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The Journal of Clinical Endocrinology... Apr 2024Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing...
Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing genetic growth disorders. Growth-altering treatments have broadened the role of the pediatric endocrinologist to manage and sometimes become primary coordinators for genetic disorders such as Turner syndrome and Prader-Willi syndrome. We illustrate how recent advances in understanding the pathophysiology of skeletal disorders and the development of targeted treatments provide an opportunity for pediatric endocrinologists to further expand their role in managing certain skeletal dysplasias, including achondroplasia.
Topics: Child; Humans; Endocrinologists; Osteochondrodysplasias; Achondroplasia; Prader-Willi Syndrome
PubMed: 38078681
DOI: 10.1210/clinem/dgad726 -
Scientific Reports Jul 2023Opioid Use Disorder (OUD) is associated with tremendous morbidity and mortality. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable...
Opioid Use Disorder (OUD) is associated with tremendous morbidity and mortality. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable for many patients. As such, interventions aimed at promoting resilience against OUD are of immense clinical interest. Treatment with a Bioactive Dietary Polyphenol Preparation (BDPP) promotes resilience and adaptive neuroplasticity in multiple models of neuropsychiatric disease. Here, we assessed effects of BDPP treatment on behavioral and molecular responses to repeated morphine treatment in male mice. BDPP pre-treatment alters responses for both locomotor sensitization and conditioned place preference. Most notably, polyphenol treatment consistently reduced formation of preference at low dose (5 mg/kg) morphine but enhanced it at high dose (15 mg/kg). In parallel, we performed transcriptomic profiling of the nucleus accumbens, which again showed a dose × polyphenol interaction. We also profiled microbiome composition and function, as polyphenols are metabolized by the microbiome and can act as prebiotics. The profile revealed polyphenol treatment markedly altered microbiome composition and function. Finally, we investigated involvement of the SIRT1 deacetylase, and the role of polyphenol metabolites in behavioral responses. These results demonstrate polyphenols have robust dose-dependent effects on behavioral and physiological responses to morphine and lay the foundation for future translational work.
Topics: Mice; Male; Animals; Morphine; Nucleus Accumbens; Polyphenols
PubMed: 37500710
DOI: 10.1038/s41598-023-39334-9 -
Acta Neuropathologica Jan 2024Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. SCA6 is rare, and many patients are not...
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. SCA6 is rare, and many patients are not diagnosed until long after disease onset. Whether disease-causing cellular alterations differ at different disease stages is currently unknown, but it is important to answer this question in order to identify appropriate therapeutic targets across disease duration. We used transcriptomics to identify changes in gene expression at disease onset in a well-established mouse model of SCA6 that recapitulates key disease features. We observed both up- and down-regulated genes with the major down-regulated gene ontology terms suggesting mitochondrial dysfunction. We explored mitochondrial function and structure and observed that changes in mitochondrial structure preceded changes in function, and that mitochondrial function was not significantly altered at disease onset but was impaired later during disease progression. We also detected elevated oxidative stress in cells at the same disease stage. In addition, we observed impairment in mitophagy that exacerbates mitochondrial dysfunction at late disease stages. In post-mortem SCA6 patient cerebellar tissue, we observed metabolic changes that are consistent with mitochondrial impairments, supporting our results from animal models being translatable to human disease. Our study reveals that mitochondrial dysfunction and impaired mitochondrial degradation likely contribute to disease progression in SCA6 and suggests that these could be promising targets for therapeutic interventions in particular for patients diagnosed after disease onset.
Topics: Mice; Animals; Humans; Mitophagy; Spinocerebellar Ataxias; Cerebellum; Disease Progression; Mitochondrial Diseases
PubMed: 38286873
DOI: 10.1007/s00401-023-02680-z -
Kidney International Oct 2023Fabry disease is a rare disorder caused by variations in the alpha-galactosidase gene. To a degree, Fabry disease is manageable via enzyme replacement therapy (ERT). By...
Systems analyses of the Fabry kidney transcriptome and its response to enzyme replacement therapy identified and cross-validated enzyme replacement therapy-resistant targets amenable to drug repurposing.
