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While previous studies focused on the effectiveness of individual complementary and alternative medical (CAM) therapies, the value of providing patients access to an integrated program involving multiple CAM and conventional therapies remains unknown. The objective of this study is to explore the feasibility and effects of a model of multidisciplinary integrative care for subacute low-back pain (LBP) in an academic teaching hospital.This was a pilot randomized trial comparing an individualized program of integrative care (IC) plus usual care to usual care (UC) alone for adults with LBP.Twenty (20) individuals with LPB of 3-12 weeks' duration were recruited from an occupational health clinic and community health center.Participants were randomized to 12 weeks of individualized IC plus usual care versus UC alone. IC was provided by a trained multidisciplinary team offering CAM therapies and conventional medical care.The outcome measures were symptoms (pain, bothersomeness), functional status (Roland-Morris score), SF-12, worry, and difficulty performing three self-selected activities.Over 12 weeks, participants in the IC group had a median of 12.0 visits (range 5-25). IC participants experienced significantly greater improvements at 12 weeks than those receiving UC alone in symptom bothersomeness (p=0.02) and pain (p=0.005), and showed greater improvement in functional status (p=0.08). Rates of improvement were greater for patients in IC than UC in functional status (p=0.02), bothersomeness (p=0.002), and pain scores (p=0.001). Secondary outcomes of self-selected most challenging activity, worry, and the SF-12 also showed improvement in the IC group at 12 weeks. These differences persisted at 26 weeks, but were no longer statistically significant.It was feasible for a multidisciplinary, outpatient IC team to deliver coordinated, individualized intervention to patients with subacute LBP. Results showed a promising trend for benefit of treating patients with persistent LBP with this IC model, and warrant evaluation in a full-scale study.

In the early 1990's our team developed and patented one of the first percutaneous heart valve systems working with Dr. Ivan Casagrande and Dr. Domingos Moraes in Brazil. We learned in this experience that a patient is nearly always better off keeping their own heart valve it they can. The aim of

Background. International travel by US business travelers is continuing to increase with the globalization of the economy. The objective of this study was to determine if the frequency and duration of international business travel is associated with differences in travelers' health and well-being. This study expands our limited knowledge of the impact of long-haul travel on healthy lifestyle choices and traveler's perceptions of their health and well-being. Methods. 12,942 unique health risk appraisal (HRA) records of US employees of a multinational corporation were analyzed according to self-reported (objective and subjective) travel history and lifestyle habits. Results. Comparing 2,962 international travelers and 9,980 non-travelers, international business travel was significantly associated with a lower body mass index, lower blood pressure, excess alcohol consumption, sleep deprivation, and diminished confidence to keep up with the pace of work. Conclusions. This study demonstrated both positive and negative associations on the health risks and well-being of a large sample of US-based international business travelers from an US multinational company. This study identifies targeted areas for pretrip screening and counseling to proactively address potential negative effects of travel and may assist in the design of corporate travel health and employee assistance programs.

OBJECTIVE—We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct from those of Fc-fusion proteins. CNTO736 is a glucagon-like peptide 1 (GLP-1) receptor agonist engineered in our MIMETIBODY platform. It retains many activities of native GLP-1 yet has a significantly enhanced pharmacokinetic profile. Our goal was to develop a long-acting GLP-1 receptor agonist with sustained efficacy. RESEARCH DESIGN AND METHODS—In vitro and in vivo activity of CNTO736 was evaluated using a variety of rodent cell lines and diabetic animal models. RESULTS—Acute pharmacodynamic studies in diabetic rodents demonstrate that CNTO736 reduces fasting and postprandial glucose, decreases gastric emptying, and inhibits food intake in a GLP-1 receptor–specific manner. Reduction of food intake following CNTO736 dosing is coincident with detection of the molecule in the circumventricular organs of the brain and activation of c-fos in regions protected by the blood-brain barrier. Diabetic rodents dosed chronically with CNTO736 have lower fasting and postprandial glucose and reduced body weight. CONCLUSIONS—Taken together, our data demonstrate that CNTO736 produces a spectrum of GLP-1 receptor–dependent actions while exhibiting significantly improved pharmacokinetics relative to the native GLP-1 peptide.

