Showing papers by "David Eisenberg published in 2003"

Systematic Review of Herbs and Dietary Supplements for Glycemic Control in Diabetes

Abstract: OBJECTIVE —To conduct a systematic review of the published literature on the efficacy and safety of herbal therapies and vitamin/mineral supplements for glucose control in patients with diabetes. RESEARCH DESIGN AND METHODS —We conducted an electronic literature search of MEDLINE, OLDMEDLINE, Cochrane Library Database, and HealthSTAR, from database inception to May 2002, in addition to performing hand searches and consulting with experts in the field. Available clinical studies published in the English language that used human participants and examined glycemic control were included. Data were extracted in a standardized manner, and two independent investigators assessed methodological quality of randomized controlled trials using the Jadad scale. RESULTS —A total of 108 trials examining 36 herbs (single or in combination) and 9 vitamin/mineral supplements, involving 4,565 patients with diabetes or impaired glucose tolerance, met the inclusion criteria and were analyzed. There were 58 controlled clinical trials involving individuals with diabetes or impaired glucose tolerance (42 randomized and 16 nonrandomized trials). Most studies involved patients with type 2 diabetes. Heterogeneity and the small number of studies per supplement precluded formal meta-analyses. Of these 58 trials, the direction of the evidence for improved glucose control was positive in 76% (44 of 58). Very few adverse effects were reported. CONCLUSIONS —There is still insufficient evidence to draw definitive conclusions about the efficacy of individual herbs and supplements for diabetes; however, they appear to be generally safe. The available data suggest that several supplements may warrant further study. The best evidence for efficacy from adequately designed randomized controlled trials (RCTs) is available for Coccinia indica and American ginseng. Chromium has been the most widely studied supplement. Other supplements with positive preliminary results include Gymnema sylvestre , Aloe vera , vanadium, Momordica charantia , and nopal.

The primary mechanism of attenuation of bacillus Calmette–Guérin is a loss of secreted lytic function required for invasion of lung interstitial tissue

Abstract: Tuberculosis remains a leading cause of death worldwide, despite the availability of effective chemotherapy and a vaccine. Bacillus Calmette–Guerin (BCG), the tuberculosis vaccine, is an attenuated mutant of Mycobacterium bovis that was isolated after serial subcultures, yet the functional basis for this attenuation has never been elucidated. A single region (RD1), which is absent in all BCG substrains, was deleted from virulent M. bovis and Mycobacterium tuberculosis strains, and the resulting ΔRD1 mutants were significantly attenuated for virulence in both immunocompromised and immunocompetent mice. The M. tuberculosis ΔRD1 mutants were also shown to protect mice against aerosol challenge, in a similar manner to BCG. Interestingly, the ΔRD1 mutants failed to cause cytolysis of pneumocytes, a phenotype that had been previously used to distinguish virulent M. tuberculosis from BCG. A specific transposon mutation, which disrupts the Rv3874 Rv3875 (cfp-10 esat-6) operon of RD1, also caused loss of the cytolytic phenotype in both pneumocytes and macrophages. This mutation resulted in the attenuation of virulence in mice, as the result of reduced tissue invasiveness. Moreover, specific deletion of each transcriptional unit of RD1 revealed that three independent transcriptional units are required for virulence, two of which are involved in the secretion of ESAT-6 (6-kDa early secretory antigenic target). We conclude that the primary attenuating mechanism of bacillus Calmette–Guerin is the loss of cytolytic activity mediated by secreted ESAT-6, which results in reduced tissue invasiveness.

