Contribution of hypoglycemia to medical care expenditures and short-term disability in employees with diabetes

OBJECTIVE: Diabetes is the third-most expensive physical health condition among US employees. We sought to evaluate the contribution of hypoglycemia to these costs. METHODS: We studied 2664 employees using insulin for whom medical encounters and short-term disability (STD) records were available. RESULTS: Among these employees, 442 (16.6%) had a diagnosis of hypoglycemia during an average follow-up of 2.5 years. The risk of hospitalization and emergency room visits was increased twofold in this group. Much of this excess was associated with hypoglycemia. The annualized medical cost of hypoglycemia was $3241. Patients with hypoglycemia had 77% more STD days annually. The risk of STD in the week after hypoglycemia was increased fivefold. CONCLUSION: These data suggest that hypoglycemia contributes substantially to medical care utilization and to disability-related work absence among employees using insulin.     

Are child health surveillance reviews just routine examinations of normal children?

BACKGROUND: The provision and content of child health surveillance (CHS) has changed greatly since 1990. However, its value continues to be questioned. The introduction of the personal child health record (PCHR) has provided a new means of collecting data about CHS. AIM: To identify what problems are recorded at CHS reviews in the PCHR during the first year of life, and what follow-up/referrals result directly from these reviews. METHOD: A total of 28 practices were recruited from one health authority. All babies born to mothers registered with study practices during one year were followed up. Health visitors returned copies of CHS reviews recorded in children's PCHRs. Written comments on returned reviews were analysed. RESULTS: In all, 2308 babies were entered into the study and 2001 (87%) were followed up for one year. A total of 7848 (78%) CHS reviews were returned. Physical problems were recorded in 58% of children at the 10-14 day, 35% at the six to eight week, and 39% at the six to nine month review. Of physical problems recorded at CHS reviews, 30% required follow-up in primary care and 7% required referral to hospital. Other problems were recorded less frequently and health promotion was recorded at only 7.5% of CHS reviews. CONCLUSION: Child health surveillance provides important opportunities to discuss problems that may cause parental concern and to identify children requiring treatment or follow-up. The design and use of the PCHR needs to change to reflect increasing emphasis on health promotion.     

The role of arthrography in the management of dysplasia epiphysealis hemimelica

Dysplasia epiphysealis hemimelica can be diagnesed on plain radiographs of the affected areas. However, double contrast arthrography in three new cases provided additional information. The cartilaginous portions of the lesion at the articular surface of the bone were precisely demonstrated, aiding the orthopedic surgeon in deciding which patients should have surgery and planning the extent of operation necessary.     

Adjuvant systemic therapy for early breast cancer.

Systemic therapy (chemotherapy or hormonal therapy) as an adjuvant to modalities of local control is now an integral part of the management of almost all patients with primary breast cancer metastatic to axillary lymph nodes. In addition, recent data suggest an expanding role for such treatments in patients without axillary involvement. Although some node-negative patients should probably not receive adjuvant therapy, the precise criteria to be used for selection are still under active discussion in the literature. Of the two types of systemic treatment, it is generally accepted that chemotherapy is indicated for premenopausal patients and that tamoxifen is useful for postmenopausal patients whose tumors contain estrogen or progesterone receptors. The recent analysis of several studies has suggested that chemotherapy may add to the benefits of tamoxifen in some postmenopausal patients as well. A possible role for tamoxifen in younger patients is being evaluated. For patients at relatively low risk of systemic relapse (i.e., those with zero to three involved axillary lymph nodes), no chemotherapy regimen has yet shown an advantage over 6 months of cyclophosphamide, methotrexate and 5-fluorouracil. For patients at high risk, however, doxorubicin-based regimens have demonstrated benefits. High-dose chemotherapies, some involving autologous bone marrow support, are being investigated for patients with ten or more involved nodes who are at very high risk of the eventual development of stage IV disease.     

