The gastrointestinal status of healthy adults: a post hoc assessment of the impact of three distinct probiotics.

There is a growing awareness that supplementation with probiotic bacteria can impart beneficial effects during gastrointestinal disease, but less is known about the impact of probiotics on healthy subjects. Here, we report the outcomes of a post hoc analysis of recorded daily gastrointestinal events and bowel habits completed by healthy adults participating in a placebo-controlled, single-centre, randomised, double-blind, quadruple-arm probiotic tolerability study. Extensive screening ensured the healthy status of subjects entering the study and during a 2-week pre-intervention run-in period, a burden of gastrointestinal events (stomach pains, indigestion, acid reflux, stomach tightening, nausea and vomiting, stomach rumbling, bloating, belching and flatulence) was identified suggesting GI discomfort within the population. In the subsequent 12-week intervention period with 3 distinct probiotic formulations and a matched-placebo, reductions in the incidence rates of bloating, borborygmus, stomach pains, slow faecal transit and incomplete defecations were observed in the probiotic groups compared to the placebo. These results highlighted differing responses among the probiotic formulations tested and indicated potential anti-constipation effects. Product specific modulations in circulating interleukin-6 levels and in the composition of the gut microbiota were also detected. Together, these data suggest a role for probiotic supplementation to exert beneficial effects on the gastrointestinal functioning of healthy subjects and highlight the need for further longer-term studies in healthy populations to gain a greater understanding of the impact of probiotics.

A genome guided evaluation of the Lab4 probiotic consortium.

Draft genome sequences of the Lab4 probiotic consortium were deposited in Genbank: Bifidobacterium animalis subsp lactis CUL34 (PRJNA482550), Bifidobacterium bifidum CUL20 (PRJNA559984), Lactobacillus acidophilus CUL60 (PRJNA482335), Lactobacillus acidophilus CUL21 (PRJNA482434). Probiogenomic analyses confirmed existing taxonomies and identified putative gene sequences that were functionally related to the performance of each organism during in vitro assessments of bile and acid tolerability, adherence to enterocytes and susceptibility to antibiotics. Genomic stability predictions identified no significant risk of gene acquisition of both antibiotic resistance and virulence genes. These observations were supported by acute phase and repeat dose tolerability studies in Wistar rats. High doses of Lab4 did not result in mortalities, clinical/histopathological abnormalities nor systemic toxicity. Increased faecal numbers of Lab4 in supplemented rats implied survival through the gastrointestinal tract and/or impact the intestinal microbiota composition. In summary, this study provides multifaceted support for probiotic functionality and the safety of the Lab4 consortium.

Allopurinol-induced severe cutaneous adverse drug reactions: Risk minimization measures in Malaysia.

PURPOSE: To describe risk minimization measures (RMMs) implemented in Malaysia for allopurinol-induced severe cutaneous adverse drug reactions (SCARs) and examine their impact using real-world data on allopurinol usage and adverse drug reaction (ADR) reports associated with allopurinol. METHODS: Data on allopurinol ADR reports (2000-2018) were extracted from the Malaysian ADR database. We identified RMMs implemented between 2000 and 2018 from the minutes of relevant meetings and the national pharmacovigilance newsletter. We obtained allopurinol utilization data (2004-2018) from the Pharmaceutical Services Programme. To determine the impact of RMMs on ADR reporting, we considered ADR reports received within 1 year of RMM implementation. We used the Pearson χ2 test to examine the relation between the implementation of RMMs and allopurinol ADR reports. RESULTS: The 16 RMMs for allopurinol-related SCARs implemented in Malaysia involved nine risk communications, four prescriber or patient educational material, and three health system innovations. Allopurinol utilization decreased by 21.5% from 2004 to 2018. ADR reporting rates for all drugs (n = 144 507) and allopurinol (n = 1747) increased. ADR reports involving off-label use decreased by 6% from 2011. SCARs cases remained between 20% and 50%. RMMs implemented showed statistically significant reduction in ADR reports involving off-label use for August 2014 [χ2(1, N = 258) = 5.32, P = .021] and October 2016 [χ2(1, N = 349) = 3.85, P = .0499]. CONCLUSIONS: RMMs to promote the appropriate use of allopurinol and prescriber education have a positive impact. We need further measures to reduce the incidence and severity of allopurinol-induced SCARs, such as patient education and more research into pharmacogenetic screening.

