Treatment Period Research Articles

Comparative evaluation of the effectiveness of balneotherapy and balneotherapy in combination with intravenous laser irradiation of blood at the period of spa treatment of patients with psoriasis

Background. Psoriasis is one of the most common, chronic, recurrent dermatoses. To date, a sufficient pool of studies has been accumulated confirming the multifactorial genesis of psoriasis due to genetic and environmental factors. Aim. Сomparative assessment of the effect of different options for spa treatment (ST) balneotherapy and balneotherapy in combination with intravenous laser blood irradiation (ILBI) in patients with psoriasis vulgaris on the level of IL-6 and IL-17, dermatological and psycho-emotional status, assessment of quality of life. Methods. The comparative study involved 108 patients with psoriasis vulgaris, stationary stage (men — 57.4%, women — 42.6%; the average age was 36.2 [24.5; 47.9] years) who underwent spa treatment, which were subsequently divided into 2 groups: 52 patients who received balneotherapy along with the traditional complex of ST were included in the 1 group, 56 patients who received complex treatment were included in the 2 group. The effectiveness of ST was evaluated using the PASI index, the HARS and HDRS scale, the SF-36 questionnaire. The dynamics of IL-6 and IL-10 levels in blood plasma were evaluated. The total duration of the study was 6 months and 14 days: the treatment phase was 14 days and the follow-up phase was 3 and 6 months after the completion of ST. Results. After 14 days of ST in the group in which balneotherapy was performed in combination with IVBI, a statistically significant decrease in the PASI index was more pronounced compared to the group in which balneotherapy was performed (p). Balneotherapy did not have a pronounced effect on psychoemotional status. On the contrary, balneotherapy in combination with ILBI contributed to a statistically significant decrease in the final indicators on the HARS and HDRS scales. The decrease in IL-6 and IL-17 levels was statistically significant in both groups and there were no differences between them. The complex use of balneotherapy and ILBI in comparison with the group of balneotherapy was accompanied by a more pronounced improvement in QOL. The combined use of balneotherapy and ILBI in the follow-up phase showed a long-term positive effect: 6 months after the completion of ST, the number of patients who had clinical remission was statistically significantly higher compared to the group in which balneotherapy was performed (87.4 vs. 44.7%). Conclusion. The advantage of the combined use of balneotherapy and ILBI compared with balneotherapy in patients with psoriasis vulgaris on CL was shown. The complex use of balneotherapy and ILBI of significant indicators of inflammatory biomarkers, improvement of the dermatological and psycho-emotional state, quality of life parameters and good overpopulation. More pronounced effectiveness of the complex use of balneotherapy and ILBI compared to balneotherapy of the quality, diversity of pathophysiological mechanisms of psoriasis and the presence of several targets for pathogenetic therapy.

Effectiveness of patisiran after switching from tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN [v for variant]) is a rare, progressive disease associated with multisystemic impairments. This study assessed the real-world outcomes of patients with ATTRv-PN who switched from tafamidis to patisiran, as well as the reasons for the treatment switch. This was a retrospective chart review study at a large expert referral center. Data were extracted from medical charts of patients with ATTRv-PN who switched from tafamidis to patisiran on or before 30 August 2019. Data elements included demographic and clinical characteristics, rationale for switch, and disease measures evaluated from tafamidis initiation through the 12-month patisiran treatment period. Among the 24 patients with ATTRv-PN included in the study, 50.0% had a V30M variant, and the mean (SD) age was 67.3 (8.0) years. During tafamidis treatment (mean [SD] = 30.1 [17.5] months) before switching to patisiran, patients worsened across multiple polyneuropathy measures, including walking ability, Neuropathy Impairment Score, and autonomic function. Neuropathic disease progression on tafamidis was the principal reason for switching to patisiran. After 12 months on patisiran (mean [SD] = 11.7 [1.4] months), patients experienced attenuated disease progression or improvement in the aforementioned measures of polyneuropathy. Switching from tafamidis to patisiran attenuated the rate of functional decline, and most patients experienced stabilization or improvement of at least one polyneuropathy measure within 12 months of patisiran treatment. Timely switch from tafamidis to patisiran can be beneficial to avoid rapid disease progression in patients with ATTRv-PN.

