Exploring the Impact of Optimized Probiotic Supplementation Techniques on Diabetic Nephropathy: Mechanisms and Therapeutic Potential.

Worldwide, diabetic nephropathy (DN) is a significant contributor to end-stage renal failure and chronic kidney disease. Probiotic supplementation has recently gained popularity as a potential nutritional therapy in several clinical trials aimed at improving renal function, inflammation, oxidative stress, dyslipidemia, glycemic control, and inflammation. However, they still need to undergo a thorough assessment of DN. It is crucial that the optimal dosage, duration, and combination of probiotic strains administered for the purpose of slowing down the advancement of DN be assessed. Based on the available publications, including relevant randomized controlled trials, systematic reviews, and meta-analysis from 2013-2023 from search engines like MEDLINE (PubMed), Scopus, and Web of Science, a literature review was generated using the keywords "gut microbiota," "gut microbiome," "diabetic kidney disease," "diabetic nephropathy," "probiotic," and "prebiotic." Multiple clinical trials focusing on probiotic administration techniques revealed changes in renal, glucose, and lipid biomarkers. Probiotic supplementation using Bifidobacterium bifidum, Lactobacillus acidophilus, and Streptococcus thermophilus for 12 weeks indicated a reduction in glycosylated hemoglobin, fasting blood glucose, and the microalbuminuria/creatinine ratio. Multispecies as well as single-species probiotic administration containing Lactobacillus, Bifidobacterium, and Streptococcus thermophilus spp. greater than 4*109 colony forming units (CFU)/day for 8-12 weeks in DN patients improves renal metabolic markers and reduces the progression of disease patterns. Optimal supplementation techniques of probiotics in conjunction with prebiotics and synbiotics in DN benefit glycaemic control, renal function, blood lipid profile, inflammation, and oxidative stress. Future randomized controlled trials supplementing specific probiotics coupled with prebiotics and synbiotics, with larger sample sizes and longer follow-up times, will generate more reliable findings for the impact of probiotic supplementation on DN.

Dialysis costs for a health system participating in value-based care.

OBJECTIVES: Unplanned "crash" dialysis starts are associated with worse outcomes and higher costs, a challenging problem for health systems participating in value-based care (VBC). We examined expenditures and utilization associated with these events in a large health system. STUDY DESIGN: Retrospective, single-center study at Cleveland Clinic, a large, integrated health system participating in VBC contracts, including a Medicare accountable care organization. METHODS: We analyzed beneficiaries who transitioned to dialysis between 2017 and 2020. Crash starts involved initiating inpatient hemodialysis (HD) with a central venous catheter (CVC). Optimal starts were initiated with either home dialysis or outpatient HD without a CVC. Suboptimal starts were initiated with outpatient HD with a CVC or inpatient HD without a CVC. RESULTS: A total of 495 patients initiated chronic dialysis: 260 crash starts, 130 optimal starts, and 105 suboptimal starts. Median predialysis 12-month cost was $67,059 for crash starts, $17,891 for optimal starts, and $7633 for suboptimal starts (P < .001). Median postdialysis 12-month cost was $71,992 for crash starts, $55,427 for optimal starts, and $72,032 for suboptimal starts (P = .001). Predialysis inpatient admission per 1000 beneficiaries was 1236 per 1000 for crash starts vs 273 per 1000 for optimal starts and 170 per 1000 for suboptimal starts (P < .001). Postdialysis inpatient admission for crash starts was 853 per 1000 vs 291 per 1000 for optimal starts and 184 per 1000 for suboptimal starts (P < .001). CONCLUSIONS: In a major health system, crash starts demonstrated the highest cost and hospital utilization, a pattern that persisted after dialysis initiation. Developing strategies to promote optimal starts will improve VBC contract performance.

Incidental Colonic Masses, Cytomegalovirus Infection, and Amyloidosis in a Treatment-Naive Chronic Lymphocytic Leukemia (CLL) Patient without GI Symptoms.