Fabry disease is a rare disorder caused by variations in the alpha-galactosidase gene. To a degree, Fabry disease is manageable via enzyme replacement therapy (ERT). By understanding the molecular basis of Fabry nephropathy (FN) and ERT's long-term impact, here we aimed to provide a framework for selection of potential disease biomarkers and drug targets. We obtained biopsies from eight control individuals and two independent FN cohorts comprising 16 individuals taken prior to and after up to ten years of ERT, and performed RNAseq analysis. Combining pathway-centered analyses with network-science allowed computation of transcriptional landscapes from four nephron compartments and their integration with existing proteome and drug-target interactome data. Comparing these transcriptional landscapes revealed high inter-cohort heterogeneity. Kidney compartment transcriptional landscapes comprehensively reflected differences in FN cohort characteristics. With exception of a few aspects, in particular arteries, early ERT in patients with classical Fabry could lastingly revert FN gene expression patterns to closely match that of control individuals. Pathways nonetheless consistently altered in both FN cohorts pre-ERT were mostly in glomeruli and arteries and related to the same biological themes. While keratinization-related processes in glomeruli were sensitive to ERT, a majority of alterations, such as transporter activity and responses to stimuli, remained dysregulated or reemerged despite ERT. Inferring an ERT-resistant genetic module of expressed genes identified 69 drugs for potential repurposing matching the proteins encoded by 12 genes. Thus, we identified and cross-validated ERT-resistant gene product modules that, when leveraged with external data, allowed estimating their suitability as biomarkers to potentially track disease course or treatment efficacy and potential targets for adjunct pharmaceutical treatment.
Topics: Humans; alpha-Galactosidase; Biomarkers; Drug Repositioning; Enzyme Replacement Therapy; Fabry Disease; Kidney; Kidney Diseases; Systems Analysis; Transcriptome
PubMed: 37419447
DOI: 10.1016/j.kint.2023.06.029 -
Animals : An Open Access Journal From... Jul 2023Feces enable frequent samplings for the same animal, which is valuable in studies investigating the development of the gut microbiome in piglets. Creep feed should...
Feces enable frequent samplings for the same animal, which is valuable in studies investigating the development of the gut microbiome in piglets. Creep feed should prepare the piglet's gut for the postweaning period and shape the microbiome accordingly. Little is known about the variation that is caused by differences in fecal color and consistency and different sample types (feces versus swab samples). Therefore, this study evaluated the age-related alterations in the microbiome composition (16S rRNA gene) in feces of suckling and newly weaned piglets in the context of nutrition and fecal consistency, color and sample type from day 2 to 34 of life. Feces from 40 healthy piglets (2 each from 20 litters) were collected on days 2, 6, 13, 20, 27, 30 and 34. Weaning occurred on day 28. Half of the litters only drank sow milk during the suckling phase, whereas the other half had access to creep feed from day 10. Creep feeding during the suckling phase influenced the age-related total bacterial and archaeal abundances but had less of an influence on the relative bacterial composition. Results further showed different taxonomic compositions in feces of different consistency, color and sample type, emphasizing the need to consider these characteristics in comprehensive microbiome studies.
PubMed: 37508029
DOI: 10.3390/ani13142251 -
MBio Feb 2024Biofilms are matrix-encased microbial communities that increase the environmental fitness and infectivity of many human pathogens including . Biofilm matrix assembly is...