Mind-Body Medicine: State of the Science, Implications for Practice

Abstract: Background: Although emerging evidence during the past several decades suggests that psychosocial factors can directly influence both physiologic function and health outcomes, medicine had failed to move beyond the biomedical model, in part because of lack of exposure to the evidence base supporting the biopsychosocial model. The literature was reviewed to examine the efficacy of representative psychosocial-mind-body interventions, including relaxation, (cognitive) behavioral therapies, meditation, imagery, biofeedback, and hypnosis for several common clinical conditions. Methods: An electronic search was undertaken of the MEDLINE, PsycLIT, and the Cochrane Library databases and a manual search of the reference sections of relevant articles for related clinical trials and reviews of the literature. Studies examining mind-body interventions for psychological disorders were excluded. Owing to space limitations, studies examining more body-based therapies, such as yoga and tai chi chuan, were also not included. Data were extracted from relevant systematic reviews, meta-analyses, and randomized controlled trials. Results: Drawing principally from systematic reviews and meta-analyses, there is considerable evidence of efficacy for several mind-body therapies in the treatment of coronary artery disease (eg, cardiac rehabilitation), headaches, insomnia, incontinence, chronic low back pain, disease and treatment-related symptoms of cancer, and improving postsurgical outcomes. We found moderate evidence of efficacy for mind-body therapies in the areas of hypertension and arthritis. Additional research is required to clarify the relative efficacy of different mind-body therapies, factors (such as specific patient characteristics) that might predict more or less successful outcomes, and mechanisms of action. Research is also necessary to examine the cost offsets associated with mind-body therapies. Conclusions: There is now considerable evidence that an array of mind-body therapies can be used as effective adjuncts to conventional medical treatment for a number of common clinical conditions.

Patterns and perceptions of care for treatment of back and neck pain: results of a national survey.

Abstract: Study design We conducted a nationally representative random household telephone survey to assess therapies used to treat back or neck pain. Objectives The main outcome was complementary therapies used in the last year to treat back or neck pain. Summary of background data Back pain and neck pain are common medical conditions that cause substantial morbidity. Despite the presumed importance of complementary therapies for these conditions, studies of care for back and neck pain have not gathered information about the use of complementary therapies. Methods Our nationally representative survey sampled 2055 adults. The survey gathered detailed information about medical conditions, conventional and complementary therapies used to treat those conditions, and the perceived helpfulness of those therapies. Results We found that of those reporting back or neck pain in the last 12 months, 37% had seen a conventional provider and 54% had used complementary therapies to treat their condition. Chiropractic, massage, and relaxation techniques were the most commonly used complementary treatments for back or neck pain (20%, 14%, and 12%, respectively, of those with back or neck pain). Chiropractic, massage, and relaxation techniques were rated as "very helpful" for back or neck pain among users (61%, 65%, and 43%, respectively), whereas conventional providers were rated as "very helpful" by 27% of users. We estimate that nearly one-third of all complementary provider visits in 1997 (203 million of 629 million) were made specifically for the treatment of back or neck pain. Conclusions Chiropractic, massage, relaxation techniques, and other complementary methods all play an important role in the care of patients with back or neck pain. Treatment for back and neck pain was responsible for a large proportion of all complementary provider visits made in 1997. The frequent use and perceived helpfulness of commonly used complementary methods for these conditions warrant further investigation.

The discovery of the! -helix and" -sheet, the principal structural features of proteins

Abstract: PNAS papers by Linus Pauling, Robert Corey, and Herman Branson in the spring of 1951 proposed the α-helix and the β-sheet, now known to form the backbones of tens of thousands of proteins. They deduced these fundamental building blocks from properties of small molecules, known both from crystal structures and from Pauling's resonance theory of chemical bonding that predicted planar peptide groups. Earlier attempts by others to build models for protein helices had failed both by including nonplanar peptides and by insisting on helices with an integral number of units per turn. In major respects, the Pauling–Corey–Branson models were astoundingly correct, including bond lengths that were not surpassed in accuracy for >40 years. However, they did not consider the hand of the helix or the possibility of bent sheets. They also proposed structures and functions that have not been found, including the γ-helix.

Use of Genetic Profiling in Leprosy to Discriminate Clinical Forms of the Disease

Abstract: Leprosy presents as a clinical and immunological spectrum of disease. With the use of gene expression profiling, we observed that a distinction in gene expression correlates with and accurately classifies the clinical form of the disease. Genes belonging to the leukocyte immunoglobulin-like receptor (LIR) family were significantly up-regulated in lesions of lepromatous patients suffering from the disseminated form of the infection. In functional studies, LIR-7 suppressed innate host defense mechanisms by shifting monocyte production from interleukin-12 toward interleukin-10 and by blocking antimicrobial activity triggered by Toll-like receptors. Gene expression profiles may be useful in defining clinical forms of disease and providing insights into the regulation of immune responses to pathogens.

