Novel paradigm enables accurate monthly gestational screening to prevent congenital toxoplasmosis and more.

Background: Congenital toxoplasmosis is a treatable, preventable disease, but untreated causes death, prematurity, loss of sight, cognition and motor function, and substantial costs worldwide. Methods/Findings: In our ongoing USA feasibility/efficacy clinical trial, data collated with other ongoing and earlier published results proved high performance of an Immunochromatographic-test(ICT) that enables accurate, rapid diagnosis/treatment, establishing new paradigms for care. Overall results from patient blood and/or serum samples tested with ICT compared with gold-standard-predicate-test results found ICT performance for 4606 sera/1876 blood, 99.3%/97.5% sensitive and 98.9%/99.7% specific. However, in the clinical trial the FDA-cleared-predicate test initially caused practical, costly problems due to false-positive-IgM results. For 58 persons, 3/43 seronegative and 2/15 chronically infected persons had false positive IgM predicate tests. This caused substantial anxiety, concerns, and required costly, delayed confirmation in reference centers. Absence of false positive ICT results contributes to solutions: Lyon and Paris France and USA Reference laboratories frequently receive sera with erroneously positive local laboratory IgM results impeding patient care. Therefore, thirty-two such sera referred to Lyon's Reference laboratory were ICT-tested. We collated these with other earlier/ongoing results: 132 of 137 USA or French persons had false positive local laboratory IgM results identified correctly as negative by ICT. Five false positive ICT results in Tunisia and Marseille, France, emphasize need to confirm positive ICT results with Sabin-Feldman-Dye-test or western blot. Separate studies demonstrated high performance in detecting acute infections, meeting FDA, CLIA, WHO ASSURED, CEMark criteria and patient and physician satisfaction with monthly-gestational-ICT-screening. Conclusions/Significance: This novel paradigm using ICT identifies likely false positives or raises suspicion that a result is truly positive, rapidly needing prompt follow up and treatment. Thus, ICT enables well-accepted gestational screening programs that facilitate rapid treatment saving lives, sight, cognition and motor function. This reduces anxiety, delays, work, and cost at point-of-care and clinical laboratories. Author's Summary: Toxoplasmosis is a major health burden for developed and developing countries, causing damage to eyes and brain, loss of life and substantial societal costs. Prompt diagnosis in gestational screening programs enables treatment, thereby relieving suffering, and leading to > 14-fold cost savings for care. Herein, we demonstrate that using an ICT that meets WHO ASSURED-criteria identifying persons with/without antibody to Toxoplasma gondii in sera and whole blood with high sensitivity and specificity, is feasible to use in USA clinical practice. We find this new approach can help to obviate the problem of detection of false positive anti- T.gondii IgM results for those without IgG antibodies to T.gondii when this occurs in present, standard of care, predicate USA FDA cleared available assays. Thus, this accurate test facilitates gestational screening programs and a global initiative to diagnose and thereby prevent and treat T.gondii infection. This minimizes likelihood of false positives (IgG and/or IgM) while maintaining maximum sensitivity. When isolated IgM antibodies are detected, it is necessary to confirm and when indicated continue follow up testing in ∼2 weeks to establish seroconversion. Presence of a positive ICT makes it likely that IgM is truly positive and a negative ICT makes it likely that IgM will be a false positive without infection. These results create a new, enthusiastically-accepted, precise paradigm for rapid diagnosis and validation of results with a second-line test. This helps eliminate alarm and anxiety about false-positive results, while expediting needed treatment for true positive results and providing back up distinguishing false positive tests.

Aspergillus flavipes group osteomyelitis.

Lumbar vertebral osteomyelitis caused by Aspergillus Flavipes group organisms developed in a nonchronically immunosuppressed patient. Diagnosis was confirmed morphologically and culturally from both closed needle biopsy of the vertebrae and subsequent lumbar laminectomy. The patient was treated with 3 g of amphotericin B with apparent eradication of the organism.

Cerebrospinal fluid lymphocyte transformations in meningitis.

Cerebrospinal fluid lymphocytes from 13 patients with nonsuppurative meningitis were cultured with antigens derived from Mycobacterium tuberculosis, Sporotrichum schenckii, and herpes simplex. When CSF lymphocytes from five patients with infections associated with these organisms were incubated with "correct" antigen there was increased incorporation of thymidine. The levels were higher than those seen when the cells were incubated with different antigens or when CSF lymphocytes from patients with other causes for their meningitis were cultured with these antigens. A compartmentalization of antigen-specific cells was suggested as CSF lymphocytes had greater stimulation than did peripheral blood lymphocytes from the same patient when incubated with the correct antigen. Transformational assays of CSF lymphocytes may provide a valuable diagnostic aid in certain cases of chronic meningitis.