The functional role of IL-12 and IL-23 in host defense and disease following viral infection of the CNS was determined. Instillation of mouse hepatitis virus (MHV, a positive-strand RNA virus) into the CNS of mice results in acute encephalitis followed by a chronic immune-mediated demyelinating disease. Antibody-mediated blocking of either IL-23 (anti-IL-23p19) or IL-12 and IL-23 (anti-IL-12/23p40) signaling did not mute T-cell trafficking into the CNS or antiviral effector responses and mice were able to control viral replication within the brain. Therapeutic administration of either anti-IL-23p19 or anti-IL-12/23p40 to mice with viral-induced demyelination did not attenuate T-cell or macrophage infiltration into the CNS nor improve clinical disease or diminish white matter damage. In contrast, treatment of mice with anti-IL-12/23p40 or anti-IL-23p19 resulted in inhibition of the autoimmune model of demyelination, experimental autoimmune encephalomyelitis (EAE). These data indicate that (1) IL-12 and IL-23 signaling are dispensable in generating a protective T-cell response following CNS infection with MHV, and (2) IL-12 and IL-23 do not contribute to demyelination in a model independent of autoimmune T-cell–mediated pathology. Therefore, therapeutic targeting of IL-12 and/or IL-23 for the treatment of autoimmune diseases may offer unique advantages by reducing disease severity without muting protective responses following viral infection.

Toll-like receptors are a family of pattern-recognition receptors that contribute to the innate immune response. Toll-like receptor 3 (TLR3) signals in response to foreign, endogenous and synthetic ligands including viral dsRNA, bacterial RNA, mitochondrial RNA, endogenous necrotic cell mRNA and the synthetic dsRNA analog, poly(I:C). We have generated a monoclonal antibody (mAb CNTO2424) that recognizes the extracellular domain (ECD) of human TLR3 in a conformation-dependent manner. CNTO2424 down-regulates poly(I:C)-induced production of IL-6, IL-8, MCP-1, RANTES, and IP-10 in human lung epithelial cells. In addition, mAb CNTO2424 was able to interfere with the known TLR3-dependent signaling pathways, namely NF-κB, IRF-3/ISRE, and p38 MAPK. The generation of this neutralizing anti-TLR3 mAb provides a unique tool to better understand TLR3 signaling and potential cross-talk between TLR3 and other molecules.

Unmethlylated CpG dinucleotides induce a strong T-helper-1-like inflammatory response, presumably mediated by Toll-like receptor 9 (TLR9). However, the nature and cellular localization of TLR9 in primary human cells remain controversial. Here we demonstrate, using flow cytometry and immunofluorescence microscopy techniques, that TLR9 can be expressed at the cell surface. The primary human cell subsets that were positive for TLR9 expression were distinct depending on the tissues analyzed. Specifically, in human peripheral blood mononuclear cells (PBMC) the majority of cell surface TLR9+cells were confined to the major histocompatibility complex (MHC) class II+CD19−populations that express CD11c and/or CD14, whereas in tonsils the same gated population contained primarily MHC class II+CD19+cells. Cells positive for surface expression represented a minor fraction of the total cell populations examined, varying between 2 and 10%. In addition, we found that TLR9 expression at the surface of PBMC was up-regulated approximately fourfold following stimulation with the gram-negative bacterial cell wall component lipopolysaccharide, suggesting a potential modulatory role of TLR4 agonists on TLR9 expression. Taken together, these data validate human TLR9 expression at the surface of primary cells, in addition to the previously described intracellular localization. Further, our results suggest that human antigen-presenting cells comprise the major cell populations expressing cell surface TLR9.

Dihydrofolate reductase (DHFR) inhibitors such as trimethoprim (TMP) have long played a significant role in the treatment of bacterial infections. Not surprisingly, after decades of use there is now bacterial resistance to TMP and therefore a need to develop novel antibacterial agents with expanded spectrum including these resistant strains. In this study, we investigated the optimization of 2,4-diamnoquinazolines for antibacterial potency and selectivity. Using structure-based drug design, several 7-aryl-2,4-diaminoquinazolines were discovered that have excellent sub-100 picomolar potency against bacterial DHFR. These compounds have good antibacterial activity especially on gram-positive pathogens including TMP-resistant strains.

A critical step in the infectious cycle ofLeishmaniais the differentiation of parasites within the sand fly vector to the highly infective metacyclic promastigote stage. Here, we establish tetrahydrobiopterin (H4B) levels as an important factor controlling the extent of metacyclogenesis. H4B levels decline substantially during normal development, and genetic or nutritional manipulations showed that low H4B caused elevated metacyclogenesis. Mutants lacking pteridine reductase 1 (PTR1) had low levels of H4B, remained infectious to mice, and induced larger cutaneous lesions (hypervirulence). Thus, the control of pteridine metabolism has relevance to the mechanism ofLeishmaniadifferentiation and the limitation of virulence during evolution.