Optimal fuzzy P + Dµ controller for cancer chemotherapy

This paper aims to develop a robust, effective, and optimal controller for an automatic intravenous drug delivery system for the chemotherapy treatment of cancer patients. For this purpose, a novel hybrid control method, namely the Fuzzy P + Dµ controller, is designed by combining fractional calculus and fuzzy logic controller (FLC). Particle swarm optimization (PSO) algorithm is employed to tune the controller parameters optimally. To evaluate the performance of the proposed controller, a cancer patient model that considers cumulative drug toxicity, one of the most common side effects of chemotherapy, is utilized. Limits on toxicity and drug concentration for patient safety are incorporated into the controller design and optimization process. The graphical and numerical simulation results show that almost no cancerous cells are left at the end of the treatment period. The effectiveness of the controller is proven by the performance index (PI) obtained. Our optimal hybrid Fuzzy P + Dµ outclasses other control techniques in previous related studies with the best PI of 44.426 and the minimum final number of cancerous cells (FNCCs) of 5.084E-08. Moreover, in robustness tests perturbing intra-patient parameters and using different treatment protocols, the cumulative drug toxicity level is kept within safe limits, and almost no cancerous cells remain.

Rosmarinic Acid Content and Antioxidant Activity in Ehretia asperula Zollinger et Moritzi Cell Suspension Cultures

Background: Ehretia asperula Zollinger et Moritzi is a medicinal tree abundant in rosmarinic acid, the primary phenolic component, with numerous beneficial biological properties, including antioxidant, antibacterial, antiviral, anti-allergy, anti-arthritis, asthma and anti-cancer. Methods: The cell suspension cultures of E. asperula Zollinger et Moritzi derived from the leaf in vitro callus were established in liquid B5 medium added with 0.4 mg/L NAA, 0.1 mg/L BA and 45 g/L glucose. After four weeks, 50 mg/L of chitosan was given to the cell suspension cultures to stimulate rosmarinic acid (RA) production after a 48-hour treatment period. RA content was analyzed using the HPLC and spectrophotometry method after four weeks and 48 hours of chitosan treatment. In addition, the antioxidant capacity of the extracts from E. asperula Zollinger et Moritzi was also tested using DPPH free radical scavenging assay. Result: The RA content and antioxidant capacity of E. asperula Zollinger et Moritzi’ extracts from the leaf in vitro greater than callus derived from the leaf in vitro greater than field-grown leaf greater than biomass of cell suspension cultures. These results suggested a strong correlation between RA concentration and antioxidant capacity. The use of E. asperula Zollinger et Moritzi cell suspension cultures with chitosan as an elicitor for RA production and evaluation of antioxidant activity is presented in this study for the first time. Our results suggest that cell suspension cultures and others may be a good source of RA, an antioxidant compound.

Exploring the multifaceted therapeutic mechanism of Schisanlactone E (XTS) in APP/PS1 mouse model of Alzheimer's disease through multi-omics analysis.

Schisanlactone E, also known as XueTongSu (XTS), is an active compound extracted from the traditional Tujia medicine Kadsura heteroclita ("XueTong"). Recent studies highlight its anti-inflammatory and antioxidant properties, yet the mechanisms of XTS's therapeutic effects on Alzheimer's disease (AD) are unclear. This study aims to elucidate the therapeutic efficacy and mechanisms of XTS in AD. Ten C57BL/6 mice were assigned to the control group (NC), and twenty APP/PS1 transgenic mice were randomly divided into the model group (M) (10 mice) and the XTS treatment group (Tre) (10 mice). After an acclimatization period of 7 days, intraperitoneal injections were administered over a 60-day treatment period. The NC and M groups received saline, while the Tre group received XTS at 2 mg/kg. Learning and memory abilities were assessed using the Morris Water Maze (MWM) test. Histopathological changes were evaluated using hematoxylin and eosin (HE) and Nissl staining, and immunofluorescence was used to assess pathological products and glial cell activation. Cytokine levels (IL-1β, IL-6, TNF-α) in the hippocampus were quantified by qPCR. 16S rDNA sequencing analyzed gut microbiota metabolic alterations, and metabolomic analysis was performed on cortical samples. The KEGG database was used to analyze the regulatory mechanisms of XTS in AD treatment. XTS significantly improved learning and spatial memory in APP/PS1 mice and ameliorated histopathological changes, reducing Aβ plaque aggregation and glial cell activation. XTS decreased the expression of inflammatory cytokines IL-1β, IL-6, and TNF-α. It also enhanced gut microbiota diversity, notably increasing Akkermansia species, and modulated levels of metabolites such as isosakuranetin, 5-KETE, 4-methylcatechol, and sphinganine. Pathway analysis indicated that XTS regulated carbohydrate metabolism, neuroactive ligand-receptor interactions, and alanine, aspartate, and glutamate metabolism, mitigating gut microbiota dysbiosis and metabolic disturbances. XTS ameliorates cognitive deficits, pathological changes, and inflammatory responses in APP/PS1 mice. It significantly modulates the gut microbiota, particularly increasing Akkermansia abundance, and influences levels of key metabolites in both the gut and brain. These findings suggest that XTS exerts anti-AD effects through the microbial-gut-brain axis (MGBA).

