Pharmacokinetics of bromoform in dairy heifers.

AIMS: To determine the pharmacokinetics in dairy heifers after oral and IV administration of bromoform, a potential antimethanogenic agent found in red seaweed, Asparagopsis spp. METHODS: Twenty-four dairy heifers with a mean weight of 319 (SD 36.9) kg were used. The study was conducted in two phases, and each cohort of 12 heifers received an escalating dose of bromoform. In the first phase, 12 heifers successively received doses of 200, 400, 800, and 1600 mg of bromoform orally, separated by a 72-hour washout period. In the second phase, a different cohort of 12 dairy heifers was used. Each heifer received a total of four doses of bromoform separated by a wash-out period of 72 hours. Sequentially the treatments were (for each of the 12 heifers) an oral dose of 50 mg, followed by an IV dose of 50 mg, followed by an oral dose of 100 mg and finally an IV dose of 100 mg.Blood samples were assayed by gas chromatography-mass spectrophotometry for bromoform and dibromomethane to estimate the pharmacokinetic parameters using a non-compartmental analysis. RESULTS: Bromoform was rapidly absorbed as indicated by a short time to the maximum observed concentration of 15 minutes. For the routes of administration and dose ranges investigated, the mean terminal half-life ranged from 0.32 (SE 0.03) hours to 5.73 (SE 1.64) hours when administered orally or IV. With values for the mean area under the curve (AUC) to dose ratio ranging from 0.25 (SE 0.04) to 0.82 (SE 0.19) for oral and 1.39 (SE 0.39) to 4.02 (SE 0.37) for IV administration, bromoform appeared to exhibit non-proportional pharmacokinetic behaviour. The mean absolute bioavailability was 39.13 (SE 10.4)% and 3.36 (SE 0.83)% for 50-mg and 100-mg doses, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Bromoform is rapidly absorbed and exhibits dose dependent elimination kinetics.

Similar success rate in proximal and distal colonic stent placement: a retrospective multi-center study.

OBJECTIVES: Stenting of malignant colon obstruction is used as a bridge to surgery or as an alternative to surgical colostomy in a palliative setting. Current guidelines recommend stent placement as the first line of treatment in colonic obstruction in both curative and palliative settings. However, it is unclear whether the location of the malignant obstruction influences the outcome of the stenting procedure. The goal of this study was to compare the outcomes of colonic stents between proximal and distal colonic strictures with regard to technical and clinical success and the risk of adverse events. METHODS: A multi-center retrospective cohort was composed of patients who underwent a colonic stent placement at two tertiary hospitals between 2013 and 2021. The technical and clinical outcome, stent type used, duration of post-procedural hospital stay and complications were noted. RESULTS: A total of 148 patients who underwent colonic stenting were identified. 41 patients underwent stent placement in the proximal colon and 107 patients underwent a distal stent placement. There was no difference in technical success (100% vs 96.3%, p = 0.209), clinical success (97.0% vs 89.6%, p = 0.199) or complications (24.4% vs 37.4%, p = 0,135). CONCLUSION: Technical success and clinical success rates are high and do not differ between stent locations. There is no significant difference in complication rates between proximal and distal colonic stents.

What can the Interventional Endoscopist Offer in the Management of Upper Gastrointestinal Malignancies?

The therapeutic possibilities of endoscopy have rapidly increased in the last decades and now allow organ-sparing treatment of early upper gastrointestinal malignancy as well as an increasing number of options for symptom palliation. This review contains an overview of the interventional endoscopic procedures in upper gastrointestinal malignancies. It describes endoscopic treatment of early oesophageal and gastric cancers, and the palliative options in managing dysphagia and gastric outlet obstruction. It also provides an overview of the therapeutic possibilities of biliary endoscopy, such as retrograde stenting and radiofrequency biliary ablation. Endoscopic ultrasound-guided therapeutic options are discussed, including biliary drainage, gastrojejunostomy and coeliac axis block. To aid in clinical decision making, the procedures are described in the context of their indication, efficacy, risks and limitations.

