Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Loss of vacuolar H+-ATPase (V-ATPase) activity in yeast generates an iron deprivation signal that is moderated by induction of the peroxiredoxin TSA2.

Vacuolar H(+)-ATPases (V-ATPases) acidify intracellular organelles and help to regulate overall cellular pH. Yeast vma mutants lack V-ATPase activity and allow exploration of connections between cellular pH, iron, and redox homeostasis common to all eukaryotes. A previous microarray study in a vma mutant demonstrated up-regulation of multiple iron uptake genes under control of Aft1p (the iron regulon) and only one antioxidant gene, the peroxiredoxin TSA2 (Milgrom, E., Diab, H., Middleton, F., and Kane, P. M. (2007) Loss of vacuolar proton-translocating ATPase activity in yeast results in chronic oxidative stress. J. Biol. Chem. 282, 7125-7136). Fluorescent biosensors placing GFP under transcriptional control of either an Aft1-dependent promoter (P(FIT2)-GFP) or the TSA2 promoter (P(TSA2)-GFP) were constructed to monitor transcriptional signaling. Both biosensors were up-regulated in the vma2Δ mutant, and acute V-ATPase inhibition with concanamycin A induced coordinate up-regulation from both promoters. PTSA2-GFP induction was Yap1p-dependent, indicating an oxidative stress signal. Total cell iron measurements indicate that the vma2Δ mutant is iron-replete, despite up-regulation of the iron regulon. Acetic acid up-regulated P(FIT2)-GFP expression in wild-type cells, suggesting that loss of pH control contributes to an iron deficiency signal in the mutant. Iron supplementation significantly decreased P(FIT2)-GFP expression and, surprisingly, restored P(TSA2)-GFP to wild-type levels. A tsa2Δ mutation induced both nuclear localization of Aft1p and P(FIT2)-GFP expression. The data suggest a novel function for Tsa2p as a negative regulator of Aft1p-driven transcription, which is induced in V-ATPase mutants to limit transcription of the iron regulon. This represents a new mechanism bridging the antioxidant and iron-regulatory pathways that is intimately linked to pH homeostasis.

Administrative outcomes five years after opening an acute palliative care unit at a comprehensive cancer center.

PURPOSE: We examined administrative outcomes after opening an oncology acute palliative care unit (APCU), to determine attainment of administrative targets related to the unit's function of acute palliation. METHODS: We retrospectively reviewed the administrative database for our APCU for the 5 years following its opening in 2003. Data were abstracted on demographic information, as well as source of admission, primary reason for admission, discharge destination, inpatient death rate, and length of stay. Linear regression and the Cochran-Armitage trend test were used for analysis. In keeping with targets set at the unit's opening, our primary hypotheses were that outpatient admissions, admissions for symptom control, and discharges home would increase over the study period; secondary hypotheses were that length of stay and inpatient death rate would decrease. RESULTS: There were 1748 admissions during the study period: the median age was 64, 54% were women, and the most common cancer sites were gastrointestinal (24%), lung (20%), and gynecologic (13%). There were significant changes for all primary endpoints: outpatient admissions increased from 47% to 70% (p < 0.0001), admissions for symptom control increased from 42% to 75% (p < 0.0001), and discharges home increased from 18% to 39% (p < 0.0001). The secondary end points of death rate and length of stay decreased from 65% to 40% (p < 0.0001) and 12 to 11 days (p = 0.54), respectively. CONCLUSION: Setting and adhering to administrative targets for an APCU is possible with appropriate admission criteria, adequate community resources, and education of patients, families and health professionals regarding the model of care.

The effectiveness of hydrotherapy in the management of fibromyalgia syndrome: a systematic review.

Hydrotherapy is often used in the treatment of fibromyalgia syndrome (FMS), however there has been limited evaluation of its effectiveness. The aim of this systematic review was therefore to examine the effectiveness of hydrotherapy in the management of FMS. AMED, BNI, CINAHL, The Cochrane Library, EMBASE, MEDLINE, ProQuest, PubMed, Science Direct and Web of Science were searched (1990-July 2006). Key words used 'fibromyalgia' and 'hydrotherapy', 'balneotherapy', 'aqua therapy', 'pool therapy', 'water therapy', 'swimming', 'hydrogalvanic', 'spa therapy', 'physiotherapy', 'physical therapy' and 'rehabilitation'. Searches were supplemented with hand searches of selected journals. Randomised controlled trials (RCTs) were assessed for methodological quality using the van Tulder scale. Ten RCTs met the inclusion criteria. Mean methodological quality was 4.5/9 on the van Tulder scale. Positive outcomes were reported for pain, health-status and tender point count. There is strong evidence for the use of hydrotherapy in the management of FMS.

Structural and functional separation of the N- and C-terminal domains of the yeast V-ATPase subunit H.

The H subunit of the yeast V-ATPase is an extended structure with two relatively independent domains, an N-terminal domain consisting of amino acids 1-348 and a C-terminal domain consisting of amino acids 352-478. We have expressed these two domains independently and together in a yeast strain lacking the H subunit (vma13Delta mutant). The N-terminal domain partially complements the growth defects of the mutant and supports approximately 25% of the wild-type Mg(2+)-dependent ATPase activity in isolated vacuolar vesicles, but surprisingly, this activity is both largely concanamycin-insensitive and uncoupled from proton transport. The C-terminal domain does not complement the growth defects, and supports no ATP hydrolysis or proton transport, even though it is recruited to the vacuolar membrane. Expression of both domains in a vma13Delta strain gives better complementation than either fragment alone and results in higher concanamycin-sensitive ATPase activity and ATP-driven proton pumping than the N-terminal domain alone. Thus, the two domains make complementary contributions to structural and functional coupling of the peripheral V(1) and membrane V(o) sectors of the V-ATPase, but this coupling does not require that they be joined covalently. The N-terminal domain alone is sufficient for activation of ATP hydrolysis in V(1), but the C-terminal domain is essential for proper communication between the V(1) and V(o) sectors.