Genetic selection pressure in TLR9 gene may enforce risk for SLE in Indian Tamils.

Objectives Lupus is a classical systemic autoimmune disease with genetics as one of the well known causative factors for the disease pathogenesis. Toll-like receptors are the major pattern recognition receptors associated with innate immunity and also act as an interface with the adaptive immunity. Genetic polymorphisms in genes encoding TLRs were implicated in the development of infections, malignancies and autoimmune diseases. TLR9 is a member of TLR family, and recognizes the CpG DNA motifs of pathogens. Though the incidence rate of lupus in Asians was reported to be low (30 - 50/100,000 population), poor disease prognosis due to higher incidence of renal complications and aggressive disease worsens the scenario. The ability of TLR9 to detect and elicit an immune response against double-stranded DNA makes TLR9 a relevant factor to be tested for its association with the clinical and serological phenotypes of lupus. However, lack of relevant genetic data on normative frequencies of the TLR9 (rs187084) polymorphism may serve as a constraint to derive the sample size to conduct case control association studies. Hence this study was conducted to establish the normative frequency of TLR9 (rs187084) polymorphism in Indian Tamils. Materials and methods The TLR9 (rs187084) polymorphism was screened in South Indian Tamils ( n = 208) by PCR-RFLP. Results and discussion We observed a higher occurrence of the mutant allele (65%) in South Indian Tamils. No gender disparity with respect to the mutant allele frequency was observed. The higher incidence of mutant allele in both genders suggests that this population had undergone a genetic selection pressure as an evolutionary genetic measure to withstand the prevailing endemic infections like TB and malaria. Though the enhanced expression of TLR9 was protective against infections, it may also influence the development of autoimmune diseases. Conclusion The higher incidence of theTLR9 (rs187084) over-expression mutation in Indian Tamils is suggestive of a genetic adaptation or selection pressure to withstand the prevailing endemic infectious and parasitic diseases. However, this genetic adaptation poses a greater risk to develop autoimmune diseases like SLE etc through complex gene environment interactions. The normative frequency of the TLR9 (rs187084) polymorphism established in our population could now be used to define the sample size for future case control studies.

Absolute dosimetry on a dynamically scanned sample for synchrotron radiotherapy using graphite calorimetry and ionization chambers.

The absolute dose delivered to a dynamically scanned sample in the Imaging and Medical Beamline (IMBL) on the Australian Synchrotron was measured with a graphite calorimeter anticipated to be established as a primary standard for synchrotron dosimetry. The calorimetry was compared to measurements using a free-air chamber (FAC), a PTW 31 014 Pinpoint ionization chamber, and a PTW 34 001 Roos ionization chamber. The IMBL beam height is limited to approximately 2 mm. To produce clinically useful beams of a few centimetres the beam must be scanned in the vertical direction. In practice it is the patient/detector that is scanned and the scanning velocity defines the dose that is delivered. The calorimeter, FAC, and Roos chamber measure the dose area product which is then converted to central axis dose with the scanned beam area derived from Monte Carlo (MC) simulations and film measurements. The Pinpoint chamber measures the central axis dose directly and does not require beam area measurements. The calorimeter and FAC measure dose from first principles. The calorimetry requires conversion of the measured absorbed dose to graphite to absorbed dose to water using MC calculations with the EGSnrc code. Air kerma measurements from the free air chamber were converted to absorbed dose to water using the AAPM TG-61 protocol. The two ionization chambers are secondary standards requiring calibration with kilovoltage x-ray tubes. The Roos and Pinpoint chambers were calibrated against the Australian primary standard for air kerma at the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA). Agreement of order 2% or better was obtained between the calorimetry and ionization chambers. The FAC measured a dose 3-5% higher than the calorimetry, within the stated uncertainties.

