Late presentation of HIV infection: a consensus definition.

OBJECTIVES: Across Europe, almost a third of individuals infected with HIV do not enter health care until late in the course of their infection. Surveillance to identify the extent to which late presentation occurs remains inadequate across Europe and is further complicated by the lack of a common clinical definition of late presentation. The objective of this article is to present a consensus definition of late presentation of HIV infection. METHODS: Over the past year, two initiatives have moved towards a harmonized definition. In spring 2009, they joined efforts to identify a common definition of what is meant by a 'late-presenting' patient. RESULTS: Two definitions were agreed upon, as follows. Late presentation: persons presenting for care with a CD4 count below 350 cells/µL or presenting with an AIDS-defining event, regardless of the CD4 cell count. Presentation with advanced HIV disease: persons presenting for care with a CD4 count below 200 cells/µL or presenting with an AIDS-defining event, regardless of the CD4 cell count. CONCLUSION: The European Late Presenter Consensus working group believe it would be beneficial if all national health agencies, institutions, and researchers were able to implement this definition (either on its own or alongside their own preferred definition) when reporting surveillance or research data relating to late presentation of HIV infection.

Toward a theory of variability discrimination: finding differences.

We sketch the outlines of a theory of variability discrimination that aggregates localized differences to mediate variability discrimination. This Finding Differences Model was compared to a Positional Entropy Model across four different data sets. Although the two models provide strong and similar fits across three of the data sets, only the Finding Differences Model is applicable to investigations involving multidimensional variability. Furthermore, the Finding Differences Model is based on an activation map that has been shown to have utility for visual search tasks, thus establishing its generality across task domains.

Compound-specific, quantitative characterization of organic fluorochemicals in biological matrices.

Since the early 1980s, there has been a steady increase in the use of nonvolatile fluorinated organic compounds for a variety of industrial and commercial applications. The industrial use of these relatively stable compounds has initiated debate over the fate of fluorochemicals in the environment and, ultimately, the bioavailability of these compounds. In this manuscript, we present quantitative results from a study of 65 human sera samples purchased from biological supply companies that provide characterization of specific organic fluorochemicals present in the sera of nonindustrially exposed humans. Summed together, the compound-specific characterization data reported here agree closely with levels of nonspeciated organic fluorine that were originally reported to be present in sera in 1970. The compound-specific method for the extraction of extremely low levels of several commercial organic fluorochemicals from sera and liver with quantitative detection by negative ion electrospray tandem mass spectrometry described represents a robust, previously undescribed approach to quantifying specific organic fluorochemicals in biological matrices.

Payer-based case management: perspectives on managing brain-injured patient.

As the payer environment is carved into many segments, each with its own accountability relative to its financial liability, family members, providers, and even other case managers often find it difficult to comprehend the perspectives of the various parties represented. Indeed, one brain injury case I recently evaluated had four payer case managers: one from the patient's health plan, one from a disease management program for his premorbid diabetes, and two from Medicaid-sponsored programs for the disabled. For payer-based case managers, the ubiquitous case manager role confusion compounds product unfamiliarity.

Pervasive occult gastrointestinal bleeding in an Alaska native population with prevalent iron deficiency. Role of Helicobacter pylori gastritis.

OBJECTIVE: To confirm prevalent iron deficiency among Yupik Eskimos living in Alaska and to explore the frequency of and potential lesions accounting for occult gastrointestinal bleeding. DESIGN: Descriptive survey. SETTING: Rural Arctic community. SUBJECTS: A total of 140 adult volunteers from 3 villages in the Yukon-Kuskokwim Delta region of western Alaska. MAIN OUTCOME MEASURES: Daily iron intake, hematologic and biochemical indexes of iron status, fecal hemoglobin levels, stool parasites, and endoscopic findings. RESULTS: While dietary iron intake by Yupiks was similar to that of a reference population, iron deficiency prevalence was increased 13-fold in Yupik men and 4-fold in Yupik women. Fecal hemoglobin levels were elevated in 90% of subjects contrasted with only 4% of a reference group; median levels were 5.9 and 0.5 mg of hemoglobin per gram of stool, respectively. Among 70 Yupik subjects with elevated fecal hemoglobin levels who had endoscopy performed, 68 (97%) had an abnormal gastric appearance consisting of erythema, mucosal thickening, diffuse mucosal hemorrhages, erosions, or ulcerations. Gastric biopsies revealed chronic active gastritis with associated Helicobacter pylori in 68 (99%) of 69. No other hemorrhagic gastrointestinal disease was detected. CONCLUSIONS: Based on this study sample, occult gastrointestinal bleeding appears to be pervasive in the Yupik population and likely underlies the prevalent iron deficiency. An atypical hemorrhagic gastritis associated with H pylori infection is present almost universally and may represent the bleeding source.