Biofilms are matrix-encased microbial communities that increase the environmental fitness and infectivity of many human pathogens including . Biofilm matrix assembly is essential for biofilm formation and function. Known components of the biofilm matrix are the polysaccharide polysaccharide (VPS), matrix proteins RbmA, RbmC, Bap1, and extracellular DNA, but the majority of the protein composition is uncharacterized. This study comprehensively analyzed the biofilm matrix proteome and revealed the presence of outer membrane proteins (OMPs). Outer membrane vesicles (OMVs) were also present in the biofilm matrix and were associated with OMPs and many biofilm matrix proteins suggesting that they participate in biofilm matrix assembly. Consistent with this, OMVs had the capability to alter biofilm structural properties depending on their composition. OmpU was the most prevalent OMP in the matrix, and its absence altered biofilm architecture by increasing VPS production. Single-cell force spectroscopy revealed that proteins critical for biofilm formation, OmpU, the matrix proteins RbmA, RbmC, Bap1, and VPS contribute to cell-surface adhesion forces at differing efficiency, with VPS showing the highest efficiency whereas Bap1 showing the lowest efficiency. Our findings provide new insights into the molecular mechanisms underlying biofilm matrix assembly in , which may provide new opportunities to develop inhibitors that specifically alter biofilm matrix properties and, thus, affect either the environmental survival or pathogenesis of .IMPORTANCECholera remains a major public health concern. , the causative agent of cholera, forms biofilms, which are critical for its transmission, infectivity, and environmental persistence. While we know that the biofilm matrix contains exopolysaccharide, matrix proteins, and extracellular DNA, we do not have a comprehensive understanding of the majority of biofilm matrix components. Here, we discover outer membrane vesicles (OMVs) within the biofilm matrix of . Proteomic analysis of the matrix and matrix-associated OMVs showed that OMVs carry key matrix proteins and polysaccharide (VPS) to help build biofilms. We also characterize the role of the highly abundant outer membrane protein OmpU in biofilm formation and show that it impacts biofilm architecture in a VPS-dependent manner. Understanding biofilm formation is important for developing a better prevention and treatment strategy framework.
Topics: Humans; Vibrio cholerae; Membrane Proteins; Extracellular Polymeric Substance Matrix; Proteomics; Bacterial Proteins; Biofilms; Polysaccharides; DNA
PubMed: 38206049
DOI: 10.1128/mbio.03304-23 -
Cureus Jul 2023Neurosarcoidosis (NS) is a rare manifestation of sarcoidosis, a multisystem inflammatory granulomatous disease. We describe a unique case of NS with confusion and speech...
Neurosarcoidosis (NS) is a rare manifestation of sarcoidosis, a multisystem inflammatory granulomatous disease. We describe a unique case of NS with confusion and speech alteration as presenting symptoms. A 65-year-old male with a history of Ramsay Hunt syndrome and Lyme infection presented to the emergency room after an acute episode of disorientation, garbled speech, and left facial droop, along with months of worsening generalized fatigue, gait ataxia, left-sided periorbital headaches, bilateral peripheral neuropathy, and bladder disturbance. A recent CT scan of his chest showed mediastinal lymphadenopathy, and a lymph node biopsy revealed non-necrotizing granulomas, Langhans giant cells, and focal Schaumann bodies. A brain MRI revealed a mildly enlarged anterior pituitary gland, mild prominent enhancement of the trigeminal nerves bilaterally, and right frontal, parietal, and superior temporal leptomeningeal enhancement. Lumbar puncture cerebrospinal fluid analyses were consistent with aseptic meningitis. A diagnosis of probable NS was made. The patient received IV methylprednisolone 1 g for three days, followed by a prednisone taper with clinical improvement. NS is a diagnostic challenge due to the variability of clinical presentations of the disease. This case demonstrates how vague chronic neurologic symptoms preceding an unusual acute clinical presentation delayed the diagnosis of NS in a patient with sarcoidosis.
PubMed: 37641764
DOI: 10.7759/cureus.42627 -
Archives of Pathology & Laboratory... Dec 2023Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized.
CONTEXT.—
Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized.
OBJECTIVE.—
To investigate their morphologic, immunohistochemical, and molecular features.
DESIGN.—
Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing.
RESULTS.—
The mean age at diagnosis was 69 years (42-81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%).
CONCLUSIONS.—
Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous.