Comparison of the NMIJ and the ARPANSA standards for absorbed dose to water in high-energy photon beams.

The authors report the results of an indirect comparison of the standards of absorbed dose to water in high-energy photon beams from a clinical linac and (60)Co radiation beam performed between the National Metrology Institute of Japan (NMIJ) and the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA). Three ionisation chambers were calibrated by the NMIJ in April and June 2013 and by the ARPANSA in May 2013. The average ratios of the calibration coefficients for the three ionisation chambers obtained by the NMIJ to those obtained by the ARPANSA were 0.9994, 1.0040 and 1.0045 for 6-, 10- and 15-MV (18 MV at the ARPANSA) high-energy photon beams, respectively. The relative standard uncertainty of the value was 7.2 × 10(-3). The ratio for (60)Co radiation was 0.9986(66), which is consistent with the results published in the key comparison of BIPM.RI(I)-K4.

Direct megavoltage photon calibration service in Australia.

The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) maintains the Australian primary standard of absorbed dose. Until recently, the standard was used to calibrate ionisation chambers only in (60)Co gamma rays. These chambers are then used by radiotherapy clinics to determine linac output, using a correction factor (k Q) to take into account the different spectra of (60)Co and the linac. Over the period 2010-2013, ARPANSA adapted the primary standard to work in megavoltage linac beams, and has developed a calibration service at three photon beams (6, 10 and 18 MV) from an Elekta Synergy linac. We describe the details of the new calibration service, the method validation and the use of the new calibration factors with the International Atomic Energy Agency's TRS-398 dosimetry Code of Practice. The expected changes in absorbed dose measurements in the clinic when shifting from (60)Co to the direct calibration are determined. For a Farmer chamber (model 2571), the measured chamber calibration coefficient is expected to be reduced by 0.4, 1.0 and 1.1 % respectively for these three beams when compared to the factor derived from (60)Co. These results are in overall agreement with international absorbed dose standards and calculations by Muir and Rogers in 2010 of k Q factors using Monte Carlo techniques. The reasons for and against moving to the new service are discussed in the light of the requirements of clinical dosimetry.

Absolute x-ray dosimetry on a synchrotron medical beam line with a graphite calorimeter.

PURPOSE: The absolute dose rate of the Imaging and Medical Beamline (IMBL) on the Australian Synchrotron was measured with a graphite calorimeter. The calorimetry results were compared to measurements from the existing free-air chamber, to provide a robust determination of the absolute dose in the synchrotron beam and provide confidence in the first implementation of a graphite calorimeter on a synchrotron medical beam line. METHODS: The graphite calorimeter has a core which rises in temperature when irradiated by the beam. A collimated x-ray beam from the synchrotron with well-defined edges was used to partially irradiate the core. Two filtration sets were used, one corresponding to an average beam energy of about 80 keV, with dose rate about 50 Gy/s, and the second filtration set corresponding to average beam energy of 90 keV, with dose rate about 20 Gy/s. The temperature rise from this beam was measured by a calibrated thermistor embedded in the core which was then converted to absorbed dose to graphite by multiplying the rise in temperature by the specific heat capacity for graphite and the ratio of cross-sectional areas of the core and beam. Conversion of the measured absorbed dose to graphite to absorbed dose to water was achieved using Monte Carlo calculations with the EGSnrc code. The air kerma measurements from the free-air chamber were converted to absorbed dose to water using the AAPM TG-61 protocol. RESULTS: Absolute measurements of the IMBL dose rate were made using the graphite calorimeter and compared to measurements with the free-air chamber. The measurements were at three different depths in graphite and two different filtrations. The calorimetry measurements at depths in graphite show agreement within 1% with free-air chamber measurements, when converted to absorbed dose to water. The calorimetry at the surface and free-air chamber results show agreement of order 3% when converted to absorbed dose to water. The combined standard uncertainty is 3.9%. CONCLUSIONS: The good agreement of the graphite calorimeter and free-air chamber results indicates that both devices are performing as expected. Further investigations at higher dose rates than 50 Gy/s are planned. At higher dose rates, recombination effects for the free-air chamber are much higher and expected to lead to much larger uncertainties. Since the graphite calorimeter does not have problems associated with dose rate, it is an appropriate primary standard detector for the synchrotron IMBL x rays and is the more accurate dosimeter for the higher dose rates expected in radiotherapy applications.