Complementary and alternative medical therapies: implications for medical education.

Abstract: Increased use of complementary and alternative medicine (CAM) has made it imperative that these topics be included in medical education from the preclinical years through residency and beyond. There has been progress in this direction in recent years, with a steady increase in the number of medical schools that include CAM therapies in their curricula. There remains, however, a lack of clear goals and concrete suggestions for implementing these changes. This article examines the questions that arise when medical educators consider how to incorporate CAM therapies as an integral part of the medical curriculum. It offers practical suggestions for finding time in an already packed curriculum, getting started, including faculty and students in the process, and sustaining the initiative with the necessary administrative and institutional support.

Seeded conversion of recombinant prion protein to a disulfide-bonded oligomer by a reduction-oxidation process.

Abstract: The infectious form of prion protein, PrPSc, self-propagates by its conversion of the normal, cellular prion protein molecule PrPC to another PrPSc molecule. It has not yet been demonstrated that recombinant prion protein can convert prion protein molecules from PrPC to PrPSc. Here we show that recombinant hamster prion protein is converted to a second form, PrPRDX, by a redox process in vitro and that this PrPRDX form seeds the conversion of other PrPC molecules to the PrPRDX form. The converted form shows properties of oligomerization and seeded conversion that are characteristic of PrPSc. We also find that the oligomerization can be reversed in vitro. X-ray fiber diffraction suggests an amyloid-like structure for the oligomerized prion protein. A domain-swapping model involving intermolecular disulfide bonds can account for the stability and coexistence of two molecular forms of prion protein and the capacity of the second form for self-propagation.

Sharing publication-related data and materials: responsibilities of authorship in the life sciences.

Abstract: Thomas R. Cech, (Chair), Howard Hughes Medical Institute, Chevy Chase, Maryland Sean R. Eddy, Howard Hughes Medical Institute; Washington University, St. Louis, Missouri David Eisenberg, Howard Hughes Medical Institute; University of California, Los Angeles Karen Hersey, Massachusetts Institute of Technology, Cambridge Steven H. Holtzman, Infinity Pharmaceuticals, Inc., Boston, Massachusetts George H. Poste, Health Technology Networks, Gilbertsville, Pennsylvania Natasha V. Raikhel, University of California, Riverside Richard H. Scheller, Genentech, Inc., South San Francisco, California David B. Singer, GeneSoft, Inc., South San Francisco, California Mary C. Waltham, Independent Publishing Consultant, Princeton, New Jersey

Inference of protein function and protein linkages in Mycobacterium tuberculosis based on prokaryotic genome organization: a combined computational approach

Abstract: The genome of Mycobacterium tuberculosis was analyzed using recently developed computational approaches to infer protein function and protein linkages. We evaluated and employed a method to infer genes likely to belong to the same operon, as judged by the nucleotide distance between genes in the same genomic orientation, and combined this method with those of the Rosetta Stone, Phylogenetic Profile and conserved Gene Neighbor computational methods for the inference of protein function.

Crystal structures of a pantothenate synthetase from M. tuberculosis and its complexes with substrates and a reaction intermediate