Gastrointestinal (GI) involvement by chronic lymphocytic leukemia (CLL) is quite uncommon and generally presents with GI bleeding, abdominal pain, and obstruction. However, presentation of CLL as discrete masses without GI symptoms is very rare. A notable complication for patients with CLL is infection due to immunological dysregulation and is typically caused by encapsulated bacteria involving the respiratory tract while viral infections often happen post treatment. Here we present a 78-years-old female with history of treatment-naïve CLL who was incidentally found to have discrete colonic masses secondary to CLL, as well as cytomegalovirus (CMV) and herpes simplex virus (HSV) infections during endoscopic studies for colostomy reversal. On follow-up computed tomography, she was found to have pulmonary amyloidosis as well. We recommend that gastrointestinal tract evaluation should be a part of the complete assessment of the treatment response and remission status in CLL patients to permit early and appropriate therapeutic intervention.

Rapidly Evolving and Fatal Miliary Tuberculosis and COVID-19 Infection in an Infant.

Tuberculosis (TB) and SARS-CoV-2 (COVID-19) are two important infectious diseases causing morbidity and mortality worldwide. Active TB infection can stimulate host immune responses and together with COVID-19, may lead to cytokine storm and immune dysregulation leading to multi-organ failure. We present a rare case of both miliary tuberculosis and SARS-CoV-2 co-infection in an infant who was a 6-month-old previously healthy term boy. He had persistent cough and congestion, became severely ill, and was brought to the emergency department. He was found to be COVID-19 positive by PCR test. Laboratory studies showed pancytopenia, elevated inflammatory markers, and an abnormal coagulation profile with coagulopathy. He developed strokes, severe sepsis, and electrolyte abnormalities, and declined rapidly within 6 days. Autopsy examination showed multifocal micro-abscesses in multiple organs, which on microscopic examination showed necrotic foci teeming with Mycobacteria and were culture positive for M. tuberculosis Neuropathological examination showed infarction in the right middle and posterior cerebral artery territories. This patient helps illuminate some immunological and pathological aspects of two co-occurring infectious diseases and the susceptibility for the development of fatal complications with SARS-CoV-2 infection in the pediatric population.

Generation of two induced pluripotent stem cell (iPSC) lines from patients with Duchenne muscular dystrophy (IGIBi006-A and IGIBi008-A) carrying exonic deletions in the dystrophin gene.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with defect in dystrophin gene that shows features of degeneration of muscle tissue at an early age. Here, we describe iPSC lines generated from LCL of two patients of Indian origin carrying 46-48 and 49-50 exons deletions in DMD. The resulting iPSC lines IGIBi006-A and IGIBi008-A showed all the characteristic features of pluripotency, differentiated into cells of three germ layers in vitro and have no major genetic alterations due to reprogramming process. These lines can serve as a useful cell model for studying disease pathogenesis and will aid in precision therapy.

Therapeutic Management of Chronic Lymphocytic Leukemia Presenting with Recurrent Massive Ascites.

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy that is categorized by the production and accumulation of CD5+ monoclonal B cell lymphocytes, commonly in the spleen, bone marrow, and peripheral blood; these are morphologically mature lymphocytes with abnormal immune function. Ascites, although common in solid organ malignancies such as ovarian, breast, and gastrointestinal, is a rare clinical manifestation in hematological malignancies. The case presented herein describes an elderly male patient with CLL who presented with transudative ascites 7 years after the completion of chemotherapy. Microscopic analysis and flow cytometry of the patient's ascitic fluid were consistent with CLL, and he was treated with six cycles of obinutuzumab immunotherapy with the addition of acalabrutinib, resulting in near resolution of malignant ascites. A few cases have reported CLL manifesting as transudative or exudative ascites in elderly patients. A few previous cases have reported the development of ascites between 12 and 21 months after the initial treatment of CLL with chemotherapy. A unique feature of our patient is the presentation with malignant ascites nearly 7 years after the initial CLL treatment with chemotherapy. The intent of this case report is to bring awareness of ascites as a possible initial presenting symptom of CLL in patients with isolated abdominal distention with or without common clinical features of leukemia (i.e., splenomegaly, lymphadenopathy, and B-symptoms) and the therapeutic management thereafter. Malignant ascites may be associated with relapse or the transformation of leukemia; thus, prompt diagnosis and treatment should not be delayed.

