Gut dysbiosis in cutaneous T-cell lymphoma is characterized by shifts in relative abundances of specific bacterial taxa and decreased diversity in more advanced disease.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) patients often suffer from recurrent skin infections and profound immune dysregulation in advanced disease. The gut microbiome has been recognized to influence cancers and cutaneous conditions; however, it has not yet been studied in CTCL. OBJECTIVES: To investigate the gut microbiome in patients with CTCL and in healthy controls. METHODS: A case-control study was conducted between January 2019 and November 2020 at Northwestern's busy multidisciplinary CTCL clinic (Chicago, Illinois, USA) utilizing 16S ribosomal RNA gene amplicon sequencing and bioinformatics analyses to characterize the microbiota present in fecal samples of CTCL patients (n = 38) and age-matched healthy controls (n = 13) from the same geographical region. RESULTS: Gut microbial α-diversity trended lower in patients with CTCL and was significantly lower in patients with advanced CTCL relative to controls (P = 0.015). No differences in ß-diversity were identified. Specific taxa were significantly reduced in patient samples; significance was determined using adjusted P-values (q-values) that accounted for a false discovery rate threshold of 0.05. Significantly reduced taxa in patient samples included the phylum Actinobacteria (q = 0.0002), classes Coriobacteriia (q = 0.002) and Actinobacteria (q = 0.03), order Coriobacteriales (q = 0.003), and genus Anaerotruncus (q = 0.01). The families Eggerthellaceae (q = 0.0007) and Lactobacillaceae (q = 0.02) were significantly reduced in patients with high skin disease burden. CONCLUSIONS: Gut dysbiosis can be seen in patients with CTCL compared to healthy controls and is pronounced in more advanced CTCL. The taxonomic shifts associated with CTCL are similar to those previously reported in atopic dermatitis and opposite those of psoriasis, suggesting microbial parallels to the immune profile and skin barrier differences between these conditions. These findings may suggest new microbial disease biomarkers and reveal a new angle for intervention.

Reprint of: Overview of avian toxicity studies for the Deepwater Horizon Natural Resource Damage Assessment.

The Oil Pollution Act of 1990 establishes liability for injuries to natural resources because of the release or threat of release of oil. Assessment of injury to natural resources resulting from an oil spill and development and implementation of a plan for the restoration, rehabilitation, replacement or acquisition of natural resources to compensate for those injuries is accomplished through the Natural Resource Damage Assessment (NRDA) process. The NRDA process began within a week of the Deepwater Horizon oil spill, which occurred on April 20, 2010. During the spill, more than 8500 dead and impaired birds representing at least 93 avian species were collected. In addition, there were more than 3500 birds observed to be visibly oiled. While information in the literature at the time helped to identify some of the effects of oil on birds, it was not sufficient to fully characterize the nature and extent of the injuries to the thousands of live oiled birds, or to quantify those injuries in terms of effects on bird viability. As a result, the US Fish and Wildlife Service proposed various assessment activities to inform NRDA injury determination and quantification analyses associated with the Deepwater Horizon oil spill, including avian toxicity studies. The goal of these studies was to evaluate the effects of oral exposure to 1-20ml of artificially weathered Mississippi Canyon 252 oil kg bw-1 day-1 from one to 28 days or one to five applications of oil to 20% of the bird's surface area. It was thought that these exposure levels would not result in immediate or short-term mortality but might result in physiological effects that ultimately could affect avian survival, reproduction and health. These studies included oral dosing studies, an external dosing study, metabolic and flight performance studies and field-based flight studies. Results of these studies indicated changes in hematologic endpoints including formation of Heinz bodies and changes in cell counts. There were also effects on multiple organ systems, cardiac function and oxidative status. External oiling affected flight patterns and time spent during flight tasks indicating that migration may be affected by short-term repeated exposure to oil. Feather damage also resulted in increased heat loss and energetic demands. The papers in this special issue indicate that the combined effects of oil toxicity and feather effects in avian species, even in the case of relatively light oiling, can significantly affect the overall health of birds.

