Opioid analgesic use among patients with kidney disease: a systematic review.

INTRODUCTION: Opioid analgesics are often used to manage moderate to severe pain. A significant proportion of patients taking opioids have compromised kidney function. This systematic review aimed to examine the available evidence on the safety and analgesic effect of opioid use in adults with kidney disease. METHODS: We searched eight electronic databases from inception to 26th January 2023. Published original research articles in English reporting on opioid use and pharmacokinetic data among adults with reduced renal function were included. Article screening, data extraction, and quality assessment were conducted by at least two investigators independently. This review was registered prospectively on PROSPERO (ID: CRD42020159091). RESULTS: There were 32 observational studies included, 14 of which reported on morphine use, three involved fentanyl use, two involved hydromorphone use and 13 articles reported on other opioids including codeine, dihydrocodeine, and buprenorphine. CONCLUSION: There is limited and low-quality evidence to inform the safety and analgesic effect of opioid use in reduced renal function. Morphine remains the opioid for which there is the most evidence available on safety and analgesic effect in the context of renal disease. Greater caution and consideration of potential risks and benefits should be applied when using other opioids. Further high-quality studies examining clinical outcomes associated with the use of different opioids and opioid doses in renal disease are warranted.

Transplant-associated penile Kaposi sarcoma managed with single agent paclitaxel chemotherapy: a case report.

BACKGROUND: Kaposi's sarcoma is an uncommon complication in renal transplant patients, and typically presents with cutaneous lesions on the lower extremities. Penile involvement has been reported only rarely. Management of cutaneous-limited disease is primarily reduction of immunosuppression and conversion to an mTOR-inhibitor, whereas the treatment of disseminated disease in transplant patients is more variable. CASE PRESENTATION: A 75-year-old male, originally from Somalia, received a deceased-donor kidney transplant for diabetic and hypertensive nephropathy. Seven months post-transplant he presented with lower limb lesions, oedema and bilateral deep vein thromboses. He then developed a fast-growing painful lesion on his penile shaft. A biopsy of this lesion confirmed KS, and a PET scan demonstrated disseminated disease in the lower extremities, penis and thoracic lymph nodes. His tacrolimus was converted to sirolimus, and his other immunosuppression was reduced. He was treated with single agent paclitaxel chemotherapy in view of his rapidly progressing, widespread disease. The penile lesion completely resolved, and the lower extremity lesions regressed significantly. His kidney allograft function remained stable throughout treatment. CONCLUSION: This case illustrates a rare presentation of an uncommon post-transplant complication and highlights the need for a high index of suspicion of KS in transplant patients presenting with atypical cutaneous lesions. It serves to demonstrate that the use of single agent paclitaxel chemotherapy, switch to an mTORi and reduction in immunosuppression where possible produces excellent short-term outcomes, adding to the body of evidence for this management strategy in disseminated Kaposi's sarcoma.

Genome-wide identification of miR-200 targets reveals a regulatory network controlling cell invasion.

The microRNAs of the miR-200 family maintain the central characteristics of epithelia and inhibit tumor cell motility and invasiveness. Using the Ago-HITS-CLIP technology for transcriptome-wide identification of direct microRNA targets in living cells, along with extensive validation to verify the reliability of the approach, we have identified hundreds of miR-200a and miR-200b targets, providing insights into general features of miRNA target site selection. Gene ontology analysis revealed a predominant effect of miR-200 targets in widespread coordinate control of actin cytoskeleton dynamics. Functional characterization of the miR-200 targets indicates that they constitute subnetworks that underlie the ability of cancer cells to migrate and invade, including coordinate effects on Rho-ROCK signaling, invadopodia formation, MMP activity, and focal adhesions. Thus, the miR-200 family maintains the central characteristics of the epithelial phenotype by acting on numerous targets at multiple levels, encompassing both cytoskeletal effectors that control actin filament organization and dynamics, and upstream signals that locally regulate the cytoskeleton to maintain cell morphology and prevent cell migration.

Changing environmental conditions have altered the feeding ecology of two keystone Arctic marine predators.

