Systematic review and meta-analysis investigating the efficacy and safety of probiotics in people with cancer.

BACKGROUND/OBJECTIVES: Probiotics are living microorganisms that confer a health benefit on the host when administered. This systematic review and meta-analysis investigates the efficacy and safety of probiotics in adult and paediatric patients diagnosed with cancer. METHODS: A systematic review and meta-analysis was undertaken (PROSPERO registration: CRD42016050252). Randomised controlled trials (RCT), identified through screening multiple databases were included for analysis of efficacy. Non-randomised controlled trials and case reports were included for safety analysis. Outcomes included the reduction in the incidence and severity of diarrhoea, and adverse events. Where possible, data were combined for meta-analysis using a random-effects model. Planned subgroup analyses were not possible through marked heterogeneity of study characteristics. RESULTS: Twenty one studies (N = 2982 participants) were included for assessment of efficacy. Probiotics may reduce the incidence of diarrhoea in patients with cancer [odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.34-0.78, 95% prediction interval (PI) 0.3-0.92, I-sq 36.9%, 5 studies] and the duration of pyrexia [standardised mean difference 0.39 days, 95% CI 0.35-0.43, I-sq 0.01%, 5 studies]. Twenty five studies (N = 2242) were included in the safety analysis. Five case reports showed probiotic-related bacteraemia/fungaemia/positive blood cultures. Definitions and reporting of adverse events were variable and inconsistent. CONCLUSIONS: There remain insufficient studies to assess the true effect of probiotics in people with cancer. Meta-analysis suggests probiotics may be beneficial but further studies are still required. Improved reporting of outcomes and adverse events in clinical trials are required to improve accuracy and confidence of conclusions drawn in future updates.

Feasibility of early physical therapy for dizziness after a sports-related concussion: A randomized clinical trial.

The purpose of this study was to (a) assess the feasibility of recruitment/retention of participants, protocol/resource management, and participant safety, and (b) estimate the size of the effect between the experimental and control groups. This was a feasibility study conducted as a prospective pilot double-blind randomized clinical trial. Subjects aged 10-23 years old with acute concussion and dizziness were enrolled from sports medicine centers. Forty-one participants were randomized into treatment and were seen for physical therapy beginning at 10 days post-concussion. Subjects in the experimental group received individually tailored, pragmatically delivered progressive interventions. Subjects in the control received prescriptive sham to minimally progressive interventions. The two primary outcomes were medical clearance for return-to-play and symptomatic recovery. The median number of days to medical clearance for the experimental group was 15.5 and for the control was 26. The median number of days to symptomatic recovery was 13.5 for the experimental group and was 17 for the control. According to Cox proportional hazards regression for time to medical release for return-to-play, the experimental group demonstrated a hazard ratio of 2.91 (95% CI: 1.01, 8.43) compared to the control. For time-to-symptomatic recovery, those in the experimental group demonstrated a hazard ratio of 1.99 (95% CI: 0.95, 4.15) compared to the control. The results indicate that it is feasible and safe to complete this type of intervention study. The results provide strong support for the allocation of resources to conduct well-powered randomized clinical trials of this intervention.

Docosahexaenoic Acid and Periodontitis in Adults: A Randomized Controlled Trial.