Overview of avian toxicity studies for the Deepwater Horizon Natural Resource Damage Assessment.

The Oil Pollution Act of 1990 establishes liability for injuries to natural resources because of the release or threat of release of oil. Assessment of injury to natural resources resulting from an oil spill and development and implementation of a plan for the restoration, rehabilitation, replacement or acquisition of natural resources to compensate for those injuries is accomplished through the Natural Resource Damage Assessment (NRDA) process. The NRDA process began within a week of the Deepwater Horizon oil spill, which occurred on April 20, 2010. During the spill, more than 8500 dead and impaired birds representing at least 93 avian species were collected. In addition, there were more than 3500 birds observed to be visibly oiled. While information in the literature at the time helped to identify some of the effects of oil on birds, it was not sufficient to fully characterize the nature and extent of the injuries to the thousands of live oiled birds, or to quantify those injuries in terms of effects on bird viability. As a result, the US Fish and Wildlife Service proposed various assessment activities to inform NRDA injury determination and quantification analyses associated with the Deepwater Horizon oil spill, including avian toxicity studies. The goal of these studies was to evaluate the effects of oral exposure to 1-20ml of artificially weathered Mississippi Canyon 252 oil kg bw-1 day-1 from one to 28 days or one to five applications of oil to 20% of the bird's surface area. It was thought that these exposure levels would not result in immediate or short-term mortality but might result in physiological effects that ultimately could affect avian survival, reproduction and health. These studies included oral dosing studies, an external dosing study, metabolic and flight performance studies and field-based flight studies. Results of these studies indicated changes in hematologic endpoints including formation of Heinz bodies and changes in cell counts. There were also effects on multiple organ systems, cardiac function and oxidative status. External oiling affected flight patterns and time spent during flight tasks indicating that migration may be affected by short-term repeated exposure to oil. Feather damage also resulted in increased heat loss and energetic demands. The papers in this special issue indicate that the combined effects of oil toxicity and feather effects in avian species, even in the case of relatively light oiling, can significantly affect the overall health of birds.

Molecular and functional assessment of bacterial community convergence in metal-amended soils.

Species diversity and the structure of microbial communities in soils are thought to be a function of the cumulative selective pressures within the local environment. Shifts in microbial community structure, as a result of metal stress, may have lasting negative effects on soil ecosystem dynamics if critical microbial community functions are compromised. Three soils in the vicinity of a copper smelter, previously contaminated with background, low and high levels of aerially deposited metals, were amended with metal-salts to determine the potential for metal contamination to shape the structural and functional diversity of microbial communities in soils. We hypothesized that the microbial communities native to the three soils would initially be unique to each site, but would converge on a microbial community with similar structure and function, as a result of metal stress. Initially, the three different sites supported microbial communities with unique structural and functional diversity, and the nonimpacted site supported inherently higher levels of microbial activity and biomass, relative to the metal-contaminated sites. Amendment of the soils with metal-salts resulted in a decrease in microbial activity and biomass, as well as shifts in microbial community structure and function at each site. Soil microbial communities from each site were also observed to be sensitive to changes in soil pH as a result of metal-salt amendment; however, the magnitude of these pH-associated effects varied between soils. Microbial communities from each site did not converge on a structurally or functionally similar community following metal-salt amendment, indicating that other factors may be equally important in shaping microbial communities in soils. Among these factors, soil physiochemical parameters like organic matter and soil pH, which can both influence the bioavailability and toxicity of metals in soils, may be critical.

Treatment of Paget's disease of bone: a survey of clinical practice in Australia.