A simple carbon monoxide breath test to estimate erythrocyte turnover.

Carbon monoxide is stoichiometrically released when heme is converted to bilirubin. This report describes and validates a novel technique that permits the estimation of heme turnover and red blood cell survival from the carbon monoxide concentration of end-expiratory breath samples. The end-alveolar Pco of a subject was corrected for environmental carbon monoxide exposure with a simple device that equilibrates with atmospheric carbon monoxide at the same rate as does the subject. The resultant value (endogenous Pco) was tested for its ability to predict heme turnover and red blood cell survival. Red cell survival times of 32 healthy subjects, as calculated from the endogenous Pco, averaged 101 +/- 19 days, a value close to the expected 110-day survival time; 13 patients with clinical evidence of shortened red blood cell survival times had measured erythrocyte life spans ranging from 10 to 59 days. The endogenous Pco of each of seven patients increased after red blood cell transfusion, demonstrating that this technique detected the known rapid turnover of a small fraction of transfused cells. A good correlation (r = 0.91) was observed between heme turnover calculated from endogenous Pco and total fecal biliary pigment output. Carbon monoxide measurements reflect red blood cell destruction in both the marrow and the circulation, therefore yielding shorter life spans than did chromium 51 survival studies. This breath test appears to yield a rapid, semiquantitative assessment of heme turnover and red blood cell survival that is not provided by any other presently available technique. This simple, noninvasive carbon monoxide breath test may find widespread use in the evaluation of anemia and jaundice.

Inhibition of increases in ornithine decarboxylase and putrescine has no effect on rat liver regeneration.

Polyamines are considered critical for cell proliferation. During liver regeneration in the rat, ornithine decarboxylase (ODC) mRNA and enzyme activity and polyamines (primarily putrescine and spermidine) are known to increase substantially. We examined the effect of inhibition of polyamine synthesis with alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of the ODC enzyme, on regenerating liver weight and total DNA, RNA, and protein, [3H]thymidine and [14C]leucine incorporation, number of mitotic figures, and putrescine, spermidine, and spermine contents. Rats received DFMO beginning 4 days before or immediately after two-thirds partial hepatectomy. In control rats, ODC activity, putrescine, and spermidine increased significantly during regeneration, whereas spermine was unchanged. In rats receiving DFMO, ODC and putrescine changed minimally but spermidine increased as usual. Spermine levels were modestly higher in rats receiving DFMO beginning 4 days before partial hepatectomy. However, despite ODC inhibition and substantially lower levels of putrescine, the course of liver regeneration in rats treated with DFMO was not affected. Total liver mass, DNA, RNA, and protein increased over 5 days equally in rats receiving DFMO and control rats. In addition, there were no differences in [3H]thymidine incorporation into DNA, [14C]leucine incorporation into protein or mitotic indexes between DFMO-treated and control rats at 24 and 48 h after partial hepatectomy. These results suggest that the well-known increases in ODC activity and polyamines that occur during regeneration are not required for liver to undergo its proliferative response to partial hepatectomy.

Aging alters ornithine decarboxylase and decreases polyamines in regenerating rat liver but putrescine replacement has no effect.

Aging decreases rat liver regeneration. We (1) compared the expression of ornithine decarboxylase (ODC), a critical enzyme for liver regeneration, and polyamine levels in regenerating liver of 6-week-old and 1-year-old rats and (2) evaluated the effect of exogenous putrescine supplementation on liver regeneration in 1-year-old rats. ODC messenger ribonucleic acid (mRNA) transcript sizes were the same in rats of both ages. ODC mRNA content and enzyme activity were higher in the younger rats; however, magnitudes of increase after partial hepatectomy were greater in the older rats. From peak levels, the rate of decline of the mRNA was slower in the older rats, but enzyme activity declined at the same rate in both ages. ODC apoenzyme content was significantly less in normal liver tissue from 1-year-old rats, but there was little change after partial hepatectomy in rats of either age. No change in ODC transcriptional activity was found. Hepatic putrescine levels were lower in 48 hours regenerating liver tissue from 1-year-old rats. To determine whether supplemental putrescine would increase liver regeneration in 1-year-old rats, putrescine (600 mumol/kg IP every 4 hours) was administered beginning 4 days before or at the time of partial hepatectomy. This raised polyamine levels and decreased ODC activity significantly, but there was no change in regenerating liver weight, total DNA and RNA content, and tritiated thymidine incorporation at 48 hours. These results indicate that ODC expression is different and polyamine levels are lower in 1-year-old rats than in 6-week-old rats. However, putrescine supplementation that is sufficient to decrease ODC activity has no apparent effect on regeneration.

