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The following information has been compiled from publicly available sources. StratCom does not assume any responsibility for the accuracy or the authenticity of the information and StratCom cannot be held liable for errors.

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Research News for June 1996

Protein reverses antibiotic resistance
XOMA Corporation is developing a line of BPI protein products to be used concurrently with antibiotics to improve the treatment of patients with serious bacterial infections. BPI (bactericidal/permeability-increasing protein) is a naturally-occurring human host-defense protein that kills bacteria, neutralizes bacterial endotoxin and inhibits the growth of new blood vessels. XOMA is developing a family of pharmaceuticals derived from BPI to treat infections and complications of infections, trauma and surgery. BPI enhances the efficacy of certain classes of commonly-used antibiotics. In particular, BPI can synergise with certain antibiotics and in many instances reverse the resistance of certain gram-negative organisms to these antibiotics.

Blood cultures not always necessary
A team of physicians from Children's Hospital of Pittsburgh and Children's Hospital of Columbus, Ohio, have put together data that indicates that blood cultures are not necessary for the outpatient care of children with pneumonia. (Annals of Emergency medicine June 1996). Dr. Robert W. Hickey of Pittsburgh and his colleagues reviewed the histories of 939 children with positive chest X-rays for pneumonia. Blood culturing was performed in 409 children and, in this group, only 11 cultures or 2.7% grew pathogenic bacteria. They therefore conclude that the often-quoted prevalence rate of bacteremia in children with pneumonia in the 10-to-25% range is over inflated because the figures come from studies of hospitalized patients, newborns, patients with hospital-acquired infections or patients from developing countries. Patients who require do blood cultures include those with risk factors for either severe disease like cystic fibrosis and sickle cell anemia, or unusual pathogens. Otherwise, because only two therapies for pneumonia exist--antibiotics and hospitalization--laboratory blood cultures don't contribute much to patient care, according to the authors. The report adds: "In addition to yielding a low incidence of pathogens, the practice of obtaining blood cultures does not result in changes in clinical management. Specifically, antibiotic regimens were not altered on the basis of laboratory reports, and patients initially managed as outpatients were not subsequently admitted to the hospital."

MI survival prognosis available
Circulating levels of brain natriuretic peptide are known to be increased in patients with heart failure in proportion to the severity of the disease. Brain natriuretic peptide and atrial natriuretic peptide share the same receptors on endothelial cells. In patients with heart failure, treatment with these proteins produces a reduction in preload and afterload, increased stroke volume, enhanced natriuresis and diuresis and a reduction in aldosterone. Dr. Torbjorn Omland and a multicenter team of Scandinavian physicians evaluated the diagnostic and prognostic value of plasma brain natriuretic peptide as an indicator of left ventricular dysfunction and long-term survival after acute myocardial infarction in 131 patients. They also compared its utility as a marker and predictor of these outcomes to the utility of atrial natriuretic peptide and its N-terminal moiety, N-atrialnatriuretic peptide. In the June 1 issue of Circulation, they report that all three peptides were significant predictors of long-term prognosis after myocardial infarction. The article concludes, this finding has "...important implications regarding current and future risk strategies and management. Measurement of plasma levels of brain natriuretic peptide may be a cost-effective means of identifying patients who are candidates for angiotensin-converting enzyme inhibition after myocardial infarction, especially in situations in which measurement of ejection fraction is not possible."

Chromium effective in Type II diabetes
A study conducted in China by the U.S. Department of Agriculture shows that large daily doses of the essential mineral chromium may help to normalize blood glucose levels in patients with type II diabetes. Chromium is essential for metabolizing carbohydrates and fats, and it's long been known that many people don't absorb sufficient amounts of the substance in their daily diets. The study involved a randomized group of 180 patients with type II diabetes divided into three groups: patients who received placebo, patients who received 200 mg of chromium per day and patients who received 1 gm of chromium per day. After two months of study, patients in the high-dose chromium group showed significant reductions in glycated hemoglobin, in both fasting and postprandial blood glucose levels and in cholesterol levels. Patients also exhibited a normalization of insulin levels. Patients taking low-dose chromium showed some changes toward normalization of glucose and insulin parameters, but the changes were not all significant.

CMV common in Toronto day-care centers
Dr. E. Lee-Ford Jones and associates at the University of Toronto conducted a prospective study of 38 day-care centers in Toronto have found that both caretakers and children often harbor cytomegalovirus infection. They tested urine and blood samples from 68 caregivers and 471 children between the ages of 3 months and 4 years and found viruria in 67% of caregivers and in 17% of children. Some 12.5% of caregivers later seroconverted. Further investigation determined that infected caregivers: were more likely to have been born outside of Canada, have children under the age of 5 years at home, come from large households, are younger than 30 years and do not use gloves for diaper changes. The researchers say strict hygiene measures designed to prevent CMV spread in hospitals may be difficult to achieve in day-care centers where children are continuously mobile. Thus, day care workers should be informed of the risk.