Probiotic therapy in couples with infertility: A systematic review.

The reproductive microbiome is becoming increasingly recognised for its influence on fertility. While there has been much work to investigate the treatment of bacterial vaginosis and disordered microbiomes in optimizing outcomes in Assisted Reproductive Technology (ART), the role of routinely prescribed probiotics is yet to be established. The therapeutic potential of probiotic therapy remains an exciting opportunity in ART and this review endeavours to summarise its evidence to date. A systematic review of MEDLINE (Pubmed), Allied Health Literature (CINAHL), EMBASE, Web of Science and the Cochrane database was performed on 7th May 2019, and repeated on 26th August 2019. The search was built using the terms 'subfertility;' 'probiotic therapy;' 'clinical pregnancy rate' and 'assisted reproductive outcomes.' The primary outcome was change in clinical pregnancy rate. Secondary outcomes included improvements in male and female fertility parameters and microbial assessment. The initial search found 882 articles, of which 26 full manuscripts were reviewed. Four articles were eligible for inclusion. Of the two studies that reported the primary outcome, only one study found probiotics increased the clinical pregnancy rate non-significantly (48.0%-58.8%, p = 0.47). It also found higher miscarriage rate (30 % vs 16.6 %, p = 0.47) in the group treated with probiotics. Both studies on males with oral probiotic found significantly improved sperm motility. While benefit in sperm motility has been observed with male probiotic therapy, there is conflicting evidence on the efficacy of probiotic therapy for women undergoing assisted reproduction. High quality randomized studies are needed to definitively examine probiotic therapy and establish its benefit for couples undergoing assisted reproduction.

Optimising delivery of care in coeliac disease - comparison of the benefits of repeat biopsy and serological follow-up.

BACKGROUND: The majority of deleterious health consequences of coeliac disease (CD) are most likely to be secondary to intestinal inflammation; hence, mucosal recovery is a desirable goal of therapy. Follow-up in CD is controversial and serological response is often used as a surrogate for histological recovery. AIMS: To inform the clinical management of CD using comparative serological and histological data from a biopsy-driven pathway of care. METHODS: A retrospective analysis of the Cambridge Coeliac Clinic database of 595 patients routinely followed up by biopsy and serology. RESULTS: Paired biopsy results were available for 391 patients (15% seronegative). Persisting villous atrophy (VA) occurred in 182 patients (47%). The sensitivity of anti-tissue transglutaminase (TTG) antibody for ongoing VA was only 43.6%. Information on dietetic management and further biopsy to assess response was available for 94 initially unresponsive patients, in whom targeted dietetic intervention by removal of identified gluten sources or avoidance of trace amounts of gluten led to resolution of persistent VA in 50%. The effects of institution of a formal care pathway are analysed in 298 patients. Discharge to primary care and clinical management was facilitated by the information derived from repeat biopsy. CONCLUSIONS: Serology appears to be a poor surrogate marker for mucosal recovery on a gluten-free diet; dietary assessment fails to identify a potential gluten source in many patients with ongoing villous atrophy. The benefits of re-biopsy on diet include stratification of patients with coeliac disease suitable for early discharge from secondary care or those requiring more intensive clinical management.

A massive occult pericardial effusion in an athletic young male.

We present a case of a 27-year-old Royal Marine with a massive pericardial effusion, presenting with minimal clinical findings, suggesting that high levels of physical fitness may effectively mask the normal symptoms of this potentially life-threatening condition.

Endoscopy and implantable electronic devices.

The increasing use of implantable electronic devices such as cardiac pacemakers and neurostimulators means that they are being increasingly encountered in endoscopy departments. The electromagnetic fields generated during electrosurgery and with magnetic imaging systems have the potential to interfere with such devices. The authors present a case that highlights some of the steps necessary for minimising risk, review the evidence and summarise the currently available guidance.

Sodium valproate in combination with ganciclovir induces lysis of EBV-infected lymphoma cells without impairing EBV-specific T-cell immunity.