An arsenical resistant cloned line of Trypanosoma brucei brucei was derived from a parent sensitive clone by repeated selection in vivo with the pentavalent melaminophenyl arsenical, sodium melarsen. The melarsen-resistant line was tested in vivo in mice against a range of trypanocidal compounds and found to be cross-resistant to the trivalent arsenicals, melarsen oxide, melarsoprol and trimelarsen (33, 67 and 122-fold, respectively). A similar pattern of cross-resistance was found in vitro using a spectrophotometric lysis assay (greater than 200-fold resistance to melarsen oxide and greater than 20-fold resistance to both trimelarsen and melarsoprol). Both lines were equally sensitive to lysis by the lipophilic analogue phenylarsine oxide in vitro, suggesting that the melamine moiety is involved in the resistance mechanism. Although trypanothione has been reported to be the primary target for trivalent arsenical drugs [1], levels of trypanothione and glutathione were not significantly different between the resistant and sensitive lines. Statistically significant differences were found in the levels of trypanothione reductase (50% lower in the resistant clone) and dihydrolipoamide dehydrogenase (38% higher in the resistant clone). However, the Km for trypanothione disulphide, the Ki for the competitive inhibitor Mel T (the melarsen oxide adduct with trypanothione) and the pseudo-first order inactivation rates with melarsen oxide were the same for trypanothione reductase purified from both clones. The melarsen-resistant line also showed varying degrees of cross-resistance to the diamidines: stilbamidine (38-fold), berenil (31.5-fold), propamidine (5.7-fold) and pentamidine (1.5-fold). Cross-resistance correlates with the maximum interatomic distance between the amidine groups of these drugs and suggests that the diamidines and melaminophenyl arsenicals are recognised by the same transport system.

Acute respiratory distress syndrome (ARDS) manifests clinically as a consequence of septic and/or traumatic injury in the lung. Oxygen therapy remains a major therapeutic intervention in ARDS, but this can contribute further to lung damage. Patients with ARDS are highly susceptible to viral infection and it may be due to altered Toll-like receptor (TLR) expression.To evaluate the role of TLR3 in ARDS.TLR3 expression and signaling was determined in airway epithelial cells after in vitro hyperoxia challenge. Using a murine model of hyperoxia-induced lung injury, the role of TLR3 was determined using either TLR3-gene deficient mice or a specific neutralizing antibody directed to TLR3.Increased TLR3 expression was observed in airway epithelial cells from patients with ARDS. Further, hyperoxic conditions alone were a major stimulus for increased TLR3 expression and activation in cultured human epithelial cells. Interestingly, TLR3(-/-) mice exhibited less acute lung injury, activation of apoptotic cascades, and extracellular matrix deposition after 5 days of 80% oxygen compared with wild-type (TLR3(+/+)) mice under the same conditions. Administration of a monoclonal anti-TLR3 antibody to TLR3(+/+) mice exposed to hyperoxic conditions likewise protected these mice from lung injury and inflammation.The potential for redundancy in function as well as cross-talk between distinct TLRs may indeed contribute to whether the inflammatory cascade can be effectively disrupted once signaling has been initiated. Together, these data show that TLR3 has a major role in the development of ARDS-like pathology in the absence of a viral pathogen.

The use of targeting moieties is a new and exciting field of scientific research for facilitating the specific delivery of therapeutic agents in HIV-infected patients. The interaction of a potential targeting moiety with its ligand is a crucial factor in the evaluation of a targeted approach for chemotherapeutic intervention. Therefore, we have further characterized the interaction between a potential targeting agent, the monoclonal human antibody F105, and its ligand gp120, a glycoprotein expressed on the surface of HIV-1 infected cells. We demonstrate the specificity of binding and entry of F105 to infected cells. F105 was rapidly taken up into the cell and accumulated in the Golgi apparatus. Kinetic analysis of the F105-gp120 interaction revealed an equilibrium dissociation constant ( K D ) of 0.62 nM, compared with the gp120-CD4 interaction where the K D was determined at 35 nM. Consequently, F105 displayed a higher gp120 affinity. This was due to a slower dissociation as compared with the natural ligand. These data further underline the potential of monoclonal antibodies as targeting agents, and offer new insights into the possibility of F105 as a targeting moiety for the delivery of antiretroviral drugs to HIV-1 infected cells.