Direct MC conversion of absorbed dose to graphite to absorbed dose to water for 60Co radiation.

The ARPANSA calibration service for (60)Co gamma rays is based on a primary standard graphite calorimeter that measures absorbed dose to graphite. Measurements with the calorimeter are converted to the absorbed dose to water using the calculation of the ratio of the absorbed dose in the calorimeter to the absorbed dose in a water phantom. ARPANSA has recently changed the basis of this calculation from a photon fluence scaling method to a direct Monte Carlo (MC) calculation. The MC conversion uses an EGSnrc model of the cobalt source that has been validated against water tank and graphite phantom measurements, a step that is required to quantify uncertainties in the underlying interaction coefficients in the MC code. A comparison with the Bureau International des Poids et Mesures (BIPM) as part of the key comparison BIPM.RI(I)-K4 showed an agreement of 0.9973 (53).

Spectral differences in 6 MV beams with matched PDDs and the effect on chamber response.

The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) has installed an Elekta Synergy platform linac to establish a direct megavoltage primary standard calibration service, instead of relying on calibrations derived from (60)Co. One of the 6 MV beams of the ARPANSA linac has been approximately matched to the Varian high energy platform 6 MV photon beam. The electron beam energy was adjusted to match the percentage depth dose (PDD) curve and TPR(20,10). This work calculates the error introduced when using a calibration factor from this Elekta Synergy Platform linac on a Varian high-energy platform beam at 6 MV. Monte Carlo models of the Varian and matched Elekta accelerator accurately predict the measured PDDs and profiles, but show significantly different energy spectra, resulting mainly from differences in target thickness between the two accelerators. Monte Carlo modelling of the energy correction factor k(Q) of a secondary standard NE2561 chamber shows a difference of 0.4% between the Varian and the Varian-matched Elekta beams. Although small, this is a significant discrepancy for primary standard calibrations. Similar variations are expected for chambers of similar construction, and additional variations may occur with other linac manufacturers. The work has also investigated the design of a custom flattening filter to precisely match the energy spectrum of the Varian beam on the Elekta platform.

Finasteride inhibits the disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis.

Progesterone (P) plays an important role in seizure susceptibility in women with epilepsy. Preclinical and experimental studies suggest that P appears to interrupt epileptogenesis, which is a process whereby a normal brain becomes progressively susceptible to recurrent, unprovoked seizures due to precipitating risk factors. Progesterone has not been investigated widely for its potential disease-modifying activity in epileptogenic models. Recently, P has been shown to exert disease-modifying effects in the kindling model of epileptogenesis. However, the mechanisms underlying the protective effects of P against epileptogenesis remain unclear. In this study, we investigated the role of P-derived neurosteroids in the disease-modifying activity of P. It is hypothesized that 5α-reductase converts P to allopregnanolone and related neurosteroids that retard epileptogenesis in the brain. To test this hypothesis, we utilized the mouse hippocampus kindling model of epileptogenesis and investigated the effect of finasteride, a 5α-reductase and neurosteroid synthesis inhibitor. Progesterone markedly retarded the development of epileptogenesis and inhibited the rate of kindling acquisition to elicit stage 5 seizures. Pretreatment with finasteride led to complete inhibition of the P-induced retardation of the limbic epileptogenesis in mice. Finasteride did not significantly influence the acute seizure expression in fully kindled mice expressing stage 5 seizures. Thus, neurosteroids that potentiate phasic and tonic inhibition in the hippocampus, such as allopregnanolone, may mediate the disease-modifying effect of P, indicating a new role of neurosteroids in acquired limbic epileptogenesis and temporal lobe epilepsy.