Environmental change in the Arctic has impacted the composition and structure of marine food webs. Tracking feeding ecology changes of culturally-valued Arctic char (Salvelinus alpinus) and ringed seals (Pusa hispida) can provide an indication of the ecological significance of climate change in a vulnerable region. We characterized how changes in sea ice conditions, sea surface temperature (SST), and primary productivity affected the feeding ecology of these two keystone species over a 13- and 18-year period, respectively, in northern Labrador, Canada. Arctic char fed consistently on pelagic resources (δ13C) but shifted over time to feeding at a higher trophic level (δ15N) and on more marine/offshore resources (δ34S), which correlated with decreases in chlorophyll a concentration. A reduction in Arctic char condition factor and lipid content was associated with higher trophic position. Ringed seals also shifted to feeding at a higher trophic level, but on more pelagic resources, which was associated with lower SST and higher chlorophyll a concentrations. Years with abnormally high SSTs and reduced sea ice concentrations resulted in large isotopic niche sizes for both species, suggesting abrupt change can result in more variable feeding. Changes in abundance and distribution of species long valued by the Inuit of Labrador could diminish food security.

Novel bacterial isolate from Permian groundwater, capable of aggregating potential biofuel-producing microalga Nannochloropsis oceanica IMET1.

Increasing petroleum costs and climate change have resulted in microalgae receiving attention as potential biofuel producers. Little information is available on the diversity and functions of bacterial communities associated with biofuel-producing algae. A potential biofuel-producing microalgal strain, Nannochloropsis oceanica IMET1, was grown in Permian groundwater. Changes in the bacterial community structure at three temperatures were monitored by two culture-independent methods, and culturable bacteria were characterized. After 9 days of incubation, N. oceanica IMET1 began to aggregate and precipitate in cultures grown at 30°C, whereas cells remained uniformly distributed at 15°C and 25°C. The bacterial communities in cultures at 30°C changed markedly. Some bacteria isolated only at 30°C were tested for their potential for aggregating microalgae. A novel bacterium designated HW001 showed a remarkable ability to aggregate N. oceanica IMET1, causing microalgal cells to aggregate after 3 days of incubation, while the total lipid content of the microalgal cells was not affected. Direct interaction of HW001 and N. oceanica is necessary for aggregation. HW001 can also aggregate the microalgae N. oceanica CT-1, Tetraselmis suecica, and T. chuii as well as the cyanobacterium Synechococcus WH8007. 16S rRNA gene sequence comparisons indicated the great novelty of this strain, which exhibited only 89% sequence similarity with any previously cultured bacteria. Specific primers targeted to HW001 revealed that the strain originated from the Permian groundwater. This study of the bacterial communities associated with potential biofuel-producing microalgae addresses a little-investigated area of microalgal biofuel research and provides a novel approach to harvest biofuel-producing microalgae by using the novel bacterium strain HW001.

Brief Report: Validation of the D:A:D Chronic Kidney Disease Risk Score Incorporating Proteinuria in People Living With HIV in Harare, Zimbabwe.

OBJECTIVE: We sought to validate the D:A:D risk score for chronic kidney disease (CKD) in people living with HIV in a cohort from Harare, Zimbabwe. In addition, we aimed to evaluate proteinuria as a predictive variable in the risk score model, being the first study to do so. DESIGN: Data from people living with HIV attending a clinic in Harare were evaluated. Those with a baseline estimated the glomerular filtration rate >60 mL/min/1.73 m 2 , and at least 2 subsequent estimated glomerular filtration rate measurements were included. A modified version of the D:A:D risk score model was applied to categorize participants as "low," "medium," and "high-risk" of progression to CKD. Potential predictors of renal impairment were assessed by logistic regression in univariate and multivariate models. Proteinuria was evaluated in a nested model using D:A:D risk categories. RESULTS: Two thousand seven hundred ninety-three participants were included. Forty participants (1.4% of the cohort) progressed to CKD during the median follow-up time of 4.2 years. Progression rates were 1%, 3%, and 12% in the low, medium, and high-risk groups, respectively. Proteinuria data were available for 2251 participants. The presence of proteinuria was strongly associated with progression to CKD [(OR 7.8, 95% CI: 3.9 to 15.7), and its inclusion in the risk score improved the discrimination of the model with the c-statistic increasing from 0.658 to 0.853]. CONCLUSION: A modified version of the D:A:D CKD risk score performed well in predicting CKD events among this sub-Saharan African cohort of people living with HIV. Inclusion of proteinuria into the risk score model significantly improved predictability.

Examination of marine-based cultivation of three demosponges for acquiring bioactive marine natural products.

