oxidation of thiols which are inaccessible for reduction by GSH, since we demonstrate existence of different classes of thiols relevant to Ca2+-ATPase activity. Activated oxygen has an exaggerated effect on Ca2+-ATPase of GSH-depleted cells. Sickle erythrocytes treated with dithiothreitol show a heterogeneous response of Ca2+-ATPase activity. These findings are potentially relevant to oxidant-induced hemolysis. They also may be pertinent to oxidative alteration of functional or structural membrane components in general, since many components share with Ca2+-ATPase both free thiols and close proximity to unsaturated lipid.

Abnormal redox status of membrane-protein thiols in sickle erythrocytes.

Although sickle erythrocytes (RBC) undergo excessive autooxidation, investigators have not found evidence for abnormal oxidation of protein thiols in sickle RBC membranes (e.g., protein aggregates linked by intermolecular disulfide bonds). However, the conventional techniques heretofore used cannot detect more subtle changes in thiol status such as abnormal intramolecular disulfide bonds. We examined RBC membranes using thiol-disulfide exchange chromatography which partitions sodium dodecyl sulfate-solubilized proteins on the basis of reactive thiols, yielding gel-bound (reduced-thiol) and filtrate (oxidized/blocked-thiol) fractions. Membranes from normal RBC partition so that only 13.6 +/- 1.4% of all membrane protein is found in the filtrate fraction. An abnormally increased amount of membrane protein from sickle RBC (21.5 +/- 4.3%) partitions into the filtrate fraction (P less than 0.001). Since sickle RBC do not have high molecular weight aggregates of membrane protein, this indicates abnormal intramolecular thiol oxidation in sickle RBC membranes. Treatment of normal RBC with thiol blockers and oxidants simulates this shift of membrane protein into the filtrate fraction. Analysis using polyacrylamide gel electrophoresis reveals that the filtrate fraction derived from normal RBC consists mostly of band 7 and glycophorins, with only trace amounts of other membrane proteins. Superimposed upon this normal background, sickle RBC filtrates are enriched with all proteins (including cytoskeletal protein bands 1, 2, 2.1, and 4.1), suggesting a generalized oxidative perturbation of sickle RBC membranes. These observations support the concept that excessive RBC autooxidation may play a role in sickle disease pathophysiology, and they perhaps help explain the development of those membrane abnormalities that may reflect cytoskeletal dysfunction in sickle erythrocytes.

A histopathologic study of gastric and small intestinal graft-versus-host disease following allogeneic bone marrow transplantation.

Twenty-two stomach and 14 small intestinal biopsy specimens from 24 allogeneic bone marrow transplant recipients were reviewed to evaluate the histopathologic changes of graft-versus-host disease (GVHD) in these organs. Associations between these results and clinical symptoms and other biopsy results were sought. In both organs, single epithelial cell necrosis was found to correlate with GVHD. Gastric GVHD was diagnosed in eight patients and small intestinal GVHD in four. Gastric GVHD was characterized by nausea, vomiting, and upper abdominal pain without diarrhea (the latter being present in only two patients), while all four of the patients with small intestinal GVHD had upper gastrointestinal symptoms and diarrhea. These symptoms correlated with concurrent rectal biopsy findings; pathologic alterations were seen in only one of six specimens from patients with gastric GVHD but in three of four with small intestinal GVHD. These findings suggest that stomach biopsy may be necessary to diagnose GVHD in patients with upper gastrointestinal symptoms but no diarrhea and normal rectal biopsy specimens. Diagnostic problems may arise in the early posttransplantation period, when the effects of cytoreductive therapy may simulate GVHD, and in patients with gastrointestinal cytomegalovirus infection, which may also produce changes identical to those of GVHD.

Increased adsorption of cytoplasmic proteins to the erythrocyte membrane in ATP-depleted normal and pyruvate kinase-deficient mature cells and reticulocytes.

How the metabolic defect of pyruvate kinase deficiency (PK(-)) accelerates red blood cell (RBC) destruction is not established, but may be related to RBC membrane abnormalities associated with altered cellular metabolism. Furthermore, it has been shown that PK(-) reticulocytes are especially sensitive to metabolic depletion. Therefore, we compared the membranes of reticulocyte-rich PK(-) RBC, both fresh and ATP depleted, with membranes of fresh and ATP depleted normal mature RBC and reticulocytes. There was no difference between the specific gravity (SG) of the membranes of normal mature RBC (SG 1.152 +/- 0.004) and membranes of reticulocyte-rich RBC from several anemias (SG 1.150 +/- 0.002). However, membranes from fresh, reticulocyte-rich PK(-) RBC were dense with SG of 1.165 +/- 0.004 which correlated with a corresponding increase of protein to lipid phosphorus ratio of 66 +/- 8 micrograms protein/micrograms lipid phosphorus (normal 52 +/- 6 micrograms/micrograms). The membrane density of PK(-) RBC was further increased when the PK(-) RBC ATP was depleted by anaerobic incubation (SG 1.188 +/- 0.004) or cyanide inhibition (SG 1.182 +/- 0.001). When ATP was depleted in normal RBC and in non-PK(-) reticulocytes, corresponding increases in membrane SG occurred. A distinctive 50,000 MW peptide is adsorbed from the cytoplasm to the membranes of reticulocytes (both normal and PK(-) when these cells were depleted of ATP. The increased membrane adsorption of cytoplasmic proteins by PK(-) RBC was not associated with increased RBC calcium uptake, sulfhydryl oxidation, or altered membrane protein phosphorylation. All the observed abnormalities of PK(-) RBC membranes could by reproduced by ATP depletion of reticulocyte-enriched non-PK(-) RBC.

Post-transfusion purpura as a gynecologic complication.

Post-transfusion purpura (PTP) is a recently separated category of thrombocytopenic purpura occurring mainly in women. It is an acute, severe thrombocytopenic state with clinical manifestations of hemorrhage that may be fatal. It usually occurs 5 to 8 days after transfusion, usually after administration of whole blood. The typical patient is a middle-aged, multiparous white woman who has received a transfusion and has undergone an operation, often a gynecologic procedure. Diagnosis may be suspected by normal clotting studies, bone marrow biopsy showing increased megakaryocytes, and demonstration of a potent antibody reactive against platelets by clot-retraction inhibition, complement fixation, or 51Cr-release studies. The treatment of choice is exchange transfusion or plasmapheresis, unless these procedures are medically contraindicated. Because of the lack of reports in the gynecology literature on PTP, a case report and discussion are presented.

Another look at keratoacanthoma.

In a retrospective survey over a three-year period there were found 199 patients with keratoacanthoma among 3,180 patients with malignant skin disease. The clinical features of the series are presented, with particular attention to the diagnostic error. Amongst experienced clinicians there was an 8.5% error in calling an invasive squamous cell lesion a keratoacanthoma. Pertinent features of the clinical nature of keratoacanthoma with particular reference to immunological surveillance are discussed.