Defective diacylglycerol-induced Ca2+ entry but normal agonist-induced activation responses in TRPC6-deficient mouse platelets.

BACKGROUND: Platelet adhesion, activation and aggregation at sites of vascular injury are essential processes for primary hemostasis. Elevation of the intracellular Ca(2+) concentration is a central event in platelet activation but the underlying mechanisms are not fully understood. Store-operated calcium entry (SOCE) through Orai1 was shown to be the main Ca(2+) influx pathway in murine platelets, but there are additional non-store-operated Ca(2+) (non-SOC) and receptor operated Ca(2+) (ROC) channels expressed in the platelet plasma membrane. OBJECTIVE: Canonical transient receptor potential (TRPC) channel 6 is found both in human and murine platelets and has been proposed to mediate diacylglycerol (DAG) activated ROCE but also a role in the regulation of SOCE has been suggested. METHODS: To investigate the function of TRPC6 in platelet Ca(2+) signaling and activation, we analyzed platelets from mice deficient in TRPC6 using a wide range of in vitro and in vivo assays. RESULTS: In the mutant platelets, DAG activated Ca(2+) influx was found to be abolished. However, this did not significantly affect SOCE or agonist induced Ca(2+) responses. Platelet function in vitro and in vivo was also unaltered in the absence of TRPC6. CONCLUSION: Our results indicate that DAG activated ROCE is mediated exclusively by TRPC6 in murine platelets, but this Ca(2+) influx has no major functional relevance for hemostasis and thrombosis. Further, in contrast to previous suggestions, based on studies with human platelets, TRPC6 appears to play an insignificant role in the regulation of SOCE in murine platelets.

In vitro antiplasmodial activity of methanolic extracts from seaweeds of South West Coast of India.

OBJECTIVE: To identify the in vitro antiplasmodial activity of seaweed plants against Plasmodium falciparumstrains. METHODS: A total of eight seaweeds were collected from Kanyakumari district, Tamilnadu, India. The in vitro antiplasmodial activity was performed in 96 well plates against Plasmodium falciparum, and preliminary phytochemcial analysis were performed for the extracts. RESULTS: Of the selected plants Enteromorpha intestinalis (2.61%) showed maximum percentage of extraction. The minimum concentration of inhibitory (IC50) value was observed with Chaetomorpha antennina [(26.37±4.14) µg/mL] further, the positive controls such as chloroquine and artemether showed antiplasmodial activities (IC50) with (19.10±5.93) and (6.03±0.21) µg/mL concentrations, respectively. The preliminary phytochemical analysis of the seaweed extracts showed a variety of phytochemical constituents such as carboxylic acids, phenols, protein, resins, steroids and sugars. CONCLUSIONS: The antiplasmodial activity of the seaweed extract might due to the presence of sugars and phenolic compounds. From the present findings, it is concluded that, the seaweed extract of Chaetomorpha antennina can be further used as a putative antiplasmodial drugs in near future.

Ultrasound examination at 37 weeks' gestation in the prediction of pregnancy outcome: the value of cervical assessment.

OBJECTIVE: To examine the potential value of routine measurement of cervical length in singleton low-risk pregnancies at 37 weeks of gestation in the prediction of onset and outcome of labor. METHODS: Cervical length was measured by transvaginal sonography at 37 weeks in 1571 singleton low-risk pregnancies. Outcome measures were gestation at spontaneous onset of labor, post-term delivery, duration of labor and mode of delivery. RESULTS: The median cervical length at 37 weeks was 30 mm and there was a significant association between cervical length and gestation at delivery, which increased from a mean of 38 weeks for cervical length of 10 mm to 41 weeks for cervical length of 35 mm. The incidence of delivery after 40 weeks and 10 days was 296 (18.8%) and the incidence increased with cervical length at 37 weeks from 0% to 6%, 35% and 68% for respective cervical lengths of < 20, 21-30, 31-40 and 41-50 mm. In the pregnancies with spontaneous onset of labor the incidence of Cesarean section for failure to progress increased from 3.6% to 6.0%, 6.4% and 11.8% for cervical lengths of < 20, 21-30, 31-40 and 41-50 mm, respectively. In the pregnancies requiring induction for post-term the incidence of Cesarean section for failed induction or failure to progress increased from 7.5% to 20.1% to 25.0% for cervical lengths of 21-30, 31-40 and 41-50 mm, respectively. CONCLUSION: Measurement of cervical length at 37 weeks can define the likelihood of spontaneous delivery before 40 weeks and 10 days and the risk of Cesarean section in those requiring induction for prolonged pregnancy.