Marine sponges are an extremely rich and important source of natural products. Mariculture is one solution to the so-called "supply problem" that often hampers further studies and development of novel compounds from sponges. We report the extended culture (767 days) at sea in depths of 10 and 20 m of three sponge species: Negombata magnifica, Amphimedon chloros and Theonella swinhoei that produce latrunculin-B, halitoxin and swinholide-A, respectively. Since sponge-associated microorganisms may be the true producers of many of the natural products found in sponges and also be linked to the health of the sponges, we examined the stability of the bacterial communities in cultured versus wild sponges. Growth rate of the sponges (ranging from 308 to 61 and -19 (%)(year(-1)) in N. magnifica, A. chloros and T. swinhoei, respectively) differed significantly between species but not between the two depths at which the species were cultivated. Survivorship varied from 96% to 57%. During culture all species maintained the content of the desired natural product. Denaturing gradient gel electrophoresis analysis of the sponge-associated bacterial consortia revealed that differences existed between cultured and wild sponges in T. swinhoei and A. chloros but the communities remained quite stable in N. magnifica. The cultivation technique for production of natural products was found to be most appropriate for N. magnifica, while for T. swinhoei and A. chloros it was less successful, because of poorer growth and survival rates and shifts in their bacterial consortia.

H2O2 activates Nox4 through PLA2-dependent arachidonic acid production in adult cardiac fibroblasts.

Stimulated production of reactive oxygen species (ROS) by plasma membrane-associated nicotinamide adenine dinucleotide phosphate oxidases (Nox) in non-phagocytic cells regulates a number of biological processes including growth, vessel tone, and oxygen sensing. The purpose of this study was to investigate H(2)O(2)-stimulated ROS production in primary adult cardiac fibroblasts (CF). Results demonstrate that CF express an H(2)O(2)-inducible oxidant generating system that is inhibitable by diphenylene iodonium (DPI) and sensitive to antioxidants. In addition to H(2)O(2), generation of ROS was stimulated potently by 1-oleoyl-2-acetyl-sn-glycerol (OAG) and arachidonic acid (AA) in a protein kinase C-independent manner. Pretreatment with arachidonyl trifluoromethyl ketone was nearly as effective as DPI at reducing H(2)O(2)- and OAG-stimulated oxidant generation indicating a central role for phospholipase A(2) (PLA(2)) in this signaling pathway. Co-stimulation with H(2)O(2) and OAG did not increase ROS generation as compared to OAG alone suggesting both agonists signal through a shared, rate-limited enzymatic pathway involving PLA(2). Co-stimulation with H(2)O(2) and AA had additive effects indicating these two agonists stimulate oxidant production through a parallel activation pathway. Reverse transcriptase-coupled polymerase chain reaction and Western blotting demonstrate primary cardiac fibroblasts express transcripts and protein for Nox4, p22, p47, and p67 phox. Transfections with Nox4 small inhibitory ribonucleic acid oligonucleotides or p22 phox antisense oligonucleotides significantly downregulated stimulated Nox activity. Inhibitors of nitric oxide synthases were without effect. We conclude adult CF express Nox4/p22 phox-containing oxidant generating complex activated by H(2)O(2), OAG, and AA through a pathway that requires activation of PLA(2).

An analysis of the sponge Acanthostrongylophora igens' microbiome yields an actinomycete that produces the natural product manzamine A.

Sponges have generated significant interest as a source of bioactive and elaborate secondary metabolites that hold promise for the development of novel therapeutics for the control of an array of human diseases. However, research and development of marine natural products can often be hampered by the difficulty associated with obtaining a stable and sustainable production source. Herein we report the first successful characterization and utilization of the microbiome of a marine invertebrate to identify a sustainable production source for an important natural product scaffold. Through molecular-microbial community analysis, optimization of fermentation conditions and MALDI-MS imaging, we provide the first report of a sponge-associated bacterium (Micromonospora sp.) that produces the manzamine class of antimalarials from the Indo-Pacific sponge Acanthostrongylophora ingens (Thiele, 1899) (Class Demospongiae, Order Haplosclerida, Family Petrosiidae). These findings suggest that a general strategy of analysis of the macroorganism's microbiome could significantly transform the field of natural products drug discovery by gaining access to not only novel drug leads, but the potential for sustainable production sources and biosynthetic genes at the same time.

Marine-based cultivation of diacarnus sponges and the bacterial community composition of wild and maricultured sponges and their larvae.