Periodontitis is a common chronic inflammatory disease initiated by bacteria, resulting in bone resorption, tooth loss, and systemic inflammation. Long-chain omega-3 fatty acids such as docosahexaenoic acid (DHA) reduce periodontitis in animals. We aimed to determine whether DHA supplementation with low-dose aspirin would reduce periodontitis in humans. We conducted a double-blind placebo-controlled parallel trial lasting 3 mo. Fifty-five adults with moderate periodontitis were randomized to 2,000 mg of DHA or identical soy/corn oil capsules. All participants received 81 mg of aspirin but received no other treatments. We analyzed the primary outcome of per-pocket change in pocket depth using mixed models among teeth with pocket depth ≥5 mm. Secondary outcomes assessed with generalized estimating equations included gingival index, plaque index, and bleeding on probing. Gingival crevicular fluid samples were analyzed for changes in high-sensitivity C-reactive protein (hsCRP) and interleukins 6 and 1ß (IL-6 and IL-1ß). Plasma was analyzed for changes in systemic inflammatory markers, including hsCRP. We confirmed adherence with erythrocyte fatty acid measurement. Forty-six participants completed the trial. While similar at baseline, the proportion of DHA in red blood cell plasma membranes increased from 3.6% ± 0.9% to 6.2% ± 1.6% in the intervention group but did not change among controls. DHA supplementation decreased mean pocket depth (-0.29 ± 0.13; p = .03) and gingival index (-0.26 ± 0.13; p = .04). Plaque index and bleeding on probing did not change. Significant adjusted differences were found between DHA and control for both gingival crevicular fluid hsCRP (-5.3 ng/mL, standard error [SE] = 2.4, p = .03) and IL-1ß (-20.1 pg/mL, SE = 8.2, p = .02) but not IL-6 (0.02 pg/mL, SE = 0.71, p = .98) or systemic hsCRP (-1.19 mg/L, SE = 0.90, p = .20). In this randomized controlled trial, aspirin-triggered DHA supplementation significantly improved periodontal outcomes in people with periodontitis, indicating its potential therapeutic efficacy (clinicaltrials.gov NCT01976806).

The efficacy and safety of probiotics in people with cancer: a systematic review.

BACKGROUND: Probiotics are living microorganisms that are generally thought of as being beneficial to the recipient. They have been shown to be effective in people with acute infectious diarrhoea, and cost-effective in antibiotic-associated diarrhoea. Probiotics may have a role in people with cancer, as various cancer treatments often lead to diarrhoea. However, as people with cancer are often immunocompromised, it is important to assess for adverse events (AEs) such as infection, which could potentially be a consequence of deliberate ingestion of living microorganisms. DESIGN: A systematic review was carried out to collect, analyse and synthesise all available data on the efficacy and safety of probiotics in people with cancer (PROSPERO registration: CRD42012003454). Randomised, controlled trials, identified through screening multiple databases and grey literature, were included for analysing efficacy, while all studies were included for the analysis of safety of probiotics. Primary outcomes were the reduction in duration, severity and incidence of antibiotic-associated diarrhoea and chemotherapy-associated diarrhoea, and AEs, especially probiotic-associated infection. Where possible, data were combined for meta-analysis by a random-effects model, assessing causes of heterogeneity, including differences in strains, dosage and patient characteristics. RESULTS: Eleven studies (N = 1557 participants) were included for assessing efficacy. Results show that probiotics may reduce the severity and frequency of diarrhoea in patients with cancer and may reduce the requirement for anti-diarrhoeal medication, but more studies are needed to assess the true effect. For example comparing probiotic use to control 25 groups on effect on Common Toxicity Criteria ≥2 grade diarrhoea, odds ratio (OR) = 0.32 [95% confidence interval (CI) of 0.13-0.79; P = 0.01]. Seventeen studies (N = 1530) were included in the safety analysis. Five case reports showed probiotic-related bacteraemia/fungaemia/positive blood cultures. CONCLUSIONS: Probiotics may be a rare cause of sepsis. Further evidence needs to be collated to determine whether probiotics provide a significant overall benefit for people with cancer.

Dogs vaccinated with gentamicin-attenuated Leishmania infantum or infected with wild-type parasite can be distinguished by Western blotting.