Histone deacytelase inhibitiors (HDACi) represent a new class of anti-lymphoma therapeutics. Data in the clinical setting regarding on- and off-target effects of these agents are limited. Epstein-Barr virus (EBV)-positive lymphomas represent a highly defined system in which to make these observations. We present a case of a patient with multiple relapsed EBV-positive Diffuse Large B-cell Lymphoma that was chemo-refractory to anthracylcines, alkylating agents and rituximab. Treatment was commenced with the HDACi sodium valproate (VPA) in combination with the anti-viral nucleoside analogue ganciclovir (GCV). Therapy resulted in detectable cell-free unencapsulated circulating EBV-DNA providing supportive evidence for the first-time that lysis of virus infected lymphoma cells is induced using this therapeutic combination. EBV-specific CD8+ effector T-cell immunity was not impaired by VPA/GCV. Although GCV/VPA was insufficient to induce clinical remission, our data furthers the rationale that more potent HDAC inhibitors such as butyrate or gemcitabine together with GCV, perhaps in combination with chemotherapy, should be further investigated as therapy in relapsed/refractory EBV-positive lymphomas.

The number of single nucleotide polymorphisms and on-farm data required for whole-herd parentage testing in dairy cattle herds.

New platforms utilizing single nucleotide polymorphisms (SNP) offer operational advantages over the conventional microsatellite-based ones, making them a promising alternative for parentage exclusion. Through simulation and empirical data, a 40-SNP panel (where the minor allele frequency was 0.35 on average) was shown to be a comparable or better diagnostic tool than the current 14-microsatellite panel that is used to parentage test New Zealand dairy animals. The 40 SNP alone did not have sufficient power of exclusion to match more than 75% of the progeny to the correct sire and dam. Utilizing mating records and grouping progeny and dams by birth and calving dates, respectively, decreased the number of sire-dam combinations that each progeny was tested against and dramatically increased the utility of the SNP. These results highlight the importance of combining genotypes with on-farm data to maximize the ability to assign parentage in the New Zealand dairy herd.

A developmental study of the acquisition of Russian colour terms.

We report a study of the acquisition of colour terms by Russian children which had two main aims: first, to test Berlin & Kay's (1969) theory of colour universals using acquisition order as a measure of basicness; and secondly, to see if the two BLUE terms of Russian are genuinely basic. Two hundred children aged from three to six-years-old were tested on three colour-tasks--colour term listing, colour term production and colour term comprehension. To a reasonable approximation, the order of colour term acquisition was in accord with Berlin & Kay's theory, but the data are also consistent with the weaker claim that primary terms tend to be learned before derived terms. On balance the data were consistent with Russian exceptionally, having an extra term for the BLUE region. But, the two BLUE terms--goluboj 'light blue' and sinij 'dark blue'--were confused more often than other pairs of terms even by the five- to six-year-old sample.

In vitro reduction kinetics of hexavalent chromium in human blood.

This study examines time- and concentration-dependent changes in distribution of hexavalent chromium [Cr(VI)] and total chromium [Cr-(TOT)] in reconstituted human blood following addition of potassium dichromate. Fresh human blood stabilized with EDTA was obtained from human volunteers soon after meal ingestion and at 2.5 h after a light meal (herein defined as "2.5-h fasted" conditions). Cr(VI) spiked into plasma under 2.5-h fasting conditions at 3.0-12.5 micrograms/L was stable for several hours, indicating a lack of appreciable reductive capacity in isolated plasma. Spiked plasma following a recent meal exhibited immediate but variable reduction of Cr(VI) up to 300 micrograms/L. When the spiked plasma was recombined with the red blood cell (RBC) fraction, rapid reduction occurred in both the plasma and the RBC fractions based on measurement of Cr(VI) and Cr(TOT). The data indicate that plasma reduction capacity is enhanced by a recent meal, but may be overwhelmed at Cr(VI) concentrations between 2000 and 10,000 micrograms/L. These data also suggest that the RBC fraction apparently has the capacity to reduce Cr(VI) at concentrations in blood up to 15,000 micrograms/L, and that the rate of Cr(VI) uptake into RBCs may not exceed the rate of intracellular reduction at these concentrations.

