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High-level nitrofurantoin resistance in a clinical isolate of Klebsiella pneumoniae: a comparative genomics and metabolomics analysis.
Hussein, M, Sun, Z, Hawkey, J, Allobawi, R, Judd, LM, Carbone, V, Sharma, R, Thombare, V, Baker, M, Rao, GG, et al
mSystems. 2024;(1):e0097223
Abstract
Nitrofurantoin is a commonly used chemotherapeutic agent in the treatment of uncomplicated urinary tract infections caused by the problematic multidrug resistant Gram-negative pathogen Klebsiella pneumoniae. The present study aims to elucidate the mechanism of nitrofurantoin action and high-level resistance in K. pneumoniae using whole-genome sequencing (WGS), qPCR analysis, mutation structural modeling and untargeted metabolomic analysis. WGS profiling of evolved highly resistant mutants (nitrofurantoin minimum inhibitory concentrations > 256 mg/L) revealed modified expression of several genes related to membrane transport (porin ompK36 and efflux pump regulator oqxR) and nitroreductase activity (ribC and nfsB, involved in nitrofurantoin reduction). Untargeted metabolomics analysis of total metabolites extracted at 1 and 4 h post-nitrofurantoin treatment revealed that exposure to the drug caused a delayed effect on the metabolome which was most pronounced after 4 h. Pathway enrichment analysis illustrated that several complex interrelated metabolic pathways related to nitrofurantoin bacterial killing (aminoacyl-tRNA biosynthesis, purine metabolism, central carbohydrate metabolism, and pantothenate and CoA biosynthesis) and the development of nitrofurantoin resistance (riboflavin metabolism) were significantly perturbed. This study highlights for the first time the key role of efflux pump regulator oqxR in nitrofurantoin resistance and reveals global metabolome perturbations in response to nitrofurantoin, in K. pneumoniae.IMPORTANCEA quest for novel antibiotics and revitalizing older ones (such as nitrofurantoin) for treatment of difficult-to-treat Gram-negative bacterial infections has become increasingly popular. The precise antibacterial activity of nitrofurantoin is still not fully understood. Furthermore, although the prevalence of nitrofurantoin resistance remains low currently, the drug's fast-growing consumption worldwide highlights the need to comprehend the emerging resistance mechanisms. Here, we used multidisciplinary techniques to discern the exact mechanism of nitrofurantoin action and high-level resistance in Klebsiella pneumoniae, a common cause of urinary tract infections for which nitrofurantoin is the recommended treatment. We found that the expression of multiple genes related to membrane transport (including active efflux and passive diffusion of drug molecules) and nitroreductase activity was modified in nitrofurantoin-resistant strains, including oqxR, the transcriptional regulator of the oqxAB efflux pump. Furthermore, complex interconnected metabolic pathways that potentially govern the nitrofurantoin-killing mechanisms (e.g., aminoacyl-tRNA biosynthesis) and nitrofurantoin resistance (riboflavin metabolism) were significantly inhibited following nitrofurantoin treatment. Our study could help inform the improvement of nitrofuran derivatives, the development of new pharmacophores, or drug combinations to support the resurgence of nitrofurantoin in the management of multidrug resistant K. pneumouniae infection.
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A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.
Swift, IJ, Rademakers, R, Finch, N, Baker, M, Ghidoni, R, Benussi, L, Binetti, G, Rossi, G, Synofzik, M, Wilke, C, et al
Alzheimer's research & therapy. 2024;(1):66
Abstract
BACKGROUND Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
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Astrocyte activities in the external globus pallidus regulate action-selection strategies in reward-seeking behaviors.
Kang, S, Hong, SI, Kang, S, Song, M, Yang, MA, Essa, H, Baker, M, Lee, J, Bruce, RA, Lee, SW, et al
Science advances. 2023;(24):eadh9239
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Abstract
An imbalance in goal-directed and habitual behavioral control is a hallmark of decision-making-related disorders, including addiction. Although external globus pallidus (GPe) is critical for action selection, which harbors enriched astrocytes, the role of GPe astrocytes involved in action-selection strategies remained unknown. Using in vivo calcium signaling with fiber photometry, we found substantially attenuated GPe astrocytic activity during habitual learning compared to goal-directed learning. The support vector machine analysis predicted the behavioral outcomes. Chemogenetic activation of the astrocytes or inhibition of GPe pan-neuronal activities facilitates the transition from habit to goal-directed reward-seeking behavior. Next, we found increased astrocyte-specific GABA (γ-aminobutyric acid) transporter type 3 (GAT3) messenger RNA expression during habit learning. Notably, the pharmacological inhibition of GAT3 occluded astrocyte activation-induced transition from habitual to goal-directed behavior. On the other hand, attentional stimuli shifted the habit to goal-directed behaviors. Our findings suggest that the GPe astrocytes regulate the action selection strategy and behavioral flexibility.