An attenuated line of Leishmania infantum (the H-line), developed through exposure to gentamicin, has been shown to protect dogs against canine visceral leishmaniasis. A specific diagnostic test to differentiate dogs vaccinated with the attenuated line from dogs infected with L. infantum wild-type (L. infantum WT) could be a valuable tool in evaluating the effectiveness of canine vaccination. In this study, 28 healthy dogs were allocated into four groups. In Group I and Group II (eight dogs per group), dogs were immunized subcutaneously (s.c.) with L. infantum H-line, and the dogs of Group II challenged s.c. with L. infantum WT, at 2 months post-immunization. In Group III, eight animals were challenged s.c. with L. infantum WT, and four dogs of Group IV were injected s.c. with PBS. We found that sera from vaccinated dogs recognize a 21 kDa antigen of promastigotes of L. infantum H-line but not of L. infantum WT, whereas sera from unvaccinated dogs challenged with L. infantum WT, recognized a 21 kDa antigen of promastigotes of L. infantum WT but not of L. infantum H-line. Sera from dogs challenged with L. infantum WT with prior vaccination with L. infantum H-line, recognized a 21 kDa antigen of both L. infantum WT and L. infantum H-line. These results suggest that the Western blot analysis of antibodies against 21 kDa antigens of L. infantum H-line and WT may be a useful technique for distinguishing between dogs vaccinated with L. infantum H-line and dogs naturally infected with L. infantum WT.

The impact of a managed transition of care upon psychosocial characteristics and patient satisfaction in a cohort of adult survivors of childhood cancer.

OBJECTIVE: Many adult survivors of childhood cancer receive care in paediatric departments, despite national policy to transition their care to adult services. When long-term follow-up care for survivors of childhood cancer in our region moved from a paediatric to an adult environment in 2009, we prospectively assessed the impact of this change on patient satisfaction. METHODS: Questionnaire data were collected in paediatric and adult clinical environments regarding the level of satisfaction with care and potential mediators: quality of life, psychological health and social difficulties. Predictors of satisfaction and optimum longitudinal risk-based care were described using path analysis and compared with previously described models. RESULTS: There was no significant difference in satisfaction between the paediatric and adult settings. Short waiting times and increased understanding of the purpose of follow-up were significantly associated with increased satisfaction. Those with a higher perception of health problems and those that were older were more likely to not attend all of their clinic appointments. CONCLUSIONS: Within our service, transition to adult care did not impact significantly upon patient satisfaction. Shorter waits and knowing why participants were attending the clinic increased satisfaction. Joint working between adult and paediatric cancer professionals enabled adult survivors of childhood cancer to receive highly satisfactory care in adult services.

Cerebral malaria protection in mice by species-specific Plasmodium coinfection is associated with reduced CC chemokine levels in the brain.

Cerebral malaria is a major pathological complication of Plasmodium falciparum infection in humans. Epidemiological observations have suggested that the clinical evolution of P. falciparum infections may be influenced by the concurrent presence of another Plasmodium species. Infection of susceptible mouse strains with P. berghei ANKA (PbA) provides an experimental model of cerebral malaria which has been extensively used to identify different components of the immune system involved in cerebral malaria. This model has also been employed to investigate the influence of experimental mixed-Plasmodium-species infections on the expression of cerebral malaria; PbA-induced cerebral malaria is completely inhibited by the simultaneous presence of P. yoelii yoelii 17 X clone 1.1 parasites, and accumulation of CD8(+) T cells in the brain vasculature is abolished. We investigated whether brain levels of CD8(+) -T-cell-chemoattractant chemokines CCL3, CCL4 and CCL5 are reduced in these protected coinfected mice compared with PbA-infected mice. Coinfected mice were found to exhibit significantly reduced levels of all three chemokines on day 6 post-infection. This finding may contribute to the abolition of the accumulation of CD8(+) T cells in the brain vasculature and the prevention of the development of cerebral malaria in coinfected mice.

Immune responses of NIH mice infected with avirulent and virulent strains of Plasmodium chabaudi adami single and mixed infections.

An understanding of the nature of the immune response to asexual erythrocytic stages of malaria parasites will facilitate vaccine development by identifying which responses the vaccine should preferentially induce. The present study examined and compared the immune responses of NIH mice in either single or mixed infections with avirulent (DK) or virulent (DS) strains of Plasmodium chabaudi adami using the ELISA test for detecting and measurement of cytokines and antibody production. In both single and mixed infections, the study showed that both cell- and antibody-mediated responses were activated. In all experiments, an early relatively high level of IFN-gamma and IgG2a during the acute phase of the infection, and later elevation of IL-4 and IgG1, suggested that there was a sequential Th1/Th2 response. However, in the avirulent DK strain infection a stronger Th1 response was observed compared to the virulent DS strain-infection or in mixed infections. In the virulent DS infection, there was a stronger Th2 response compared to that in the DK and mixed infections. The faster proliferation rate of the virulent DS strain compared to the DK strain was also evident.