Exploring the multifaceted therapeutic mechanism of Schisanlactone E (XTS) in APP/PS1 mouse model of Alzheimer’s disease through multi-omics analysis

BackgroundSchisanlactone E, also known as XueTongSu (XTS), is an active compound extracted from the traditional Tujia medicine Kadsura heteroclita (“XueTong”). Recent studies highlight its anti-inflammatory and antioxidant properties, yet the mechanisms of XTS’s therapeutic effects on Alzheimer’s disease (AD) are unclear. This study aims to elucidate the therapeutic efficacy and mechanisms of XTS in AD.MethodsTen C57BL/6 mice were assigned to the control group (NC), and twenty APP/PS1 transgenic mice were randomly divided into the model group (M) (10 mice) and the XTS treatment group (Tre) (10 mice). After an acclimatization period of 7 days, intraperitoneal injections were administered over a 60-day treatment period. The NC and M groups received saline, while the Tre group received XTS at 2 mg/kg. Learning and memory abilities were assessed using the Morris Water Maze (MWM) test. Histopathological changes were evaluated using hematoxylin and eosin (HE) and Nissl staining, and immunofluorescence was used to assess pathological products and glial cell activation. Cytokine levels (IL-1β, IL-6, TNF-α) in the hippocampus were quantified by qPCR. 16S rDNA sequencing analyzed gut microbiota metabolic alterations, and metabolomic analysis was performed on cortical samples. The KEGG database was used to analyze the regulatory mechanisms of XTS in AD treatment.ResultsXTS significantly improved learning and spatial memory in APP/PS1 mice and ameliorated histopathological changes, reducing Aβ plaque aggregation and glial cell activation. XTS decreased the expression of inflammatory cytokines IL-1β, IL-6, and TNF-α. It also enhanced gut microbiota diversity, notably increasing Akkermansia species, and modulated levels of metabolites such as isosakuranetin, 5-KETE, 4-methylcatechol, and sphinganine. Pathway analysis indicated that XTS regulated carbohydrate metabolism, neuroactive ligand-receptor interactions, and alanine, aspartate, and glutamate metabolism, mitigating gut microbiota dysbiosis and metabolic disturbances.ConclusionXTS ameliorates cognitive deficits, pathological changes, and inflammatory responses in APP/PS1 mice. It significantly modulates the gut microbiota, particularly increasing Akkermansia abundance, and influences levels of key metabolites in both the gut and brain. These findings suggest that XTS exerts anti-AD effects through the microbial-gut-brain axis (MGBA).

Estimation of the Likelihood Ratio of Different Symptoms for Six Homeopathic Medicines: Prognostic Factor Research.

Arsenicum album, Causticum, Nux vomica, Pulsatilla nigricans, Rhus toxicodendron and Sulphur are frequently prescribed homeopathic medicines; however, their symptoms, as mentioned in different homeopathic literature works, have rarely been investigated systematically. Likelihood ratio (LR), based on Bayesian statistics, may reflect a better estimation of the strengths of symptoms than the existing entries in the homeopathic literature. A prospective, longitudinal, analytical patient outcome study was conducted in the outpatient departments of D. N. De Homeopathic Medical College and Hospital, Kolkata, on 1,954 patients over 21 months. The outcomes were recorded at each follow-up using the Outcome Related to Impact on Daily Living (ORIDL) +4 to -4 scale. The average period of treatment for each participant was 3 months. The LRs of four symptoms for each of the six selected medicines were calculated. One hundred and two different remedies were prescribed. The prevalence, LR + , and LR - , with respective 95% confidence intervals, of different symptoms were reported. The study found that the following symptoms had particularly high LR+ scores: "intense sympathy for the suffering of others" (Causticum, LR+ = 12.0); "dyspepsia from business anxiety" (Nux vomica, LR+ = 27.4); "burning pain relieved by heat" (Arsenicum album, LR+ = 29.6); "envy" (Pulsatilla nigricans, LR+ = 13.2); "desire for milk" (Rhus toxicodendron, LR+ = 7.5); "very selfish, no regard for others" (Sulphur, LR+ = 20.6). The findings corroborated well with the presentation of the symptoms in different homeopathic materia medica and repertories. ORIDL scores of +2 or greater were identified most prominently for Pulsatilla nigricans (n = 138) and Sulphur (n = 119). There was adequate evidence to attribute all the assessed symptoms to the medicines investigated. Further studies with a larger population are warranted to tackle the possible confirmation bias.