Abstract: Pantothenate biosynthesis is essential for the virulence of Mycobacterium tuberculosis, and this pathway thus presents potential drug targets against tuberculosis. We determined the crystal structure of pantothenate synthetase (PS) from M. tuberculosis, and its complexes with AMPCPP, pantoate, and a reaction intermediate, pantoyl adenylate, with resolutions from 1.6 to 2 Å. PS catalyzes the ATP-dependent condensation of pantoate and β-alanine to form pantothenate. Its structure reveals a dimer, and each subunit has two domains with tight association between domains. The active-site cavity is on the N-terminal domain, partially covered by the C-terminal domain. One wall of the active site cavity is flexible, which allows the bulky AMPCPP to diffuse into the active site to nearly full occupancy when crystals are soaked in solutions containing AMPCPP. Crystal structures of the complexes with AMPCPP and pantoate indicate that the enzyme binds ATP and pantoate tightly in the active site, and brings the carboxyl oxygen of pantoate near the α-phosphorus atom of ATP for an in-line nucleophilic attack. When crystals were soaked with, or grown in the presence of, both ATP and pantoate, a reaction intermediate, pantoyl adenylate, is found in the active site. The flexible wall of the active site cavity becomes ordered when the intermediate is in the active site, thus protecting it from being hydrolyzed. Binding of β-alanine can occur only after pantoyl adenylate is formed inside the active site cavity. The tight binding of the intermediate pantoyl adenylate suggests that nonreactive analogs of pantoyl adenylate may be inhibitors of the PS enzyme with high affinity and specificity.

Visualization and interpretation of protein networks in Mycobacterium tuberculosis based on hierarchical clustering of genome-wide functional linkage maps.

Abstract: Genome-wide functional linkages among proteins in cellular complexes and metabolic pathways can be inferred from high throughput experimentation, such as DNA microarrays, or from bioinformatic analyses. Here we describe a method for the visualization and interpretation of genome-wide functional linkages inferred by the Rosetta Stone, Phylogenetic Profile, Operon and Conserved Gene Neighbor computational methods. This method involves the construction of a genome-wide functional linkage map, where each significant functional linkage between a pair of proteins is displayed on a two-dimensional scatter-plot, organized according to the order of genes along the chromosome. Subsequent hierarchical clustering of the map reveals clusters of genes with similar functional linkage profiles and facilitates the inference of protein function and the discovery of functionally linked gene clusters throughout the genome. We illustrate this method by applying it to the genome of the pathogenic bacterium Mycobacterium tuberculosis, assigning cellular functions to previously uncharacterized proteins involved in cell wall biosynthesis, signal transduction, chaperone activity, energy metabolism and polysaccharide biosynthesis.

The oligomerization and ligand-binding properties of Sm-like archaeal proteins (SmAPs)