[Spatial structure and mechanism of tyrosine phenol-lyase and tryptophan indole-lyase].

The bacterial tyrosine phenol-lyase (EC 4.1.99.2) and tryptoptophan indole-lyase (EC 4.1.99.1) belong to pyridoxal-5'-phosphate dependent beta-eliminating lyases, catalysing the reversible decomposition of L-tyrosine and L-tryptophan to pyruvate, ammonia, and phenol or indole correspondingly. Data on the three dimentional structures of the holoenzymes of tyrosine phenol-lyase and tryptophan indole-lyase and several enzyme-inhibitor complexes, modeling distinct reaction stages of the beta-elimination of L-tyrosine are described in the paper and structural bases of monovalent cations influence of activity of the enzymes are discussed. The spectral and catalytic properties of the mutant enzymes were studied. The data thus obtained have allowed us to elucidate the catalytic functions of a number of amino acid residues and conclude that the acid-base properties of the catalytic groups of the enzymes under the optimal for the catalysis conditions in hydrophobic active sites of tyrosine phenol-lyase and tryptoptophan indol-lyase are different from those in water solutions. Study of the mechanisms of labilization of Calpha-proton of the bound amino acids and activation of the leaving groups of the substrates during the catalytic process has demonstrated that in certain cases concerted reaction pathways are realized instead of stepwise ones.

Aspartic acid 214 in Citrobacter freundii tyrosine phenol-lyase ensures sufficient C--H-acidity of the external aldimine intermediate and proper orientation of the cofactor at the active site.

In the X-ray structure of tyrosine phenol-lyase (TPL) Asp214 is located at H-bonding distance from the N1 atom of the cofactor. This residue has been replaced with Ala and Asn and the properties of the mutant enzymes have been studied. The substitutions result in a decrease in the cofactor affinity of about four orders of magnitude. D214A and D214N TPLs do not catalyze the decomposition of l-Tyr and 3-fluoro-l-Tyr. They decompose substrates, containing better leaving groups with rates reduced by one or two orders of magnitude. Lognormal resolution of the spectra of the mutant enzymes revealed that the N1 atom of the cofactor is deprotonated. Spectral characteristics of internal and external aldimines of the mutant TPLs and the data on their interaction with quasisubstrates demonstrate that replacements of Asp214 lead to alteration of active site conformations. The mutant enzymes do not form noticeable amounts of a quinonoid upon interaction with inhibitors, but catalyze isotope exchange of C-alpha-proton of a number of amino acids for deuterium in (2)H(2)O. The k(ex) values for the isotope exchange of l-phenylalanine and 3-fluoro-l-tyrosine are close to the k(cat) values for reacting substrates. Thus, for the mutant TPLs the stage of C-alpha-proton abstraction may be considered as a rate-limiting for the whole reaction.

Parasite-specific IgM plays a significant role in the protective immune response to asexual erythrocytic stage Plasmodium chabaudi AS infection.

A comparison of Plasmodium chabaudi AS infection in BALB/c and BALB/c IgM-deficient mice demonstrated a protective role for IgM during infection. IgM-/- mice, unlike microMT mice, display competent B cell humoral immune responses. Increased susceptibility of IgM-/- mice was demonstrated by increased mortality, an advanced ascending infection and higher peak parasitaemia, as well as enhanced anaemia and weight loss compared with wild-type mice. The recrudescent parasitaemias were also higher in the IgM-/- mice. Early specific IgM production in P. chabaudi-infected wild-type mice was followed by IgG1 and IgG2a production, while IgG1 and IgG2a production in IgM-/- mice was preceded by specific IgD production. No protective role for natural IgM against P. chabaudi AS infection was detected as passive transfer of naïve WT serum into IgM-/- mice did not alter the disease outcome or reduce parasite numbers. Passive transfer of WT antiserum, containing predominantly specific IgM, into IgM-/- mice delayed the ascending parasitaemia and reduced mortality. Similarly, coating parasitized red blood cells with WT antiserum, but not IgM-/- antisera, prior to infection also slightly delayed the ascending acute parasitaemia. Specific IgM therefore plays an important role in the limitation of parasite replication during asexual erythrocytic P. chabaudi AS infection.