A cross-cultural study of colour grouping: evidence for weak linguistic relativity.

We report a cross-cultural study of colour grouping carried out as a test of the Sapir-Whorf hypothesis (linguistic relativity theory). Speakers of English, Russian and Setswana-languages that differ in their number of basic colour terms, and in how the blue-green region is categorized--were compared on a colour sorting task. Informants sorted a representative set of 65 colours into groups so that members of the groups looked similar to each other, with no restriction on the number of groups formed. If linguistic relativity theory is true, then there should be reliable differences between the three samples in the composition of the groups they formed associated with the differing positions of colour category boundaries in the languages. The most striking feature of the results, inconsistent with linguistic relativity theory, was the similarity amongst the patterns of choice of the three samples. However, there were also significant differences amongst the samples. Setswana speakers (who have a single basic term for BLUE or GREEN) were more likely to group BLUE colours with GREEN colours than either English or Russian speakers. But Russian speakers (who have two basic colour terms for BLUE) were no more likely than English speakers to group light and dark BLUE separately. In addition there were general structural differences in grouping among the samples: they differed in the level of consensus in grouping, the number of groups formed and in the distribution of the number of colours placed in a group. These structural differences may reflect differences in the availability and salience of the colour categories across the languages. Our data support perceptual universalism modulated by weaker linguistic effects.

Systemic uptake of chromium in human volunteers following dermal contact with hexavalent chromium (22 mg/L).

This study examined the systemic uptake of chromium in four human volunteers following three hours of contact with water containing hexavalent chromium [Cr(VI)] at a concentration of 22 mg/L. Volunteers were immersed below the shoulders in water at 91 +/- 2.5 degrees F. On the day prior to the experiment and for five days afterwards, samples of urine, plasma, and red blood cells (RBCs) were collected and analyzed for total chromium. Red blood cell chromium concentrations were used as a specific biomarker for systemic uptake of Cr(VI). Although total chromium concentrations in RBCs and plasma increased relative to historical background concentrations on the day of exposure, no sustained elevation of chromium concentrations was observed in RBCs or plasma of the volunteers tested. Since absorption of chromium in the hexavalent state would result in the irreversible binding of Cr(VI) to hemoglobin within the RBC (manifested as a sustained elevation of total chromium concentrations in the RBC), the pattern of blood uptake and urinary excretion observed was consistent with uptake and distribution of chromium in the trivalent state. Small increases were observed in the concentration of total chromium in urine within 48 h of exposure, indicating that some trivalent chromium [Cr(III)] may have penetrated the skin at a rate of about 3.3 x 10(-5) to 4.1 x 10(-4) micrograms/ cm2-h. In short, the data indicated that a 3-h contact with Cr(VI) at concentrations in water plausible for environmental exposure (e.g., swimming) was not expected to result in systemic uptake of measurable amounts of Cr(VI), although a small quantity of Cr(VI) may have penetrated the skin where it was subsequently reduced to Cr(III) prior to systemic uptake.

Estimates of the chromium(VI) reducing capacity in human body compartments as a mechanism for attenuating its potential toxicity and carcinogenicity.