Abstract: Excision of noncoding regions (introns) is a vital step in the maturation of precursor mRNAs. Most eukaryotic protein-coding genes contain multiple introns (Long et al. 1995), and thus high-fidelity pre-mRNA processing is essential to ensure production of mature mRNAs with correctly registered exons. The simultaneous excision of introns and splicing of exons in eukaryotic pre-mRNA is catalyzed by a transiently stable assembly of five small nuclear ribonucleoproteins (snRNPs). This large assembly of uridine-rich snRNPs (U snRNPs) is known as the spliceosome, and at various stages in its catalytic cycle it consists of the U1, U2, U4/U6, and U5 snRNPs (Yu et al. 1999). Five small nuclear RNAs (snRNAs) and at least 80 proteins are contained within the spliceosome (Burge et al. 1999), making it roughly the same size as the ribosome (sedimentation coefficient of ~60S; Muller et al. 1998); furthermore, assembly of U snRNPs into spliceosomes is likely to be independent of pre-mRNA binding, as suggested by recent isolation of a novel U1•U2•U4/U6•U5 penta-snRNP devoid of mRNA (Stevens et al. 2002). Extensive biochemical and genetic data have shown that a key step in snRNP assembly is stepwise binding of seven cytoplasmic Sm proteins to exported snRNAs (Will and Luhrmann 2001). Each U snRNP is a complex formed from an ~110–180-nucleotide (nt) snRNA and two classes of proteins: (1) snRNP-specific proteins that confer snRNP-specific functions (e.g., U1A protein of U1 snRNPs) and (2) the Sm or Sm-like (Lsm) proteins that are common to each snRNP core (Will and Luhrmann 1997). The snRNAs contain a single Sm or Lsm binding site with the uridine-rich consensus sequence PuAU~4–6GPu (Pu = purine). However, specificity for this sequence is not stringent and there can be redundancy in Sm-snRNA binding (Jones and Guthrie 1990). The Sm sites are predicted to be single-stranded RNA regions flanked by stem-loop structures (Burge et al. 1999; Yu et al. 1999). Sm binding is highly sensitive to modifications of the flanking stem-loops and the Sm site of a given snRNA, and varies from one snRNA to another (Jarmolowski and Mattaj 1993). Sm-snRNA binding also may be modulated by interactions between certain Sm proteins and the survival of motor neurons (SMN) protein complex (Selenko et al. 2001), and by symmetric dimethylation of arginine residues in some of the RG dipeptide repeats of Sm (Brahms et al. 2000; Friesen et al. 2001; Meister et al. 2001) and Lsm (Brahms et al. 2001) proteins by a putative “methylosome” (Friesen et al. 2002). In eukaryotes, Sm D1•D2 and E•F•G heteromers simultaneously bind to snRNA to yield a “subcore” snRNP complex (Raker et al. 1996, 1999; Will and Luhrmann 2001). The final component to join the Sm complex is the B/B′•D3 heterodimer, and this triggers hypermethylation of the 5′ m7G cap of snRNA to a trimethylated guanosine cap (m3G). The m3G cap and the snRNA•Sm core complex form a bipartite nuclear localization signal that results in transit of the snRNP core to the nucleus, where association of various snRNP-specific proteins completes the assembly process. The importance of Sm proteins in RNP assemblies is underscored by their phylogenetic distribution: In addition to the canonical Sm and Lsm proteins found in eukaryotes ranging from yeast to humans, an Sm-like archaeal protein (“SmAP”) family has been discovered (Salgado-Garrido et al. 1999; Mura et al. 2001). The recent demonstration that the E. coli bacteriophage host factor Hfq is an Sm-like protein provides the first example of a eubacterial Sm protein (Moller et al. 2002; Zhang et al. 2002). These results imply fundamental roles for Sm proteins in the early evolution of RNA metabolism. Sm proteins probably mediate critical RNA-RNA, RNA-protein, and protein-protein interactions in snRNP cores. The vast network of protein-protein interactions in which Sm proteins participate was recently suggested by genome-wide two-hybrid screens of yeast Lsm proteins (Fromont-Racine et al. 2000). Sm proteins have a tendency to associate into cyclic oligomers. Prompted by biochemical and genetic data, electron microscopic (EM) investigations of U snRNP particles revealed the “doughnut-shaped” ultrastructure of Sm and Lsm cores (Kastner et al. 1990; Achsel et al. 1999). The realization that Sm and Lsm proteins occur in groups of at least seven paralogs within the genome of a given organism suggests that snRNP cores are formed from Sm heteroheptamers, and two recent results verify this. First, Stark et al. (2001) reconstructed a 10 Å-resolution map of the U1 snRNP by cryo-EM and found that a model of the Sm heptamer could be docked into the ring-shaped body of the snRNP. Next, the in vivo stoichiometry of Sm proteins in yeast spliceosomal snRNPs was determined by a differential tag/pull-down assay, showing that the snRNP core domain contains a single copy of each of the seven Sm proteins (Walke et al. 2001). Stable subheptameric Sm complexes have been suggested as intermediates along the snRNP core assembly pathway (e.g., a D1•D2•E•F•G complex that binds snRNA; Raker et al. 1996), and ultracentrifugation and EM show that some of these oligomers can form ring-like structures that resemble intact, heptameric snRNP cores (e.g., a (E•F•G)2 hexamer in Plessel et al. 1997). Such findings emphasize the importance of cyclic Sm heptamers in the snRNP core, and raise the possibility of other oligomeric states. There is no atomic-resolution structure of a eukaryotic snRNP core. Nonetheless, the crystal structures of Sm-like archaeal proteins from Afu (Toro et al. 2001), Pae (Mura et al. 2001), and Mth (Collins et al. 2001) reveal a cyclic Sm homoheptamer and provide a model for snRNA binding in the snRNP core. Sm monomers fold as strongly bent, five-stranded antiparallel β-sheets (Kambach et al. 1999a) and form toroidal heptamers that surround a conserved cationic pore. The inner surface of this pore appears to be the oligouridine-binding site. The similarity between SmAP1 monomer and dimer structures and the nearly identical human Sm D1•D2 and D3•B heterodimers (Kambach et al. 1999b) supports SmAP-based models for the heptameric snRNP core.