Differences in the neurochemical characteristics of the cortex and striatum of mice with cerebral malaria.

Fatal murine cerebral malaria is an encephalitis and not simply a local manifestation in the brain of a systemic process. Histopathologically, murine cerebral malaria has been characterized by monocyte adherence to the endothelium of the microvasculature, activation of microglial cells, swelling of endothelial cell nuclei, microvasculature damage, and breakdown of the blood-brain barrier with cerebral oedema. Brain parenchymal cells have been proposed to be actively involved in the pathogenesis of murine cerebral malaria. We, therefore, compared the neurochemical characteristics of Plasmodium berghei ANKA-infected mice with controls to determine whether cerebral malarial infection significantly impairs specific neuronal populations. Between 6 and 7 days after infection, we found a significant loss of neurones containing substance P, with preservation of cells containing somatostatin, neuropeptide Y and calbindin in the striatum of infected mice compared with controls. In the cortex of infected mice, we found a significant reduction in the number of cells containing substance P, somatostatin and neuropeptide Y. The number of calbindin-containing neurones was unchanged. This study found significant changes in the neurochemical characteristics of the cortex and striatum of mice infected with P. berghei ANKA, which may contribute to their cerebral symptoms.

Indole can act as an extracellular signal to regulate biofilm formation of Escherichia coli and other indole-producing bacteria.

We demonstrated previously that genetic inactivation of tryptophanase is responsible for a dramatic decrease in biofilm formation in the laboratory strain Escherichia coli S17-1. In the present study, we tested whether the biochemical inhibition of tryptophanase, with the competitive inhibitor oxindolyl-L-alanine, could affect polystyrene colonization by E. coli and other indole-producing bacteria. Oxindolyl-L-alanine inhibits, in a dose-dependent manner, indole production and biofilm formation by strain S17-1 grown in Luria-Bertani (LB) medium. Supplementation with indole at physiologically relevant concentrations restores biofilm formation by strain S17-1 in the presence of oxindolyl-L-alanine and by mutant strain E. coli 3714 (S17-1 tnaA::Tn5) in LB medium. Oxindolyl-L-alanine also inhibits the adherence of S17-1 cells to polystyrene for a 3-h incubation time, but mutant strain 3714 cells are unaffected. At 0.5 mg/mL, oxindolyl-L-alanine exhibits inhibitory activity against biofilm formation in LB medium and in synthetic urine for several clinical isolates of E. coli, Klebsiella oxytoca, Citrobacter koseri, Providencia stuartii, and Morganella morganii but has no affect on indole-negative Klebsiella pneumoniae strains. In conclusion, these data suggest that indole, produced by the action of tryptophanase, is involved in polystyrene colonization by several indole-producing bacterial species. Indole may act as a signalling molecule to regulate the expression of adhesion and biofilm-promoting factors.

Inhibition of tyrosine phenol-lyase from Citrobacter freundii by 2-azatyrosine and 3-azatyrosine.

