Iron Regulatory Protein 1 is Required for the Propagation of Inflammation in Inflammatory Bowel Disease.

Objective: Inflammatory bowel diseases (IBD) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation are known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution and that this in turn perpetuates the inflammation. Design: This study analyzed human biopsies, animal models and cellular systems to decipher the role of iron homeostasis in IBD. Results: We found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP)1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular co-culture model was established, that replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. Conclusion: These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD.

Evaluation of a new hepatitis B triple-antigen vaccine in inadequate responders to current vaccines.

In this double-blind, randomized, controlled study, healthcare professionals with a history of inadequate response to currently available single-antigen hepatitis B vaccines confirmed by measuring hepatitis B surface antibody titer before entry to the study were revaccinated with a 20-microg dose either of a novel triple-antigen (S, pre-S1, and pre-S2) recombinant vaccine or of a present single-antigen (S only) vaccine. Hepatitis B surface antibody titers were measured 8 weeks' post revaccination. A total of 925 individuals were randomized and vaccinated, of whom 915 (98.9%) completed the study and were included in the efficacy analysis. A single dose of the new triple-antigen hepatitis B vaccine (Hepacare) produced a successful response in over three quarters of these subjects who had not mounted an adequate response to current vaccines. The antibody response was statistically significantly superior (P =.002) to that after a single dose of current vaccines. An evaluation of the overall response showed that only the triple-antigen vaccine was able to raise the average antibody response (geometric mean titer [GMT]) to over 100 IU/L. The superior effect of the new vaccine was most pronounced in subjects who were previously complete nonresponders to currently available hepatitis B vaccines. Both vaccines were well tolerated and had similar safety profiles. This study demonstrated that in healthcare workers who had responded inadequately to at least a full course of immunization (median, 5 doses), a single 20-microg dose of a new triple-antigen vaccine induced protective antibody level in more vaccinees (P =.002) and increased the average antibody titer (GMT) in those protected successfully to a greater degree (P <.001) than a further attempt with a current vaccine (Engerix-B).

Adult hepatitis B vaccination using a novel triple antigen recombinant vaccine.

Present hepatitis B vaccines use multidose prolonged regimens, which even healthcare workers at risk do not always complete. Moreover, when vaccination is completed there remain some who fail to achieve adequate protection. The protection of adults at risk could be improved if there were a more potent vaccine and/or a shorter vaccination regimen available. Vaccine-naive adults were randomized to vaccination with either Engerix-B (SmithKline Biologicals, Rixensart, Belgium) or a novel triple antigen (S, pre-S1, and pre-S2) recombinant vaccine (Hepacare; Medeva Pharma Plc, Speke, UK). The primary efficacy parameter was the degree of seroprotection 6 or 7 months (26 +/- 2 weeks) after beginning vaccination. A total of 304 adults entered the study. Of these, 16 failed to complete the study (9 on Hepacare and 7 on Engerix-B). With the Engerix-B standard (0, 1, 6) regimen, 88% of subjects were protected by month 7, whereas with the triple antigen vaccine a 2-dose regimen (0, 1) provided equivalent protection (91%) within 6 months and a 3-dose (0, 1, 6) regimen was significantly superior (98% seroprotected by 7 months after starting vaccination P <.001). With adults at risk for a suboptimal response (i.e., older adults, the obese, men, and smokers) the triple antigen vaccine produced a greater degree of protection. The vaccines had similar safety profiles. Both vaccines were well tolerated. In healthy normal adults, a triple antigen hepatitis B vaccine containing S and pre-S antigens produced an enhanced immunologic response and was as effective as a 2- and 3-dose regimen.

Mood changes in adolescents using depot-medroxyprogesterone acetate for contraception: a prospective study.

STUDY OBJECTIVE: Depot-medroxyprogesterone acetate (DMPA) is thought to cause changes in mood among patients using it for contraception. The purpose of this study was to evaluate changes in negative and positive affect among adolescent females using DMPA as a contraceptive agent. DESIGN, SETTING, PARTICIPANTS: This prospective study was set in an urban hospital adolescent clinic. Thirty-nine adolescents choosing DMPA as a contraceptive agent and 24 adolescents not using any hormonal contraception were enrolled as subjects and controls, respectively. Two standardized questionnaires, the Beck Depression Inventory (BDI) and the Multiple Affect Adjective Checklist-Revised (MAACL-R), were administered at baseline to all participants and readministered at 3, 6, and 12 months. MAIN OUTCOME MEASURES: Changes in negative affect from baseline to 3, 6, and 12 months were evaluated by the BDI and by "dysphoria" subscale scores of the MAACL-R. Paired t-tests were used to measure these changes in subjects and controls separately. RESULTS: The mean change in BDI scores from baseline to one year for those who completed one year was -4.8 for subjects (P =.02) and +.3 (P =.84) for controls. The mean change in the dysphoria subscale scores was -5.7 (P =.21) for the subjects and -.1 (P =.98) for the controls while the change in the positive affect scores over a period of one year were -2.1 (P =.46) and +.1 (P =.98) for subjects and controls, respectively. CONCLUSIONS: Adolescents using DMPA do not show depressive symptoms when using DMPA as a contraceptive agent over a period of 12 months as measured by the BDI and show no significant changes in negative or positive affect as measured by the MAACL-R.