Structure and assembly of an augmented Sm-like archaeal protein 14-mer

Abstract: To better understand the roles of Sm proteins in forming the cores of many RNA-processing ribonucleoproteins, we determined the crystal structure of an atypical Sm-like archaeal protein (SmAP3) in which the conserved Sm domain is augmented by a previously uncharacterized, mixed alpha/beta C-terminal domain. The structure reveals an unexpected SmAP3 14-mer that is perforated by a cylindrical pore and is bound to 14 cadmium (Cd(2+)) ions. Individual heptamers adopt either "apical" or "equatorial" conformations that chelate Cd(2+) differently. SmAP3 forms supraheptameric oligomers (SmAP3)(n = 7,14,28) in solution, and assembly of the asymmetric 14-mer is modulated by differential divalent cation-binding in apical and equatorial subunits. Phylogenetic and sequence analyses substantiate SmAP3s as a unique subset of SmAPs. These results distinguish SmAP3s from other Sm proteins and provide a model for the structure and properties of Sm proteins >100 residues in length, e.g., several human Sm proteins.

Role of the C-Terminal 28 Residues of β2-Microglobulin in Amyloid Fibril Formation†

Abstract: Beta2microglobulin (beta2m) is the major protein component of the fibrillar amyloid deposits isolated from patients diagnosed with dialysis-related amyloidosis (DRA). While investigating the molecular mechanism of amyloid fibril formation by beta2m, we found that the beta2m C-terminal peptide of 28 residues (cbeta2m) itself forms amyloid fibrils. When viewed by electron microscopy, cbeta2m aggregates appear as elongated unbranched fibers, the morphology typical for amyloids. Cbeta2m fibers stain with Congo red and show apple-green birefringence in polarized light, characteristic of amyloids. The observation that the beta2m C-terminal fragment readily forms amyloid fibrils implies that beta2m amyloid fibril formation proceeds via interactions of amyloid forming segments, which become exposed when the beta2m subunit is partially unfolded.

Heterogeneity of molecular targets on clonal cancer lines derived from a novel hormone-refractory prostate cancer tumor system.

Abstract: OBJECTIVE We recently described a new hormone refractory prostate cancer cell line, CL1, derived from LNCaP via in vitro androgen deprivation. To study gene expression during prostate cancer progression and to identify molecular targets for therapy, a pure clonal tumor system was generated. METHODS Limiting dilution of CL1 stably transfected with a green fluorescent protein, generated 35 single-cell clones, which were expanded into stable cell lines. In vitro responses to various therapeutic modalities were assessed in each clone. Gene expression was determined using reverse transcriptase-polymerase chain reaction and oligonucleotide microarrays. In vivo biology was assessed following orthotopic injection into intact and castrated severe combined immunodeficient mice. RESULTS In vitro, all clones demonstrated similar resistance to traditional therapeutic efforts including chemotherapy and radiation therapy, but differential sensitivity to cell-mediated cytotoxicity. The clones demonstrated differential gene expression relative to each other and to the parental CL1 and LNCaP cell lines. Following orthotopic injection into mice, three distinct growth patterns were observed: fast growth with widespread metastasis; slower grower with widespread metastasis; and no tumor formation. Using oligonucleotide microarrays, several genes were identified as differentially expressed between the most aggressive and the nontumorigenic clone. CONCLUSIONS We have described a novel fluorescent-labeled clonal hormone refractory prostate cancer tumor system that exhibited marked heterogeneity in its response to various therapeutic modalities, gene expression, and in vivo biology. Our data suggests that given the marked clonal heterogeneity, multi-modality approaches directed against multiple molecular targets rather than single agent therapy will be necessary to adequately eradicate the entire malignant cell population. Clonal tumor lines may allow more accurate examination of molecular pathways involved in tumor progression and resistance to treatment. Prostate 55: 299–307, 2003. © 2003 Wiley-Liss, Inc.