Triglycerides & Lp(a) predict CVD
Elevated serum levels of triglycerides and lipoprotein(a) identify middle-aged men at risk of major coronary events. Dr. Gerd Assmann and associates at the University of Munster in Germany evaluated 4,849 men between the ages of 40 and 65 years and followed them for 8.5 years for the occurrence of cardiac events. During that time, 181 subjects experienced nonfatal MIs, 49 others died of MI and 28 died suddenly. Age, LDL, HDL, diabetes, smoking, systolic blood pressure, family history of MI, and angina were confirmed as risk factors. They further evaluated a subgroup of 878 men with high Lp(a) levels. Thirty-three probands had major cardiac events, and all had significantly higher Lp(a) levels than men without cardiac problems. The group therefore recommends that both triglycerides and Lp(a) be measured when evaluating cardiac risk in males.

Enteric Bacteria linker to RA
Reporting in the June issue of Annals of the Rheumatic Diseases Japanese investigators led by Dr. Shigehisa Aoki of the Aichi Medical University in Aichi found that patients with rheumatoid arthritis had significantly higher levels of antibodies to Escherichia coli in serum and synovial fluid than did healthy controls or patients with osteoarthritis, and results of absorption and immunoblot analyses in the study patients suggested the presence of antigens common among Enterobacteriaceae. There were no differences between men and women, between patients with mild or severe symptoms, or between patients with recent onset or long-term symptoms.

Osteoporosis beware - bone formation stimulated
Scientists have used gene therapy to stimulate new bone formation in rats. Dr. Jeffrey Bonadio at the University of Michigan in Ann Arbor and colleagues reported their work in the June issue of the Proceedings of the National Academy of Sciences. They removed a 5-millimeter section of the femur in adult rats and then implanted gene-activated matrices (GAMs) into the gaps. New bone grew in all 14 rats receiving the gene therapy, while fibrous scar tissue formed in 36 rats who did not receive gene therapy.

1,5AG better glycemia monitor
Dr. Toshikazu Yamanouchi and coworkers at the University of Tokyo have shown that 1,5AG (1,5-anhydroglucitol) in serum accurately detects even slight changes in glycemia. The protein is minimally metabolized or degraded in the body. Renal reabsorption of 1,5AG is competitively inhibited by the glycosuria induced by hyperglycemia. Therefore, as urine levels of 1,5AG increase, serum levels of 1,5AG decrease. The research shows there is a close correlation between the reduction in serum 1,5AG and the amount of glucose excreted in the urine. Thus, checking fluctuations in serum levels is a good way to monitor diabetes control. Dr. Yamanouchi suggests that measurement of serum 1,5AG is more informative than measurement of serum levels of glycated hemoglobin (HbA1c) in diabetic patients. Dr. Yamanouchi notes that HbA1c is a marker of glycation, rather than of glycemia and envisions "...the end of glycated markers as markers of glycemia..." when antiglycation drugs under development for treatment of diabetes become available.

G-CSF a marker for neonatal sepsis
Investigators at the University of New Mexico have data that indicates levels of granulocyte-colony stimulating factor (G-CSF) appears to be a reliable marker of sepsis in neonates, Their report in the June issue of the Journal of Pediatrics presents their study of 176 evaluations for sepsis in 156 preterm infants with gestational ages ranging from 24 to 43 weeks. When they separated the infants into groups according to culture results and evidence of sepsis, they found that, regardless of age, mean granulocyte-colony stimulating factor levels were significantly higher in babies with positive bacterial or fungal blood culture results or with negative cultures but evidence of clinical sepsis than in the babies with negative cultures and no or weak evidence of sepsis. They found, on the basis of a cutoff level of 200 pg/mL, the sensitivity of the test for G-CSF levels in blood cultures was 95%, specificity 73%, positive predictive value 40% and negative predictive value 99%.

Antiphospholipid Antibodies predict vascular disease
Results of a prospective study, conducted by a team of physicians from 16 Italian institutions, of patients with antiphospholipid antibodies show that high titers of these antibodies and a history of thrombosis are predictive of vascular complications, and that asymptomatic patients are at low risk for adverse events. Dr. Guido Finazzi of the Ospedali Riuniti in Bergamo and colleagues observed 360 patients with lupus anticoagulant antibodies or anticardiolipin antibodies for four years. In the May issue of The American Journal of Medicine, they report that, "Patients with antiphospholipid antibodies at presentation might be divided into two groups," suggests Dr. Finazzi. "The first, the asymptomatic subjects, has a low risk of vascular complications and needs only careful observation. The second, patients with previous thrombosis and high antiphospholipid antibody titer, require active therapy."