Comparison of a triple antigen and a single antigen recombinant vaccine for adult hepatitis B vaccination.

Hepatitis B and its sequelae are a major public health problem. Vaccines have been available for almost 20 years; however the disease still remains a global problem. Many factors contribute to the failure to control hepatitis B, including the limited nature of the vaccination programs implemented initially. Only relatively recently has mass childhood vaccination begun to be implemented and vaccination of high-risk groups, other than healthcare workers, is still not general policy. Additional factors contributing to continued persistence of hepatitis B in the developed world are that the present vaccines are not fully used by those recommended to be vaccinated and even when vaccination is carried out appropriately, there remain some who fail to achieve adequate protection. Clearly, the protection of at-risk groups who have inadequate response to current vaccines, and those who are unwilling or unable to comply with protracted multi-dose vaccine regimens, could be improved if there were a more potent vaccine and/or a shorter vaccination regimen available. Adults who had never been vaccinated against hepatitis B were randomised to receive a vaccination course of either a present single antigen (S) vaccine (Recombivax-HB) or a novel triple antigen (S, pre-S1, and pre-S2) recombinant vaccine (Hepacare Medeva Pharma plc). Doses were given at baseline and 1 month and 6 months later. Hepatitis B surface antibody (anti-HBs) levels were measured at 2, 4, 6, and 7 months after beginning vaccination. The primary efficacy parameter was the degree of protection, measured as the percentage of subjects with anti-HBs titres > or = 10 IU/L, 6 or 7 months (26 +/- 2 weeks) after beginning vaccination. A total of 303 adult subjects entered the study and were vaccinated. Of these, 11 failed to complete the study (4 on Hepacare and 7 on Recombivax-HB); however all but 2 (1 to receive the triple antigen vaccine and 1 to receive Recombivax-HB) were included in the intent-to-treat population for efficacy evaluation. Treatment randomisation was stratified at entry based on age (above and below 40 years old) and gender. The standard three-dose/6-month vaccination regimen of the single antigen vaccine protected 83% of subjects by 7 months after starting vaccination whereas the triple antigen vaccine as a two-dose/1-month regimen protected 88% within 6 months and as a three-dose/6-month regimen protected 97% by 7 months after starting vaccination. Thus the protection rate provided by the shortened (0, 1) regimen of the novel vaccine was "essentially equivalent" (i.e., not statistically inferior) to that provided by the full (0, 1, and 6) regimen of today's vaccine (88% vs. 81%, P < 0.001), and the protection rate provided by a three-dose/6-month (0, 1, and 6) regimen of the new vaccine was significantly superior to that provided by present vaccines (97% vs. 83% P < 0.001). The percentage of subjects protected increases with time after beginning vaccination and at all time points up to and including 6 months was significantly greater with the two-dose regimen of the triple antigen vaccine than with the single antigen vaccine regimen. In adults at risk for a reduced response to hepatitis B vaccination [i.e., older adults (>/=40), the obese, males, and smokers], the triple antigen vaccine produced a significantly greater percentage of protected subjects (P < 0.001) and higher geometric mean titre (P < 0.001). Indeed as a three-dose/6 month regimen, the triple antigen vaccine raised the level of protection in these vulnerable subgroups to that seen when a single antigen vaccine is used in the optimal younger adult group. Both vaccines were well tolerated and had similar safety profiles. The most frequently (> or = 10%) reported adverse events with the use of either vaccine were pain at the site of injection (38% vs. 41% vs. 20% for the two-dose Hepacare regimen, the three-dose Hepacare regimen, and the three-dose Recombivax-HB regimen, respectively), infections at the site of injection (1% vs. 14% vs. 9%), headache (9% vs. 13% vs. 11%), and nausea (7% vs. 11% vs. 3%). It is concluded that in healthy normal adults, a triple antigen hepatitis B vaccine that contained S and pre-S antigens produced an enhanced immunological response. This was exemplified by the novel vaccine's ability to overcome factors such as advancing age (> or = 40 years), obesity, and smoking, each of which is known to reduce the potential for protection with present recombinant S only vaccines. A two-dose/1-month (0 and 1) regimen of this triple antigen vaccine was as effective as the standard three-dose/6 month (0, 1, and 6) regimen of present single antigen vaccines. (c) 2001 Wiley-Liss, Inc.

Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs.

Many peptides and transmitters found within the brain also have peripheral sites of action. We now demonstrate that the brain releases functionally active neurotransmitters/neuromodulators directly from the brain into the blood through a saturable P-glycoprotein (Pgp) transport system. Downregulating Pgp1 expression with antisense reduced the brain-to-blood transport of morphine, beta-endorphin and other opioids. Lowering Pgp expression significantly enhanced systemic morphine analgesia and prevented tolerance, but diminished the analgesic activity of centrally administered morphine, implying that supraspinal analgesia resulted from a combination of central and peripheral mechanisms activated by morphine transported from the brain to the blood. Similarly, mice with a disruption of the Mdr1a gene were more sensitive to systemic morphine and less sensitive to morphine given centrally. This ability of the Pgp transport system to pump functionally active compounds from the brain to periphery defines a potentially important mechanism for the central nervous system to modulate peripheral systems.