Therapeutic Massage Intervention for Hospitalized Patients with Cancer: A Pilot Study

Abstract: F orty-two (42) percent of Americans use some form of alternative medicine, spending 21.2 billion dollars annually,1 and one of the most commonly sought alternative and complementary medicine (ACM) therapies is therapeutic massage, which was used by an estimated 11 percent of the U.S. adult population in 1998. In that year, adults made an estimated 114 million office visits to receive massage treatments.2 Massage has been used as a therapeutic intervention for a variety of illnesses for thousands of years. The Asian roots of massage go back a t lea s t to 1000 BC and so do the or ig in s o f Ayurvedic medicine. Descriptions of massage appear in the ancient medical texts of India, China, Japan, and Tibet. The European roots of massage can be traced back to the seventh century BC. Massage was associated with the cures offered at the temples of Aesculepius and was described in the writings of Hippocrates. Massage has been used to promote relaxation and relieve pain and has been suggested as a useful adjunctive treatment for symptom control for patients at the end of life. Pain is one of the most common symptoms experienced by dying patients. More than 40 percent of patients’ families reported that patients experienced severe pain in the last 3 days of life.3 Others have reported that 60 percent of patients who have cancer have pain.4,5 In many cases (42 percent), pain was inadequately treated in patients with cancer.6 Nearly 80 percent of hospitalized patients have reported pain, while less than half had any mention of pain noted in progress notes by their doctors.7 Even in palliative medicine and in hospice settings, 64–88 percent of patients had inadequately relieved pain, and the most severe symptoms occurred 2 days prior to death.8 During the last 7 days of life, narcotic usage increased significantly. Although symptoms of pain and nausea were reduced, drowsiness worsened substantially and resulted in worse symptom distress scores. Between 15 and 20 percent of patients needed treatment for pain, requiring complete sedation to obtain relief.9 Caregivers often experience symptoms of anxiety and sadness near the end of a patient’s life. Grief phenomena have been welldescribed. Compared to their experience 6 months following death, feelings of sadness are most intrusive in the 6 weeks following the patient’s death as are symptoms such as tearfulness, depression, and anxiety.10 Physical symptoms, such as pain, are most prominent at 6 weeks as well. Small studies have suggested that interventions that provide support to caregivers can improve their satisfaction with care as well as decreasing their physical and emotional stress.11 Only a few studies on the use of massage at the end of life have been reported. In a small study of massage given to patients in a hospice, investigators reported that slow-stroke back massage resulted in changes in vital signs, suggesting improved relaxation.12 Other studies have indicated that massage may be useful in managing cancer pain.13,14 Studies on other populations have suggested a number of potential benefits of massage that are relevant to patients with metastatic cancer. For example, massage has been shown to promote relaxation, reduce anxiety and depression, and improve sleep patterns.15–18 In addition, other studies have indicated that massage may reduce patients’ experience of pain ,13 ,14 ,19–22 ease breathing,23 faci l i tate weight gain,24–26 and increase alertness.27 Finally, data indicate that giving as well as receiving massage may reduce anxiety and depression,28 suggesting that caregivers may benefit from providing massage to patients. In this pilot study, we provided daily massage to hospitalized patients with metastatic or end stage lung or gastrointestinal (GI) cancer. Hospital admissions were screened daily to identify eligible patients. Patients received daily therapeutic massage and family caregivers were also instructed in the use of massage during hospitalization. Data were collected from massage therapists’ detailed documentation and from patients’ daily questionnaires about their experiences with the massage therapy. We also collected data from medical records via chart reviews and interviews with patients’ nurses and physicians.