Lab resource: Single cell line generation and characterization of a human-derived induced pluripotent stem cell line (IGIBi005-A) from a patient with spastic paraplegia/ataxia/ALS phenotype due to the mutation of the gene Kinesin Family Member 5A (KIF5A).

Human Kinesin Family Member 5A (KIF5A) gene mutations have been identified as a putative genetic cause of amyotrophic lateral sclerosis (ALS). Disease modelling using human-induced pluripotent stem cells (HiPSCs) is the next-generation approach to studying numerous human diseases. For the current investigation, we report the generation of patient-specific KIF5A iPSC lines with a mutation at the splice site mutation (c.3020 + 3 A > T) in the intronic region. The resulting line displayed markers for pluripotency, a healthy karyotype, the ability to differentiate into three germ layers in vitro, vector clearance, the KIF5A mutation, STR-based genomic identity, and contamination-free culture.

Technical Note: Newly Reformulated Total and Free PSA Immunoassay on Cobas e411 Analyzer Is Virtually Free from Biotin Interference.

OBJECTIVE: Total and free prostate specific antigens (PSA) have been used as diagnostic markers for monitoring progress of therapy in patients with prostate cancer as well as for screening purpose. Roche total and free PSA immunoassay utilizes biotinylated antibody in assay design. As a result, both assays are affected by elevated serum biotin levels. Recently, Roche reformulated these assays to reduce biotin interference. We evaluated biotin interference in these products. MATERIALS AND METHODS: We prepared three serum pools with one pool containing high amount of total PSA. Then aliquots of each serum pool were further supplemented with various concentrations of biotin (100-1500 ng/mL) followed by measuring both total and free PSA using Roche total and free PSA immunoassay and Cobas e411 analyzer. RESULTS: We observed no significant interference of biotin in both total and free PSA assays up to biotin concentration of 1200 ng/mL. CONCLUSION: We concluded that newly reformulated total and free PSA immunoassays are virtually free from biotin interference.

An Unusual Presentation of Extracavitary Primary Effusion Lymphoma: Internal Jugular Vein Occlusion, Intractable Symptoms of Intracranial Hypertension, and Prolonged Remission after Highly Active Antiretroviral Therapy.

Primary involvement of the skeletal muscle by extracavitary primary effusion lymphoma (PEL) is an extremely rare phenomenon. We report an unusual case of PEL involving the jugulodigastric skeletal muscle without serous cavity involvement which resulted in complete occlusion of the ipsilateral proximal internal jugular vein, causing the patient to present with clinical features of intractable throbbing headache, photophobia, acute confusion state, sporadic syncopal attacks, and dyspnea without obvious palpable neck swellings. This led to an initial clinical suspicion, dedicated diagnostic workup, and empiric therapy for acute meningoencephalitis, severe atypical pneumonia, and acute pulmonary embolism. Owing to his refractory symptoms, exploratory CT imaging eventually revealed a heterogenous jugulodigastric mass, and finally, a pathologic diagnosis of extracavitary PEL was identified as the cause of his intracranial hypertension. The patient remains in remission 22 months after commencing a dolutegravir-based HAART regimen without any chemotherapeutic intervention.

CD2-negative lymphoma-associated T-cells: a potential mechanism of immune-evasion in diffuse large B-cell lymphoma.

CD2 is a costimulatory protein expressed in all mature T/NK-cells, in particular memory T-cells. CD58 (or LFA-3) is the receptor for CD2 and is ubiquitously expressed. CD2-CD58 interaction has key functions in T-cell activation and organization of the immunological synapse between T- and antigen-presenting cells. Cancer cells have developed multiple mechanisms to evade immune surveillance. Loss of CD58 expression is one frequently reported in diffuse large B-cell lymphomas (DLBCL). On the other hand, in non-hematological neoplasms, tumor infiltrating lymphocytes (TILs) with reduced expression of CD2 have been associated with defective cytotoxicity and T-cell exhaustion. Here, we reported a case of DLBCL involving the jejunal mucosa associated with a rim of cytotoxic reactive T-cells with features of immune evasion (CD2- and TCR-) and T-cell exhaustion (PD1 + high). This case likely exemplifies a previously unrecognized immune evasion mechanism in lymphoma involving a decreased CD2 expression in the lymphoma-associated T-cells.