Marine organisms including sponges (Porifera) contain many structurally diverse bioactive compounds, frequently in a low concentration that hampers their commercial production. Two solutions to this problem are: culturing sponge explants for harvesting the desired compound and cultivation of sponge-associated bacteria. These bacteria (often considered the source of the desired compounds) include the Actinobacteria, from which many novel drugs were developed. In a long-term experiment (lasting 767 days), we evaluated the culture amenability of the sponge Diacarnus erythraenus in a mariculture system, placed at 10- and 20-m depths. The growth and survival rates of sponge fragments were monitored. Wild and maricultured sponges from both depths and their larvae were sampled at different time intervals for denaturing gradient gel electrophoresis (DGGE) profiling of the bacterial community residing within them. 16S rRNA gene sequences of both cultured bacterial isolates and clone libraries of unculturable bacteria were composed and compared, focusing on Actinobacteria. Sponges from both depths did not differ significantly either in mean growth rates (percent weight change year⁻¹ ± S.E.) (64.5% ± 21% at 10 m and 79.3% ± 19.1% at 20 m) or in seasonal growth rates. Survival was also very similar (72% at 10 m and 70% at 20 m). There were 88 isolates identified from adults and 40 from their larvae. The isolates and clone libraries showed diverse bacterial communities. The DGGE profiles of wild and maricultured sponges differed only slightly, without a significant effect of depths or dates of sampling. This long-term experiment suggests that D. erythraenus probably remained healthy and indicates its mariculture suitability.

Are unexplained vaginal symptoms associated with psychosocial distress? A pilot investigation.

AIM: Vaginal complaints cannot be definitively diagnosed in approximately one-third of women. We sought to determine if women without a diagnosis had higher levels of psychiatric disorders. METHODS: This was an observational study in an urban family practice clinic. Prior to seeing a clinician, women with vaginal complaints completed the Patient Health Questionnaire (PHQ); symptoms were measured by the Vaginal Complaints Scale (VCS). Patients were then examined and treated by a family physician. At one and two weeks' time patients were contacted by phone regarding symptom resolution and clinical outcomes. RESULTS: We enrolled 47 patients; one patient was excluded. A diagnosis was made in 36. Eighteen had bacterial vaginosis, 16 had candida, three trichomonas, two HSV, one chlamydia; there were eight dual diagnoses. PHQ diagnoses were slightly less common in women without an identified cause for their symptoms. We obtained follow-up data from 45 subjects at one week and 34 subjects at two weeks' time. At two weeks' follow-up, 97% of subjects had complete resolution or improvement of their symptoms. Symptom improvement was equivalent among women with a diagnosis and those without. We estimate 180 subjects would be needed to detect a clinically meaningful difference in PHQ diagnoses. DISCUSSION: Our pilot study did not find an association between psychiatric diagnoses made by the PHQ and unexplained vaginal symptoms. Nearly all patients experienced rapid resolution of symptoms irrespective of whether a diagnosis had been made or not. These findings are limited primarily by the small sample size.

Comparison of the bacterial communities of wild and captive sponge Clathria prolifera from the Chesapeake Bay.

The red-beard sponge Clathria prolifera, which is widely distributed in the USA, has been widely used as a model system in cell biology and has been proposed as a suitable teaching tool on biology and environmental sciences. We undertook the first detailed microbiological study of this sponge on samples collected from the Chesapeake Bay. A combination of culture-based studies, denaturing gradient gel electrophoresis, and bacterial community characterization based on 16S rRNA gene sequencing revealed that C. prolifera contains a diverse assemblage of bacteria that is different from that in the surrounding water. C. prolifera individuals were successfully maintained in a flow-through or recirculation aquaculture system for over 6 months and shifts in the bacterial assemblages of sponges in aquaculture compared with wild sponges were examined. The proteobacteria, bacteroidetes, actinobacteria, and cyanobacteria represented over 90% of the species diversity present in the total bacterial community of the wild C. prolifera. Actinobacteria, cyanobacteria, and spirochetes were not represented in clones obtained from C. prolifera maintained in the aquaculture system although these three groups comprised ca. 20% of the clones from wild C. prolifera, showing a significant effect of aquaculture on the bacterial community composition. This is the first systematic characterization of the bacterial community from a sponge found in the Chesapeake Bay. Changes in sponge bacterial composition were observed in sponges maintained in aquaculture and demonstrate the importance of monitoring microbial communities when cultivating sponges in aquaculture systems.

Diversity and distribution of Escherichia coli genotypes and antibiotic resistance phenotypes in feces of humans, cattle, and horses.