Estimates of the overall reducing capacity of hexavalent chromium(VI) in some human body compartments were made by relating the specific reducing activity of body fluids, cell populations or organs to their average volume, number, or weight. Although these data do not have absolute precision or universal applicability, they provide a rationale for predicting and interpreting the health effects of chromium(VI). The available evidence strongly indicates that chromium(VI) reduction in body fluids and long-lived non-target cells is expected to greatly attenuate its potential toxicity and genotoxicity, to imprint a threshold character to the carcinogenesis process, and to restrict the possible targets of its activity. For example, the chromium(VI) sequestering capacity of whole blood (187-234 mg per individual) and the reducing capacity of red blood cells (at least 93-128 mg) explain why this metal is not a systemic toxicant, except at very high doses, and also explain its lack of carcinogenicity at a distance from the portal of entry into the organism. Reduction by fluids in the digestive tract, e.g. by saliva (0.7-2.1 mg/day) and gastric juice (at least 84-88 mg/day), and sequestration by intestinal bacteria (11-24 mg eliminated daily with feces) account for the poor intestinal absorption of chromium(VI). The chromium(VI) escaping reduction in the digestive tract will be detoxified in the blood of the portal vein system and then in the liver, having an overall reducing capacity of 3300 mg. These processes give reasons for the poor oral toxicity of chromium(VI) and its lack of carcinogenicity when introduced by the oral route or swallowed following reflux from the respiratory tract. In terminal airways chromium(VI) is reduced in the epithelial lining fluid (0.9-1.8 mg) and in pulmonary alveolar macrophages (136 mg). The peripheral lung parenchyma has an overall reducing capacity of 260 mg chromium(VI), with a slightly higher specific activity as compared to the bronchial tree. Therefore, even in the respiratory tract, which is the only consistent target of chromium(VI) carcinogenicity in humans (lung and sinonasal cavities), there are barriers hampering its carcinogenicity. These hurdles could be only overwhelmed under conditions of massive exposure by inhalation, as it occurred in certain work environments prior to the implementation of suitable industrial hygiene measures.

Chloroplast DNA variability in wild and cultivated rice (Oryza spp.) revealed by polymorphic chloroplast simple sequence repeats.

Short mononucleotide repeats analogous to nuclear microsatellites or simple sequence repeats (SSRs) have been identified in chloroplast genomes. Primers flanking mononucleotide repeats in the fully sequenced rice chloroplast genome have been used in conjunction with PCR to amplify genomic DNA from 42 wild rice accessions. The amplification products exhibited length polymorphism, which allowed the levels of chloroplast variability detected to be quantified. Seven primer pairs that amplified products from different regions of the rice chloroplast were used, five of which also amplified polymorphic products in cultivated rice (Oryza sativa). Diversity values ranged from 0.5224 +/- 0.0845 (SE) to 0.8298 +/- 0.0085 in the wild accessions, which was higher than that detected in the O. sativa accessions. Both intra- and inter-specific polymorphism was detected, and the extent of chloroplast genomic differentiation based on chloroplast simple sequence repeat (cpSSR) assays was quantified using the RST statistic. Primers designed to amplify cpSSRs in O. sativa can also be used to generate polymorphic chloroplast markers in related taxa. The potential of using cpSSR to trace the origin of rice polyploid species is discussed.

Ingestion of chromium(VI) in drinking water by human volunteers: absorption, distribution, and excretion of single and repeated doses.

This study examines the magnitude of hexavalent chromium [Cr(VI)] absorption, distribution, and excretion following oral exposure to 5 and 10 mg Cr(VI)/L in drinking water administered as a single bolus dose (0.5 L swallowed in 2 min) or for 3 d at a dosage of 1 L/d (3 doses of 0.33 L each day, at 6-h intervals). Adult male volunteers ingested deionized water containing various concentrations of potassium chromate, and samples of urine, plasma, and red blood cells (RBCs) were collected and analyzed for total chromium throughout the studies. In the bolus dose studies, a fairly consistent pattern of urinary chromium excretion was observed, with an average half life of about 39 h. However, 4-d total urinary chromium excretion and peak concentrations in urine and blood varied considerably among the 5 volunteers. Studies of repeated exposure to smaller volumes ingested at a more gradual rate (i.e., 0.33 L over 5-15 min) showed similar urinary chromium excretion patterns but generally lower chromium uptake/excretion. Given that sustained elevations in RBC chromium levels provide a specific indication of chromium absorption in the hexavalent state, these data suggest that virtually all (> 99.7%) of the ingested Cr(VI) at 5 and 10 mg Cr(VI)/L was reduced to Cr(III) before entering the blood-stream. The interindividual differences in total chromium uptake and excretion are plausibly explained by ingestion of appreciable doses on an empty stomach, which likely results in the formation of well-absorbed Cr(III) organic complexes in gastrointestinal tissues and possibly the blood. The lack of any clinical indications of toxicity in the volunteers and the patterns of blood uptake and urinary excretion of chromium are consistent with a predominant uptake of Cr(III) organic complexes [derived from Cr(VI)] that are excreted more slowly than inorganic forms of Cr(III). Therefore, it appears that the endogenous reducing agents within the upper gastrointestinal tract and the blood provide sufficient reducing potential to prevent any substantial systemic uptake of Cr(VI) following drinking-water exposures at 5-10 mg Cr(VI)/L. Based on these data, the chemical environment in the gastrointestinal tract and the blood is effective even under relative fasting conditions in reducing Cr(VI) to one or more forms of Cr(III).