Topics: Humans; Male; Female; Aged; Bile Ducts; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Carcinoma, Papillary; Bile Duct Neoplasms
PubMed: 36821179
DOI: 10.5858/arpa.2022-0343-OA -
Frontiers in Human Neuroscience 2024Human brain imaging research using functional MRI (fMRI) has uncovered flexible variations in the functional connectivity between brain regions. While some of this... (Review)
Review
Human brain imaging research using functional MRI (fMRI) has uncovered flexible variations in the functional connectivity between brain regions. While some of this variability likely arises from the pattern of information flow through circuits, it may also be influenced by rapid changes in effective synaptic strength at the molecular level, a phenomenon called Dynamic Network Connectivity (DNC) discovered in non-human primate circuits. These neuromodulatory molecular mechanisms are found in layer III of the macaque dorsolateral prefrontal cortex (dlPFC), the site of the microcircuits shown by Goldman-Rakic to be critical for working memory. This research has shown that the neuromodulators acetylcholine, norepinephrine, and dopamine can rapidly change the strength of synaptic connections in layer III dlPFC by (1) modifying the depolarization state of the post-synaptic density needed for NMDA receptor neurotransmission and (2) altering the open state of nearby potassium channels to rapidly weaken or strengthen synaptic efficacy and the strength of persistent neuronal firing. Many of these actions involve increased cAMP-calcium signaling in dendritic spines, where varying levels can coordinate the arousal state with the cognitive state. The current review examines the hypothesis that some of the dynamic changes in correlative strength between cortical regions observed in human fMRI studies may arise from these molecular underpinnings, as has been seen when pharmacological agents or genetic alterations alter the functional connectivity of the dlPFC consistent with the macaque physiology. These DNC mechanisms provide essential flexibility but may also confer vulnerability to malfunction when dysregulated in cognitive disorders.
PubMed: 38384333
DOI: 10.3389/fnhum.2024.1353043 -
Clinical Oral Investigations Aug 2023The effects of water flossing on dental plaque removal have been suggested, but its ecological impact on dental plaque microbiota needs further investigation. In... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
The effects of water flossing on dental plaque removal have been suggested, but its ecological impact on dental plaque microbiota needs further investigation. In addition, whether this plaque control measure by water flossing promotes the control of halitosis still needs clinical validation. The aim of this study was to evaluate the effects of water flossing on gingival inflammation and supragingival plaque microbiota.
MATERIALS AND METHODS
Seventy participants with gingivitis were randomly assigned to control (toothbrushing) and experimental (toothbrushing + water flossing) groups (n = 35). Participants were recalled at 4, 8, and 12 weeks, and their gingival index, sulcus bleeding index, bleeding on probing, dental plaque index, and oral malodor values were measured. The microbiota of supragingival plaque was further investigated using 16S rRNA sequencing and qPCR.
RESULTS
Sixty-three participants completed all revisits (control: n = 33; experimental: n = 30). The experimental and control groups exhibited similar clinical characteristics and dental plaque microbiota at baseline. Adjunctive water flossing effectively reduced the gingival index and sulcus bleeding index as compared to the toothbrushing control group. The water-flossing group showed reduced oral malodor at week 12 as compared to the baseline. Consistently, the water-flossing group exhibited altered dental plaque microbiota at week 12, characterized by a depletion of Prevotella at genus level and Prevotella intermedia at species level as compared to the toothbrushing control. In addition, the plaque microbiota of water-flossing group exhibited a more aerobic phenotype, while the control group was more anaerobic.
CONCLUSIONS
Daily water flossing can effectively alleviate gingival inflammation and reduce oral malodor, possibly by depleting oral anaerobes and altering the oral microbiota to a more aerobic phenotype.
CLINICAL RELEVANCE
Water flossing adjunctive to toothbrushing effectively alleviated gingival inflammation, representing a promising oral hygiene practice to promote oral health.
CLINICAL TRIAL REGISTRATION
The trial was registered in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/showprojen.aspx?proj=61797 , #ChiCTR2000038508) on September 23, 2020.
Topics: Humans; Dental Devices, Home Care; Dental Plaque; Halitosis; Water; RNA, Ribosomal, 16S; Dental Plaque Index; Toothbrushing; Gingivitis; Inflammation
PubMed: 37231271
DOI: 10.1007/s00784-023-05081-4