Restructuring the electronic medical record to incorporate full digital signature capability.

The security of Electronic Medical Records can be enhanced by the addition of digital signatures that guarantee data integrity, authenticate the signer, and establish non-repudiation through the use of public key encryption. The task is complicated by the contribution of multiple providers to an encounter and the entry of data at multiple points in time Dividing encounters into an episode of care and redesigning the data model of the EMR will facilitate full signature capabilities. Generation of digital signatures is best accomplished using microprocessors on smart cards that control visibility of the private keys and assist in user authentication. The Java Programming Language including cryptography extensions and a smart card API is a useful tool for adding digital signature to an EMR. Inter-operability of signatures and continuity of signature will require attention to standards and preservation of cryptography and authentication certificate archives. Digital signatures will need to accommodate changes in data storage formats when information is transported between EMR systems using XML or other transaction standards because the original signatures will not validate if the data storage format changes. The costs of adding digital signature to EMR mandates serious examination of the business case for digital signature within an EMR as compared with transactions such as electronic prescriptions. At present, there is no regulatory requirement for digital signature of an EMR.

CD34 selection as a stem cell purging strategy for neuroblastoma: preclinical and clinical studies.

BACKGROUND: The suitability of CD34 selection for purging peripheral blood progenitor cells (PBPC) collected from patients with neuroblastoma (NB) has been called into question, largely because of reports of detection of low levels of CD34 on the surface of some NB cell lines and tumors. PROCEDURE: We used three approaches to address the issue of purging of NB from stem cell specimens and possible labeling of NB: 1) Flow cytometric detection of CD34 on NB cell lines. We assessed CD34 expression using a panel of anti-CD34 monoclonal antibodies (MoAbs) including 9C5, 12.8, and QBend10 and showed no increase in labeling over secondary-only control. 2) Spiking experiments with the Isolex 50 system. NB cell lines were used to contaminate aliquots of PBPC collections, after which the products were purified using the Isolex 50. Purging of NB was assessed by quantitative multiplex RT-PCR (TaqMan system) using a tumor-specific transcript, GAGE. We demonstrated >2 logs of tumor cell depletion from these specimens. 3) Analysis of clinical specimens. PBPC pre- and post-CD34 selection were analyzed from patients treated on the CHP-594 transplant trial. RESULTS: In nine specimens selected using the Ceprate LC CD34 selection system where tumor was detectable by immunocytochemistry preselection, we observed >2.4 to >4.6 logs of NB purging after selection. We then analyzed 23 aliquots of PBPC infused into patients post-CD34 selection and compared them to the product preselection; 20/23 specimens showed depletion of NB, although some level of GAGE message was observed in most post-CD34 selection specimens. CONCLUSION: These data show that purging of NB from PBPC specimens using CD34 selection is feasible, yielding infused products that are negative at the level of ICC but often positive at the level of RT-PCR.

Creating a vision for the twenty-first century healthcare organization.

Management approaches used by healthcare organizations have often lagged behind other businesses in more competitive industries. Companies operating in such dynamic environments have found that to cope with the rapid pace of change they must have an articulated understanding of their organization's capabilities and consensus on where the organization is headed based on predictions about the future operating environment. This statement of identity and strategic direction takes the form of a vision statement that serves as the compass for the organization's decisions for a five- to ten-year period. This article discusses the importance of vision statements in tomorrow's healthcare organizations, presents an overview of future scenarios that may provide context for organizational visions, and suggests a process for developing a vision statement. A case study is presented to illustrate how a vision statement is created. Following the guidelines presented in this article and reviewing the case study should assist healthcare executives and their boards in crafting better visions of their organizations' futures, developing more effective strategies to realize these visions, and adapting to more frequent and more significant change.

Current topics in hepatitis B.

Over two billion people around the world have been infected with hepatitis B virus, of whom over 350 million are chronic carriers. Some 25% of carriers develop progressive liver disease. The annual mortality from hepatitis B infection and its sequelae is 1-2 million people worldwide.The following current topics are reviewed: immunization strategies against hepatitis B and the kinetics and antibody response; the controversy on screening blood donors for anti-core antibodies; mutations of hepatitis B surface antigen, including evidence that not all such mutants are detectable by current laboratory tests and, finally, the introduction of second generation nucleoside analogues for treatment of chronic hepatitis B infection, including treatment of patients with decompensated liver disease and liver transplantation.

Leveraging strategic planning for improved financial performance.

Healthcare providers increasingly are relying on strategic planning to guide the allocation of capital and other resources. Strategic planning helps identify and prioritize opportunities for financial improvement, particularly revenue-generating initiatives, which offer the greatest opportunity for significant long-term benefits. New revenue usually can be generated in one of five ways: increase market share, expand service area, fill gaps in the continuum of services, develop niche services where needed in the service area, and repackage existing services to address specific market segments. Once a strategic plan is implemented, it should be reviewed periodically and modified as necessary.