Bile porphyrin analysis in the evaluation of variegate porphyria.

BACKGROUND: Variegate porphyria is a genetic disorder of porphyrin metabolism in which patients may have both neurologic dysfunction and photocutaneous lesions. Biochemical confirmation of the diagnosis can be difficult, particularly in patients without neurologic dysfunction at the time of testing. The demonstration of increased fecal excretion of porphyrin is frequently used for this purpose, but levels may be normal. Since elevated fecal porphyrin levels in variegate porphyria are presumably a consequence of increased biliary excretion, we evaluated whether analysis of porphyrins in bile distinguishes better between patients with variegate porphyria and controls. METHODS: Bile samples were collected by duodenal aspiration from 10 patients with proved variegate porphyria who had no neurologic symptoms when they were studied and 17 control subjects. Bile and fecal porphyrin levels were measured fluorometrically. RESULTS: The mean total porphyrin concentration in bile in the patients with variegate porphyria was significantly higher than that in the controls (67.8 vs. 0.71 mumol per liter; P less than 0.00002). There was more than a ninefold difference between the highest level in any control subject and the lowest level in any patient with variegate porphyria. The mean fecal porphyrin level in the patients with variegate porphyria also differed significantly from that in the controls (0.79 vs. 0.14 mumol per gram of dry weight; P less than 0.007), but four patients had levels within the control range. CONCLUSIONS: The concentration of porphyrin in bile is higher in patients with variegate porphyria than in controls, and the difference is greater than that for fecal porphyrin. Bile porphyrin measurements may be helpful in the evaluation of asymptomatic patients suspected of having variegate porphyria.

Causes of iron deficiency in adolescent athletes.

Seventy-two high school cross-country runners were studied during the running session for possible etiologic factors associated with iron deficiency, which was defined as a serum ferritin level less than or equal to 12 ng/ml and a transferrin saturation of less than or equal to 16% occurring simultaneously. Iron deficiency was observed during the running season in 34% of female cross-country runners, compared with 8% of male runners. Increased iron losses through gastrointestinal bleeding occurred in 9 of 20 female runners; 7 of these 9 had iron deficiency. Dietary iron intake was low in both iron-deficient and iron-sufficient female runners, but dietary instruction did not increase iron intake significantly. Iron deficiency could not be prevented in 35% of the female runners treated with 60 mg of elemental iron daily, but adequate treatment was achieved with 180 mg. Iron losses in urine, sweat, and plasma were small and did not appear to be increased in iron-deficient runners. These findings indicate that female cross-country runners have a high incidence of iron deficiency that is associated with initially decreased iron stores and gastrointestinal bleeding.

A stool collection device: the first step in occult blood testing.

Despite widespread fecal blood testing, the technique of gathering stool for sampling has remained uncontrolled. We sought to describe how patients have contended with this awkward step, to study artifact caused by toilet water, and to construct a collection device that prevents sampling problems. A survey of 250 patients showed that most (56%) had retrieved stools from the toilet basin, 17% used a pan or other household receptacle, 10% used newspaper or tissue paper, and 17% had been unable or unwilling. Sampling stool from the toilet basin introduces error because 4% to 75% of blood leaches from the fecal surface into surrounding water after only 4 to 12 minutes, and many toilet sanitizers cause false-positive guaiac reactions. We describe an inexpensive, disposable stool collector; outpatient compliance has been 97% using this device. To avoid biochemical artifact and facilitate stool sampling, we advocate that a collection device be incorporated into the occult blood testing process.

Methylene blue protects intestinal mucosa from free radical-mediated sublethal radiation damage.

Susceptibility of the intestine to radiation damage is a primary reason for the failure of external beam radiation to cure intra-abdominal cancer. High-dose irradiation causes intestinal denudation, fluid loss, and resultant shock. Simple and effective methods for protecting the intestine from irradiation damage are not available. Many biological effects of ionizing irradiation are caused by free radical intermediates. We have previously reported that many of the toxicities of doxorubicin, a classic free radical generating anticancer agent, are blocked by methylene blue pretreatment. We have now found that pretreatment with methylene blue protects rats from intestinal damage, as measured histologically and by quantitative stool blood determinations. Whereas the exact mechanisms of this protection remain elusive, we believe this method of modulating the therapeutic index of ionizing radiation deserves additional preclinical and clinical study.