Consensus guidelines for the treatment of Paget's disease of bone have been published, but it is not known how closely these reflect clinical practice. We conducted a multi-centre, stratified, retrospective review of case notes of 531 subjects treated for Paget's disease of bone between 2000 and 2005 in 29 Australian centres. The subjects received 1072 courses of bisphosphonate treatment (pamidronate 363, alendronate 324, risedronate 208, tiludronate 103, zoledronic acid 69, and etidronate 5). The most recent treatment received was oral therapy in 57% of patients (alendronate 29%, risedronate 24%, and tiludronate 4%) and intravenous in 43% (pamidronate 33%, and zoledronic acid 10%). For oral bisphosphonates, the percentages of courses which were at the recommended dosage and duration were: alendronate 33%, risedronate 60% and tiludronate 29%. Pamidronate was administered in a wide range of dosing schedules, most commonly 60 mg every 3 months (18%), 6 months (17%) or annually (12%), whereas zoledronic acid was mainly given as a 4 mg infusion (98%) as a single dose (52%) or annually (19%). Most clinicians reported taking into account symptoms, plasma alkaline phosphatase activity and anatomical location of disease in determining the need for treatment. Patient preference, intolerance of oral therapy and compliance were ranked highest in determining the choice between oral and intravenous therapy. We conclude that oral and intravenous bisphosphonate dosing regimens are both commonly used to treat Paget's disease of bone in Australia. Only a minority of courses of oral bisphosphonate treatment are at the recommended dosage and duration, and there is a lack of consensus on regimens for intravenous treatment.

Effects of combined insulin-sulfonylurea therapy in type II patients.

We conducted a double-blind crossover study to determine which patient characteristics best predict a beneficial response to combined insulin-glyburide therapy. Glyburide (15 mg/day) or placebo was added to the treatment regimen of 31 insulin-treated type II (non-insulin-dependent) diabetic subjects. During glyburide therapy, there was a significant improvement in glycemic control with a reduction in glycosylated hemoglobin from 9.9 +/- 1.3 to 9.1 +/- 1.3% (P less than .001). Patients who responded had higher fasting C-peptide levels (P less than .001) and shorter durations of insulin therapy (P less than .01) than those who did not respond. Glyburide withdrawal was associated with a greater than expected deterioration in glycemic control. Patients on insulin therapy for greater than 8 yr are unlikely to benefit significantly from the addition of glyburide to their treatment regimen.

Thyroid function in patients in clinical remission after medical treatment of thyrotoxicosis.

This paper described the changes in the levels of serum triiodothyronine, serum thyroxine,serum thyrotrophin and other indices of thyroid function between 2-5 y after completion of antithyroid drug therapy in 35 patients who were euthyroid on clinical criteria. There was a small but significant elevation of the mean triiodothyronine and thyroxine levels with a relative hypersecretion of Triiodothyronine. No correlation was found between the levels of either thyroid hormone measured or their ratio and the radioiodine uptakes and clearance rate, the plasma inorganic iodine level, the absolute iodine uptake or the serum TSH level. There was no case of clinical hypothyroidism but in one patient the TSH level was at the upper limit of the nrmal range and an exaggerated TSH response to TRH was found.

Antihypertensive efficacy and safety of perindopril in mild-to-moderate essential hypertension: results of a double-blind multicenter study versus atenolol.