Potential of Pandan anggur (Sararanga Sinuosa Hemsley) as immunomodulator

Background: Pandan Anggur plant is an endemic plant of the Papua archipelago in Indonesia, and the fruit called Pandan Anggur Fruit (PAF) is freshly consumed or prepared as a juice. Based on previous studies on the phytochemical content of PAF, the ethanol and water extract contain flavonoids, which act as immunomodulators, to regulate the response of immunity. Objectives: This study aimed to examine the potential of PAF as an immunomodulator in malnutrition cases, by evaluating six parameters which are phagocytosis capacity and nitric oxide (NO) production of peritoneal macrophage, spleen lymphocyte proliferation, IFN-γ and IL-4 in lymphocyte culture, and intestinal sIgA levels. By proving the potential of PAF as an immunomodulator, this research will lead to significant development of functional food products of Pandan Anggur. Methods: A total of 35 Sprague Dawley rats were used as animal models divided into seven different groups named standard group (healthy standard), malnourished (negative control), malnourished rats given Imboost Force (positive control), as well as PAF ethanol extract doses of I, II, III, and PAF water extract. The treatment lasted for seven weeks in total and the measurement of immunomodulator parameters was carried out at the end of the treatment period. The immunomodulator parameters included phagocytosis capacity and nitric oxide (NO) production of peritoneal macrophage, spleen lymphocyte proliferation, IFN-γ and IL-4 in lymphocyte culture, and intestinal sIgA levels. Result: The results indicated that the administration of PAF ethanol extract at a dose of 3.15 mg/mL provided an optimum immunostimulant effect, by increasing the macrophage phagocytosis capacity, nitric oxide, lymphocyte proliferation, IL-4, and sIgA levels in rat intestine. However, increasing the dose of extract did not produce a better effect, but led to suppression of immunity. Conclusion: PAF extract at a dose of 3.15 mg/mL provides an immunostimulant effect. Keywords: In Vivo, IL-4, IF-γ, sIgA, lymphocyte proliferation, macrophage, Pandan Anggur Fruit

Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials

ObjectivesAcute anterior uveitis (‘uveitis’) is a common axial spondyloarthritis (axSpA) extramusculoskeletal manifestation. Interleukin (IL)-17 is implicated in its pathogenesis, however, there is conflicting evidence for IL-17A inhibition in uveitis management....

Potential of Pandan anggur (Sararanga Sinuosa Hemsley) as immunomodulator

Background: Pandan Anggur plant is an endemic plant of the Papua archipelago in Indonesia, and the fruit called Pandan Anggur Fruit (PAF) is freshly consumed or prepared as a juice. Based on previous studies on the phytochemical content of PAF, the ethanol and water extract contain flavonoids, which act as immunomodulators, to regulate the response of immunity. Objectives: This study aimed to examine the potential of PAF as an immunomodulator in malnutrition cases, by evaluating six parameters which are phagocytosis capacity and nitric oxide (NO) production of peritoneal macrophage, spleen lymphocyte proliferation, IFN-γ and IL-4 in lymphocyte culture, and intestinal sIgA levels. By proving the potential of PAF as an immunomodulator, this research will lead to significant development of functional food products of Pandan Anggur. Methods: A total of 35 Sprague Dawley rats were used as animal models divided into seven different groups named standard group (healthy standard), malnourished (negative control), malnourished rats given Imboost Force (positive control), as well as PAF ethanol extract doses of I, II, III, and PAF water extract. The treatment lasted for seven weeks in total and the measurement of immunomodulator parameters was carried out at the end of the treatment period. The immunomodulator parameters included phagocytosis capacity and nitric oxide (NO) production of peritoneal macrophage, spleen lymphocyte proliferation, IFN-γ and IL-4 in lymphocyte culture, and intestinal sIgA levels. Result: The results indicated that the administration of PAF ethanol extract at a dose of 3.15 mg/mL provided an optimum immunostimulant effect, by increasing the macrophage phagocytosis capacity, nitric oxide, lymphocyte proliferation, IL-4, and sIgA levels in rat intestine. However, increasing the dose of extract did not produce a better effect, but led to suppression of immunity. Conclusion: PAF extract at a dose of 3.15 mg/mL provides an immunostimulant effect. Keywords: In Vivo, IL-4, IF-γ, sIgA, lymphocyte proliferation, macrophage, Pandan Anggur Fruit

Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double-blind, randomized, placebo-controlled study in healthy subjects.