The effects of ascorbic acid and flavonoids on the occurrence of symptoms normally associated with the common cold.

A controlled study was made of the effects of natural orange juice, synthetic orange juice, and placebo in the prevention of the common cold; both natural and synthetic orange juices contained 80 mg of ascorbic acid daily. Three-hundred sixty-two healthy normal young adult volunteers, ages 17 to 25 years, were studied for 72 days with 97% of participants completing the trial. There was a 14 to 21% reduction in total symptoms due to the common cold in the supplemented groups that was statistically significant (P less than 0.05). Ascorbic acid supplementation also increased the number of "episode-free" subjects. However, the clinical usefulness of the results does not support prophylactic ascorbic acid supplements in the well-nourished adult. The results in this study with both natural and synthetic orange juice of physiological content of ascorbic acid, are similar to those obtained using a "megadose" of ascorbic acid.

Metabolic response to low- and very-low-calorie diets.

We compared the metabolic effects of 8-wk caloric restrictions with 330 or 780 kcal/d in two groups of eight obese hospitalized subjects; six control subjects were also studied. Loss of weight but not of adipose tissue was significantly greater on the 330-kcal/d diet. It is likely that dehydration rather than protein catabolism was responsible for additional loss of fat-free mass in the 330-kcal/d group because the nitrogen deficit was not excessive. The thermic response to food was blunted only in the 330-kcal/d group whereas resting oxygen uptake decreased by equal amounts in both groups. There was a decrease in 24-h urinary noradrenaline in the 330-kcal/d group but plasma fT4 was sustained when compared with the 780-kcal/d group; fT3 decreased significantly more quickly in the 330-kcal/d group. There was no correlation between plasma hormone levels and changes in oxygen uptake. Hunger scores were greater on the 780-kcal/d diet.

An open-label trial of stavudine, lamivudine and efavirenz in the treatment of HIV-positive, treatment-naive patients, and implications for clinical practice.

A phase II, open-label study of stavudine, lamivudine and efavirenz resulted in significant reductions in plasma HIV-1 RNA over a 24 week period in human immunodeficiency virus (HIV)-infected individuals. The trial currently has 68 patients, and this presentation covers data on the first 42 patients enrolled for 24 weeks. The mean plasma HIV-1 RNA on entry was 75858 HIV RNA copies/ml, and the mean CD4 count was 380 cells/mm3. After 24 weeks, the CD4 count increased by 169 cells/mm3 above baseline. plasma HIV-1 RNA was markedly reduced: at 24 weeks, more than 97% of patients had <50 HIV RNA copies/ml based on observed data, and 89% of patients had <50 copies/ml based on strict intent-to-treat analysis (non-completer=failure). The favourable interactions of these agents resulted in no discontinuations owing to adverse effects. This regimen provides an important first-line treatment for antiretroviral-naive patients.

Staphylococcus aureus bacteremia and endocarditis associated with a removable infected intravenous device.

Records of 21 patients with Staphylococcus aureus bacteremia associated with a removable infected intravenous device were reviewed. Sixteen patients had a peripheral intravenous catheter, four had a central venous catheter and one had a transvenous cardiac pacer. The duration of the indwelling intravenous device in situ prior to the detection of infection ranged from two to 11 (mean 5.2) days. The infected intravenous device was promptly removed as soon as bacteremia was suspected. Endocarditis was diagnosed in eight patients: in two patients an aortic murmur developed; in two the diagnosis was made clinically and was confirmed at necropsy (one mitral and one aortic); in four the diagnosis was made at necropsy (two tricuspid and two atrial wall). In patients with Staph. aureus bacteremia associated with a removable infected intravenous device, the risk of endocarditis developing was significant.

Treatment of Clostridium difficile colitis and diarrhea with vancomycin.