MyD88-dependent signaling protects against anthrax lethal toxin-induced impairment of intestinal barrier function

MyD88-deficient mice were previously shown to have increased susceptibility to Bacillus anthracis infection relative to wild-type animals. To determine the mechanism by which MyD88 protects against B. anthracis infection, knockout mice were challenged with nonencapsulated, toxigenic B. anthracis or with anthrax toxins. MyD88-deficient mice had increased susceptibility to B. anthracis and anthrax lethal toxin but not to edema toxin. Lethal toxin alone induced marked multifocal intestinal ulcers in the knockout animals, compromising the intestinal epithelial barrier. The resulting enteric bacterial leakage in the knockout animals led to peritonitis and septicemia. Focal ulcers and erosion were also found in MyD88-heterozygous control mice but with far lower incidence and severity. B. anthracis infection also induced a similar enteric bacterial septicemia in MyD88-deficient mice but not in heterozygous controls. We show that lethal toxin and B. anthracis challenge induce bacteremia as a result of intestinal damage in MyD88-deficient mice. These results suggest that loss of the intestinal epithelial barrier and enteric bacterial septicemia may contribute to sensitizing MyD88-deficient mice to B. anthracis and that MyD88 plays a protective role against lethal toxin-induced impairment of intestinal barrier.     

Mouse monoclonal antibodies to anthrax edema factor protect against infection

Bacillus anthracis is the causative agent of anthrax, and the tripartite anthrax toxin is an essential element of its pathogenesis. Edema factor (EF), a potent adenylyl cyclase, is one of the toxin components. In this work, anti-EF monoclonal antibodies (MAb) were produced following immunization of mice, and four of the antibodies were fully characterized. MAb 3F2 has an affinity of 388 pM, was most effective for EF detection, and appears to be the first antibody reported to neutralize EF by binding to the catalytic C(B) domain. MAb 7F10 shows potent neutralization of edema toxin activity in vitro and in vivo; it targets the N-terminal protective antigen binding domain. The four MAb react with three different domains of edema factor, and all were able to detect purified edema factor in Western blot analysis. None of the four MAb cross-reacted with the lethal factor toxin component. Three of the four MAb protected mice in both a systemic edema toxin challenge model and a subcutaneous spore-induced foreleg edema model. A combination of three of the MAb also significantly delayed the time to death in a third subcutaneous spore challenge model. This appears to be the first direct evidence that monoclonal antibody-mediated neutralization of EF alone is sufficient to delay anthrax disease progression.     

Two chronic motor training paradigms differentially influence acute instrumental learning in spinally transected rats

The effect of two chronic motor training paradigms on the ability of the lumbar spinal cord to perform an acute instrumental learning task was examined in neonatally (postnatal day 5; P5) spinal cord transected (i.e., spinal) rats. At approximately P30, rats began either unipedal hindlimb stand training (Stand-Tr; 20-25min/day, 5days/week), or bipedal hindlimb step training (Step-Tr; 20min/day; 5days/week) for 7 weeks. Non-trained spinal rats (Non-Tr) served as controls. After 7 weeks all groups were tested on the flexor-biased instrumental learning paradigm. We hypothesized that (1) Step-Tr rats would exhibit an increased capacity to learn the flexor-biased task relative to Non-Tr subjects, as locomotion involves repetitive training of the tibialis anterior (TA), the ankle flexor whose activation is important for successful instrumental learning, and (2) Stand-Tr rats would exhibit a deficit in acute motor learning, as unipedal training activates the ipsilateral ankle extensors, but not flexors. Results showed no differences in acute learning potential between Non-Tr and Step-Tr rats, while the Stand-Tr group showed a reduced capacity to learn the acute task. Further investigation of the Stand-Tr group showed that, while both the ipsilateral and contralateral hindlimbs were significantly impaired in their acute learning potential, the contralateral, untrained hindlimbs exhibited significantly greater learning deficits. These results suggest that different types of chronic peripheral input may have a significant impact on the ability to learn a novel motor task, and demonstrate the potential for experience-dependent plasticity in the spinal cord in the absence of supraspinal connectivity.     

Novel Chimpanzee/Human Monoclonal Antibodies That Neutralize Anthrax Lethal Factor,and Evidence for Possible Synergy with Anti-Protective Antigen Antibody