A 3-month double-blind multicenter trial compared the efficacy and safety of perindopril, a new angiotensin-converting enzyme (ACE) inhibitor, with atenolol in mild-to-moderate essential hypertension. A total of 190 patients, 49 of whom were diabetic, entered the perindopril-atenolol comparison. Of these, 163 had been previously treated and had a 4-week run-in period on placebo; 27 had previously been untreated and received placebo for 2 weeks. At entry, all patients who had a supine diastolic blood pressure (DBP) of 95-115 mm Hg were randomized to receive perindopril 2 mg or atenolol 25 mg, once daily. Patients were assessed at 2 weekly intervals for the first month and then monthly for 2 more months. If supine DBP was greater than 90 mm Hg, treatment was increased by stepwise doubling of dose up to 8 mg perindopril or 100 mg atenolol once daily, and later by the addition of hydrochlorothiazide 25 mg, (indapamide 2.5 mg in diabetic patients) once daily. The two groups were homogeneous prior to treatment except for supine and erect heart rate, which were higher in the perindopril group than in the atenolol group (p less than 0.05). Mean supine DBP was 101.1 +/- 0.6 mm Hg in the perindopril group (n = 94) and 99.9 +/- 0.6 mm Hg in the atenolol group (n = 96). After 3 months' active treatment, 74% of patients in the perindopril group achieved a supine DBP of less than or equal to 90 mm Hg and 73% of patients in the atenolol group achieved the same goal. Monotherapy controlled supine DBP in 67% of the perindopril group and 63% of the atenolol group. The decrease in supine DBP was not significantly different between the two groups (-12.9 +/- 0.9 versus -14.7 +/- 0.9 mm Hg) but the decrease in erect DBP was lower in the perindopril group (-10.3 +/- 0.9 versus - 13.4 +/- 1.0 mm Hg, p less than 0.02). Heart rate was reduced in the atenolol group (p less than 0.001). Sixteen patients withdrew from the study; nine were attributed to adverse events, two in the perindopril group and seven, including one death, in the atenolol group. Cough was spontaneously reported by 13% patients of the perindopril group and 1% patients of the atenolol group. In 5% of the perindopril cases this was mild and associated with upper respiratory tract infection. The nature and incidence of other symptoms were similar with both drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Toxicological foundations of ecological risk assessment: biomarker development and interpretation based on laboratory and wildlife species.

Ecological risk assessments based on chemical residue analysis and species demographics tend to ignore the bioavailability and bioaccumulation of the chemicals of concern. This study describes the incorporation of mechanistically based biomarkers into an ecological risk assessment of a poly-cyclic aromatic hydrocarbon (PAH)-contaminated site. A combination of soil residue analysis, tissue residue analysis, biomarkers in one-site trapped animals and biomarkers in animals confined to enclosures was used. In particular, the use of captured deer mice (Peromyscus maniculatus) for these studies is compared to the use of laboratory-raised deer mice placed in enclosures. This study indicates that the higher degree of variability in the responses of wild deer mice make the use of enclosure studies advantageous. Positive control studies performed by dosing laboratory-raised deer mice with the same PAHs as found on the site were used to validate this approach. These studies indicate that immune suppression occurred at PAH concentrations an order of magnitude below those required for the induction of ethoxyresorufin-O-dealkylase activity.

Single-day intravenous pamidronate in Paget's disease.

Although the efficacy of pamidronate (APD) in Paget's disease is established, the optimal dose and regimen are not known. In this article, further findings using a single-day intravenous infusion are reported, comparing the responses of 114 subjects treated with doses of 20 mg (n = 35), 30 mg (n = 26), 45 mg (n = 29), and 60 mg (n = 24). Assessments of clinical and biochemical response were made at 2, 4, 8, 12, and 24 weeks. Patients with persistent disease activity were retreated after 24 weeks. The single-day infusion of APD was followed by a rapid and sustained biochemical response, but in only 24% of patients did alkaline phosphatase (AP) levels normalize. Of patients in whom the serum AP level normalized, 93% had initial values less than three times the upper limit of normal. Although there was no significant difference in response between the lower dosage groups, there was a greater response in patients treated with a higher dose of APD. The percentage decrease in AP from baseline was similar after the first and second infusions. These findings show that a single-day infusion of APD is effective in the treatment of Paget's disease and that a dose-response relationship exists.

Rat brain acetylcholinesterase activity: developmental profile and maturational sensitivity to carbamate and organophosphorus inhibitors.