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A neonate with ornithine aminotransferase deficiency; insights on the hyperammonemia-associated biochemical phenotype of gyrate atrophy.
Kaczmarczyk, A, Baker, M, Diddle, J, Yuzyuk, T, Valle, D, Lindstrom, K
Molecular genetics and metabolism reports. 2022;:100857
Abstract
UNLABELLED Gyrate atrophy of the choroid and retina (GACR) secondary to deficiency of ornithine aminotransferase (OAT) is a rare autosomal recessive metabolic disorder usually diagnosed in childhood when patients develop myopia and a characteristic retinal degeneration accompanied by hyperornithinemia. Plasma ammonia is normal or sub-normal after the neonatal period. A few GACR patients present in early infancy with hyperammonemia, encephalopathy and a biochemical profile of low plasma ornithine, citrulline and arginine, with increased urinary excretion of homocitrulline and orotic acid, resembling a primary urea cycle disorder. In these patients, ornithine levels do not increase until late infancy or following arginine or citrulline supplementation. We describe a patient with OAT deficiency who presented in the first month of life with episodes of lethargy, vomiting, and hypothermia. He had two episodes of hyperammonemia associated with subnormal levels of plasma ornithine, citrulline and arginine as well as elevated urinary excretion of homocitrulline and orotic acid. Unlike previously reported cases, intermittent hyperornithinemia was observed prior to the first hyperammonemic episode and citrulline supplementation. The latter alleviated the symptoms, normalized ammonia level, and led to increased plasma ornithine concentration. Furthermore, despite a protein restricted diet and ammonia scavenger treatment, continued supplemental citrulline was necessary to prevent hyperammonemia. Molecular analysis confirmed OAT deficiency, differentiating it from proximal urea cycle disorders and deficiency of the mitochondrial ornithine transporter, ORC1, (Hyperammonemia-Hyperornithinemia-Homocitrullinuria syndrome). SYNOPSIS Hyperornithinemia alternating with hypoornithinemia and hyperammonemia in a neonatal-onset case of gyrate atrophy with ornithine aminotransferase deficiency.
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International consensus to standardise histopathological scoring for small bowel strictures in Crohn's disease.
Gordon, IO, Bettenworth, D, Bokemeyer, A, Srivastava, A, Rosty, C, de Hertogh, G, Robert, ME, Valasek, MA, Mao, R, Li, J, et al
Gut. 2022;(3):479-486
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Abstract
OBJECTIVE Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion. DESIGN Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures. RESULTS In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials. CONCLUSION Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.
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The Efficacy of Exercise Training for Cutaneous Microvascular Reactivity in the Foot in People with Diabetes and Obesity: Secondary Analyses from a Randomized Controlled Trial.
Lanting, S, Way, K, Sabag, A, Sultana, R, Gerofi, J, Johnson, N, Baker, M, Keating, S, Caterson, I, Twigg, S, et al
Journal of clinical medicine. 2022;(17)
Abstract
It is unclear if cutaneous microvascular dysfunction associated with diabetes and obesity can be ameliorated with exercise. We investigated the effect of 12-weeks of exercise training on cutaneous microvascular reactivity in the foot. Thirty-three inactive adults with type 2 diabetes and obesity (55% male, 56.1 ± 7.9 years, BMI: 35.8 ± 5, diabetes duration: 7.9 ± 6.3 years) were randomly allocated to 12-weeks of either (i) moderate-intensity continuous training [50−60% peak oxygen consumption (VO2peak), 30−45 min, 3 d/week], (ii) low-volume high-intensity interval training (90% VO2peak, 1−4 min, 3 d/week) or (iii) sham exercise placebo. Post-occlusive reactive hyperaemia at the hallux was determined by laser-Doppler fluxmetry. Though time to peak flux post-occlusion almost halved following moderate intensity exercise, no outcome measure reached statistical significance (p > 0.05). These secondary findings from a randomised controlled trial are the first data reporting the effect of exercise interventions on cutaneous microvascular reactivity in the foot in people with diabetes. A period of 12 weeks of moderate-intensity or low-volume high-intensity exercise may not be enough to elicit functional improvements in foot microvascular reactivity in adults with type 2 diabetes and obesity. Larger, sufficiently powered, prospective studies are necessary to determine if additional weight loss and/or higher exercise volume is required.