Toxigenic Clostridium difficle is the major cause of antibiotic-associated colitis and is susceptible to vancomycin at fecal concentrations achieved with oral therapy. The effect of oral vancomycin was studied in 16 patients with C. difficile-related diarrhea or colitis, 12 of whom had colitis documented by endoscopy, biopsy, and/or barium enema. Four patients had antibiotic-associated diarrhea and possibly antibiotic-associated colitis, because sigmoidoscopy either showed normal results (two patients) or was not performed (two patients). Nineteen episodes of diarrhea were treated with oral vancomycin in two dosage regimens for three to 14 days. Twelve patients received 2 g daily, and four patients initially received 1 g or less per day. Within 48 hours of the start of vancomycin therapy, 14 of 16 patients (87 percent) showed a decrease in temperature, abdominal pain and diarrhea. Diarrhea ceased completely within two days of the start of vancomycin in nine episodes, within three to seven days in six episodes, and within eight to 14 days in the remaining four episodes, and within eight to 14 days in the remaining four episodes. Diarrhea recurred in two of these patients (12 percent) when the drug inciting the initial episode of colitis was given again 42 days or more after vancomycin therapy was stopped; both patients responded again to retreatment with vancomycin. Oral vancomycin is an effective treatment of C. difficile-related colitis and diarrhea.

Circadian variation and blood pressure: response to rapid weight loss by hypocaloric hyponatraemic diet in obesity.

Ambulatory intra-arterial blood pressure was monitored in 15 obese hypertensive and 10 obese normotensive subjects weighing more than 30% of their ideal body weight. Measurements were taken before and after 1 month in hospital on a diet of 330kCal/day designed to ensure 34 g protein and 65 mmol sodium. Mean +/- s.d. body mass index in the whole group fell from 40.8 +/- 7.6 to 37.2 +/- 7.4 kg/m2 (P less than 0.0001). Daytime intra-arterial blood pressure fell from 176 +/- 19/102 +/- 14 to 162 +/- 16/95 +/- 14 mmHg (P less than 0.0005 and P less than 0.002) in the hypertensive group and from 141 +/- 15/82 +/- 5 to 131 +/- 13/79 +/- 4 mmHg (P less than 0.005 for systolic pressure) in the normotensive group. Circadian variation of systolic intra-arterial blood pressure comparing the mean daytime with the mean night-time blood pressure recordings showed a day-night difference of 27 +/- 10 mmHg in the normotensive group compared with 12 +/- 13 mmHg in the hypertensive group (P less than 0.01). This trend was reversed after weight loss, when the normotensive group showed a day-night difference of 20 +/- 13 mmHg compared with 18 +/- 17 mmHg in the hypertensive group. Thus, circadian variation of systolic intra-arterial blood pressure in the hypertensive group was significantly (P less than 0.01) reduced compared with the normotensive group prior to, but not after, weight loss. These data show that, in obese subjects, weight loss produced a significant reduction in ambulatory intra-arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis of acute myocardial infarction from sequential enzyme measurements obtained within 12 hours of admission to hospital.

A prospective study was made of sequential changes in serum creatine kinase (CK) and CK-MB isoenzyme activity within the 12 hours following admission to the coronary care unit on 65 patients with recent chest pain. CK determinations were performed in the laboratory or in the coronary care unit using a dry reagent strip analyser. Slope values for log CK/hour and log CK-MB/hour were calculated, used to confirm or exclude the diagnosis of myocardial infarction, and compared with diagnosis by conventional means. Compared with retrospective diagnosis using all available information, the CK slope had a sensitivity of 100% and a specificity of 94%. This compared with a sensitivity of 94% and specificity of 90% for diagnosis using upper reference limits alone. Determination of CK slope permits very rapid and accurate biochemical confirmation or exclusion of myocardial infarction and the possibility of performing the measurements on the coronary care unit. It additionally offers the prospect of major cost savings resulting from early discharge or transfer from the coronary care unit.

Metabolic responses to dietary supplements of bran.

During a metabolic ward study, the addition of dietary fiber in the form of wheat bran biscuits to the diet of five volunteer subjects resulted in an increase in the stool wet weight and fecal solids. The excretion of fecal solids was highly correlated with the intake of unavailable carbohydrates, and fecal losses of water were similarly correlated with fecal excretion of these constituents. The major component of the increase in fecal solids was due to the noncellulosic polysaccharide fraction of dietary fiber. There was an increased fecal excretion of nitrogen fat and energy by most subjects when the supplement was eaten. However, the increased loss of energy in the feces was only 40-80 kcal/day, and therefore a large supplemental intake of dietary fiber had only minor effects on energy metabolism. Supplemental fiber is thus unlikely to induce a useful loss of calories in the management of obesity. The addition of dietary fiber caused an increased excretion of most inorganic constituents, particularly sodium and phosphorus; increased excretion of iron and magnesium was also found in two subjects.

The effects of two dietary fiber supplements on gastrointestinal transit, stool weight and frequency, and bacterial flora, and fecal bile acids in normal subjects.