Human ingestion of chromium (VI) in drinking water: pharmacokinetics following repeated exposure.

Regulatory agencies have established safe drinking water concentrations for hexavalent chromium [Cr(VI)] based in part on the presumed capability of human gastric juices to rapidly reduce Cr(VI) to nontoxic trivalent chromium [Cr(III)] prior to systemic absorption. This study examines dose-related pharmacokinetics in humans following repeated oral exposure to Cr(VI) in drinking water. In particular, we sought to examine whether plausible drinking water exposures to Cr(VI) caused a sustained increase in red blood cell chromium levels, a specific marker for systemic uptake of Cr(VI). Adult male volunteers ingested a liter (in three volumes of 333 ml, at approximate 6-hr intervals) of deionized water containing Cr(VI) concentrations ranging from 0.1 to 10.0 mg/liter. Samples of urine, plasma, and red blood cells were collected and analyzed for chromium. A dose-related increase in urinary chromium excretion was observed in all volunteers. Red blood cell and plasma chromium concentrations became elevated in certain individuals at the highest doses. The RBC chromium profiles suggest that the ingested Cr(VI) was reduced to Cr(III) before entering the bloodstream, since the chromium concentration in the RBCs dropped rapidly postexposure. These findings suggest that the human gastrointestinal tract has the capacity to reduce ingested Cr(VI) following ingestion of up to 1 liter of water containing 10.0 mg/liter of Cr(VI), which is consistent with USEPA's position that the Cr(VI) drinking water standard of 0.10 mg Cr(VI)/liter is below the reductive capacity of the stomach.

Absorption and elimination of trivalent and hexavalent chromium in humans following ingestion of a bolus dose in drinking water.

These studies investigate the magnitude and valence state of chromium absorbed following plausible drinking water exposures to chromium(VI). Four adult male volunteers ingested a single dose of 5 mg Cr (in 0.5 liters deionized water) in three choromium mixtures: (1) Cr(III) chloride (CrCl3), (2) potassium dichromate reduced with orange juice (cr(III)-OJ); and (3) potassium dichromate [Cr(VI)]. Blood and urine chromium levels were followed for 1-3 days prior to and up to 12 days after ingestion. The three mixtures showed quite different pharmacokinetic patterns. CrCl3 was poorly absorbed (estimated 0.13% bioavailability) and rapidly eliminated in urine (excretion half-life, approximately 10 hr), whereas Cr(III)-OJ was absorbed more efficiently (0.60% bioavailability) but more slowly (half-life, approximately 17 hr), and Cr(VI) had the highest bioavailability (6.9%) and the longest half-life (approximately 39 hr). All three chromium mixtures caused temporary elevations in red blood cell (RBC) and plasma chromium concentrations, but the magnitude and duration of elevation showed a clear trend (Cr(VI) > Cr(III)-OJ > CrCl3). The data suggest that nearly all the ingested Cr(VI) was reduced to Cr(III) before entering the bloodstream based on comparison to RBC and plasma chromium patterns in animals exposed to high doses of Cr(VI). These findings support our prior work which suggests that water-soluble organic complexes of Cr(III) formed during the reduction of Cr(VI) in vivo explain the patterns of blood uptake and urinary excretion in humans at drinking water concentrations of 10 mg/liter or less.