Structure of superoxide dismutase from Pyrobaculum aerophilum presents a challenging case in molecular replacement with multiple molecules, pseudo‐symmetry and twinning

Abstract: The crystal structure of superoxide dismutase from the hyperthermophilic crenarchaeon Pyrobaculum aerophilum was determined by molecular replacement at 1.8 A resolution. The structure determination was made especially challenging by the large number of molecules (24) in the asymmetric unit, the presence of a pseudo-crystallographic twofold operator close to a twinning operator and the inability to detect twinning by conventional means. Molecular replacement proceeded at low resolution in pseudo (apparent) space group P3(2)12 and was facilitated by examination of the self-rotation function and native Patterson map. Refinement, however, stalled at an R factor of 40% when high-resolution data were included. Expanding to the lower symmetry space group P3(2) decreased R (to 22%) and R(free) (to 26%), but not by as much as expected for the quality of data. Finally, despite the apparent lack of evidence from conventional twinning tests [i.e. plots of the second moment of I and N(Z) distributions], a twinning operator was included in the refinement, lowering R and R(free) to 16.2 and 21.7%, respectively. The early detection of twinning appears to have been masked by a deviation in the expected intensity distribution caused by the presence of non-crystallographic translational symmetry. These findings suggest the importance of testing twinning operators in cases where pseudo-translational symmetry can explain negative results from conventional twinning tests. The structure reveals a tetrameric assembly with 222 symmetry, similar to superoxide dismutase structures from other organisms. The current structural model represents the metal-free state of the enzyme.

Visit time as a framework for reimbursement: time spent with chiropractors and acupuncturists.

Abstract: Context Visit length is an important component of physician payment systems. As use and insurance coverage of complementary and alternative medicine (CAM) increases, equitable reimbursement strategies for CAM providers will be needed. Little information is available about the time CAM providers spend with patients. Objective To describe the length of visit and determinants of visit time to chiropractors and acupuncturists. Design Survey of CAM practitioners that collected information on providers (e.g., socio-demographics, practice patterns, training) and professional visit encounters (e.g., patient demographics, payment source, problem acuity, visit length, procedures performed). Subjects Random sample of 130 licensed chiropractors and 133 licensed acupuncturists surveyed in 1998-1999, each from one Western and one Northeastern US state. Measures Patient, provider, and visit factors associated with visit duration were analyzed using weighted linear regression. Results Data were available on 2550 chiropractic and 2561 acupuncture visits. Mean chiropractic visit length was 21.5 minutes (SE = 0.8). Mean acupuncture visit length was 56.6 minutes (SE = 0.7) In both professions, new patient visits took longer, while visits for wellness or chronic problems were shorter. Preventive counseling by the chiropractor increased visit time, as did use of manual (vs. instrument) spinal manipulation, soft tissue techniques and physiotherapeutics. Acupuncture visits were shorter when specialized needling techniques (e.g. auricular or scalp acupuncture) were used, and longer with other adjunctive Asian therapies (e.g., cupping or magnets). Self-paid acupuncture visits were longer, as were visits with acupuncturists who had less practice experience or fewer years of training. Conclusions For both chiropractic and acupuncture, certain visit factors, provider characteristics, and procedures increase visit length, many of which parallel those observed in conventional medical settings. Thus, a similar time-based payment scheme may be a reasonable starting point for developing methods for reimbursing CAM providers.

1.1 angstrom resolution crystal structure of a secreted mycobacterium tuberculosis disulfide oxidoreductase homologous to e. coli dsbe: implications for functions

Abstract: PDB ID : 1LU4 Title : 1.1 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF A SECRETED MYCOBACTERIUM TUBERCULOSIS DISULFIDE OXIDOREDUCTASE HOMOLOGOUS TO E. COLI DSBE: IMPLICATIONS FOR FUNCTIONS Authors : Goulding, C.W.; Apostol, M.I.; Gleiter, S.; Parseghian, A.; Bardwell, J.; Gennaro, M.; Eisenberg, D.; TB Structural Genomics Consortium (TBSGC) Deposited on : 2002-05-21 Resolution : 1.12 Å(reported)