Attention-deficit/hyperactive disorder: making a case for multidisciplinary management.

Attention Deficit/Hyperactivity Disorder (AD/HD) is characterized by a cluster of age-inappropriate behavioral abnormalities comprising inattentivity, hyperactivity and impulsivity. The definition is controversial and without an accurate diagnosis. Therefore, it seems prudent that a multidisciplinary treatment protocol should begin with non-drug psychological and behavioral strategies plus nutritional intervention.

Diagnosis of dental caries: a comparison of three radiograph viewing techniques.

Interproximal caries scores for identical surfaces were compared across the three visualization techniques. First, the scores obtained by the naked eye method were compared to the scores obtained using the magnified view box. The second comparison looked at difference in scores between the magnified view box technique and the D.E.T.E.C.T. machine. A third comparison between the naked eye technique scores and the D.E.T.E.C.T machine scores was also made for each of the two operators. The comparison of caries score between the magnified view box and the digital image enhancement D.E.T.E.C.T. machine showed a more homogenous result. More caries was scored by both operators using the digital image enhancement system than with the view box technique. The difference in caries scores between the two techniques assigned for every surface by the two operators were statistically significant (p < 0.05). It is clear from this study that image enhanced interpretations of conventional radiographs is a necessary step to fine-tune the caries diagnosis process.

Dental findings in a patient with biliary atresia.

The dental treatment of a 3-year-old male with biliary atresia is discussed. The patient was scheduled for a liver transplant and was receiving Cyclosporine A. Due to the severity of the dental condition and to reduce the possibility of infection, all twenty primary teeth were extracted. The extracted teeth displayed a marked greenish discoloration of both the crowns and the roots. Histological examination revealed extensive interglobular dentin, a number of faint yellow-brown lines contouring the developmental pattern and a distinctive fluorescent line. The dental and pharmacological considerations relating to the treatment plan for this case are reviewed.

Prevention of overbite and overjet development in the 3 to 8 year old by controlled nighttime guidance of incisal eruption: a study of 43 individuals.

The purpose of this study conducted at Tufts University School of Dental Medicine is to investigate the possibility of limiting the development of an excessive vertical overbite and horizontal overjet during sleeping hours in young children prior to and during the eruption of the permanent incisors. A sample of 43 individuals, whose mean age was 6.17 years, wore a Preventive Eruption Guidance Appliance passively only while sleeping at night for 13 months (mean) to control the development of the overbite as the permanent incisors erupted and to correct the excessive overjet. The mean initial overbite of the sample was 3.4 mm and was reduced to 1.4 mm. The mean initial overjet was 3.0 mm and was reduced to 1.4 mm. Fourteen percent (6 cases) of the sample had an open bite of 1.84 mm (mean), which was reduced to a mean open-bite of 0.81 mm. As a result of the statistical comparison between the treatment sample to the control sample of 50 non-treated individuals, it was shown that the reduction of the overbite and overjet was accomplished solely by altering the problematic dentition without affecting the normal growth pattern or facial morphology as measured from nine lineal dimensions. It was also shown that the change in overbite and overjet was a significant improvement over what would have occurred if no intervention had been instituted, and that the overbite was corrected by restricting continued excessive eruption of the maxillary incisors with only nighttime passive use of the appliance.