Three chimpanzee Fabs reactive with lethal factor (LF) of anthrax toxin were isolated and converted into complete monoclonal antibodies (MAbs) with human γ1 heavy-chain constant regions. In a macrophage toxicity assay, two of the MAbs, LF10E and LF11H, neutralized lethal toxin (LT), a complex of LF and anthrax protective antigen (PA). LF10E has the highest reported affinity for a neutralizing MAb against LF (dissociation constant of 0.69 nM). This antibody also efficiently neutralized LT in vitro, with a 50% effective concentration (EC₅₀) of 0.1 nM, and provided 100% protection of rats against toxin challenge with a 0.5 submolar ratio relative to LT. LF11H, on the other hand, had a slightly lower binding affinity to LF (dissociation constant of 7.4 nM) and poor neutralization of LT in vitro (EC₅₀ of 400 nM) and offered complete protection in vivo only at an equimolar or higher ratio to toxin. Despite this, LF11H, but not LF10E, provided robust synergistic protection when combined with MAb W1, which neutralizes PA. Epitope mapping and binding assays indicated that both LF10E and LF11H recognize domain I of LF (amino acids 1 to 254). Although domain I is responsible for binding to PA, neither MAb prevented LF from binding to activated PA. Although two unique MAbs could protect against anthrax when used alone, even more efficient and broader protection should be gained by combining them with anti-PA MAbs.Anthrax is a highly lethal infectious disease caused by the spore-forming bacterium Bacillus anthracis. The deliberate distribution of anthrax spores through the U.S. mail system in 2001 resulted in five deaths among the 11 individuals who contracted inhalational anthrax (18). This incident highlighted the great threat posed by the potential use of anthrax in terrorism and warfare. The lethality of inhalational anthrax is primarily due to the action of anthrax toxins. The bacterium produces three toxin components; these are protective antigen (PA) (83 kDa), lethal factor (LF) (85 kDa), and edema factor (EF) (89 kDa) (13, 32). PA binds to host cell anthrax toxin receptors and is cleaved by cell surface furin to produce a 63-kDa peptide, PA63 (activated PA). Anthrax toxin receptor-bound PA63 oligomerizes to a heptamer and translocates up to three molecules of LF or EF from the cell surface via endosomes to the cytosol. Therefore, PA functions as a vehicle to mediate the cellular uptake of LF and EF (for a review, see reference 44). PA with LF forms lethal toxin (LT), and PA with EF forms edema toxin (ET). LF is a zinc-dependent endopeptidase that cleaves mitogen-activated protein kinase kinases and disrupts intracellular signaling (8, 30, 40). LT can replicate symptoms of anthrax disease when injected into animals (27). EF is a calcium-calmodulin-dependent adenylate cyclase that transforms ATP to cyclic AMP, and ET has a range of toxic effects in the host (12, 20). These toxins are the dominant virulence factors for anthrax disease, and vaccination against their common component, PA, is sufficient for protection against anthrax disease.Currently antibiotics are the only choice for clinical treatment of anthrax disease. Although effective, antibiotics have limitations. Exposure to the bacterium followed by bacterial division leads to production of large quantities of the anthrax toxins. Thus, unless exposure is diagnosed early enough for antibiotic treatment to prevent significant replication, patients will succumb to disease even after the killing of all bacteria. The current PA-based vaccine approved by the U.S. Food and Drug Administration is also not effective postexposure in protecting newly infected individuals, as it requires repeated administration and at least 4 weeks for development of anti-PA protective titers. Thus, in the absence of any small-molecule toxin inhibitors, monoclonal antibodies (MAbs) against toxin components are the only viable candidates for immediate neutralization of the effects of toxin. Although PA has been the primary target for passive protection (5, 25, 31, 35, 41, 43), it has been suggested that immunity to LF and EF can also play an important role in protection (14, 33, 34), and thus these proteins may represent alternative targets for antibody therapy against anthrax. In a previous study, the protective effects of anti-PA and anti-LF antibodies were greatly synergized by their combination (3). Furthermore, concerns that PA may be mutated within currently recognized neutralization epitopes such that anti-PA therapies would no longer be effective against this toxin warrant the further development of antibodies targeting the other toxin components. A cocktail of more than one MAb that could recognize distinct epitopes on multiple toxin proteins (PA, LF, and EF) could certainly broaden the spectrum of protection against anthrax. In recent years, several anti-LF neutralizing MAbs have been reported (1, 21, 24, 37, 46). However, only one of them was a human antibody; the others were rodent MAbs that would need further manipulation before use in humans.Chimpanzee immunoglobulins (Igs) are virtually identical to human Igs and may have clinically useful applications (9). As part of a larger study (5), we recovered chimpanzee MAbs specific for LF from a combinatorial cDNA library of antibody genes developed from chimpanzees that had been immunized with anthrax toxins. In this work we describe the detailed characterization of these anti-LF antibodies.