The effect of dietary supplements of sugar-cane fiber (bagasse), on stool weight, solids, and water content were studied in normal ambulant volunteers over a 9-mo period; a second inpatient study was done with bran supplements. The addition on 10.5 g of bagasse containing 5.1 g of crude fiber to a normal diet containing 3.7 g of crude dietary fiber daily raised the mean fecal weight from 88.3 +/- 6.4 g to 139.7 +/- 10.2 g/day (p less than 0.005). There was also a significant rise in fecal solids and fecal water, although the percentage of water in the stools remained unchanged. Bagasse supplements accelerated gastrointestinal transit when measured by the carmine marker technique. Radiopaque "shapes" showed a trend toward more rapid transit with bagasse supplements. Daily supplements of 39 g of wheat bran or 10.5 g of bagasse increased the total daily excretion of fecal bacteria, but there were no changes in bacteria excreted per gram of feces. The composition of the bacterial flora showed no change. There was increased excretion of fecal acid sterols on the bagasse supplement, but this failed to occur with bran. No changes attributable to fiber supplements occurred in the plasma triglycerides or cholesterol. Future work may define specific dietary fiber supplements for different therapeutic purposes. One fiber may be used as a bulk expander in diverticular disease and another as a hypocholesteremic fiber.

Obesity and insurance risk: the insurance industry's viewpoint.

Obesity is regarded by insurance companies as a substantial risk for both life and disability policies. This risk increases proportionally with the degree of obesity. Mortality statistics for life insurance were the earliest indicator that the cost of obesity to the individual was a decreased life span and increased illness, particularly that affecting the cardiovascular and musculoskeletal systems. The prevalence of coronary heart disease rises with increases in the body mass index in both men and women. Cigarette smoking greatly augments these risks in both sexes. Hypertension and diabetes are very common in obese persons and add further to the risks of vascular disease. Abdominal obesity (when the abdominal girth measured round the umbilicus exceeds the maximum measurement round the hips) is correlated with the risk of cardiac disease and stroke, independently of bodyweight. Insurance companies consider abdominal obesity as unfavourable and rate it accordingly. Obesity (even that of moderate degree) greatly increases the chances of disability due to cardiovascular disease or musculoskeletal illness. In one study of 51 522 adult Finns, 25% of disability pensions in women were found to result directly from obesity. Obesity causes increased health expenditure, decreased life span and productivity, and premature retirement. Insurance companies are compelled to build these risks into their policies. However, because the excess mortality occurs late in mild to moderate obesity, some companies may minimise this risk for life policies that mature early.

Early diagnosis of acute myocardial infarction by CK-MB mass measurements.

We have studied the changes in creatine kinase (CK) and creatine kinase MB (CK-MB) activity and concentration for the diagnosis of acute myocardial infarction in 73 patients admitted to the coronary care unit with cardiac symptoms of 12 h duration or less. Serial blood samples were obtained for an 8 h period following admission and CK, CK-MB activity and concentration measured. We compared the performance of single values at optimized diagnostic cut-offs and incremental change (log slope) for all three measurements. CK slope combined with CK-MB concentration measurements allowed accurate diagnosis at 4 h from admission. CK-MB concentration determination 8 h from admission (12-16 h from the onset of chest pain) was the most efficient single measurement. Rapid diagnostic categorization and possible selection of patients for thrombolysis in patients with an uncertain admission diagnosis is possible by these techniques.

Rapid enzyme diagnosis of patients with acute chest pain reduces patient stay in the coronary care unit.

We have studied the effect of early exclusion of myocardial infarction using rapid biochemical diagnosis on the management of patients admitted to the coronary care unit of a district general hospital. Diagnosis was based on the rate of creatine kinase increase in serial samples obtained over the 8 h following admission. For an initial 3-month familiarization period serial creatinine kinase results were made available at the end of working day to supplement clinical management, supported by our traditional protocol of admission and daily enzyme determinations. Subsequently, for a 4-month period, the admission to 8 h serial values were provided by 1100 h each day and usually within 24 h of admission. There was a net reduction in length of stay on the coronary care unit to a median 2 days (n = 66) compared with 3 days (n = 41) for patients without further cardiac symptoms or electrocardiographic changes suggestive of ischaemia or infarction. This change was significant, P = 0.007, Mann-Whitney U test. Reversion to the original protocol of daily enzyme estimations resulted in an increase in the length of stay on the coronary care unit back to a median of 3 days for this patient group. Rapid diagnostic protocols, applied within routine clinical practice, have the potential for real reduction in coronary care unit stay.

Prognostic factors in Staphylococcus aureus endocarditis and results of therapy with a penicillin and gentamicin.