Dopamine beta-hydroxylase (DβH) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS). A single-centre, prospective, double-blind, randomized, placebo-controlled, crossover study evaluated the effect of 400 mg zamicastat in 22 healthy male subjects. Cold pressor test (CPT) was performed at screening and each treatment period on Days -1 and 10. Plasma and 24 h-urine levels of dopamine (DA), epinephrine (EPI) and norepinephrine (NE), and plasma DβH activity, were measured. Compared to placebo, zamicastat showed a - 4.62 mmHg decrease in systolic blood pressure during the cold stimulus vs. rest phases on Day 10 of CPT (P = .020). Zamicastat decreased mean arterial pressure response to cold stimulus during CPT (-2.62 mmHg; P = .025). At Day 10, zamicastat significantly increased plasma DA, before CPT (12.63 ng/L; P = .040) and after CPT (19.22 ng/L; P = .001) as well as the estimated plasma EPI change from baseline after CPT (P = .040). Inhibition of plasma DβH activity ranged from 19.8% to 25.0%. At Day 10, significant reductions in 24-h urinary excretion of EPI (P = .002) and NE (P = .001) were observed. Zamicastat Cτ geometric mean ± GSD ranged from 45.86 ± 1.46 ng/mL on Day 3 to 58.64 ± 1.52 ng/mL on Day 10, with moderate inter-individual variability (CV: 32.6%-36.6%). Steady state was already achieved on Day 6. Our results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.

The effects of Ganoderma leucocontextum triterpenoids treatment on the D-galactose and aluminum chloride-induced Alzheimer-like pathology in mouse brain

Ethnopharmacology relevanceGanoderma leucocontextum T.H. Li, W. Q. Deng M. Wang & H.P.Hu. is a highland herbal medicine that has been shown to nourish the nervesand prolong life. Nevertheless, there is no evidence to indicate that Ganoderma leucocontextum triterpenoids (GLTs) reduce the damage triggered by Alzheimer's disease (AD). Aim of the studyThe aim of this investigation was to ascertain the protective effects of GLTs on AD mice models and cells, as well as to look into potential pathways. Materials and methodsIn this study, the phytochemical characterization of GLTs was performed by High Performance Liquid Chromatography (HPLC) and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). The AD mouse model was induced by injecting intraperitoneally with D-galactose (120 mg/kg) and administering orally with aluminum chloride (20 mg/kg) daily for 28 days. After that, donepezil (5 mg/kg) and GLTs (0.4, 0.8, and 1.6 g/kg) were administered orally for 35 days. During the treatment period, aluminum chloride (20 mg/kg) and D-galactose (120 mg/kg) were continuously administered. And the behavior of the animals and the molecular changes of the hippocampus were determined after the whole experimental procedure. Furthermore, BV-2 cells were employed to validate GLTs' anti-neuroinflammatory properties. ResultsThe total triterpenoids content was 443.12 ± 0.21 g/kg and was inferred to contain 19 classes of substances such as organic acids, amino acids, vitamins, flavonoids, and other chemicals in GLTs. Treatment of D-galactose/aluminum chloride-induced mouse with GLTs can ameliorate AD symptoms, counteract cognitive decline, improve Aβ1-42 deposition, reduce the expression level of pro-apoptotic proteins, and attenuate the activation of hippocampal microglia and astrocytes. GLTs significantly increased the expression of antioxidant enzymes and significantly reduced the expression of inflammatory factors. GLTs inhibits nuclear factor kappa B (NF-κB) nuclear translocation and preserves myd88/traf6-mediated mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, GLTs (2 and 5 mg/mL) inhibited the generation of nitric oxide and protected lipopolysaccharide (1 mg/L)-induced neuroinflammation in BV-2 cells. ConclusionsTaken together, Ganoderma leucocontextum triterpenoids can improve cognitive functions, including learning and memory, by reducing neuroinflammation and oxidative stress, preventing apoptosis, and controlling amyloid genesis.