Role of Pentacyclic Triterpenoid Acids in the Treatment of Bladder Cancer.

Bladder cancer carries a poor prognosis and has proven resistance to chemotherapy. Pentacyclic Triterpenoid Acids (PTAs) are natural bioactive compounds that have a well-known impact on cancer research because of their cytotoxic and chemopreventive activities. This review focuses on bladder cancer which can no longer be successfully treated by DNA damaging drugs. Unlike most of the existing drugs against bladder cancer, PTAs are non-toxic to normal cells. Collecting findings from both in vitro and in vivo studies, it has been concluded that PTAs may serve as promising agents in future bladder cancer therapy. In this review, the roles of various PTAs in bladder cancer have been explored, and their mechanisms of action in the treatment of bladder cancer have been described. Specific PTAs have been shortlisted from each of the chief skeletons of pentacyclic triterpenoids, which could be effective against bladder cancer because of their mode of action. This review thereby throws light on the multi targets and mechanisms of PTAs, which are responsible for their selective anticancer effects and provides guidelines for further research and development of new natural antitumor compounds.

Induction of apoptosis in human bladder cancer cells by triterpenoids isolated from Holarrhena antidysenterica through differential reactive oxygen species generation.

A novel triterpenoid, holarol(1),3ß-lup-20(31)-en-3,29,30-triol along with one seco-triterpenoid, dihydrocanaric acid(2) and one known pentacyclic triterpenoid, betulin(3) have been isolated from Holarrhena antidysenterica (L.)Wall. (Family: Apocynaceae). The structures of the compounds were elucidated by extensive IR, 1D, 2D NMR and mass spectrometric analysis. The optimised geometry of (1) was calculated by density-functional theory (DFT) using M06-2X hybrid functional and 6-31 G(D) basis set. The compounds showed differential cytotoxic activities in the cell lines-HeLa, EAC, Raji and T24. Seco-triterpenoid (2) showed highest sensitivity (IC50: 1.710 µg/mL) against the bladder cancer cell line T24 followed by (1) (IC50 9.698 µg/mL) and (3) (IC50 11.769 µg/mL). Compound (1) showed highest reactive oxygen species (ROS) generation in T24 cell line followed by (3) and (2) resulting in induction of apoptosis through activation of caspase, cleavage of PARP and reduction of Bcl-2/Bax ratio. Thus compounds (1), (2) along with (3) could be potent anticancer agents.

In silico analysis of new flavonoids from Pongamia pinnata with a therapeutic potential for age-related macular degeneration.

Age-related macular degeneration (AMD) leads to progressive degeneration of the macula which ultimately results in the complete loss of central vision. The present study aims to identify the new therapeutic agents for curing AMD. In the present study we have isolated, and compared the activity of natural flavonoids (Karanjin, Karanjachromene, Pongachromene, Pongapin) from plant species Pongamia pinnata (L.) Pierre (Family: Fabaceae) with known flavonol, Quercetin, and a drug Pazopanib through in silico approaches. Chemical structures of isolated flavonoids passed the ADME and PASS analysis, showed drug-like properties without violation of Lipinski parameters. Molecular docking studies were also performed for all isolated flavonoids with the receptors responsible for AMD viz. P2X7, PPAR, RAGE, and TLR3. Docking scores of the flavonoids with the receptors were found to be comparable to that of Quercetin, and Pazopanib (drugs already known for AMD treatment). Among all the flavonoids, Karanjachromene [P2X7 (- 31.39)] and Pongachromene [PPAR (- 65.13), RAGE (- 43.42)] showed a very good binding affinity with receptors predicting them to be the new potent chemical entities for the treatment of AMD.

Role of radical quenching activity of dihydrocanaric acid in the treatment of cancer-experimental and theoretical.