Data on 40 patients with Staphylococcus aureus endocarditis treated with appropriate antibiotics in adequate dosage at the University of Cincinnati Medical Center hospitals between January 1961 and June 1975 were analyzed. The overall mortality was 40 per cent. The mortality was 11.1 per cent in patients under 50 years old and 63.6 per cent in patients over 50 years old (p less than 0.01). Seven patients were narcotic addicts who had no underlying disease and were under 50 years old; all survived. For patients without underlying diseases, the mortality was 0 per cent in those under 50 years old and 75 per cent in those over 50 years old. Patients who died had a greater number of major underlying diseases (pre-existing cardiac disease, diabetes mellitus, alcoholism and/or cirrhosis) than the survivors. Patients over 50 years old had significantly more major underlying diseases than patients under 50 years old (p less than 0.001). Among patients over 50 years old, those who died had more complications than the survivors while the number of underlying diseases were comparable. A group of patients treated with gentamicin during the first two to three weeks of therapy in addition to a penicillin was compared to a similar group treated with a single antibiotic. The mortality of both groups was 40 per cent.

Case report. Tularemia in Ohio: report of two cases and clinical review.

Although unusual, human tularemia continues to be reported from areas of the United States which are not heavily endemic for the disease. Two patients with ulceroglandular tularemia diagnosed in Ohio are described. The causative microorganism, Francisella tularensis, is a small, pleomorphic gram negative coccobacillus which requires special microbiological media for laboratory isolation. In nature, the organism is usually transmitted to man by the handling of infected animal tissues and body fluids or by an arthropod vector. There are several clinical forms of tularemia of which the ulceroglandular type is most common. Laboratory diagnosis is usually made by demonstrating a four-fold increase in the serologic agglutinating antibody titer to Francisella tularensis. Streptomycin is the drug of choice in the treatment of tularemia.

Legionnaires' disease with acute renal failure.

We describe two patients with Legionnaires' disease (LD) and acute renal failure not associated with hypotension or therapy with nephrotoxic antibiotics. The first patient ran a fulminant course unresponsive to erythromycin therapy and intensive supportive care including mechanical assisted ventilation and peritoneal dialysis. The second patient recovered after erythromycin therapy and hemodialysis. The clinical course of both patients and the renal pathology of the first patient were compatible with acute tubular necrosis. LD is a disease with many extrapulmonary manifestations. The pathogenic mechanism of acute renal failure in LD is presently unknown.

Case report. Clinical manifestations and treatment of Legionnaires' disease.

Eight patients with atypical pneumonia caused by the Legionnaires' disease organism were seen during the spring and summer of 1977. Two died of the acute illness. All patients were febrile and presented with symptoms of acute respiratory infection. Other symptoms included malaise, anorexia, chills, myalgia, and headache. Severe hypoxemia was a striking feature. Conventional methods to determine the etiology of these pneumonias were unsuccessful but subsequent serological studies confirmed the diagnosis of Legionnaires' disease. Seven patients were treated with beta-lactam antibiotics alone or with an aminoglycoside and all failed to respond. Six were subsequently treated with erythromycin and five who received this drug for at least 48 hours were markedly improved within this time period. We believe that erythromycin is effective in the treatment of Legionnaires' disease.

Repeated dose study of sucralose tolerance in human subjects.

Two tolerance studies were conducted in healthy human adult volunteers. The first study was an ascending dose study conducted in eight subjects, in which sucralose was administered at doses of 1, 2. 5, 5 and 10mg/kg at 48-hour intervals and followed by daily dosing at 2mg/kg for 3 days and 5mg/kg for 4 days. In the second study, subjects consumed either sucralose (n=77) or fructose (50g/day) (n=31) twice daily in single blind fashion. Sucralose dosage levels were 125mg/day for weeks 1-3, 250mg/day during weeks 4-7, and 500mg/day during weeks 8-12. No adverse experiences or clinically detectable effects were attributable to sucralose in either study. Similarly, haematology, serum biochemistry, urinalysis and EKG tracings were unaffected by sucralose administration. In the 13-week study, serial slit lamp ophthalmologic examination performed in a random subset of the study groups revealed no changes. Fasting and 2-hour post-dosing blood sucralose concentrations obtained daily during week 12 of the study revealed no rising trend for blood sucralose. Sucralose was well tolerated by human volunteers in single doses up to 10mg/kg/day and repeated doses increasing to 5mg/kg/day for 13 weeks. Based on these studies and the extensive animal safety database, there is no indication that adverse effects on human health would occur from frequent or long-term exposure to sucralose at the maximum anticipated levels of intake.