Hong Guo Ginseng Guo (HGGG) protects against kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome and regulating intestinal flora

BackgroundDiabetic nephropathy (DN) is one of the most serious complications of diabetes which leads to end-stage renal failure and approximately one-third of patients need dialysis. There is still a lack of effective and specific treatment for DN. Searching new drugs from natural foods is an alternative approach to treat diabetes and its complications. Hong Guo Ginseng Guo (HGGG), a berry with palatability and nutritional benefits, has exhibited medicinal properties to mitigate the progression of DN. PurposeThis study investigates the effects of HGGG on streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats and elucidates the mechanisms underlying its reno-protective and diabetes management benefits. MethodsThe LC-MS spectra method identified the primary ingredients in HGGG. To induce DN, male Sprague-Dawley (SD) rats received a single intraperitoneal injection of 75 mg/kg STZ. Over an eight-week treatment period, we assessed biochemical parameters including blood glucose, urine albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), and urine N-acetyl-beta-d-glucosaminidase (NAG). Tissue pathology was examined using Masson's trichrome, Periodic Acid-Schiff (PAS), and Hematoxylin-Eosin (H&E) stains. We analyzed pro-inflammatory mediators and tissue fibrosis extent using Western blotting and immunohistochemistry. Gut microbiota composition was characterized via 16S rDNA sequencing. ResultsSeventeen chemical compounds were identified, with lobetyolin, luteolin, and rutin highlighted as the primary active elements. HGGG extract appeared to confer renal protection, demonstrated by improvements in UACR, BUN, and urine NAG levels. The reno protective effects in HGGG-treated DN rats were linked to reduced renal fibrosis and inhibition of the NLRP3 inflammasome. Additionally, HGGG administration improved gut barrier integrity and altered the gut microbiota in DN rats, increasing the relative abundance of beneficial bacteria known for regulating polyamines and producing short-chain fatty acids (SCFAs), including Ruminococcus, Barnesiella_sp, Anaerovoracaceae, and Prevotellaceae_NK3B31. Meanwhile, treatment with HGGG decreasing the presence of Oscillospira, potential pathogens responsible for producing lipopolysaccharide (LPS). ConclusionHGGG has potential as a beneficial fruit for managing diabetes and its associated complications through modulation of the gut microbiota.

Effective Application of Biocompatible Magnetite Nanoparticles in the Treatment of Multiple Sclerosis: Results of a Clinical Study

Multiple sclerosis (MS) is a serious neurological disorder due to its widespread prevalence, chronic nature, frequent progression to disability, and tendency to affect young people. The pathogenesis of MS is based on the immunopathogenesis hypothesis. Biocompatible magnetite nanoparticles, which exhibit selective sorption activity towards cell membrane surface proteins, circulating immune com-plexes, lymphocytotoxic antibodies, and the complement system, as well as enhance phagocytic ac-tivity and the completion index of leukocyte phagocytosis, can be effectively used for immunocor-rection. The main goal of the study is to slow the progression of MS, improve the neurological status and overall condition of the patient, and reduce the dynamics of the spread of demyelinating lesions in the brain. Materials and methods: A patient diagnosed with multiple sclerosis, secondary progres-sive type, cerebrospinal form, at the clinical aggravation stage was included in the study. Neurologi-cal status and disability were assessed using the EDSS scale, and brain MRI with contrast enhance-ment was performed. The nanodevice Micromage-B was administered orally as an immunosorbent and immunomodulator. The regimen and dosage of Micromage-B were personalized. Assessments of general condition and neurological status were conducted every 7 days for 6 months, with contrast-enhanced brain MRI performed in the 5th month. Results: The use of Micromage-B in MS treatment led to an objective improvement in neurological status, with reduced stiffness and fatigue in the lower extremities. Gait and coordination improved, hand tremors decreased, depression and concen-tration disorders subsided, appetite was restored, and speech improved. Throughout the treatment period, positive dynamics in the normalization of neurological status were observed. After 6 months, the total score on the EDSS scale decreased from 210 to 45. The most significant improvements were observed in the evaluation of the pyramidal system and coordination, with the EDSS Disability Scale score decreasing from 6.0 to 5.0. For the first time, contrast-enhanced brain MRI showed a reduction in the number of new demyelination foci by the 4th month of Micromage-B administra-tion. The positive changes in neurological status correlated with the MRI results. The recovery of central nervous system activity in MS is likely not only due to the immunosuppressive properties of magnetite nanoparticles but also due to the activation of remyelination mechanisms and oligoden-drocyte differentiation through enzymatic methylation. Conclusion: The use of biocompatible nanodevices in the complex treatment of MS is promising. Further improvement and study of the regimen and method of using biocompatible magnetite nanoparticles to enhance MS treatment effec-tiveness are required.