A growing body of evidence indicates that young animals exhibit an increased susceptibility to the lethal effects of cholinesterase (ChE)-inhibiting insecticides. Our laboratory is engaged in defining factors which may explain this age-related sensitivity. This report includes results from experiments designed to compare the developmental profiles, kinetic parameters and intrinsic (i.e. in vitro) sensitivity of developing male rat brain acetylcholinesterase (AChE) activity to carbamate and organophosphorus anticholinesterases. Total ChE activity in whole brain for each age was composed of about 90% AChE and 10% butyrylcholinesterase (BuChE) activity for the six ages examined. Brain AChE activity showed an age-related increase in Vmax until postnatal day 17 with no change in Km (average of all six ages approximately equal to 72 microM). Optimal substrate (acetylthiocholine) concentration for each age was 1 mM, and there was substrate inhibition (approximately 10%) at 2.5 mM. IC50s (the concentration of compound that inhibits 50% of the AChE activity in 30 min at 26 degrees C) defined concomitantly for postnatal day 4 and adult brain AChE using either aldicarb, carbaryl, chlorpyrifos-oxon or malaoxon were virtually identical at both ages with average IC50 values being: aldicarb = 2.4 microM, carbaryl = 1.7 microM, chlorpyrifos-oxon = 4.9 nM and malaoxon = 140 nM. In summary, AChE in young and adult brain differs mostly in specific activity while the Km(s), substrate profiles, and in vitro sensitivity to selected anticholinesterase insecticides are not different. Therefore, these data support the hypothesis that the greater sensitivity of the young animals to anticholinesterase pesticides is not due to the greater sensitivity of the target molecule AChE to these inhibitors.

Age-dependent changes in plasma and brain cholinesterase activities of eastern bluebirds and European starlings.

Age-dependent changes in plasma and brain cholinesterase (ChE) activity were characterized in two altricial passerine species: eastern bluebirds (Sialia sialis) and European starlings (Sturnus vulgaris). Plasma acetylcholinesterase (AChE) activity declined rapidly immediately after hatching, while plasma butyrylcholinesterase (BChE) activity increased throughout the nestling period. These patterns continued after birds fledged, since the BChE: AChE ratio was higher in adult birds than fledglings. This is the first confirmation of age-dependent changes in plasma ChE activity in altricial species. Total plasma ChE activity increased with age in both species, which is the reverse of results previously reported for several precocial species. Brain ChE activity increased with age in both species, and did not reach asymptotic levels before young fledged. This corresponded with patterns previously documented in European starlings and three other altricial species. We propose that age and degree of precocity in young birds must be considered when examining sensitivity or evaluating field exposure of birds to ChE-inhibiting compounds.

Carbofuran poisoning in herons: diagnosis using cholinesterase reactivation techniques.

Exposure to the carbamate insecticide carbofuran was detected using brain cholinesterase (ChE) reactivation techniques in heron carcasses collected from a potential pesticide exposure incident. Great egrets (Nycticorax nycticorax), great blue herons (Ardea herodias), and black-crowned night herons (Casmerodius albus) were exposed to carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate) either by dermal exposure while wading or through ingestion of contaminated food items. Carcasses may have been in the field up to 5 days prior to collection. Brain ChE, substantially inhibited in most samples, increased 7.9-208% in the reactivation assay after 4 to 96 hours at 37 C, providing evidence of exposure to a carbamate pesticide. Crayfish (Procambarus clarkii) identified in the crops of some herons contained carbofuran residues of up to 0.6 parts per million wet weight, providing additional evidence of exposure. Reactivated brain ChE in several samples approached the range of control values.

Cyclophosphamide effects on immune function of European starlings.

We developed and tested a battery of immune function assays on adult European starlings (Sturnus vulgaris) exposed to the immunotoxicant cyclophosphamide (CY). Starlings were injected intraperitoneally for three consecutive days with saline or 20 mg/kg CY. Cyclophosphamide did not affect body mass or packed cell volume. However, spleen to body mass ratios and the number of viable spleen cells were lower in CY-treated birds when compared to controls. Peripheral white blood cell numbers were reduced in CY-treated starlings, and the decrease affected all cell types. Phagocytic ability of macrophages cultured from peripheral blood monocytes was impaired in cells from CY-treated birds. Additionally, CY treatment resulted in decreased lymphocyte blastogenesis to the T-cell mitogen Concanavalin A. The hemagglutination response to sheep erythrocytes was lower in birds that had received CY. Thus, these immunological methods detected chemically-induced immune dysfunction in starlings.