In the present study, we have experimentally and theoretically studied the free-radical quenching property of dihydrocanaric acid (DCA) isolated from seedpods of Holarrhena antidysenterica. A modified method was used to estimate the nitric oxide scavenging effect of the DCA (significant activity of 75.22%) along with methanolic extract of seed pods of Holarrhena antidysenterica (72.80%) compared to the ascorbic acid as standard (40.60%). Studies have also been conducted for superoxide scavenging activity of the DCA (78.82%) and methanolic extract of seed pods (84.28%) compared to quercetin as standard (82.08%). Theoretically, it has been determined by density-functional theory(DFT) calculations using M06-2X hybrid functional and the double-ζ- split-valence 6-31G (d, p) basis set that the nitric oxide scavenging activity of the compound is by the addition of NO radical at double bond position. Predicted biological activity profile of DCA suggests that it has less activity probability (Pa) for toxicity (Pa = 0.730), cytotoxicity (Pa = 0.208), compared to those chemical entities that are already known as anticancer agents indicating that DCA is less toxic and more tolerable for normal cells. Furthermore, molecular docking studies of the DCA with different studied cancer-related receptors [Estrogen receptor (- 60.12 kcal/mol), epidermal growth factor receptor (EGFR) (- 30.33 kcal/mol), estrogen receptor alpha (- 4.82 kcal/mol), uPAR (- 32.55 kcal/mol) and an enzyme having lipid kinase activity phosphoinositide 3-kinase (- 55.94 kcal/mol)] were found to have better binding affinities compared to betulinic acid and doxorubicin. Thus, our findings suggest that the DCA could be a safer and effective alternative in fighting cancer with minimal side effects.

Role of nitric oxide-scavenging activity of Karanjin and Pongapin in the treatment of Psoriasis.

In the present study, Karanjin and Pongapin, two important furanoflavone, constituents of Pongamia pinnata were studied in the management of Psoriasis. Presently, we have experimentally studied the free radical quenching property of Karanjin and Pongapin. A modified method was used to estimate the scavenging effect of the Karanjin (the highest activity of 95.60%) and Pongapin (68.05%) compared to the ascorbic acid as standard (11.60%) against nitric oxide. Furthermore, Molecular docking studies were performed using CLC drug discovery workbench software version 3.0 of the studied flavones (Karanjin and Pongapin) with the receptors responsible for psoriasis (viz. IL-17A, IL-17F, IL-23, RORγt, and TLR-7). Docking scores of Karanjin and Pongapin with different studied receptors were found to be comparable to that of Methotrexate, a known drug for treating Psoriasis. Docking results suggest that Karanjin and Pongapin might also help in controlling the disease. Overall, our results indicate that flavones (Karanjin and Pongapin) could be a natural and better alternative in curing psoriasis without any side effects.

A novel biflavonyloxymethane from Pongamia pinnata and its radical quenching activity.

The root bark of Pongamia pinnata Pierre (syn P. glabra Vent.) has afforded a new biflavonyloxymethane, pongabiflavone, along with a known furanoflavone, 3-methoxy-(7, 8, 2", 3") furanoflavone. The structure of this new compound was elucidated from extensive spectral studies, including 2D-NMR spectroscopic experiments. The antioxidant, radical quenching activity- superoxide and nitric oxide quenching activities of both pongabiflavone and previously isolated karanjabiflavone have been evaluated which can be a key to cure Psoriasis.

A new biflavonyloxymethane from Pongamia pinnata.

The root bark of Pongamia pinnata Pierre Syn Pongamia glabra (Family: Fabaceae) has afforded a new biflavonyloxymethane, karanjabiflavone, along with a known furanoflavone, pongapin. The structure of this new biflavonyloxymethane was elucidated from extensive spectral studies including 2D-NMR experiments. Both of these compounds possess antioxidant activity.

A new sesquiterpenoid coumarin from Ferula assafoetida.

The gum resin of Ferula assafoetida Linn. afforded one new sesquiterpene, asimafoetida 1 and three known sesquiterpenoid coumarins. The structure has been established from extensive 2D NMR spectral studies as 7'-[7-(1R,3S)-5-Hydroxy-6,6-dimethyl-2-methylene-cyclohexyl]-9-methyl-9-pentenyl]oxy]-2H-1-benzopyran-2-one. The other three known compounds are ferulic acid, farnesiferol A and farnesiferol C.