A New Casjensviridae Bacteriophage Isolated from Hospital Sewage for Inactivation of Biofilms of Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates.

Klebsiella pneumoniae, a member of the ESKAPE pathogen group, is a prominent cause of hospital-acquired infections. The WHO has recognized carbapenem-resistant K. pneumoniae as a critical-one priority pathogen. These resilient superbugs have the ability to form biofilms and present a significant global threat. In the present study, we isolated and characterized a bacteriophage SAKp02, from hospital sewage, infectious to carbapenem-resistant K. pneumoniae patient isolates. SAKp02 could infect 43 of 72 clinical isolates, indicating a broad host spectrum. Whole genome analysis classified SAKp02 within the family Casjensviridae, with a 59,343 bp genome encoding 82 ORFs. Comparative genomic analysis revealed significant differences between SAKp02 and its closest viruses, indicating a distinct genetic makeup positioning it as a novel phage strain within the lineage. The SAKp02 genome comprises bacteriolytic enzymes, including holin, endolysin, and phage depolymerase, crucial for bacterial lysis and biofilm disruption. It reduced biofilm biomass by over threefold compared to the control and eradicated 99% of viable cells within a 4 h treatment period. Scanning electron microscopy corroborated the ability of the phage to dismantle biofilm matrices and lyse bacterial cells. Safe and effective treatments are warranted, and hence, the fully characterized lytic phages with therapeutic potential against drug-resistant clinical isolates of bacteria are needed. Our study is the first to report the antibacterial and antibiofilm activity of Casjensviridae phages, and our discovery of a novel K. pneumoniae phage broadens the arsenal against the bacteria.

Effective Application of Biocompatible Magnetite Nanoparticles in the Treatment of Multiple Sclerosis: Results of a Clinical Study

Multiple sclerosis (MS) is a serious neurological disorder due to its widespread prevalence, chronic nature, frequent progression to disability, and tendency to affect young people. The pathogenesis of MS is based on the immunopathogenesis hypothesis. Biocompatible magnetite nanoparticles, which exhibit selective sorption activity towards cell membrane surface proteins, circulating immune com-plexes, lymphocytotoxic antibodies, and the complement system, as well as enhance phagocytic ac-tivity and the completion index of leukocyte phagocytosis, can be effectively used for immunocor-rection. The main goal of the study is to slow the progression of MS, improve the neurological status and overall condition of the patient, and reduce the dynamics of the spread of demyelinating lesions in the brain. Materials and methods: A patient diagnosed with multiple sclerosis, secondary progres-sive type, cerebrospinal form, at the clinical aggravation stage was included in the study. Neurologi-cal status and disability were assessed using the EDSS scale, and brain MRI with contrast enhance-ment was performed. The nanodevice Micromage-B was administered orally as an immunosorbent and immunomodulator. The regimen and dosage of Micromage-B were personalized. Assessments of general condition and neurological status were conducted every 7 days for 6 months, with contrast-enhanced brain MRI performed in the 5th month. Results: The use of Micromage-B in MS treatment led to an objective improvement in neurological status, with reduced stiffness and fatigue in the lower extremities. Gait and coordination improved, hand tremors decreased, depression and concen-tration disorders subsided, appetite was restored, and speech improved. Throughout the treatment period, positive dynamics in the normalization of neurological status were observed. After 6 months, the total score on the EDSS scale decreased from 210 to 45. The most significant improvements were observed in the evaluation of the pyramidal system and coordination, with the EDSS Disability Scale score decreasing from 6.0 to 5.0. For the first time, contrast-enhanced brain MRI showed a reduction in the number of new demyelination foci by the 4th month of Micromage-B administra-tion. The positive changes in neurological status correlated with the MRI results. The recovery of central nervous system activity in MS is likely not only due to the immunosuppressive properties of magnetite nanoparticles but also due to the activation of remyelination mechanisms and oligoden-drocyte differentiation through enzymatic methylation. Conclusion: The use of biocompatible nanodevices in the complex treatment of MS is promising. Further improvement and study of the regimen and method of using biocompatible magnetite nanoparticles to enhance MS treatment effec-tiveness are required.