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Making the invisible visible: Developing and evaluating an intervention to raise awareness and reduce lead exposure among children and their caregivers in rural Bangladesh.
Jahir, T, Pitchik, HO, Rahman, M, Sultana, J, Shoab, AKM, Nurul Huda, TM, Byrd, KA, Islam, MS, Yeasmin, F, Baker, M, et al
Environmental research. 2021;:111292
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Abstract
Lead exposure is harmful at any time in life, but pre-natal and early childhood exposures are particularly detrimental to cognitive development. In Bangladesh, multiple household-level lead exposures pose risks, including turmeric adulterated with lead chromate and food storage in lead-soldered cans. We developed and evaluated an intervention to reduce lead exposure among children and their caregivers in rural Bangladesh. We conducted formative research to inform theory-based behavioral recommendations. Lead exposure was one of several topics covered in the multi-component intervention focused on early child development. Community health workers (CHWs) delivered the lead component of the intervention during group sessions with pregnant women and mother-child dyads (<15 months old) in a cluster-randomized trial. We administered household surveys at baseline (control n = 301; intervention n = 320) and 9 months later at endline (control n = 279; intervention n = 239) and calculated adjusted risk and mean differences for primary outcomes. We conducted two qualitative assessments, one after 3 months and a second after 9 months, to examine the feasibility and benefits of the intervention. At endline, the prevalence of lead awareness was 52 percentage points higher in the intervention arm compared to the control (adjusted risk difference: 0.52 [95% CI 0.46 to 0.61]). Safe turmeric consumption and food storage practices were more common in the intervention versus control arm at endline, with adjusted risk differences of 0.22 [0.10 to 0.32] and 0.13 [0.00 to 0.19], respectively. Semi-structured interviews conducted with a subset of participants after the intervention revealed that the perceived benefit of reducing lead exposure was high because of the long-term negative impacts that lead can have on child cognitive development. The study demonstrates that a group-based CHW-led intervention can effectively raise awareness about and motivate lead exposure prevention behaviors in rural Bangladesh. Future efforts should combine similar awareness-raising efforts with longer-term regulatory and structural changes to systematically and sustainably reduce lead exposure.
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NSAIDs in CKD: Are They Safe?
Baker, M, Perazella, MA
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2020;(4):546-557
Abstract
The management of pain in patients with chronic kidney disease (CKD) is challenging for many reasons. These patients have increased susceptibility to adverse drug effects due to altered drug metabolism and excretion, and there are limited safety data for use in this population despite a high pain burden. Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been regarded as dangerous for use in patients with CKD because of their risk for nephrotoxicity and thus alternative classes of analgesics, including opioids, have become more commonly used for pain control in this population. Given the well-established risks that opioids and other analgesics pose, further characterization of the risk posed by NSAIDs in patients with CKD is warranted. NSAID use has been associated with acute kidney injury, progressive loss of glomerular filtration rate in CKD, electrolyte derangements, and hypervolemia with worsening of heart failure and hypertension. The risk for these nephrotoxicity syndromes is modified by many comorbid conditions, risk factors, and characteristics of use, and in patients with CKD, the risk differs between levels of glomerular filtration rate. In this review, we offer recommendations for the cautious use of NSAIDs in the CKD population after careful consideration of these risk factors on an individualized basis.
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Hippocampal plasticity underpins long-term cognitive gains from resistance exercise in MCI.