Protozoan parasites of the trypanosomatid genus Leishmania are pteridine auxotrophs, and have evolved an elaborate and versatile pteridine salvage network capable of accumulating and reducing pteridines. This includes biopterin and folate transporters (BT1 and FT1), pteridine reductase (PTR1), and dihydrofolate reductase‐thymidylate synthase (DHFR-TS). Notably, PTR1 is a novel alternative pteridine reductase whose activity is resistant to inhibition by standard antifolates. In cultured promastigote parasites, PTR1 can function as a metabolic by-pass under conditions of DHFR inhibition and thus reduce the efficacy of chemotherapy. To test whether pteridine salvage occurred in the infectious stage of the parasite, we examined several pathogenic species of Leishmania and the disease-causing amastigote stage that resides within human macrophages. To accomplish this we developed a new sensitive HPLC-based assay for PTR1 activity. These studies established the existence of the pteridine salvage pathway throughout the infectious cycle of Leishmania, including amastigotes. In general, activities were not well correlated with RNA transcript levels, suggesting the occurrence of at least two different modes of post-transcriptional regulation. Thus, pteridine salvage by amastigotes may account for the clinical inefficacy of antifolates against leishmaniasis, and ultimately provide insights into how this may be overcome in the future. © 2001 Elsevier Science B.V. All rights reserved.

THE human immunodeficiency virus (HIV) matrix protein, p17, forms the outer shell of the core of the virus, lining the inner surface of the viral membrane1–4. The protein has several key functions. It orchestrates viral assembly via targeting signals that direct the gag precursor polyprotein, p55, to the host cell membrane1,5–7 and it interacts with the transmembrane protein, gp41, to retain the env-encoded proteins in the virus8. In addition, pi7 contains a nuclear localization signal that directs the preintegration complex to the nucleus of infected cells9. This permits the virus to infect productively non-dividing cells, a distinguishing feature of HIV and other lentiviruses. We have determined the solution structure of p17 by nuclear magnetic resonance (NMR) with a root-mean square deviation for the backbone of the well-defined regions of 0.9 A. It consists of four helices connected by short loops and an irregular, mixed β-sheet which provides a positively charged surface for interaction with the inner layer of the membrane. The helical topology is unusual; the Brookhaven protein database contains only one similar structure, that of the immune modulator interferon-γ.

In a study of the effects of percentage of mediation-pairs and control pairs in a 3-list chaining paradigm, 5 groups of Ss learned lists in which 0, 20, 40, 60, and 80% of the pairs were chaining pairs, and the remainder were “warm-up” control-pairs. The results did not support a hypothesized direct relationship between mediation-effect and percentage of mediation-pairs. Rather, the 20 and 80% groups showed the greatest mediation-effect, the 60% group showed little mediation-effect, and the 40% group showed no mediation-effect. Results were interpreted in terms of intralist interference resulting from differences in the discriminability of mediation and control conditions.

Two groups of 10 rats each were trained to cross increasing levels of electrical shock in a straight alley runway for food. The group receiving masking white noise (88 db) showed a significantly higher shock tolerance than controls that received no white noise. The results were interpreted as supporting the audioanalgesic effect and as suggesting a need to examine the use of masking white noise in studies using shock

Summary.-32 male and 38 female (mean age 28.2 yr.) subjects were shown a video-taped counseling session in which they saw a woman who exhibited signs of depression, anxiety, and indecision resulting from an unplanned and unwanted pregnancy. Subjects rated the woman on 15 biopolar adjective pairs as to how they saw her now and for the future. Generally a married woman was seen more negatively than a single woman. More positive characteristics were attributed to the woman in the future, and female subjects tended to increase the positiveness of their ratings for the future more than did males. Abortion vs birth had no significant effect. Item analyses indicated that several adjectivepairs discriminated among the various conditions (marital status, sex, and problem solution). Multiple discriminant function analysis detected a group of seven adjectives which could be combined to classify correctly 58% of the subjects into groups. This smdy presented subjects with the task of judging the competency, maturity, emotional warmth, KC., of a woman experiencing anxiety and distress related to an unwanted pregnancy. The purpose was to investigate the effects of information about the woman's marital scams and her resolution of the problem pregnancy (birth or induced abortion) on attitudes toward her. Most of the research on attitudes concerning abortion has used questions, asked to physicians, women, and the general population, concerning abortion per se. Little research has been directed toward assessment by others of the woman who has the problem pregnancy and/or an induced abortion. In one relevant study Char and McDermott (1972) reported acute psychological reactions to abortion-work by nurses soon after the hospitals started performing abortions under the new law in 1970. The nurses showed symptoms of anxiety and depression of a transient, reactive type. The most common reactions were (a) over-identification with the fetus, (b) hostility toward abortion-patients, and (c) acute idencity-crisis with the role of the nurse. The importance of the attitudes of others toward such a woman was illustrated in a paper by Bracken, Hachamovitch, and Grossman ( 1974), who report more favorable postabortion reactions in women who perceived they had partner-support (or parental support in younger women) for the abortion. An understanding of the reactions and attitudes of people toward women who have problem pregnancies