The interactions of 2-azatyrosine and 3-azatyrosine with tyrosine phenol-lyase (TPL) from Citrobacter freundii have been examined. 2-Aza-DL-tyrosine and 3-aza-DL-tyrosine were synthesized by standard methods of amino acid synthesis, while the L-isomers were prepared from 3-hydroxypyridine and 2-hydroxypyridine, respectively, with TPL (Watkins, E. B., and Phillips, R. S. (2001) Bioorg. Med. Chem. Lett. 11, 2099-2100). 3-Azatyrosine was examined as a potential transition state analogue inhibitor of TPL. Both compounds were found to be competitive inhibitors of TPL, with K(i) values of 3.4 mM and 135 microM for 3- and 2-aza-L-tyrosine, respectively. Thus, 3-azatyrosine does not act as a transition state analogue, possibly due to the lack of tetrahedral geometry at C-1. However, 2-aza-L-tyrosine is the most potent competitive inhibitor of TPL found to date. The K(i) value of 2-aza-L-tyrosine is half that of 2-aza-DL-tyrosine, indicating that the D-enantiomer is inactive as an inhibitor. Neither azatyrosine isomer was shown to be a substrate for beta-elimination, based on coupled assays with lactate dehydrogenase and on HPLC measurements. Both isomers of azatyrosine form equilibrium mixtures of external aldimine and quinonoid intermediates when they bind to TPL. However, 2-azatyrosine reacts about 10-fold faster to form a quinonoid intermediate than does 3-azatyrosine. Since 2-azatyrosine is in the zwitterion or phenolate ion form at all the pH values examined, the strong binding of this compound suggests that L-tyrosine may be bound to the active site of TPL as the phenolate anion.

Health care paraprofessionals' awareness of the symptoms of geriatric depression.

1. Depression is not part of the normal aging process. 2. It is important to increase awareness of the symptoms of geriatric depression among health care paraprofessionals. 3. If depressed elderly people are identified and appropriate referrals are made, treatment for depression is available and effective. 4. Health care paraprofessionals can be taught to recognize geriatric depression.

Physician-reviewers' perceptions and judgments about quality of care.

OBJECTIVE: Although Peer Review Organizations (PROs) and researchers rely on physicians to assess quality of care, little is known about what physicians think about when they judge quality. We sought to identify features of individual cases that are associated with physicians' judgments. DESIGN: Using 1994 Medicare data, we selected hospitalizations for 1134 beneficiaries in 42 acute care hospitals in California and Connecticut. The sample was enriched with 17 surgical and six medical complications identified using diagnosis and procedure codes. PRO physicians confirmed quality problems using a structured implicit chart review instrument and provided written open-ended comments about each case. We coded physicians' comments for factors presumed to influence judgments about quality. RESULTS: In crude and adjusted comparisons, reviewers questioned quality more frequently in cases with serious or fatal outcomes, technical mishaps and inadequate documentation. Among surgical (but not medical) patients, they were less likely to record poor quality among patients presenting with an acute illness. CONCLUSION: Factors other than the adequacy of key processes of care are associated with physician-reviewers' judgments about quality.

Intention to discontinue care among primary care patients: influence of physician behavior and process of care.

BACKGROUND: Specific elements of health care process and physician behavior have been shown to influence disenrollment decisions in HMOs, but not in outpatient settings caring for patients with diverse types of insurance coverage. OBJECTIVE: To examine whether physician behavior and process of care affect patients' intention to return to their usual health care practice. DESIGN: Cross-sectional patient survey and medical record review. SETTING: Eleven academically affiliated primary care medicine practices in the Boston area. PATIENTS: 2,782 patients with at least one visit in the preceding year. MEASUREMENT: Unwillingness to return to the usual health care practice. RESULTS: Of the 2,782 patients interviewed, 160 (5.8%) indicated they would not be willing to return. Two variables correlated significantly with unwillingness to return after adjustment for demographics, health status, health care utilization, satisfaction with physician's technical skill, site of care, and clustering of patients by provider: dissatisfaction with visit duration (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4 to 7.4) and patient reports that the physician did not listen to what the patient had to say (OR, 8.8; 95% CI, 2.5 to 30.7). In subgroup analysis, patients who were prescribed medications at their last visit but who did not receive an explanation of the purpose of the medication were more likely to be unwilling to return (OR, 4.9; 95% CI, 1.8 to 13.3). CONCLUSION: Failure of physicians to acknowledge patient concerns, provide explanations of care, and spend sufficient time with patients may contribute to patients' decisions to discontinue care at their usual site of care.

Enzymatic synthesis of aza-l-tyrosines.

Tyrosine phenol-lyase from Citrobacter freundii synthesizes 2-aza-L-tyrosine and 3-aza-L-tyrosine from 3-hydroxypyridine and 2-hydroxypyridine, respectively, and ammonium pyruvate.