Testosterone & ischemic stroke linked
Low levels of testosterone may increase the risk of stroke in elderly men, according to results of a study of 144 male stroke patients, average age 72, and 47 healthy male controls. A team of researchers headed by Dr. Lise Leth Jeppesen of UCSF, report that men with a history of ischemic stroke had testosterone levels close to 19% lower than men without a history of stroke. Moreover, they found that total and free testosterone levels were "...significantly inversely associated with stroke severity and 6-month mortality, and total testosterone was significantly inversely associated with infarct size. The study was reported in the June issue of Arteriosclerosis, Thrombosis and Vascular Biology.

Folic acid linked to CVD
Data from the Nutrition Canada Survey show that low folic acid levels are associated with a significantly increased risk of death from coronary heart disease. Dr. Howard I. Morrison and his colleagues at the Health Canada in Ottawa conducted a retrospective cohort study of 5,056 men and women ages 35 to 79 with no history of self-reported coronary heart disease. At 15 years' follow-up, the researchers found that risk of death from coronary heart disease "...increased in a stepwise fashion as the serum folate levels decreased." According to the report, individuals with serum folate levels less than 6.8 nmol/L had a 69% increased risk of coronary mortality compared with people with serum folate levels above 13.6 nmol/L. Although neither age, sex, nor serum cholesterol significantly modified the relationship between serum folate level and fatal coronary heart disease, the investigators did note that, "...the magnitude of the protective effect of folic acid appeared to be greater for women than for men and slightly greater for those younger than 65 years."

Lyme disease ticks also transmit ehrlichiosis
Scientists at the Harvard School of Public Health have found that deer ticks that transmit Lyme disease may also carry the agent that transmits human granulocytic ehrlichiosis, an emerging rickettsial disease. For the first time, the Harvard researchers have described the propagation of the ehrlichiosis pathogen and estimated the force of its transmission in nature. Human granulocytic ehrlichiosis produces symptoms similar to Lyme disease, except no rash forms around the bite. The main source of human granulocytic ehrlichiosis infection is the white-footed mouse, which is also known to be a reservoir for Lyme disease spirochetes and the protozoa that cause babesiosis. The deer tick Ixodes dammini, the main American vector of Lyme disease, ingests and transmits a human-derived strain of the ehrlichiosis bacterium to the mice. In field studies, about 10% of host-seeking deer ticks were infected with ehrlichiae, and of these, 20% also contained Lyme spirochetes.

PERT assay for plasma RNA HIV-1
A new assay, called the product-enhanced reverse transcriptase (PERT) assay, provides a more accurate method of detecting plasma RNA HIV-1 compared with the polymerase chain reaction (PCR) assay. Dr. Jurg Boni and colleagues at the University of Zurich used the PERT assay to measure particle-associated reverse transcriptase activity in 30 plasma samples from HIV-1-positive patients and in 160 samples from healthy blood donors. All the samples from the HIV-1 positive patients showed reverse transcriptase activity, and levels significantly correlated with viral RNA concentrations ranging from 553-417,000 particles per milliliter. In HIV-1 low titer performance and seroconversion panels, the PERT assay detected more positives than PCR for viral RNA. The PERT assay can detect less than 100 HIV-1 particles per milliliter and because the PERT assay is not influenced by sequence variation, all conceivable variants of HIV-1 can be detected. The PERT assay may be useful for investigation of other disorders thought to involve retroviruses, such as some neoplastic and autoimmune diseases, Dr. Boni said. The PERT assay may also be useful for testing of the safety of cell-free biological products such as fresh plasma, blood coagulation factors or vaccines, and for screening of transmissible retroviruses prior to transplantation and transfusion.

Retest HCV patients
Patients with chronic hepatitis C should be tested for serum hepatitis C virus RNA one year after a sustained biochemical response to interferon-A therapy to determine whether response is complete and permanent. A team of researchers lead by Dr. Liliana Chemello from the University of Padova, Italy, followed a group of outpatients with chronic hepatitis C who maintained normal aminotransferase levels as long as 12 months after interferon therapy. The investigators found that hepatitis C virus RNA was detected in 25% of the patients with a sustained biochemical response, while 75% tested negative. Positive patients were generally older, had received smaller doses of interferon, and were more frequently infected with the hepatitis C virus genotype 2. Liver histologic findings were active in 57% of patients positive for HCV RNA, despite normal liver enzyme levels, compared with only 12% of RNA negative patients.

Enzyme key to autoimmune disease
Scientists at the Weitzmann Institute in Israel report to have identified a key enzyme involved in the development of autoimmune diseases. Dr. David Wallach and his team of graduate students describe their findings in the June issue of Cell. The enzyme called MACH, acts, by dividing up vital proteins within a cell so that the cell ceases to function normally and dies. MACH does not require other cellular process to mediate its action; rather, it targets receptors on cells directly and very little is required to initiate the destruction of cells. The finding is expected to further research into treatments for such autoimmune diseases as juvenile diabetes and multiple sclerosis.

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