Inbred crosses and inherited muscular dystrophy of the chicken.

Inbred normal and genetically dystrophic chickens of New Hampshire and White Leghorn backgrounds, respectively, have been crossed to yield hybrids of normal and dystrophic genotypes in order to provide genetically homogeneous but heterozygous experimental animals. This study examined carcass and pectoral muscle weights, pectoral muscle fiber diameters, serum creatine kinase (CK) levels, muscle acetylcholinesterase (AChE), lactic dehydrogenase (LDH), and creatine kinase, and response to daily injections of corticosterone-21-acetate (C21A) of these hybrid chickens and their inbred parental lines. With the exception of pectoral muscle weight, dystrophic hybrids exhibited symptoms of dystrophy: high serum CK and high muscle AChE and low LDH levels. The results support the hypothesis that neither early muscle fiber hypertrophy nor atrophy is invariably associated with expression of the dystrophic gene; both are the result of secondary gene interactions. One experiment showed that muscle AChE levels decreased and LDH levels rose after C21A treatments.

Thyrotoxicosis factitia complicating Graves' disease.

A patient with Graves' disease remained clinically and biochemically hyperthyroid after intravenous therapeutic(131)I, although thyroidal uptake fell to normal. Previously she had taken antithyroid drugs irregularly and vomited twice after oral(131)I. She was treated with carbimazole and thyroxine 0.2 mg daily because of severe exophthalmos. However, she maintained her hypermetabolic state by surreptitiously taking thyroxine in excess of the prescribed dose. When drug treatment was stopped under supervision she rapidly became euthyroid. By tracing prescriptions supplied to the patient it was shown that she had obtained amounts of thyroxine grossly in excess of her requirements.

Arsenic, cadmium, copper, lead, and selenium in migrating blue-winged teal (Anas discors L.).

The blue-winged teal (Anas discors L.), an abundant waterfowl species in North America, winters primarily in Mexico, Central America, and South America. Its transcontinental migratory behavior provides the opportunity to examine contaminant acquisition across a diverse biogeographic landscape that has varied environmental regulations and wildlife laws. We determined concentrations of arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), and selenium (Se) in liver samples of blue-winged teal migrating through southern Texas during autumn 1998 (n = 47) and spring 1999 (n = 46). Concentrations for As (range 0.006 to 0.22 microg/g wet weight [ww]), Cd (range 0.007 to 8.14 microg/g ww), and Pb (range 0.012 to 1.79 microg/g ww) were at background levels for birds, whereas Cu (8.1 to 227.3 microg/g ww) and Se (0.36 to 5.07 microg/g ww) were increased in several individuals. All 24 hatch-year (HY) blue-winged teal had detectable levels of Cd, Cu, Pb, and Se, and eight had detectable levels of As. A seasonal effect was found for Cd, in which the mean Cd concentration in autumn was lower (p < 0.015) than in spring. Comparisons between autumn-collected HY and autumn-collected after-hatch-year (AHY) blue-winged teal found the mean concentration of Cd was higher (p < 0.001) in AHY birds. A seasonal effect occurred for Cu, in which the mean concentration was higher (p < 0.001) in autumn than in spring. Comparisons between seasons using only AHY blue-winged teal found that the mean concentration of Cu was higher (p < 0.001) in autumn than in spring. No sex effects (p > 0.05) were found for the five elements examined. Results indicated that blue-winged teal were acquiring all five elements; that HY blue-winged teal were exposed to these elements in North America; and that increased Se concentrations in 15% of the 93-bird sample were at levels known to cause impairment in birds.