Escherichia coli is the most completely characterized prokaryotic model organism and one of the dominant indicator organisms for food and water quality testing, yet comparatively little is known about the structure of E. coli populations in their various hosts. The diversities of E. coli populations isolated from the feces of three host species (human, cow, and horse) were compared by two subtyping methods: ribotyping (using HindIII) and antibiotic resistance analysis (ARA). The sampling effort required to obtain a representative sample differed by host species, as E. coli diversity was consistently greatest in horses, followed by cattle, and was lowest in humans. The diversity of antibiotic resistance patterns isolated from individuals was consistently greater than the diversity of ribotypes. E. coli populations in individuals sampled monthly, over a 7- to 8-month period, were highly variable in terms of both ribotypes and ARA phenotypes. In contrast, E. coli populations in cattle and humans were stable over an 8-h period. Following the cessation of antibiotic therapy, the E. coli population in the feces of one human experienced a rapid and substantial shift, from a multiply antibiotic-resistant phenotype associated with a particular ribotype to a relatively antibiotic-susceptible phenotype associated with a different ribotype. The high genetic diversity of E. coli populations, differences in diversity among hosts, and temporal variability all indicate complex population dynamics that influence the usefulness of E. coli as a water quality indicator and its use in microbial source tracking studies.

Alternate binding mode of C-terminal phenethylamine analogs of G(t)alpha(340-350) to photoactivated rhodopsin.

The C-terminus of the Galpha-subunit of transducin plays an important role in receptor recognition. Synthetic peptides corresponding to the last 11 residues of the subunit have been shown to stabilize the photoactivated form of rhodopsin, Rh*. The Rh*-bound structure of the G(t)alpha(340-350) peptide has been determined using transferred nuclear overhauser effect NMR. In that structure, we observed two interactions between Lys341 and Phe350, a cation-pi interaction between the epsilon-amine and the aromatic ring of Phe350 and a salt-bridge between the epsilon-amine and the C-terminal carboxylate. A series of C-terminal phenethylamine analogs of the G(t)alpha(340-350) peptide were synthesized, lacking the C-terminal carboxylate group, to investigate the forces that contribute to the stability of the Rh*-bound conformation of the peptide. Rh*-stabilization assay data suggest that the C-terminal carboxylate is not necessary to maintain binding affinity. Transferred nuclear overhauser effect NMR experiments reveal that these C-terminal phenethylamine peptides adopt an Rh*-bound structure that is similar overall, but lacking some of the intramolecular interactions observed in the native Rh*-bound G(t)alpha(340-350) structure. These studies suggest that the binding site for G(t)alpha(340-350) on Rh* is adaptable, and we propose that the charged carboxylate of Phe350 does not play a significant role in the interaction with Rh*, but helps stabilize the Rh*-bound confirmation of the native peptide.

Relative strength of cation-pi vs salt-bridge interactions: the Gtalpha(340-350) peptide/rhodopsin system.

Interactions between cationic and aromatic side chains of amino acid residues, the so-called cation-pi interaction, are thought to contribute to the overall stability of the folded structure of peptides and proteins. The transferred NOE NMR structure of the G(t)alpha(340-350) peptide bound to photoactivated rhodopsin (R*) geometrically suggests a cation-pi interaction stabilizing the structure between the epsilon-amine of Lys341 and the aromatic ring of the C-terminal residue, Phe350. This interaction has been explored by varying substituents on the phenyl ring to alter the electron density of the aromatic ring of Phe350 and observing the impact on binding of the peptide to R*. The results suggest that while a cation-pi interaction geometrically exists in the G(t)alpha(340-350) peptide when bound to R*, its energetic contribution to the stability of the receptor-bound structure is relatively insignificant, as it was not observed experimentally. The presence of an adjacent and competing salt-bridge interaction between the epsilon-amine of Lys341 and the C-terminal carboxylate of Phe350 effectively shields the charge of the ammonium group. Experimental data supporting a significant cation-pi interaction can be regained through a series of Phe350 analogues where the C-terminal carboxyl has been converted to the neutral carboxamide, thus eliminating the shielding salt-bridge. TrNOE NMR experiments confirmed the existence of the cation-pi interaction in the carboxamide analogues. Various literature estimates of the strength of cation-pi interactions, including some that estimate strengths in excess of salt-bridges, are compromised by omission of the relevant anion in the calculations.