Evaluation of a fluorometric method for the quantitative assay of fecal hemoglobin in the dog.

Feces from 27 dogs were evaluated to establish baseline fecal hemoglobin (Hb) concentrations when the dogs were fed diets containing varying amounts of Hb. Fecal Hb concentration was measured, using a quantitative fluorometric assay that was based on the conversion of nonfluorescing Hb heme to fluorescing porphyrins. Mean fecal Hb concentration was 0.31 mg/g of feces when the dogs were fed a dry diet low in Hb. This corresponded to a daily fecal blood loss of 0.043 ml/kg of body weight. The fecal Hb concentration was directly related to the dietary Hb concentration. The average recovery of orally ingested blood was 41% in 4 dogs. This fluorometric assay quantitatively detected small amounts of gastrointestinal bleeding over a wide range of fecal Hb concentrations for which feces appeared normal. Results of this study establish dietary conditions necessary for quantitative evaluation of experimental and clinical gastrointestinal bleeding.

Quantitative fecal recovery of ingested hemoglobin-heme in blood: comparisons by HemoQuant assay with ingested meat and fish.

Blood, meat, or fish, or any combination thereof, were ingested by 9 normal volunteers to permit studies of the contained hemes during total gastrointestinal transit. Quantitative analysis of ingested heme and of fecal heme and its degradation products was made possible by a new specific and extremely sensitive test, HemoQuant. The average fecal recovery of hemoglobin-heme from 10 to 36 ml of blood was 88%, as determined in 13 separate studies. All Hemoccult tests remained negative despite greater than 20-fold increases in fecal heme. Up to 83% of the blood heme was converted in the intestinal tract to porphyrins. These porphyrins are included in the HemoQuant, but not in Hemoccult or other leukodye assays. Negligible amounts of heme were found in fish and fowl, and their ingestion led to no significant increase in fecal heme. An average of only 25% of the heme in ingested meat was subsequently recovered in feces. Control fecal values represented an average of approximately 0.5 ml of blood per day. The recovery data obtained show that fecal HemoQuant results reliably reflect the total amount of blood hemoglobin that enters the gastrointestinal tract.

HemoQuant, a new quantitative assay for fecal hemoglobin. Comparison with Hemoccult.

HemoQuant, an assay based on heme-derived porphyrin, quantifies both total fecal hemoglobin ant that fraction already converted to porphyrin by gut flora (the intestinal converted fraction). Recovery by HemoQuant of blood added to stools exceeded 99% and was not affected by ascorbic acid, iron, or other additives. HemoQuant was used to evaluate the performance of Hemoccult on 1018 stools. Hemoccult sensitivity differed widely, remaining negative with up to 42.5 mg hemoglobin per gram of stool (about 43 mL/d of blood) but positive with only 0.04 mg of hemoglobin per gram of stool. Driest stools tended to be Hemoccult-negative and the wettest Hemoccult-positive. Hemoccult-negative stools became positive after aqueous dilution independent of hemoglobin concentration. The intestinal converted fraction, not detected by guaiac tests, often constituted most of the fecal hemoglobin equivalents and was significantly higher in Hemoccult-negative than in Hemoccult-positive stools. Hemoccult lost reactivity during fecal storage due to progressive heme degradation. Frequent false-negative and false-positive reactions of Hemoccult were explained largely by variations in stool liquidity and heme degradation.

The "HemoQuant" test: a specific and quantitative determination of heme (hemoglobin) in feces and other materials.

We describe a new, specific, quantitative method for fecal blood, based on conversion of nonfluorescing heme to fluorescing porphyrins, that obviates serious deficiencies inherent in currently used tests. A two-reagent system is used to determine the two hemoglobin-related fractions that are found in feces. The hot citric acid extract includes only the variable fraction of porphyrins that have been preformed from heme in the intestinal tract; this often is the major fraction. Total hemoglobin is indirectly determined by reaction with heated oxalic acid:FeSO4 reagent, which converts the remaining heme to porphyrin without loss of the preformed porphyrins. A three-step purification procedure eliminates interfering materials. Analytical recovery of added hemoglobin is linearly related to concentration over a several-thousand-fold range. The assay is equally applicable to whole blood or to sub-microgram amounts of hemoglobin in the 8-mg (wet weight) fecal sample tested. Quality control by liquid chromatographic and fluorometric analysis documents fluorescence specificity of the heme-derived porphyrins.