A New Casjensviridae Bacteriophage Isolated from Hospital Sewage for Inactivation of Biofilms of Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates

Klebsiella pneumoniae, a member of the ESKAPE pathogen group, is a prominent cause of hospital-acquired infections. The WHO has recognized carbapenem-resistant K. pneumoniae as a critical-one priority pathogen. These resilient superbugs have the ability to form biofilms and present a significant global threat. In the present study, we isolated and characterized a bacteriophage SAKp02, from hospital sewage, infectious to carbapenem-resistant K. pneumoniae patient isolates. SAKp02 could infect 43 of 72 clinical isolates, indicating a broad host spectrum. Whole genome analysis classified SAKp02 within the family Casjensviridae, with a 59,343 bp genome encoding 82 ORFs. Comparative genomic analysis revealed significant differences between SAKp02 and its closest viruses, indicating a distinct genetic makeup positioning it as a novel phage strain within the lineage. The SAKp02 genome comprises bacteriolytic enzymes, including holin, endolysin, and phage depolymerase, crucial for bacterial lysis and biofilm disruption. It reduced biofilm biomass by over threefold compared to the control and eradicated 99% of viable cells within a 4 h treatment period. Scanning electron microscopy corroborated the ability of the phage to dismantle biofilm matrices and lyse bacterial cells. Safe and effective treatments are warranted, and hence, the fully characterized lytic phages with therapeutic potential against drug-resistant clinical isolates of bacteria are needed. Our study is the first to report the antibacterial and antibiofilm activity of Casjensviridae phages, and our discovery of a novel K. pneumoniae phage broadens the arsenal against the bacteria.

Does high hepatic bioavailability enhance the effect of oral compared to subcutaneous glucocorticoids?

Glucocorticoids (GC) are important in the treatment of autoinflammatory disorders. Oral prednisolone ≤5 mg/day can be effective, but such doses are at or even below physiological daily endogenous GC production. We hypothesised that their immunosuppressive effect might be explained by high hepatic bioavailability of oral GC, exposing the liver to supraphysiological GC via the portal circulation. We tested this by comparing the effect of oral versus subcutaneous low-dose prednisolone, on erythrocyte sedimentation rate (ESR). Patients with rheumatoid arthritis or psoriatic arthritis, elevated ESR (≥30 mm/h) and no current or recent GC therapy were eligible. In a pilot study (n=5), 5 mg/day oral prednisolone decreased ESR significantly, suggesting a sample size of 10 patients for a randomised, non-blinded crossover trial. Patients received 5 mg/day prednisolone for 2 periods of 4 days: one treatment period orally and one subcutaneously with a 10-day washout period between treatments. ESR was measured before (day 1 and 15) and after (day 5 and 19) each treatment course. 10 patients were included. ESR decreased after both oral and subcutaneous prednisolone, by -5.6 (20.9) and -5.8 (3.0) mm/h, respectively (p=0.98). The treatment order had no effect on the outcome. . Short-term oral low-dose GC therapy is not more effective than parental GC in decreasing ESR, arguing against therapeutic high hepatic bioavailability effects. More likely, systemic concentration peaks following administration explain why oral physiological steroid doses are clinically effective.

Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer

BackgroundRecurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy.MethodsWe conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator’s choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival.ResultsA total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P=0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects.ConclusionsIn patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.)

Safety and efficacy of linaclotide in children aged 2-5 years with functional constipation: Phase 2, randomized study.

Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years of age with functional constipation (FC). This study evaluated the dose-response, safety, and efficacy of 4 weeks of linaclotide compared with placebo in children 2-5 years of age with FC. In this phase 2, randomized, double-blind, placebo-controlled, multidose study, 35 children with FC (based on Rome III criteria) were randomized 3:1 to receive linaclotide (18, 36, or 72 μg, for groups 1, 2, and 3, respectively) and 5:1 to receive linaclotide 9, 18, 36, or 72 μg (group 4), or matching placebo. Key endpoints were the changes from baseline in overall spontaneous bowel movement (SBM) frequency (SBMs/week), stool consistency, and straining, as well as the proportion of days with fecal incontinence during the study intervention period. Adverse events (AEs) were recorded. Of the randomized patients, 34 (97.1%) completed the treatment period and 33 (94.3%) completed the posttreatment period. Mean change from baseline over the treatment period for three of the four key efficacy endpoints showed greater improvement in the linaclotide 72 μg group versus placebo. A dose-response trend was seen for stool consistency in patients receiving linaclotide. Four patients randomized to linaclotide experienced treatment-emergent AEs, one of which was treatment-related (mild diarrhea). All AEs were mild or moderate and none were severe. Linaclotide was well tolerated in this pediatric population and an efficacy trend was seen with linaclotide 72 μg versus placebo.