Broadhouse, KM, Singh, MF, Suo, C, Gates, N, Wen, W, Brodaty, H, Jain, N, Wilson, GC, Meiklejohn, J, Singh, N, et al
NeuroImage. Clinical. 2020;:102182
Abstract
Dementia affects 47 million individuals worldwide, and assuming the status quo is projected to rise to 150 million by 2050. Prevention of age-related cognitive impairment in older persons with lifestyle interventions continues to garner evidence but whether this can combat underlying neurodegeneration is unknown. The Study of Mental Activity and Resistance Training (SMART) trial has previously reported within-training findings; the aim of this study was to investigate the long-term neurostructural and cognitive impact of resistance exercise in Mild Cognitive Impairment (MCI). For the first time we show that hippocampal subareas particularly susceptible to volume loss in Alzheimer's disease (AD) are protected by resistance exercise for up to one year after training. One hundred MCI participants were randomised to one of four training groups: (1) Combined high intensity progressive resistance and computerised cognitive training (PRT+CCT), (2) PRT+Sham CCT, (3) CCT+Sham PRT, (4) Sham physical+sham cognitive training (SHAM+SHAM). Physical, neuropsychological and MRI assessments were carried out at baseline, 6 months (directly after training) and 18 months from baseline (12 months after intervention cessation). Here we report neuro-structural and functional changes over the 18-month trial period and the association with global cognitive and executive function measures. PRT but not CCT or PRT+CCT led to global long-term cognitive improvements above SHAM intervention at 18-month follow-up. Furthermore, hippocampal subfields susceptible to atrophy in AD were protected by PRT revealing an elimination of long-term atrophy in the left subiculum, and attenuation of atrophy in left CA1 and dentate gyrus when compared to SHAM+SHAM (p = 0.023, p = 0.020 and p = 0.027). These neuroprotective effects mediated a significant portion of long-term cognitive benefits. By contrast, within-training posterior cingulate plasticity decayed after training cessation and was unrelated to long term cognitive benefits. Neither general physical activity levels nor fitness change over the 18-month period mediated hippocampal trajectory, demonstrating that enduring hippocampal subfield plasticity is not a simple reflection of post-training changes in fitness or physical activity participation. Notably, resting-state fMRI analysis revealed that both the hippocampus and posterior cingulate participate in a functional network that continued to be upregulated following intervention cessation. Multiple structural mechanisms may contribute to the long-term global cognitive benefit of resistance exercise, developing along different time courses but functionally linked. For the first time we show that 6 months of high intensity resistance exercise is capable of not only promoting better cognition in those with MCI, but also protecting AD-vulnerable hippocampal subfields from degeneration for at least 12 months post-intervention. These findings emphasise the therapeutic potential of resistance exercise; however, future work will need to establish just how long-lived these outcomes are and whether they are sufficient to delay dementia.
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Randomized Trial of Reverse Colocated Integrated Care on Persons with Severe, Persistent Mental Illness in Southern Texas.
Errichetti, KS, Flynn, A, Gaitan, E, Ramirez, MM, Baker, M, Xuan, Z
Journal of general internal medicine. 2020;(7):2035-2042
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BACKGROUND Persons with severe, persistent mental illness (SPMI) are at high risk for poor health and premature mortality. Integrating primary care in a mental health center may improve health outcomes in a population with SPMI in a socioeconomically distressed region of the USA. OBJECTIVE To examine the effects of reverse colocated integrated care on persons with SPMI and co-morbid chronic disease receiving behavioral health services at a local mental health authority located at the US-Mexico border. DESIGN Randomized trial evaluating the effect of a reverse colocated integrated care intervention among chronically ill adults. PARTICIPANTS Participants were recruited at a clinic between November 24, 2015, and June 30, 2016. INTERVENTIONS Receipt of at least two visits with a primary care provider and at least one visit with a chronic care nurse or dietician, compared with usual care (behavioral health only). MAIN MEASURES The primary outcome was blood pressure. Secondary outcomes included HbA1c, BMI, total cholesterol, and depressive symptoms. Sociodemographic data were collected at baseline, and outcomes were measured at baseline and 6- and 12-month follow-ups. KEY RESULTS A total of 416 participants were randomized to the intervention (n = 249) or usual care (n = 167). Groups were well balanced on almost all baseline characteristics. At 12 months, intent-to-treat analysis showed intervention participants improved their systolic blood pressure (β = - 3.86, p = 0.04) and HbA1c (β = - 0.36, p = 0.001) compared with usual care participants when controlling for age, sex, and other baseline characteristics. No participants withdrew from the study due to adverse effects. Per-protocol analyses yielded similar results to intent-to-treat analyses and found a significantly protective effect on diastolic blood pressure. Older and diabetic populations differentially benefited from this intervention. CONCLUSIONS Colocation and integration of behavioral health and primary care improved blood pressure and HbA1c after 1-year follow-up for persons with SPMI and co-morbid chronic disease in a US-Mexico border community. TRIAL REGISTRATION clinicaltrials.gov , Identifier: NCT03881657.